classic presentation of diabetes mellitus type 2

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PARITA PATEL, MD, AND ALLISON MACEROLLO, MD

Am Fam Physician. 2010;81(7):863-870

A more recent article on diabetes mellitus is available .

See related editorial on page 843 .

Author disclosure: Nothing to disclose.

Based on etiology, diabetes is classified as type 1 diabetes mellitus, type 2 diabetes mellitus, latent autoimmune diabetes, maturity-onset diabetes of youth, and miscellaneous causes. The diagnosis is based on measurement of A1C level, fasting or random blood glucose level, or oral glucose tolerance testing. Although there are conflicting guidelines, most agree that patients with hypertension or hyperlipidemia should be screened for diabetes. Diabetes risk calculators have a high negative predictive value and help define patients who are unlikely to have diabetes. Tests that may help establish the type of diabetes or the continued need for insulin include those reflective of beta cell function, such as C peptide levels, and markers of immune-mediated beta cell destruction (e.g., autoantibodies to islet cells, insulin, glutamic acid decarboxylase, tyrosine phosphatase [IA-2α and IA-2β]). Antibody testing is limited by availability, cost, and predictive value.

Prevention, timely diagnosis, and treatment are important in patients with diabetes mellitus. Many of the complications associated with diabetes, such as nephropathy, retinopathy, neuropathy, cardiovascular disease, stroke, and death, can be delayed or prevented with appropriate treatment of elevated blood pressure, lipids, and blood glucose. 1 – 4

In 1997, the American Diabetes Association (ADA) introduced an etiologically based classification system and diagnostic criteria for diabetes, 5 which were updated in 2010. 1 Type 2 diabetes accounts for approximately 90 to 95 percent of all persons with diabetes in the United States, and its prevalence is increasing in adults worldwide. 6 With the rise in childhood obesity, type 2 diabetes is increasingly being diagnosed in children and adolescents. 6

The risk of diabetes is increased in close relatives suggesting a genetic predisposition, although no direct genetic link has been identified. 7 Type 1 diabetes accounts for 5 to 10 percent of persons with diabetes 6 and is characterized by insulin deficiency that is typically an autoimmune-mediated condition.

Latent autoimmune diabetes in adults includes a heterogenous group of conditions that are phenotypically similar to type 2 diabetes, but patients have autoantibodies that are common with type 1 diabetes. Diagnostic criteria include age of 30 years or older; no insulin treatment for six months after diagnosis; and presence of autoantibodies to glutamic acid decarboxylase, islet cells, tyrosine phosphatase (IA-2α and IA-2β), or insulin.

Patients with maturity-onset diabetes of youth typically present before 25 years of age, have only impaired insulin secretion, and have a monogenetic defect that leads to an autosomal dominant inheritance pattern. These patients are placed in a subcategory of having genetic defects of beta cell. 8

The old terminology of prediabetes has now been replaced with “categories of increased risk for diabetes.” This includes persons with impaired fasting glucose, impaired glucose tolerance, or an A1C level of 5.7 to 6.4 percent. 1 , 9 , 10

Diagnostic Criteria and Testing

The 1997 ADA consensus guidelines lowered the blood glucose thresholds for the diagnosis of diabetes. 5 This increased the number of patients diagnosed at an earlier stage, although no studies have demonstrated a reduction in long-term complications. Data suggest that as many as 5.7 million persons in the United States have undiagnosed diabetes. 6 Table 1 compares specific diagnostic tests for diabetes. 11 – 14

TESTS TO DIAGNOSE DIABETES

Blood Glucose Measurements . The diagnosis of diabetes is based on one of three methods of blood glucose measurement ( Table 2 ) . 1 Diabetes can be diagnosed if the patient has a fasting blood glucose level of 126 mg per dL (7.0 mmol per L) or greater on two separate occasions. The limitations of this test include the need for an eight-hour fast before the blood draw, a 12 to 15 percent day-to-day variance in fasting blood glucose values, and a slightly lower sensitivity for predicting microvascular complications. 15 , 16

Diabetes can also be diagnosed with a random blood glucose level of 200 mg per dL (11.1 mmol per L) or greater if classic symptoms of diabetes (e.g., polyuria, polydipsia, weight loss, blurred vision, fatigue) are present. Lower random blood glucose values (140 to 180 mg per dL [7.8 to 10.0 mmol per L]) have a fairly high specificity of 92 to 98 percent; therefore, patients with these values should undergo more definitive testing. A low sensitivity of 39 to 55 percent limits the use of random blood glucose testing. 15

The oral glucose tolerance test is considered a first-line diagnostic test. Limitations include poor reproducibility and patient compliance because an eight-hour fast is needed before the 75-g glucose load, which is followed two hours later by a blood draw. 17 The criterion for diabetes is a serum blood glucose level of greater than 199 mg per dL (11.0 mmol per L).

In 2003, the ADA lowered the threshold for diagnosis of impaired fasting glucose to include a fasting glucose level between 100 and 125 mg per dL (5.6 and 6.9 mmol per L). Impaired glucose tolerance continues to be defined as a blood glucose level between 140 and 199 mg per dL (7.8 and 11.0 mmol per L) two hours after a 75-g load. Patients meeting either of these criteria are at significantly higher risk of progression to diabetes and should be counseled on effective strategies to lower their risk, such as weight loss and exercise. 1 , 9

A1C . A1C measurement has recently been endorsed by the ADA as a diagnostic and screening tool for diabetes. 1 One advantage of using A1C measurement is the ease of testing because it does not require fasting. An A1C level of greater than 6.5 percent on two separate occasions is considered diagnostic of diabetes. 18 Lack of standardization has historically deterred its use, but this test is now widely standardized in the United States. 19 A1C measurements for diagnosis of diabetes should be performed by a clinical laboratory because of the lack of standardization of point-of-care testing. Limitations of A1C testing include low sensitivity, possible racial disparities, and interference by anemia and some medications. 15

TESTS TO IDENTIFY TYPE OF DIABETES

Tests that can be used to establish the etiology of diabetes include those reflective of beta cell function (e.g., C peptide) and markers of immune-mediated beta cell destruction (e.g., insulin, islet cell, glutamic acid decarboxylase, IA-2α and IA-2β autoantibodies). Table 3 presents the characteristics of these tests. 20 – 27

C peptide is linked to insulin to form proinsulin and reflects the amount of endogenous insulin. Patients with type 1 diabetes have low C peptide levels because of low levels of endogenous insulin and beta cell function. Patients with type 2 diabetes typically have normal to high levels of C peptide, reflecting higher amounts of insulin but relative insensitivity to it. In a Swedish study of patients with clinically well-defined type 1 or 2 diabetes, 96 percent of patients with type 2 diabetes had random C peptide levels greater than 1.51 ng per mL (0.50 nmol per L), whereas 90 percent of patients with type 1 diabetes had values less than 1.51 ng per mL. 20 In the clinically undefined population, which is the group in which the test is most often used, the predictive value is likely lower.

Antibody testing is limited by availability, cost, and predictive value, especially in black and Asian patients. Prevalence of any antibody in white patients with type 1 diabetes is 85 to 90 percent, 5 whereas the prevalence in similar black or Hispanic patients is lower (19 percent in both groups in one study). 28 In persons with type 2 diabetes, the prevalence of islet cell antibody is 4 to 21 percent; glutamic acid decarboxylase antibody, 7 to 34 percent; IA-2, 1 to 2 percent; and any antibody, 11.6 percent. 24 , 25 , 29 In healthy persons, the prevalence of any antibody marker is 1 to 2 percent 30 ; thus, overlap of the presence of antibodies in various types of diabetes and patients limits the utility of individual tests.

As with any condition, a rationale for screening should first be established. Diabetes is a common disease that is associated with significant morbidity and mortality. It has an asymptomatic stage that may be present for up to seven years before diagnosis. The disease is treatable, and testing is acceptable and accessible to patients. Early treatment of diabetes that was identified primarily by symptoms improves microvascular outcomes. 31 However, it is not clear whether universal screening reduces diabetes-associated morbidity and mortality. Table 4 presents screening guidelines from several organizations. 1 , 8 , 32 – 38

TYPE 1 DIABETES

Screening for type 1 diabetes is not recommended because there is no accepted treatment for patients who are diagnosed in the asymptomatic phase. The Diabetes Prevention Trial identified a group of high-risk patients based on family history and positivity to islet cell antibodies. However, treatment did not prevent progression to type 1 diabetes in these patients. 39

TYPE 2 DIABETES

Medications and lifestyle interventions may reduce the risk of diabetes, although 20 to 30 percent of patients with type 2 diabetes already have complications at the time of presentation. 40 Although a recent analysis suggests that screening for and treating impaired glucose tolerance in persons at risk of diabetes may be cost-effective, the data on screening for type 2 diabetes are less certain. 41 It is unclear whether the early diagnosis of type 2 diabetes through screening programs, with subsequent intensive interventions, provides an incremental benefit in final health outcomes compared with initiating treatment after clinical diagnosis.

Guidelines differ regarding who should be screened for type 2 diabetes. The U.S. Preventive Services Task Force (USPSTF) recommends limiting screening to adults with a sustained blood pressure of greater than 135/80 mm Hg. 34 , 42 The American Academy of Family Physicians concurs, but specifically includes treated and untreated patients. 43 The Canadian Task Force on Preventive Health Care recommends screening all patients with hypertension or hyperlipidemia. 33 The ADA recommends screening a much broader patient population based on risk. 1

There are several questionnaires to predict a patient's risk of diabetes. The Diabetes Risk Calculator was developed using data from the National Health and Nutrition Examination Survey III and incorporates age, height, weight, waist circumference, ethnicity, blood pressure, exercise, history of gestational diabetes, and family history. 13 , 14 For diagnosis of diabetes, it has a positive predictive value (PPV) of 14 percent and a negative predictive value (NPV) of 99.3 percent. The tool is most valuable in helping define which patients are very unlikely to have diabetes. 13

GESTATIONAL DIABETES

Whether patients should be screened for gestational diabetes is unclear. The USPSTF states that there is insufficient evidence to recommend for or against screening. 34 The ADA and the American College of Obstetricians and Gynecologists recommend risk-based testing, although most women require testing based on these inclusive guidelines. 36 The Glucola test is the most commonly used screening test for gestational diabetes and includes glucose testing one hour after a 50-g oral glucose load. An abnormal Glucola test result (i.e., blood glucose level of 140 mg per dL or greater) should be confirmed with a 75-g or 100-g oral glucose tolerance test. Whether screening and subsequent treatment of gestational diabetes alter clinically important perinatal outcomes is unclear. Untreated gestational diabetes is associated with a higher incidence of macrosomia and shoulder dystocia. 44 A randomized controlled trial found that treatment led to a reduction in serious perinatal complications, with a number needed to treat of 34. Treatment did not reduce risk of cesarean delivery or admission to the neonatal intensive care unit, however. 44

New-Onset Symptomatic Hyperglycemia

Patients may initially present with diabetic ketoacidosis or hyperglycemic hyperosmolar state ( Table 5 ) , 45 both of which are initially managed with insulin because they are essentially insulin deficiency states. Both groups of patients may present with polyuria, polydipsia, and signs of dehydration. Diagnostic criteria of diabetic ketoacidosis include a blood glucose level greater than 250 mg per dL (13.9 mmol per L), pH of 7.3 or less, serum bicarbonate level less than 18 mEq per L (18 mmol per L), and moderate ketonemia. However, significant ketosis has also been shown to occur in up to one third of patients with hyperglycemic hyperosmolar state. 46

Although diabetic ketoacidosis typically occurs in persons with type 1 diabetes, more than one half of newly diagnosed black patients with unprovoked diabetic ketoacidosis are obese and many display classic features of type 2 diabetes—most importantly with a measurable insulin reserve. 47 Thus, the presentation does not definitively determine the type of diabetes a patient has. Presence of antibodies, particularly glutamic acid decarboxylase antibody, predicts a higher likelihood of lifelong insulin requirement. There is, however, an overlap of presence of antibodies in type 1 and type 2 diabetes, and among patients with type 2 diabetes who may not require insulin. 48

A Swedish population-based study showed that among the 9.3 percent of young adults with newly diagnosed diabetes that could not be classified as type 1 or type 2, the presence of glutamic acid decarboxylase antibody was associated with a need for insulin within three years (odds ratio = 18.8; 95% confidence interval, 1.8 to 191). 26 The PPV for insulin treatment was 92 percent in those with the antibody. It should be noted that among patients who were negative for antibodies, 51 percent also needed insulin within three years. In contrast, the United Kingdom Prospective Diabetes Study found that only 5.7 percent of patients without glutamic acid decarboxylase antibody eventually needed insulin therapy, giving the test an NPV of 94 percent. 25 With these conflicting data, clinical judgment using a patient's phenotype, history, presentation, and selective laboratory testing is the best way to manage patients with diabetes.

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Sabbah E, Savola K, Kulmala P, et al. Diabetes-associated autoanti-bodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes in Finland Study Group. J Clin Endocrinol Metab. 1999;84(5):1534-1539.

Tuomi T, Carlsson A, Li H, et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes. 1999;48(1):150-157.

Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group [published correction appears in Lancet . 1998;351(9099):376]. Lancet. 1997;350(9087):1288-1293.

Bottazzo GF, Bosi E, Cull CA, et al. IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71) [published correction appears in Diabetologia . 2005;48(6):1240]. Diabetologia. 2005;48(4):703-708.

Törn C, Landin-Olsson M, Ostman J, et al. Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as type 1 diabetes on clinical grounds. Diabetes Metab Res Rev. 2000;16(6):442-447.

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• Patient Care & Health Information
• Diseases & Conditions
• Type 2 diabetes

Type 2 diabetes is a condition that happens because of a problem in the way the body regulates and uses sugar as a fuel. That sugar also is called glucose. This long-term condition results in too much sugar circulating in the blood. Eventually, high blood sugar levels can lead to disorders of the circulatory, nervous and immune systems.

In type 2 diabetes, there are primarily two problems. The pancreas does not produce enough insulin — a hormone that regulates the movement of sugar into the cells. And cells respond poorly to insulin and take in less sugar.

Type 2 diabetes used to be known as adult-onset diabetes, but both type 1 and type 2 diabetes can begin during childhood and adulthood. Type 2 is more common in older adults. But the increase in the number of children with obesity has led to more cases of type 2 diabetes in younger people.

There's no cure for type 2 diabetes. Losing weight, eating well and exercising can help manage the disease. If diet and exercise aren't enough to control blood sugar, diabetes medications or insulin therapy may be recommended.

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Symptoms of type 2 diabetes often develop slowly. In fact, you can be living with type 2 diabetes for years and not know it. When symptoms are present, they may include:

• Increased thirst.
• Frequent urination.
• Increased hunger.
• Unintended weight loss.
• Blurred vision.
• Slow-healing sores.
• Frequent infections.
• Numbness or tingling in the hands or feet.
• Areas of darkened skin, usually in the armpits and neck.

When to see a doctor

See your health care provider if you notice any symptoms of type 2 diabetes.

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Type 2 diabetes is mainly the result of two problems:

• Cells in muscle, fat and the liver become resistant to insulin As a result, the cells don't take in enough sugar.
• The pancreas can't make enough insulin to keep blood sugar levels within a healthy range.

Exactly why this happens is not known. Being overweight and inactive are key contributing factors.

How insulin works

Insulin is a hormone that comes from the pancreas — a gland located behind and below the stomach. Insulin controls how the body uses sugar in the following ways:

• Sugar in the bloodstream triggers the pancreas to release insulin.
• Insulin circulates in the bloodstream, enabling sugar to enter the cells.
• The amount of sugar in the bloodstream drops.
• In response to this drop, the pancreas releases less insulin.

The role of glucose

Glucose — a sugar — is a main source of energy for the cells that make up muscles and other tissues. The use and regulation of glucose includes the following:

• Glucose comes from two major sources: food and the liver.
• Glucose is absorbed into the bloodstream, where it enters cells with the help of insulin.
• The liver stores and makes glucose.
• When glucose levels are low, the liver breaks down stored glycogen into glucose to keep the body's glucose level within a healthy range.

In type 2 diabetes, this process doesn't work well. Instead of moving into the cells, sugar builds up in the blood. As blood sugar levels rise, the pancreas releases more insulin. Eventually the cells in the pancreas that make insulin become damaged and can't make enough insulin to meet the body's needs.

Risk factors

Factors that may increase the risk of type 2 diabetes include:

• Weight. Being overweight or obese is a main risk.
• Fat distribution. Storing fat mainly in the abdomen — rather than the hips and thighs — indicates a greater risk. The risk of type 2 diabetes is higher in men with a waist circumference above 40 inches (101.6 centimeters) and in women with a waist measurement above 35 inches (88.9 centimeters).
• Inactivity. The less active a person is, the greater the risk. Physical activity helps control weight, uses up glucose as energy and makes cells more sensitive to insulin.
• Family history. An individual's risk of type 2 diabetes increases if a parent or sibling has type 2 diabetes.
• Race and ethnicity. Although it's unclear why, people of certain races and ethnicities — including Black, Hispanic, Native American and Asian people, and Pacific Islanders — are more likely to develop type 2 diabetes than white people are.
• Blood lipid levels. An increased risk is associated with low levels of high-density lipoprotein (HDL) cholesterol — the "good" cholesterol — and high levels of triglycerides.
• Age. The risk of type 2 diabetes increases with age, especially after age 35.
• Prediabetes. Prediabetes is a condition in which the blood sugar level is higher than normal, but not high enough to be classified as diabetes. Left untreated, prediabetes often progresses to type 2 diabetes.
• Pregnancy-related risks. The risk of developing type 2 diabetes is higher in people who had gestational diabetes when they were pregnant and in those who gave birth to a baby weighing more than 9 pounds (4 kilograms).
• Polycystic ovary syndrome. Having polycystic ovary syndrome — a condition characterized by irregular menstrual periods, excess hair growth and obesity — increases the risk of diabetes.

Complications

Type 2 diabetes affects many major organs, including the heart, blood vessels, nerves, eyes and kidneys. Also, factors that increase the risk of diabetes are risk factors for other serious diseases. Managing diabetes and controlling blood sugar can lower the risk for these complications and other medical conditions, including:

• Heart and blood vessel disease. Diabetes is associated with an increased risk of heart disease, stroke, high blood pressure and narrowing of blood vessels, a condition called atherosclerosis.
• Nerve damage in limbs. This condition is called neuropathy. High blood sugar over time can damage or destroy nerves. That may result in tingling, numbness, burning, pain or eventual loss of feeling that usually begins at the tips of the toes or fingers and gradually spreads upward.
• Other nerve damage. Damage to nerves of the heart can contribute to irregular heart rhythms. Nerve damage in the digestive system can cause problems with nausea, vomiting, diarrhea or constipation. Nerve damage also may cause erectile dysfunction.
• Kidney disease. Diabetes may lead to chronic kidney disease or end-stage kidney disease that can't be reversed. That may require dialysis or a kidney transplant.
• Eye damage. Diabetes increases the risk of serious eye diseases, such as cataracts and glaucoma, and may damage the blood vessels of the retina, potentially leading to blindness.
• Skin conditions. Diabetes may raise the risk of some skin problems, including bacterial and fungal infections.
• Slow healing. Left untreated, cuts and blisters can become serious infections, which may heal poorly. Severe damage might require toe, foot or leg amputation.
• Hearing impairment. Hearing problems are more common in people with diabetes.
• Sleep apnea. Obstructive sleep apnea is common in people living with type 2 diabetes. Obesity may be the main contributing factor to both conditions.
• Dementia. Type 2 diabetes seems to increase the risk of Alzheimer's disease and other disorders that cause dementia. Poor control of blood sugar is linked to a more rapid decline in memory and other thinking skills.

Healthy lifestyle choices can help prevent type 2 diabetes. If you've received a diagnosis of prediabetes, lifestyle changes may slow or stop the progression to diabetes.

A healthy lifestyle includes:

• Eating healthy foods. Choose foods lower in fat and calories and higher in fiber. Focus on fruits, vegetables and whole grains.
• Getting active. Aim for 150 or more minutes a week of moderate to vigorous aerobic activity, such as a brisk walk, bicycling, running or swimming.
• Losing weight. If you are overweight, losing a modest amount of weight and keeping it off may delay the progression from prediabetes to type 2 diabetes. If you have prediabetes, losing 7% to 10% of your body weight may reduce the risk of diabetes.
• Avoiding long stretches of inactivity. Sitting still for long periods of time can increase the risk of type 2 diabetes. Try to get up every 30 minutes and move around for at least a few minutes.

For people with prediabetes, metformin (Fortamet, Glumetza, others), a diabetes medication, may be prescribed to reduce the risk of type 2 diabetes. This is usually prescribed for older adults who are obese and unable to lower blood sugar levels with lifestyle changes.

More Information

• Diabetes prevention: 5 tips for taking control
• Professional Practice Committee: Standards of Medical Care in Diabetes — 2020. Diabetes Care. 2020; doi:10.2337/dc20-Sppc.
• Diabetes mellitus. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed Dec. 7, 2020.
• Melmed S, et al. Williams Textbook of Endocrinology. 14th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Dec. 3, 2020.
• Diabetes overview. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/all-content. Accessed Dec. 4, 2020.
• AskMayoExpert. Type 2 diabetes. Mayo Clinic; 2018.
• Feldman M, et al., eds. Surgical and endoscopic treatment of obesity. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 11th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 20, 2020.
• Hypersmolar hyperglycemic state (HHS). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hyperosmolar-hyperglycemic-state-hhs. Accessed Dec. 11, 2020.
• Diabetic ketoacidosis (DKA). Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetic-ketoacidosis-dka. Accessed Dec. 11, 2020.
• Hypoglycemia. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/hypoglycemia. Accessed Dec. 11, 2020.
• 6 things to know about diabetes and dietary supplements. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/tips/things-to-know-about-type-diabetes-and-dietary-supplements. Accessed Dec. 11, 2020.
• Type 2 diabetes and dietary supplements: What the science says. National Center for Complementary and Integrative Health. https://www.nccih.nih.gov/health/providers/digest/type-2-diabetes-and-dietary-supplements-science. Accessed Dec. 11, 2020.
• Preventing diabetes problems. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/all-content. Accessed Dec. 3, 2020.
• Schillie S, et al. Prevention of hepatitis B virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recommendations and Reports. 2018; doi:10.15585/mmwr.rr6701a1.
• Caffeine: Does it affect blood sugar?
• GLP-1 agonists: Diabetes drugs and weight loss
• Hyperinsulinemia: Is it diabetes?
• Medications for type 2 diabetes

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• v.10(4); Oct-Dec 2020

Pathophysiology of diabetes: An overview

Mujeeb z. banday.

Department of Biochemistry, Government Medical College and Associated Shri Maharaja Hari Singh Hospital, Srinagar, Kashmir, India

Aga S. Sameer

1 Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdul Aziz University for Health Sciences, King Abdullah International Medical Research Centre, National Guard Health Affairs, Jeddah, Saudi Arabia

Saniya Nissar

Diabetes mellitus is a chronic heterogeneous metabolic disorder with complex pathogenesis. It is characterized by elevated blood glucose levels or hyperglycemia, which results from abnormalities in either insulin secretion or insulin action or both. Hyperglycemia manifests in various forms with a varied presentation and results in carbohydrate, fat, and protein metabolic dysfunctions. Long-term hyperglycemia often leads to various microvascular and macrovascular diabetic complications, which are mainly responsible for diabetes-associated morbidity and mortality. Hyperglycemia serves as the primary biomarker for the diagnosis of diabetes as well. In this review, we would be focusing on the classification of diabetes and its pathophysiology including that of its various types.

INTRODUCTION

Diabetes mellitus (DM), also known simply as diabetes is a complex metabolic disorder characterized by hyperglycemia, a physiologically abnormal condition represented by continued elevated blood glucose levels. Hyperglycemia results from anomalies in either insulin secretion or insulin action or both and manifests in a chronic and heterogeneous manner as carbohydrate, fat, and protein metabolic dysfunctions. Diabetes follows a progressive pattern with complex pathogenesis and varied presentation.[ 1 , 2 ]

Hyperglycemia and its associated carbohydrate, fat, and protein metabolic dysfunctions affect multiple organs of the body and disrupt their normal functioning. These disruptions progress gradually and arise mostly due to the adverse effects of hyperglycemia and its associated metabolic anomalies on the normal structure and functioning of micro- and macrovasculature, which lie at the core of organ structure, and function throughout the body. The structural and functional disruptions in organ system vasculature lead to micro- and macrovascular complications. Organ damage, dysfunction, and, ultimately, organ failure characterize these complications and affect body organs, which include, in particular, eyes, kidneys, heart, and nerves. Eye-related complications result in retinopathy with progression to blindness. Kidney-associated complications lead to nephropathy and potential renal failure. Heart-related complications include hypertension and coronary heart disease. Nerve-associated complications lead to neuropathy, which can be autonomic and/or peripheral. Cardiovascular, gastrointestinal, and genitourinary (including sexual) dysfunctions are characteristic manifestations of autonomic neuropathy, whereas foot infections including ulcers requiring amputations and Charcot joint (osteoarthropathy) are often associated with long-term peripheral neuropathy.[ 3 , 4 , 5 ] The cerebrovascular disease, peripheral arterial disease, and coronary heart disease, together termed as atherosclerotic cardiovascular disease, are of common occurrence in diabetes and constitute one of the major causes of diabetes-associated morbidity and mortality.[ 1 , 4 , 5 ]

Diabetes with its ever-increasing global prevalence has emerged as one of the most important and challenging health issues confronting the human population of the present world. The increase in the prevalence of diabetes in most regions across the globe has been parallel to the rapid economic development, leading to urbanization and adoption of modern lifestyle habits.[ 6 ] In the year 2019, the number of adult people aged 20–79 years with diabetes has been estimated to be about 463 million, which represents 9.3% of the total world adult population. By the year 2030, this number has been estimated to increase to 578 million, representing 10.2% of the total world adult population and further increase to 700 million by the year 2045, which represents 10.9% of the total world adult population. In the year 2019, the prevalence of diabetes among men and women has been estimated to be 9.6% and 9.0%, respectively, of the total respective gender world population.[ 7 ] Furthermore, in the year 2019, approximately 4.2 million adult people aged 20–99 years died due to diabetes, and its associated complications and health expenditure on diabetes estimated to at least 760 billion USD, which represents 10% of the total spending on adults. Diabetes during pregnancy has been estimated to have affected more than 20 million live births (1 in 6 live births) in the year 2019.[ 8 ]

CLASSIFICATION AND PATHOPHYSIOLOGY

DM is characterized by complex pathogenesis and varied presentation and any classification of this disorder, therefore, is arbitrary, but nevertheless useful, and is often influenced by the physiological conditions present at the time of assessment and diagnosis. The classification currently used is based on both the etiology and the pathogenesis of disease and is useful in the clinical assessment of disease and for deciding the required therapy. According to this classification, diabetes can be divided into four main types or categories: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), and diabetes caused or associated with certain specific conditions, pathologies, and/or disorders [ Figure 1 ].[ 1 , 9 ]

Four types of diabetes mellitus

Type 1 diabetes mellitus

T1DM, also known as type 1A DM or as per the previous nomenclature as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes, constitutes about 5–10% of all the cases of diabetes. It is an autoimmune disorder characterized by T-cell-mediated destruction of pancreatic β-cells, which results in insulin deficiency and ultimately hyperglycemia.[ 10 , 11 ] The pathogenesis of this autoimmunity, though not yet fully understood, has been found to be influenced by both genetic and environmental factors. The rate of development of this pancreatic β-cell-specific autoimmunity and the disorder itself is rapid in most of the cases as in infants and children (juvenile onset) or may be gradual as in adults (late onset).

