Basics
Description
Spectrum of liver diseases characterized by the accumulation of large fat droplets in hepatocytes (macrovesicular steatosis) in the absence of excessive amount of alcohol consumption
- Most patients are asymptomatic.
- Only patients with abnormal liver function tests (LFTs) during routine testing or findings of hepatomegaly come to medical attention.
- Other causes of liver disease, such as viral hepatitis, alcohol abuse, autoimmune hepatitis, and genetic diseases, must be excluded.
- Nonalcoholic fatty liver disease (NAFLD)
- Spectrum includes simple steatosis, NASH, and cryptogenic cirrhosis with fatty liver.
- Fat in the liver >5 " 10% by weight
- Compatible imaging studies and biopsy
- Nonalcoholic steatohepatitis (NASH)
- Subset of NAFLD at risk for progression to cirrhosis
- Histological findings include: Steatosis, hepatocyte ballooning degeneration, acute and chronic inflammation, and pericellular fibrosis (steatohepatitis)
- Cryptogenic cirrhosis is most commonly caused by nonalcoholic fatty liver.
- Natural history of the disease is still controversial.
- The progression from steatosis without inflammation to steatohepatitis is debated.
- NASH may progress to cirrhosis, although timing and percent of those who progress has not been established.
Epidemiology
Prevalence parallels obesity epidemic.
- NAFLD is the most common cause of chronic liver disease affecting 20 " 46% of the general population in industrialized Western countries.
- Common in 4th " 6th decade
- Occurs in 2.6% of all children and 22 " 52% of children that are obese.
- Most prevalent in Hispanic Americans follow by whites. Least prevalent in African Americans.
Incidence
Unknown
Prevalence
- Prevalence of NAFLD in the US is 15 " 46%.
- Majority of patients with NAFLD have simple steatosis and do not progress to advanced liver disease.
- It is estimated that 10 " 25% of those with NAFLD have NASH.
Risk Factors
- Obesity
- Diabetes mellitus
- Hyperlipidemia
- Hypertension
- Note: NAFLD can also occur in nonobese patients.
Genetics
- Family clusters have been described.
- Presence of hemochromatosis gene mutations may accelerate the disease process.
General Prevention
Metabolic syndrome is an important predisposing factor. Prevention includes weight control, diet, and exercise.
Pathophysiology
Not fully understood. Proposed mechanisms:
- NAFLD: Insulin resistance leads to increased free fatty acids circulating in the blood stream ultimately overwhelming the liver 's ability to metabolize them causing fat accumulation in the liver.
- NASH: A "second hit " occurs due to oxidative stress (i.e., metabolic syndrome, endotoxins) which causes inflammatory cytokines to promote liver damage and fibrosis deposition.
Etiology
- Metabolic syndrome plays a major role.
- Metabolic syndrome is an inflammatory condition modulating proinflammatory cytokines.
- Fat tissueespecially truncalis metabolically activesecreting some of the key cytokines and neuroendocrine mediators involved in the pathogenesis of NAFLD: Tumor necrosis factor-alpha adiponectin, leptin.
- The role of each cytokine in the process is the subject of intense investigation.
Associated Conditions
- Obesity
- Metabolic syndrome
- Diabetes mellitus
- Hyperlipidemia
- Hypertension
- Lipodystrophy
Diagnosis
Diagnostic goals:
- Establish diagnosis of NAFLD
- Differentiate simple fatty liver from NASH with or without cirrhosis
History
- Inquire about alcohol consumption (>40 mg/alcohol per day) and confirm history with family members.
- Toxin exposure
- Medications and recreational drugs
- Concomitant illness: Diabetes mellitus, insulin resistance, hyperlipidemia, hypertension
- History of gastric bypass resulting in rapid weight loss
- Signs and symptoms:
- Vague right upper quadrant pain, fatigue, malaise
Physical Exam
- Obesity, hepatomegaly
- With cirrhosis
- Splenomegaly, spider angiomata, palmar erythema, ascites, jaundice
Tests
Lab
- NAFLD
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2 " 4 times normal, alkaline phosphatase and gamma glutamyl transpeptidase (GGT) 2 " 3 times normal, ferritin elevated
- Fasting glucose, random glucose, hemoglobin A1c to assess for insulin resistance and diabetes mellitus
- Fasting lipid profile
- NAFLD with cirrhosis
- Evidence of decreased liver synthetic function (i.e., hypoalbuminemia, elevated INR)
- Thrombocytopenia due to splenomegaly from portal hypertension
- Hyperbilirubinemia due to hepatic dysfunction
- Exclude other causes of liver disease.
- Iron studies (ferritin, transferring saturation) +/ " genetic test for hemochromatosis, autoimmune markers: Antinuclear (ANA), antimitochondrial Ab (AMA), antismoothmuscle Ab (ASMA), anti-liver/kidney/microsomal Ab (anti-LKM), ceruloplasmin, alpha-1 antitrypsin, viral serologies for Hepatitis B, C
Imaging
Liver ultrasound and CT scan may be helpful in diagnosis of NAFLD.
- Ultrasound sensitive and specific for diagnosis of fatty deposition in the liver.
- Imaging technique cannot discriminate between steatosis and NASH.
Surgery
Liver biopsy is the gold standard and has the best prognostic value.
- Differentiates simple steatosis from NASH and NASH with cirrhosis
- The need for liver biopsy is controversial.
- It has associated morbidity and mortality.
- There are limited specific therapeutic options regardless of the biopsy results.
- Excluding other potential causes and careful monitoring for disease progression are advocated by many.
- Aggressive therapy with novel agents should be done only for selected group of patients with established histological diagnosis of NASH.
