para>Male gender
Hypothyroidism, hypopituitarism, sleep apnea, and polycystic ovary syndrome
Procedures leading to rapid weight loss (small bowel resections, gastric bypass, and jejunal bypass) may increase risk of NAFLD.
Medications: corticosteroids, synthetic estrogens, amiodarone, tamoxifen, methotrexate
Other conditions: Wilson disease, hemochromatosis, abetalipoproteinemia, galactosemia, glycogen storage diseases
General Prevention
- Maintain ideal weight, normal lipoprotein, and serum glucose profiles.
- Avoid alcohol.
- Avoid hepatotoxic substances.
Commonly Associated Conditions
Obesity, type 2 diabetes mellitus, hypertension, hypertriglyceridemia
Diagnosis
History
- Most patients with NAFLD are asymptomatic.
- In symptomatic patients, malaise, fatigue, nausea, and right upper quadrant discomfort are most common.
- Review medical history for comorbid conditions associated with insulin resistance or metabolic syndrome.
- Diagnosis of NAFLD requires no recent or ongoing history of significant alcohol consumption (>21 drinks per week in men, >14 drinks per week in women) (2)[C].
Physical Exam
- Hepatomegaly is the most common physical finding in subjects with NAFLD and is present in 75% of patients with NASH.
- Few patients present with peripheral stigmata of chronic liver disease or portal hypertension (palmar erythema, caput medusa, telangiectasias, Dupuytren contracture).
Differential Diagnosis
Viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, hemochromatosis, Wilson disease, a1-antitrypsin deficiency
Diagnostic Tests & Interpretation
Initial Tests (lab, imaging)
- Liver enzyme tests
NAFLD is associated with AST and ALT values under 250 IU/L and/or modest elevation of alkaline phosphatase (4).
ALT or AST value >300 IU/L should raise suspicion of alternate pathology (toxins, medications, or infection) (4).
AST:ALT ratio <1 suggests NAFLD, whereas AST:ALT ratio >2 suggests alcoholic liver disease. Values between 1 and 2 may be present with either alcoholic liver disease or NASH with advanced fibrosis (4).
- Serum albumin, prothrombin, and bilirubin levels are usually normal.
- Mildly elevated serum ferritin is common (nonspecific inflammatory marker) and does not necessarily indicate increased iron stores.
- Sonographic features of NAFLD are nonspecific and include increased hepatic parenchymal echotexture and vascular blurring (PPV 62%) (2).
- Hepatic steatosis can be diagnosed with CT imaging (decreased hepatic parenchymal attenuation relative to the spleen, PPV 76%) or MRI. Noninvasive imaging cannot distinguish between fatty liver and steatohepatitis, and the stage of fibrosis cannot be determined unless features of portal hypertension are present (4).
- The NAFLD fibrosis score (http://nafldscore.com) is based on 6 variables (age, body mass index [BMI], hyperglycemia, platelet count, albumin, AST:ALT ratio) and is clinically useful for identifying patients with bridging fibrosis and/or cirrhosis (2)[B].
Follow-Up Tests & Special Considerations
- Exclude coexisting etiologies for liver disease: viral hepatitis, hemochromatosis, autoimmune liver disease, and Wilson disease.
Diagnostic Procedures/Other
- Liver biopsy is the gold standard for characterizing liver histology in patients with suspected NAFLD.
- Consider biopsy in patients with NAFLD who are at increased risk of steatohepatitis and advanced fibrosis or in whom competing etiologies for hepatic steatosis and coexisting chronic liver disease cannot otherwise be excluded (2)[B].
Test Interpretation
- Histologic diagnosis of NASH is based on a composite pattern of injury rather than a single defining feature.
- The NAFLD Activity Score (NAS) is based on the presence/severity of the following histologic features:
- Most patients with NASH have an NAS of 5 or greater, whereas NAS of 2 or less is usually not associated with a diagnosis of NASH (5)[B].
Treatment
Treatment entails the following: 1) maximizing control of associated comorbidities, 2) avoiding factors that promote progression of liver disease, and 3) specific treatment for NASH.
General Measures
- Weight loss of at least 3 " 5% of body weight improves steatosis. Greater weight loss (up to 10%) appears necessary to improve necroinflammation (2)[B].
- Avoid alcohol and hepatotoxic substances.
Medication
No firmly established evidence-based treatment exists for NASH.
First Line
- Intensive lifestyle changes leading to weight loss consistently show the most benefit.
- Vitamin E administered at daily doses of 800 IU/day improves liver histology in nondiabetic adults with biopsy-proven NASH and should be considered as 1st therapy (2)[B].
- Vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrosis, or cryptogenic cirrhosis (2)[C].
- HMG CoA reductase inhibitors (statins) can be used to treat dyslipidemia in patients with NAFLD and NASH but should not be used specifically to treat NASH (2)[B].
Second Line
- Pharmacologic treatment of obesity may be considered in those with a BMI >30 kg/m2 or a BMI >27 kg/m2 with associated obesity-related comorbidities (4).
- Pioglitazone can be used to treat steatohepatitis in patients with biopsy-proven NASH, but the long-term safety and efficacy of pioglitazone in patients with NASH is not established, and most patients in this trial were nondiabetic (2)[B].
