Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management

Abstract

About 30% of patients with cirrhosis have diabetes mellitus (DM). Nowadays, it is a matter for debate whether type 2 DM in the absence of obesity and hypertriglyceridemia may be a risk factor for chronic liver disease. DM, which develops as a complication of cirrhosis, is known as "hepatogenous diabetes". Insulin resistance in muscular and adipose tissues and hyperinsulinemia seem to be the pathophysiologic bases of diabetes in liver disease. An impaired response of the islet beta-cells of the pancreas and hepatic insulin resistance are also contributory factors. Non-alcoholic fatty liver disease, alcoholic cirrhosis, chronic hepatitis C (CHC) and hemochromatosis are more frequently associated with DM. Insulin resistance increases the failure of the response to treatment in patients with CHC and enhances progression of fibrosis. DM in cirrhotic patients may be subclinical. Hepatogenous diabetes is clinically different from that of type 2 DM, since it is less frequently associated with microangiopathy and patients more frequently suffer complications of cirrhosis. DM increases the mortality of cirrhotic patients. Treatment of the diabetes is complex due to liver damage and hepatotoxicity of oral hypoglycemic drugs. This manuscript will review evidence that exists in relation to: type 2 DM alone or as part of the metabolic syndrome in the development of liver disease; factors involved in the genesis of hepatogenous diabetes; the impact of DM on the clinical outcome of liver disease; the management of DM in cirrhotic patients and the role of DM as a risk factor for the occurrence and exacerbation of hepatocellular carcinoma.

Figure 1

Type 2 diabetes mellitus may give raise to non-alcoholic fatty liver disease (NAFLD) which could progress to cirrhosis and hepatocellular carcinoma (HCC).

Figure 2

Liver damage caused by type 2 DM. Insulin resistance promotes release of free fatty acids (FFA) from adipose tissue. The FFAs are accumulated in the liver cells, and de novo liponeogenesis (DNL) contributes also. The reduced secretion of very low density lipoprotein (VLDL) by hepatic cells saturates hepatocytes producing steatosis. Mitochondrial oxidative stress is increased as a result of excess intracellular FFAs and the influence of adipokines (leptin and tumor necrosis factor alpha (TNF-α). Excess of oxidative stress produces free radicals which in turn induces inflammation and cellular necrosis. Tissue inflammation stimulates the stellate cells to produce collagen.

Figure 3

Etiology of liver cirrhosis most frequently associated with diabetes mellitus.

Figure 4

Pathophysiology of hepatogenous diabetes. One of the main abnormalities is insulin resistance in muscular cells and the hepatic tissue. Insulin resistance in muscle impairs non-oxidative and oxidative glucose metabolism. The reduction of insulin clearance by the damaged liver and the presence of portosystemic shunts in one hand and the desensitization of the beta cells of the pancreas produced by diverse factors on the other hand may produce hyperinsulinemia. With progression of the diabetes there is a reduction in sensitivity of β-cells for production of insulin.