April 10, 2015
Fatty Liver Disease – Part 3
The following is a discussion of diabetes management in patients with liver disease. There are points everyone should be aware of and include in their management.
Treatment of type 2 diabetes in patients with liver disease may be compromised by poor nutritional status and general health. More than 50% of patients with severe liver disease are malnourished. A number of uncontrolled studies indicate that weight loss decreases hepatic steatosis. The durability of weight loss on hepatic steatosis remains to be determined. Low-glycemic, low-calorie diets with a weight loss of 1–2 kg/week seem reasonable. Low-fat diets should be avoided. Exercise improves peripheral insulin sensitivity, albeit not specific to patients with diabetic liver disease. Alcohol should be avoided not only because of its toxic effects on the liver, but also because of its high caloric content and potential interaction with sulfonylureas.
Drug therapy of type 2 diabetes in patients with liver diseases is, for the most part, the same as for those without liver disease. While there are theoretical concerns about altered drug metabolism and hepatotoxicity, only patients with evidence of liver failure such as ascites, coagulopathy, or encephalopathy have altered drug metabolism. Furthermore, there is no evidence that patients with liver disease are predisposed to hepatotoxicity. Underlying liver disease, however, may compromise the diagnosis and increase the severity of drug-induced liver disease.
First-line therapy with metformin is appropriate in most patients but not recommended in patients with advanced hepatic disease because of a perceived increased risk of lactic acidosis. Given that insulin resistance is the core defect in fatty liver disease, the case can be made for thiazolidinediones (TZDs) as front line therapy in these patients. Recent trials with pioglitazone and rosiglitazone have shown improvement in ALT and liver histology. Weight gain is a concern with TZDs, and cost is prohibitive for many patients. If metformin or TZDs are contraindicated, drug therapy can begin with a secretagogue such as a sulfonylurea with rapid advancement to insulin if glycemic control is not achieved.
Sulfonylureas are generally safe in patients with liver disease but may not overcome the insulin resistance and defects in insulin secretion seen in patients with coexistent alcoholic liver disease and pancreatic damage. Sulfonylureas with a short half-life such as glipizide or glyburide are preferred in these patients. Patients with decompensated cirrhosis, i.e., encephalopathy, ascites, or coagulopathy, may have a reduced ability to counteract hypoglycemia, and thus, the response to therapy should be monitored closely. Historically, chlorpropamide was associated with hepatitis and jaundice.
Metformin may be particularly useful in obese patients in whom it may cause mild weight loss. It is relatively contraindicated in patients with advanced liver disease or in binge drinkers because it may predispose to lactic acidosis. It is unclear whether the liver disease or alcohol is the predisposing factor. Metformin has not been reported to cause hepatotoxicity and has shown some benefit in patients with NAFLD.
The α-glucosidase inhibitors may be particularly useful in patients with liver disease because they act directly on the gastrointestinal tract to decrease carbohydrate digestion and thus glucose absorption, thereby decreasing postprandial hyperglycemia
Acarbose frequently causes mild transient elevations of ALT and, on rare occasions, severe liver disease. While the labeling of acarbose has a warning for patients with liver disease, it appears to be safe and effective in patients with hepatic encephalopathy and type 2 diabetes. Miglitol, another α-glucosidase inhibitor, has not been associated with hepatotoxicity.
TZDs may be especially useful because they enhance insulin sensitivity, the underlying defect in NAFLD. In pre-approval clinical trials of rosiglitazone and pioglitazone, threefold elevations of ALT were seen with the same frequency for rosiglitazone (0.26%), pioglitazone (0.2%), and placebo (0.2 and 0.25%)
It is currently recommended that serum ALT levels be evaluated before the initiation of rosiglitzone and pioglitazone therapy and that therapy not be initiated if there is evidence of active liver disease or if the serum ALT level exceeds 2.5 times ULN (product labeling, 2005). Monitoring is recommended periodically thereafter as clinically indicated rather than every 2 months as previously recommended. Paradoxically, TZDs are emerging as the treatment of choice for NASH (nonalcoholic steatohepatitis).
Insulin treatment is frequently required in patients with diabetes and liver disease. Insulin requirements, however, may vary. For example, in patients with decompensated liver disease, the requirement may be decreased due to reduced capacity for gluconeogenesis and reduced hepatic breakdown of insulin. However, patients with impaired hepatic function may have an increased need for insulin due to insulin resistance. Thus, careful glucose monitoring and frequent dose adjustments of insulin may be necessary. In patients with hepatic encephalopathy who require high-carbohydrate diets, resulting in postprandial hyperglycemia, rapid-acting insulin analogs such as insulin lispro, aspart, or glulisine may be particularly useful.
Other drugs used in the management of disorders associated with type 2 diabetes
Statins are frequently used in patients with type 2 diabetes to treat hyperlipidemia and prevent cardiovascular events. Statin therapy, like all cholesterol-lowering therapy including bariatric surgery, causes minor but transient elevations in liver enzymes. However, the liver adapts with continuing therapy, and there are no long-term consequences of these abnormalities. Severe liver damage and liver failure are very rare. Paradoxically, statins are currently used to treat NAFLD, and recent studies suggest that statins are hepatoprotective in patients with HCV (hepatitis C virus).
All of the ACE inhibitors have been implicated in hepatic injury including fulminant hepatic failure. The reactions are mostly hepatocellular, but cholestatic reactions have also been reported. Although losartan has been associated with hepatotoxicity, it has also been used to treat fatty liver disease. There are no current recommendations for hepatic monitoring of these idiosyncratic events.
Even aspirin is potentially hepatotoxic although at very high doses. Hepatotoxicity has not been described at doses used for cardioprotection.