Nonalcoholic Fatty Liver Disease (Clinical)

Definition

Fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy has alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) or nonalcoholic subtypes.

Nonalcoholic fatty liver Nonalcoholic fatty liver Fatty liver finding without excessive alcohol consumption. Nonalcoholic Fatty Liver Disease disease (NAFLD):^[1,3,5,7]

• Chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease characterized by liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy pathology of steatosis Steatosis Nonalcoholic Fatty Liver Disease (triglyceride accumulation within hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy), with or without inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
• No history of increased alcohol intake (defined as  > 1 drink/day for women, or > 2 drinks/day in men)
• NAFLD types:
  • Nonalcoholic fatty liver Nonalcoholic fatty liver Fatty liver finding without excessive alcohol consumption. Nonalcoholic Fatty Liver Disease (NAFL): hepatic steatosis Steatosis Nonalcoholic Fatty Liver Disease (> 5% of hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy) without inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Nonalcoholic steatohepatitis Nonalcoholic Steatohepatitis Nonalcoholic Fatty Liver Disease (NASH): 
    • Features: hepatic steatosis Steatosis Nonalcoholic Fatty Liver Disease with lobular inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and ballooned hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy
    • Pathology similar to alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) steatohepatitis Steatohepatitis Drug-Induced Liver Injury but patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship do not have significant alcohol consumption

Epidemiology and Risk Factors

Epidemiology^[1,3,4,7]

• NAFLD is the most common cause of chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease in the United States.
• Affects about 25% of adults 
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship diagnosed mostly in their 40s and 50s
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency highest in Hispanic Americans (50%), due to a higher prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
• When cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis develops, incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy cancer is up to 3%.

Risk factors^[1,3,4,7,8]

• Metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome
• Central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
• Type 2 diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus ( DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus)
• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
• Hypertriglyceridemia Hypertriglyceridemia A condition of elevated levels of triglycerides in the blood. Lipid Disorders
• Rapid weight loss Weight loss Decrease in existing body weight. Bariatric Surgery or gain
• Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
• Polycystic ovarian syndrome Polycystic ovarian syndrome Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome
• Endocrinopathies (e.g., Cushing syndrome Cushing syndrome A condition caused by prolonged exposure to excess levels of cortisol (hydrocortisone) or other glucocorticoids from endogenous or exogenous sources. It is characterized by upper body obesity; osteoporosis; hypertension; diabetes mellitus; hirsutism; amenorrhea; and excess body fluid. Endogenous Cushing syndrome or spontaneous hypercortisolism is divided into two groups, those due to an excess of adrenocorticotropin and those that are acth-independent. Paraneoplastic Syndromes)

Pathophysiology

Pathophysiology of NAFLD^[1,3,6]

1. Risk factors (↑ insulin resistance Insulin resistance Diminished effectiveness of insulin in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent hyperglycemia or ketosis. Diabetes Mellitus, DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, sedentary lifestyle) contribute to lipid accumulation:
   • Increased supply of fat (from high-fat diet and adipose lipolysis Lipolysis The metabolic process of breaking down lipids to release free fatty acids, the major oxidative fuel for the body. Lipolysis may involve dietary lipids in the digestive tract, circulating lipids in the blood, and stored lipids in the adipose tissue or the liver. A number of enzymes are involved in such lipid hydrolysis, such as lipase and lipoprotein lipase from various tissues. Nonalcoholic Fatty Liver Disease)
   • Decreased fat export (↓ very-low-density lipoprotein Very-low-density lipoprotein A class of lipoproteins of very light (0. 93-1. 006 g/ml) large size (30-80 nm) particles with a core composed mainly of triglycerides and a surface monolayer of phospholipids and cholesterol into which are imbedded the apolipoproteins B, E, and C. VLDL facilitates the transport of endogenously made triglycerides to extrahepatic tissues. As triglycerides and apo C are removed, VLDL is converted to intermediate-density lipoproteins, then to low-density lipoproteins from which cholesterol is delivered to the extrahepatic tissues. Cholesterol Metabolism secretion Secretion Coagulation Studies)
   • Decreased free fatty acid ( FFA FFA Macular Degeneration) beta-oxidation
   • Increased de novo lipogenesis Lipogenesis De novo fat synthesis in the body. This includes the synthetic processes of fatty acids and subsequent triglycerides in the liver and the adipose tissue. Lipogenesis is regulated by numerous factors, including nutritional, hormonal, and genetic elements. Nonalcoholic Fatty Liver Disease
2. The processes lead to ↑ triglyceride synthesis Synthesis Polymerase Chain Reaction (PCR) and ↑ hepatic uptake of fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance.
3. Accumulating FFAs and byproducts (e.g., reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Nonalcoholic Fatty Liver Disease) damage hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy by oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death → lipotoxicity Lipotoxicity Nonalcoholic Fatty Liver Disease (cellular injury and death resulting from lipid intermediates) 
4. Injured and dying cells induce immune responses (inflammatory cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response and cells) to repair and replace hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy.

