How Would You Manage This Man With Non-alcoholic Fatty Liver Disease

You see a 48-year-old white man for his annual examination. He is in good health with no major medical problems and an unremarkable medical history. He states he regularly drinks one or two beers a day on the weekend but not usually on weekdays. He denies blood transfusions, tattoos or intravenous drugs. His father had diabetes. Physical examination is notable for the patient being mildly obese with a body mass index (BMI) of 32.

A screening chemistry panel is normal except for an aspartate aminotransferase (AST, formerly SGOT) level of 85 U/L (normal 15-50 U/L) and an alanine aminotransferase (ALT, formerly SGPT) level of 98 U/L (normal 5-50 U/L). Laboratory evaluation, including viral hepatitis serology are negative. An abdominal ultrasound reveals fatty liver with no evidence of biliary disease. Secondary causes of hepatic steatosis are excluded and you make the diagnosis of non-alcoholic fatty liver disease (NAFLD).

When would a liver biopsy be indicated?

Liver biopsy remains the gold standard for characterizing the liver histology in patients with NAFLD. However, it carries some morbidity and very rare mortality risk. Thus, it should be performed in those who would benefit the most from diagnostic, therapeutic guidance, and prognostic perspectives. Liver biopsy should be considered in patients with NAFLD who are at increased to have steatohepatitis and advanced fibrosis.

The presence of the metabolic syndrome and the NAFLD fibrosis score may be used for identifying patients who are at risk for steatohepatitis and advanced fibrosis. The NAFLD fibrosis score is a non-invasive scoring system based on several simple laboratory tests (ALT, AST, platelets and serum albumin) that help to estimate the degree of fibrosis in the liver.

The score can be accessed on-line and is calculated using a published formula (http://nafldscore.com). Liver biopsy should be considered in patients with suspected NAFLD in whom competing etiologies for hepatic steatosis and co-existing chronic liver diseases cannot be excluded without a liver biopsy. A liver biopsy should be considered in patients with NAFLD that are undergoing a cholecystectomy or bariatric surgery.

What lifestyle interventions would you recommend?

Diet, regular exercise and weight reduction should be first consideration when treating patients with NAFLD. All the studies on weight reduction and lifestyle modification have shown substantial benefits in patients with NAFLD. Improvement of the liver enzymes and a decrease in fatty infiltration on ultrasound has been seen after a weight loss of 10% from the baseline weight.

Two prospective randomized studies using baseline and follow up liver biopsies showed a significant improvement in steatosis, inflammation and NASH Activity Score. Exercise alone, independent of weight loss, may have histologic benefits as well. Regular exercise improved insulin resistance and can modify the risks for cardiovascular disease as well. The problem with exercise and diet is that the patients do not adhere to lifestyle interventions. Only 15% of the patients are going to achieve weight loss. Fatigue was a common reason not to exercise. Nevertheless, weight loss and lifestyle modifications should be recommended to all patients with NAFLD.

Some benefits of drinking coffee have been seen in patients with chronic diseases such as diabetes mellitus, Parkinson’s disease, prostate cancer and hepatitis C. Two studies showed that drinking coffee regularly (>2 cups of regular coffee) had a protective effect in patients with NASH through the reduction of hepatic inflammation and fibrosis.

What is the role of pharmacologic therapy?

There are many studies that have been done in an attempt to find a pharmacologic treatment for NASH. These studies have used different medications approaching the different metabolic steps in the pathophysiology of NASH. However, none has given us enough convincing benefit to start using it in the general population.

Most of the studies did not follow basic design requirements for clinical trials. Disappointing results have not led to a clear recommendation to treat patients with NASH. Given the very slow progressive nature of NASH, only surrogate markers of clinical outcome can be used. Having said that, I will mention only the most relevant trials in the treatment of NASH.

With insulin resistance at the theoretical forefront of NAFLD pathogenesis, insulin sensitizers should have an impact on NAFLD. There are 4 placebo controlled trials with pioglitazone and 2 with rosiglitazone. Histologic improvement was seen in most of the trials but no improvement in fibrosis. The safety of pioglitazone in non-diabetic patients with NASH has not been established. Side effects of the thiazolidinediones include weight gain, heart failure, bone loss and bladder cancer. One study showed that histologic benefits may not be maintained after the first year of therapy.

Metformin has been used for the treatment of NASH. It is commonly recommended in the treatment of diabetes mellitus type II. It decreases hepatic glucose output and inhibits lipolysis. None the 6 placebo controlled trials in the treatment of NASH showed histologic improvement.

