INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Fatty liver disease can range from fatty liver alone (steatosis) to fatty liver associated with inflammation (steatohepatitis). This condition can occur with the use of alcohol (alcohol-related fatty liver) or in the absence of alcohol (nonalcoholic fatty liver disease).

Fatty liver disease is now the most common cause for elevated liver function tests in the United States.

Fatty liver associated with the use of alcohol may occur with as little as 10 oz of alcohol ingested per week. Identical lesions also can be caused by other diseases or toxins.

If steatohepatitis is present but a history of alcohol use is not, the condition is termed nonalcoholic steatohepatitis (NASH). Fatty change in the liver results from excessive accumulation of lipids within hepatocytes. Simple fatty liver is believed to be benign, but NASH can progress to cirrhosis and can be associated with hepatocellular carcinoma. The main risk factors for simple fatty liver (NAFLD) and NASH are obesity, diabetes, and high triglyceride levels.

Pathophysiology

Fatty liver is the accumulation of triglycerides and other fats in the liver cells. In some patients, this may be accompanied by hepatic inflammation and liver cell death (steatohepatitis).

Potential pathophysiological mechanisms include the following: (1) decreased mitochondrial fatty acid beta-oxidation, (2) increased endogenous fatty acid synthesis or enhanced delivery of fatty acids to the liver, and (3) deficient incorporation or export of triglycerides as very low-density lipoprotein.

Frequency

United States

Steatosis affects approximately 25-35% of the general population. Steatohepatitis may be related to alcohol-induced hepatic damage or may be unrelated to alcohol (ie, NASH). NASH has been detected in 1.2-9% of patients undergoing routine liver biopsy. NAFLD is found in over 80% of patients who are obese. Over 50% of patients undergoing bariatric surgery have NASH.

International

Danish and Australian studies show less intense disease progression than studies in the United States.

Mortality/Morbidity

A recent natural history study from Olmsted County, Minnesota, revealed that 10% more patients with NAFLD died versus control subjects over a 10-year period. Malignancy and heart disease were the top 2 causes of death. Liver-related disease was the third cause of death (13%), as compared to the 13th cause of death (<1%) for control subjects.

• Steatosis was once believed to be a benign condition, with rare progression to chronic liver disease. Steatohepatitis may progress to liver fibrosis and cirrhosis and may result in liver-related morbidity and mortality.
• Fibrosis or cirrhosis in the liver is present in 15-50% of patients with NASH. Approximately 30% of patients with fibrosis develop cirrhosis after 10 years. Many cases of cryptogenic cirrhosis may represent so-called burnt-out NASH because a high proportion is associated with obesity, type II diabetes, or hyperlipidemia.
• Some patients with drug-induced fatty liver present dramatically with the rapid evolution of hepatic failure. Some patients with inborn errors of metabolism, such as tyrosinemia, may rapidly progress to cirrhosis.

Sex

• As many as 75% of patients in initial reported studies were females.
• In more recent studies, 50% of patients are females.

Age

• Fatty liver occurs in all age groups.
• NASH is the most common liver disease among adolescents in the United States. Older age often is predictive of more severe grading of fibrosis.
• NASH is the third most common cause of chronic liver disease in adults in the United States (after hepatitis C and alcohol). It is now probably the leading reason for mild elevations of transaminases.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Most patients with fatty liver are asymptomatic. However, if questioned, more than 50% of patients with fatty liver or NASH report persistent fatigue, malaise, or upper abdominal discomfort.
• Symptoms of liver disease, such as ascites, edema, and jaundice, may arise in patients with cirrhosis due to progressive NASH. Laboratory abnormalities during blood donations or life insurance physical examinations often reveal elevated alanine aminotransferase (ALT) levels and ultimately lead to the diagnosis of fatty liver disease.

Physical

• Hepatomegaly is common.
• Splenomegaly and stigmata of portal hypertension (eg, ascites, edema, spider angiomas, varices, gynecomastia, menstrual disorders) may occur in patients with cirrhosis.
• Patients with drug-induced fatty liver may present with rapid fulminant liver failure.
• In patients who abuse alcohol, extrahepatic effects, such as skeletal muscle wasting, cardiomyopathy, pancreatitis, or peripheral neuropathy, may be present.

