Non-Alcoholic Fatty Liver Disease (NAFLD)

Definitions

  • Non-Alcoholic Fatty Liver Disease (NAFLD): by definition, occurs in patients with little or no history of alcohol consumption
    • Non-Alcoholic Fatty Liver (NAFL): hepatic steatosis without significant inflammation
    • Non-Alcoholic Steatohepatitis (NASH): hepatic steatosis with inflammation (with or without concurrent hepatic fibrosis)
      • Common etiology of cryptogenic cirrrhosis
      • This inflammation may be indistinguishable from that seen in alcoholic hepatitis (see xxxx, [[Alcoholic Hepatitis]])
      • May progress to cirrhosis in 20% of patients

Epidemiology

  • Determination of Prevalence of Fatty Liver Using the Fatty Liver Index (FLI) in the US Population from National Health and Nutrition Examination Survey (NHANES) Data (2015) [MEDLINE]: prevalence of fatty liver in the U.S. population increased significantly over the last two decades
    • The US FLI included age, race-ethnicity, waist circumference, GGT activity, fasting insulin, and fasting glucose
    • Defining Fatty Liver as US FLI ≥30
      • 1988-1991: prevalence of 18%
      • 1999-2000: prevalence of 29%
      • 2011-2012: prevalence of 31%
  • Race
    • More common in hispanics than caucasians
    • Least common in blacks

Etiology of Fatty Liver (Hepatic Steatosis)

Metabolic

  • Abetaliproteinemia
  • Acute Fatty Liver of Pregnancy
  • Cholesterol Ester Storage Disease: inborn error of metabolism
  • Glycogen Storage Disease
  • LCAT Deficiency: inborn error of metabolism
  • Lipodystrophy
  • Metabolic Syndrome
  • Weber-Christian Disease
  • Wolman Disease: inborn error of metabolism

Nutritional

  • Gastric Bypass
  • Jejunal Diverticulosis with Bacterial Overgrowth
  • Jejunoileal Bypass
  • Malnutrition (see Malnutrition, [[Malnutrition]])
  • Refeeding Syndrome (see Refeeding Syndrome, [[Refeeding Syndrome]])
  • Severe Weight Loss
  • Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition, [[Total Parenteral Nutrition]]): usually macrovesicular steatosis

Drug/Toxin

  • Amiodarone (Cordarone) (see Amiodarone, [[Amiodarone]]): usually macrovesicular steatosis
  • Diltiazem (see Diltiazem, [[Diltiazem]])
  • Ethanol Abuse (see Ethanol, [[Ethanol]]): due to production of toxic aldehydes in the liver
  • Glucocorticoids (see Corticosteroids, [[Corticosteroids]]): usually macrovesicular steatosis
  • Highly Active Antiretroviral Therapy (HAART) (see xxxx, [[]])
  • Methotrexate (see Methotrexate, [[Methotrexate]]): usually macrovesicular steatosis
  • Metoprolol (Toprol) (see Metoprolol, [[Metoprolol]]): usually macrovesicular steatosis
  • Non-Steroidal Anti-Inflammatory Drugs (NSAID’s) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal Anti-Inflammatory Drug]]): usually macrovesicular steatosis
  • Phosphorous (see Phosphorous, [[Phosphorous]])
  • Tamoxifen (see Tamoxifen, [[Tamoxifen]]): usually macrovesicular steatosis
  • Tetracycline (see Tetracycline, [[Tetracycline]]): when used at high doses intravenously
  • Toxic Mushrooms (see Toxic Mushrooms, [[Toxic Mushrooms]])
  • Valproic Acid (see Valproic Acid, [[Valproic Acid]])

