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Guidelines for Nonalcoholic Fatty Liver Disease Issued CME/CE

News Author: Laurie Barclay, MD
CME Author: Penny Murata, MD

Faculty and Disclosures

CME/CE Released: 08/03/2012; Valid for credit through 08/03/2013

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Clinical Context

Nonalcoholic fatty liver disease (NAFLD) is defined by evidence of hepatic steatosis on imaging or histology tests and absence of causes for secondary hepatic fat accumulation. NAFLD is most commonly linked with metabolic risk factors, including obesity, diabetes mellitus, and dyslipidemia. NAFLD can be histologically classified as nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH).

NAFL is defined as hepatic steatosis with no hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as hepatic steatosis and inflammation with hepatocyte injury with or without fibrosis. The risk for progression to cirrhosis and liver failure is higher with NASH and is minimal with NAFL.

This practice guideline from the American Association for the Study of Liver Diseases, the American College of Gastroenterology, and the American Gastroenterological Association presents recommendations for the diagnosis and management of NAFLD, based on literature review from a MEDLINE search up to June 2011, the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines, guideline policies of the 3 societies, and consensus opinion of the authors and independent reviewers.

Study Synopsis and Perspective

Suitable interventions in some patients with NAFLD may include weight loss, vitamin E, and/or pioglitazone, according to a new practice guideline. The American Association for the Study of Liver Diseases, American College of Gastroenterology, and American Gastroenterological Association issued the new recommendations for NAFLD diagnosis and management, which are published in the June issue of Hepatology.

“The definition of [NAFLD] requires that (a) there is evidence of hepatic steatosis, either by imaging or by histology and (b) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication or hereditary disorders,” write Naga Chalasani, MD, FACG, from the Indiana University School of Medicine in Indianapolis, and colleagues. “In the majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. NAFLD is histologically further categorized into …NAFL and …NASH.”

Highlights of the recommendations in adults include the following:

• Weight loss generally reduces hepatic steatosis, but up to 10% weight loss may be needed to improve necroinflammation.
• Patients with NAFLD should not consume heavy amounts of alcohol.
• Vitamin E (a-tocopherol), 800 IU/day, improves liver histology in nondiabetic adults with biopsy-proven NASH. It should therefore be considered as a first-line pharmacotherapy for this patient population, but not in other patients, pending further evidence supporting its efficacy.
• Omega-3 fatty acids may be considered as first-line therapy for hypertriglyceridemia in patients with NAFLD, but it is premature to recommend them for the specific treatment of NAFLD or NASH.
• Metformin is not recommended as a specific treatment for liver disease in adults with NASH.
• Pioglitazone may be used to treat steatohepatitis in patients with biopsy-proven NASH, but long-term safety and efficacy have not been established.
• Foregut bariatric surgery is not contraindicated in otherwise eligible obese individuals with NAFLD or NASH but without established cirrhosis. However, it is premature to consider foregut bariatric surgery as an established option to specifically treat NASH.
• Statins can be used to treat dyslipidemia in patients with NAFLD and NASH, but they should not be used to specifically treat NASH, pending evidence from randomized controlled trials.
• Clinicians should look for metabolic risk factors and alternate etiologies for hepatic steatosis in patients who have other types of chronic liver disease and who also have steatosis and steatohepatitis.
• Patients with NASH cirrhosis should be screened for gastroesophageal varices and should be considered for hepatocellular carcinoma screening according to the American Association for the Study of Liver Diseases and American College of Gastroenterology practice guidelines.
• Because of uncertainties surrounding diagnostic tests, treatment options, long-term benefits, and cost-effectiveness, screening for NAFLD is not advised among adults attending primary care clinics or high-risk groups attending diabetes or obesity clinics.
• Systematic screening of family members of patients with NAFLD is currently not recommended.
• Competing etiologies for steatosis and coexisting common chronic liver disease must be excluded in patients with suspected NAFLD.
• Persistently high serum ferritin and increased iron saturation may warrant a liver biopsy, especially in patients with homozygous or heterozygous C282Y HFE (hemochromatosis) gene mutations.
• Patients with high serum titers of autoantibodies and other features suggesting autoimmune liver disease (eg, very high aminotransferases or high globulin levels) should undergo a more thorough work-up for autoimmune liver disease.
• Metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD and can therefore be used to target patients for a liver biopsy.
• The NAFLD Fibrosis Score helps to identify patients with NAFLD who have a higher likelihood of having bridging fibrosis and/or cirrhosis.
• Liver biopsy should be considered in patients with suspected NAFLD in whom competing etiologies for hepatic steatosis and coexisting chronic liver diseases cannot be otherwise excluded.

This clinical practice guideline also provides recommendations for the management and treatment of NAFLD in children.

