Severe Insulin Resistance in a Treatment-Naive Chronic Hepatitis C Patient

The association between diabetes mellitus (DM), insulin resistance, and chronic hepatitis C (CHC) has been noted but, as of yet, is not fully understood. Much of this discussion has centered on the relationship between type II DM and CHC infection that is presumed to be secondary to interferon therapy for CHC. We report the case of a man with CHC infection, DM, and the sudden, severe worsening of glycemic control. Here, we discuss a case of severe insulin resistance as a complication of CHC infection and review the associated literature.

Case Report

A 43-year-old man with a history of type II DM, hypertension, normocytic anemia, depression, past cocaine abuse, and ongoing alcohol abuse began experiencing markedly increased insulin requirements and simultaneously began to suffer frequent florid episodes of diabetic ketoacidosis (DKA). During the ensuing year, he was hospitalized more than 10 times with florid acidemia due to ketonemia. Insulin requirements over the course of that year were exceptional; even after resolution of his diabetic ketoacidotic state, the patient required in excess of 1,500 units daily of a short-acting insulin administered via a sliding-scale system. Multiple attempts to introduce intermediate- or long-acting insulin preparations were unsuccessful and resulted in additional medical attention for symptomatic hypoglycemia. Due to a history of nonadherence, it was felt that the patient was not an appropriate candidate for an insulin pump. Prior to his first episode of DKA, the patient had been controlled on less than 100 units daily of an intermediate-acting insulin for approximately 4 years prior.

During the same year that the patient's DM became difficult to control, he was diagnosed with CHC infection, with an initial viral load of 517,000 copies. On the assumption that his severe insulin resistance was associated with the underlying CHC infection, the patient was initiated on plasmapheresis. Although plasmapheresis resulted in a modest and transient improvement in blood sugar control, procedure-associated hypotension prevented the ongoing use of this therapy. The patient did not undergo liver biopsy, though he did have sonographic findings consistent with cirrhotic liver disease. He was not considered a candidate for antiviral therapy secondary to a history of alcohol and cocaine abuse and poor support system.

An anti-insulin receptor antibody level was obtained and found to be negative. HIV testing and hepatitis B testing, additionally, were negative. However, the patient, in several instances, tested positive for cocaine metabolites on toxicology screening.

Discussion

Although advanced liver disease of any etiology may alter glucose metabolism, evidence is accruing to support a particular association between CHC and DM.^1–3 In the case of our patient, it remains unclear why the requirement for insulin increased so dramatically, particularly in the absence of interferon therapy. The majority of reported cases of DM in association with CHC appear to be of the noninsulin-dependent variety and occur during or after treatment with interferon therapy.⁴ Our patient represents an unusual and, as of yet, unreported example of a severely insulin-resistant, treatment-naive CHC patient. To the best of our knowledge, this case report is the first reported case of severe insulin resistance seen in a patient with concurrent DM and CHC without interferon administration.

Several mechanisms have been suggested for the reported association between DM and CHC, including increased levels of tumor necrosis factor-α (TNF-α) as well as changes at the cellular level induced by the hepatitis C virus. Increased activity of TNF-α results in a number of metabolic changes at the molecular level, including inhibition of insulin-stimulated tyrosine phosphorylation of insulin receptor and insulin receptor substrate-1 (IRS-1); stimulation of lipolysis; increased hepatic insulin resistance; and interference with beta-cell function.⁵ The primary source of increased TNF-α appears to be due to hepatic macrophages that are upregulated as part of the immune response to the hepatitis C virus.⁶ No TNF-α studies were conducted on this patient.

Further discussion has centered upon the intrinsic effect of the hepatitis C virus and subsequent mutation at the genetic level. Evidence has shown that the virus core may induce the suppressor of cytokine signaling-3 gene (SOCS3) to promote proteasomal degradation of IRS-1 and -2, thereby resulting in downregulation of insulin receptors.⁷ Another proposed mechanism may include changes in the sterol regulatory element-binding protein synthesis pathway that may further alter insulin signaling.⁸ Finally, extrahepatic effects of the virus may include injury to islet cells, leading to beta-cell dysfunction.⁹ Whether this dysfunction is due to the effect of the virus itself or to the autoimmune reaction induced by the virus is unclear. Genetic studies were not conducted on this patient.

There is ongoing discussion regarding the factors that may influence the level of insulin resistance. Postulated factors include the extent of the level of liver injury and the genotype of the virus.^1,2 The patient underwent virologic and biochemical assessments, but he did not have histologic assessment of his liver injury.

In conclusion, there are multiple mechanisms under discussion that may explain insulin resistance in CHC infection. It appears likely that the hepatitis C virus has direct effects on hepatic genetic machinery, resulting in changes in glucose metabolism. Most current discussion has focused on interferon-induced type II DM, but in this treatment-naive patient, the severe insulin resistance most likely appears to be due to effects of the hepatitis C virus itself. Although the patient's confirmed cocaine and alcohol abuse could have certainly contributed to his altered glucose handling, the degree and sustained nature of his insulin requirements make the attribution of his hyperglycemia and ketonemia to drug abuse alone appear to be less likely.