Causes

The most common association with fatty liver disease is metabolic syndrome. This includes carrying the diagnosis of type II diabetes, obesity, and/or hypertriglyceridemia. Other factors, such as drugs (eg, amiodarone, tamoxifen, methotrexate), alcohol, metabolic abnormalities (eg, galactosemia, glycogen storage diseases, homocystinuria, tyrosemia), nutritional status (overnutrition, severe malnutrition, total parenteral nutrition [TPN], starvation diet), or other health problems (eg, celiac sprue, Wilson disease) may contribute to fatty liver disease. There are reports of lean NASH families.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The differential diagnosis is broad. The diagnosis of steatohepatitis requires the exclusion of many factors, including drugs, such as amiodarone, perhexiline maleate, methotrexate, corticosteroids, and estrogens. A diagnosis of NASH can be established only when alcohol excess (>10 g/d) can be excluded. Acute fatty liver can occur during pregnancy and likely results from maternal-fetal interactions related to genetic abnormalities in mitochondrial beta-oxidation of fatty acids.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No laboratory studies can help definitively establish a diagnosis of fatty liver or NASH.
• Aminotransferases
• • The only abnormality may be an elevated aspartate aminotransferase (AST) or ALT level. These levels may be elevated as much as 10-fold. However, the AST and ALT levels may be normal in some patients with fatty liver or NASH.
  • In the absence of cirrhosis, an AST-to-ALT ratio of greater than 2 suggests alcohol use, whereas a ratio of less than 1 may occur in patients with NASH.

• Alkaline phosphatase
• • This level can be elevated in some patients with NASH.
  • Usually, it is less than 2- to 3-times normal.

• Lipids
• • Hyperlipidemia may be present.
  • Increased triglycerides are common in children.

• Iron studies
• • Elevations in serum ferritin, iron, and/or decreased transferrin saturation may occur in patients with NASH.
  • Although iron overload occurs in a small proportion of patients with NASH, these patients have more severe disease. An iron index score may be ordered on a liver biopsy specimen to evaluate for phlebotomy. Hemochromatosis gene testing is recommended when the ferritin is significantly elevated.

• Viral serological markers: Before the diagnosis of NASH can be made, viral markers should be tested and viral infection excluded.
• Autoimmune markers, such as antinuclear antibody (ANA) and anti–smooth muscle antibody (ASMA), are often slightly elevated in NASH.
• • Positive antibodies are associated with more severe fibrosis levels.
  • In the appropriate clinical setting, serum protein electrophoresis (SPEP) and anti–liver-kidney antibody may lead to a diagnosis of autoimmune liver disease.

• Fasting insulin and glucose levels will alert the clinician to potential glucose intolerance and may lead to more effective therapies.

Imaging Studies

• Ultrasound
• • The liver is hyperechogenic or bright.
  • Steatosis is detected only when substantial (30% or more) fatty change is present.

• Computed tomography
• • The mean CT (Hounsfield unit) number is lower in the liver than in the spleen.
  • CT scans may be used to monitor the course of the disease on successive scans.
  • Focal fatty lesions may be identified by dual-energy CT scans that demonstrate increased attenuation with increasing energy and no change in normals.

• Magnetic resonance imaging
• • MRI may be useful for excluding fatty infiltration. Phase-contrast imaging correlates with the quantitative assessment of fatty infiltration across the entire range of liver disease.
  • Loss of intensity on T1-weighted images may be useful in identifying focal fat.

• Noninvasive studies, such as ultrasound, CT scan, and MRI, may identify the presence of a fatty liver. However, these imaging techniques cannot distinguish between benign steatosis and steatohepatitis. Benign steatosis may be focal or diffuse, whereas steatohepatitis is usually diffuse.

Procedures

• Liver biopsy
• • A liver biopsy and histopathologic examination are required to establish the diagnosis.
  • The diagnosis should be considered in all patients with unexplained elevations in serum aminotransferases (eg, with findings negative for viral markers or autoantibodies or with no history of alcohol use).

Histologic Findings

The diagnosis of fatty liver or NASH can be established only with a liver biopsy. Specific histologic findings include the following: (1) steatosis, which usually is macrovesicular but may be microvesicular or mixed; (2) inflammatory infiltrates consist of mixed neutrophilic and mononuclear cells, and portal infiltrates usually are not seen (unlike in hepatitis C); (3) ballooning degeneration; and (4) fibrosis. The first 3 findings are used to calculate the NAFLD activity score (0-8).