Other

  • Alpha-1 Antitrypsin Deficiency (see Alpha-1 Antitrypsin Deficiency, [[Alpha-1 Antitrypsin Deficiency]])
  • Cystic Fibrosis (CF) (see Cystic Fibrosis, [[Cystic Fibrosis]])
  • HELLP Syndrome (see HELLP Syndrome, [[HELLP Syndrome]])
  • Hepatitis C (see Hepatitis C Virus, [[Hepatitis C Virus]]): especially genotype 3
  • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
  • Inflammatory Bowel Disease (see xxxx, [[]]
  • Obstructive Sleep Apnea (OSA) with Nocturnal Hypoxemia (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]])
    • Epidemiology
      • Nocturnal Cumulative Time Spent <90% SaO2 is a Risk Factor for the Development of Hepatic Steatosis [MEDLINE]
    • Probable Mechanism: OSA with chronic intermittent hypoxemia results in increased lipogenesis, increased triglyceride levels, and decreased hepatic beta oxidation
  • Reye Syndrome (see Reye Syndrome, [[Reye Syndrome]])
    • Acetylsalicylic Acid (Aspirin) (see Salicylates, [[Salicylates]])
  • Wilson Disease (see Wilson Disease, [[Wilson Disease]])

Physiology

  • Unclear Mechanism of NAFLD: may involve insulin resistance and a “second hit” (such as an oxidative injury from leptin, hepatic iron, anti-oxidant deficiency, or intetsinal bacteria)

Diagnosis

  • Liver Function Tests (LFT’s)
    • Mild-moderate AST and ALT elevations (generally, 2-5x the upper limit of normal): however, the presence of normal aminotransferases do not exclude the diagnosis of NAFLD
    • AST/ALT Ratio: <1 (in contrast to alcholic fatty liver disease, where the AST/ALT ratio is typically >2)
    • Degree of aminotransferase elevation does not predict the degree of hepatic inflammation or fibrosis
  • Hyperferritinemia (see Hyperferritinemia, [[Hyperferritinemia]]): may be abnormal (although this is non-specific)
  • Abdominal CT: decreased hepatic attenuation
  • Right Upper Quadrant (RUQ) Ultrasound: increased hepatic echogenicity
  • Abdominal MRI: increased hepaic fat signal
  • Liver Biopsy: not required in most patients
    • General Indications for Liver Biopsy
      • Peripheral Stigmata of Chronic Liver Disease: suggestive of cirrhosis
      • Splenomegaly: suggestive of cirrhosis
      • Cytopenias: suggestive of cirrhosis
      • Ferritin >1.5x Upper Limit of Normal: suggestive of NASH and advanced fibrosis
      • Age >45 y/o with Associated Diabetes Mellitus or Obesity: suggests increased risk of advanced fibrosis
    • Liver biopsy findings in NASH are indistinguishable from those of alcoholic steatohepatitis

Clinical

General Comments

  • Asymptomatic: most cases
    • Many cases are diagnosed due to abnormal liver function tests or incidental detection on abdominal imaging
  • Requirements for Diagnosis of NAFLD
    • Demonstration of Hepaic Steatosis by Imaging or Biopsy
    • Exclusion of Significant Ethanol Consumption
    • Exclusion of Other Etiologies of Hepatic Steatosis

Endocrinologic Manifestations

  • Features of Metabolic Syndrome: present in cases where Metabolic Syndrome is etiologic

Gastrointestinal Manifestations

  • Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]]): variable
    • It has been suggested that hepatomegaly is more common in those with advanced fibrosis
  • Vague Right Upper Quadrant (RUQ) Pain (see Abdominal Pain, [[Abdominal Pain]]): may be seen in some NASH cases

Neurologic Manifestations

  • Fatigue: may be seen in some NASH cases
  • Malaise: may be seen in some NASH cases

Pulmonary Manifestations

  • Increased Risk of Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]]) [MEDLINE]: even in the absence of obesity

Treatment

  • xxxx
  • xxxx
  • xxxx

References

  • Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis. Obes Surg 2013;23(11): 1815-1825 [MEDLINE]

  • Nonalcoholic fatty liver disease, nocturnal hypoxia, and endothelial function in patients with sleep apnea. Chest 2014;145(3):525-533 [MEDLINE]

  • Risk of obstructive sleep apnea with daytime sleepiness is associated with liver damage in non-morbidly obese patients with nonalcoholic fatty liver disease. PLoS One 2014;9(4):e96349 [MEDLINE]

  • Fatty liver indices in the multiethnic United States National Health and Nutrition Examination Survey. Aliment Pharmacol Ther. 2015 Jan;41(1):65-76. Epub 2014 Nov 6 [MEDLINE]