A Patient With Type 2 Diabetes and Cirrhosis of the Liver

A.G. is a 47-year-old white man with a history of type 2 diabetes diagnosed at age 30. At his visit in July 1996, he weighed 275 lb with a height of 6'0” (BMI 37 kg/m²) and had measured A1C of 8.7%, mildly elevated triglycerides and LDL cholesterol, low HDL cholesterol, and normal transaminase levels. He had no signs or symptoms of complications from his disease and felt well.

Over the years, his history has been one of variable follow-up in the office with nonadherence to his diet and exercise regimen. His A1C results have fluctuated from 8.0 to 11.5%, his weight has remained > 250 lb, and his medical regimen has intensified to include an ACE inhibitor, a statin,aspirin, a sulfonylurea, and the maximum dose of metformin.

In February 2003, after 18 months of absence from follow-up, a bedtime dose of insulin glargine was added to A.G.'s regimen when he presented with thirst,polyuria, and weight loss to 221 lb. His A1C result was 10.6%, and liver function tests revealed aspartate aminotransferase (AST) of 67 units/l and alanine aminotransferase (ALT) of 78 units/l. He had early symptoms of sensory neuropathy in the feet and retinopathy on dilated retinal exam.

Repeat assessment 3 months later, in May 2003, demonstrated resolution of leg cramps, urinary frequency, and blurred vision with an A1C of 8.3%. He was given parameters for continued titration of his bedtime insulin, yet he once again failed to return for reassessment until February 2005.

At his visit in February 2005, A.G.'s A1C was again elevated to 10.8% and a complete blood count revealed a white blood cell count of 3,200 and platelet count of 58,000. His liver function assessment revealed minimal ALT and AST elevations.

On 28 April 2005, A.G. presented to the hospital emergency department with hematemesis and anemia. Endoscopy revealed multiple bleeding esophageal varices, and banding procedures were performed. A computed tomography scan of the abdomen revealed diffuse fatty infiltration of the liver with evidence of portal hypertension. The patient was readmitted on 10 May 2005, for another episode of upper gastrointestinal bleeding requiring transfusion and repeat banding of bleeding esophageal varices.

Laboratory work-up including viral serologies, iron studies, and anti-nuclear antibody were negative, and a liver biopsy revealed stage 4 fibrosis with hepatitis and steatosis, confirming the diagnosis of nonalcoholic steatohepatitis (NASH).

A.G. has no history of drinking alcohol and is clinically stable at present, undergoing evaluation for possible future liver transplantation. He is maintained on a β-blocker and spironolactone, feels well, and has a weight of 207 lb and an A1C of 6.2%, with a renewed interest in his diet and exercise regimen.

1. What is the distinction between nonalcoholic fatty liver disease (NAFLD)and NASH?

2. What are the risk factors for NAFLD and NASH?

3. Are there proven effective therapies for NAFLD and NASH?

NAFLD represents a spectrum of diseases from simple fatty liver(steatosis), to steatosis with inflammation, necrosis, and possible cirrhosis,that occurs in people who drink little or no alcohol. NAFLD affects more women than men and can be found in all age groups, including children. NASH represents the more severe end of the spectrum and is associated with progressive liver disease, fibrosis, and cirrhosis.

The etiology of NASH is unclear, and the cellular basis for fat accumulation in the liver is not known. Like A.G., most patients with NASH are obese and have associated type 2 diabetes, hyperlipidemia, and insulin resistance. A study at the University of Virginia in 1999 examined 70 consecutive patients with cryptogenic cirrhosis to assess major risks for liver disease. Both diabetes and obesity were significantly more common in the cryptogenic cirrhotic patients compared with cirrhotic patients with primary biliary cirrhosis or hepatitis C. The prevalence of diabetes and obesity was similar to that in NASH patients, suggesting that NASH may play an underrecognized role in patients with cryptogenic cirrhosis.

A.G.'s case is typical in that patients with NASH generally feel well, with no overt signs or symptoms of liver disease. Some patients may come to diagnosis during the work-up of persistent, mild transaminase abnormalities or when imaging studies such as ultrasound or CT scan are performed for other reasons. Eliminating other possible causes for chronic liver disease must be undertaken, and the diagnosis must be confirmed by liver biopsy.

Preferred treatments for NAFLD and NASH include weight loss, exercise,improved diabetes control, and the use of lipid-lowering medications. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)recently conducted a study of a 48-week course of pioglitazone in 21 nondiabetic patients with NASH. Serum aminotransferase levels and liver histology improved in most patients, and the improvements correlated with changes in insulin sensitivity.

Patients are currently being enrolled in another NIDDK study to treat 20 nondiabetic patients with NASH with metformin for 48 weeks. After an initial evaluation, patients will receive gradually increasing doses of metformin to a maximum of 2,000 mg daily. Primary end points of successful therapy will be improvement in hepatic histology, with secondary end points being improvement in insulin sensitivity, body fat distribution, and liver biochemistry.

• Liver disease is rarely, if ever, mentioned as a potential complication from type 2 diabetes. With the increasing prevalence of obesity and patients with insulin resistance and type 2 diabetes, many experts believe that NAFLD and NASH will become increasingly common.

• Health care providers have yet another reason to continue to push for improvements in metabolic parameters in patients with type 2 diabetes,emphasizing weight loss, exercise, and control of both glucose and lipids.

• More research is needed to understand the cellular basis for fat accumulation in the liver and the progression to fibrosis and cirrhosis and for effective therapies to reverse the disease processes in NAFLD and NASH.