- The use of metformin and ursodeoxycholic acid are not recommended for treatment of NAFLD/NASH (2)[A,B].
Pediatric Considerations
- NAFLD has been reported in children as early as 2 years of age and NASH-related cirrhosis as early as age 8 years (2).
- Screening for NAFLD in overweight and obese children is controversial. A recent expert committee recommends biannual screening with liver enzyme measurements in overweight children (2)[B].
- Children with fatty liver who are very young or who are not overweight should be tested for other causes of liver disease, such as fatty acid oxidation defects, lysosomal storage diseases, peroxisomal disorders, hepatitis, Wilson disease, and autoimmune diseases (2)[C].
- Liver biopsy in children with suspected NAFLD should be performed when the diagnosis is unclear, where there is possibility of multiple diagnoses, or before starting therapy with potentially hepatotoxic medications (2)[B].
- 1st-line treatment for children with NAFLD is weight loss and lifestyle modifications (2)[B].
Issues for Referral
Referral to a hepatologist with/without liver biopsy helps with staging and prognosis.
Surgery/Other Procedures
- The lack of randomized clinical trials precludes assessment of the benefits and harms of bariatric surgery as a therapeutic approach for patients with NASH (6)[A].
- Although abdominal weight loss surgery coupled with rapid weight loss has been implicated as contributing to development of NASH, it is not contraindicated in otherwise eligible obese patients (2)[A].
Complementary & Alternative Medicine
- Probiotic therapies can reduce liver aminotransferases, total cholesterol, and TNF-α and improve insulin resistance in NAFLD patients (7)[A].
- Omega-3 fatty acids may be used to treat hypertriglyceridemia in patients with NAFLD (2,8)[B].
Ongoing Care
Follow-up Recommendations
- All patients should be tested for hepatitis A and B and vaccinated, if appropriate.
- Patients with NASH cirrhosis should be considered for hepatocellular carcinoma screening according to the AASLD/ACG practice guidelines (http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf) (2)[B].
- Current evidence does not support routinely repeat liver biopsies in patients with NAFLD or NASH (2)[C].
Patient Monitoring
Patients with fatty liver disease should be seen regularly to detect disease progression through the following:
- Patient complaints (encephalopathy, ascites, fatigue)
- Physical exam findings (spider telangiectasia, palmar erythema, splenomegaly)
- Laboratory findings (changes in liver enzyme tests, decreasing platelets, elevated bilirubin, decreasing albumin)
- Incidental imaging study findings (cirrhotic liver, splenomegaly, varices, ascites)
Diet
Restrictions of total calories, simple carbohydrates, and alcohol are required to control diabetes, weight, and lipids.
Patient Education
Ongoing follow-up and motivational interviewing to assess lifelong changes in diet, exercise, and alcohol use
Prognosis
- 25 " 35% of NASH patients develop fibrosis, whereas 9 " 20% develop cirrhosis (3).
- Patients with NAFLD have greater all-cause mortality. The most common causes of death are cardiovascular disease, malignancy, and hepatic failure.
Complications
- Steatohepatitis may progress to cirrhosis, with complications including variceal bleeding, ascites, encephalopathy, liver failure, and development of hepatocellular carcinoma.
References
1.Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274 " 285. [View Abstract]2.Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005 " 2023. [View Abstract]3.Schneider AL, Lazo M, Selvin E, et al. Racial differences in nonalcoholic fatty liver disease in the U.S. population. Obesity (Silver Spring). 2014;22(1):292 " 299. [View Abstract]4.Ramesh S, Sanyal AJ. Evaluation and management of non-alcoholic steatohepatitis. J Hepatol. 2005;42(Suppl 1):S2 " S12. [View Abstract]5.Bondini S, Kleiner DE, Goodman ZD, et al. Pathologic assessment of non-alcoholic fatty liver disease. Clin Liver Dis. 2007;11(1):17 " 23, vii. [View Abstract]6.Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database of Syst Rev. 2010;(1):CD007340. [View Abstract]7.Ma YY, Li L, Yu CH, et al. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol. 2013;19(40):6911 " 6918. [View Abstract]8.Dasarathy S, Dasarathy J, Khiyami A, et al. Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis. J Clin Gastroenterol. 2015;49(2):137 " 144. [View Abstract]
Codes
ICD10
- K75.81 Nonalcoholic steatohepatitis (NASH)
- K76.0 Fatty (change of) liver, not elsewhere classified
ICD09
- 571.8 Other chronic nonalcoholic liver disease
SNOMED
- 442685003 nonalcoholic steatohepatitis (disorder)
- 197315008 Non-alcoholic fatty liver (disorder)
Clinical Pearls
- Prevalence of NAFLD and NASH is higher in patients with metabolic syndrome or any one of its components (diabetes, obesity, hypertriglyceridemia).
- Liver biopsy is the gold standard for diagnosis.
- Lifestyle changes to treat components of the metabolic syndrome are central to the treatment of NAFLD.
- Vitamin E should be considered as 1st-line therapy in nondiabetic patients with biopsy-proven NASH.
- Statins should be considered in patients who have NAFLD with dyslipidemia