Some of the guideline authors and reviewers report various financial relationships involving Gilead, Genentech, Mochida, Amylin, Eli Lilly, Ikaria, Intercept, Cumberland Pharmaceuticals, J & J, Merck, GlaxoSmithKline, Karo Bio, Salix, Advanced Life Sciences, Bristol-Myers Squibb, Teva Pharmaceuticals, Abbott, Biolex, sanofi-aventis, Vertex, Tibotec, Norgine, Celgene, Pfizer, Geneva Foundation, Daichi-Sankyo, Roche, Quark Pharmaceuticals, Synageva BioPharma, Raptor Pharmaceuticals, Takeda, Astella, Exhalenz, Immuron, Schering-Plough, and/or Rottapharm.

Hepatology. 2012;55:2005-2023. Full text

Study Highlights

• Alcohol intake can be defined as more than 21 drinks for men and more than 14 drinks for women per week when suspected NAFLD is assessed.
• For hepatic steatosis incidentally detected on imaging, asymptomatic patients with normal liver biochemistry results can be assessed for metabolic risk factors or other causes. However, liver biopsy is not recommended. Symptomatic patients should be assessed for NAFLD.
• Screening for NAFLD in adults in primary care clinics, obesity or diabetes clinics, or in family members of patients with NAFLD is not recommended.
• Initial evaluation of NAFLD includes the exclusion of other causes for steatosis and coexisting chronic liver disease, liver biopsy for persistently high levels of serum ferritin and iron saturation, and workup for autoimmune liver disease if high serum titers of autoantibodies or other features.
• Noninvasive assessment for steatohepatitis and fibrosis in NAFLD includes the presence of metabolic syndrome and the NAFLD Fibrosis Score. Serum/plasma cytokeratin-18 is a promising marker but is not yet routinely recommended.
• Liver biopsy should be considered in those with NAFLD at increased risks for steatohepatitis and advanced fibrosis and in those with suspected NAFLD in whom liver biopsy is needed to exclude competing causes for hepatic steatosis and coexisting chronic liver disease.
• A subsequent liver biopsy for NAFL or NASH is not needed.
• Treatment of improving liver disease is indicated for those with NASH.
• Lifestyle interventions of weight loss of at least 3% to 5% can reduce steatosis. Weight loss of up to 10% can reduce necroinflammation, and exercise alone can reduce steatosis.
• Metformin has no effect on liver histologic features.
• Pioglitazone can be used to treat steatohepatitis in nondiabetic patients with biopsy-proven NASH, but the efficacy in nondiabetic patients and long-term effects are not known.
• Vitamin E (α-tocopherol) 800 IU/day is first-line pharmacotherapy for nondiabetic adults with biopsy-proven NASH but is not recommended for diabetic patients with NASH, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.
• Ursodeoxycholic acid is not recommended for NAFLD or NASH.
• Omega-3 fatty acids can be first-line treatment of hypertriglyceridemia.
• Foregut bariatric surgery is not contraindicated in otherwise eligible obese patients with NAFLD or NASH, but guidelines are not established for those with cirrhosis.
• Patients with NAFLD should not consume heavy amounts of alcohol.
• Statins can be used for dyslipidemia in patients with NAFLD and NASH.
• Patients with other types of chronic liver disease and steatosis and steatohepatitis should be assessed for other causes and metabolic risk factors.
• In patients with other types of chronic liver disease and coexisting NASH and NAFLD, vitamin E or pioglitazone is not indicated.
• Patients with NASH cirrhosis should be screened for gastroesophageal varices and possible hepatocellular carcinoma.
• Children with fatty liver who are very young or are not overweight should be assessed for other causes.
• Liver biopsy indications in children with suspected NAFLD are unclear diagnosis and the possibility of multiple diagnoses. A liver biopsy should be performed before treatment with potentially hepatotoxic medications or pharmacologic treatment of NASH.
• Screening for NAFLD in overweight or obese children is not formally recommended, despite an expert committee recommendation for biannual screening with liver enzyme tests.
• The histopathologic features of NAFLD in children are unique and can differ from those of adults.
• The first-line treatment in children with NAFLD is lifestyle modification.
• In children, metformin 500 mg twice daily for NAFLD is not beneficial, and more studies are needed to confirm benefits of vitamin E for biopsy-proven or borderline NASH.

Clinical Implications

• Liver biopsy should be considered for patients with NAFLD at increased risk for steatohepatitis and advanced fibrosis and in those with suspected NAFLD to exclude other causes for hepatic steatosis and coexisting chronic liver disease. Metabolic syndrome and the NAFLD Fibrosis Score can be used to identify patients at risk for steatohepatitis and advanced fibrosis.

In nondiabetic adults with biopsy-proven NASH, first-line pharmacotherapy is vitamin E 800 IU per day. However, vitamin E is currently not recommended for treatment of NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.