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

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

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
- Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
- Hyperlipidemia (see Hyperlipidemia, [[Hyperlipidemia]])
- Hypertension (see Hypertension, [[Hypertension]])
- Obesity
Weber-Christian Disease
Wolman Disease: inborn error of metabolism

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

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]])

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]])

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)

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

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

Features of Metabolic Syndrome: present in cases where Metabolic Syndrome is etiologic
- Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
- Hyperlipidemia (see Hyperlipidemia, [[Hyperlipidemia]])
- Hypertension (see Hypertension, [[Hypertension]])
- Obesity

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

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

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]