Nonalcoholic fatty liver Nonalcoholic fatty liver Fatty liver finding without excessive alcohol consumption. Nonalcoholic Fatty Liver Disease^[1,5,6]

• Fat accumulation (usually macrovesicular hepatosteatosis)
• Large fat droplet and/or smaller fat droplets Droplets Varicella-Zoster Virus/Chickenpox in the hepatocyte cytoplasm, pushing the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles to the periphery and bloating Bloating Constipation the cells
• Reversible condition

Nonalcoholic steatohepatitis Nonalcoholic Steatohepatitis Nonalcoholic Fatty Liver Disease^[1,5,6]

• Morphologic manifestation of lipotoxicity Lipotoxicity Nonalcoholic Fatty Liver Disease 
• Ballooning Ballooning Varicella-Zoster Virus/Chickenpox hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation ( wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing response to the hepatocellular injury)
• With intervention, NASH is reversible, but as repairs depend on extent of damage, outcomes vary.

Potential outcomes^[1,4,5]

If progression is not reversed, NAFL can lead to NASH. With further liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy damage, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy carcinoma (both irreversible) become potential outcomes:

• Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis: Ineffective healing and repair produce fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans with nodular regeneration Regeneration The physiological renewal, repair, or replacement of tissue. Wound Healing and scarring Scarring Inflammation.
• Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases ( HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases): Repair and regenerative process produce malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology.

Clinical Presentation

Symptoms^[1,7,11]

• Often asymptomatic
• Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, malaise Malaise Tick-borne Encephalitis Virus
• Right upper quadrant Right upper quadrant Anterior Abdominal Wall: Anatomy (RUQ) discomfort

Signs^[1,7,11]

• Incidental finding of abnormal liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests or hepatic steatosis Steatosis Nonalcoholic Fatty Liver Disease on ultrasound
• Hepatomegaly
• Disease progression to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis presents with spider angiomata Spider Angiomata Portal Hypertension, palmar erythema Palmar Erythema Cirrhosis, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, and ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites.

Diagnosis

The diagnostic steps for NAFLD/NASH may vary depending on testing availability and practice setting. The following information is based primarily on US and UK recommendations for adults. See your local guidelines for additional guidance.

History and clinical findings^{[7,8,10–12]} 

When incidental liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy findings are noted (e.g., ↑ transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis, steatosis Steatosis Nonalcoholic Fatty Liver Disease on imaging or biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma), NAFLD should be considered if the following are noted during the patient evaluation:

• Presence of risk factors (e.g., diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, dyslipidemia)
• No significant alcohol consumption:
  • Significant alcohol consumption is defined as:
    • Men: > 21 standard drinks per week (on average)
    • Women: > 14 standard drinks per week (on average)
• No coexisting chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease
• No potentially causative medications (list is not exhaustive):
  • Amiodarone Amiodarone An antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance. Pulmonary Fibrosis
  • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
  • Doxycycline
  • Antiretroviral drugs
  • Valproate Valproate A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs
  • Tamoxifen Tamoxifen One of the selective estrogen receptor modulators with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the endometrium. Antiestrogens
  • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy
• No other recognized causes of hepatic steatosis Steatosis Nonalcoholic Fatty Liver Disease

Laboratory testing^{[1,7,8,10,11,17]}

While LFT abnormalities are often found incidentally, other laboratory tests are also important in the assessment of risk factors and to rule out other diagnoses.