The variability in the rate at which the immune-mediated destruction of the pancreatic β-cells occurs often defines the eventual progression of this disease. In some cases, children and adolescents, the β-cell destruction and subsequent failure occur suddenly, which can lead to diabetic ketoacidosis (DKA), often described as the first manifestation of the disease. In others, the disease progression is very slow with a mild increase in fasting blood glucose levels, which assumes a severe hyperglycemic form with or without ketoacidosis, only in the presence of physiological stress conditions such as severe infections or onset of other disorders. In some other cases, which include adults, β-cells may retain some degree of function to secrete only that quantity of insulin, which is only sufficient to prevent ketoacidosis for many years. However, due to progressive insulin deficiency, these individuals become insulin-dependent with the emergence of severe hyperglycemia and subsequent ketoacidosis. Despite the variable progression of this type of diabetes, the affected individuals in the beginning or in the middle or even in the later stages of their life become severely or absolutely insulin-deficient and become dependent on insulin treatment for their survival. This severe or absolute insulin deficiency irrespective of its occurrence at any age manifests itself as low or undetectable levels of plasma C-peptide.[ 1 , 10 , 11 ]

T1DM is an autoimmune disorder characterized by several immune markers, in particular autoantibodies. These autoantibodies are associated with the immune-mediated β-cell destruction, characteristic of this disease. The autoantibodies include glutamic acid decarboxylase autoantibodies (GADAs) such as GAD65, islet cell autoantibodies (ICAs) to β-cell cytoplasmic proteins such as autoantibodies to islet cell antigen 512 (ICA512), autoantibodies to the tyrosine phosphatases, IA-2 and IA-2α, insulin autoantibodies (IAAs), and autoantibodies to islet-specific zinc transporter isoform 8 (ZnT8). At least one of these autoantibodies can be used for the clinical diagnosis of this disease but usually more of these immune markers have been observed in approximately 85–90% of patients with new-onset T1DM.[ 1 , 12 ] Of these autoantibodies, GAD65 is the most important and is present in about 80% of all T1DM individuals at the time of diagnosis, followed by ICAs present in 69–90% and IA-2α found in 54–75% of all T1DM individuals at clinical presentation.

The IAAs are important immune markers present in infants and young children who are prone to diabetes and its prevalence decreases as the age of onset of diabetes increases. The presence of IAAs in these individuals who have not been previously treated with insulin is an important indication of developing T1DM. IAAs are present in about 70% of all infants and young children at the time of diagnosis. The IAAs also play an important inhibitory role toward insulin function in patients on insulin therapy. Although not often clinically significant but nevertheless, this immune response has been observed with varying degrees of severity in at least 40% of patients on insulin treatment and therefore shows differential clinical manifestations.[ 13 ] These autoantibodies mostly consist of polyclonal immunoglobulin G (IgG) antibodies and differ in their affinities and binding capacities toward insulin. IAAs can either be high insulin affinity/low insulin-binding capacity or low insulin affinity/high insulin-binding capacity. The low insulin affinity/high insulin-binding capacity IAAs are responsible for clinical manifestations. At high titers, the binding of these antibodies to insulin prevents or delays its action and is responsible for characteristic hyperglycemia in the immediate postprandial period, which leads to significantly increased insulin requirements followed by unpredictable hypoglycemic episodes (postprandial hypoglycemia) observed later.[ 14 ]

These autoantibodies assume more clinical and diagnostic importance in some cases, particularly adults, with late-onset of this disease where the destruction of the pancreatic β-cells occurs at a very slow rate and often the disease masquerades as in T2DM. In such cases, these autoantibodies enable the correct diagnosis of this disorder as the T1DM, rather than the most common T2DM. This type of diabetes is often described as “Latent Autoimmune Diabetes in Adults (LADA),” also known as “slowly progressing insulin-dependent diabetes.”[ 15 ]

LADA is the most common form of adult-onset autoimmune diabetes and accounts for 2–12% of all diabetic cases in the adult population.[ 16 ] Of the autoantibodies, GADAs are the most important and sensitive markers for LADA followed by ICAs. However, the IAAs, autoantibodies to the tyrosine phosphatases—IA-2 and IA-2α, and autoantibodies to islet-specific zinc transporter isoform 8 (ZnT8) which are observed in patients with juvenile- or young-onset T1DM are detectable in only a small number of cases in LADA.[ 17 ] In a study on LADA (Action LADA study), GADAs were the only diabetes-specific autoantibodies detected in 68.6% of total screened subjects whereas IA-2α and ZnT8A represented the single-type autoantibody detections in 5% and 2.3% of all the screened study subjects. In the same study, more than one type of autoantibody was detected in 24.1% of study subjects.[ 18 ] LADA is also sometimes referred to as T2DM with ICAs.

Besides the characteristic immune-mediated pancreatic β-cell destruction, several other autoimmune disorders including myasthenia gravis, Addison’s disease (primary adrenal insufficiency), celiac sprue (celiac disease), pernicious anemia, vitiligo, Hashimoto’s thyroiditis, Graves’ disease, dermatomyositis, autoimmune gastritis, and autoimmune hepatitis have been observed with an increased incidence in patients with T1DM.[ 1 , 10 , 19 , 20 ] The autoimmune nature of this disease and its association with other autoimmune conditions mainly stem from the strong association of this disorder with human leukocyte antigen (HLA), its linkage to the DQA and DQB genes, and its direct influence by DRB genes. All of these are hotspot gene regions associated with immune response including autoimmunity. The genome-wide association studies have shown a strong association of this disease with HLA-DR3 and HLA-DR4 haplotypes and the exclusive association of DR4-DQB1I0302 haplotype with the autoimmune destruction of the β-cells. As with other diseases, these various HLA haplotypes can increase or decrease the susceptibility toward the T1DM.[ 21 , 22 , 23 ] However, several non-HLA genes or gene regions also influence the susceptibility to this disease. The most prominent among them is the insulin gene (INS) region, designated as IDDM2 located on chromosome 11p5.5. The variable number of tandem repeats in the promoter region of this gene region has been observed to influence the susceptibility toward this disease.[ 24 ] Besides IDDM2, CTLA-4, PTPN-22, and CD25 are other non-HLA genes associated with the disease.[ 25 ] The patients with this type of diabetes can be but are rarely obese at the time of assessment and diagnosis.[ 1 , 10 ]

Idiopathic diabetes

Idiopathic diabetes, also referred to as ICA-negative or type 1B diabetes, includes the forms of diabetes which are similar to T1DM in presentation but characterized by variable nonimmune β-cell dysfunction without any observed HLA association unlike T1DM and hence, sometimes it is also described as a separate type of DM. This type of diabetes exhibits a strong pattern of inheritance and has been observed in only a minority of patients, of Asian or African-Caribbean origin. The etiology of idiopathic diabetes remains largely unknown.

The disease is characterized by severe but varying degrees of insulin deficiency (insulinopenia) which can exhibit episodic patterns concomitant with varying degrees of severity and episodic DKA. These patients, therefore, may require insulin replacement therapy initially but the need for the therapy may not be absolute and may vary in accordance with the episodic patterns of insulinopenia and ketoacidosis characteristic of these forms of T1DM.[ 26 ]

Type 2 diabetes mellitus

T2DM, also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, as per the previous nomenclature, constitutes about 90–95% of all the cases of diabetes. This type of diabetes is characterized by two main insulin-related anomalies: insulin resistance and β-cell dysfunction.[ 27 , 28 , 29 ] Insulin resistance results from disruption of various cellular pathways, which lead to a decreased response, or sensitivity of cells in the peripheral tissues, in particular the muscle, liver, and adipose tissue toward insulin. In the early stages of the disease, decreased insulin sensitivity triggers β-cells hyperfunction to achieve a compensatory increase in insulin secretion to maintain normoglycemia. The higher levels of circulating insulin (hyperinsulinemia), thus, prevent hyperglycemia. However, gradually, the increased insulin secretion by β-cells is not able to compensate sufficiently for the decrease in insulin sensitivity. Moreover, β-cell function begins to decline and β-cell dysfunction eventually leads to insulin deficiency. As a result, normoglycemia can no longer be maintained and hyperglycemia develops. Although insulin levels are decreased, the secretion of insulin in most cases is sufficient to prevent the occurrence of DKA.[ 29 ] But DKA may occur during severe stress conditions such as those associated with infections or other pathophysiological scenarios. DKA may also be precipitated by the use of certain drugs including sodium-glucose co-transporter-2 (SGLT2) inhibitors, corticosteroids, and atypical antipsychotics (second-generation antipsychotic drugs).[ 30 , 31 ] In absence of any severe physiological stress conditions, patients with T2DM often do not require any insulin therapy both at the time of disease onset and even after, throughout their lifetime.[ 27 , 28 , 29 ]

T2DM progresses very slowly and asymptomatically with even mild hyperglycemia developing over years and as such remains largely undiagnosed until the appearance of classic symptoms associated with severe hyperglycemia such as weight loss, growth impairment, blurred vision, polyuria, and polydipsia in the advanced stages of the disease. The pathogenesis/etiology of this form of diabetes is complex and involves multiple known and unknown factors, which in a conclusive manner can be described as a combination of genetic (polygenic) predispositions and strong environmental influences. T2DM has been more frequently associated with increasing age, obesity, family history of diabetes, physical inactivity, and adoption of modern lifestyles: with prior GDM in women and with pathophysiological conditions such as hypertension and dyslipidemia. It occurs more frequently in individuals belonging to certain racial or ethnic groups including Native Americans (American Indians), Asian Americans, African Americans, Hispanic, and Latino. The frequent occurrence of T2DM in the mentioned racial or ethnic groups and its observed strong association with first-degree blood relations point strongly toward the role of genetic factors in the etiology of this disease, but these factors are complex and remain largely unspecified. However, unlike T1DM, no association of this disease has been found with genes involved in the immune response including autoimmunity and consequently there is no immune-mediated pancreatic β-cell destruction.[ 32 , 33 ]

Obesity plays an important role in the homeostatic regulation of systemic glucose due to its influence on the development of insulin resistance through its effect on the sensitivity of tissues to insulin and as such most but not all patients with T2DM are overweight or obese.[ 34 ] The increased body fat content, a characteristic of obesity, is such an important risk factor for T2DM that not only the total amount but also the distribution of body fat itself defines the development of insulin resistance and subsequently hyperglycemia. The increased abdominal fat or visceral obesity has been frequently associated with this type of diabetes in comparison to increased gluteal/subcutaneous fat or peripheral obesity.[ 35 ] Due to its strong association with increased body fat content or obesity, the patients with T2DM often present with various cardiovascular risk factors such as hypertension and lipoprotein metabolic abnormalities characterized by elevated triglycerides and low levels of high-density lipoproteins (HDLs). Due to its lifelong duration and associated diverse metabolic derangements characteristic of hyperglycemia, T2DM, particularly in the middle and later decades, is frequently associated with the development of various microvascular and macrovascular complications. Figure 2 enlists some of the main risk factors of T2DM.

Some of the main risk factors of type 2 diabetes mellitus

Gestational diabetes mellitus

GDM is defined as any degree of glucose intolerance or diabetes diagnosed at the outset or during pregnancy, usually the second or third trimester. This definition earlier also included any undetected T2DM which may begin prior to or occur at the time of pregnancy onset. However, the latest recommendations of the International Association of the Diabetes and Pregnancy Study Groups exclude from this definition diabetes diagnosed at the pregnancy onset or afterward in high-risk women such as with obesity where any degree of glucose intolerance is described as previously undiagnosed overt diabetes rather than GDM. GDM is different from any preexisting diabetes in women undergoing pregnancies and usually resolves soon after childbirth or termination of pregnancy.[ 1 , 36 ]

During early pregnancy, both the fasting and post-prandial blood glucose levels are usually lower than normal but the blood glucose levels increase during the third trimester of pregnancy, and in cases where this blood glucose level reaches the diabetic levels, the condition is described as GDM. More than 90% of all the cases of diabetes and its complications that occur during pregnancy can be attributed to GDM. The incidence of GDM varies from 1% to 14% of all pregnancies and its prevalence is greatly influenced by the populations under study. GDM occurs more frequently in certain racial or ethnic groups than others and this influence of ethnicity on risk of GDM is very important and has long been established. The prevalence of GDM is highest among Asian Indians, higher in aboriginal Australians, Middle Eastern (Lebanese, Syrian, Iranian, Iraqi, or Afghanistan), Filipina, Pacific Islanders, and Chinese, Japanese, Korean, and Mexican women. The prevalence is lower in blacks and lowest among non-Hispanic white women.[ 37 , 38 ] The risk of GDM increases with age, obesity, previous pregnancy with large babies, and any previous history of impaired glucose tolerance or GDM.[ 39 , 40 ] Furthermore, GDM has been associated with an increased lifetime risk of developing T2DM. The regular and lifetime screening for any kind of glucose impairment is, therefore, highly recommended in order to ensure early diagnosis of T2DM in such individuals.[ 41 , 42 , 43 ]

Other types of diabetes

Besides T1DM, T2DM, and GDM, diabetes in various other forms, though in smaller percentages with respect to overall diabetic incidence scenario, has been found to be associated with some specific conditions including various pathologies and/or several disorders. The prominent among these types of diabetes include diabetes resulting from the monogenic defects in β-cell function and those due to genetic abnormalities in insulin action, endocrinopathies, exocrine pancreatic pathologies, and several other specific conditions.

Diabetes caused due to the monogenic defects in β-cell function

Diabetes resulting from monogenic defects in β-cell function constitutes only 0.6–2% of all the cases of diabetes and mainly includes maturity-onset diabetes of the young (MODY) and neonatal diabetes, besides other but rare types.

Maturity-onset diabetes of the young

MODY is a genetically, metabolically, and clinically heterogeneous group of mostly non-insulin-dependent diabetes, resulting from mutations in several specific genes involved in pancreatic β-cell function, which affects glucose sensing and subsequent insulin secretion with no or minimal defects, if any, in insulin action. MODY, as the name suggests, has an early onset with glucose tolerance impairment and hyperglycemia occurring usually before the age of 25 years and is often misdiagnosed as T1DM or T2DM.[ 44 , 45 ] MODY accounts for less than 2% of all the cases of diabetes[ 46 ] and 1–6% of all the pediatric cases of diabetes.[ 47 ] MODY follows an autosomal dominant inheritance pattern and typically involves the vertical transmission of the disorder through at least three generations and exhibits a phenotype shared by all family members with diabetes.[ 48 ] To date, MODY has been associated with mutations in one of the 14 genes identified so far and these genes are mostly located on different chromosomes.[ 1 , 9 , 46 , 49 ] Figure 3 provides a graphical representation of various MODY subtypes along with their alternative names based on genes involved. The most common forms of this group of diabetes are designated as MODY2 and MODY3 which together account for more than 80% of all the cases of this type of diabetes.[ 50 , 51 ]

Types of maturity-onset diabetes of the young and their alternative names based on genes involved

MODY2 (GCK MODY ). MODY2 results from one or several of more than 200 loss-of-function mutations in the glucokinase (GCK) gene located on chromosome 7p13 and accounts for 15–25% of all MODY cases.[ 50 , 52 ] GCK gene codes for GCK enzyme, which catalyzes the first and rate-limiting step of glycolytic phosphorylation of glucose to glucose-6-phosphate at a rate proportional to the glucose concentration. This unique catalytic property allows the GCK enzyme to function as a sort of a glucose sensor and enables the β-cells to elicit an insulin secretion response appropriate to the existing concentrations of glucose.[ 53 ] The loss-of-function mutations characteristic of MODY2 disrupt this glucose-sensing function of the GCK enzyme such that only hyperglycemic but not normoglycemic levels can elicit a normal insulin secretion response from the β-cells. In MODY2, the fasting hyperglycemia remains mild but persistent and stable and the disorder is non-insulin-dependent. MODY2 is clinically nonprogressive with mild or no symptoms and is usually not associated with the development of microvascular and macrovascular complications. GCK gene is a mutational hotspot region and more than 600 mutations have been identified in the 10 exons of this gene, which have been associated with both hyperglycemia and hypoglycemia.[ 54 ]

MODY3 (HNF-1α MODY) and MODY1 (HNF-4α MODY ). MODY3 results from the loss-of-function mutations in hepatocyte nuclear factor (HNF)-1α gene located on chromosome 12q24, which codes for the transcription factor, HNF-1α (transcription factor MODY) and accounts for 30–50% of all MODY cases.[ 51 ] HNF-1α is expressed in the kidney, liver, intestine, and pancreatic β-cells and is involved in regulating the expression of several hepatic genes many of which are involved in glucose metabolism including glucose transporter 1 and 2 (GLUT1 and GLUT2). More than 400 mutations have been identified in HNF-1α gene.[ 55 ] MODY3 presents with a symptomatic rapid progression to overt diabetes reflected through a progressive impairment from glucose intolerance to severe hyperglycemia, often leading to T1DM and T2DM like microvascular and macrovascular complications. MODY3 has been associated with a decreased pancreatic β-cell mass due to an increased rate of β-cell apoptosis, particularly from the third decade of life onward, and therefore, MODY3 is characterized by a progressive decrease in insulin secretion.[ 56 ] Depending on the hyperglycemic severity and duration since onset, MODY3 may be or may not be insulin-dependent.

MODY1 accounts for around 5% of all MODY cases. MODY1 is caused due to the loss-of-function mutations in the transcription factor, HNF-4α gene located on chromosome 20q13. HNF-4α is mainly expressed in the liver and also in kidney and pancreatic β-cells and regulates the expression of genes involved in glucose transport, metabolism, and nutrient-induced insulin secretion and also triglyceride metabolism and lipoprotein biosynthesis.[ 57 ] HNF-4α mutation is characterized by a progressive defect and a decline in insulin secretion from infancy onward and resembles clinically with MODY3. It is associated with hyperinsulinemic hypoglycemia in the neonatal period, which begins to remit during infancy, and as such, the decline in insulin production starts in infancy but the emergence of hyperglycemia and subsequent full-blown diabetes occurs during adolescence.[ 47 , 58 ] HNF-4α mutation and hence MODY1 have been associated with decreased levels of apolipoprotein—apoAII, apoCIII, and apoB and HDLs and increased levels of low-density lipoproteins (LDLs).

Hyperglycemia associated with HNF-1α and HNF-4α mutations in MODY3 and MODY1, respectively, can be efficiently controlled through the treatment with low-dose sulfonylureas. These agents maintain efficacy or remain effective for many years and are preferred first-line of treatment in these patients compared to insulin and other therapies used in T1DM and T2DM. However, to ensure proper treatment, an early and accurate diagnosis is very important to avoid mislabeling these MODY types as T1DM or T2DM and prevent administration of inappropriate avoidable therapies in these patients.[ 59 , 60 ]

MODY5 (HNF-1β MODY ). MODY5 results from mutations in the transcription factor, HNF-1β gene located on chromosome 17q12 and accounts for around 5% of all cases of MODY.[ 61 , 62 ] HNF-1β is involved in the regulation of genes that are associated with various embryonic developmental processes, in particular, the genesis of various organs including the liver, pancreas, lungs, gut, kidney, and genitourinary tract.[ 63 ] MODY5 develops in early adolescence or adulthood. HNF-1β mutations that result in MODY5 often present as renal cysts, renal cysts and diabetes syndrome, renal dysplasia, hypoplastic glomerulonephritic kidney disease, urinary tract malformation,[ 64 , 65 ] and reduced birth weight.[ 66 ] Some of these conditions are evident from the 17th week of gestation[ 65 ] or are seen in infants or young children, independent of the hyperglycemic status.[ 47 ] Renal dysfunction,[ 65 ] liver dysfunction, and pancreatic abnormalities[ 67 ] are common as the disorder develops and end-stage renal disease develops in half of the patients with MODY5 by 45 years of age independent of diabetic kidney disease status.[ 65 ] Genitourinary tract malformations especially uterine abnormalities such as rudimentary uterus in addition to vaginal aplasia have also been reported in MODY5.[ 67 ] Insulin dependence develops relatively earlier due to liver and pancreatic abnormalities, in particular, hepatic insulin resistance and pancreatic hypoplasia.[ 47 , 68 ] Hyperuricemia, gout, low HDL levels, and elevated triglyceride levels are commonly observed in patients with MODY5.[ 61 , 69 ]

Other types of MODY . Relatively rare and less common types of MODY, which account for less than 1% of all MODY cases, include as follows:

• MODY4 (PDX-1/IPF-1 MODY ): MODY4 results from mutations in the transcription factor, pancreatic and duodenal homeobox-1(PDX-1), also known as insulin promoter factor (IPF)-1 gene located on chromosome 13q12.2.[ 70 ] PDX-1/IPF-1 is involved in the development of exocrine and endocrine pancreas and plays an important role in regulating the expression of insulin, glucagon, GLUT2, and GCK encoding genes.[ 71 , 72 ] Homozygous mutations in PDX-1/IPF-1 gene result in pancreas agenesis, hypoplasia, and pancreatic exocrine insufficiency and in permanent neonatal diabetes (PND) whereas heterozygous PDX-1/IPF-1 gene mutations cause β-cell impairment, which leads to defective insulin secretion and hyperglycemia.[ 73 , 74 ]
• MODY6 (NEUROD1 MODY ): MODY6 results from mutations in the transcription factor, neurogenic differentiation factor-1(NEUROD1) gene located on chromosome 2q31.[ 75 ] NEUROD1 belongs to the basic helix-loop-helix family of transcription factors and is involved in the regulation of several cell differentiation pathways associated with neuronal and pancreatic development, in particular, those involved in endocrine islet cells (islets of Langerhans) differentiation including the pancreatic β-cells. NEUROD1 gene mutations interfere with the maturation of β-cells and impair their glucose-sensing ability and as a result, their insulin secretion response. Homozygous NEUROD1 gene mutations lead to neonatal diabetes and are associated with neurological abnormalities whereas heterozygous mutations result in childhood- or adult-onset diabetes.[ 76 , 77 ]

The other types of MODY in this category include MODY7 (KLF11 MODY), which results from the mutations in Kruppel-like factor 11 (KLF11) gene located on chromosome 2p25[ 78 ] and MODY8 (CEL MODY), which arises from the mutations in carboxyl ester lipase (CEL) gene located on chromosome 9q34.[ 79 ] This category also includes MODY9 (PAX4 MODY), caused due to the mutations in PAX family transcription factor, Paired box gene 4 (PAX4) gene located on chromosome 7q32[ 80 ] and MODY10 (INS MODY), which results from the mutations in the INS located on chromosome 11p15[ 81 , 82 ]; also, MODY11 (BLK MODY), which arises due to the mutations in the human homolog of a B-lymphocyte-specific protein tyrosine kinase (BLK) gene located on chromosome 8p23.1.[ 83 ]

Furthermore, there is MODY12 (ABCC8-MODY), which results from the mutations in ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene located on chromosome 11p15 and ABCC8 which encodes sulfonylurea receptor-1 (SUR1) protein, a subunit of ATP-sensitive potassium (KATP) channel. MODY12 is responsive to sulfonylureas.[ 84 ]

The remaining types include MODY13 (KCNJ11-MODY) and MODY14 (APPL1-MODY). MODY13 (KCNJ11-MODY) is caused due to the mutations in potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene located on chromosome 11p15.1 which encodes β-cell inward rectifier, BIR (inwardly rectifying potassium channel Kir6.2), a subunit of ATP-sensitive potassium (KATP) channel.[ 85 , 86 ] MODY14 (APPL1-MODY) results from the mutations in Adaptor Protein, Phosphotyrosine Interacting With PH Domain and Leucine Zipper 1 (APPL1) or DCC-interacting protein 13-α (DIP13-α) gene located on chromosome 3p14.3.[ 87 ]

Neonatal diabetes mellitus

Neonatal diabetes mellitus (NDM), also known as early-onset or congenital diabetes, is the diabetes diagnosed during the first 6 months of life. It is a rare disorder with a global incidence rate of 1 per 500,000–300,000 (1:500,000–1:300,000)[ 88 , 89 ] live births; though a study in Italy has reported a higher incidence of 1 per 90,000 (1:90,000).[ 88 ] NDM is predominantly of genetic origin with 80–85% cases occurring due to monogenic defects and is characterized by severe uncontrolled hyperglycemia along with hypoinsulinemia and requires insulin replacement therapy.[ 89 ] The genetic abnormalities lead to β-cell dysfunction and decreased β-cell mass due to increased apoptotic or non-apoptotic β-cell death. These defects also result in developmental abnormalities of pancreas and/or its islets or in very rare cases their complete absence leading to decreased production and secretion of insulin or hypoinsulinemia and in the latter case an absolute insulin deficiency.[ 90 ] Neonatal diabetes is highly distinct from early-onset T1DM and differs from it both in the origin and pattern of inborn pancreatic disorder and mostly occurs during the first 6 months of life whereas T1DM mostly develops after 6 months of life. Based largely on the clinical features, NDM can assume either of these two forms: transient neonatal diabetes mellitus (TNDM) and permanent neonatal diabetes mellitus (PNDM).

TNDM is the more common form representing approximately 55–60% of all cases of neonatal diabetes. It usually resolves within 12–18 months after birth but in a majority of cases, NDM relapses during the later years of life from late childhood to early or late adulthood and presents itself as T2DM, indicating the presence of varying degrees of severity, but persistent β-cell dysfunction, which leads to possible inadequate insulin secretion and/or insulin resistance. Furthermore, the diabetes may also precipitate under stress conditions such as hormonal changes as observed in puberty or in certain diseases.[ 89 , 91 ] TNDM results most often from the abnormalities in chromosome 6 specifically involving the overexpression of imprinted and paternally expressed genes in the 6q24 region. This includes the HYMAI (hydatiform mole associated and imprinted) gene, zinc finger protein, ZAC gene, and pituitary adenylate cyclase activating polypeptide-1 (PACAP1) gene. A small percentage of TNDM cases arises from the mutations in the ATP binding cassette subfamily C member 8 (ABCC8) gene also known as sulfonylurea receptor-1 (SUR1) gene and rarely from the mutations in the potassium voltage-gated channel subfamily J member 11 (KCNJ11 or Kir6.2).[ 89 ] Both ABCC8 and KCNJ11genes are functionally linked together as these genes encode for the proteins that constitute the individual subunits of the β-cell K ATP channel. The K ATP channel is an eight-subunit ATP-sensitive potassium channel with two types of subunits: four regulatory subunits encoded by ABCC8 (SUR1) gene and four pore-forming subunits encoded by KCNJ11 (Kir6.2) gene. This channel regulates the secretion of insulin from the pancreatic β-cells, thus providing a direct link with normal glucose homeostasis and its dysregulation in diabetes.