There are several trials using vitamin E in the treatment of NASH. All have varying criteria, use different doses, use unclear formulations, use other drugs and have limited histologic data. The PIVENS trial is a prospective randomized controlled trial comparing placebo, pioglitazone and vitamin E. Patients on vitamin E showed improvement of the aminotranferase elevations, improvement in steatosis, inflammation and resolution of steatohepatitis. No effect was noted on hepatic fibrosis.

Two publication later stated that vitamin E (>400 IU a day) increases overall mortality and also increases the risk for prostate cancer. Because vitamin E improved liver histology in non-diabetic adults with biopsy- proven NASH, the American Association for the Study of Liver Disease guideline recommends using it as a first line pharmacotherapy in this patient population.

Prospective clinical trials of HMG Co A reductase inhibitors (statins) in the treatment of NASH showed improvement in the ALT, decrease in steatosis, decrease in cardiovascular morbidity but no improvement in fibrosis. Therefore, statins are not recommended to treat patients with NASH but are safe to be used to treat hyperlipidemia.

Ursodeoxycholic acid and pentoxifylline have been studied for the treatment of NASH in several randomized controlled trials without evidence of efficacy. A multicenter, randomized, placebo-controlled trial (FLINT) trial using obeticholic acid for the treatment of NASH was ended early because of improved efficacy of obeticholic acid during a second interim analysis. Forty five percent of patients taking obeticholic acid had histologic improvement compared with 21% in the placebo group. Side effects included pruritus, hyperlipidemia and insulin resistance.

The lack of adherence to exercise and lifestyle modifications by the patients and the lack of effective pharmacologic therapy have fuelled the demand for weight loss surgery in the last couple of decades. Laparoscopic adjustable gastric banding in obese patients with NAFLD showed significant weight loss, improvement of the liver tests, improvement of the metabolic syndrome and histologic improvement in 91% of the patients. Similar results using the Roux en Y gastric bypass were noted. A systematic review of 15 studies on the effect of bariatric surgery on NAFLD showed a decrease in BMI, improvement or resolution of steatosis in 91% and 81% of patients for steatohepatitis. Improvement in fibrosis was also seen in 65% of patients.

One year later the patient develops type 2 diabetes. His lipid panel reveals a LDL cholesterol of 162 mg/dL, HDL cholesterol of 35 mg/dL, and serum triglycerides of 220 mg/dL.

Can statin therapy be safely prescribed?

Yes, statin therapy appears to be safe in the treatment of hyperlipidemia in patients with non-alcoholic fatty liver disease. Hydroxymethylglutaryl-CoA reductase inhibitors or statins, are the most potent, best tolerated and most widely used cholesterol lowering agents and represent some of the most commonly prescribed medications in the United States. Statins are generally well tolerated and shown to have a good safety profile.

All of the statins have been associated with mild-to-moderate serum aminotransferase elevations during therapy that are typically transient, asymptomatic, and may resolve even with continuation without dose adjustment. All have also been associated with rare instances of clinically apparent acute liver injury.

The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study demonstrated a reduction of cardiovascular events in patients with NAFLD with coronary artery disease who were prescribed atorvastatin. Aminotransferases did not exceed 3-times the upper limit of normal in this study. The safety and efficacy of statins in patients with chronic liver disease was demonstrated in a randomized clinical trial of pravastatin versus placebo. No patient had to discontinue pravastatin due to elevations in the liver tests.

Pravastatin was effective in lowering total cholesterol and low-density lipoprotein. In a separate study of 68 patients with NAFLD, there was a reduction in the amount of steatosis in the statin group on serial liver biopsies. Patients who were not on statins did not have a significant reduction in steatosis between baseline and follow up liver biopsies. Other studies showed that statins may have beneficial effects in patients with cirrhosis, including reducing portal hypertension and hepatocellular carcinoma.

Recommendations for the Management of Patients with NAFLD

1) Regular exercise.

2) Well-balanced diet.

3) Weight control.

4) Control of diabetes mellitus.

5) Treatment of hyperlipidemia

6) Avoid alcohol.

7) Regular coffee.

8) Avoid fructose.

9) Vitamin E 800 IU/day in non-diabetics with biopsy-proven NASH. Weigh benefits versus risks regarding risk for prostate cancer and increased overall mortality.

10) Pioglitazone 30 mg qd in diabetic patients with biopsy-proven NASH. Weigh benefits versus risks (heart failure, bladder cancer)

11) Bariatric surgery:

· BMI >40 kg/m2who have failed diet and exercise (with or without drug therapy)

· BMI >35 kg/m2 and obesity related co morbidities (hypertension, diabetes mellitus, dyslipidemia, sleep apnea).

12) Surveillance for hepatocellular carcinoma with abdominal ultrasound and serum alpha-fetoprotein every 6 months in patients with chronic liver disease.