• General studies may reveal ↑ aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids aminotransferase ( AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests), alanine Alanine A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system. Synthesis of Nonessential Amino Acids aminotransferase ( ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests):
  • Chronic elevation (> 6 months) should raise suspicion.
  • AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests: ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests ratio is often < 1 (compared to alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) hepatitis, where AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests > ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests).
  • Note: Normal levels do not exclude NAFLD.
• Evaluate risk factors:
  • HbA_1c
  • Serum glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
  • Serum triglyceride and cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism levels
• Perform additional testing to rule out other causes of chronic hepatitis and chronic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease:
  • Viral hepatitis → hepatitis screen
  • Wilson disease Wilson disease Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder caused by various mutations in the ATP7B gene, which regulates copper transport within hepatocytes. Dysfunction of this transport mechanism leads to abnormal copper accumulations in the liver, brain, eyes, and other organs, with consequent major and variably expressed hepatic, neurologic, and psychiatric disturbances. Wilson Disease:
    • Ceruloplasmin Ceruloplasmin A multi-copper blood ferroxidase involved in iron and copper homeostasis and inflammation. Wilson Disease level
    • 24-hour urine copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements
  • Autoimmune liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease:
    • Antinuclear antibody
    • Antimitochondrial antibody
    • Anti–smooth muscle antibody
    • Anti–liver-kidney microsomal-1 antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions
    • Quantitative immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions
  • Hemochromatosis Hemochromatosis A disorder of iron metabolism characterized by a triad of hemosiderosis; liver cirrhosis; and diabetes mellitus. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. Hereditary Hemochromatosis:
    • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements
    • Ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis
    • Transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism saturation
    • Total iron-binding capacity
  • Alpha-1 antitrypsin Alpha-1 antitrypsin Plasma glycoprotein member of the serpin superfamily which inhibits trypsin; neutrophil elastase; and other proteolytic enzymes. Alpha-1 Antitrypsin (AAT) Deficiency deficiency → alpha-1 antitrypsin Alpha-1 antitrypsin Plasma glycoprotein member of the serpin superfamily which inhibits trypsin; neutrophil elastase; and other proteolytic enzymes. Alpha-1 Antitrypsin (AAT) Deficiency level

Imaging^[7,10,12]

Imaging studies cannot be used to make the diagnosis but will often show characteristics of steatosis Steatosis Nonalcoholic Fatty Liver Disease.

• Ultrasonography (US):
  • Often used as a screening Screening Preoperative Care tool
  • May be ordered to assess ↑ LFTs or during the workup of another condition
  • Not able to differentiate NAFLD from NASH
  • May show echogenic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy texture Texture Dermatologic Examination (due to fatty infiltration)
• CT or MRI may also demonstrate steatosis Steatosis Nonalcoholic Fatty Liver Disease but cannot reliably differentiate NAFLD from NASH.

Fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans risk assessment Risk assessment The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. Preoperative Care^{[7–9,12,13,27]}

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with NAFLD should undergo risk stratification for fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans with the fibrosis-4 index (FIB-4), which can help guide the next steps. Cutoff values vary depending on the guideline; however, in general terms, it can categorize patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship as:

• Low risk:
  • Management per primary care physician and/or endocrinologist
  • Obesity management Obesity management An integrated professional approach to screening, evaluation, control, and reduction of abnormal weight gain. Obesity and cardiovascular disease (CVD) prevention
  • Consider reassessing FIB-4 in 1–2 years^[7,13]
• Indeterminate risk:
  • A secondary noninvasive test should be ordered.
  • If risk is still indeterminate, refer to hepatologist for possible liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.
• High risk:
  • Refer to hepatologist for further workup.
  • Multidisciplinary team approach to prevent cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis and CVD

Secondary noninvasive testing^[7,10,17]

• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy stiffness measurement (LSM):
  • Advanced imaging-based technique assessing liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy stiffness to determine severity of fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
  • Vibration-controlled transient elastography (VCTE):
    • Measures speed of mechanically generated shear wave across the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
    • Typically ultrasound-based method
  • Other options exist, including magnetic resonance elastography (MRE).
• Enhanced liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans test (ELF):
  • Blood test
  • Measures several markers of hepatic extracellular matrix Extracellular matrix A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. Hypertrophic and Keloid Scars
  • Estimates rate of extracellular matrix Extracellular matrix A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. Hypertrophic and Keloid Scars metabolism → reflects severity of fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans

Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma^[1,7,8,10]

• Best diagnostic test but rarely performed
• Done if diagnosis is unclear
• Distinguishes NAFLD from NASH, and detects cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis (which increases risk of hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases)

Diagnosis and next steps algorithm^[7,13]

Management

Follow local institutional protocols, when available. The following information is based on US and UK recommendations. In cases of advanced fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans, guidance should be sought from a hepatologist.

