Approximately two-thirds of persons infected with chronic hepatitis C virus experience nonliver manifestations of the disease. Do you know what to look for?
Persons with hepatitis C virus (HCV) infection are well known to be at high risk of developing cirrhosis and liver cancer; in fact, liver-related mortality is estimated at 350 000 deaths annually.1 Evidence has accumulated to suggest approximately two-thirds of those infected with the virus may also experience extrahepatic manifestations, some common and others rare, but all adding to the burden of a multisystem disease.1
Following is a short quiz to help you assess your knowledge of nonliver diseases associated with HCV. Would you know one if you saw it?
1. Individuals with HCV can develop cryoglobulinemia, which most often manifests as Meltzer Triad. Which of the following is not included in Meltzer Triad?
B. Renal disease
Answer: B. Renal disease. Cryoglobulinemia refers to monoclonal or mixed polyclonal immunoproteins that precipitate out of blood when it is cooled below body temperature. The condition can develop when immune complexes with HCV particles deposit in vascular walls, causing vasculitis, chronic stimulation of B-lymphocytes and increased risk for B-cell non-Hodgkin lymphoma.2 HCV-related cryoglobulinemia commonly presents at Meltzer Triad (purpura, myalgia, and arthralgia). Other signs of the condition include chronic leg ulcers, weakness, and peripheral neuropathy.2
2. A 55-year-old man with chronic HCV has new-onset hypertension. Which of the following extrahepatic manifestations of HCV should not be considered as a possible cause of his elevated blood pressure?
C. Lichen planus
D. Membrane proliferative glomerulonephritis
Answer: C. Lichen planus. Hypertension in individuals with HCV can be a symptom of several extrahepatic conditions: nephropathy, cryoglobulinemia, and membrane proliferative glomerulonephritis. Lichen planus is a skin manifestation of HCV infection that appears as flat-topped, purple, itchy bumps that usually appear on the flexor surfaces of the arms and legs.2
3. People with chronic HCV infection are at increased risk for developing type 2 diabetes (T2DM). In this case, insulin resistance is caused by HCV and weight reduction is not considered central to management.
Answer: B. False. People with chronic HCV may have up to 70% increased risk for T2DM, compared to those without HCV.3 While the precise mechanism underlying the vulnerability remains unknown, possibilities include the effect of HCV- related fibrosis and cirrhosis on insulin resistance; a direct effect of the virus on inflammatory cytokines; and the dual impact of obesity and HCV on insulin signaling.2 A key part of management for T2DM in HCV infection includes weight reduction and exercise, along with antihyperglycemics when needed.2
4. Which of the following statements is true regarding chronic HCV and B-cell non-Hodgkin lymphoma?
A. Eliminating HCV infection eliminates the increased risk for virus-associated B-cell non-Hodgkin lymphoma
B. Successfully treating HCV can cause regression of low-grade lymphomas
C. Simultaneous treatment of active HCV and chemotherapy for aggressive B-cell lymphomas is associated with worse prognosis
D. Both A and C
Answer: B. Successfully treating HCV can cause regression of low-grade lymphomas. HCV is associated with increased risk for B-cell non-Hodgkin lymphoma. Eliminating HCV decreases the risk for this cancer but does not eliminate it. Accumulating evidence suggests that successfully treating HCV may lead to regression of low-grade lymphomas.2 Some evidence supports treating these patients with direct-acting antivirals (DAAs) without immediate chemotherapy, followed by close surveillance.2 Studies suggest that treatment for active HCV and chemotherapy for aggressive B-cell lymphomas may improve lymphoma response. Using DAAs may cause less toxicity than interferon-based regimens.2
5. Confirmation of HCV-related renal disease requires which of the following?
B. Microscopic hematuria
C. Decreased creatinine clearance
D. Renal biopsy
Answer: D. Renal biopsy. Confirmation of HCV-related renal disease requires renal biopsy. The most common type of HCV-related renal disease is membranoproliferative glomerulonephritis secondary to type II mixed cryoglobulinemia.2 In this condition, biopsy findings characteristically show immune complex deposition in glomeruli inflammatory cells. Some individuals with HCV, especially those age <60 years, can have albuminuria without overt clinical disease.2
1. Cacoub P. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis. 2016;3:3–14. doi: 10.1177/2049936115585942
2. University of Washington. Extrahepatic conditions related to hepatitis C. Accessed May 9 2019 at: https://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/extrahepatic-conditions/core-concept/all#overview-extrahepatic-manifestations
3. White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49:831-44. doi: 10.1016/j.jhep.2008.08.006.