PNDM is the less common form of NDM, which unlike TNDM does not go into remission and persists permanently. PNDM most commonly results from the heterozygous autosomal dominant mutations in the ABCC8 and the KCNJ11 genes encoding, respectively, the SUR1 and Kir6.2 subunits of the β-cell K ATP channel.[ 9 , 89 ] Several mutations identified in the INS also cause PNDM.[ 9 ] Besides, this type of neonatal diabetes is associated with several syndromes including the immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and Wolcott–Rallison syndrome. IPEX syndrome is an autoimmune disorder that results from the mutations in the FOXP3 gene. The autoimmune disorders that characterize IPEX syndrome include autoimmune enteropathy (an autoimmune disorder of the intestines), dermatitis or eczema (an autoimmune disorder of the skin), and polyendocrinopathy (multiple autoimmune disorders of the endocrine glands, including pancreas and thyroid).[ 9 , 89 , 92 ] WRS is an autosomal recessive disorder, which results from the mutations in the EIF2AK3 gene.[ 9 , 89 , 93 ] The main characteristics of this disorder include multiple epiphyseo-metaphyseal dysplasia and hepatic dysfunction. Diabetes is a permanent feature associated with this syndrome and in consanguineous families; WRS has emerged as the most frequent cause of PNDM.[ 94 , 95 ] Clinically, it is not possible to predict whether a particular neonatal dysfunction of glucose homeostasis will eventually develop into TNDM or PNDM, which makes the correct diagnosis, and the assessment of the underlying cause of the disorder including the genetic factors involved, an important aspect in the management of this disorder.

Besides MODY and NDM, there are several other monogenic defects in β-cell function which result in DM. These include the point mutations in mitochondrial DNA such as 3243A-G mutation in the mitochondrial transfer RNA leucine-1 (MTTL1) gene, which leads to deafness and diabetes[ 96 ] and the autosomal dominant mutations, which result in a total inability or abnormal conversion of proinsulin to insulin.[ 97 ] Furthermore, it also includes the mutations that lead to the production of structurally abnormal insulin molecules with impaired receptor binding.

Diabetes caused due to genetic abnormalities in insulin action

Several genetic abnormalities in insulin action resulting either from insulin receptor functional impairment or decrease in the number of insulin receptors, caused mainly due to the mutations in insulin receptor (INSR) gene located on chromosome 19, have been identified. These abnormalities in insulin action lead to hyperinsulinemia or insulin resistance and subsequent mild to modest hyperglycemia or may even cause severe hyperglycemia characteristic of overt diabetes.[ 1 ] The various forms of diabetes resulting from the abnormalities in insulin action, often described as inherited severe insulin resistance syndromes, include type A insulin resistance syndrome, lipoatrophic diabetes, Donohue syndrome (leprechaunism), and Rabson–Mendenhall syndrome (RMS).

Type A insulin resistance syndrome results from mutations in INSR gene. This syndrome is associated with menstruation disorders (primary amenorrhea or oligomenorrhea) and specific forms of polycystic ovarian syndrome characterized by hirsutism due to hyperandrogenism and multiple enlarged cysts on the ovaries, in females[ 98 ]; also, acanthosis nigricans, a skin pigmentation disorder, most often in females than in males[ 99 ] and obesity,[ 100 ] most often in males than in females and severe insulin resistance.

Lipoatrophic diabetes is a monogenic but heterogeneous insulin resistance syndrome associated with lipoatrophy and lipodystrophy and characterized by paucity (insufficiency) of fat, insulin resistance, and dyslipidemia, more specifically, hypertriglyceridemia.[ 101 ] Lipoatrophic diabetes arises due to the mutations in several different genes, which manifests as different genetic syndromes. It may result from the mutations in Laminin A/C (LMNA) gene located on chromosome 1q21–22 and manifest as an autosomal dominant disorder known as familial partial lipoatrophy, also known as Dunnigan or Koberling-Dunnigan syndrome.[ 102 ] Lipoatrophic diabetes may also result from the mutations, either in the AGPAT2 gene or in the BSCL2 gene. AGPAT2 gene located on chromosome 9q34 encodes the enzyme 1-acyl-sn-glycerol-3-phosphate- d -acetyltransferase-2, which is involved in triglyceride synthesis. Berardinelli-Seip congenital lipodystrophy type-2 (BSCL2) gene, also known as γ3-linked gene (GNG3) or seipin gene, located on chromosome 11q13 encodes seipin, an endoplasmic reticulum-associated protein involved in lipid droplet biogenesis. Both these mutations manifest as an autosomal recessive disorder known as Congenital generalized lipoatrophy or Berardinelli-Seip syndrome.[ 103 , 104 ]

Furthermore, the mutations in insulin receptor gene may also lead to the Donohue syndrome (leprechaunism) and the RMS, both of which manifest in infancy, and diabetes in these syndromes is characterized by strong insulin resistance and severe hyperglycemia.[ 105 ]

Endocrinopathies

Several endocrinopathies resulting in or from abnormal functioning of various hormones can lead to diabetes. These include the endocrinopathies that involve the hyperactivity of those hormones which partly or fully antagonize the function of insulin such as Cushing syndrome, acromegaly, pheochromocytoma, glucagonoma, and hyperthyroidism, which result from hyperactivity of cortisol, growth hormone, norepinephrine (and epinephrine), glucagon, and thyroid hormones, respectively. Diabetes associated with these endocrine disorders usually occurs when a defect in insulin secretion and/or action is already present.[ 106 , 107 ] Some endocrinopathies induce diabetes through inhibition of insulin secretion and these include somatostatinoma, which leads to the excessive secretion of somatostatin and primary hyperaldosteronism[ 108 ] or Conn’s syndrome induced hypokalemia, which involves the hypersecretion and hyperactivity of the hormone, aldosterone.[ 109 ] Diabetes caused due to various endocrinopathies usually resolves when endocrinopathies are treated or managed.

Exocrine pancreatic pathologies

Several diseases of the exocrine pancreas have been found to cause diabetes but the contribution of these diseases to the overall incidence of diabetes is minimal with less than 0.5% of all the cases of diabetes resulting from the diseases of the exocrine pancreas. These include chronic pancreatitis (fibrocalculous pancreatopathy), trauma (pancreatectomy), infection, hereditary hemochromatosis, secondary hemochromatosis, cystic fibrosis, and pancreatic neoplasia (adenocarcinoma and glucagonoma).[ 110 , 111 , 112 ] All these pancreatic pathologies, with the exception of pancreatic neoplasia, lead to diabetes only when they are severe enough to cause extensive pancreatic damage, involving the endocrine pancreas, including the islets of Langerhans, which leads to a considerable reduction in the β-cell mass and impairment of β-cell function.[ 113 ] The pancreatic neoplasia-associated diabetes occurs even without any reduction in β-cell mass.[ 1 ]

Several infections caused by viruses are known to cause β-cell dysfunction, mainly through β-cell destruction, and lead to hyperglycemia, which gradually presents as overt diabetes. These include infections caused by cytomegalovirus, adenovirus, Coxsackie virus B, and mumps. Besides, congenital rubella syndrome, caused by rubella virus, has also been closely linked with diabetes, but this diabetes in most of the cases is associated with the presence of HLA and other immune markers, which are characteristic of T1DM.[ 1 , 114 , 115 ] Furthermore, insulin resistance has been associated with chronic hepatitis C virus infection and progression of fibrosis and a very high prevalence of T2DM has been reported among the individuals infected with the hepatitis C virus.[ 116 , 117 ]

Drug- or chemical-induced

Several drugs and chemicals are known to induce diabetes. These agents induce diabetes either through the impairment of insulin production or secretion, which mainly results from the destruction of β-cells or through a decrease in the sensitivity of tissues to insulin, which causes insulin resistance. Diabetes resulting from the drug- or chemical-induced increase in insulin resistance occurs only in susceptible individuals. Furthermore, these agents may worsen or increase the severity of hyperglycemia in individuals with already existing overt diabetes. The drugs and chemicals known to induce diabetes include glucocorticoids, diazoxide, thiazides, β 2 -receptor agonists (salbutamol and ritodrine), nonselective β-adrenergic antagonists, dilantin, hormones including growth hormone (in very high doses), thyroid hormone (thyroxine/triiodothyronine), somatostatin, estradiol, levonorgestrel, and glucagon. These also include γ-interferon, protease inhibitors (indinavir, nelfinavir, ritonavir, and saquinavir), nicotinic acid, and β-cell toxins including streptozocin (streptozotocin), cyclosporine, rodenticide vacor and pentamidine, and several antipsychotics.[ 118 , 119 ] Furthermore, immune checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, used in cancer immunotherapy for treatment of advanced-stage cancers, including head and neck cancer, renal cancer, urothelial cancers, non-small-cell lung carcinoma, and melanoma besides other cancers[ 120 , 121 , 122 , 123 , 124 , 125 ] have been reported to induce new-onset T1DM, through immune-mediated β-islet cell dysfunction.[ 125 , 126 ]

Other genetic syndromes associated with diabetes

There are many others, besides the already mentioned genetic syndromes, that are usually associated with an increased incidence of diabetes. These include Down’s syndrome, Turner’s syndrome, Wolfram’s syndrome, Klinefelter’s syndrome, Huntington’s chorea, Friedreich’s ataxia, myotonic dystrophy, Laurence-Moon-Biedl syndrome, Porphyria, and Prader-Willi syndrome among others.[ 127 ]

Uncommon forms of immune-mediated diabetes

The uncommon forms of immune-mediated diabetes are very rare in occurrence and mainly include diabetes associated with Moersch-Woltman syndrome (stiff-person syndrome [SPS]), anti-insulin receptor antibodies (AIRAs), and insulin autoimmune syndrome (IAS; Hirata’s disease).

Moersch-Woltman syndrome or the SPS is a very rare autoimmune disorder that affects the central nervous system and is characterized by progressive fluctuating rigidity of the axial muscles (muscles of the trunk and head), accompanied by painful muscle spasms. Patients with SPS generally present with high titers of GADAs and are frequently associated with various diseases including pernicious anemia, thyroiditis, vitiligo, and type 1-like diabetes. Although GADAs are detected in most of the individuals with T1DM alone; but the individuals with SPS with or without diabetes have 50–100 times more titers of GADAs.[ 128 ]

The AIRAs are often associated with various autoimmune diseases, including primary biliary cholangitis, systemic lupus erythematosus, and Hashimoto thyroiditis. AIRAs generally bind to insulin receptors on various insulin target tissues, which block the binding of insulin to these receptors and hence the subsequent signaling pathways. This leads to diabetes characterized by a rapidly progressive and extreme form of insulin resistance, earlier termed as type B insulin resistance. Alternatively, AIRAs once bound to target receptors may sometimes cause spontaneous hyperinsulinemic hypoglycemia by acting as insulin agonists. Diabetes associated with AIRAs is often characterized by acanthosis nigricans and impaired insulin degradation.[ 129 , 130 ]

IAS or Hirata’s disease is described as a condition, which is characterized by the presence of autoantibodies to the endogenous insulin (IAA) in the absence of any previous exposure to the exogenous insulin, absence of any pathological abnormalities of the pancreatic islets and presents as endogenous hyperinsulinemia hypoglycemia. Although, the predisposition to this condition is present from birth, but the overt disease most often presents itself during adulthood and can be triggered by exposure to certain drugs and viruses. IAS can be controlled through simple dietary management.[ 131 ]

Ketosis-prone diabetes mellitus

Ketosis-prone diabetes mellitus (KPD) describes another heterogeneous group of diabetes, which like T2DM, characteristically does not involve the immune-mediated destruction of pancreatic β-cells but unlike T2DM, this type presents with frequent episodes of DKA or unprovoked ketosis.[ 132 ] KPD occurs most frequently in African Americans and Africans in sub-Saharan Africa but has now been observed increasingly in Hispanic, Chinese, and Japanese populations.[ 132 , 133 , 134 , 135 ] One of the best described subtypes of this diabetes is Flatbush diabetes which along with characteristic episodic DKA is frequently associated with HLA-DR3 and/or HLA-DR4 haplotypes.[ 136 ] The patients with KPD show periodic but absolute requirement of insulin replacement therapy, concomitant with the episodes of DKA and outside of the frequent episodes of DKA, the diabetes can be controlled through simple diet management without insulin replacement therapy.

CONCLUSIONS

DM is a heterogeneous metabolic disease, represented by diverse forms, each with a distinct pathophysiological origin but often manifest as a disorder with overlapping and difficult-to-differentiate characteristics. The treatment and management of each of these diabetic types are distinct in some characteristics but share a great deal of similarity as well as is the case with the disorder itself. All this emphasizes the importance of correct and timely diagnosis of each of these diabetic types and the critical role of their pathophysiological understanding. This is vital to safeguard diabetic individuals from exposures to potential adverse effects of improper, ineffective, or avoidable pharmaceutical interventions, which often delays the desired prognosis and increases the duration of hyperglycemic exposures. The long-term hyperglycemia, in turn, has often been associated with increased risk of microvascular and macrovascular diabetic complications, which affect the quality of life and mainly contribute to the diabetes-associated morbidity and mortality. For diabetes in general, and in particular, the diabetes types resulting from genetic mutations or associated genetic anomalies, the correct and timely molecular diagnosis can help in disease risk analysis and help in disease prediction and timely identification of individuals at an increased risk to the disorder, in particular, the family members. The predictive molecular/genetic testing and preventive management can play a vital role in such cases. Furthermore, irrespective of the diabetes type, various lifestyle modifications and interventions such as extensive diet control, physical exercises, change of daily sedentary routine, and control of obesity are important in the prevention and the management of diabetes. The educational campaigns, which make the general population aware of the pathogenesis of this disease and the various controllable risk factors associated with it, are also a vital tool in the management and control of diabetes mellitus.

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Diabetes Mellitus Clinical Presentation

During prediabetes and the early stages of diabetes, the majority of patients are asymptomatic. As a result, obtaining a diagnosis may be delayed for many years if routine screening measures for diabetes, such as laboratory work, are not performed during regular healthcare visits. Typically, patients with type 1 diabetes mellitus (T1DM) present with symptomatic hyperglycemia and sometimes with diabetic ketoacidosis (DKA). DKA is defined as an acute metabolic complication of diabetes distinguished by hyperglycemia, hyperketonemia, and metabolic acidosis. DKA occurs primarily in T1DM and is less common in T2DM; it can present with nausea, vomiting, and abdominal pain and cause cerebral edema, coma, and death. DKA may be the initial presentation in an estimated 25% of adults with T1DM. The most common symptoms associated with T1DM are polyuria, polydipsia, and polyphagia, along with lethargy, nausea, and blurred vision, all of which result from the hyperglycemia. The onset of symptoms may be abrupt. Polyuria is caused by osmotic diuresis secondary to hyperglycemia. In young children, severe nocturnal enuresis secondary to polyuria could be a warning sign of diabetes onset. In T1DM, thirst is a response to the hyperosmolar state and dehydration. The American Diabetes Association notes that adults with new-onset T1DM may present with a short duration of illness of 1 to 4 weeks or more, a gradually progressing process that can be misinterpreted as type 2 diabetes mellitus (T2DM). Patients with T1DM may also present with fatigue, weakness, and weight loss despite normal appetite. Patients with T2DM may present with symptomatic hyperglycemia but are frequently asymptomatic for diabetes, and T2DM is often discovered during routine checkups and laboratory testing. Classic symptoms of T2DM include polyuria, polydipsia, polyphagia, and weight loss. Other symptoms that may suggest hyperglycemia include blurred vision, lower-extremity paresthesia, and delayed wound healing. In some patients, initial symptoms may actually be indicative of diabetic complications (such as neuropathy, retinopathy, skin acanthosis, and recurring Candida infections), signifying that the T2DM has been present for some time. This highlights the need for routine screening, especially in high-risk patient populations. In some patients, a hyperosmolar hyperglycemic state occurs initially, particularly during a period of extreme stress or when glucose metabolism is further impaired by use of certain pharmacologic agents, such as corticosteroids. Since early diagnosis and clinical intervention are essential for preventing and/or reducing the complications associated with poorly controlled diabetes, patients should be reminded to maintain routine healthcare and seek medical care if they are experiencing any symptoms associated with hyperglycemia. The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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Type 2 Diabetes-Etiology, Epidemiology, Pathogenesis, Treatment

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Diabetes is one of the largest health problems facing the world today. It is estimated that by the year 2030 over 7 % of the world’s adult population will have diabetes. Numerous risk factors play into an individual’s risk of developing diabetes. Some are modifiable such as obesity, diet, and exercise. Other risk factors including genetic and environmental factors are topics of ongoing research. The physiology of diabetes is a complex interplay between beta-cell function and insulin resistance. Other hormones such as GLP-1 and leptin also play a role. The classic presentation of type 2 diabetes is polyuria, polydipsia, and unintentional weight loss. However, many people are diagnosed with diabetes on routine screening either with a hemoglobin A1c test or an oral glucose tolerance test. The treatment of type 2 diabetes is multifaceted and crosses multiple disciplines. Patient education regarding diet and exercise and adjustment of modifiable risk factors remain the cornerstone of treatment. Patients should be screened for microvascular and macrovascular complications. While studies have shown a benefit of intensive glycemic control for type 2 diabetes in reducing microvascular complications, the effect on macrovascular complications has been less clear. Long-term studies do suggest that good glycemic control near the time of diagnosis can have beneficial impact decades later.

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Type 2 Diabetes: Etiology, Epidemiology, Pathogenesis, Treatment

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Management of Diabetes Mellitus

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Burns, C., Sirisena, I. (2015). Type 2 Diabetes-Etiology, Epidemiology, Pathogenesis, Treatment. In: Ahima, R. (eds) Metabolic Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-319-12125-3_34-1

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Differential Diagnoses

Differential diagnosis i.

Diabetes mellitus type 2 is an ailment involving hyperglycemia and insulin resistance.

Rationale: The patient is presenting with fatigue and weight loss which may be indicative of diabetes mellitus type 2, and his blood glucose is abnormally high.  Classic symptoms for diabetes mellitus type 2 include: Polyuria, polydipsia, polyphagia, blurred vision, fatigue and weight loss.  Other presentations include: Lower-extremity paresthesias, yeast infections in females, balanitis in males and slow-healing wounds.

Diagnosis of diabetes mellitus includes any of the following:

• A glycosolated hemoglobin, or hemoglobin A1C, greater than or equal to 6.5%,  or
• Fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher, or
•  2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
• A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis

From McCance and Huether (2014).

Differential Diagnosis II

Metabolic syndrome is a group of risk factors thought to be linked to insulin resistance. It can occur in patients with normal glucose tolerance, prediabetes, and diabetes.

Rationale: The patient’s presentation could be indicative of metabolic syndrome.

Metabolic Syndrome is diagnosed when 3 of 5 conditions exist

• Abdominal obesity
• Elevated triglyceride level
• Low level of high-density lipoprotein (HDL) cholesterol
• Elevated blood pressure
• Fasting glucose value of 100 mg/dL or higher

Differential Diagnosis III

Hyperthyroidism  is over activity of the thyroid gland as a result of an overproduction  of thyroxine.

Rationale: Weight loss and fatigue could be indicative of hyperthyroidism.  Classic symptoms: Excessive sweating, weight loss, tachycardia, hand tremors, anxiety, fatigue, muscle weakness and insomnia

• Thyroid function tests confirm the diagnosis
• The presence of autoantibodies rule out hyperthyroid
• Thyroid imaging rules out other causes, such as nodules, inflammation or overactivity

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Type 1 Diabetes Mellitus Clinical Presentation

• Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD  more...
• Sections Type 1 Diabetes Mellitus
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Complications
• Laboratory Studies
• Tests to Differentiate Type 1 from Type 2 Diabetes
• Approach Considerations
• Self-Monitoring of Glucose Levels
• Continuous Glucose Monitoring
• Insulin Therapy
• Management of Hypoglycemia
• Management of Hyperglycemia
• Management of Complications
• Glycemic Control During Serious Medical Illness and Surgery
• Glycemic Control During Pregnancy
• Consultations
• Medication Summary
• Antidiabetics, Insulins
• Antidiabetics, Amylinomimetics
• Hypoglycemia Antidotes
• Monoclonal Antibodies
• Allogeneic Islet Cells
• Questions & Answers

The most common symptoms of type 1 diabetes mellitus (DM) are polyuria, polydipsia, and polyphagia, along with lassitude, nausea, and blurred vision, all of which result from the hyperglycemia itself.

Polyuria is caused by osmotic diuresis secondary to hyperglycemia. Severe nocturnal enuresis secondary to polyuria can be an indication of onset of diabetes in young children. Thirst is a response to the hyperosmolar state and dehydration.

Fatigue and weakness may be caused by muscle wasting from the catabolic state of insulin deficiency, hypovolemia, and hypokalemia. Muscle cramps are caused by electrolyte imbalance. Blurred vision results from the effect of the hyperosmolar state on the lens and vitreous humor. Glucose and its metabolites cause osmotic swelling of the lens, altering its normal focal length.

Symptoms at the time of the first clinical presentation can usually be traced back several days to several weeks. However, beta-cell destruction may have started months, or even years, before the onset of clinical symptoms.

The onset of symptomatic disease may be sudden. It is not unusual for patients with type 1 DM to present with diabetic ketoacidosis (DKA), which may occur de novo or secondary to the stress of illness or surgery. An explosive onset of symptoms in a young lean patient with ketoacidosis always has been considered diagnostic of type 1 DM.

Over time, patients with new-onset type 1 DM will lose weight, despite normal or increased appetite, because of depletion of water and a catabolic state with reduced glycogen, proteins, and triglycerides. Weight loss may not occur if treatment is initiated promptly after the onset of the disease.

Gastrointestinal (GI) symptoms of type 1 DM are as follows:

Nausea, abdominal discomfort or pain, and change in bowel movements may accompany acute DKA

Acute fatty liver may lead to distention of the hepatic capsule, causing right upper quadrant pain

Persistent abdominal pain may indicate another serious abdominal cause of DKA (eg, pancreatitis

Chronic GI symptoms in the later stage of DM are caused by visceral autonomic neuropathy

Neuropathy affects up to 50% of patients with type 1 DM, but symptomatic neuropathy is typically a late development, developing after many years of chronic prolonged hyperglycemia. Peripheral neuropathy presents as numbness and tingling in both hands and feet, in a glove-and-stocking pattern; it is bilateral, symmetric, and ascending.

History in patients with established diabetes

It is important to inquire about the type and duration of the patient’s diabetes and about the care the patient is receiving for diabetes. Determination of the type of diabetes is based on history, therapy, and clinical judgment. The chronic complications of diabetes are related to the length of time the patient has had the disease.

Ask about the type of insulin being used, delivery system (pump vs injections), dose, and frequency. Also ask about oral antidiabetic agents, if any. Of course, a full review of all medications and over-the-counter supplements being taken is crucial in the assessment of patients with type 1 DM.

Patients using a pump or a multiple-injection regimen have a basal insulin (taken through the pump or with the injection of a long-acting insulin analogue) and a premeal rapid-acting insulin, the dose of which may be determined as a function of the carbohydrate count plus the correction (to adjust for how high the premeal glucose level is). In these patients, ask about the following:

Basal rates (eg, units per hour by pump, generally 0.4-1.5 U/h, potentially varying on the basis of time of day); the total daily dose as basal insulin is a helpful value to know

Carbohydrate ratio (ie, units of insulin per grams of carbohydrate, generally 1 unit of rapid-acting insulin per 10-15 g carbohydrate)

Correction dose (ie, how far the blood glucose level is expected to decrease per unit of rapid-acting insulin, often 1 U of insulin per 50-mg/dL decrease, though individuals with insulin resistance may need 1 U per 25-mg/dL decrease)

Some patients may be taking premeal pramlintide (an amylin analogue)

A focused diabetes history should also include the following questions:

Is the patient’s diabetes generally well controlled, with near-normal blood glucose levels? (Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications)

Does the patient have severe hypoglycemic reactions? (If the patient has episodes of severe hypoglycemia and therefore is at risk for losing consciousness, this possibility must be addressed, especially if the patient drives)

Does the patient have diabetic nephropathy that might alter the use of medications or intravenous (IV) radiographic contrast material?

Does the patient have macrovascular disease, such as coronary artery disease (CAD), which should be considered in the emergency department (ED)?

Does the patient self-monitor his or her blood glucose levels? (Note the frequency and range of values at each time of day; an increasing number of patients monitor with continuous sensors)

When was the patient’s hemoglobin A 1c (HbA 1c ) value (an indicator of long-term glucose control) last measured? What was it?

In assessing glycemic exposure of a patient with established type 1 DM, review of self-monitored blood glucose levels is necessary. Ideally, this done by uploading time- and date-stamped levels from the patient’s meter to assure full understanding of the frequency of testing and the actual levels.

Questions regarding hypoglycemia and hyperglycemia

Hypoglycemia and hyperglycemia should be considered. Ask the following questions as needed:

Has the patient experienced recent polyuria, polydipsia, nocturia, or weight loss?

Has the patient had episodes of unexplained hypoglycemia? If so, when, how often, and how does the patient treat these episodes?

Does the patient have hypoglycemia unawareness (ie, does the patient lack the adrenergic warning signs of hypoglycemia)? (Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia)

Questions regarding microvascular complications

Microvascular complications, such as retinopathy and nephropathy, should be considered as well. Ask the following questions as appropriate:

When was the patient’s last dilated eye examination? What were the results?

Does the patient have known kidney disease?

What were the dates and results of the last measurements of urine protein and serum creatinine levels?

Questions regarding macrovascular complications

Macrovascular complications should be explored. Questions should include the following:

Does the patient have hypertension? What medications are taken?

Does the patient have symptoms of claudication or a history of vascular bypass?

Has the patient had a stroke or transient ischemic attack?

What are the patient’s most recent lipid levels?

Is the patient taking lipid-lowering medication?

Questions regarding neuropathy

Potential neuropathy should be taken into account. Ask whether the patient has a history of neuropathy or symptoms of peripheral neuropathy or whether autonomic neuropathy is present (including erectile dysfunction if the patient is a man).

Other questions

The possibility of foot disease should be addressed. Inquire as to whether the patient has a history of foot ulcers or amputations or whether any foot ulcers are present. (See Diabetic Foot and Diabetic Foot Infections .)

The possibility of infection also should be considered. Be sure to inquire about whether frequent infections are a problem and, if so, at what sites.

In new cases of diabetes, physical examination findings are usually normal. Patients with DKA, however, will have Kussmaul respiration, signs of dehydration, hypotension, and, in some cases, altered mental status.

In established cases, patients should be examined every 3 months for macrovascular and microvascular complications. They should undergo funduscopic examination for retinopathy and monofilament testing for peripheral neuropathy.

Diabetes-focused examination

A diabetes-focused physical examination includes assessment of vital signs, funduscopic examination, limited vascular and neurologic examinations, and foot examination. Other organ systems should be assessed as indicated by the patient’s clinical situation. A comprehensive examination is not necessary at every visit.

