Increasing serum levels of IgM anti-HCV are diagnostic of recurrent hepatitis C in liver transplant patients with ALT flares

Summary.  Recurrent hepatitis and acute rejection share common features which make difficult for diagnosis in liver transplant hepatitis C virus (HCV) positive patients. We studied the usefulness of quantitative monitoring of HCV RNA and immunoglobulin (Ig)M anti-HCV in the differential diagnosis between recurrent hepatitis and acute rejection in 98 consecutive anti-HCV positive liver transplant patients. Aminotransferase levels, serum HCV RNA and IgM anti-HCV were measured at the time of transplantation and monthly thereafter. A liver biopsy (LB) was obtained when serum aminotransferase levels increased to twice or more than normal. During a mean follow-up of 16 months 86 aminotransferase flares were observed. Histology was compatible with recurrent hepatitis C in 44 cases and with acute rejection in 28, doubtful in 14. The fluctuations of HCV RNA serum levels were not significantly different in the three groups. Serum IgM anti-HCV levels increased (from negative to positive or with value variations ≥ 0.18) in 36 of 44 cases with recurrent hepatitis C at the time of alanine aminotransferase (ALT) flare. IgM anti-HCV remained unchanged in all rejection cases ( P  < 0.001), but increased in 10 of 11 histologically doubtful cases that were diagnosed as hepatitis at the second LB. Increasing serum levels of IgM anti-HCV at the time of ALT flares are significantly associated with recurrent hepatitis C in liver transplant patients. The quantitative monitoring of IgM anti-HCV appears to be an additional diagnostic tool for distinguishing recurrent hepatitis C from acute graft rejection with a 100% specificity; 100% positive predictive value and 88.9% diagnostic accuracy.     

Detectable levels of IgM antibodies to hepatitis C virus core protein predict breakthrough in patients with chronic hepatitis C treated with interferon-α

Summary. The predictive value of IgM antibodies to hepatitis C virus core antigen (HCcAb) is controversial. We studied 79 patients undergoing interferon-α (IFN-α) treatment and we found that detectable levels of IgM HCcAb could predict breakthrough on treatment.     

Predictive value of IgM antibodies to hepatitis C virus in patients with chronic hepatitis C undergoing interferon-α therapy. Analysis by two different methods

SUMMARY. To determine the predictive value of IgM anti-hepatitis C virus (HCV) testing in patients with chronic hepatitis C infections undergoing interferon-α (IFN-α) therapy, IgM anti-HCV reactivity was analysed by two different methods (non-commercial and commercial) in 19 patients and monitored at times 0 (pre-treatment), 3, 6, 12. and 24 months during follow-up. Eight patients were non-responders, five remained in sustained response 1 year after stopping treatment, and six had a relapse. No correlation between alanine transaminase (ALT) levels and IgM anti-HCV reactivity was found by either method in baseline samples. In addition, neither the presence nor absence of IgM anti-HCV in baseline samples, nor the loss of specific IgM reactivity during treatment, had any predictive value. Finally, no other parameters analysed (age, sex, risk group and histological diagnosis), were significantly associated with IgM anti-HCV reactivity in our study. In summary, these results suggest that baseline detection and monitoring of IgM anti-HCV reactivity are not useful in predicting the sustained response to IFN-α therapy in chronic hepatitis C infection.     

The effects of hepatitis C recurrence on health‐related quality of life in liver transplant recipients

Orthotopic liver transplantation (OLT) remains the definitive treatment for hepatitis C (HCV). Although HCV is the number one indication for OLT in the USA, health‐related quality of life (HRQOL) scores are consistently lower for HCV patients when compared with all OLT indications. HCV is unique in that 95% of transplanted patients experience virological recurrence of HCV hepatitis. Despite few physical manifestations of disease at the time of HCV recurrence, patients report an impaired quality of life and functional status compared with OLT recipients without recurrence. Studies show that patient knowledge of the diagnosis of recurrent HCV alone can negatively impact HRQOL. This suggests that patients perceive themselves as unwell and have significant changes in their mental and physical health despite the absence of disease‐related complications. Multiple studies show that patients with HCV recurrence report significantly higher scores for depression, anxiety and psychological distress. However, only a limited number of studies have investigated the influence of gender, HCV genotype, or HCV antiviral treatment on the HRQOL of OLT recipients with HCV recurrence. This review article describes what is currently known about the impact of recurrent HCV on HRQOL specifically after OLT. Understanding modifiable factors on HRQOL after HCV recurrence in OLT patients can greatly aid in tailoring multidimensional interventions to improve patient HRQOL.     

