NONALCOHOLIC FATTY LIVER DISEASE Debra Hefner, DO January 8, 2013

Nonalcoholic Fatty Liver Disease Nonalcoholic Fatty Liver Disease (NAFLD)-Refers to the presence of hepatic steatosis when no other causes for secondary hepatic fat accumulation (i.e. heavy alcohol consumption) are present NAFLD may progress to cirrhosis and is likely an important cause of cryptogenic cirrhosis.

NONALCOHOLIC FATTY LIVER DISEASE NAFLD is subdivided into nonalcoholic fatty liver(NAFL) and nonalcoholic steatohepatitis (NASH). In NAFL, hepatic steatosis is present without evidence of significant inflammation, whereas in NASH, hepatic steatosis is associated with hepatic inflammation that may be histologically indistinguishable from alcoholic steatohepatitis.

NONALCOHOLIC STEATOHEPATITIS Other terms that have been used to describe NASH include : Pseudoalcoholic hepatitis Alcohol-like hepatitis Fatty liver hepatitis Steatonecrosis Diabetic hepatitis

EPIDEMIOLOGY Prevalence –NAFLD is seen worldwide and is the most common liver disorder in Western industrialized countries, where the major risk factors for NAFLD, central obesity, Type 2 DM, dyslipidemia, and metabolic are common. In the US, studies report a prevalence of NAFLD of 10-46%. Worldwide, NAFLD has a reported prevalence of 6-35%.

EPIDEMIOLOGY In the US, the prevalence of NAFLD has been increasing over time. This increase was demonstrated in a comparison of 3 cycles of the National Health and Nutrition Examination Survey(NHANES).

PREVALENCE NHANES DATA Time Period: Prevalence of NAFLD: 1988-1994 5.5% 1999-2004 9.8% 2005-2008 11.0% Accounting for 47, 63 and 75% of chronic liver disease during those time periods, respectively. However, it should be noted that the definition of NAFLD used in the study (elevated serum aminotransferase levels in the absence of an alternative explanation) could lead to misclassification and likely underestimated the true prevalence of NAFLD, since patients with NAFLD may have normal serum aminotransferases.

PREVALENCE Over the same three time periods, the study also noted increases in the rates of other components of the metabolic syndrome, including obesity, Type2 DM and systemic hypertension. Obesity DM2 Systemic HTN 1988-1994 22 6 23 1999-2004 30 8 33 2005-2008 33 9 34

PATIENT DEMOGRAPHICS Most patients are diagnosed with NAFLD in their 40’s or 50’s. Studies very with regards to sex distribution of NAFLD, with some suggesting it is more common in women and others suggesting it is more common in men.

ASSOCIATION WITH OTHER DISORDERS Patients with NAFLD (particularly those with NASH) often have one or more components of the metabolic syndrome: Obesity Systemic hypertension Dyslipidemia Insulin resistance or overt diabetes

PATHOGENESIS The pathogenesis of NAFLD has not been fully elucidated. The most widely supported theory implicates insulin resistance as the key mechanism leading to hepatic steatosis, and perhaps also to steatohepatitis. Others have proposed that a “second hit”, or additional oxidative injury, is required to manifest the necroinflammatory component of steatohepatitis. Hepatic iron, leptin, antioxidant deficiencies, and intestinal bacteria have all been suggested as potential oxidative stressors.

CLANICAL MANIFESTATIONS Most patients with NAFLD are asymptomatic, although some patients with nonalcoholic steatohepatitis (NASH) may c/o fatigue, malaise and vague right upper abdominal discomfort. Patients are more likely to come to attention because laboratory testing revealed elevated liver aminotransferases or hepatic steatosis was detected incidentally on abdominal imaging.

CLINICAL MANIFESTATIONS Physical Findings: Patients with NAFLD may have hepatomegaly on physical examination due to fatty infiltration of the liver. In some patients, hepatomegaly is the presenting sign of NAFLD. However, the reported prevalence is highly variable.

CLINICAL MANIFESTATIONS Laboratory Findings: Patients with NAFLD may have mild or moderate elevations in the aspartate aminotransferase (AST) and alanine aminotransferase (ALT), although normal aminotransferase levels do not exclude NAFLD. When elevated, the AST and ALT are typically 2 to 5 times the upper limit of normal, with an AST to ALT ratio of less than one (unlike alcoholic fatty liver disease, which typically has a ratio greater than two). The degree of aminotransferase does not predict the degree of hepatic inflammation or fibrosis.

CLINICAL MANIFESTATIONS Laboratory Findings: The alkaline phosphatase may be elevated 2-3 times the upper limit of normal. Patients with NAFLD may have an elevated serum ferritin concentration or transferrin saturation. There is evidence that a serum ferritin greater than 1.5 times the upper limit of normal in patients with NAFLD is associated with a higher nonalcoholic fatty liver disease activity score (and thus, NASH) and with advanced hepatic fibrosis.

CLINICAL MANIFESTATIONS Radiographic Findings: In patients with NAFLD, these include increased echogenicity on ultrasound, decreased hepatic attenuation on computed tomography (CT) and an increased fat signal on magnetic resonance imaging (MRI).

