Hepatitis C virus (HCV) is one of the leading causes of liver damage.1 About 3.2 million people in the United States are thought to be infected with hepatitis C virus, with the highest prevalence among people born between 1945-1965.2 Hepatitis C is a blood borne pathogen which is transmitted through risk factors including injection-drug use, intranasal drug use, accidental needle pricks and tattoos to name a few.3 Recently a link has been found between the HCV and metabolic syndromes showing that HCV acts as an independent predictive factor for diabetes mellitus.1 Understanding the way HCV works and the medications that show the most benefit is important in patient better outcomes.
The HCV has been found to play a role in many areas leading to insulin resistance:
· Proteins on the virus play a role in the cascade of inflammation reactions through numerous pathways leading to an overall increase in interleukin-6, interleukin 8, tumor necrosis factor-α and transforming growth factor- β which lead to oxidative stress.1
· HCV inhibits peroxisome proliferator-activated receptor (PPAR)γ and PPARα which are needed for proper metabolism triglycerides and lipids causing an accumulation of hepatic lipids and an increase in insulin resistance.1
· Decreased levels of adiponectin receptors are seen in HCV patients. Since adiponectin has anti-arthogenic and anti-inflammatory properties, decrease in activity leads to insulin resistance.1
· HCV plays a role in down regulation of some insulin receptors decreasing the effects of insulin in the body.1
· HCV is found to upregulate activity of dipeptidyl peptidase-1 (DDP4) in the liver. Since DDP4 is the enzyme responsible for breakdown of GLP1 there is a decrease in GLP-1 in the body.4
One issue to consider HCV is that the virus has numerous genotypes which each have a different response in terms exactly how the insulin resistance is caused.5 Knowing the patients genotype can help guide the medication choice with the treatment of insulin resistance. Genotype 1 and 4 have shown significant insulin resistance.6 Genotype 3a on the other hand has shown to have a greater effect on fatty acid synthase. PPAR plays a key role with the genotype 3a making the use of thiazolidinediones, such as pioglitazone, useful in these patients. Researchers have looked both at the effects of treating HCV with antivirals to improve insulin resistance as well as adding metformin or pioglitazone to HCV treatment to increase viral response to antiviral agents.5,7,8 Mixed results have been found in both areas which might be related to the type of HCV genotype the patient is infected with If the genotype is not reactive to the mechanism being treated little or no effect could be seen.
Additionally, DPP4 plays a role in insulin resistance in HCV patients. Based on the fact that DPP4 levels are alternated by HCV the hypothesis can be made that DPP4 inhibitors would be effective in hepatitis C patients, but they have yet to be tested.
Much more research needs to be done in this area to help develop the correct treatment plan for our patients with hepatitis C and insulin resistance. Proper treatment and education will help the patient in with HCV.
Take home points:
- A full medical history is always important when treating our patients.
- In a patient with a normal BMI that is not positive to insulin antibodies and GAD, recommend a hepatitis C titer to rule out the possibility of insulin resistance from HCV.
- Researchers have found that metformin is a good option for the treatment on patients with HCV. In a patient with genotype 3, pioglitazone might also be an effective option.
- DPP4 antagonists have not been tested in patient for efficacy but research shows they might have a roll in treatment.
- Knowing the status of a patients hepatitis C can impact their diabetes treatment as well as the medication options. Information on HCV genotype can help in proper treatment of the patient.
- Since viral load can impact insulin resistance, follow during and after HCV treatment will help assess if any medication adjustments are needed.
References
1) Sheikh et al, Hepatitis C Virus infection: molecular pathways to metabolic syndrome, hepatology 2008; 47:2127- 2133.
2) Center for Disease Control, CDC DVH – Hepatitis C Information for the Health Professional - http://www.cdc.gov/hepatitis/hcv/. Accessed February 8, 2014.
3) American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. Recommendations for Testing, Managing, and Treating Hepatitis C, Full report. HCV testing and linkage to care. http://www.hcvguidelines.org/full-report/hcv-testing-and-linkage-care. Accessed February 5, 2014.
4) Ahmadieh H and Azay ST, Liver disease and diabetes: association, pathophysiology, and management. Diabetes Research and Clinical Practice. In press corrected proof. Available online 14 January 2014 http://www.sciencedirect.com.ezproxy.mcphs.edu/science/article/pii/S0168822714000059#. Accessed February 8, 2014.
5) Harrison et al. Chronic Hepatitis C Genotype 1 patients with insulin resistance treated with pioglitazone and peginterferon alpha-2a plus ribavirin. Hepatology 2012; 56:464-473.
6) Serfaty L and Capeau J, Hepatitis C, insulin resistance and diabetes: clinical and pathogenic data. Liver international 2009; 29(s2): 13-25
7) Romero-Gomez M, Diago M, Andrade RJ, Calleja JL, et al. Treatment of Insulin Resistance with Metformin in Naïve Genotype 1 Chronic Hepatitis C patients Receiving Peginterferon Alfa-2a Plus Ribavirin. Hepatology 2009; 50: 1702-1708.
8) Yu Jian-Wu, Sun Li-Jie, Zhao Yong-Hua, Kang Peng, Yan Bing-Zan. The Effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance. International J of Inf Dis 2012; 16: e436-e441.
Illinois CB Blog was written by Denise MacKenzie, BSPharm, PharmD Candidate 2014 Illinois