Mortality predictors in liver transplant recipients with recurrent hepatitis C cirrhosis.

BACKGROUND/AIM: Recipients of orthotopic liver transplant for hepatitis C (HCV) invariably develop recurrent disease. The risk factors for death and retransplantation following the development of cirrhosis from HCV are unclear. The aim of this study was to identify predictors of survival in liver transplant recipients who develop cirrhosis from recurrent HCV. METHODS: We reviewed records of patients who underwent liver transplantation for cirrhosis due to HCV between January 1990 and December 2001. Prognostic factors of patient survival following the development of recurrent cirrhosis were identified through multivariate analysis. RESULTS: During the study period, 511 patients underwent transplantation for HCV cirrhosis. Of these, 65 patients (13%) developed biopsy proven recurrent cirrhosis from HCV; 43 (8%) were relisted for transplantation, and 24 (5%) underwent retransplantation. The overall Kaplan-Meier patient survival rates after the histologic diagnosis of cirrhosis at 1 and 5 years were 66% and 30%, respectively. A multivariate Cox proportional hazards model showed patients with higher last (i.e. at follow-up or prior to retransplantation) International normalized ratio (INR) values (hazard ratios (HR)=2.02, 95% confidence interval 1.26, 3.24, P<0.01) to have an increased risk of death. CONCLUSION: Our results suggested survival was decreased after the diagnosis of cirrhosis from recurrent HCV. Higher INR was associated with an increased risk of death following the development of cirrhosis.     

IgM and IgA antibodies generated against hepatitis C virus core antigen in patients with acute and chronic HCV infection

Antibody subclasses directed against the core protein (HCc) of hepatitis C virus (HCV) were measured in 27 patients with acute non-A, non-B (NANB) hepatitis, and 99 patients with chronic HCV-associated liver disease. IgM, IgA, and IgG anti-HCc responses were observed in 11 (40.7%), 7 (25.9%), and 18 (67%) patients with acute NANB hepatitis, respectively. Twenty-four (24.2%) and 40 (40.4%) patients with chronic HCV infection also had detectable IgM and IgA, respectively. IgM anti-HCc inconsistently detected acute infection, and HCV ribonucleic acid (RNA) could be detected preceding the rise in anti-HCc antibodies in five consecutive patients with acute hepatitis. IgM anti-HCc also could not distinguish acute from chronic infection and did not correlate with histologic progression. However, the form of IgA present (polymeric vs monomeric) did discriminate acute from chronic infection and the IgA anti-HCc titer correlated with histologic evidence of liver disease in patients with chronic HCV infection.     

Serum levels of anti-hepatitis C virus IgM core antibodies may predict the response to interferon-α therapy in chronic hepatitis C

SUMMARY. We measured the optical densities (OD) of serum anti-hepatitis C virus IgM core antibodies in 40 HCV-positive patients (24 males and 16 females) with histologically proven chronic active hepatitis but without cirrhosis. All patients were treated with i.m. injections of 3 MU thrice weekly of interferon-α (IFN-α) for 6 months and followed-up monthly. Optical densities were evaluated in thawed sera before beginning treatment and 6 months after completion, and in fresh sera obtained at the end of an 8–12-month follow-up period. Patients were grouped into three categories according to the OD obtained: <0.3 (negative test): 0.3-0.6 (intermediate positivity): >0.6 (high positivity). According to the response to treatment during the follow-up period, patients were further divided into three classes: sustained responders: relapsers or partial responders: non-responders. In each patient, the OD values were similar in the three determinations before, after therapy and at the end of the follow-up period. All patients with an intermediate positive test for anti-HCV IgM core antibodies were relapsers or partial responders, and all patients with high OD values were non-responders. Conversely, 71% of the patients with a negative test were sustained responders. We conclude that this cheap and easily performed test may be useful in predicting the response to IFN therapy.     