Staging

The stage of disease is determined by the NAFLD activity score and the amount of fibrosis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Abstinence from alcohol may reverse steatosis in patients with alcohol-related fatty liver. Weight loss and control of comorbidities appear to slow the disease and to possibly reverse some of the steatosis and fibrosis. No established treatment is available for NASH. Several empiric treatment strategies have been suggested, as outlined below.

• Dieting
  • Diets associated with improvement include those restricted in rapidly absorbed carbohydrates and those with a high protein-to-calorie ratio. Weight loss should be gradual, moderate, and controlled.
  
  
  • Exercise added to diet appears to improve results and to increase insulin sensitivity by increasing muscle mass.


• Multiple national studies are ongoing to evaluate the role of lipid-lowering agents as well as insulin sensitizers. Specifically, thiazolidinediones (eg, pioglitazone, rosiglitazone), metformin, gemfibrozil, and atorvastatin have all shown laboratory and histologic improvement in patients in small noncontrolled trials.
  • Thiazolidinediones (glitazones)
    • This class of medication results in improved insulin sensitivity and universal weight gain.
      
    
    
    • A recent randomized placebo-controlled trial evaluating pioglitazone (Actos) with diet versus diet alone has shown improvement of transaminases and steatosis. However, the fibrosis score improved only within the pioglitazone group before versus after the 6-month treatment. The differences posttreatment between the pioglitazone group and the placebo group were not statistically significant. This study is well done, with 55 patients undergoing liver biopsy before and after a treatment specifically for NASH. Larger, longer studies are expected.
      
    
    
    • Rosiglitazone (Avandia) has been studied for 48 weeks in 30 patients with NASH and resulted in biochemical as well as histologic improvement.
      
    
    
    • The US Food and Drug Administration issued an alert on May 21, 2007 to patients and health care professionals of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity. The drug is highly selective and a potent agonist for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing both blood glucose concentrations and hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large scale phase III trial (RECORD) is currently underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.
      
    
    
    • For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (the heart.org from WebMD), including the following articles: (1) Rosiglitazone increases MI and CV death in meta-analysis, (2) The rosiglitazone aftermath: Legitimate concerns or hype?, and (3) RECORD interim analysis of rosiglitazone safety: No clear-cut answers.
      
    
    
  • The published studies to date on metformin do not include histologic data but do show short-term radiologic and biochemical improvement.
    
  
  
  • Cholesterol-lowering studies
    • Atorvastatin was studied for 1 year with repeat biopsies and revealed improvement in ballooning degeneration and inflammation.
      
    
    
    • Gemfibrozil has resulted in biochemical improvement, but histologic data are lacking.


• Orlistat has shown histologic and chemical improvement in patients using the drug for several months.
  


• Vitamin E and ursodeoxycholic acid have shown improvement in specific populations.
  


• Urso has conflicting data in both adults and children. Some studies show biochemical and histologic improvement, whereas other studies show no difference when compared to placebo.

Surgical Care

• Bariatric surgery
• • Several studies are emerging that indicate that bariatric surgery with appropriate weight loss results in both chemical improvement and histologic improvement of NASH.

  • Roux-en-Y gastric bypass with repeat biopsy within 2 years has shown improvement in 100% of patients. One study showed 94% of repeat liver biopsies no longer met the pathologic criteria for NAFLD or NASH. Another study, which only rebiopsied livers of patients with NASH (not NAFLD), demonstrated that 89% no longer had NASH.
  • Early studies reporting possible worsening hepatic function after rapid weight loss have not been substantiated. This may be a viable option in the appropriate candidate.

Consultations

The only way to firmly diagnosis NASH is with a liver biopsy. Often, a clinical picture of obesity, hypertriglyceridemia, and elevated transaminases is enough to conclude that a patient has NASH. However, underlying alcohol or other drug ingestion as well as smoldering autoimmune or hemochromatosis must be ruled out. Referral to a hepatologist with or without liver biopsy may help in staging and prognosis.

Diet

• Abstinence from alcohol may reverse steatosis in patients with alcohol-related fatty liver.
• A low-fat, American Diabetes Association (ADA) diet is recommended.
• A weight loss goal of 1-2 pounds per week is recommended.