Assessment of vital signs

Patients with established diabetes and autonomic neuropathy may have orthostatic hypotension. Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy. Measurement of the pulse is important, in that relative tachycardia is a typical finding in autonomic neuropathy, often preceding the development of orthostatic hypotension. If the respiratory rate and pattern suggest Kussmaul respiration, DKA must be considered immediately, and appropriate tests must be ordered.

Funduscopic examination

The funduscopic examination should include a careful view of the retina. Both the optic disc and the macula should be visualized. If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, which cannot be evaluated accurately unless the patients’ pupils are dilated.

Foot examination

The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections: poor lower-extremity blood flow can delay healing and increase the risk of amputation.

Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patient’s ability to protect the feet and ankles. If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for the prevention of foot ulcers and lower-extremity amputation. (See Diabetic Foot and Diabetic Foot Infections .)

Infections cause considerable morbidity and mortality in patients with diabetes. Infection may precipitate metabolic derangements, and conversely, the metabolic derangements of diabetes may facilitate infection. (See Infections in Patients with Diabetes Mellitus .)

Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resultant poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury.

Diabetes increases susceptibility to various types of infections. The most common sites are the skin and urinary tract. Dermatologic infections that occur with increased frequency in patients with diabetes include staphylococcal follicular skin infections, superficial fungal infections, cellulitis, erysipelas, and oral or genital candidal infections. Both lower urinary tract infections and acute pyelonephritis are seen with greater frequency.

A few infections, such as malignant otitis externa, rhinocerebral mucormycosis, and emphysematous pyelonephritis, occur almost exclusively in patients with diabetes, though they are fairly rare even in this population. Infections such as staphylococcal sepsis occur more frequently and are more often fatal in patients with diabetes than in others. Infections such as pneumococcal pneumonia affect patients with diabetes and other patients with the same frequency and severity. [ 84 ]

A study reported that out of 178 adult patients hospitalized with coronavirus disease 2019 (COVID-19), at least one underlying condition was found in 89.3%, the most common being hypertension (49.7%), obesity (48.3%), chronic lung disease (34.6%), diabetes mellitus (28.3%), and cardiovascular disease (27.8%). [ 85 ]

According to a report by Stokes et al, out of 287,320 US cases of COVID-19 in which the patient’s underlying health status was known, diabetes was the second most common underlying condition (30%), after cardiovascular disease (32%), which in this study included hypertension. [ 86 , 87 ]

The aforementioned study by Barrera et al found the overall prevalence of diabetes in patients with COVID-19 to be 12%, with the prevalence being 18% in severe COVID-19. [ 63 , 64 ]

In patients with type 1 DM who were diagnosed with COVID-19, a study by Ebekozien et al found that high blood glucose (48.5%), elevated temperature (45.5%), dry cough (39.4%), excess fatigue (33.3%), vomiting (33.3%), shortness of breath (30.3), nausea (30.2%), and body aches/headaches (21.2%) were the most prevalent presenting symptoms reported. Moreover, diabetic ketoacidosis was the most prevalent adverse outcome (45.5%) among these patients. [ 88 , 89 ]

The Centers for Disease Control and Prevention (CDC) includes type 2 DM in the list of conditions that increase the likelihood of severe illness in persons with COVID-19, and type 1 DM in the list of conditions that may increase this likelihood. [ 90 ]

Ophthalmologic complications

Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt the patient to seek emergency care. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations.

This effect, which is caused by osmotic fluxes of water into and out of the lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and some patients are almost completely unable to read small print or do close work during this period.

Patients with diabetes tend to develop senile cataracts at a younger age than persons without diabetes. Rarely, patients with type 1 DM that is very poorly controlled (eg, those with frequent episodes of DKA) can acutely develop a “snowflake” (or “metabolic”) cataract. Named for their snowflake or flocculent appearance, these cataracts can progress rapidly and create total opacification of the lens within a few days.

Whether diabetes increases the risk of glaucoma remains controversial; epidemiologic studies have yielded conflicting results. [ 91 ] Glaucoma in diabetes relates to the neovascularization of the iris (ie, rubeosis iridis diabetica).

Diabetic retinopathy is the principal ophthalmologic complication of DM. (See Diabetic Retinopathy .) Diabetic retinopathy is the leading cause of blindness in the United States in people younger than 60 years and affects the eyes in the following different ways:

Background retinopathy involves retinal small vessel abnormality leading to hard exudates, hemorrhages, and microaneurysms; it does not affect acuity

Proliferative retinopathy involves extensive proliferation of new retinal small blood vessels; a sudden loss of vision can occur because of vitreous hemorrhage from proliferating new vessels or retinal detachment

Maculopathy involves edema and hard exudate or retinal ischemia; it causes a marked reduction of acuity

Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control. [ 92 , 93 , 94 ] The following are the 5 stages in the progression of diabetic retinopathy:

Dilation of the retinal venules and formation of retinal capillary microaneurysms

Increased vascular permeability

Vascular occlusion and retinal ischemia

Proliferation of new blood vessels on the surface of the retina

Hemorrhage and contraction of the fibrovascular proliferation and the vitreous

The first 2 stages of diabetic retinopathy are jointly referred to as background or nonproliferative retinopathy. Initially, the retinal venules dilate, then microaneurysms (tiny red dots on the retina that cause no visual impairment) appear. The microaneurysms or retinal capillaries become more permeable, and hard exudates appear, reflecting leakage of plasma.

Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears. Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina.

The patient may not notice a change in visual acuity unless the center of the macula is involved. Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision. (See Macular Edema in Diabetes .)

Preproliferative (stage 3) and proliferative diabetic retinopathy (stages 4 and 5) are the next phases in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts from capillary occlusion and appear as off-white to gray patches with poorly defined margins.

Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous.

Diabetic nephropathy

About 20–30% of patients with type 1 DM develop evidence of nephropathy, [ 95 ] and all patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. Chronically elevated blood pressure contributes to the decline in renal function. The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. Although most recover from contrast medium–induced renal failure within 10 days, some have irreversible renal failure. (See Diabetic Nephropathy .)

Diabetic neuropathy

In the peripheral nerves, diabetes causes peripheral neuropathy. (See Diabetic Lumbosacral Plexopathy and Diabetic Neuropathy .) The 4 types of diabetic neuropathy are as follows:

Peripheral distal symmetrical polyneuropathy, predominantly sensory

Autonomic neuropathy

Proximal painful motor neuropathy

Cranial mononeuropathy (ie, cranial nerve III, IV, or VI)

Of these 4 types, distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most common. [ 96 ] Besides causing pain in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation.

Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cranial neuropathies, the third cranial nerve (oculomotor) is most commonly affected, followed by the sixth nerve (abducens) and the fourth nerve (trochlear).

Patients can present with diplopia and eye pain. In diabetic third-nerve palsy, the pupil is usually spared, whereas in third-nerve palsy due to intracranial aneurysm or tumor, the pupil is affected in 80-90% of cases.

It is important to consider nondiabetic causes of cranial nerve palsies, including intracranial tumors, aneurysms, and brainstem stroke. [ 97 ] Therefore, evaluation should include nonenhanced and contrast-enhanced compute4d tomography (CT) or, preferably, magnetic resonance imaging (MRI). Neurologic consultation is recommended. Acute cranial-nerve mononeuropathies usually resolve in 2-9 months. Acute thrombosis or ischemia of the blood vessels supplying the structure involved is thought to cause these neuropathies.

Macrovascular complications

People with diabetes experience accelerated atherosclerosis, affecting the small arteries of the heart, brain, lower extremity, and kidney. Coronary atherosclerosis often occurs at a younger age and is more severe and extensive than in those without diabetes, increasing the risk of ischemic heart disease. Atherosclerosis of the internal carotid and vertebrobasilar arteries and their branches predisposes to cerebral ischemia.

Severe atherosclerosis of the iliofemoral and smaller arteries of the lower legs predisposes to gangrene. Ischemia of a single toe or ischemic areas on the heel are characteristic of diabetic peripheral vascular disease; these result from the involvement of much smaller and more peripheral arteries.

Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia, which is a significant component of multiple renal lesions in diabetes. However, not all people with type 1 DM are at risk for nephropathy, because there are some polymorphisms in the various factors involved in its pathogenesis, which can modulate the course of this disease from one person to the other.

Risk factors for macrovascular disease

Macrovascular disease is the leading cause of death in patients with diabetes, causing 65-75% of deaths in this group, compared with approximately 35% of deaths in people without diabetes. Diabetes by itself increases the risk of myocardial infarction (MI) 2-fold in men and 4-fold in women, and many patients have other risk factors for MI as well.

The HbA1c value per se, rather than self-reported diabetes status or other established risk factors, robustly predicts MI odds. Each 1% increment in HbA1c independently predicts 19% higher odds for MI. [ 98 ] The risk of stroke in people with diabetes is double that of nondiabetic people, and the risk of peripheral vascular disease is 4 times that of people without diabetes.

Patients with diabetes may have an increased incidence of silent ischemia. [ 99 ] Diastolic dysfunction is common in patients with diabetes and should be considered in patients who have symptoms of congestive heart failure and a normal ejection fraction.

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Contributor Information and Disclosures

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinology , American College of Physicians , American Diabetes Association , Endocrine Society Disclosure: Nothing to disclose.

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine George T Griffing, MD is a member of the following medical societies: American Association for Physician Leadership , American Association for the Advancement of Science , American College of Medical Practice Executives , American College of Physicians , American Diabetes Association , American Federation for Medical Research , American Heart Association , Central Society for Clinical and Translational Research , Endocrine Society , International Society for Clinical Densitometry , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center

Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha , American Academy of Emergency Medicine , American College of Chest Physicians , American College of Emergency Physicians , American College of Physicians , American Heart Association , American Thoracic Society , Arkansas Medical Society , New York Academy of Medicine , New York Academy ofSciences ,and Society for Academic Emergency Medicine

Aneela Naureen Hussain, MD, FAAFM Assistant Professor, Department of Family Medicine, State University of New York Downstate Medical Center; Consulting Staff, Department of Family Medicine, University Hospital of Brooklyn

Aneela Naureen Hussain, MD, FAAFM is a member of the following medical societies: American Academy of Family Physicians , American Medical Association , American Medical Women's Association , Medical Society of the State of New York , and Society of Teachers of Family Medicine

Anne L Peters, MD, CDE Director of Clinical Diabetes Programs, Professor, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, Los Angeles County/University of Southern California Medical Center

Anne L Peters, MD, CDE is a member of the following medical societies: American College of Physicians and American Diabetes Association

Disclosure: Amylin Honoraria Speaking and teaching; AstraZeneca Consulting fee Consulting; Lilly Consulting fee Consulting; Takeda Consulting fee Consulting; Bristol Myers Squibb Honoraria Speaking and teaching; NovoNordisk Consulting fee Consulting; Medtronic Minimed Consulting fee Consulting; Dexcom Honoraria Speaking and teaching; Roche Honoraria Speaking and teaching

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American Diabetes Association , American Federation for Medical Research , Central Society for Clinical Research , and Endocrine Society

Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Miriam T Vincent, MD, PhD Professor and Chair, Department of Family Practice, State University of New York Downstate Medical Center

Miriam T Vincent, MD, PhD is a member of the following medical societies: Alpha Omega Alpha , American Academy of Family Physicians , American Association for the Advancement of Science , Medical Society of the State of New York , North American Primary Care Research Group , Sigma Xi , and Society of Teachers of Family Medicine

Disclosure: Joslin Diabetes Group, Harvard Honoraria Speaking and teaching

Scott R Votey, MD Director of Emergency Medicine Residency, Ronald Reagan UCLA Medical Center; Professor of Medicine/Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine

Scott R Votey, MD is a member of the following medical societies: Society for Academic Emergency Medicine

Frederick H Ziel, MD Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists , American College of Endocrinology , American College of Physicians , American College of Physicians-American Society of Internal Medicine , American Diabetes Association , American Federation for Medical Research , American Medical Association , American Society for Bone and Mineral Research , California Medical Association , Endocrine Society , andInternational Society for Clinical Densitometry

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Clinical presentation of type 2 diabetes mellitus in children and adolescents

Affiliation.

• 1 Vestische Hospital for Children and Adolescents, University of Witten/Herdecke, Datteln, Germany. [email protected]
• PMID: 16385761
• DOI: 10.1038/sj.ijo.0803065

Objective: Recent reports indicate an increasing prevalence of type 2 diabetes mellitus (TD2M) in children and adolescents around the world in all ethnicities, possibly due to increasing prevalence of obesity. Therefore, it is essential that clinicians are aware of the clinical features of T2DM in these age groups.

Methods: All published cases of T2DM in children and adolescents were evaluated and the different clinical presentations of T2DM in minorities and Caucasian described.

Results: Manifestation of T2DM is usually at mid-to-late puberty with few symptoms such as mild-polyuria or polydipsia. Most of the children and adolescents are extremely obese. The great majority of children and adolescents with T2DM have relatives with T2DM, and show other clinical features of the insulin resistance syndrome such as hypertension, dyslipidemia, polycystic ovarian syndrome (PCOS) or acanthosis nigricans. One-third of the minority children with T2DM and the majority of the Caucasian children with T2DM were detected by screening in the absence of symptoms.

Conclusions: It is becoming increasingly clear that overweight children above the age of 10 y with (1) clinical signs of insulin resistance (acanthosis nigricans, dyslipidemia, hypertension, PCOS), or (2) relatives with T2DM, or (3) of particular ethnic populations (Asian, Indians, Africa-Americans, Hispanics), or (4) extremely obese children should be screened for T2DM.

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• Type 2 diabetes mellitus in children and adolescents. Marcovecchio M, Mohn A, Chiarelli F. Marcovecchio M, et al. J Endocrinol Invest. 2005 Oct;28(9):853-63. doi: 10.1007/BF03347581. J Endocrinol Invest. 2005. PMID: 16370570 Review.
• Clinical characteristics of type 2 diabetes mellitus in overweight European caucasian adolescents. Reinehr T, Andler W, Kapellen T, Kiess W, Richter-Unruh A, Schönau E, Seewi O, Heinze E, Wabitsch M. Reinehr T, et al. Exp Clin Endocrinol Diabetes. 2005 Mar;113(3):167-70. doi: 10.1055/s-2005-837522. Exp Clin Endocrinol Diabetes. 2005. PMID: 15789276
• Exploring the Surge in Paediatric Type 2 Diabetes in an Inner-City London Centre-A Decade-Long Analysis of Incidence, Outcomes, and Transition. Abdelhameed F, Giuffrida A, Thorp B, Moorthy MK, Gevers EF. Abdelhameed F, et al. Children (Basel). 2024 Jan 29;11(2):173. doi: 10.3390/children11020173. Children (Basel). 2024. PMID: 38397285 Free PMC article.
• Positive Additive and Multiplicative Interactions among Clustered Components of Metabolic Syndrome with Type 2 Diabetes Mellitus among Brazilian Adolescent Students. Deusdará R, de Moura Souza A, Szklo M. Deusdará R, et al. Nutrients. 2022 Nov 3;14(21):4640. doi: 10.3390/nu14214640. Nutrients. 2022. PMID: 36364903 Free PMC article.
• Isolated compounds from Dracaena angustifolia Roxb and acarbose synergistically/additively inhibit α-glucosidase and α-amylase: an in vitro study. Yi J, Zhao T, Zhang Y, Tan Y, Han X, Tang Y, Chen G. Yi J, et al. BMC Complement Med Ther. 2022 Jul 2;22(1):177. doi: 10.1186/s12906-022-03649-3. BMC Complement Med Ther. 2022. PMID: 35780093 Free PMC article.
• Clinical Characteristics, Glycemic Control, and Microvascular Complications Compared Between Young-Onset Type 1 and Type 2 Diabetes Patients at Siriraj Hospital - A Tertiary Referral Center. Preechasuk L, Tantasuwan S, Likitmaskul S, Santiprabhob J, Lertbannaphong O, Plengvidhya N, Tangjittipokin W, Nitiyanant W, Lertwattanarak R. Preechasuk L, et al. Diabetes Metab Syndr Obes. 2022 May 2;15:1375-1387. doi: 10.2147/DMSO.S354787. eCollection 2022. Diabetes Metab Syndr Obes. 2022. PMID: 35528720 Free PMC article.
• Association of Polymorphisms within HOX Transcript Antisense RNA (HOTAIR) with Type 2 Diabetes Mellitus and Laboratory Characteristics: A Preliminary Case-Control Study. Sargazi S, Ravanbakhsh M, Nia MH, Mirinejad S, Sheervalilou R, Majidpour M, Danesh H, Saravani R. Sargazi S, et al. Dis Markers. 2022 Mar 22;2022:4327342. doi: 10.1155/2022/4327342. eCollection 2022. Dis Markers. 2022. PMID: 35359879 Free PMC article.
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Clinical pearls, case study: type 1 and type 2, too.

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Heidi L. Gassner , Stephen E. Gitelman; Case Study: Type 1 and Type 2, Too?. Clin Diabetes 1 July 2003; 21 (3): 140–141. https://doi.org/10.2337/diaclin.21.3.140

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R.M. is a 17-year-old African-American girl with new-onset diabetes, presumed to be type 2 diabetes. She presented to her pediatrician during the winter months with the classic symptoms of polyuria and polydipsia. She reported weight loss over the preceding weeks, but was otherwise well. Her family history was positive for type 2 diabetes in grandparents and some distant relatives and negative for autoimmune diseases.

Physical examination revealed a blood pressure of 103/53 mmHg, pulse of 79, and temperature of 38°C. Her weight was 60 kg (132 lb, 50–75th percentile), height was 155 cm (61 inches, 10th percentile), and body mass index (BMI) was 25 kg/m 2 (85th percentile). She had acanthosis nigricans and was at Tanner V stage of sexual development.

Urinalysis revealed a glucose level of >1,000 mg/dl and ketones of 40 mg/dl. Her initial laboratory studies included a blood glucose measurement of 726 mg/dl, bicarbonate of 21 mmol/l (normal range 23–32 mmol/l), venous pH of 7.37, hemoglobin A 1c (A1C) of 8.6%, and C-peptide of 1.0 ng/ml (normal range 0.6–3.2 ng/ml).

R.M. was admitted to the hospital for subcutaneous insulin therapy, fluids, and diabetes education. She was discharged to her home on metformin, 500 mg twice daily, and a split-mixed insulin regimen of NPH and lispro at ∼1 unit/kg/day, with two-thirds being taken in the morning and one-third in the evening. She was also started on a fixed carbohydrate, reduced-fat meal plan.

At her first follow-up visit 1 month later, R.M. was found to be positive for islet cell autoantibodies (ICAs), glutamic acid decarboxylase (GAD) antibodies, and ICA-512 antibodies. Her A1C was 7.8%. Her insulin doses had been slowly decreased, with glucose levels consistently <150 mg/dl and total daily insulin requirements of ∼0.5 units/kg/day. Her metformin was discontinued given her positive antibody studies and near-euglycemic blood glucose range.

At another follow-up 3 months later, R.M. was still off metformin, and her blood glucose levels were in a euglycemic range on <0.4 units/kg/day (10 units of NPH with 4 units of lispro at breakfast and 6 units of NPH with 3 units of lispro at dinner). Her A1C was 5.9%. She had not required any adjustments for high blood glucose levels.

How does one distinguish between type 1 diabetes and type 2 diabetes?

When should autoantibodies be measured?

In patients who have type 1 diabetes with evidence of insulin resistance, what treatment options are available?

Most practitioners today would have assumed that this adolescent had recent-onset type 2 diabetes. The risk factors include non-Caucasian ancestry, positive family history, presence of acanthosis in someone with an elevated BMI, and hyperglycemia without ketoacidosis. 1  

In the past, type 1 diabetes would account for the majority of diabetes seen in this age-group. Yet, the national obesity epidemic has changed the types of diabetes being seen, especially in pediatrics. The most recent National Health and Nutrition Examination Survey noted that 30% of adolescents are now overweight, 2 and there has been a commensurate rise in the number of cases of type 2 diabetes found in adolescents. 3 Recently, in a cohort of obese adolescents, 20% were noted to have impaired glucose tolerance, and 4% had undiagnosed type 2 diabetes. 4 In some pediatric diabetes practices, type 2 diabetes now accounts for 25–50% of the patient population, and this continues to increase. 1  

The incidence of type 2 diabetes in American adolescents is highest among African-Americans, Latinos, and Asians. 1 For the African American population, this increased risk for type 2 diabetes results at least in part from the fact that African-American prepubertal children and adolescents have greater insulin resistance than their Caucasian counterparts, even when matched for BMI. 5 , 6  

Given the increase of obesity in our society, we expect that many children who present with new-onset diabetes will have evidence of obesity and acanthosis, which are strongly suggestive of type 2 diabetes. Yet, rather than assume that they have type 2 diabetes, clinicians must test for autoantibodies to clarify the underlying etiology.

R.M. was found to have positive antibodies directed against the β-cells and thus, clearly, has autoimmune-mediated type 1 diabetes. However, she also has evidence of insulin resistance, which is found in type 2 diabetes. Some have referred to this condition as “double diabetes,” or “type 1.5 diabetes.”

Multiple studies have shown that up to 90% of new-onset type 1 diabetic patients will have evidence of at least one antibody at diagnosis, and ∼40–50% will have two or more. 7 Tests for four autoantibodies are now available through commercial laboratories. The traditional assay to measure ICAs involves incubating a patient’s serum with a section of normal pancreas and assessing reactivity via indirect immunoflurosence. The other three antibody tests now available are for GAD, ICA-512 (also known as IA-2 or tyrosine phosphatase), and insulin autoantibodies (IAAs). The IAA measurement must be obtained within 10 days to 2 weeks from the initiation of exogenous insulin therapy, because exogenous insulin may induce antibody positivity.

Although most patients with type 1 diabetes are autoantibody-positive, ethnicity confers notable differences and may make confirmation of type 1 diabetes more difficult. African-American adolescents with new-onset type 1 diabetes have up to a fourfold greater chance of exhibiting no autoantibodies compared to their Caucasian counterparts (17.4 vs. 4.6%, respectively). 8 Thus, African-American adolescents with type 1 diabetes may initially present as antibody-negative, which may prove misleading in making therapy decisions.

The presence of autoantibodies has important implications for patient care. In the U.K. Prospective Diabetes Study, subjects presumed to have type 2 diabetes, yet who were noted to have one or more autoantibodies, progressed more rapidly to β-cell failure and required insulin therapy. 9 Up to 90% of patients who were positive for ICA and GAD antibodies required insulin within 6 years. 9  

In this case, had one assumed that this was a case of type 2 diabetes and treated R.M. solely with metformin, the patient may have done well initially, during her honeymoon phase. However, she would have been at high risk for progression to diabetic ketoacidosis as her honeymoon period waned or when faced with an intercurrent illness or stress. Furthermore, intensive insulin therapy is one potential means to prolong the honeymoon phase and protect endogenous insulin secretion, 10 and she would have been denied this potential benefit.

Despite the evidence that R.M. has type 1 diabetes, we must return to considerations about type 2 diabetes. Although she tested positive for autoantibodies, she did present with acanthosis nigricans, an elevated BMI, a positive family history, and was from a higher-risk ethnic group. If we had studied her formally, she would almost certainly have exhibited increased insulin resistance, and she may have ultimately developed type 2 diabetes later in life if she had not had earlier autoimmune destruction of her β-cells.

One question to consider is whether there is a role for insulin sensitizers in such a situation. Metformin may be a useful addition to insulin for adolescents with type 1 diabetes and insulin resistance. 11 Preliminary studies have found that metformin lowered A1C, decreased insulin dosage, and caused no weight gain in adolescents with type 1 diabetes and poor metabolic control. 11 Clinicians initiating such therapy must carefully inform the patient and family about the risks of lactic acidosis and the increased risk for hypoglycemia with combined therapy. Further studies with metformin and other insulin sensitizers (such as thiazolidinediones) are needed before this will become established therapy.

For R.M., we elected to continue her subcutaneous low-dose insulin regimen at 0.4 units/kg/day during the honeymoon phase, but we may consider adding metformin therapy in the future.

With the surge in obesity, we are witnessing a rise in type 2 diabetes, especially among children and adolescents. These patients often present in puberty, at a time of increased insulin resistance.

All pediatric patients who are diagnosed with new-onset diabetes need antibody studies obtained to distinguish type 1 from type 2 diabetes in order to provide appropriate therapies. Autoantibodies may not always be positive in African Americans with new-onset type 1 diabetes.

Patients who have type 1 diabetes and evidence of insulin resistance may benefit from the addition of metformin as an insulin-sensitizing agent. However, the use of metformin in these patients is still under investigation and has not yet gained approval from the Food and Drug Administration.

Heidi L. Gassner, MD, is a pediatric endocrine fellow, and Stephen E. Gitelman, MD, is an associate professor of clinical pediatrics in the Department of Pediatric Endocrinology at the University of California, San Francisco.

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Hypercortisolism Prevalence High in Poorly Controlled T2D

Alicia Ault

June 28, 2024

ORLANDO, Florida — Almost a quarter of patients with poorly controlled type 2 diabetes enrolled in the prevalence-phase of a new study had hypercortisolism, suggesting there may need to be a shift in managing these individuals, said investigators.

Researchers participating in the CATALYST trial reported that 24% (253) of the 1055 patients being studied had hypercortisolism. They presented their findings at the 84th Scientific Sessions of the American Diabetes Association (ADA).

"The investigators were shocked that it was 24% in this study," lead author John Buse, MD, PhD, Verne S. Caviness Distinguished Professor and director of the Diabetes Center at the University of North Carolina School of Medicine, Chapel Hill, North Carolina, told reporters in a press briefing before the main presentation.

If that incidence was extrapolated, "we're talking more than a million people in the United States, theoretically have this condition, just from poorly controlled diabetes," Buse said at the briefing.

According to the ADA, 39%-77% of people with type 2 diabetes have uncontrolled diabetes.

Based on reports in the literature, the investigators expected the prevalence would be closer to 8%, he said. But the understanding of hypercortisolism prevalence, especially in the United States, has been limited. Symptoms of hypercortisolism — known as Cushing syndrome — can include weight gain, high blood pressure, muscle weakness, and mood changes, according to the ADA. Hypercortisolism is also a potential driver of type 2 diabetes.

Cushing has been thought to be relatively rare, at about 1.2-3.2 cases per million per year. As recently reported by Medscape Medical News , it may be more prevalent in the United States than previously thought.

Given CATALYST's prevalence findings, clinicians might want to rethink how they approach these patients, said Buse.

Currently, patients are typically only screened — usually following Endocrine Society guidelines — for hypercortisolism if there's a high suspicion. Patients with poorly controlled diabetes are rarely screened, said Buse.

However, most patients with hypercortisolism don't appears as if they have classic Cushing syndrome, Richard Auchus, MD, PhD, The James A. Shayman and Andrea S. Kevrick Professor of Translational Medicine at the University of Michigan Medical School, Ann Arbor, Michigan, said at the ADA meeting.

"As endocrinologists, we've gotten hung up with cutpoints," said Auchus. He urged clinicians to think of hypercortisolism "as a continuum." There should be a simple way to screen, "and we should think about doing that in the right clinical setting," he said.