The fluctuations of hepatitis C virus RNA and IgM anti-HCV (core) serum levels correlate with those of alanine aminotransferases during the hepatitis relapses of patients treated with interferon

Summary. Variations in the serum levels of hepatitis C virus (HCV) RNA, IgM antibody against the HCV 'core' structural protein (c22) and alanine aminotransferase (ALT) were measured in 23 patients with chronic hepatitis C who underwent therapy with interferon-α2a (IFNα2a). Low pretreatment levels of viraemia and undetectable IgM anti-core were significantly associated with a long-term response to treatment. In patients with hepatitis relapses after the end of treatment, HCV RNA levels increased before or at the same time as ALT in 29 out of 34 cases (85%). ALT flares occurred before or simultaneously with IgM anti-core elevations in 18 out of 20 cases (90%). Therefore, post-treatment hepatitis C exacerbations show the same sequence of events seen as in hepatitis B exacerbations (increases of viraemia followed by those of ALT and IgM anti-'core'). These findings underscore the diagnostic and prognostic usefulness of monitoring anti-HCV-positive patients with quantitative assays for HCV markers.     

Calcineurin inhibition and disease recurrence in the hepatitis C virus-positive liver transplant recipient.

Development of hepatitis C virus (HCV)-related disease following liver transplantation is more aggressive than in non-transplant individuals, and accounts for approximately 10% of liver allograft failures. HCV disease progression appears to have accelerated in recent years, possibly due to the aging donor population and/or changing immunosuppression regimens, and survival among HCV-negative patients is falling. Various risk factors have been proposed for HCV disease recurrence, but choice of calcineurin inhibitor is one of the few that can potentially be modified by the physician. Cyclosporine (CsA) has been shown in vitro to suppress HCV replication as effectively as interferon alpha (IFN-alpha), an effect that is separate from the immunosuppressive activity of CsA. Data from bone marrow patients and non-transplant patient populations confirm that CsA inhibits HCV replication. This anti-HCV effect is not seen with tacrolimus. Histologically, there is evidence that progression of fibrosis in HCV-positive liver transplant patients may be slower with CsA than tacrolimus. The clinical implications of the anti-HCV effect of CsA require evaluation versus tacrolimus in a large-scale multicenter study.     

Risk factors for hepatitis C recurrence after liver transplantation

Summary.  Hepatitis C virus (HCV)-related end-stage liver disease is the main indication for liver transplantation performed in Europe and the United States. Recurrence of hepatitis C in the graft is universal and may lead to chronic hepatitis in most patients and to cirrhosis in 20–30% of patients within 5–10 years of transplantation. The natural history of HCV recurrence is highly variable but leads to a lower survival rate than other recurrent liver diseases. The immunosuppressed status and several other factors have been linked with the pattern and severity of recurrence. What remains controversial are those factors associated with fibrosis progression and how these could be modified to improve outcome of recurrent hepatitis C. No single factor but a combination of several factors is associated with fibrosis progression on the graft. The major factors associated with accelerated disease recurrence include: high viral load pre- (>10⁶ IU / mL) and / or early post-transplantation (>10⁷ IU / mL at 4 months), donor older than 40–50 years, prolonged ischaemic time, cytomegalovirus coinfection, over immunosuppression and / or abrupt changes in immunosuppression, HIV coinfection, infection by genotype 1b. Cautious follow-up of the pathology of the graft is mandatory including routine biopsies and / or noninvasive monitoring of fibrosis.     

A simple,noninvasive test for the diagnosis of liver fibrosis in patients with hepatitis C recurrence after liver transplantation

Summary. Recurrent hepatitis C is a common cause of graft loss in patients undergoing liver transplantation, and serial protocol liver biopsies have been used to identify patients at risk of graft loss from rapid fibrosis progression. The aim of this study was to derive a simple noninvasive index to predict fibrosis in patients with recurrent hepatitis C post‐transplant. A retrospective study was performed assessing serial liver biopsies for post‐transplant chronic hepatitis C infection. One hundred eighty‐five patients were included in the analysis; median age 53 years (interquartile range 48–59) and 140 (76%) were male. Liver histology showed 53 (29%) had Ishak fibrosis stages F0/F1, 31 (17%) had F2, 29 (16%) had F3, 19 (10%) had F4 and 53 (29%) had F5/F6. The London Transplant Centres’ (LTC) score was derived combining aspartate aminotransferase (AST IU/L), time from liver transplant (TFLT months), international normalized ratio and platelets. Diagnostic accuracy of the LTC score was assessed using area under receiver‐operating characteristic (ROC) curves. The area under the ROC curve for moderate fibrosis (F ≥ 2) was 0.78 (95% CI, 0.70–0.86; P < 0.0001), for advanced fibrosis (F4–6) was 0.80 (95% CI, 0.72–0.87; P < 0.0001) and for cirrhosis was 0.80 (95% CI, 0.72–0.88; P < 0.0001). An optimal cut‐off value of 6.3 distinguished patients with no or mild fibrosis (F ≤ 1) odds ratio 10.8 (95% CI, 5.1–22.9); P < 0.0001), sensitivity 88%, specificity 60%, negative predictive value 67% and positive predictive value 84%. The LTC score can identify patients with Hepatitis C virus recurrence following liver transplant with a low risk of significant fibrosis, thus avoiding the need for protocol biopsy.     