Activity

Exercise that includes both cardiovascular fitness and weight training should improve NASH. Cardiovascular fitness often results in weight loss. Weight training will increase muscle mass and improve insulin sensitivity. Both of these activities together help relieve the underlying derangements of NASH. However, no randomized trials with weight-bearing exercise have been published to date.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No proven medical therapy is available.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• All patients with chronic liver disease should be tested for hepatitis A total antibodies and vaccinated if needed. Physicians should also consider testing for hepatitis B surface antibody and vaccinating in the appropriate clinical situation (ie, life expectancy, >20 y).
• All patients with chronic liver disease are at risk of liver disease progression.
• • Patients should be educated to avoid alcohol and other hepatotoxic substances. If patients have a liver insult from another liver problem, they may have a longer recovery than a person without fatty liver disease.
  • Patients with fatty liver disease should be seen regularly by a primary care physician who may be able to detect disease progression through physical examination findings (eg, spider telangiectasia, palmar erythema, splenomegaly), laboratory findings (eg, decreasing platelets, elevated bilirubin, decreasing albumin), patient complaints (eg, encephalopathy, ascites, fatigue), or incidental imaging study findings (eg, cirrhotic liver, splenomegaly, varices, ascites).

Complications

• Steatohepatitis may progress to cirrhosis, with complications that include variceal bleeding, ascites, encephalopathy, and liver failure.
• The rate of progression appears to be worse if more than one liver disease (eg, alcoholic liver disease, chronic viral hepatitis) is present. Also, the lack of control of diabetes and hypertriglyceridemia appears to predict worse fibrosis.
• The rate of formation of hepatocellular carcinoma appears to be the same as with other forms of liver disease.

Prognosis

• Steatosis may be reversible with weight loss and/or stopping alcohol use.
• Of patients with steatohepatitis, 10% will progress to fibrosis and cirrhosis. This rate is the same as that of alcoholics progressing to cirrhosis.
  Long-term natural history studies of patients with NAFLD who undergo repeat biopsies have shown that 30% progress, 30% remain stable, and 30% improve over a 3-year period without pharmacologic intervention.
• Abnormal glucose tolerance testing is an independent risk factor for progression of NASH.

Patient Education

• For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article Cirrhosis.
• The American Diabetes Association has excellent dietary and lifestyle advice for patients who would like to lose weight and to make better lifestyle choices.
• Nutrition and lifestyle education are the mainstay of therapy. Ideally, during every health care provider encounter, the issues of food choices, food portions, and exercise, including weight-bearing exercise, should be emphasized and reviewed.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Fatty liver was once believed to be an entirely benign condition, but now this is not always true. Patient education on dietary decisions and portions is of utmost importance.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Adams LA, Angulo P, Abraham SC, et al. The effect of the metabolic syndrome, hepatic steatosis and steatohepatitis on liver fibrosis in hereditary hemochromatosis. Liver Int. Apr 2006;26(3):298-304.
• Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. Jul 2005;129(1):113-21.
• Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. Jan 2005;42(1):132-8.
• Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol. Dec 2004;99(12):2365-8.
• Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology. Oct 1994;107(4):1103-9. [Medline].
• Barker KB, Palekar NA, Bowers SP, et al. Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery. Am J Gastroenterol. Feb 2006;101(2):368-73.
• Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. Nov 30 2006;355(22):2297-307.
• Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. May 2004;53(5):750-5.
• Diehl AM. Nonalcoholic steatohepatitis. Semin Liver Dis. 1999;19(2):221-9. [Medline].
• Harrison SA, Neuschwander-Tetri BA. Pharmacologic management of nonalcoholic fatty liver disease. Clin Liver Dis. Aug 2004;8(3):715-28, xii. [Medline].
• Haukeland JW, Konopski Z, Linnestad P, et al. Abnormal glucose tolerance is a predictor of steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease. Scand J Gastroenterol. Dec 2005;40(12):1469-77.
• Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. Aug 2003;38(2):420-7.
• Jaskiewicz K, Raczynska S, Rzepko R, Sledzinski Z. Nonalcoholic fatty liver disease treated by gastroplasty. Dig Dis Sci. Jan 2006;51(1):21-6.
• Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. Jun 2005;41(6):1313-21. [Medline].
• Ong JP, Younossi ZM. Approach to the diagnosis and treatment of nonalcoholic fatty liver disease. Clin Liver Dis. Nov 2005;9(4):617-34, vi.
• Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. Jan 1990;11(1):74-80.
• Vial P, Riquelme A, Pizarro M, et al. Pentoxifylline does not prevent neither liver damage nor early profibrogenic events in a rat model of non-alcoholic steatohepatitis. Ann Hepatol. Jan-Mar 2006;5(1):25-9.

Article Last Updated: Jun 6, 2007