Two-third of patients with chronic hepatitis C show extrahepatic manifestations due to HCV infection of B lymphocytes, such as mixed cryoglobulinemia and non-Hodgkin B-cell lymphoma, or develop a chronic inflammatory status that may favor the development of adverse cardiovascular events, kidney diseases or metabolic abnormalities.DAAs treatments induce HCV eradication in 95% of treated patients, which also improves the clinical course of extrahepatic manifestations, but with some limitations. After HCV eradication a good compensation of T2DM has been observed, but doubts persist about the possibility of obtaining a stable reduction in fasting glucose and HbA1c levels.Chronic HCV infection is associated with low total and LDL cholesterol serum levels, which however increase significantly after HCV elimination, possibly due to the disruption of HCV/lipid metabolism interaction. Despite this adverse effect, HCV eradication exerts a favorable action on cardiovascular system, possibly by eliminating numerous other harmful effects exerted by HCV on this system.DAA treatment is also indicated for the treatment of patients with mixed cryoglobulinemia syndrome, since HCV eradication results in symptom reduction and, in particular, is effective in cryoglobulinemic vasculitis. Furthermore, HCV eradication exerts a favorable action on HCV-related lymphoproliferative disorders, with frequent remission or reduction of clinical manifestations.There is also evidence that HCV clearance may improve impaired renal functions, but same conflicting data persist on the effect of some DAAs on eGFR.

To summarize the current knowledge about the potential relationship between hepatitis C virus (HCV) infection and the risk of several extra-liver cancers.

We performed a systematic review of the literature, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) Statement. We extracted the pertinent articles, published in MEDLINE and the Cochrane Library, using the following search terms: neoplasm/cancer/malignancy/tumor/carcinoma/adeno-carcinoma and non-Hodgkin lymphomas, kidney/renal-, cholangio-, pancreatic-, thyroid-, breast-,oral-, skin-, prostate-, lung-, colon-, stomach-, haematologic. Case series, case-series with control-group, case-control, cohort-studies as well as meta-analyses, written in English were collected. Some of the main characteristics of retrieved trials, which were designed to investigate the prevalence of HCV infection in each type of the above-mentioned human malignancies were summarised. A main table was defined and included a short description in the text for each of these tumours, whether at least five studies about a specific neoplasm, meeting inclusion criteria, were available in literature. According to these criteria, we created the following sections and the corresponding tables and we indicated the number of included or excluded articles, as well as of meta-analyses and reviews: (1) HCV and haematopoietic malignancies; (2) HCV and cholangiocarcinoma; (3) HCV and pancreatic cancer; (4) HCV and breast cancer; (5) HCV and kidney cancer; (6) HCV and skin or oral cancer; and (7) HCV and thyroid cancer.

According to available data, a clear correlation between regions of HCV prevalence and risk of extra-liver cancers has emerged only for a very small group of types and histological subtypes of malignancies. In particular, HCV infection has been associated with: (1) a higher incidence of some B-cell Non-Hodgkin-Lymphoma types, in countries, where an elevated prevalence of this pathogen is detectable, accounting to a percentage of about 10%; (2) an increased risk of intra-hepatic cholangiocarcinoma; and (3) a correlation between HCV prevalence and pancreatic cancer (PAC) incidence.

To date no definitive conclusions may be obtained from the analysis of relationship between HCV and extra-hepatic cancers. Further studies, recruiting an adequate number of patients are required to confirm or deny this association.

The etiology of non-Hodgkin's lymphoma is unknown in the majority of the cases. Although Epstein-Barr virus, human T-cell leukemia-lymphoma virus and human herpes virus-8 have been established as casual agents in the pathogenesis of specific types of lymphoma, the role of hepatitis C virus (HCV) in lymphomagenesis remains controversial, with marked geographic variability. We conducted an epidemiologic study to evaluate the prevalence of hepatitis C virus infection in patients with lymphoma in South Florida. Ninety consecutive patients with lymphoma and 96 consecutive control patients with solid tumors were tested for HCV. HCV infection was detected in 2 patients with NHL (2.2%) and in 4 control patients (4.1%). Our study does not support the association between HCV and lymphoma in South Florida, US.

There have been various reports on the association of hepatitis C virus (HCV) infection with B lymphocyte proliferative disorders, such as non-Hodgkin lymphoma (NHL). We experienced a case (Case 1) of anti-HCV antibody (HCV-Ab)-positive NHL in which HCV nonstructural protein 3 (NS3) expression was observed in lymphoma tissue at the time of recurrence and in which the serum HCV RNA level exhibited a transient increase prior to recurrence. We investigated the HCV RNA genome in lymphoma tissue in Case 1, and it could be detected at recurrence. We also investigated HCV NS3 protein expression in lymphoma tissue and changes in serum HCV RNA level during the clinical course in four other cases of HCV-Ab-positive NHL treated in our hospital. We examined lymphoma tissues for HCV NS3 protein expression in four of the five cases, but it was not identified except for in Case 1 at recurrence. In three cases with no recurrence, serum HCV RNA levels showed a tendency to decrease after completion of chemotherapy and became stable thereafter. Further studies are necessary to clarify the association between serum HCV RNA and the onset and exacerbation of NHL.

Although a high prevalence of hepatitis C virus (HCV) infection among non-Hodgkin's lymphoma (NHL) patients had been reported, subsequent epidemiological studies conducted to examine a causal association between HCV and NHL have provided inconsistent results across studies. A strikingly positive association has been reported primarily from Italy and Japan, while no association was found in other regions of the world. To clarify the association between HCV and NHL, we conducted a systematic literature review. Eligible study designs were nested case-control studies, population-based case-control studies, and hospital-based case-control studies using non-cancer subjects as controls. The studies published through January 1991 to August 2003 were searched through Medline. Ultimately, 23 studies with 4049 NHL patients and 1,813,480 controls were identified. Summary statistics were crude odds ratios (ORs) comparing the anti-HCV seropositive and seronegative subjects. As we identified heterogeneity between studies, summary statistics were calculated based on a random-effect model. We did not find any evidence of publication bias. The major sources of variation were the use of blood donor controls and year of publication. The summary OR for NHL was 5.70 (95% confidence interval (CI), 4.09-7.96, P < 0.001). The subgroup analysis by phenotype showed a similar trend for B-cell (5.04, 95% CI: 3.59-7.06) and T-NHL (2.51, 95% CI: 1.39-4.56). In conclusion, we found a strongly positive association between anti-HCV seropositive test subjects and risk of NHL. Further biological studies examining this association are warranted.