Buse said he and other investigators "are sort of holding off on pushing the American Diabetes Association to say, everybody with inadequately controlled diabetes, despite good faith efforts — two, three drugs — really should be treated for hypercortisolism."

"We're not ready to say that yet," he said. Researchers may urge a change once data are in from the ongoing second phase of the study, which will randomize the CATALYST enrollees to placebo or mifepristone (Korlym, Corcept Therapeutics), said Buse.

Rigorous Screening of Hypercortisolism

To be eligible for the CATALYST trial, patients had to have an A1c of 7.5-11.5%, be taking three or more antihyperglycemic drugs, taking insulin plus another antihyperglycemic, taking two or more antihyperglycemics and have one or more micro- or macrovascular complications, or be taking two or more antihyperglycemics and two or more antihypertensive medications.

The mean age was 61 years. Forty-five percent of the enrollees were women, 71% were White individuals, 19% were Black individuals, the mean A1c was 8.8, and the mean body mass index was 33.5 kg/m 2 .

Seventy percent were taking more than three antihyperglycemic medications. A third were taking insulin plus a sodium-glucose co-transporter-2 inhibitor, and about a third were taking insulin plus a glucagon-like peptide 1 (GLP-1) receptor agonist.

To ensure the exclusion of those with falsely elevated cortisol, the trial did not enroll patients using oral contraceptives, or anyone with excess alcohol consumption, severe psychiatric illness or severe untreated sleep apnea, type 1 diabetes, or night shift work.

Investigators used the 1-mg dexamethasone overnight suppression test to detect endogenous hypercortisolism. Positive results were verified with lab evaluation of adrenocorticotropic hormone, dehydroepiandrosterone sulfate, and cortisol and adrenal CT scans.

Interestingly, 66% of the enrollees with hypercortisolism had no abnormality on imaging. Twenty-three percent had a unilateral adrenal adenoma, and about 10% had another adrenal abnormality.

Multiple Medications, Higher Risk

The risk for hypercortisolism was highest in those taking two or more antihyperglycemic medications and two or more antihypertensives (odds ratio, 1.871; 95% CI, 1.406-2.491), reported investigator Vivian Fonseca, MD, professor of medicine and pharmacology, Tulane University Health Sciences Center, New Orleans, at the meeting.

The likelihood of having the condition also went up with overall medication burden. Those taking any cardiovascular medication, including antihypertensives, lipid medications, psychiatric drugs, and analgesics and opioids, all had a higher risk, said Fonseca.

Those taking three or more blood pressure-lowering medications seemed to be at special risk. Twenty-one percent of CATALYST enrollees were taking three or more antihypertensives. The odds of having hypercortisolism was two times as high for these patients. Some 35% of them were found to have the condition, Fonseca reported.

Other characteristics more strongly associated with hypercortisolism included non-Hispanic ethnicity, fibrates, and the dual glucose-dependent insulinotropic polypeptide/GLP-1 tirzepatide.

Too Early to Change Practice

Asked to comment on the study, Lynnette Nieman, MD, senior investigator with the Diabetes, Endocrine and Obesity Branch at the National Institute of Diabetes and Digestive and Kidney Diseases, said that it is "a very provocative study."

Nieman told Medscape Medical News that the 24% prevalence figure, "on the face of it at least, this is a surprising number, a surprisingly high percentage."

But she noted that the data presented is just in the screening phase. The full study aims to determine whether mifepristone, a glucocorticoid receptor antagonist, might help better control diabetes.

Glucocorticoid antagonists have the potential to cause adrenal insufficiency, which can be dangerous and even can cause death, said Nieman. "I would not change how I approach diabetic patients at this point," she said, adding that it's reasonable to look carefully for signs and symptoms of Cushing "in anybody who has difficult to control hypertension or diabetes."

"It will be very interesting to see the entirety of the data in published form," Nieman said, adding that she would "want to understand whether any of these patients had overt Cushing Syndrome or whether they have mild autonomous cortisol excess."

The results of the CATALYST trial "will be eagerly awaited to determine whether or not treatment is appropriate and safe in these patients," said Nieman.

The study was supported by Corcept Therapeutics. Buse made multiple disclosures, including that he is a paid consultant and receives research support from Corcept. Auchus did not receive support from Corcept but is a consultant for Lundbeck, Novo Nordisk, Sparrow Pharmaceuticals, and Xeris Pharmaceuticals. Fonseca is a consultant for Corcept and Abbott, Bayer, and Sun Pharmaceutical Industries. Nieman disclosed that National Institutes of Health receives research funding from Crinetics Pharmaceuticals, which makes a Cushing's treatment.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on X @aliciaault.

Send comments and news tips to [email protected] .

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What are the types of diabetes? Hint: It's more than just Type 1 and Type 2.

Diabetes is one of the leading causes of death and disability in the U.S., states the Centers for Disease Control and Prevention. Around 37.3 million Americans have diabetes, according to the American Diabetes Association's statistics from 2019. This makes up 11.3% of the population.

Each year, 1.4 million people are diagnosed with diabetes mellitus in the U.S., according to the association. Despite the disease's prevalence and medical documentation, many may not know the different types of diabetes and what causes them.

Here's what you need to know about the differences between Type 1 and Type 2 diabetes, gestational diabetes and the so-called "Type 3 diabetes."

What is Type 1 diabetes?

Only 5-10% of all diabetics have Type 1, which occurs when the cells meant to produce insulin in the body do not function properly, said Dr. Kevin Peterson, Vice President of Primary Care at the American Diabetes Association.

Insulin is an essential hormone that regulates blood sugar. When you eat carbohydrates, your body breaks it down into blood sugar, which is used for energy.

Beta cells in the pancreas make insulin. The hormone helps glucose reach the body’s other cells. Without insulin, glucose would build up in the bloodstream.

While its exact cause is not clear, Type 1 diabetes is believed to be impacted by an autoimmune reaction , states the CDC. This leads to the destruction of beta cells. If you have Type 1 diabetes, your body does not produce insulin, said Peterson.

Type 1 diabetes can develop at any age, but usually occurs when a person is younger. Its symptoms include:

• Polyuria, or urinating often
• Polydipsia, or feeling thirsty
• Extreme fatigue, or feeling very tired

The symptoms for Type 1 often come more suddenly than in comparison to Type 2, according to the Mayo Clinic.

Although it is not a hereditary disease, you are more likely to get Type 1 if a relative has it, such as a sister, brother or parent, said Peterson.

What is Type 2 diabetes?

When you have Type 2 diabetes, your body stops producing enough insulin or is not using it properly, which is known as " insulin resistance ." Type 2 is generally caused by genetic and lifestyle factors, including critical social determinants of health .

It is associated with changing eating habits, engaging in lower rates of physical activity and being overweight, said Peterson. Though not considered a hereditary disorder, the likelihood of developing Type 2 is higher if a first-degree relative has the condition.

Historically, it was believed Type 2 only occurred in adults, but the disease can affect any age, said Peterson.

Those with Type 2 diabetes experience similar symptoms to Type 1. However, the symptoms may come on slower, said Peterson. Someone could be diabetic for years without noticing or presenting any symptoms.

Type 2 is largely preventable with certain lifestyle changes, such as eating a healthy, balanced diet and exercising.

What is gestational diabetes?

Gestational diabetes is "diabetes diagnosed for the first time during pregnancy (gestation)," according to the Mayo Clinic. Gestational diabetes is similar to other types of diabetes in that it affects how your cells use sugar (glucose), but gestational diabetes also causes high blood sugar that can have adverse effects on the pregnancy and the baby's health, reports the Mayo Clinic.

Gestational diabetes affects up to 10% of pregnancies , according to the American Diabetes Association. And despite the considerable stigma surrounding diabetes and its causes, the ADA says we still don't know what causes gestational diabetes.

Patients who have gestational diabetes during pregnancy are also more likely to develop Type 2 diabetes after giving birth, experts say.

What is Type 3 diabetes?

Over the past two decades Alzheimer's has been referred to as "Type 3" diabetes because of a link between insulin resistance and the neurodegenerative disease. But Type 3 diabetes is more of a research term than a medical term, explained neuroscientist and researcher Guojun Bu in an interview in Everyday Health .

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USA TODAY is exploring the questions you and others ask every day. From " How do you get diabetes? " to " What causes dehydration? " to " How often can you donate blood? " − we're striving to find answers to the most common questions you ask every day. Head to our  Just Curious section  to see what else we can answer for you.

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ACG Clinical Guideline: Focal Liver Lesions

Frenette, Catherine MD 1 ; Mendiratta-Lala, Mishal MD 2 ; Salgia, Reena MD 3 ; Wong, Robert J. MD, MS, FACG 4 ; Sauer, Bryan G. MD, MSc, FACG 5 ; Pillai, Anjana MD, FACG 6

1 Family Health Centers of San Diego, San Diego, California, USA;

2 Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA;

3 Department of Gastroenterology/Hepatology, Henry Ford Health, Detroit, Michigan, USA;

4 Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, Palo Alto, California, USA;

5 Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA;

6 Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Chicago Medical Center, University of Chicago, Chicago, Illinois, USA.

Correspondence: Catherine Frenette, MD. E-mail: [email protected] .

Corresponding Article

Focal liver lesions (FLLs) have become an increasingly common finding on abdominal imaging, especially asymptomatic and incidental liver lesions. Gastroenterologists and hepatologists often see these patients in consultation and make recommendations for management of multiple types of liver lesions, including hepatocellular adenoma, focal nodular hyperplasia, hemangioma, and hepatic cystic lesions including polycystic liver disease. Malignancy is important to consider in the differential diagnosis of FLLs, and healthcare providers must be familiar with the diagnosis and management of FLLs. This American College of Gastroenterology practice guideline uses the best evidence available to make diagnosis and management recommendations for the most common FLLs.

The guideline is structured in the format of statements that were considered to be clinically important by the content authors. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process was used to assess the quality of evidence for each statement ( 1 ) ( Table 1 ). The quality of evidence is expressed as high (we are confident in the effect estimate to support a particular recommendation), moderate, low, or very low (we have very little confidence in the effect estimate to support a particular recommendation) based on the risk of bias of the studies, evidence of publication bias, heterogeneity among studies, directness of the evidence, and precision of the estimate of effect ( 2 ). A strength of recommendation is given as either strong (recommendations) or conditional (suggestions) based on the quality of evidence, risks vs benefits, feasibility, and costs taking into account perceived patient and population-based factors ( 3 ). Furthermore, a narrative evidence summary for each section provides important details for the data supporting the statements.

This writing group was invited by the American College of Gastroenterology to update existing guidelines to the diagnostic approach and management of focal liver lesions (FLLs). Regular meetings were conducted among this writing group throughout the guideline development process to formulate Problem, Intervention, Comparison, Outcome (PICO) questions that guided the subsequent literature search, development of recommendation statements and key concepts, GRADE assessments, and the preparation of the full guideline document.

We conducted an electronic search using Embase and Ovid MEDLINE through September 2022. We limited the search to English language and included Epub Ahead of Print, In-Process, In-Data-Review, & Other Non-Indexed Citations. For each PICO question developed, we comprehensively reviewed the existing literature, with a focus on studies of the highest quality of evidence (e.g., when available, systematic reviews and meta-analyses, followed by randomized controlled trials, followed by observational studies).

In addition to guideline recommendations, the authors have highlighted key concept statements that were not included in the GRADE assessment. Key concepts are statements that the GRADE process has not been applied to and can include both expert opinion recommendations and definitions/epidemiological statements. Table 2 is a summary of recommendations, whereas Table 3 summarizes the key concept statements.

These guidelines are established to support clinical practice and suggest preferable approaches to a typical patient with a particular medical problem based on the currently available published literature. When exercising clinical judgment, particularly when treatments pose significant risks, healthcare providers should incorporate this guideline in addition to patient-specific medical comorbidities, health status, and preferences to arrive at a patient-centered care approach.

FLLs are solid or cystic lesions, which are identified as an abnormality in the liver. For the purposes of this update, the term “lesion” will be used instead of “mass” because first, the term lesion can be used to describe a solid or cystic mass, and second, it is in keeping with the updated Liver Imaging Reporting and Data System lexicon ( 4 ). This guideline will be focused predominantly on the diagnosis and management of FLLs in people without known liver disease.

INTRODUCTION

With the continued dramatic rise in the widespread role of imaging in diagnosis and management of patients, there is a resultant rise in detection of asymptomatic incidental liver lesions. Common imaging modalities in which incidental liver lesions are detected include ultrasonography (US) with or without contrast agent (CEUS), computed tomography (CT), and magnetic resonance imaging (MRI) for abdominal or nonabdominal indications (breast and spine). Studies show a continued upward trend in utilization of CT/MRI/US imaging in adults in the United States and Canada, inevitably resulting in increased detection of incidental FLLs within the liver ( 5 ). In fact, some studies show that up to 52% of patients without cancer have a benign liver lesion at autopsy ( 6 ). The American College of Radiology reports that up to 15% of patients have an incidental liver lesion detected on routine nonsurveillance imaging ( 7 ). Therefore, it is critical to understand appropriate management of incidentally detected benign FLLs because they have differing clinical implications from malignant lesions such as hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and metastatic disease.

Initial evaluation and management of incidental FLLs

Incidental liver lesions can be defined as unsuspected findings within the liver, which are often identified on outpatient or emergency department imaging performed to investigate an unrelated clinical symptom such as pain, weight loss, or trauma. Imaging studies performed under these circumstances are usually either an abdominal ultrasound or contrast-enhanced single portal venous phase CT. Although these modalities will detect an FLL, they cannot adequately characterize the lesion itself. Because most patients with incidentally detected FLL are asymptomatic, the question then arises whether further workup is necessary, and if so, what is the management recommendation for an incidentally detected FLL?

Given the extensive categories of benign and malignant pathologies of FLLs, as well as differences in management, liver-directed imaging is often needed for adequate clarification ( 8,9 ). There are a few instances where further workup of incidental FLLs is not necessary, specifically if the imaging appearance on abdominal ultrasound or single-phase CT is characteristic for a hemangioma or benign uncomplicated cyst. The imaging appearances of these 2 lesions will be discussed later in these clinical guidelines.

In most instances, characterization of liver lesions requires careful investigation of the medical history, clinical symptomatology, physical examination, laboratory workup, and imaging. History should include any medical history and current clinical symptoms and should determine whether the individual has any predisposing condition, which would be associated with the development of liver lesions. Possible histories that would suggest the increased risk of FLLs include history of previous cancer, presence of constitutional symptoms (anorexia, weight loss, night sweats, or fever), history of foreign travel, medications (oral contraceptive pills [OCPs], hormone supplementation, or steroids), and perhaps most important is identifying risk factors for chronic liver disease. The latter is critical to adequately characterize FLLs on imaging because some benign and malignant lesions may have overlap in imaging features, and history is key to categorize lesions. Pertinent questions regarding risk factors for chronic liver disease include history of viral hepatitis or cirrhosis, history of blood product transfusions, tattoos, intravenous drug use, alcohol use, and features of the metabolic syndrome (obesity, type 2 diabetes mellitus, hypertension, hyperlipidemia, and/or cardiovascular disease). Often, imaging findings of a nodular liver morphology, hepatic steatosis, or imaging features of portal hypertension can be obtained from the incidental imaging study in which the FLL was discovered.

Although history and laboratory data are an important part of the workup for FLLs, proper imaging workup is critical. Studies suggest that up to 95% of FLLs detected on grayscale ultrasound can be diagnosed with proper contrast-enhanced imaging without the need for biopsy ( 10,11 ). In addition, 97% of lesions detected in patients with known risk factors for chronic liver disease with characteristic imaging features for HCC based on Liver Imaging Reporting and Data System diagnostic categorization and American Association for the Study of Liver Diseases (AASLD) guidelines do not need pathologic confirmation for diagnosis and management. However, discussion on FLL in patients with chronic liver disease is not the intent of this review ( 12–14 ). Diagnostic imaging can be performed with CEUS, multiphasic contrast-enhanced CT, or multiphasic dynamic postcontrast MRI.

Standardization of the technical specifications of postcontrast imaging is important to ensure appropriate characterization of FLLs. Liver transplant consensus recommendations provide specifications for postcontrast CT and MRI, and although the report focuses on HCC diagnosis, the same technical aspects can be applied in the evaluation of benign FLLs ( 15 ). Key elements to diagnostic imaging include the need for intravenous contrast agents and multiple postcontrast phases of imaging, specifically late arterial, portal venous, and delayed phase of imaging. Of note, on CT, this is ordered as a triple-phase liver protocol (in contradistinction to a routine abdominal CT, which includes only a single portal venous phase of imaging), and on MRI, it is a dynamic postcontrast liver MRI. CEUS has been shown to have high sensitivity, specificity, and positive predictive values of 97.8%, 83.9%, and 82.2%, for benign FLL characterization ( 16 ).

One challenge for clinicians is understanding which imaging modality should be used for workup of FLLs. A review of literature has shown no statistically significant difference between CT and MRI in diagnosis of FLLs ( 17 ). However, advanced MRI techniques have improved the detection and differentiation of different FLLs, and thus in general, MRI is favored for characterization of suspected benign FLLs ( 18–22 ). In addition, the lack of ionizing radiation makes MRI a more attractive study for younger individuals without risk factors when ongoing surveillance imaging is required.

A frequent clinical dilemma is understanding whether to order an MRI with extracellular vs hepatobiliary contrast agent. Because hepatobiliary agents are partially excreted by the biliary system, lesions with biliary pathology (focal nodular hyperplasia [FNH]) will be hyperintense on hepatobiliary phase (HBP) of imaging, allowing for imaging-based diagnosis requiring no further workup. On the other hand, most other lesions will be hypointense on HBP of imaging. Therefore, in a young patient with no known risk factors for malignancy, MRI with hepatobiliary agent allows for diagnosis of FNH vs adenoma, both of which have different management recommendations ( 23 ). Follow-up thereafter can be with extracellular or hepatobiliary contrast agent because the diagnosis has already been confirmed. In other clinical scenarios where FNH may not be a consideration, there is no consensus on use of extracellular vs hepatobiliary contrast agent as first line for imaging diagnosis. Based on expert opinion, extracellular contrast agent is favored because hepatobiliary agent–induced respiratory motion (acute transient dyspnea) and lack of adequate dynamic-phase enhancement are limitations of hepatobiliary agents ( 24,25 ).

When a diagnosis cannot be definitively made on imaging, a multidisciplinary discussion and core biopsy should be considered ( 26 ). In FLLs that cannot be characterized with contrast-enhanced cross-sectional imaging and are not amenable to biopsy (secondary to technical challenges), surveillance imaging is recommended to detect changes in lesion size, lesion appearance, and development of new lesions. Surveillance intervals are individualized and depend on the suspected diagnosis, patient risk factors, and often multidisciplinary discussion and generally range from 3 to 6 months.

The remainder of this document will discuss specific solid and cystic liver lesions, with recommendations on appropriate diagnosis and management. Figure 1 summarizes the guidance document in a flowchart form.

This flowchart is a diagram outline of the recommendations made within this guidance document. Further details of each recommendation made can be found within the text. Figure 1a outlines recommendations for solid focal liver lesions. Figure 1b outlines recommendations for cystic focal liver lesions. For any situation that is not included in this flowchart, please refer to the text for further discussion.

Key concepts

• 1. In an asymptomatic patient without known liver disease and an incidentally detected liver lesion, workup includes a thorough patient history (history of previous cancer), constitutional symptoms (weight loss, loss of appetite, and fevers), medication history (OCPs and steroids), risk factors for chronic liver disease (viral hepatitis, transfusion history, tattoos, intravenous drug use, and alcohol excess), features of metabolic syndrome (obesity, dyslipidemia, insulin resistance, hypertension, and cardiovascular disease), blood tests (liver enzymes, tumor markers, and viral hepatitis panel), and contrast-enhanced imaging (CEUS, MRI, and CT).
• 2. Inadequately characterized and/or atypical FLLs should be reviewed at a multidisciplinary liver tumor board.
• 3. Multiphasic postcontrast MRI and CT have shown no statistically significant difference in diagnostic accuracy for FLLs, although MRI confers many advantages.
• 4. Most solid FLLs in patients with no associated risk factors will be benign, including hemangioma, adenoma, or FNH.

Recommendation

• 1. In patients with an FLL of uncertain etiology, we recommend multiphasic contrast-enhanced imaging, preferably MRI or CT performed with late arterial, portal venous, and delayed phases (strong recommendation, low level of evidence).

SOLID LIVER LESIONS

Hepatocellular adenoma, epidemiology and risk factors..

Hepatocellular adenoma (HCA) is a benign frequently asymptomatic neoplasm of the liver, with limited prevalence data, reported to be around 0.007%–0.012% ( 27 ). Risk factors include females taking OCPs, anabolic steroid use, obesity, glycogen storage disease, and polycystic ovarian syndrome (PCOS).

Females taking OCPs have an incidence of 3–4 per 100,000 users compared with 0.13–1.0 per 100,000 in nonusers, with modern-era OCPs having markedly decreased concentration of estrogen and progesterone compared with the 1960s ( 27–29 ). Discontinuation of OCPs or estrogen-impregnated intrauterine devices has been associated with regression of adenomas in many cases ( 30,31 ).

Males and females taking anabolic androgenic steroids are also at an increased risk of the development of hepatic adenomas ( 32,33 ). The incidence of HCA in men is believed to have increased because of the use of anabolic steroids particularly in the setting of weightlifting, although these can be used for treatment of medical conditions such as aplastic anemia or paroxysmal nocturnal hemoglobinuria ( 34 ). There are limited data currently suggesting the use of exogenous hormonal or steroid therapy in transgender individuals increases risk of hepatic adenoma development ( 35 ).

Obesity has emerged as a notable risk factor for hepatic adenoma development, likely owing to the endogenous estrogen production through activation of aromatase in adipose tissue. Patients with metabolic syndrome and particularly hepatic steatosis are also at risk of development of adenomas; many of these patients having overlapping risk factors of obesity, OCP use (often because of concomitant PCOS), and other risk factors of metabolic syndrome, also promoting disease progression ( 33,36 ). In lean patients with HCA, weight gain is also discouraged owing to the association of HCA growth with increased body mass index. A future study is planned looking at the impact of a low-calorie ketogenic diet on weight reduction and HCA size ( 37 ).

Glycogen storage disease, particularly types Ia and III, carries a particularly high lifetime incidence of adenoma development, including a risk of hepatic adenomatosis. This particular group of patients is noted to have a male predominance (2:1) and often present at a younger age, as early as the second or third decades of life ( 38–40 ). Cases of HCA have also been noted in patients with PCOS and other sex hormone imbalance conditions, although it is unclear whether this establishes causality.

Key concept

• 5. The use of anabolic steroids, obesity, PCOS, glycogen storage disease, and possibly exogeneous hormonal therapy in men, women, and transgender individuals are risk factors for development of hepatic adenomas.

Recommendations

• 2. We recommend discontinuation of OCPs or intrauterine devices that are hormone-impregnated in patients with hepatic adenomas (strong recommendation, low quality of evidence).
• 3. We suggest encouraging weight loss in overweight or obese patients with hepatic adenomas (conditional recommendation, very low quality of evidence).

Pathophysiology and natural history.

HCAs represent a benign proliferation of mature hepatocytes, which can develop in a background of an otherwise normal liver, or one affected by steatosis or glycogenosis. This tumor is usually well-defined but rarely encapsulated, highly vascular, variable in size, and solitary or multifocal. The presence of multifocal (>10) nodules has been defined as adenomatosis ( 41,42 ).

The initial diagnosis is often made incidentally during abdominal imaging. Alternatively, patients can present with abdominal pain. Currently, there is no formal recommendation for HCA screening with metabolic risk factors or duration of OCP exposure.

Most hepatic adenomas are benign and asymptomatic. However, different from other benign liver lesions, hepatic adenomas are associated with a risk of hemorrhage (up to 15%) and/or malignant transformation (up to 5%) ( 42,43 ). The risk of hemorrhagic complications is associated with the clinical subtype of HCA as well as the size and rate of growth of the lesion. Similarly, the likelihood of malignant transformation, although rare, is associated with specific HCA subtypes, sex, size, and growth patterns. Men carry a higher risk of malignant transformation because they are more commonly diagnosed with the β-catenin mutated variant. As further described below, this molecular subtyping can risk-stratify patients ( 44,45 ) ( Table 4 ). Recommendations for surveillance and management are mainly based on the presence of symptoms (i.e., abdominal pain), risk factor modification, clinical subtype, adenoma size, and number. Typically, adenomas that are associated with these complications are >5 cm in size, although complications can arise in smaller lesions ( 46,47 ). A patient presenting with adenoma rupture and associated hemorrhage may present with signs and symptoms of acute abdominal pain, anemia, and/or hemorrhagic shock. Emergent cross-sectional imaging is essential to assess for hemorrhagic rupture of HCA, followed by angiography for potential embolization of active extravasation.

Because of the benign nature of most hepatic adenomas, treatment is often unnecessary. Stabilization or regression of HCA lesions has been noted with elimination of hormonal stimuli and can be seen with aggressive management of metabolic risk factors ( 48–50 ).

• 6. Hepatic adenomas are generally benign but can be associated with an increased risk of hemorrhage and/or malignant transformation.

Imaging and diagnosis.

The initial diagnosis of hepatic adenomas is often made through abdominal imaging, including US or cross-sectional imaging. Patients with metabolic risk factors or glycogen storage disease may have evidence of hepatic steatosis, or metabolic dysfunction-associated steatotic liver disease. Although adenomas may form in a cirrhotic liver, it is less common to see benign liver lesions form de novo in the presence of cirrhosis, and any lesion in a patient with cirrhosis must be considered HCC until proven otherwise. The presence of a solid liver lesion on ultrasound should lead to further evaluation with contrast-enhanced multiphase CT, MRI, or CEUS. The imaging appearance of HCAs can vary depending on the molecular subtype, which can allow for imaging-based diagnosis of the subtype, particularly when using MRI for evaluation. On postcontrast CT or MRI with extracellular agent, HCA will demonstrate arterial phase hyperenhancement that becomes isoenhancing on the portal venous and equilibrium phases. On MRI, the lesion will generally demonstrate mild T2 hyperintensity and T1 hypointense-to-isointense signal. There may be intralesional lipid. On HBP MRI, HCAs are usually devoid of signal, in contradistinction to FNH (discussed below). However, in some atypical inflammatory and β-catenin mutated HCAs, the presence of the biliary transporter, OATP1B1/B3 (organic anion transporter polypeptide 1B1/B3), results in increased retention of gadoxetic acid in the HBP and thus hyperintense signal ( 51,52 ). These lesions remain a diagnostic dilemma because they do not have imaging characteristics definitive for FNH or HCA; thus, these lesions may be biopsied, followed, and/or discussed at multidisciplinary liver tumor board ( 53 ). If there has been previous hemorrhage in an adenoma, the appearance can be hyperdense on noncontrast CT or hyperintense on T1 precontrast MRI. CEUS can be used to aid in the diagnosis of HCA, although it is not specific enough to subtype the adenoma.

