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Nonalcoholic Fatty Liver Disease

Nonalcoholic 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 disease is a spectrum 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 pathology that arises due to accumulation of triglycerides Triglycerides Fatty Acids and Lipids in hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy. Risk factors include diabetes mellitus Diabetes mellitus 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, 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 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, 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, and 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, among others. Nonalcoholic 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 disease ranges from 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 or hepatic steatosis Hepatic Steatosis Imaging of the Liver and Biliary Tract but can lead to nonalcoholic steatohepatitis Steatohepatitis Drug-induced Liver Injury (NASH), which features fatty deposits 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. Progressive 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 injury and fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans irreversibly develop into 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, possibly, primary 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. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are usually asymptomatic but may present with hepatomegaly and right upper quadrant Right upper quadrant Anterior Abdominal Wall: Anatomy discomfort. Although 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 is the diagnostic gold standard, the diagnosis can also be established by clinical history, imaging, and laboratory tests. The mainstay of management is lifestyle modifications ( weight loss Weight loss Decrease in existing body weight. Bariatric Surgery and exercise) with control of associated 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.

Last updated: 13 Apr, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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 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 (NAFLD):

  • 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 (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 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 (NAFL): hepatic steatosis Hepatic Steatosis Imaging of the Liver and Biliary Tract (> 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 Steatohepatitis Drug-induced Liver Injury (NASH): 

Epidemiology and Etiology

Epidemiology

  • 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 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%)
  • 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%.

Etiology

  • Risk factors:
    • 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 Type 2 Spinal Muscular Atrophy diabetes mellitus Diabetes mellitus 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 ( 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’s syndrome)
  • Medications: 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

Pathophysiology

Pathophysiology of NAFLD

  1. Risk factors (↑ 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 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, 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)
    • 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
  2. The processes lead to ↑ triglyceride synthesis Synthesis Polymerase Chain Reaction (PCR) and ↑ hepatic uptake of fatty acids Fatty acids Organic, monobasic acids derived from hydrocarbons by the equivalent of oxidation of a methyl group to an alcohol, aldehyde, and then acid. Fatty acids are saturated and unsaturated. Fatty Acids and Lipids.
  3. Accumulating FFAs and byproducts (e.g., reactive oxygen species) 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 (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 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

  • Fat accumulation (usually macrovesicular hepatosteatosis)
  • Large fat droplet 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 Steatohepatitis Drug-induced Liver Injury

  • Morphologic manifestation of lipotoxicity 
  • 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

If progression is not reversed, NAFL leads 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 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.
Progression of liver disease

Progression 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 disease due to steatosis:
1: Healthy hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy: no 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
2: Bloated 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 steatosis (distended by fat droplets Droplets Varicella-Zoster Virus/Chickenpox), no 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: NAFL/steatosis (still reversible)
3: Inflamed and dying 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 possible fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans: nonalcoholic steatohepatitis Steatohepatitis Drug-induced Liver Injury (still reversible)
4: Dead cells: 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 (irreversible 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)

Image by Lecturio.

Clinical Presentation

Symptoms

Signs

  • 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 Hepatic Steatosis Imaging of the Liver and Biliary Tract 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

  • History and clinical findings: 
  • 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:
    • Best diagnostic test but rarely performed
    • Done if diagnosis is unclear
    • Distinguishes NAFL 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)
  • Ultrasound (US): 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)
  • Laboratory tests:
    • 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) but may be normal
    • Often with abnormal 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 level
    • ↑ Serum triglyceride/ 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
  • Tests to rule out other causes of chronic hepatitis:
    • Alcoholic liver disease Alcoholic Liver Disease Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Alcoholic Liver Disease
    • Viral hepatitis
    • Wilson’s disease
    • 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
    • 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

Management

General considerations to reduce 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

  • Avoid heavy alcohol intake and smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases.
  • Update immunizations (for 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), including standard recommendations.

Monitoring of NAFLD

  • Monitor 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 (worsening and/or change in clinical status warrant further evaluation).
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma-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
    • Options include serum fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans markers and vibration Vibration A continuing periodic change in displacement with respect to a fixed reference. Neurological Examination-controlled transient elastography (VCTE) (measures fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans based 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 stiffness).
  • NAFLD- 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: Screen 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.

Management of NAFLD

  • No specific pharmacologic therapies for NAFLD
  • Lifestyle changes for reduction of 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:
    • 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)
    • Aim to lose at least 5%–10% of body weight.
    • Moderate exercise
  • Control of co-morbidities (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, dyslipidemia)
  • 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 avoid 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. Prostate, Seminal, and Bulbourethral Glands: Anatomy cancer (↑ risk).
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with end-stage 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: Consider liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases.

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 liver disease Alcoholic Liver Disease Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Alcoholic Liver 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 abuse) typically helps differentiate alcoholic liver disease Alcoholic Liver Disease Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to cirrhosis secondary to chronic alcohol abuse. Excessive and prolonged consumption of alcohol results in impairment of the lipolysis pathway, causing inflammatory changes within the hepatocytes. Patients typically present during the hepatitis stage with jaundice, fever, and abdominal pain. Alcoholic Liver 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.

References

  1. Abdelmalek M.F., & Diehl, A. (2018). Nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis. Jameson J, & Fauci A.S., & Kasper D.L., & Hauser, S.L., & Longo, D.L., & Loscalzo, J.(Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. 
  2. Chopra, S. Lai, M. (2020) Management of nonalcoholic fatty liver disease in adults. UpToDate. Retrieved 10 Nov 2020, from https://www.uptodate.com/contents/management-of-nonalcoholic-fatty-liver-disease-in-adults
  3. Friedman L.S. (2021). Nonalcoholic fatty liver disease. Papadakis M.A., & McPhee S.J., & Rabow M.W.(Eds.), Current Medical Diagnosis & Treatment 2021. McGraw-Hill.
  4. Sheth, S. (2020). Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults. UpToDate. Chopra, S, Lindor, K and Robson, K. (Eds). Retrieved 12 Nov, 2020, from https://www.uptodate.com/contents/epidemiology-clinical-features-and-diagnosis-of-nonalcoholic-fatty-liver-disease-in-adults?search=Fatty%20Liver%20Disease&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H3
  5. Takahashi, Y.,Fukusato, T. (2014) Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 20(42): 15539–15548.
  6. Tendler, D. (2020) Pathogenesis of nonalcoholic fatty liver disease.  Lindor, K., Robson, K. (Eds.) Uptodate. Retrieved 10 Nov, 2020, from https://www.uptodate.com/contents/pathogenesis-of-nonalcoholic-fatty-liver-disease

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