Complications and Comorbidities> Gastrointestinal>

DEFINITION

• Nonalcoholic fatty liver disease (NAFLD): fatty infiltration of the liver, exceeding 5% of liver weight. In biopsy specimens, >5-10% macrosteatotic hepatocytes.
• By definition, requires exclusion of alcohol as a potential cause. Acceptable levels of alcohol consumption are controversial but in general <20 grams/day (2 drinks) in men and <10 grams/day (1 drink) in women are considered safe, and below the cutoff associated with increased risk of cirrhosis (30 grams/day in men and 20 grams/day in women).
• Primary NAFLD: common term for typical NAFLD associated with central obesity and/or type 2 diabetes (T2DM) or insulin resistance (IR), without another specific etiology.
• Secondary NAFLD: used to defined as NAFLD in the absence of insulin resistance and associated with other causes such as: medication use (glucocorticoids, tamoxifen, amiodarone, HAART, diltiazem), disorders of lipid metabolism (abetalipoproteinemia, lipodystrophy, Weber-Christian syndrome, Andersen's disease), total parenteral nutrition and jejunoileal bypass surgery. Many cases of "secondary" NAFLD likely represent an exacerbation of often unrecognized "primary" NAFLD.
• Nonalcoholic steatohepatitis (NASH) is the more severe form of NAFLD characterized by inflammation, ballooned hepatocytes, and/or fibrosis on biopsy. NAFLD can progress to cirrhosis.

EPIDEMIOLOGY

• NAFLD considered the most common chronic liver disease in the United States (Clark) and probably worldwide.
• In the general population, prevalence of  NAFLD based on liver enzymes or imaging (ultrasound or MRI) ranges from 3-30% (Lazo; Argo)
• Among people with T2DM, prevalence of  NAFLD is 50-80%. (Lazo)
• Adults with T2DM are at much higher risk for cirrhosis compared to the general population, possibly due to NAFLD. (Clark; Caldwell)
• Non-Hispanic whites and Hispanics at higher risk.
• Predictors of more severe disease: age >40-50 years; female sex; severe obesity; hypertension; diabetes; hypertriglyceridemia; elevated ALT, AST, GGT; AST: ALT ratio >1.

DIAGNOSIS

• All spectrums of disease can be seen even with normal liver test levels.
• The American Gastroenterological Association (AGA) Medical Position Statement recommends a progressive diagnostic approach. Step (1): Serum liver tests: AST, ALT, alkaline phosphatase, serum bilirubin, albumin levels and prothrombin time; Step (2): Evaluate for coexisting treatable conditions (hepatitis C, autoantibodies); Step (3): A alcohol consumption evaluation by interviewing the patient and family members. If AST or ALT are abnormal, ongoing alcohol consumption <20-30 grams/day (2-3 drinks) and other causes of liver disease excluded, then Step (4): Perform imaging (ultrasonography, CT scan or MRI)
• Currently, no imaging method distinguishes between fatty liver, steatohepatitis and fibrosis but can help exclude biliary tract or focal liver diseases.
• To detect the presence of liver fat, sonography is more sensitive than CT scan, less expensive and has no radiation risk. MRI primarily used in research settings to quantify the amount of fat in the liver.
• Transient elastography: based on ultrasound technology measures tissue elasticity and correlates well with liver stiffness in patients with viral hepatitis. Not validated in NAFLD patients who tend to be overweight or obese.
• Gold standard for diagnosis is liver biopsy, staging (extent of injury) and grading (degree of activity) of NAFLD. NAFLD activity score (NAS) ranging from 0 to 8 is a composite score based on findings of steatosis, inflammation and hepatocyte injury. Fibrosis scored separately, ranging from 0 to 4: 0-2=minimal, 3-4=bridging fibrosis and cirrhosis. A higher NAS indicates greater damage. Designed for use in clinical trials of NASH.
• Limitations of liver biopsy: patient inconvenience, potential for complications and sampling error.
• Non-invasive markers of fibrosis: proprietary fibrosis scores (Fibrospect, Hepascore, and Fibroscore) based on a combination of biochemical serum assays and routine lab tests and can reliably identify those with either minimal or advanced disease , however a substantial gray zone precluding accurate fibrosis diagnosis and staging. Currently, none have been FDA approved and their utility in NAFLD remains uncertain.
• Many patients have elevated cholesterol and triglycerides.

SIGNS AND SYMPTOMS

• Most common: asymptomatic (48-100%), fatigue (70%), right upper quadrant pain (up to 50%)
• Palmar erythema and spider angiomas in cirrhosis
• Clinical findings associated with metabolic syndrome commonly seen
• Hepatomegaly, acanthosis nigricans in children
• Lipoatrophy/lipodystrophy

CLINICAL TREATMENT

• Diet and exercise are the cornerstones of therapy. Weight loss of 5-7% effectively improves steatosis and other histological features of NAFLD and reduces risk of progression. (Harrison, Promrat)
• Avoid rapid weight loss, which can cause histological exacerbation.
• Exercise only without weight loss: Recent evidence suggests it may help. Encourage increased physical activity level even in the absence of weight loss.
• Diet composition: The effects of specific diets on NAFLD are not known. Recommend a balanced diet such as that endorsed by the American Diabetes Association or American Heart Association.

• Thiazolidinediones: Pioglitazone and to a lesser extent Rosiglitazone significantly improve histological outcomes (Sanyal; Ratziu) and because of other benefits in the treatment of T2DM, can be considered drugs of choice for NAFLD in those with T2DM.
• Biguanides: Metformin usually used only in research settings. Pilot data have shown mixed results.
• Antioxidants: Pilot data suggest improvement with Vitamin E (Sanyal). 
• Cytoprotective agents: Large RCT of ursodeoxycholic acid showed no histologic benefit.

• Glycemic control: ideally A1c <7%.
• Alcohol use: limited especially if more severe disease.
• Concomitant use of medications that may promote steatohepatitis (e.g. amiodarone, tamoxifen) requires weighing risk and benefits.
• Avoid workplace exposure to hepatotoxic substances (e.g. hydrocarbon solvents).
• Patient education / immunization to prevent viral hepatitis.

FOLLOW UP

• No conclusive recommendations for disease surveillance.
• Most commonly used endpoints: histological, liver test (enzymes) and metabolic parameters.
• Other less commonly used endpoints: serologic fibrosis markers, imaging techniques.
• Referral to a gastrointestinal specialist may be indicated for consideration of a liver biopsy and/or experimental therapies.

EXPERT COMMENTS

• Patients with T2DM have higher risk of liver-related morbidity and mortality
• Biopsy is the gold standard method to diagnose, stage and grade NAFLD; however, it is not usually performed in the initial evaluation.
• Laboratory tests to rule out other potential causes of liver disease are the most common initial approach.
• Lifestyle changes remain a cornerstone of initial management.
• Currently, no FDA-approved medication therapy although thiazolidinediones may be preferred in patients with both NAFLD and T2DM.

Basis for Recommendations

• Sanyal AJ, American Gastroenterological Association; AGA technical review on nonalcoholic fatty liver disease.; Gastroenterology; 2002; Vol. 123; pp. 1705-25;
  ISSN: 0016-5085;
  PUBMED: 12404245
  Rating: Basis for recommendation
  Comments:Most comprehensive and recent official review of Nonalcoholic Fatty Liver Disease.
  
  

REFERENCES