Anti-HCV immunoglobulin M antibody in patients with hepatitis C

Anti-hepatitis C virus (HCV) immunoglobulin M antibody titres were measured by an enzyme-linked immunosorbent assay method in 16 patients with non-A, non-B acute hepatitis (NANB AH), 13 with non-A, non-B fulminant hepatitis (NANB FH) and nine with type C chronic hepatitis. Anti-HCV IgM was positive in one of the 16 patients with NANB AH, six of the 13 with NANB FH, and five of the nine with type C chronic hepatitis. Anti-HCV IgG was positive in eight of the 16 patients with NANB AH and eight of the 13 with NANB FH. Either anti-HCV IgM or anti-HCV IgG were positive in 10 of the 13 patients with NANB FH. All of the five anti-HCV IgM positive patients with type C chronic hepatitis were undergoing an exacerbation of the diseases, while all of the anti-HCV IgM negative patients were in a remission stage which had lasted for more than 6 months. The findings of this study suggest that anti-HCV IgM is useful for the early diagnosis of type C FH and may be a useful marker of diseases activity in type C chronic hepatitis.     

Immunopathogenesis of hepatitis C virus in the immunosuppressed host

The prevalence of chronic hepatitis C virus (HCV) infection among various groups of immunosuppressed patients is high. These groups include patients co‐infected with human immunodeficiency virus (HIV), recipients of organ transplants, and those with hypogammaglobulinemia. The liver disease in the immunosuppressed host is typically severe with an unusually rapid progression to cirrhosis. This is somewhat paradoxical, as the classical model for HCV‐induced liver disease assumes that cell‐mediated immune responses induce liver injury. It is likely that a combination of viral‐related factors and host‐related factors plays a role in this accelerated natural history of HCV. Data are accumulating in immunocompromised hosts that address the immunopathogenesis of liver injury, although there are still fundamental gaps in our understanding of this process. In this review, we will focus on our current understanding of the mechanisms of liver injury and how it relates to the accelerated liver disease progression in immunocompromised hosts.     

Repeated radiofrequency ablation for the distant recurrence in the liver in patients with chronic hepatitis C virus infection achieving long-term survival

Recurrence of hepatocellular carcinoma (HCC) is frequently observed in patients with hepatitis C virus (HCV) infection and the incidence of HCC recurrence is as high as 20% in these patients even after a complete curative treatment is given for the HCC nodules. We report a 57-year-old female who was referred to our hospital for the treatment of a HCC nodule of 1.8 cm diameter in S5 and having liver cirrhosis of Child–Pugh A classification with HCV infection in April 1999. The HCC nodule showed hypervascularity by computed tomography during hepatic arteriography (CTHA) and was coagulated by microwave under peritoneoscopy. Complete necrosis was confirmed by enhanced-CT scan after microwave coagulation. Thereafter, interferon alfa-2b (3MU, twice weekly) was given but HCV RNA continued to be positive. Thereafter, recurrence of HCC was noted five times in S1, S2, S6; treatment by radiofrequency ablation was given four times; and transarterial chemoembolization was carried out once. Since January 2004, peg-interferon alfa-2a (90 µm/week) has been administered, and no recurrence has been detected until August 2005. She is currently 63 years old, and quite well. Five-year-survival rate in HCC patients treated by radiofrequency ablation is 62.7% in our hospital, however, the recurrence rate is as high as 26.4% per year in the patients with chronic HCV infection. It is a point of controversy when liver transplantation should be recommended in HCC patients with liver cirrhosis of Child-Pugh A classification having chronic HCV infection because of the high incidence of recurrence.     

