Relationship Between HCV Infection and Haematological Malignancies
Hepatitis C virus (HCV) is a positive sense, single-stranded RNA virus of 9.6 Kb in length belonging to the Flaviviridae family. The viral genome encodes for a polyprotein that is cleaved by cellular and viral proteases to yield 10 individual proteins, which can be classified as structural (core, E1 and E2) and nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B). Chronic HCV infection is a major cause of cirrhosis and HCC and accounts for approximately 25% of deaths due to cirrhosis and 20% of deaths due to HCC globally. The prevalence of chronic HCV is estimated to be around 2.5%–3% translating to an estimated 71 million persons worldwide. HCV prevalence varies widely among countries. It is higher than 10% in some African and Eastern Mediterranean countries and can reach almost 20% among adults in Egypt. In the United States, the prevalence ranges between 1.3% and 1.9% while in Europe it ranges between 0.4% in Northern European and 3% in Mediterranean countries. A prevalence over 5% has been reported in some communities in central Italy, and a survey conducted in a southern Italian town in 1996 showed a prevalence in the general population as high as 12.6%.[12–15]
About 15%-45% of acutely infected persons spontaneously clear the virus within 6 months, whereas the remaining 55%-85% of persons will become chronically infected and 15%-30% of them will develop liver cirrhosis within 20 years. Once cirrhosis develops, 2%-4% of patients may evolve towards liver failure or HCC annually. Several host, viral and environmental factors may influence the rate of disease progression.
Chronic HCV infection is also associated with several extrahepatic manifestations, which include keratoconjunctivitis sicca, lichen planus, glomerulonephritis, porphyria cutanea tarda, autoimmune thyroid dysfunction and essential mixed cryoglobulinemia. These extrahepatic manifestations are mostly related to the lymphotropism of HCV and to the chronic persistent antigenemia resulting in sustained B-cell activation. It is estimated that 40%-74% of patients with chronic HCV infection may develop at least one extrahepatic manifestation during the course of the infection.[18,19]
Chronic HCV infection is responsible for up to 90% of all cases of essential mixed cryoglobulinemia (EMC) syndrome. The syndrome is the result of the production of polyclonal IgG and monoclonal (type II) or polyclonal (type III) IgM with rheumatoid factor activity. Clinical manifestations range from mild vasculitis with purpura, arthralgias and weakness to a more severe vasculitis with renal and central nervous system involvement. Serologically, EMC is characterized by the presence of circulating cryoglobulins, low complement levels and positive rheumatoid factor. Cryoglobulins are immunoglobulins that precipitate at a temperature below 37°C. The prevalence of EMC varies geographically and is more prevalent in Southern Europe than Northen Europe and North America. EMC is more common in females with a female/male ratio of 3:1. The clinical diagnosis of EMC is often difficult because the patient may present with one predominant clinical symptom such skin ulcers or hepatitis or glomerulonephritis rather than the complete syndrome, that can delay the correct diagnosis. Sometimes, patients show a typical cryoglobulinemic syndrome without measurable cryoglobulins in serum. This is a transient phenomenon linked to the variability of the percentage of cryoprecipitable immune-complexes. Therefore, several cryoglobulin determinations are necessary in these patients to make a correct diagnosis. Over time, EMC can evolve into frank B-cell lymphoma. Persistent viral infection stimulates the proliferation of B-cell clones suggesting a role for HCV in pathogenesis of the malignancy. About 5% of patients with EMC type II develop a malignant B-cell lymphoma.
Persons with chronic HCV infection have a higher risk of developing non-hepatic malignacies than the general population. A large cohort of 12 126 US patients with chronic hepatitis C followed to assess the incidence of non-hepatic malignancy reported a significantly higher incidence of the following cancers: liver (SRR, 48.6 [95% CI, 44.4–52.7]), pancreas (2.5 [1.7–3.2]), rectum (2.1 [1.3–2.8]), kidney (1.7 [1.1–2.2]), non-Hodgkin lymphoma (NHL) (1.6 [1.2–2.1]) and lung (1.6 [1.3–1.9]). Numerous studies demonstrated a strong association between HCV and NHL with a predominantly B-cell type.[24–26] Moreover, several meta-analyses report an association of variable magnitude, which may be explained by different geographical prevalence of HCV and study designs.[25,27] Two recent meta-analyses found a 2/3-fold increased risk of NHL among HCV-positive patients.[28,29] In addition, the association between HCV and NHL is strongest in geographical areas where the prevalence of viral infection is very high. Furthermore, regression of NHL after successful HCV eradication with antiviral therapy has been demonstrated.[31,32] However, despite the extensive epidemiological evidence supporting a link between HCV infection and development of NHL, direct mechanistic evidence is lacking.
J Viral Hepat. 2019;27(1):4-12. © 2019 Blackwell Publishing