Patient education^{[1,7,8,10–13,17]}

All patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with NAFLD and NASH should be counseled on weight loss Weight loss Decrease in existing body weight. Bariatric Surgery and physical activity:

• Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery (best therapy):
  • Gradual weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, average of 0.5–1 kg/week (rapid weight loss Weight loss Decrease in existing body weight. Bariatric Surgery can worsen liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease)
  • Goals:^[12]
    • Steatosis Steatosis Nonalcoholic Fatty Liver Disease: 3%–5% body weight reduction
    • NASH: 7%–10% body weight reduction to improve histopathologic features
  • Usually results in improved AST AST Enzymes of the transferase class that catalyze the conversion of l-aspartate and 2-ketoglutarate to oxaloacetate and l-glutamate. Liver Function Tests and ALT ALT An enzyme that catalyzes the conversion of l-alanine and 2-oxoglutarate to pyruvate and l-glutamate. Liver Function Tests levels
  • Improved metabolic parameters
• Create an energy deficit: reduce saturated fat, starch, and added sugar
• Moderate exercise:
  • Performed in combination with weight loss Weight loss Decrease in existing body weight. Bariatric Surgery 
  • Aerobic exercise 30–60 min/day (3–5 days/wk)
  • Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing training 20–30 min/day (2–3 days/wk)

Management of comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus

Because of the increased risk of cardiovascular morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status and mortality Mortality All deaths reported in a given population. Measures of Health Status in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with NAFLD/NASH, comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus should be aggressively managed.^[12]

Dyslipidemia:^[7,8,12]

• 1st-line: statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
  • Not contraindicated in NAFLD/NASH!
  • Avoid in decompensated cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
• 2nd-line (if not at goal LDL-C):
  • Ezetimibe Ezetimibe An azetidine derivative and anticholesteremic agent that inhibits intestinal sterol absorption. It is used to reduce total cholesterol; ldl cholesterol, and apolipoproteins B in the treatment of hyperlipidemias. Lipid Control Drugs
  • PCSK9 inhibitors PCSK9 inhibitors Lipid Control Drugs
  • Bempedoic acid Bempedoic Acid Lipid Control Drugs
  • Inclisiran
• Hypertriglyceridemia Hypertriglyceridemia A condition of elevated levels of triglycerides in the blood. Lipid Disorders:
  • Fibrates Fibrates Lipid Control Drugs
  • Omega-3 fatty acids Omega-3 fatty acids A group of unsaturated fatty acids occurring mainly in fish oils, with three double bonds at particular positions in the hydrocarbon chain. Lipid Control Drugs
  • Icosapent ethyl
  • Optimize glycemic control

Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension:^[7,8]

• 1st-line: ACE inhibitors ACE inhibitors Truncus Arteriosus or ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication
• 2nd-line:
  • Beta blockers
  • Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers
  • Thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication

Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus:^{[7,8,10,12,13,17]}

• Preferred medications based on comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus:
  • CVD:
    • Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia–glucose-linked transporter-2 inhibitors (SGLT2i) 
    • Glucagon-like peptide-1 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors agonists ( GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas RA)
  • Chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease ( CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease) and heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) (HF): SGLT2i
  • NASH:
    • Pioglitazone Pioglitazone A thiazolidinedione and ppar gamma agonist that is used in the treatment of type 2 diabetes mellitus. Non-insulinotropic Diabetes Drugs
    • GLP-1 GLP-1 A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake. Insulinomas RA 
• Note: Metformin Metformin A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Non-insulinotropic Diabetes Drugs, sulfonylureas Sulfonylureas Sulfonamides and Trimethoprim, dipeptidyl peptidase-4 Dipeptidyl peptidase-4 A serine protease that catalyses the release of an n-terminal dipeptide. Several biologically-active peptides have been identified as dipeptidyl peptidase 4 substrates including incretins; neuropeptides; and chemokines. The protein is also found bound to adenosine deaminase on the t-cell surface and is believed to play a role in t-cell activation. Angioedema inhibitors, acarbose Acarbose Non-insulinotropic Diabetes Drugs, and insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin may be continued but have limited benefit on liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy histology in NAFLD.