Changes in imaging appearance over time can be suggestive of malignant transformation and include rapid increase in size, subsequent development of intralesional lipid, or new washout on portal venous or delayed phase of imaging. In these cases, biopsy should be considered. One common diagnostic dilemma, however, is that pathology of adenomas often returns as well-differentiated HCC. Pathologic features that favor HCC over HCA include more than patchy cytological atypia, thickened hepatocyte trabeculae, pseudoglandular structures, cholestasis, small cell change, and loss of reticulin staining ( 54 ). Furthermore, the 3-marker panel of glypican-3, heat shock protein 70, and GS can help distinguish HCC from HCA ( 55 ). In cases where pathology is indeterminate and a confident diagnosis of HCA vs HCC cannot be made, new pathological terms “atypical hepatocellular neoplasm” and “hepatocellular neoplasm of uncertain malignant potential” have been used ( 54,56 ). When biopsy is inconclusive, multidisciplinary discussion is warranted to determine management such as resection or close imaging surveillance.

There are no specific serum biomarkers that are diagnostic of HCA. If there is concern for possible malignant transformation, it is recommended to order an α-fetoprotein level (AFP), although this has low sensitivity for detection of HCC alone in this setting.

• 7. When a solid hepatic mass is incidentally discovered in a patient with no known risk factors, appropriate multiphasic contrast-enhanced imaging (CT or MRI) should be the first step in management and is often a sufficient test for diagnosis and subtyping of hepatic adenomas.
• 8. Biopsy should be performed when a hepatic adenoma has an uncharacteristic appearance on imaging or change in imaging features that are concerning for malignant transformation.
• 4. We suggest using multiphasic liver imaging (preferable MRI) over standard cross-sectional imaging modalities to accurately distinguish hepatic adenomas from other benign or malignant liver lesions (conditional recommendation, very low quality of evidence).

Clinical and molecular subtypes.

An enhanced understanding of hepatic adenomas has led to clinical and molecular subtyping into 3 main categories (inflammatory, hepatocyte nuclear factor-1α, and β-catenin activated) and 2 less well-understood subtypes, which include the sonic hedgehog and the unclassified cohorts ( Table 4 ). Improved imaging techniques and histologic studies allow for subtyping of up to 90% of HCAs. Subtyping has had increased relevance for understanding risks of complications of hemorrhage, malignant transformation, and risk factor modification. The currently accepted clinical and molecular subtypes are presented below by order of prevalence, of which there are characteristic imaging features, which can allow for improved imaging-based diagnosis of subtype, as described in Table 5 .

Inflammatory adenomas.

Inflammatory-type adenomas (I-HCAs) account for up to 44% of cases and are represented molecularly by the activation of the Janus kinase signal transducer and the activation transcription pathway ( 57 ). Laboratory changes can include elevations in serum alkaline phosphatase in cases of larger or multiple adenomas or elevated systemic inflammatory markers such as C-reactive protein and fibrinogen levels, although presently, there is insufficient evidence to support routinely checking CRP or fibrinogen in these cases ( 58 ). Risk factors for development of I-HCAs include those that also result in increased risk of hepatic steatosis, such as obesity, metabolic syndrome, heavy alcohol consumption, and glycogen storage disease. Because of their often larger size, subcapsular location, and high vascularity, these can be prone to hemorrhage. The risk of malignant transformation is low unless there is concomitant presence of the β-catenin mutation ( 59 ). Figure 2 shows an example of an inflammatory adenoma on imaging.

Hepatocyte nuclear factor-1α.

Up to 40% of HCAs are classified by inactivation of hepatocyte nuclear factor-1α, known as H-HCA ( 58 ). There is a strong association noted with OCP use or excess estrogen exposure and a lesser association with maturity-onset diabetes of the young 3 diabetes ( 60 ). Because of the impairment of fatty acid mobilization because of the mutated HNF-1α, there is a varying but often prominent degree of steatosis observed in H-HCAs. Compared with the other subtypes, the risk of hemorrhage and malignant transformation is among the lowest for H-HCAs ( 58 ). Figure 3 shows a representative case of an HNF-1α adenoma in a young woman.

β-catenin activated HCA.

The β-catenin mutated HCA (β-HCA) in exon 3 accounts for up to 10% of HCAs and is most prevalent in men and among individuals with risk factors such as glycogen storage disease or anabolic steroid use. When present, these tend to develop at a young age and are often large at presentation. This subtype is associated with the highest risk of transformation to HCC. As such, β-catenin mutated HCAs are at a higher risk of malignant transformation compared with other clinical subtypes and should be resected regardless of size. Recent studies have noted that the cadherin-associated protein β1 (CTNNβ1, the gene that encodes for the β-catenin protein) exon 3 mutation is associated with approximately 10% or greater risk of malignant potential, compared with no significant increased risk of malignancy when there is a mutation in CTNNβ1 exon 7 and 8, which is present in <10% of β-catenin mutated HCAs ( 44,58 ). Next-generation sequencing has also been proposed to enhance the histopathological diagnosis and subtyping of HCAs when enough tissue is available and subtyping may influence management ( 61 ).

MRI cannot reliably distinguish this variant from the other subtypes and is not specific enough to differentiate β-catenin mutated activated HCA from well-differentiated HCC, given similar imaging appearance of arterial phase hyperenhancement, washout, and capsule ( Figure 4 ). Even on pathology, distinguishing β-catenin mutated activated HCA from HCC is challenging. Although imaging of β-catenin HCA and well-differentiated HCC overlaps, the lack of risk factors for chronic hepatocellular disease renders the former the more likely diagnosis.

• 9. MRI features are beneficial for subtyping I-HCAs and HNF-1α mutated adenomas but are not specific for subtyping β-catenin mutated, sonic hedgehog, and unclassified adenomas.
• 10. Risk factors for development of I-HCAs include obesity and/or metabolic syndrome risk factors, heavy alcohol consumption, and/or glycogen storage disease.
• 11. β-catenin mutated HCAs are at a higher risk of malignant transformation compared with other clinical subtypes and should be resected regardless of size.
• 12. Hepatic adenomas that develop in men are commonly β-catenin mutated and associated with a higher risk of malignant transformation.

Management.

The management of patients with HCAs can be conservative for patients with small, asymptomatic lesions, with an overall low-risk profile. Patients with a more complicated HCA presentation or higher-risk profile can benefit from discussion with a multidisciplinary team. It has become increasingly recognized that the factors influencing risk of complications include size of the lesion, sex, and the clinical and molecular subtype. Treatment is generally more nuanced and aggressive than other benign liver lesions because of the risk of possible hemorrhage or malignant transformation. The association with endogenous and exogenous hormonal stimuli also results in potential for growth at a young age, during pregnancy, and/or with weight gain. Most patients requiring intervention should undergo surgical resection, although there are increasing reports of less invasive treatment options through interventional radiology. A meta-analysis from 2019 reviewed over 219 articles on treatment options for adenomas, and very few patients were treated with embolization or ablation. Reports of elective locoregional therapy for the treatment of HA are limited to case reports and small institutional series ( 62 ). Until further research is available, locoregional therapy with ablation or embolization cannot be recommended routinely. Ultimately given some of the uncertainty of long-term outcomes, shared decision-making will allow for patients to be engaged in their management options.

Females with adenomas <5 cm.

Females with asymptomatic HCAs diagnosed at <5 cm in size can be monitored and initially managed conservatively unless imaging prompts concerns for β-catenin mutated subtype. These are far less commonly associated with complications of hemorrhage and/or malignancy ( 63 ). The use of exogenous hormonal therapy should be discontinued ( 30,31 ). In the case of an elevated body mass index, weight loss should be encouraged, although there is no specific established weight loss target for adenoma regression ( 33,48 ). Repeat contrast-enhanced MRI should be performed after 6 months to assess for stability or regression of the adenoma, regardless of subtype. In cases that are indeterminate by imaging for HCA, or those that warrant further evaluation for malignancy, a biopsy should be performed. Cases where biopsy is positive for β-catenin mutation in exon 3 or that have transformed to HCC should proceed with resection. If the patient is not a candidate for resection, then locoregional therapy should be considered. If biopsy confirms H-HCA, I-HCA, or a low-risk HCA profile, continued surveillance is warranted. Routine biopsy for purposes of subtyping is not recommended for lesions <5 cm in female patients until there are prospective data supporting this approach.

During surveillance, if there is growth of the lesion, suggested as ≥20% as extrapolated from RECIST criteria for malignant liver tumors, resection or definitive treatment should be considered ( 64–66 ). This is also reasonable to consider for patients who prefer treatment over surveillance alone. Although regression of HCAs is possible, it is far more common for lipid-rich lesions to show stability. Ongoing surveillance every 6 months with contrast-enhanced imaging is recommended for 2 years, and then, it is reasonable to continue surveillance imaging annually. The modality of imaging can be adjusted over time to minimize radiation exposure and cost, noting that many patients when diagnosed are young and will require long-term continued follow-up ( 67 ). After 2 years, ultrasound could be considered for follow-up, and if there is any change in the adenomas, contrast-enhanced CT or MRI would be indicated. Presently, there remain insufficient data to determine whether and when to discontinue imaging surveillance, although it has been recently suggested that these patients may no longer need monitoring after menopause ( 68 ).

Females with adenomas ≥5 cm.

For females with HCAs that are 5 cm or larger, a period of 6 months of observation is reasonable with cessation of exogenous hormone use (OCPs, hormonal intrauterine devices, and anabolic steroids) and, if applicable, a recommendation for weight loss ( 69 ). In non–β-catenin mutated HCAs, it is reasonable to observe at 6-month intervals noting the greater period for regression of lesions in response to lifestyle changes ( 70 ). Any imaging features concerning for malignancy should lead to immediate treatment without a period of observation. In cases where the adenoma remains ≥5 cm after observation, definitive treatment should be pursued with surgical resection to minimize the risk of hemorrhage or malignancy. If the patient is not a resection candidate, other treatment options should be considered such as embolization. If during the observation period, the adenoma has regressed to <5 cm, continued observation with contrast-enhanced MRI is recommended. Similar to female patients with adenomas <5 cm, these patients should continue to have long-term follow-up surveillance imaging initially every 6 months, with the interval adjusted over time based on risk factors for age, premenopausal state, and stability ( 71,72 ). Although malignancy is unlikely with HCA regression to <5 cm, it has been infrequently reported to occur at this size ( 73 ). A biopsy to stratify risk based on subtype has not been shown to be beneficial in this cohort with HCA regression because the prevalence of β-catenin mutations is overall low and most reported cases proceed to definitive management. An ongoing prospective cohort study aims to study the patient-reported outcomes for interventional treatments of large adenomas compared with untreated lesions ( 74 ). Residual HCA after resection has shown varying patterns including regression, stabilization, and progression, warranting ongoing imaging surveillance and consideration to retreatment if progression is seen ( 75 ).

Males with adenomas.

For males, regardless of size or subtype, adenomas should be surgically resected or treated definitively because of the higher incidence of malignancy ( 45 ). They should also be encouraged to eliminate anabolic steroid or exogenous steroid use and recommended weight loss. The recommendation for resection is present regardless of the size of the lesion, noting the high risk of β-catenin subtype, but this recommendation is irrespective of subtype. A biopsy is not advised before surgical resection but should be performed if the patient is not a surgical candidate and will require nonsurgical therapies such as ablation (based on size of lesion) or embolization. Laparoscopic liver resection is strongly preferred over nonsurgical modalities ( 76,77 ). Ablation can have limited success in larger lesions, and embolization is associated with a risk of incomplete eradication with possible need for retreatment ( 78–80 ). These could be considered as a bridge to future more definitive therapy. After resection, embolization, or ablation, it is recommended to continue surveillance imaging every 6–12 months, although the frequency and duration of monitoring are not well established.

In the setting of pregnancy, HCAs may exhibit growth and progression. The greatest risk of complications (such as hemorrhage) is in the third trimester because of the increased hepatic vascularity and hyperdynamic circulation. This requires close monitoring, although there is no single validated approach. Repeat imaging with ultrasound every 6–12 weeks is a recommended strategy. Adenomas that remain <5 cm in size, nonexophytic, and without growth during pregnancy can be safely monitored and do not impact the modality of delivery ( 81 ). A recent prospective study of 51 pregnant women with <5-cm HCA noted a quarter of patients with HCA growth, a quarter with HCA regression, and no instances of hemorrhage ( 81 ). Adenomas that exhibit growth during pregnancy particularly to >6.5 cm in size or have high-risk features for hemorrhagic rupture including exophytic lesions should be treated with resection if early in the pregnancy or embolization before 26 weeks' gestation ( 82 ). During the third trimester, emergent surgery is recommended for hemorrhagic rupture from HCA. This should be performed in concert with obstetrics and balancing harms and benefits. Larger lesions (>6.5 cm) have demonstrated risk of hemorrhage both during pregnancy, delivery, and immediately postpartum. Preconception counseling should include a discussion of risk and optimal management strategy for patients with previously diagnosed HCAs. Pre-emptive treatment during pregnancy for HCAs that do not exhibit high-risk features is not recommended because of added risks in pregnancy ( 82 ). Before planned conception, HCAs smaller than 5 cm should be considered for resection or embolization if they are at particularly high risk of growth or hemorrhage (i.e., has exhibited growth previously with hormonal stimulation or is exophytic), and HCAs ≥5 cm should be treated to minimize need for treatment during pregnancy. Larger registry data are needed to understand the behavior of HCA during pregnancy.

Ruptured adenoma.

Because of the rich vascularity of this lesion, spontaneous rupture of HCAs is a known complication that requires emergent attention in the case of hemodynamic instability. Intralesional hemorrhage is of less significance compared with tumor rupture because of the risk of hemoperitoneum. Established risk factors include HCAs ≥5 cm, growth of the lesion, and/or exophytic location of the lesion. Management includes initial supportive care with hemodynamic stabilization and transfusion ( 83 ). If instability remains, emergent transarterial embolization (TAE) should be pursued to achieve hemodynamic stability until surgical resection can be performed ( 84–86 ). After hemorrhage with spontaneous cessation of bleeding, the treatment course for patients is not well defined. Many proceed to definitive surgery, although others have been noted to have regression of their adenoma. If the patient is a surgical candidate, residual HCA should be laparoscopically resected, minimizing risk of future recurrent hemorrhage. Post-treatment monitoring is recommended as the risk of recurrent hemorrhage or growth of residual HCA remains. There are insufficient data to show a correlation between the HCA subtype and future risk of hemorrhage. A history of HCA rupture has not been consistently associated with an increased risk of malignant transformation, although case reports have suggested coexistence of HCA rupture and malignant transformation ( 66,87 ).

Malignant transformation.

The risk of malignant transformation of HCA is reported to be <5%, although challenges remain in determining an accurate incidence. The highest risk cohort includes males with HCA (10× greater than females), β-catenin mutated HCA in exon 3, and lesions ≥5 cm ( 45 ). Patients with glycogen storage disease are also believed to be at a higher risk of malignant transformation. Diagnosis of malignant transformation can be challenging, given overlap in imaging features; however, a change in imaging characteristics and rapid growth are concerning features ( Figure 5 ). In cases where concern exists, management is variable, as described in the above sections. However, in general, multidisciplinary discussion and biopsy may be warranted, as well as surgical resection in males with HCA. Next-generation sequencing can be helpful to identify malignant transformation, in which AFP levels are not reliable ( 61 ). Patients who are not candidates for surgical resection can be treated with other modalities used for HCC treatment including ablation, embolization, radiation therapy, and/or liver transplantation.

Hepatic adenomatosis.

Hepatic adenomatosis is a variant of HCA characterized by 10 or more hepatic adenomas ( 41,85 ). This often develops in a background of hepatic steatosis and metabolic risk factors, often with the molecular subtype of HNF-1α HCAs ( 42 ). It is not uncommon to see coexisting hepatic hemangiomas or FNH in this setting. Adenomatosis can also develop in the setting of glycogen storage disease, which if previously undiagnosed should have further evaluation with genetic testing. The variant of adenomatosis is an important distinct clinical entity because these patients are at substantially higher risk of complications and thus require more aggressive treatment considerations. The risk of bleeding is substantially higher in these patients (up to 46% in some case series), and development of malignancy has been reported in up to 7% of cases ( 88 ). Unilobar disease can be managed with surgical resection or resection of a dominant larger adenoma. In the setting of bilobar involvement, management is best focused on treating the largest or dominant lesion or any that raise suspicion for complications such as hemorrhage or malignant transformation. Ongoing monitoring by imaging is recommended, at least annually. As explained below, liver transplantation is reserved for select patients with multiple HCAs ( 89 ). Lifestyle modification including removal of exogenous hormone therapy, and metabolic risk factor management, has been shown to reduce the overall burden and size of multiple HCAs ( 33 ).

Liver transplantation.

Liver transplantation has a select role for patients with HCAs. Specifically, this should be considered for patients with evidence of HCA hemorrhage or malignant transformation who are not candidates for surgical resection or other curative-intent therapy. The Organ Procurement and Transplant Network policy establishes that HCA should be a rare indication for liver transplantation and should be considered an option for patients with HCA in the background of glycogen storage disease, those with unresectable β-catenin positive adenoma, or in the case of an unresectable progressive HCA, despite medical management and/or with complications of hemorrhagic or malignant transformation ( 90–93 ). Patients meeting this highly select criteria may be offered a priority score for transplantation. The overall outcome for these patients is similar to other indications for liver transplantation; however, the strict selection criteria are essential, given the overall indolent disease course and discordance between imaging concerns and explant findings of malignancy ( 94 ).

• 13. Women with hepatic adenomas ≥5 cm should modify risk factors, undergo observation for 6–12 months, and undergo resection if the lesion does not regress to <5 cm.
• 14. Men with hepatic adenomas should consider surgical resection regardless of lesion size because of elevated risk of malignant transformation.
• 15. Hepatic adenomas should be monitored regularly during pregnancy and should be treated if there is growth to >6.5 cm or with high-risk features for hemorrhagic rupture.
• 16. Hepatic adenomas of any size that have imaging features concerning for malignant transformation should be treated as an HCC, with consideration to surgical resection, locoregional therapies, and/or liver transplantation.
• 17. Hepatic adenomatosis is a variant of HCA characterized by 10 or more hepatic adenomas, more commonly associated with background steatosis or glycogen storage disease.
• 18. Consideration for liver transplantation should be given to patients who meet the Organ Procurement and Transplant Network policy for transplantation, especially those with glycogen storage disease, unresectable β-catenin positive adenoma, or unresectable with complications of hemorrhagic or malignant transformation of hepatic adenomas.
• 5. In women with hepatic adenomas <5 cm, we suggest discontinuation of exogenous hormones and advise weight loss, if applicable, for overweight or obese individuals (conditional recommendation, very low level of evidence).
• 6. In women with hepatic adenomas <5 cm, we suggest surveillance with contrast-enhanced imaging modalities every 6 months for 2 years, then annually thereafter (conditional recommendation, low level of evidence).
• 7. In patients with hepatic adenomas requiring treatment who are unable to undergo surgical resection, we suggest embolization or ablation as alternative treatment approaches (conditional recommendation, low level of evidence).
• 8. In patients with ruptured hepatic adenomas, we suggest hemodynamic stabilization followed by embolization and/or surgical resection (conditional recommendation, very low level of evidence).

Focal nodular hyperplasia

FNH is the second most common solid liver lesion, with 0.3%–3% of people having FNH on autopsy ( 95 ). FNH is favored to arise as a local reaction to vascular abnormalities, specifically aberrant hemodynamics within the liver, usually secondary to an aberrant dystrophic artery or a vascular injury, resulting in a disturbance of local blood flow, which can result in hyperperfusion, oxidative stress from hypoxia, and hepatic stellate cell response, all of which result in a hyperplastic microenvironment and FNH development ( 96 ). This is further corroborated by cases of FNH-like lesions such as nodular regenerative hyperplasia that are seen in patients with abnormal vascular flow to the liver in cases of cardiac etiologies of cirrhosis ( 97 ).

Most FNHs are discovered incidentally, and up to 20% of patients with FNH will also have a hepatic hemangioma present ( 95 ). There is a known female preponderance, and compared with men, women tend to develop larger FNH lesions that present earlier ( 95 ). Because of these epidemiologic characteristics, it has been believed that there may be a causative role for sex hormones in FNH development; however, over time, this has been disproven because of lack of correlation between OCP use and FNH growth or prevalence and lack of evidence of change in FNH during pregnancy ( 98,99 ). Importantly, unlike adenomas, FNH do not need to be treated differently in men as compared to women and do not require monitoring during pregnancy.

Imaging most often allows the definitive diagnosis of FNH vs adenoma, which is important because management differs between the 2 lesions. An MRI with a hepatobiliary contrast agent, such as gadoxetic acid, is the preferred imaging modality of choice because it can correctly classify FNH from adenoma with an accuracy of over 90% ( 100–102 ). MRI has a specificity of almost 100% for diagnosis of an FNH ( 103 ). If the patient has a contraindication to MRI, then multiphase CT can be performed. CEUS can be used for diagnosis of FNH, with increased diagnostic accuracy in lesions measuring <3 cm in size ( 104–107 ).

On postcontrast CT or MRI, FNH usually appears as a well-circumscribed homogeneously arterial hyperenhancing mass, which becomes isoenhancing on portal venous and delayed phase of imaging ( Figure 6 ) ( 108 ). Classically, there is a central scar, which is usually hypodense/hypointense on noncontrast imaging CT/MRI, respectively, demonstrates delayed enhancement on portal venous and delayed phase of imaging, and is isointense to hyperintense on T2-weighted imaging.

Because FNH contains hepatocyte-specific membrane transport proteins, they almost always show hyperintense signal on the 20-minute HBP of imaging, rendering the diagnosis of FNH with nearly 100% confidence ( 108,109 ) ( Figure 6 ). In fact, studies show that only 2% of FNH are hypointense on 20-minute HBP of imaging ( 110 ).

Of note, with increasing use of biopsy for hepatic adenomas and newer stains allowing improved subtype classification, there is emerging evidence that 11% of inflammatory and 59% of β-catenin mutated adenomas demonstrate OETP1B3 receptor expression and therefore can demonstrate hyperintense signal on HBP of imaging. Therefore, any lesion that has atypical imaging appearance for FNH on dynamic imaging that demonstrates HBP hyperintense signal should be closely followed ( 111 ).

In the rare case that a diagnosis of FNH cannot be made by imaging, then a biopsy may be considered after discussion at multidisciplinary tumor board. Biopsy can sometimes be difficult to interpret, with some case series reporting diagnosis as low as 58%, although the interpretation can be aided with the addition of immunohistochemistry ( 112,113 ).

Once the diagnosis of FNH is confidently made, a conservative approach with no further follow-up is recommended. Given the little to no change over time in most cases, there is no benefit to continued imaging, and those lesions that do grow do not cause life-threatening complications ( 114 ). Current evidence suggests no indication that patients should avoid or discontinue OCPs or hormonal therapy, and that FNH does not need to be followed during pregnancy ( 115,116 ).

In the rare case of symptoms such as pain, surgical resection may be considered, but most FNH lesions are incidental to symptoms rather than the cause of symptoms and patients should be educated that their symptoms may not improve after surgery ( 117 ). Even in the setting of growth of an FNH, there is an extremely slim chance of malignancy, and therefore, resection is not recommended ( 117 ). Because FNH is usually supplied by a single artery, TAE seems like a logical minimally invasive method for treatment in cases that require treatment. There remains much debate, however, as to which embolic agent is best used for TAE of FNH. A few small case series suggest that TAE with bleomycin for symptomatic FNH can result in decrease in tumor size by 50%, but bland embolization is often used ( 80,118,119 ).

• 19. Advanced imaging techniques (e.g., contrast-enhanced multiphase MRI with hepatobiliary-specific contrast) can accurately diagnose FNH in most cases, and biopsy is not routinely needed.
• 20. In a patient with an FNH confirmed on imaging, no further follow-up is required.
• 21. If the diagnosis of FNH is confirmed, then even in the case of growth, resection is not required. If resection is being considered because of symptoms, then patients must be counseled that their symptoms may not improve after surgery as FNH rarely causes symptoms.
• 22. If FNH lesions are symptomatic and surgery is not an option because of comorbidities or anatomic considerations, then TAE with or without bleomycin may be considered to decrease size.
• 23. Men with FNH do not need to have any different evaluation, monitoring, or treatment compared with women.
• 9. We suggest evaluating patients with FLLs that are suspicious for FNH using multiphase MRI with hepatobiliary-specific contrast agents to distinguish FNH from HCA (conditional recommendation, low quality of evidence).
• 10. We do not suggest routinely discontinuing OCPs in patients diagnosed with FNH (conditional recommendation, very low quality of evidence).

Hemangiomas are the most common benign noncystic liver lesions, occurring in up to 20% of the population, with a reported preponderance in women at a 4:1 ratio ( 120 ). They are benign mesenchymal vascular lesions consisting of clusters of blood-filled cavities lined by endothelial cells, ranging in size from a few millimeters to greater than 20 cm ( 121 ). Hemangiomas are believed to arise from a congenital abnormality in vasculogenesis, growing slowly from birth. Increase in size of hemangiomas can occur and is favored to be due to progressive ectasia of the vasculature and not related to hypertrophy of the lesion ( 122 ). Hemangiomas are usually asymptomatic lesions, which are incidentally detected on imaging studies, although larger lesions can result in pain, poor appetite, or abdominal fullness ( 122 ). Rarely, hemangiomas can result in a consumptive coagulopathy known as Kasabach–Merritt syndrome, which can present as thrombocytopenia, systemic bleeding, and disseminated intravascular coagulation, usually seen in giant cavernous hemangiomas ( 123,124 ).

There has been no clear causative link between hemangiomas and female sex hormones, and thus, it is not recommended to avoid OCP or pregnancy in patients with hemangiomas ( 125,126 ). There are 3 classic types of hemangiomas: cavernous , capillary , and sclerosed .

Ultrasound is often the first imaging modality to detect an incidental hemangioma and can sometimes be diagnostic enough not to require further evaluation ( 127 ). However, in most instances, further evaluation with cross-sectional imaging is necessary for diagnosis confirmation, especially when a suspected hemangioma is seen in a patient with hepatitis B, cirrhosis, or underlying history of malignancy. MRI has the best sensitivity and specificity (92%–100% and 85.7%–99.4%, respectively), followed by CT (sensitivity 98.3% and specificity 55.0%) and CEUS (accuracy 97.3%) ( 128,129 ).

The typical sonographic appearance of a cavernous hemangioma is a homogeneous hyperechoic observation with posterior acoustic enhancement, usually seen in hemangiomas less than 3 cm in size. Hemangiomas tend to be “avascular” on color Doppler imaging, which is related to slow flow within the large vascular spaces within the tumor ( 127,130,131 ).

If ultrasound imaging is atypical or nondiagnostic, or in a lesion that is greater than 2 cm, further evaluation CEUS, CT, or MRI should be obtained. A recent study showed high diagnostic utility of CEUS with an accuracy of 92.7%, demonstrating classic imaging features of peripheral nodular enhancement ( 132 ). Another study evaluating 103 patients with hemangiomas showed a diagnostic rate of 90.2% for hemangiomas when using CEUS ( 133 ).

