Fatty Liver Disease – Part 4

The topic for this blog is management of liver disease in people with diabetes. The following are factors and tests your doctor will be looking for:

Abnormal liver function tests

Given the fact that at least 50% of people with type 2 diabetes have NAFLD, all people with type 2 diabetes should have an ALT and AST test done as part of their initial evaluation. At least 95% of patients with a confirmed minor elevation of ALT or AST have chronic liver disease independent of the degree of elevation. Thus, it is always necessary to obtain a specific diagnosis. The most likely etiologies of minor elevations of ALT/AST are NAFLD, hepatitis C, hepatitis B, and alcohol. Moderate social drinking, i.e., less than 20 g/day, does not cause an elevation of liver enzymes. The initial workup should include testing for hepatitis C (anti-HCV or HCV PCR), hepatitis B (HBV surface antigen), hemochromatosis (iron and iron saturation), and an abdominal ultrasound. Patients with hepatitis C, hepatitis B, and increased iron saturation need referral for further workup and treatment. Ultrasound has a positive predictive value of 96% for detecting NAFLD in the absence of other liver diseases. Unfortunately the negative predictive value is only 19%; thus, patients with a negative ultrasound will also need referral. The impact of this approach on cost of care and manpower is not known, and the cost-effectiveness of screening ALT has not been established, although the American Association for the Study of Liver Disease is now recommending yearly ALT screening for everyone.

Fatty liver disease

The diagnosis of NAFLD or NASH should be suspected in any patient with type 2 diabetes, especially if there are abnormal liver function tests. It should be specifically looked for in all obese patients with type 2 diabetes. ALT is typically elevated two- to threefold above ULN but is often normal. Mild elevations of serum alkaline phosphatase and glutamyl transferase may be present. Serum ferritin levels are frequently elevated, while iron and iron-binding capacity are normal. Ultrasound studies may reveal a diffuse increase in echogenicity, so-called “bright” liver. The sensitivity of ultrasound in patients with elevated ALT is 89% with a specificity of 93% for detecting steatosis. If the ultrasound reveals fatty liver, it is appropriate to look for etiologies other than diabetes such as dyslipidemia. There are shortcomings to this approach. The sensitivity of ultrasound decreases greatly as hepatic steatosis decreases to 30% or less. Most patients with NAFLD found incidentally or by screening ultrasound have a normal ALT. These observations suggest that the sensitivity of ultrasound overall is really not very high. In patients with abnormal ALTs and other diseases ruled out, the positive predictive value of ultrasound is 96% but the negative predictive value only 19%. Magnetic resonance spectroscopy is capable of quantitative assessment of steatosis, but is not indicated for routine clinical practice. Thus, the gold standard for diagnosis of NAFLD remains the liver biopsy. In addition, the diagnosis of progressive liver disease (i.e., NASH), the precursor of cirrhosis, can only be made by liver biopsy. However, certain patients including those with reversed ALT-to-AST ratio, hypertriglyceridemia, and thrombocytopenia are at high risk for progressive disease.

Treatment of NAFLD

Most patients do not need to be treated. Only patients with biopsy-proved NASH or the risk factors listed above should be treated. Whether or not all patients need a liver biopsy is controversial in that the sensitivity of the risk factors for progressive disease is not known. It is also not known whether treatment, other than bariatric surgery, affects the ultimate prognosis. The treatment consists of measures to lose weight as well as pharmacologic intervention. There are no FDA-approved treatments and, in fact, no FDA guidelines for approving drugs for NAFLD.

Exercise and weight reduction.

The initial treatment of NASH consists of weight loss and exercise, which enhance insulin sensitivity and result in reduction of steatosis. Rapid weight reduction, however, may increase necrosis, inflammation, and fibrosis. This paradoxical effect is thought to be due to an increase in circulating free fatty acids due to increased lipolysis seen with fasting. The ideal rate of weight loss is not known, but l.5 kg/week has been recommended. The ideal content of the diet is not known. Recent studies have demonstrated that bariatric surgery either improves or completely reverses steatosis in patients with obesity with or without diabetes.

Pharmacologic therapy.

Pharmacologic therapy of NAFLD is evolving. While many studies have shown improvement in steatosis, there are neither long-term studies to determine whether they alter the natural history of the disease nor studies to indicate whether relapse occurs after treatment withdrawal. Gemfibrozil, vitamin E, metformin, betaine, pioglitazone, rosiglitazone, atorvastatin, losartan, orlistat, and pentoxifylline have all been tried and have all been shown in small trials to improve liver enzymes. Modest histologic improvement over 6–12 months is seen with some of the agents. Long-term outcome trials with the various treatment modalities are yet to be completed.

Given that insulin resistance is central to the pathogenesis of NAFLD, insulin-sensitizing agents should have utility (even in the absence of diabetes), and there is increasing evidence that they do.

Metformin has shown mixed results in human trials with some improvement in ALT but not in histology. Two long-term trials initiated by the National Institutes of Health are underway. At this time, treatment with metformin is not recommended outside of clinical trials. In the meantime, it seems reasonable to treat patients with NASH and type 2 diabetes with TZDs, recognizing that the patients may gain weight. In the absence of a histologic diagnosis of NASH, only those with risk factors for progressive disease as mentioned above should be treated. TZDs, despite shortcomings, are emerging as the treatment of choice even in the absence of diabetes. Statins may reduce hepatic fat content in patients with hyperlipidemia and NASH.

In summary, the ideal therapy for NAFLD is yet to be identified, and no evidence-based recommendations can be made. Outside of clinical trials, therapy should be directed toward the underlying etiology.

Hepatitis C.

The most effective treatment of HCV is a combination of pegylated α-interferon and ribavirin. Interferon, however, affects insulin sensitivity and glucose tolerance. Studies in non-diabetic patients report that interferon impairs glucose tolerance. Given the unpredictable effect of interferon in diabetes, it is reasonable to monitor diabetes carefully when using interferon.

SUMMARY—

Type 2 diabetes is associated with a large number of liver disorders including elevated liver enzymes, fatty liver disease, cirrhosis, hepatocellular carcinoma, and acute liver failure. In addition, there is an unexplained association with HCV. The SMR for cirrhosis is higher than that for CVD in type 2 diabetes. Many consider NAFLD to be part of the insulin resistance syndrome. However, the presence of liver disease (unless decompensated) has little implication for the specific treatment of diabetes, and the presence of diabetes has little implication for the specific treatment of liver disease. Patients with decompensated liver disease are more susceptible to hypoglycemia and require careful monitoring. There continues to be a need for long-term placebo-controlled trials for the treatment of NAFLD and for the treatment of diabetes in patients with liver disease.