What Everyone With Diabetes Should Know About Liver Disease

Dace L. Trence, MD, FACE

Of course there is a relationship between diabetes and the pancreas, since diabetes comes from damage to the pancreas, the insulin-producing organ. But how does the liver fit into this equation? As it turns out, quite a bit.

It’s well known that diabetes increases the risk of kidney disease, nerve damage, blood vessel damage, infections, blindness and heart disease, but you may not realize diabetes can have profound effects on the liver as well.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects up to one-third of the entire adult population in industrialized countries. And if you have type 2 diabetes mellitus -- the diabetes in which your own insulin does not work properly, compounded by increasingly less and less insulin made in the pancreas — you are even more at risk of having NAFLD.

Recognition and description of NAFLD dates back to only 30 years ago, when scientists noted the appearance of liver tissue that reminded them of alcoholic hepatitis, with findings resembling chronic alcohol use, but in individuals that had no history of alcohol abuse or even alcohol intake. Although once thought uncommon, today’s medical professionals recognize that if one was looking for 20 patients with NAFLD, given the high prevalence of the disease, this number could likely be recruited within one day in a lobby of a hotel.

NAFLD is an umbrella term that includes several subtypes of liver cell appearances and clinically distinct conditions, including fatty liver (referred to as NAFL or steatosis hepatis) and more serious steatohepatitis (NASH), with or without fibrosis (scarring), that can progress to liver cirrhosis and, in a few cases, to liver cancer. Precisely differentiating between these different liver conditions can be challenging: usually a liver biopsy is needed to look at the actual appearance of the liver cells, the fat content of the liver, and any scarring or other specific tissue changes.

Hepatic steatosis is de-fined as liver fat content above 5.5 percent or when more than 5 percent of the actual liver cells contain fat in a tissue sample review. Steatosis is graded as mild (up to 10 percent of hepatocytes); moderate (10 percent to 30 percent of hepatocytes); or severe (more than 30 percent of hepatocytes) according to the proportion of liver cells containing fat in a specific pattern.

A liver biopsy may be recommended when blood tests for liver function are repeatedly and chronically elevated (e.g., for six months) and all other evaluations for the cause of the elevations are inconclusive.

A few biopsy-based studies have reported the NASH prevalence in the general population. In one study involving 400 individuals from 18 to 70 years of age, 134 liver biopsies were done on the basis of an abdominal ultrasound showing a “fatty liver.” The reported prevalence of NAFLD was a surprising 46 percent in this study participant group, while NASH was diagnosed in 12.2 percent. Ethnicity seemed to play a large role, with the highest risk for NAFLD and NASH in participants of Hispanic origin. Having diabetes mellitus increased the risk significantly (NAFLD prevalence: 74 percent, NASH prevalence: 22.2 percent). Individuals with NAFLD were more likely to be male (58.9 percent) and of older age, to have a higher BMI and to also have high blood pressure.

What is very concerning is that these liver changes are increasingly becoming more common in children as well. The prevalence of NAFLD from autopsies reported by pediatric groups was 4.2 percent in Poland and 9.6 percent in the United States. Excess bodyweight was found in 55.6 percent of the children with NAFL in the European study, and a similar association was found in the U.S. group.

So what is all the fuss about?

While the odds of heart disease are increased in those with diabetes, the odds of having serious liver problems are almost twice as high as having cardiovascular disease! An autopsy study in the U.S. has shown that patients with diabetes have an increased incidence of severe fibrosis (thickening and scarring of connective tissue). In another study, cirrhosis accounted for 12.5 percent of deaths in patients with diabetes. Cryptogenic (cause not known) cirrhosis in those with diabetes is most commonly caused by NAFLD and is now the third-leading reason for liver transplantation in the U.S.

So progression from fatty liver to steatohepatitis to cirrhosis and, in some cases, to liver cancer is of concern. A patient’s prognosis worsens with each stage of liver disease. Fortunately, not everyone’s liver disease progresses – and it’s not known why some do and some do not. While blood tests and liver ultrasound are used initially to guide further evaluation and management, the most reliable way currently of determining disease progression is liver biopsy, not a simple procedure.

To complicate matters even further, cirrhosis itself is associated with insulin not working as it should (a condition known as insulin resistance). Impaired glucose tolerance (or pre-diabetes) is seen in 60 percent of individuals and overt diabetes in 20 percent of individuals with previously diagnosed cirrhosis. The ability to process blood sugar is reduced by roughly 50 percent in individuals with known liver cirrhosis. And when type 2 diabetes does develop in those with liver cirrhosis, the diabetes is associated with decreased insulin secretion from the pancreas. It’s a complex association, that of diabetes and liver cirrhosis, and the basis of a lot of research to understand the association and, in turn, how best to then treat or prevent this problem.

What is known about possible treatments?

Many studies support the position that weight loss decreases liver fat and thus should be the cornerstone recommended treatment. Low-glycemic, low-calorie diets with a weight loss of 2.2 – 4.4 pounds (1 to 2 kilograms) per week has been recommended, but clearly any weight loss can be beneficial. Low-fat diets should be avoided. Some experts suggest a Mediterranean diet (defined as high in complex carbohydrates or starches, high in monounsaturated fats – i.e., oils, moderate amounts of wine, and low amounts of red meat) is preferred in individuals with type 2 diabetes and NAFLD. However, others very strongly recommend that alcohol should be avoided completely, not only because of its toxic effects on the liver, but also because of its high calorie content. Exercise improves insulin action for everyone.

Some medications used for the treatment of diabetes can also be beneficial for the liver. While metformin, an oral diabetes medicine that helps control blood sugar levels, is appropriate in most to treat diabetes, it should be avoided if the patient’s liver disease is quite advanced. Recent metformin trials have shown some benefit for both conditions in those with both fatty liver and type 2 diabetes. Thiazolidinedione (TZDs—type 2 diabetes oral medication) trials with pioglitazone and rosiglitazone have shown improvement in liver blood tests and liver tissue appearance. Sulfonylureas, which act by increasing insulin release from the beta cells in the pancreas, are generally safe for blood sugar control, with glipizide or glyburide preferred in these patients. In very advanced liver disease, sulfonylureas increase the risk of hypoglycemia (low blood sugar), so often are discontinued. They do not have an independent effect on liver tissues.

What about other commonly prescribed drugs? Should I be concerned?

Statins are frequently prescribed to treat high cholesterol, as a means to prevent heart attacks and stroke, and to treat NAFLD. Statin therapy can cause minor, transient increases in some liver tests, but severe liver damage and liver failure are very rare.

Among high blood pressure medications, the ACE (angiotensin-converting enzyme) inhibitors have been associated with reports of liver tissue irritation. Fortunately, given the very positive benefits of ACE inhibitors not only with blood pressure control, but also their protective benefits from kidney, possibly eye, and certainly heart disease complications, serious side effects from this drug group are rare. Although losartan (an ARB or angiotensinreceptor blocker) has been associated with liver irritation, surprisingly it has also been used to treat fatty liver disease

Even aspirin is potentially toxic to the liver, although the dose has to be very high. Liver damage has not been described at doses recommended for heart disease or stroke prevention.

Take-home message:

You’re now armed with the knowledge necessary to help take care of your liver and prevent diabetes related complications from affecting this vital organ. So, take steps to lose weight, improve your diet, limit alcohol intake...and follow your doctor’s recommendations for controlling other conditions as well.