Classic CT/MRI features of a cavernous hemangioma include hypodensity or hypointensity on noncontrast CT or T1 precontrast MRI, respectively, and peripheral nodular enhancement on early postcontrast imaging with progressive centripetal enhancement on portal venous and delayed phase of imaging, which follows arterial blood pool ( 134 ) ( Figure 7 ). Hemangiomas are light bulb bright on T2-weighted sequences. One unique imaging feature that is helpful in atypical lesions is that hemangiomas are hyperintense on low b-value diffusion-weighted images and decrease in signal with increasing b-value ( 135–137 ). Giant cavernous hemangiomas are a subtype of hemangiomas, which measure over 10 cm in size (although some authors define these as over 4–5 cm in size) and can demonstrate similar imaging appearance as mentioned above. However, they can also demonstrate areas of calcification, large areas of central nonenhancement, and can have heterogenous postcontrast enhancement.

Capillary hemangiomas, also known as flash-filling hemangiomas, tend to be under 1 cm in size and demonstrate rapid homogenous arterial phase enhancement on postcontrast CT or MRI ( 120 ). On ultrasound, these small lesions may demonstrate vascular flow, unlike the cavernous hemangiomas, because the vascular spaces are smaller ( 138 ).

A sclerosed hemangioma, also known as a thrombosed or hyalinized hemangioma, usually occurring secondary to degeneration of a cavernous hemangioma and contain large amounts of fibrosis. Sclerosed hemangiomas are a diagnostic dilemma because they do not have typical imaging appearances as mentioned above. In fact, this subtype presents as areas of thick peripheral rim enhancement on early postcontrast phases with progressive enhancement of the lesion in a noncentripetal and non-nodular fashion. Unlike cavernous hemangiomas, they are heterogeneous on T2-weighted imaging and demonstrate increasing restricted diffusion on high b-value images. In addition, they can cause upstream capsular retraction ( 139,140 ) ( Figure 8 ). These imaging features are also characteristic of iCCA or hypovascular metastasis. Thus, in these instances, careful comparison with previous imaging revealing a stable lesion or a typical hemangioma in the same location is required. In some instance, a biopsy may be required.

In general, hemangiomas are considered “do not touch lesions” because imaging is sufficient to make the diagnosis with near-complete certainty. However, if an FLL cannot be confirmed as a hemangioma, multidisciplinary review could be performed ( 26,141 ). Biopsy is generally avoided, given the vascular nature of hemangiomas, although reports have indicated that risk of bleeding with biopsy of hemangiomas is low (0.15%) if small needles are used ( 142 ). Once the diagnosis of hemangioma is confirmed, no further follow-up imaging is needed, except for patients with underlying cirrhosis or risk of HCC, because lesions can mimic hemangioma early in the course of malignancy development ( 143,144 ). These patients should undergo follow-up imaging as recommended for FLL in the AASLD Hepatocellular Carcinoma Guidance ( 145 ).

Surgical treatment of hemangiomas, including giant cavernous hemangiomas, should be avoided if the main indication is discomfort and anxiety because these symptoms nearly always recur ( 128,146–150 ). The clearest indications for treatment of a hemangioma remain complications related to the tumor, such as rupture, intratumoral hemorrhage, consumptive coagulopathy, and organ or vessel compression. Thankfully, spontaneous rupture of hepatic hemangiomas is an exceedingly rare event ( 151 ). Surgical treatment can be performed through the open approach or laparoscopically; the most common surgery is enucleation, and the second most common is nonanatomical resection ( 152 ). Larger hemangiomas (>15 cm) are more likely to have complications with surgery such as blood loss and blood transfusion or prolonged recovery ( 153 ). In patients who are not surgical candidates either because of anatomic concerns or comorbidities, other interventions can be considered such as ablation for lesions smaller than 3.5 cm (radiofrequency or microwave), radiation therapy, TAE, and in the case of life threatening Kasabach–Merritt syndrome, even a few reports of liver transplantation after discussion at multidisciplinary tumor board ( 128,154 ). Patients with asymptomatic hemangiomas do not require intervention or follow-up regardless of the size ( 155 ).

• 24a. Small echogenic avascular lesions less than 2 cm with well-defined borders in a patient with a normal liver and no underlying medical history or risk factors for liver disease or malignancy can be diagnosed as hemangioma on ultrasound.
• 24b. In patients with a lesion that does not meet the above criteria, multiphasic contrast-enhanced imaging should be performed to confirm the diagnosis.
• 25. If a suspected hemangioma cannot be confirmed on cross-sectional imaging, then the next step is to monitor and to review the case at a multidisciplinary tumor board.
• 26. Biopsy of a suspected hemangioma should be avoided when possible because of the risk of bleeding.
• 27a. Once the diagnosis of hemangioma is confirmed, no further follow-up is needed unless the patient has cirrhosis or other risk of malignancy such as hepatitis B.
• 27b. Patients who are pregnant do not need to have monitoring of the hemangioma even in the case of large, cavernous hemangiomas.
• 28. Even in patients with asymptomatic large, cavernous hemangiomas (generally >10 cm), surgical resection is not indicated. No further follow-up is required.
• 29. Indications for resection of a hemangioma are complications related to the lesion, such as rupture, intralesional hemorrhage, consumptive coagulopathy, or organ or vessel compression. These complications are rare. Resection may be performed through open or laparoscopic approach.
• 30. If surgery is not an option for a patient with complications related to the lesion, other treatments may be considered such as ablation (microwave or radiofrequency), radiation therapy, TAE, or in the very rare instance liver transplantation. Treatment options in these instances should be discussed at multidisciplinary tumor board.
• 11. In patients with cirrhosis or chronic hepatitis B who meet criteria for HCC surveillance and have a suspected hemangioma, we recommend continued imaging surveillance every 3–6 months for at least 1 year (strong recommendation, low quality of evidence).

Solid liver lesions of malignant potential

Solid liver lesions on imaging often causes concern for malignancy, and this must always be considered when determining the next step in diagnosis and management of a liver lesion. In a patient with underlying liver disease, HCC should always be on the top of the differential, and even when a solid liver lesion appears typical for another diagnosis, the patient must have ongoing surveillance to assess for growth. The AASLD recently updated the Guidance document for HCC ( 145 ). Rather than discussing HCC in more detail in this document, we encourage the reader to refer to that Guidance document.

CCA is another solid mass lesion of concern, especially when the mass appears in the hilar area, although iCCA must also be considered. Patients with primary sclerosing cholangitis and viral hepatitis are at higher risk of CCA development, and patients with underlying cirrhosis from any cause can develop mixed HCC-CCA ( 156,157 ). Again, a recent Guidance statement that is specific to CCA has recently been published, and we refer the reader to that document ( 158 ).

In patients with multiple liver lesions in the setting of symptoms suggestive of carcinoid syndrome or with concomitant mass in the pancreas or small intestine, neuroendocrine tumors (NETs) must be considered. A consensus document on pancreatic NET was published in 2020, and although this document focuses on NET of pancreatic origin, many of the same issues around imaging and therapy can be applied to NETs of other origins ( 159 ). The only area of treatment that was not addressed in this consensus statement is the role of liver transplantation in the treatment of NET. Patients with metastatic NET with the primary tumor originating in areas with portal venous drainage that is limited to the liver with the primary tumor resected and a period of disease stability seem to have long-term survival after liver transplant with a 5-year survival rate of approximately 50% and in some cases can be as high as 70%, depending on selection criteria ( 160 ). The United Network for Organ Sharing has clear guidance on who may be consider for liver transplantation, but there is no consensus on which patients should be referred and evaluated for transplant or at what time point in the disease process this should occur ( 93 ). However, given the long wait times for donor organs in many areas, it is prudent to refer patients early for evaluation and discussion of liver transplantation as a treatment option.

Metastatic liver lesions

Incidentally discovered FLLs in the setting of a previous or current malignancy should prompt a workup for rapid and accurate diagnosis, given the important prognostic and treatment implications. There are multiple imaging modalities available, and choosing the appropriate study can be difficult.

If the incidentally discovered FLL is in a patient with no history of malignancy but has an imaging appearance suspicious for extrahepatic primary, this should instigate a workup to identify the primary source. If there is a known primary extrahepatic malignancy, and an FLL is discovered on initial staging workup, then further imaging may be warranted to confirm that the incidental FLL is a liver metastasis. For most malignant liver lesions, the most sensitive and specific imaging test will be an MRI with an hepatocyte-specific MRI contrast agent in combination with diffusion-weighted imaging ( 161,162 ). A recent meta-analysis showed that the sensitivity of gadobenate (MultiHance) for detecting liver metastases on a per-lesion basis for precontrast and combined dynamic, delayed HBP imaging was 77.8%, 88.1%, and 95.1%, respectively, which is similar to that reported for gadoxetate (Primovist/Eovist) ( 21 ). Unless there is a reason for alternative imaging, we recommend MRI for evaluation of liver lesions in the setting of concurrent or previous malignancy. Contrast-enhanced CT allows for fast, accessible, and high-quality imaging with a sensitivity of 74% for detection of liver metastasis, similar to that of dynamic postcontrast MRI ( 163 ). Additional imaging modalities for the detection of hepatic metastatic disease include positron emission tomography (PET)-CT and PET-MR. One consideration is that in a patient with known primary extrahepatic malignancy, a new incidental FLL most likely represents a metastatic lesion because development of “new” benign lesions in a surveillance patient is rare. In this instance, further dedicated imaging of the liver is not indicated, and the patient can undergo repeat staging workup and/or biopsy.

For further evaluation and treatments of metastatic lesions in the liver, please refer to the appropriate guidance for the source cancer. However, in the following sections, we will briefly review a few primary liver malignancies of importance.

Metastatic colon cancer is a special case that gastroenterologists and hepatologists must be aware of because there has now been a consensus statement and recommendations on liver transplant for colorectal liver metastases ( 164 ). Patients with nonresectable colorectal liver metastases that fulfill appropriate molecular criteria and have had a response to chemotherapy for at least 6 months may be considered, at a center with experience in liver transplantation for this indication.

• 31. Patients with HCC, CCA, NET, and metastatic colon cancer that are within guidance and consensus recommendations for liver transplant should be referred early in their course to a liver transplant center experienced in that disease process.
• 32. For lesions that are suspected to be metastatic to the liver, MRI with hepatobiliary contrast enhancement and diffusion-weighted imaging is the recommended modality.

Hepatic epithelioid hemangioendothelioma

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, low-to-intermediate grade tumor that derives from vascular endothelial cells. It can occur in multiple places in the body but is most commonly known to arise in the liver. It is slightly more common in women with a ratio of men to women at 3:2 and an estimated incidence of 1–2 cases of every 1 million people. Mean age at diagnosis is in the mid-40s to early 50s, and lesions are diagnosed incidentally 25% of the time ( 165 ). Unfortunately, distant metastases are present at time of diagnosis in approximately 37% of patients, with regional disease in 27.5%. Despite the presence of metastatic disease, the prognosis has shown a median survival of 182 months ( 165 ). However, patients who present with lung or multiorgan involvement, ascites with serosal metastasis, age greater than 55 years, and male gender have poor prognosis, often under 1 year ( 166,167 ).

There are 2 types of HEHE seen at different stages. Early stage disease presents with nodular type ranging from 0.5 to 12 cm in size, usually peripheral subcapsular in location. Advanced stage disease appears as diffuse disease with the nodules coalescing ( 168 ).

On ultrasound, HEHE is usually hypoechoic and heterogeneous in appearance. Capsular retraction, calcifications, and multifocal lesions may also be seen ( 169 ). A halo can be seen on US in 20% of patients ( 170 ). Imaging findings on CEUS are nonspecific; however, rim enhancement with washout of contrast on portal venous phase should clue the radiologist that it is a malignant lesion, prompting further cross-sectional imaging.

On cross-sectional imaging (CT or MRI), HEHE is often present in a subcapsular location with capsular retraction and calcifications. Enhancement can vary and present as mild homogeneous enhancement seen on all phases or thin ring-like enhancement in the arterial phase, with progressive enhancement in the portal venous phase ( 171 ) ( Figure 9 ). The characteristic imaging sign is the “lollipop” sign, which is due to tumor spread along the portal and hepatic vein branches and sinusoids, resulting in vascular and sinusoidal narrowing and obstruction ( 172 ). As a result, there is tapering of the portal and hepatic vein branches as they approach the lesion. The narrowing and occluded vessels are like sticks on the lesion, simulating the lollipop appearance ( 173 ). Another radiographic sign of HEHE on imaging is the “target” sign, which is an inner ring that consists of a fibrotic center, a middle ring of epithelial proliferation, and an outer ring defined by an avascular zone between the nodule and the liver parenchyma ( 171 ). The presence of capsular retraction, lollipop sign, and the target sign together is fairly specific for HEHE, and the presence of these features warrants further investigation ( 174 ). HEHE is generally mildly or moderately PET avid, and PET-CT or PET-MRI may be used as part of the workup for metastatic disease, although whole-body CT or whole-body MRI is the preferred imaging modality ( 175,176 ).

Although imaging features that are highly suggestive of HEHE, they can overlap with angiosarcoma, CCA, metastatic carcinoma, and sclerosing variant of HCC, and therefore, pathology is necessary to confirm the diagnosis. If surgical resection may be considered, then the patient can proceed to resection without a biopsy beforehand, and diagnosis can be confirmed with the surgical specimen. However, if resection is not imminently planned, then core needle biopsy must be performed.

Because of the rarity of HEHE, there are few studies to inform treatment recommendations. However, it is well accepted that surgical resection is the preferred treatment with 70%–80% cure rates after an R0 resection ( 177 ). In patients who are not able to undergo surgical resection, liver transplantation is also an accepted treatment for HEHE with 5-year survival of 77%, and the United Network for Organ Sharing has a pathway for these patients to receive model for end-stage liver disease exception points ( 178 ). Notably, the presence of extrahepatic disease has not been associated with worse outcomes after liver transplant and is not considered to be a contraindication ( 93 ). In the largest reported cohort of HEHE patients, patients who underwent liver transplant had the best survival when compared with other therapies ( 179 ). For patients who are not surgical candidates, sporadic studies and expert consensus statements recommend ablative therapies or stereotactic body radiotherapy ( 176 ). Systemic therapy is not often recommended, given the slow-growing nature of HEHE and should only be considered in patients with clear progression of disease and/or marked systemic symptoms. A variety of different systemic therapies have been reported, ranging from conventional chemotherapy to targeted therapies, but results have been disappointing, with overall survival generally less than 2 years ( 180 ).

• 33. If resection is planned because of imaging being highly suspicious for HEHE, a needle biopsy does not necessarily need to be performed before surgery.
• 34. Patients with diagnosed HEHE should undergo imaging for staging of disease with whole-body contrast-enhanced CT or whole-body contrast-enhanced MRI. PET-CT or PET-MRI may be considered with the understanding that HEHE is generally only mild or moderately PET avid.
• 35. HEHE should be resected whenever possible. If resection is not feasible, then liver transplantation offers the best survival, even in the setting of extrahepatic disease.
• 36. In the setting of nonresectable and nontransplantable HEHE, there are very little data to guide treatment choices, and patients should be referred to a specialty center whenever possible. Ablative therapies and stereotactic body radiotherapy have shown some response in small studies. There is no systemic therapy that can be recommended from published evidence, given the small numbers of patients.

Fibrolamellar HCC

Fibrolamellar HCC (FLHCC) is a rare primary liver cancer, accounting for <1% of all primary liver tumors in the United States. The highest incidence of FLHCC is in White men under the age of 40 years, although there is somewhat of a bimodal age distribution between 15 and 19 years and 70–74 years ( 181 ). Typically, it arises in a noncirrhotic liver with no specific risk factors identified. It has historically been thought of as a variant of conventional HCC, although genetic profiling has determined there is a unique mutation found in FLHCC, a DNAJB1-PRKACA chimeric gene fusion RNA transcript that is very rarely found in other cancers ( 182,183 ). Typically, α-fetoprotein is not elevated in FLHCC, although the presence of elevated AFP is an independent predictor of poor survival ( 184 ).

FLHCC is most commonly presents with symptoms, such as abdominal pain, palpable mass, or rarely mental status changes from acquired ornithine transcarboxylase deficiency ( 185 ). Unlike conventional HCC, FLHCC must be diagnosed with biopsy, although imaging can be suggestive of the diagnosis. FLHCC most often presents as a large, often solitary tumor with a background normal liver. There is generally heterogeneous early contrast enhancement, and calcifications can be present ( 186 ) ( Figure 10 ). On hepatobiliary MRI, there is hypointensity in the HBP ( 187 ). A central scar can be present in up to half of patients with FLHCC, so confusion with FNH can occur ( 188 ).

FLHCC is best treated surgically, even when lymph node metastases are present, with high recurrence rates ranging from 5% to 86% ( 181 ). There are very little data available on adjuvant or neoadjuvant therapy, although database studies suggest a worse outcome with the use of adjuvant or neoadjuvant chemotherapy ( 189,190 ). Liver transplant has also been performed, with 5-year survival rates of 48% ( 191 ). Given that the overall survival after transplant is worse than conventional HCC and slightly lower than 50% at 5 years, liver transplant should be reserved for liver-localized, unresectable disease.

In patients who are not candidates for surgical treatments or have recurrence, options are somewhat limited but include radiotherapy, traditional chemotherapy, or immunotherapy. Despite the identified genetic mutation found in patients with FLHCC, initial attempts at systemic therapy targeted to this mutation have not been successful ( 192 ). Several cases of partial responses to immunotherapy have been reported, including 1 complete response to the combination of anti-CTLA4 and anti-PD-1 antibodies ( 193,194 ). Given the very limited data available, patients with FLHCC who require systemic therapy should be enrolled in clinical trials whenever feasible.

• 37. In patients with FLHCC, surgical resection is the treatment of choice. In patients who have limited liver-localized disease that is unresectable, liver transplant may be considered on a case-by-case basis.
• 38. Neoadjuvant or adjuvant systemic therapy is not recommended for FLHCC except in the setting of a clinical trial.
• 39. In patients with FLHCC, biopsy should be performed to confirm the diagnosis, but molecular analysis of the biopsy for guidance of systemic therapy is not beneficial.

Hepatic angiosarcoma

Angiosarcoma is a rare and aggressive cancer that can occasionally present as a primary liver lesion. Primary hepatic angiosarcoma accounts for less than 1% of primary malignant liver tumors and 1%–2% of all soft-tissue sarcomas ( 195 ). This tumor usually presents with symptoms once at an advanced stage, and the only known risk factors include exposure to thorium dioxide, vinyl chloride, arsenic, and radiation ( 196 ). There is a slight male predominance, and nearly 80% of patients are older than 50 years at the time of diagnosis.

On imaging, hepatic angiosarcomas can have a varied appearance and range from multiple masses to a single heterogenous mass. On CT, the lesions are most frequently hypoenhancing on all postcontrast phases, unless they hemorrhage, in which case portions of the tumor are hyperdense on noncontrast imaging ( Figure 11 ). On MRI, tumors are heterogenous on all sequences ( 197 ).

The prognosis of primary hepatic angiosarcoma is very poor, with 1-year survival at just 12.8% ( 195 ). Studies using the National Cancer Institute's Surveillance, Epidemiology, and End Results database show that surgical resection does seem to prolong survival, although recurrence is frequent ( 196,198 ). There are some small studies to suggest that adjuvant radiation or chemotherapy may be of use, but the data are mixed, and this is not routinely recommended ( 199–201 ). Given the complexity and poor outcomes, we recommend that patients with primary hepatic angiosarcoma be referred to a sarcoma specialty center for treatment whenever possible.

• 40. In patients with primary hepatic angiosarcoma, surgical resection should be performed whenever feasible.

CYSTIC LIVER LESIONS

Cystic liver lesions are an increasingly common, heterogeneous group of lesions, which are often found incidentally because of the frequent use of cross-sectional imaging studies. Early reports from laparotomy series described a prevalence of 0.2%–1%, whereas recent ultrasound and CT series report a range of 2.5%–18% ( 202–205 ). With increased use of imaging for unrelated reasons, the incidence of incidentally detected hepatic cysts rises, and thus, understanding the types of cysts and management has become increasingly important. Most cysts have an indolent course; however, it is important to differentiate benign, simple cysts from those with malignant or infectious potential such as biliary cystadenomas/cystadenocarcinomas, choledochal cysts, and hydatid cysts. Specific high-risk features such as septations, fenestrations, calcifications, mural thickening or nodularity, heterogeneity, and the presence of daughter cysts should prompt further investigation ( 206 ). In addition, patients with multiple or large cysts can present with related symptoms, which requires further management.

Simple hepatic cysts

Hepatic cysts are thin-walled structures lined by cuboidal bile duct epithelium and filled with isotonic fluid ( 202 ). They are the result of ductal plate malformation without communication with the biliary tree ( 207,208 ). They can be solitary or multiple and often coexist with other mass lesions. They are usually asymptomatic and incidentally found, unless they are very large, in which case they can be symptomatic. There is a female predominance, although there is no established correlation with OCP use or pregnancy and cyst prevalence increases with age ( 208 ).

Simple hepatic cysts can be diagnosed on conventional grayscale ultrasound with a sensitivity and specificity of 90% ( 209 ). Simple hepatic cysts are usually homogeneously anechoic with through transmission and smooth margins. Up to 2.5%–5% of simple cysts can have up to 2 septa within them and include congenital cysts, Caroli disease, biliary hamartomas, and polycystic liver disease (PCLD). When a simple cyst is seen on ultrasound with these characteristics, no further imaging or follow-up is required. On CT, simple cysts demonstrate no internal architecture, are hypodense with fluid attenuation (<20 Hounsfield units), and demonstrate absent postcontrast enhancement. On MRI, simple cysts are hypointense on T1-weighted images and hyperintense on T2-weighted images with no enhancement. There is decreasing intensity on higher b-value diffusion-weighted imaging ( 209,210 ) ( Figure 12 ).

There is no indication for intervention or follow-up of simple cysts, regardless of size, unless symptoms develop or there are characteristic high-risk features such as mural nodularity or enhancing septations. Symptoms can occur when cysts enlarge, rupture, or compress key structures, leading to significant abdominal pain or pressure, shortness of breath, early satiety, epigastric fullness, or lower extremity edema because of inferior vena cava compression. High-risk features seen on ultrasound (e.g., septations, fenestrations, calcifications, mural thickening or nodularity, heterogeneity, and presence of daughter cysts) should prompt further investigation with CT or MRI to rule out more significant pathology such as infected cysts, pyogenic abscess, cystic metastasis, hydatid cysts, or mucinous cystic neoplasms of the liver (MCN-L).

For symptomatic cysts, treatment options include surgical cyst fenestration, also known as deroofing/marsupialization, or aspiration with sclerotherapy ( 206,211–213 ). There is a lack of robust randomized controlled trials (RCTs) and long-term outcome data comparing these methods to determine best modality for treatment. Although both are effective, surgical intervention has the lowest recurrence rate and allows for histological examination of the cyst ( 213 ). However, the decision to pursue surgical intervention, including type of surgery (open or laparoscopic), should be based on the patient's operative candidacy, individual preference, and center expertise.

Aspiration sclerotherapy can be achieved with several substances including 100% ethanol, tetracycline, or other sclerosants and may take up to 6 months to see maximum benefit ( 213 ). Thus, repeat intervention within 6 months of sclerotherapy is not recommended. Cyst aspiration alone, although helpful to diagnose the cyst as the cause of symptoms, is not recommended for definitive treatment, given the high recurrence rate ( 214 ). There is no need for postintervention imaging. Serum CA 19-9 levels can be elevated in up to 50% of these patients and therefore may not help to differentiate between simple and malignant cysts ( 215,216 ). In addition, cyst fluid can contain CA 19-9, a finding that does not necessarily correlate with malignancy ( 209 ).

• 41. In patients with asymptomatic complex hepatic cysts, regardless of size, we recommend discussion at a multidisciplinary tumor board and consideration of surveillance imaging in 6–12 months.
• 12. In patients with asymptomatic simple hepatic cysts, regardless of size, we recommend expectant management without need for routine surveillance or intervention (strong recommendation, low quality of evidence).
• 13. In patients with simple hepatic cysts with specific high-risk features seen on ultrasound (e.g., septations, fenestrations, calcifications, mural thickening or nodularity, heterogeneity, and presence of daughter cysts), we recommend further investigation with CT or MRI (strong recommendation, low level of evidence).
• 14. We suggest surgical cyst fenestration or aspiration with sclerotherapy for management of patients with symptomatic simple hepatic cysts (conditional recommendation, low level of evidence).

Autosomal dominant PCLD is characterized by the presence of multiple hepatic cysts (at least >10–20) with characteristics similar to simple cysts with few or no kidney cysts. Cysts are not connected to the biliary system, and PCLD is believed to be part of a clinical spectrum of ciliopathies (a heterogenous group of genetic disorders encoding defective proteins, which result in abnormal function or formation of cilia), leading to various clinical manifestations including fibrocystic diseases of the liver ( 206,207,217 ). The most common ciliopathy phenotypes are autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant PCLD. The former is a systemic disorder characterized by renal cysts leading to renal failure, with up to 60%–80% of affected patients also having hepatic cyst involvement, often diagnosed by ultrasound ( 218–220 ). Patients with ADPKD should be screened for PCLD with abdominal ultrasound. Conversely, autosomal dominant PCLD is relatively benign, often asymptomatic and with cysts restricted only to the liver ( 221,222 ). Isolated PCLD is far less common than ADPKD with a prevalence of 1–10 per million ( 219 ). However, patients with PCLD should still obtain an initial ultrasound of the kidneys to exclude ADPKD. Patients with ADPKD have a germline mutation in 1 of 2 genes ( PKD1 and PKD2 ), whereas most cases of isolated PCLD do not have a pathologic gene identified and are genetically distinct from the PCLD seen in patients with ADPKD ( 219 ). Because of this genetic heterogeneity seen in PCLD (i.e., the 6 genes identified in PCLD only account for 30%–45% of population), genetic testing is generally not recommended in this group. However, in young patients with PCLD and few renal cysts who do not meet diagnostic criteria, genetic testing might be helpful to exclude ADPKD ( 223 ). Patients with isolated PCLD do not develop the extrarenal manifestations seen in ADPKD such as intracranial aneurysms. Overall, genetic testing does not play a significant role in PCLD.

Most patients with PCLD present later in life with a larger number and size of cysts than those with ADPKD and are often asymptomatic ( 224,225 ). PCLD has a largely female predominance (>80%), increases in prevalence with age, and has an association with pregnancy and OCP use ( 224,226 ). The role of exogenous estrogen in increasing total liver volume in these patients stems from an initial prospective study of postmenopausal patients with ADPKD who were noted to have significant increase in liver volume with hormone replacement therapy compared with controls ( 227 ). In another large cross-sectional cohort study, the use of estrogen-containing OCPs in premenopausal women worsened PCLD severity, that is, led to a 15.5% higher height adjusted total liver volume for every 10 years of use, compared with those not on therapy ( 228 ). Exogenous estrogen use should be discontinued in patients with PCLD because studies have shown an increase in cyst volume in these patients ( 229,230 ). The effect of pregnancy on cyst burden in PCLD remains unclear with older studies showing an increase in cyst burden, but more recent observational studies do not ( 230 ).