Long-term follow-up of anti-hepatitis C virus antibodies in patients with acute nonA nonB hepatitis and different outcome of liver disease

Abstract: We screened 74 patients with nonA nonB acute hepatitis (37 of post-transfusion PTH, and 37 of non-post-transfusion, NPTH, origin) for the presence of anti-HCV by tests detecting either C100–3 antibodies alone (ELISA I) or C100–3 plus C33c plus C22–3 antibodies (ELISA II). Samples were taken at the onset of disease and then serially for a period of time ranging from 12 to 60 months. An increased number of anti-HCV positive cases (86% vs 69%) and an earlier seroconversion were observed with the second compared to the first generation ELISA. Positive samples were confirmed by recombinant immunoblot assay (RIBA), which was also used to study the kinetics of the antibody response to individual HCV antigens. Anti-C33c and anti-C22–3 antibodies were the first detectable markers of HCV infection in 80% and 20% of the patients, respectively. Thirty-two percent of the patients studied showed complete and persistent biochemical recovery, whereas 68% maintained a chronic elevation of the transaminase values. Among the 20 patients who showed early and persistent normalization of the transaminase values, complete disappearance of all antibody reactivities was limited to five of them, whereas in four cases only anti-C100–3 and anti-5–1-1 became negative.     

HLA-DRB1 donor-recipient mismatch affects the outcome of hepatitis C disease recurrence after liver transplantation

BACKGROUND & AIMS: This study extends our previously reported observations that various immunological factors are associated with the occurrence of histologically proven recurrent hepatitis C. The two specific issues investigated were to confirm the associations of MHC alleles and donor/recipient mismatch with the occurrence of recurrent hepatitis C in an independent cohort of newly transplanted patients and to look for immunologic and nonimmunologic variables affecting the severity of the recurrent disease. METHODS: Two separate cohorts of consecutive patients were studied: a look-back cohort (LC) of 120 patients and a cohort for studying the disease progression (CSDP) of 190 patients. Protocol liver biopsies were obtained at least 1, 3, 5, 7, and 10 years after liver transplantation (LT). RESULTS: A fully mismatched donor/recipient pair at the DRB1 locus was confirmed to be associated with both the recurrence of histologic hepatitis in the LC (59% vs 23%, P = .0002) and its progression beyond stage 3 in the CSPD (71.4% vs 39.3%, P = .0003). Relevant immunologic and nonimmunologic variables were included into a multivariate Cox proportional model and three variables, namely, donor age, full HLA-DRB1 donor-recipient mismatch, and HLA B14, resulted in independent risk factors for the development of severe fibrosis. CONCLUSION: This study provides evidence that DRB1 donor-recipient mismatch affects both the occurrence and progression of recurrent hepatitis C disease. This information is clinically relevant as it may help to better allocate organs and to recognize patients at risk for progression so that specific interventions can be implemented.     

Epidemiological characteristics of the incidence of hepatitis C virus (C100-3) antibodies in patients with liver diseases in the Inshore Area of the Yangtze River

Abstract The Nantong area is an endemic region of hepatitis B virus (HBV) infection in the inshore area of the Yangtze River. However, no detailed data are available about hepatitis C virus (HCV) infection in this area. In this study recent reports are reviewed about the incidence of viral hepatitis and primary hepatocellular carcinoma (PHC) in China, and it is shown that the Nantong area is a high risk region for PHC. This study reports on the incidence of antibody to HCV (anti-HCV) in patients with chronic liver diseases in the Nantong area; investigated in collaboration with members of the Nantong Medical College, Jiangsu Province, the People's Republic of China. The incidence of anti-HCV (C100-3) in the Nantong area was: 0.67% (three of 451) in donor blood; 0.0% (none of 89) in patients with acute hepatitis; 2.7% (five of 186) in those with chronic hepatitis, 4.5% (two of 44) in those with liver cirrhosis; 6.3% (one of 16) in those with PHC; and 1.3% (one of 78) in patients without liver disease. The incidence of hepatitis B surface antigen in the Nantong area was: 15.7% (14 of 89) in patients with acute hepatitis; 81.2% (151 of 186) in those with chronic hepatitis; 81.8% (36 of 44) in those with liver cirrhosis; 87.5% (14 of 16) in those with PHC; and 20.5% (16 of 78) in patients without liver disease. Although the Nantong area is a high risk region for PHC, these data suggest that HCV infection is not an important aetiological factor for PHC in this area.