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.

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.

Lifestyle modification

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.

Pharmacologic therapy

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.

Insulin promoters.

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.

Biguanides.

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.

α-Glucosidase inhibitors.

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.

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.

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.

Fatty Liver Disease – Part 1

This topic is not what I thought and research has given me cause for concern. Fatty liver disease is not to be taken lightly or even dismissed. Diabetes and liver disease is by far worse than alcohol and liver cirrhosis. Whether you believe it or not, diabetes is now the most common cause of liver disease in the United States. Cryptogenic cirrhosis which is cirrhosis of unknown etiology, with no history of alcoholism or previous acute hepatitis has made diabetes the third leading indicator for liver transplantation.

Diabetes raises your risk of nonalcoholic fatty liver disease (NAFLD), a condition in which excess fat builds up in your liver even if you drink little or no alcohol. This condition occurs in at least half of those with type 2 diabetes and close to half of those with type 1 diabetes. Other medical conditions, such as obesity, high cholesterol, and high blood pressure, also raise your risk of nonalcoholic fatty liver disease. Fatty liver disease itself often causes no symptoms. But it raises your risk of developing liver inflammation or scarring (cirrhosis). It's also linked to an increased risk of liver cancer and heart disease.

Fatty liver disease may have played a role in the development of your type 2 diabetes initially. Once you have both conditions, poorly managed type 2 diabetes can make fatty liver disease worse.

Your best defense against fatty liver disease includes these strategies:

• Work with your health care team to achieve good control of your blood sugar.
• Lose weight if you need to, and try to maintain a healthy weight.
• Take steps to reduce high blood pressure.
• Keep your low-density lipoprotein (LDL, or "bad") cholesterol and triglycerides — a type of blood fat — within recommended limits.
• Don't drink too much alcohol.

If you have diabetes, your doctor may recommend an ultrasound examination of your liver when you're first diagnosed and regular follow-up blood tests to monitor your liver function.

Make sure that your non-alcoholic fatty liver disease is treated rather than letting it progress to non-alcoholic steatosis, a potential lethal condition. About seven out of 10 people with type 2 diabetes have a fatty liver. Learn how to treat or prevent this complication.

Who gets non-alcoholic fatty liver disease and why? Although researchers have tried to pin this on different ethnicities, this has not been successful. The only common denominator is obesity and this holds true regardless of ethnic background.

The severity of type 2 diabetes and the type and severity of liver disease influence the therapy. There are few clinical trials that specifically target patients with coexistent diabetes and liver disease, and all are limited by small numbers of patients.

Heart disease is the leading cause of morbidity and mortality in both Type 2 diabetes and NAFLD. Individuals with diabetes demonstrate a 74% greater risk of hospitalization due to heart failure. NAFLD, characterized by elevated serum γ-glutamyltransferase (GGT), is independently associated with heart failure. The increased incidence of cardiovascular morbidity and mortality associated with Type 2 diabetes and NAFLD, has been linked to preclinical changes in cardiac structure, function, and metabolism.

Using magnetic resonance imaging (MRI) we have previously shown pre-clinical changes in cardiac structure and function in NAFLD. To extent this work and in light of the importance of understanding early cardiac changes and reducing cardiovascular risk in people with metabolic disease, the study was designed to compare the impact of Type 2 diabetes and NAFLD upon cardiac structure, function, and metabolism and to identify potential metabolic mediators.

Changes in cardiac structure are evident in adults with Type 2 diabetes and NAFLD without overt cardiac disease and without changes in cardiac energy metabolism. The growing prevalence of metabolic disorders puts large numbers at risk of these underlying cardiac changes. Only the Type 2 diabetes group display diastolic and subendocardial dysfunction and glycemic control may be a key mediator of these cardiac changes. Managing blood glucose should therefore be a priority for clinical care teams to prevent cardiac complications in adults with Type 2 diabetes and NAFLD.

Continued in the following blogs.