Pathological Findings
- NAFLD
- Macrovesicular steatosis
- Diffuse or centrilobular
- NASH
- Parenchymal inflammation, pleomorphic, lipogranulomas
- Ballooning hepatocytes degeneration
- Hepatocyte necrosis
- Mallory bodies
- Perivenular, perisinusoidal, or periportal fibrosis
- NAFLD with cirrhosis
- Fibrous septa, bridging fibrosis
- Decreased steatosis
Differential Diagnosis
- Secondary fatty liver disease
- Alcoholic liver disease
- Wilson disease
- Hepatitis C
- Starvation
- Surgical procedures
- Gastroduodenal bypass, biliopancreatic diversion, extensive small bowel surgical resection
- Parenteral nutrition
- Drugs
- Amiodarone, methotrexate, corticosteroid, estrogen in high dose
- Genetic diseases
- Sphingolipidosis, abetalipoproteinemia, tyrosinemia
- Exclude all other causes of abnormal LFTs especially if liver biopsy is not obtained.
Treatment
Focus on risk factor modification to treat underlying metabolic syndrome (i.e., obesity, diabetes mellitus, hypertension, and hyperlipidemia)
- Diet/weight loss
- The value of caloric or specific food group restriction has not been evaluated.
- Current common practice is to advise a low-fat, low simple carbohydrate diet.
- Achieving significant weight loss with dietary modification alone is difficult.
- Weight loss and increased physical activity has been shown to improve serum aminotransferases, histology, decrease insulin resistance, and improve quality of life in patients with NASH (1)[A].
- Hypoglycemic agents
- Metformin: Randomized trials demonstrate improvement in biochemical profile but no clear improvement in histology.
- Thiazolidinedione drugs (i.e., pioglitazone and rosiglitazone) (2)[B]
- Improve insulin resistance
- Decrease plasma lipids
- Possess anti-inflammatory and immunomodulatory properties
- Improve histology in some human studies
- Statin therapy
- Liver disease does not worsen with concurrent statin use.
- Several small studies have demonstrated improved biological and histological parameters in patients with hyperlipidemia and NAFLD (3)[B].
Additional Treatment
General Measures
- Correction of known underlying risk factors: Obesity, hyperlipidemia, glucose intolerance
- Avoidance of hepatotoxic drugs and substances (i.e., alcohol)
- The aim is to increase insulin sensitivity, decrease truncal body fat tissue, and improve lipid profile.
- Vaccinate again hepatitis A and B
Issues for Referral
Refer to hepatologist for diagnosis and treatment of NAFLD
- Refer to transplant center for evaluation of patient with decompensated liver disease (i.e., cirrhosis, jaundice, ascites, hepatic encephalopathy)
- Refer to endocrinologist for treatment of metabolic syndrome, diabetes mellitus
- Refer obese patients to weight loss center
Complementary and Alternative Medicine
Vitamin E was evaluated in various liver diseases.
- Rationale: Antioxidant effect decreases oxidative stress on the liver in patients with NASH.
- In some studies shown to decrease serum aminotransferases, histological features (i.e., steatosis, lobular inflammation), and fibrosis (4)[B].
Surgery
- Bariatric surgery can be considered for morbid obesity (BMI ≥40 or ≥35 with comorbidities).
- Contraindications: High portal pressure, intra-abdominal or esophageal varices, ascites, decompensated liver disease
- Liver transplant for end-stage, decompensated liver disease
In-Patient Considerations
Admission Criteria
Decompensated liver disease may require hospitalization.
Discharge Criteria
When stabilization is achieved
Ongoing Care
Follow-Up Recommendations
- No end point of therapy has been established.
- Lifestyle modifications should be lifelong.
Patient Monitoring
Monitor patients at intervals for:
- Disease progression
- Evaluate fat content with ultrasound and if indicated with liver biopsy
- Alpha-fetoprotein and liver ultrasound every 6 months to monitor for hepatocellular carcinoma (HCC) in cirrhotic patients
- Imaging and noninvasive measures to monitor therapy results
Patient Education
Exercise " Small studies have confirmed a beneficial role of exercise in the therapy of NAFLD. Benefits include: Weight loss, increase in insulin sensitivity, modulation of inflammatory cytokines.
Prognosis
The risk of progression of NAFLD is variable. Predictors of fibrosis in NAFLD:
- Older age (>50 years), obesity, diabetes mellitus, insulin resistance, hypertension
- AST/ALT >1, triglyceride >1.7 mmol/L, ALT >2 times upper limit of normal
- Necroinflammation and iron deposition in liver biopsy
Complications
Cirrhosis and HCC
References
1Promrat K, Kleiner DE, Niemeier HM. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121 " 129. [View Abstract]2Belfort R, Harrison SA, Brown K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297 " 2307. [View Abstract]3Hyogo H, Tazuma S, Arihiro K. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dysplipidemia. Metabolism. 2008;57:1711 " 1718. [View Abstract]4Sanyal A, Chalasani N, Kowdley KV. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675 " 1685. [View Abstract]
Additional Reading
1Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology. 2006;43(2 Suppl 1):S99 " S112. [View Abstract]
Codes
ICD9
571.8 Other chronic nonalcoholic liver disease
ICD10
K76.0 Fatty (change of) liver, not elsewhere classified
SNOMED
197315008 non-alcoholic fatty liver (disorder)
Clinical Pearls
- Spectrum of diseases with common histological features and presumed etiology: Simple nonalcoholic fatty liver (steatosis), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver with cryptogenic cirrhosis
- NASH carries significant potential to progress to cirrhosis.
- Most common cause of abnormal liver function tests in the US.
- Nonalcoholic fatty liver disease (NAFLD) represents the hepatic component of metabolic syndrome. Suspect in patients with obesity and insulin resistance.
- Current therapeutic measures focus on risk factors: Obesity, diabetes, and hyperlipidemia