NAFLD DIAGNOSIS Diagnosis of NAFLD requires all of the following: Demonstration of hepatic steatosis by imaging or biopsy Exclusion of significant alcohol consumption Exclusion of other causes of hepatic steatosis

NAFLD DIAGNOSIS Radioographic

NAFLD DIAGNOSIS Radiologic Findings: In those under going a radiologic evaluation, radiologic findings are often sufficient to make the diagnosis if other causes of hepatic steatosis have been excluded. While not indicated for the majority of patients, a liver biopsy may be indicated if the diagnosis is not clear or to assess the degree of hepatic injury. In addition, liver biopsy is the only method currently available to differentiate nonalcoholic fatty liver (NAFL) from nonalcoholic steatohepatitis (NASH).

NAFLD DIAGNOSIS Which patients to biopsy: There is no clear consensus about which patients require a liver biopsy. Obtain a liver biopsy in patients with suspected NAFLD if the diagnosis is unclear after obtaining standard laboratory tests and hepatic imaging, if there is evidence of cirrhosis, if the patient wants to know if inflammation or fibrosis is present or if the patient is at risk for advanced fibrosis or cirrhosis.

NAFLD DIAGNOSIS Which Patients to Biopsy? Specifically, we obtain a biopsy if the patient: Has peripheral stigmata of chronic liver disease (suggestive of cirrhosis) Has splenomegaly (suggestive of cirrhosis) Has cytopenias (suggestive of cirrhosis) Has a serum ferritin>1.5times the upper limit of normal (suggestive of NASH and advanced fibrosis) Is >45years of age with associated obesity or diabetes (increased risk of advanced fibrosis)

NAFLD DIAGNOSIS Rule out other disorders: Differentiating NAFLD from the other items in the differential diagnosis begins with a thorough history to identify potential causes such as significant alcohol use, starvation, medication use and pregnancy-related hepatic steatosis.

DIFFERENTIAL DIAGNOSIS Alternative causes of hepatic steatosis that should be considered in a patient with suspected NAFLD: Alcoholic liver disease Hepatitis C (particularly genotype 3) Wilson Disease Lipodystrophy Starvation Parenteral Nutrition Abetalipoprteinemia Medications Reye Syndrome Acute fatty liver of pregnancy HELLP (hemolytic anemia, elevated liver enzymes, low platelet count) Syndrome

MANAGEMENT Multiple therapies have been investigated for the treatment of nonalcoholic fatty liver disease(NAFLD). However, weight loss is the only therapy with reasonable evidence suggesting it is beneficial and safe.

MANAGEMENT Recommendations for patients with NAFL or NASH: Weight loss for patients who are overweight or obese. In addition to its other benefits, weight loss has been associated with histologic improvement in patients with NAFLD. Options to promote weight loss include lifestyle modifications and, for patients who are candidates, bariatric surgery. A reasonable goal for many patients is to lose 1-2lbs/week. More rapid weight reduction may be associated with worsening of liver disease.

MANAGEMENT Histologic improvement has also been observed after bariatric surgery. Some of data is conflicted but when taken collectively, these data suggest that bariatric surgery is a promising approach in obese patients with NAFLD. However, given the potential for worsening fibrosis in some patients following bariatric surgery, patients should continue to have their liver function monitored closely.

MANAGEMENT Hepatitis A and B vaccinations should be given to patients without serological evidence of immunity. Additional vaccines recommended for patients with chronic liver disease include pneumococcal vaccination and standard immunizations recommended for the population in general (i.e. influenza, diptheria, tetanus boosters

MANAGEMENT Treatment of risk factors for cardiovascular disease. Patients with NAFLD are at increased risk for cardiovascular disease & often have multiple cardiovascular disease risk factors. Mgmt includes optimization of blood glucose control in patients with DM2 and treatment of hyperlipidemia. Statin therapy has been shown to be safe in patients with NAFLD.

MANAGEMENT In general, the use of pharmacologic agents are not recommended (i.e. Vitamin E, pioglitazone) solely for the treatment of NAFLD. However, it is suggested that Vitamin E at a dose of 400IU/day for patients with advanced fibrosis on biopsy who do not have DM or coronary artery disease. Limited evidence supports a benefit with up to 800IU/day of Vitamin E in patients w/out DM, but some observational studies suggest a possible increase in all-cause mortality with higher-dose Vitamin E (800IU/day).

MANAGEMENT Suggest that patients with NAFLD avoid all alcohol consumption. Heavy alcohol use is associated with disease progression among patients with NAFLD.

MANAGEMENT Suggest not using thiazolidinediones primarily for the treatment of NASH. Thiazolidinediones improve histologic parameters in patients with NASH, but likely need to be used long-term and their use has been associated with serious adverse events, including heart failure. Using a thiazolidinedione is reasonable in patients who are candidates for thiazolidinedione treatment for Type 2 DM.

MANAGEMENT Patients with NASH-related cirrhosis should undergo screening for hepatocellular carcinoma

WHEN TO REFER? Recommend that patients with steatohepatitis on biopsy be followed by a hepatologist. Patients with nonalcoholic fatty liver without steatohepatitis can often be followed by a primary care physician, provided the diagnosis is clear. However, if the patient develops significant aminotransferase elevations (twice the upper limit of normal) or evidence of cirrhosis, it is suggested tat a referral to a hepatologist for further evaluation & management.

REFERENCES http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/nonalcoholic http://www.uptodate.com/contents/ http://www.uptodate.com/contents/natural-history-and-mangement-of-nonalcoholic-fatty-liver-disease-in-adults