In patients who have significant cyst burden, increased cyst volume can lead to palpable hepatomegaly, early satiety, abdominal discomfort, dyspnea, lower extremity edema, and significant weight loss, leading to malnutrition, frailty, and poor quality of life factors. Patients can also have complications related to cyst rupture, infection, bleeding, compression of the inferior vena cava, portal vein, or biliary tree. Liver enzymes and synthetic function are often preserved, despite heavy cyst burden except in advanced cases. The most common elevations are seen in gamma-glutamyl transferase (GGT) and alkaline phosphatase; CA 19-9 is also elevated in ∼50% of patients without evidence of malignancy ( 221 ). Rarely, patients may develop severe protein calorie malnutrition, weight loss, sarcopenia, or symptoms of portal hypertension or hepatic venous outflow obstruction because of significant cyst burden, and those who meet specific criteria can be granted exception points on the liver transplant waitlist ( 93,219,231 ) ( Table 6 ).

Imaging appearance of cysts in PCLD is similar to that of simple cysts on all imaging modalities. The difference is that there are often numerous cysts throughout the liver, which can vary in size. Imaging surveillance of the cysts is not recommended in asymptomatic patients because there is no malignant potential ( 232 ).

Primary treatment goals for PCLD are aimed at symptom relief and improvement and preservation of quality of life. Optimal management is based on cyst location, volume, size, and number. Cyst aspiration with sclerotherapy is primarily for large cysts and, although immediately effective, has a high recurrence rate. Surgical options include surgical cyst fenestration, resection, and liver transplantation. Surgical cyst fenestration also significantly reduces cyst volume and provides immediate symptom relief. However, there is a 30% recurrence rate with this procedure, and complications can include ascites, bile leak, pleural effusion, or bleeding ( 221 ). Hepatic resection is considered when fenestration is unlikely to be successful and when liver transplantation is not required. Outcomes are excellent, and laparoscopic approach is preferred when feasible ( 233 ). Data comparing the effectiveness of these options are limited ( 206 ). Treatment should be aimed at selecting the least invasive procedure that provides the most effective outcome. Liver transplantation with or without simultaneous kidney transplantation is the only curative option and has excellent long-term survival in patients with marked synthetic dysfunction, malnutrition, or significant impairment in quality of life ( 219,234 ). Patients with PCLD with severe symptoms who are currently on dialysis, have a GFR <20 mL/min, or require a kidney transplant should undergo liver transplant simultaneously with their kidney transplant and will be granted exception points on the transplant waitlist ( 93 ) ( Table 6 ).

Data on medical management of PCLD are limited and include treatment with somatostatin analogs, mammalian target of rapamycin (mTOR) inhibitors, and bile acids. Medical management should be considered in patients with PCLD with numerous small- to medium-sized cysts throughout the liver not amenable to surgical resection, cyst fenestration, or aspiration sclerotherapy or for patients with symptomatic ADPKD with concurrent PCLD. Several clinical trials and meta-analyses have confirmed the benefits of somatostatin analogs on liver cyst volume, with the biggest reductions seen within the first 6 months of treatment and lasting for up to 2–4 years ( 227,228,235,236 ). In the largest RCT assessing the role of lanreotide in decreasing cyst burden, compared with controls, the lanreotide group had a statistically significant reduction in height-adjusted liver volume (HA-LV) by almost 6% (95% CI −9.18 to −2.63; P < 0.001), and this effect still continued with an additional 3.87% reduction at 4 months after the last injection of lanreotide ( 235 ). The recommended dose of lanreotide long-acting release (LAR) in this trial was 120 mg intramuscularly every 4 weeks. Although this reduction in HA-LV may seem clinically insignificant, this correlates to approximately 140 mL of volume reduction in the lanreotide arm, and studies have shown symptom improvement with a decrease in liver volume of >100 mL ( 237,238 ).

Unfortunately, symptoms eventually recur after treatment discontinuation. Treatment is overall well tolerated with only a small percentage of patients discontinuing medications (<5%) because of intolerance or adverse events. Steatorrhea type symptoms are the most common with somatostatin analogs and are self-limited, often fading after the first few injections.

Data for mTOR inhibitors are not as favorable. Although a small pilot trial showed initial improvement in liver volume with sirolimus in patients with ADPKD, an RCT did not show any significant improvement in cyst volume with everolimus when added to long-acting octreotide ( 239,240 ). A multicenter randomized controlled trial investigating the effect of ursodiol on PCLD did not show any improvement in cyst volume in patients with isolated PCLD but did show some improvement in liver cyst volume in patients with ADPKD in post-hoc analysis ( 241 ).

• 42. Treatment goals for PCLD should be aimed at symptom relief and preservation of quality of life.
• 43. Treatment options for PCLD including cyst aspiration with sclerotherapy, surgical cyst fenestration or resection of dominant cyst(s) should be based on cyst characteristics, underlying hepatic reserve and center expertise.
• 44. Liver transplantation with or without simultaneous kidney transplantation should be considered as a curative option in patients with PCLD with refractory symptoms because of significant cyst burden.
• 15. We suggest discontinuation of exogenous estrogen use in women with PCLD. (conditional recommendation, very low level of evidence).
• 16. For patients with PCLD with numerous small- to medium-sized cysts throughout the liver not amenable to surgical resection, cyst fenestration or aspiration sclerotherapy, or for patients with symptomatic ADPKD with concurrent PCLD, we recommend medical management using somatostatin analogs. (strong recommendation, moderate level of evidence).

Mucinous cystic neoplasms of the liver

MCN-L, previously reported as biliary cystadenoma (BC) or biliary cystadenocarcinoma, are a rare but heterogeneous group of cystic tumors within the hepatic parenchyma and account for <5% of all liver cysts. In 2019 the World Health Organization (WHO) reclassified BC into MCN-L, which is defined as an epithelial cystic neoplasm lined by cuboidal, columnar, or mucin producing epithelium and can be associated with ovarian-type subepithelial stroma ( 207,242 ). These can furthermore be classified as invasive and noninvasive subtypes ( 243 ). These cysts often have septations composed of either mucinous (95%) or serous (5%) material, can be unilocular or multilocular (90%), and do not communicate with the biliary tree; some may have papillary projection that form thick septa, or they may have enhancing septa, mural calcifications, or mural nodules ( 206,207 ). Although MCN-L account for <5% of all cystic liver lesions, historically, they were associated with up to 20%–30% malignant transformation rate to adenocarcinoma ( 244–247 ); however, with the updated WHO diagnostic criteria in 2010, recent studies suggest up to 10% risk of malignant transformation ( 243 ). There is a strong female predominance (1:4) and often manifest in the fifth or sixth decade of life; they are not clearly linked to the use of OCPs.

MCN-L can be subcategorized into those that have mesenchymal tissue resembling ovarian stroma on histology and those that do not; the former being more common and seen in women, whereas the latter is seen equally between men and women and have a high rate of recurrence of malignancy with poor prognosis ( 242,248 ). Similar to other benign lesions, MCN-L are often asymptomatic and found incidentally on imaging, although larger lesions can cause mass effect leading to palpable abdominal mass, abdominal discomfort, early satiety, nausea, dyspepsia, anorexia, or weight loss ( 206,249 ). Although MCNs can be precursors to the development of biliary cystadenocarcinomas (BCAs), the rate of progression or factors that lead to progression are not clearly identified ( 247,250 ). CA 19-9 levels are elevated in 28%–73% of BCAs; however, serum or cystic fluid CA 19-9 levels do not discriminate between simple and malignant cysts or between MCNs and BCAs ( 207 ).

The treatment of MCN-L is surgical excision because of the risk of malignant potential; however, because of its rare presentation and overlap with simple hepatic cysts, MCN-L can be misdiagnosed, and thus, an understanding of specific imaging features is important to accurately diagnose this lesion ( 251,252 ). Up to 76% of MCN-Ls occur in the left hepatic lobe, with a predilection for segment IV ( 253 ). On ultrasound, MCN-L usually appears as a hypoechoic lesion with irregular, often thickened walls, internal septations, mural nodularity, and occasionally internal echoes, which represents debris ( 254,255 ). If a complex cyst is identified on ultrasound, cross-sectional imaging with CT or MRI should be obtained. In general, MRI is the preferred modality to evaluate cystic lesions. On CT or MRI, MCN-L is usually a large encapsulated multiloculated cystic lesion, often with internal septa of varying thickness ( 256,257 ). Both the presence and the location of septa are an important distinguishing feature of MCN-L vs simple hepatic cyst. The presence of septations has shown to be 95% sensitive in the diagnosis of MCN-Ls ( 256 ). Multiplicity of septations is also a distinguishing feature of MCN-L. Furthermore, septations that arise directly from the wall of the cyst (as opposed to being located in a lobulation of the cyst) showed 100% sensitivity and 56% specificity for MCN-L as opposed to a simple hepatic cyst ( 256 ). Finally, septations resulting in an indentation of the cyst wall and septations that demonstrate enhancement are more likely to represent MCN-Ls ( 253 ). Mural calcifications have a 90% specificity for MCN-L and can be seen in up to 65% of cysts ( 253 ) ( Figure 13 ).

On MRI, MCN-L are usually T2-hyperintense and T1 variable secondary to the potential of proteinaceous and less often hemorrhagic internal debris, a finding that causes the hypoechoic appearance on ultrasound ( 258 ). The presence and enhancement of septations and mural nodularity are much better characterized on MRI, and in fact a highly sensitive feature of MCN-L, nearly 100% ( 256 ). Upstream biliary ductal dilatation suggesting biliary obstruction from a cystic lesion is another feature, which is highly specific for MCN-L ( 259 ).

Imaging differential diagnosis of an MCN-L includes intraductal papillary mucinous neoplasm of the bile duct (IPNB), simple hepatic cysts, cystic metastasis, choledochal cyst, and abscesses. Differentiation between simple cyst and MCN-L was discussed above; differentiation between IPNB and MCN-L is that the latter does not demonstrate biliary communication, lacks intraductal masses, and does not demonstrate bile duct dilatation as a dominant feature ( 260,261 ).

Appropriate management is critical, given the increased risk of malignancy and recurrence without definitive treatment. Complete surgical resection, either by laparoscopic or open method, is the gold standard for all MCNs, given high rate of recurrence or progression to cystadenocarcinoma with incomplete resection ( 246,262–266 ). Other modalities including cyst aspiration, sclerosis, partial resection, or cyst fenestration are not recommended because of the high rate of recurrence, reported at 81% in some studies ( 246,267–270 ). Therefore, for patients who are not surgical candidates, surveillance imaging is recommended, although there are no established guidelines regarding specific intervals. In these patients, if surveillance imaging shows evidence suggestive of malignant degeneration, then the case should be discussed at a multidisciplinary tumor board for consideration of nonsurgical options.

• 45. Fluid aspiration or biopsy of MCN-L is not recommended to distinguish between benign vs malignant cysts because of low sensitivity.
• 46a. MCN-L with imaging characteristics consisting of thick septations, fenestrations, nodularity, calcifications, or mixed solid and cystic components require prompt evaluation for complete surgical resection.
• 46b. For patients who are not surgical candidates, surveillance imaging should be implemented, although a specific interval cannot be recommended. Changes suggestive of malignant degeneration should be discussed at a multidisciplinary tumor board for consideration for nonsurgical options.

Biliary hamartomas and peribiliary cysts

Biliary hamartomas or von Meyenburg complexes are benign malformations of the intrahepatic bile ducts and appear as multiple cystic lesions that do not communicate with the biliary tree and can appear anywhere in the liver, although frequently peripherally, and are usually smaller than 1.5 cm in size ( 271,272 ). They do not affect liver function tests, are largely found incidentally, and do not require specific surveillance. Malignant transformation to iCCA or HCC is rare and has been described as case reports in patients with underlying liver disease or in those with congenital hepatic fibrosis or Caroli disease ( 207,273–276 ).

Unlike biliary hamartomas, peribiliary cysts are frequently perihilar, small in size (<1 cm), and seen on both sides of the bile ducts as a “string of pearls” around hilar portal veins ( 272,277 ). They do not communicate with the biliary tree, are often found incidentally, and commonly seen in patients with underlying chronic liver disease and/or portal hypertension ( 272,278,279 ). IPNB is 1 of 3 preinvasive biliary lesions: biliary intraepithelial neoplasia, IPNB, and MCN-L.

Intraductal papillary neoplasm is a precursor to CCA and is analogous to intraductal papillary mucinous neoplasm of the pancreas, except located in bile ducts and has a much higher rate of malignant transformation, because 40%–80% of IPNB can harbor malignancy. Risk factors for IPNB include hepatolithiasis, clonorchiasis, primary sclerosing cholangitis, choledochal cysts, familial adenomatous polyposis, and Gardner syndrome ( 280 ). Median age at presentation is 60–66 years with a male-to-female ratio of 2:1. Symptoms include recurrent abdominal pain, cholangitis, and jaundice ( 281 ). Imaging can vary and depends on the size and morphology of the intraductal mass, degree of mucin secretion, and tumor location. There are 4 morphologic subtypes including an intraductal mass with proximal duct dilatation, diffuse ductal dilatation without a visible mass, intraductal mass with both proximal and distal dilatation, and focal aneurysmal dilatation of the duct with a cystic and solid intraductal mass ( 261 ) ( Figure 14 ). Treatment is surgical resection of the bile duct with or without associated hepatectomy depending on size, extent, and invasiveness of the lesion ( 282,283 ). Imaging surveillance is recommended even after resection because of the high rate of undetected lesions remote from the main tumor, which are a source of recurrence.

• 47. Biliary hamartomas and peribiliary cysts are benign malformations and do not require surveillance imaging.
• 48. Intraductal papillary neoplasm of the bile ducts are premalignant biliary lesions with a high risk of malignant transformation, and thus, continued surveillance imaging is recommended even after surgical resection.

Intrahepatic choledochal cysts

Choledochal cysts are rare cystic dilatations of the intrahepatic and/or extrahepatic bile ducts, more frequently seen in women (1:4 male-to-female ratio) and more common in Asian populations compared with other ethnicities ( 284–288 ). They present predominantly in the first decade of life (80%), although incidence seems to be rising in adults. They are believed to arise from the reflux of pancreatic enzymes into the biliary tree through an anomalous pancreaticobiliary junction (APBJ) ( 289 ).

They are classified according to the Todani classification system, which is based on anatomic findings and extent of biliary involvement ( 290 ) ( Figure 15 ). Type I cysts appear as cystic or fusiform dilation of the extrahepatic bile duct and are the most commonly seen choledochal cysts in both children and adults. Type II cysts are seen as extrahepatic (supraduodenal) diverticulum, whereas type III cysts present as intraduodenal diverticulum (choledochocele). Unlike the others, type III cysts lack the female predominance and rarely have risk of malignant transformation. Type IV cysts appear as both extrahepatic and intrahepatic cystic dilations (type IVA) or multiple extrahepatic dilations (IVB) and are the second most common type of choledochal cysts. Type V cysts (Caroli disease) involve only the intrahepatic bile ducts and are the least common type. It is important to distinguish Caroli disease from Caroli syndrome, which encompasses congenital liver fibrosis and kidney cysts in addition to type V biliary dilatations.

MRI with magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography, and percutaneous transhepatic cholangiography are the best imaging modalities to evaluate for this, although MRCP may offer the advantage of detecting an APBJ and does not contaminate the biliary tree with instrumentation. Key features on MRI with MRCP include abnormalities of the intrahepatic and/or extrahepatic bile ducts as mentioned above. One key feature distinguishing biliary ductal dilatation as a choledochal cyst from malignancy causing obstruction is that malignancy usually results in diffuse intrahepatic biliary ductal dilation as opposed to more focal areas of intrahepatic biliary ductal dilation ( 291 ).

The most common symptom in both children and adults is abdominal pain (60%) ( 285 ). The classic triad of abdominal pain, jaundice, and palpable abdominal mass is rarely seen. Other common symptoms include pancreatitis, nausea and vomiting, right upper-quadrant pain, infectious complications, and jaundice ( 285,292 ).

Management and treatment of choledochal cysts will be based on symptomatology, type of cyst, risk of malignancy, and extent of operation. The estimated risk of malignancy ranges from 7.5% to 30%, with low rates in young children (<1%) and increases significantly with each decade (30%–40% risk in those older than 50 years) ( 293,294 ). The most common malignancy is CCA (∼70%), followed by gallbladder cancer (23.5%) ( 294 ). Type I or IV choledochal cysts are most commonly associated with malignancy, whereas malignant transformation is extremely rare in type II or III cysts. The presence of APBJ also seems to increase the risk of malignancy ( 295 ).

Patients with type I cysts should undergo complete cyst excision with Roux-en-Y hepaticoenterostomy. Type II cysts can undergo simple cyst excision or diverticulectomy, whereas type III cysts can be managed endoscopically by unroofing (either undergo endoscopic or transduodenal sphincteroplasty) or transduodenal excision for larger cysts ( 285,296 ). Type IV cysts are managed based on extent of intrahepatic disease and can undergo extrahepatic cyst excision with or without partial hepatectomy and hepaticoenterostomy and rarely require liver transplantation ( 297,298 ). Finally, in patients with type V cysts or Caroli disease, hepatic resection or, in select cases, liver transplantation may be necessary based on the extent of disease ( 299 ). We suggest that patients with type I and IV cysts should continue to undergo surveillance even after cyst resection because of the ongoing risk of malignancy ( 285 ).

• 49a. Management and treatment of choledochal cysts is based on type of cyst and risk of malignant transformation.
• 49b. Type I or IV choledochal cysts are most commonly associated with malignancy and should undergo surveillance imaging, although a specific interval cannot be recommended.
• 50. In both type IV and V choledochal cysts, when resection is not feasible, liver transplantation should be considered.

Hydatid/echinococcal cysts

Cystic echinococcosis or hydatid cysts are caused by an endemic helminthic disease caused by Echinococcus granulosus infection. Echinococcus infection is most commonly seen in rural sheep grazing areas and has a wide geographical distribution but is typically seen in South America, Eastern Europe, Russia, Middle East, Central Asia, China, Australia, and East Africa ( 300 ). Humans serve as accidental intermediate hosts when they consume contaminated foods, water, or soil with Echinococcus eggs or eat organ meat from infected animals such as sheep or cows ( 206 ). The eggs hatch in the small intestine of the human host and releases a 6-hooked oncosphere, which penetrates the intestinal wall and migrates into the portal venous system and into various organs including the liver and lungs. The oncospheres develop into a thin-walled, unilocular, fluid-filled cyst. The cysts often grow slowly, usually over many years, and can grow up to 10–15 cm in diameter. Cysts most commonly occur in the liver (70%) or lungs (20%) and the remainder in other organs including spleen, heart, kidney, or brain ( 301 ). The cysts have an inner germinal layer surrounding a fluid-filled central hydatid cavity and an outer, acellular laminated layer. As the cyst enlarges, it forms a combination of protoscolices (future heads of adult worms) and daughter cysts; larger cysts may have over a liter of highly antigenic fluid and millions of protoscolices ( 301,302 ). They are often high pressured because of increased fluid production with a tendency to rupture after trauma or surgical manipulation ( 206 ).

Cysts are often asymptomatic given their slow growth. Larger cysts can cause abdominal discomfort and pain based on size and location including compression of bile ducts, leading to obstructive jaundice or cholangitis. Cyst rupture or leak can lead to abdominal pain, severe allergic reactions or anaphylaxis causing peritonitis, ascites, and septic shock. Management of hydatid cysts varies based on cyst characteristics (size, location, and number), clinical presentation, and center expertise ( 303 ).

Hydatid cysts can have varying imaging appearances. The WHO-Informal Working Group on Echinococcosis classification details the characteristics of the cysts for staging purposes based on ultrasound features, which helps guide treatment options ( 304–306 ) ( Table 7 ). In the initial phase of disease, hydatid cysts appear as anechoic well-defined cysts, often with small internal echogenic foci floating within the cyst on ultrasound. In this phase, CT reveals an anechoic fluid-attenuating lesion, and MRI reveals a T2 homogeneous hyperintense, T1-hypointense nonenhancing cystic lesion. As the active phase of disease continues, the imaging appearance can vary. On ultrasound, there is often a septated cyst with internal daughter cysts. On MRI, the cyst may demonstrate intermediate T1 signal if there is internal proteinaceous debris, and the walls and septations may enhance on postcontrast imaging. The “water-lily” sign is a classic imaging feature of floating internal membranes secondary to a detached endocyst ( 307 ). Finally, the inactive phase of hydatid cysts can show a densely calcified cystic lesion, with rim calcification or internal calcifications within the septations ( Figure 16 ). Although the diagnosis of hydatid cysts is based on imaging, serologic testing can be useful; however, these tests are often limited by laboratory availability and heterogeneity of the varying assays ( 308,309 ).

Medical therapy consists of chemotherapy with antihelminthic drugs, albendazole or mebendazole, with studies indicating the former as the superior agent ( 304,310 ). Medical therapy is indicated before surgery or cyst puncture to prevent risk of recurrence, secondary seeding, or to decrease cyst pressure or in inoperable cases (i.e., multiple cysts and peritoneal involvement or poor surgical candidate) ( 301,304 ). Furthermore, the risk of anaphylaxis with percutaneous drainage can be mitigated by initiating medical therapy first. The exact duration of medical treatment before and after surgical or percutaneous therapy varies according to experts. In general, it is recommended that medical therapy be started before the above procedures and continued for 1–6 months afterward. Asymptomatic, inactive, or calcified cysts can be observed with surveillance imaging, although this is not required in all cases. Medical therapy alone is not recommended unless percutaneous aspiration or surgery is contraindicated; a large systematic review showed that >40% of hydatid cysts remain active or reactivate after 2 years of medical monotherapy ( 303 ). An important change in medical therapy is that cyclical regimens are no longer recommended, given the parasitostatic activity of these drugs and overall safety data ( 306 ). It is important to remember the side effects of albendazole including hepatic dysfunction and agranulocytosis, and patients should be monitored regularly with white cell counts and liver function tests.

Percutaneous or surgical approaches are recommended for large cysts (>5 cm), cysts that are likely to rupture, cysts that have not previously responded to medical therapy, or in patients with contraindications to medical therapy (including those with liver or bone marrow disorders) ( 303 ). Puncture, aspiration, injection of scolicidal agent, and reaspiration with adjunct antihelminthic therapy is an effective alternative to surgery ( 311–314 ). However, it is contraindicated in patients with biliary fistulas or cysts communicating with the biliary tree, in patients with complex, multiseptated cysts or percutaneously inaccessible cysts. Surgical approach is with the goal of cyst removal and obliteration of the cavity and methods may vary based on cyst characteristics from simple cyst resection to radical pericystectomy ( 304,315–317 ). Hepatic resection may be warranted in some instances to remove all the hydatid disease ( 202 ). There is a lack of prospective randomized trials to compare long-term data of surgical vs medical management. It is important that the treatment of hydatid cysts occurs in centers with clinical expertise where multimodal and multidisciplinary team management including surgical and infectious disease expertise are readily available.

• 51a. Medical therapy of hydatid cysts with antihelminthic drugs is indicated before surgery or cyst puncture in patients with symptomatic or active hydatid cysts to prevent risk of recurrence, secondary seeding, or to decrease cyst pressure or in inoperable cases.
• 51b. Medical therapy alone is not recommended because of ineffective treatment unless percutaneous aspiration or surgery is contraindicated.
• 17. We suggest surgical management in patients with complicated hydatid cysts (i.e., those with biliary fistulas or cysts communicating with the biliary tree, multiseptated cysts, rupture or hemorrhage, secondary infection, or percutaneously inaccessible cysts) provided there is no contraindication to surgery (conditional recommendation, very low level of evidence).
• 18. In patients with uncomplicated hydatid cysts in whom surgery is not an option, we suggest percutaneous treatment with puncture, aspiration, injection of scolicidal agent, and reaspiration with adjunct antihelminthic therapy (conditional recommendation, low level of evidence).

CONCLUSIONS AND FUTURE DIRECTIONS

FLLs continue to be a frequent source of concern for providers and patients alike, and detection will likely continue to rise in incidence as an increasing volume of radiographic imaging studies are being performed. Many FLLs are benign, but it is important to understand indications for further workup, including multidisciplinary discussion, biopsy, and need for surveillance imaging to ensure that a malignancy is not missed. The clinical history, physical examination, underlying comorbidities, and laboratory workup are an important part of the evaluation of these patients, which, when combined with improved diagnostic imaging, can frequently lead to a diagnosis without the need for biopsy.

The application of artificial intelligence (AI) is being studied in many areas of medicine, including radiographic diagnostics. The detection and classification of FLLs have been studied with AI applications, deep learning systems, and neural networks, and early work seems promising for the ability of AI to aid in the differential diagnosis of FLL ( 318 ). However, AI cannot replace healthcare professionals, who can integrate the imaging characteristics and the patient history to make the diagnosis. Despite the radiographic results, patients will continue to rely on their providers to make the best recommendations for ongoing care, which in the ideal scenario is the reassurance that no further follow-up is required, especially in patients without underlying comorbidities.

CONFLICTS OF INTEREST

Guarantor of the article: Catherine Frenette, MD, FAST, FAASLD.

Specific author contributions: C.F., M.M.L., R.S., and A.P. contributed to the planning, literature review and analysis, guidance statement determination, writing, and final revision of the manuscript. R.J.W. and B.G.S. provided methodology expertise and reviewed the evidence for GRADE assignments.

Financial support: None to report.

Potential competing interests: C.F.: employee and stockholder of Gilead Sciences. M.M.L.: no conflicts of interest. R.S.: speakers bureau and advisory board for Eisai. R.W.: research funding (to institution) from Exact Sciences, Gilead Sciences, Theratechnologies, and Durect Corporation and speakers bureau for Gilead Sciences and advisory board for AstraZeneca. B.G.S.: consultant for Takeda Pharmaceuticals, Sanofi, and Regeneron Pharmaceuticals and is a data and safety monitoring board member for Advarra. A.P.: advisory boards for Genentech, Exelixis, Eisai, AstraZeneca, Sirtex, and Replimune. The subjects of the images and cases described in this article have provided written informed consent to publish the included information.

ACKNOWLEDGEMENTS

We thank the ACG Practice Parameters Committee, guideline monitor Simona Jakab, MD, and Claire Neumann, MA, for their help for coordination of work for this guideline. We also thank Kayli Lala for assistance with artwork for this guideline. We acknowledge Stephanie Stebens, MLIS, and Steven J. Moore, MSLIS, from the Sladen Library at Henry Ford Health for formulating the literature search.

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liver lesion; liver mass; adenoma; liver cyst; focal nodular hyperplasia; hemangioma; choledochal cysts; cystic liver lesions; cystic neoplasms

Continuing Medical Education Questions: July 2024

Inamdar, Sumant

Official journal of the American College of Gastroenterology | ACG. 119(7):1233, July 2024.

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