Seronegative occult hepatitis C virus infection: Clinical implications

Highlights

• OCI may be implicated in 7% of cryptogenic liver cirrhosis.

• OCI seems to play a negative role in hemodialysis and in glomeruloneprihtis patients.

• In OCI the virus replicates and may be potentially infectious.

Abstract

Occult hepatitis C virus infection (OCI) was first described in anti-HCV and serum HCV-RNA negative patients with abnormal values of liver enzymes but who presented HCV-RNA in liver and in peripheral blood mononuclear cells. Up to now, two types of OCI are recognized: seronegative OCI (anti-HCV and serum HCV-RNA negative) and seropositive OCI (anti-HCV positive and serum HCV-RNA negative). The concept of OCI is still a matter of debate, probably because both types of OCI are not considered as different entities. This review focuses on seronegative OCI. The existence of seronegative OCI has been documented all around the world with the implication of different HCV genotypes (1–4). Seronegative OCI is associated with cryptogenic chronic hepatitis and liver cirrhosis and it may be involved in the appearance of hepatocellular carcinoma. Also seronegative OCI may increase the histological liver damage in chronic hepatitis B and in HIV-infected patients. It may have a negative influence in the natural history of hemodialysis patients and in immune-mediated glomerulonephritis. Seronegative OCI has been detected also in patients with haematological diseases, among healthy subjects and in drug users. Other publications indicate the potential infectivity of seronegative OCI in the setting of family members, sexual partners and liver transplantation. In summary, seronegative OCI may play a role in liver diseases and other human pathologies and may be present in healthy people but larger studies are needed to confirm these findings.

Introduction

Occult hepatitis C virus infection (OCI) was first described among patients with cryptogenic chronic hepatitis and abnormal liver function tests who were anti-HCV negative by different commercial assays and serum HCV-RNA negative by standard PCR but presented HCV-RNA in liver and could have viral RNA in peripheral blood mononuclear cells (PBMC) [1]. Later studies demonstrated that OCI may be also diagnosed by concentrating 2 ml of serum by ultracentrifugation followed by HCV-RNA detection by real-time PCR [2]. This procedure increases the sensitivity of HCV-RNA detection eightfold. Also, an in-house immunoassay for HCVcore-specific antibodies allows identification of OCI [3]. Finally, HCV specific CD4⁺ and CD8⁺ T-cell responses have also been detected in patients with OCI and the maintenance of such immune responses indicates that HCV persists and is replicating in the liver and in the PBMC of the patients [4]. For diagnosis of OCI, the most sensitive technique is HCV-RNA detection in liver (100%), followed by the detection in PBMC (up to 70%), in serum after ultracentrifugation (up to 58%) and anti-HCVcore detection (nearly 40%) [1], [5].

Further reports have evidenced the existence of two types of OCI: seronegative OCI (anti-HCV and serum HCV-RNA negative) and seropositive OCI (anti-HCV positive, serum HCV-RNA negative). In both types of infections, patients have HCV-RNA in liver and viral RNA may be detected in PBMC and/or in serum after ultracentrifugation. The seropositive OCI includes patients who presumably have resolved HCV infection (spontaneously or after antiviral therapy) and asymptomatic HCV carriers [6], [7], [8], [9], but other publications (the majority of them in sustained virological responders after antiviral therapy) have not found this seropositive OCI, thus questioning its existence [10], [11], [12], [13]. Regarding seronegative OCI there are many papers that confirm its existence [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], while only a few ones failed to detect it [34], [35], [36]. The majority of the papers that have detected seronegative OCI, confirm the specificity of HCV-RNA detection by sequencing.

There are several differences between seronegative and seropositive OCI patients. The former are anti-HCV negative, have abnormal or normal values of liver enzymes (see later) and have not been treated with antiviral therapy. The seropositive OCI cases are anti-HCV positive, have generally normal liver enzymes and the majority of the reported cases have received antiviral therapy achieving a sustained response. So, both types of OCI should be considered as separate entities to avoid misinterpretation of the results. The present review is focused only in the clinical implications of seronegative OCI, hereafter referred as OCI. It must be remarked that all the articles commented in this review include exclusively anti-HCV and serum HCV-RNA negative cases.