Additionally:^{[7,8,10,12,13,17]}

• Refer for bariatric surgery Bariatric surgery Bariatric surgery refers to a group of invasive procedures used to surgically reduce the size of the stomach to produce early satiety, decrease food intake (restrictive type) and/or alter digestion, and artificially induce malabsorption of nutrients (malabsorptive type). The ultimate goal of bariatric surgery is drastic weight loss. Bariatric Surgery in those with appropriate clinical indications.
• Use of vitamin E Vitamin E A generic descriptor for all tocopherols and tocotrienols that exhibit alpha-tocopherol activity. By virtue of the phenolic hydrogen on the 2h-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of isoprenoids. Fat-soluble Vitamins and their Deficiencies in NASH may benefit nondiabetic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship but should be avoided in those with prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. cancer (↑ risk).
• Spirulina maxima has been reported in some preliminary studies as being beneficial:^[16]
  • A cyanobacterium (a type of blue-green algae Algae Cell Types: Eukaryotic versus Prokaryotic) 
  • Uused as a food supplement because of its high content of:
    • Proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis with essential amino acids Essential amino acids Amino acids that are not synthesized by the human body in amounts sufficient to carry out physiological functions. They are obtained from dietary foodstuffs. Basics of Amino Acids
    • Carotenoids Carotenoids The general name for a group of fat-soluble pigments found in green, yellow, and leafy vegetables, and yellow fruits. They are aliphatic hydrocarbons containing 4 terpene subunits. Leukoplakia
    • B-vitamin complex
    • Minerals Minerals Electrolytes
    • γ-linolenic, ω-3, and ω-6 fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance.

Monitoring and prevention^[7,8,10,17]

• Each clinic visit:
  • Advise against heavy alcohol consumption.
  • Alcohol use should be discouraged in those with advanced fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis.
  • Advise against smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases (risk factor for hepatic fibrosis Hepatic fibrosis Autosomal Recessive Polycystic Kidney Disease (ARPKD) and HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases).
• Consider laboratory monitoring every 6 months:^[11]
  • Aminotransferases
  • CBC
  • Coagulation studies Coagulation studies Coagulation studies are a group of hematologic laboratory studies that reflect the function of blood vessels, platelets, and coagulation factors, which all interact with one another to achieve hemostasis. Coagulation studies are usually ordered to evaluate patients with bleeding or hypercoagulation disorders. Coagulation Studies
• Vaccinations:
  • Annual influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination
  • Pneumococcal vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination every 5 years
  • Hepatitis A Hepatitis A Hepatitis A is caused by the hepatitis A virus (HAV), a nonenveloped virus of the Picornaviridae family with single-stranded RNA. HAV causes an acute, highly contagious hepatitis with unspecific prodromal symptoms such as fever and malaise followed by jaundice and elevated liver transaminases. Hepatitis A Virus and B vaccinations
• Consider screening Screening Preoperative Care for HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with advanced fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans (every 6 months)
• Biopsy-proven NASH:
  • Monitor fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans (interval may depend on clinical picture and risk)
  • Options include noninvasive testing, such as VCTE.

Differential Diagnosis

• Viral hepatitis: infection from a virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology causing acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease. Presents with jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever with hepatomegaly, and the transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids elevation is often greater than in NAFLD. Further differentiation can be established by detecting viral antigens and antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions in the serum. Treatment is based on cause, and for certain types can be prevented by vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination. 
• Autoimmune hepatitis Autoimmune hepatitis Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Autoimmune Hepatitis: acute liver failure Liver failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis that presents with fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hepatomegaly, and RUQ tenderness. Drug-induced hepatitis must be ruled out using history and laboratory evaluation. Presence of the anti-smooth muscle antibody Anti-Smooth Muscle Antibody Autoimmune Hepatitis is a strong indicator Indicator Methods for assessing flow through a system by injection of a known quantity of an indicator, such as a dye, radionuclide, or chilled liquid, into the system and monitoring its concentration over time at a specific point in the system. Body Fluid Compartments of autoimmune hepatitis Autoimmune hepatitis Autoimmune hepatitis (AIH) is a rare form of chronic liver disease in which the immune system attacks the liver causing inflammation. It predominantly affects women. Clinical presentation ranges from asymptomatic cases to patients that present with symptoms of acute liver failure (jaundice, right upper quadrant pain). Autoimmune Hepatitis. Treatment is with immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants. 
• Alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease: liver failure Liver failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis associated with chronic significant alcohol consumption. Presents with similar laboratory results (elevation in transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis) and pathologic finding of steatohepatitis Steatohepatitis Drug-Induced Liver Injury. Characteristic history ( alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder) typically helps differentiate alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease from NAFLD. Treatment is alcohol cessation. 
• Other causes of hepatitis (drug-induced): presents after ingestion of a hepatotoxic drug with jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hepatomegaly, and RUQ discomfort. Injury can be hepatocellular (elevated transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis) and/or cholestatic (elevated alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma). Treatment is removal of the offending drug.