Alpha-interferon (IFN-alpha) treatment of chronic hepatitis C: analysis of some predictive factors for the response.

Interferon (IFN)-alpha is recognized today as the treatment of choice for chronic hepatitis virus C-related disease. Several factors are able to influence the response to the therapy. In the last few years, several types of IFN-alpha have been used with varying therapeutic results. In order to define the role played by the type of IFN-alpha, as a predictive factor of response to therapy, we studied clinical and biological features of 128 patients (80 males and 48 females, mean age 58.5+/-9.7 years) divided into four homogeneous groups. Four types of IFN-alpha were administered at the same dose and for an identical period. Lymphoblastoid was administered to Group A; recombinant 2a to Group B; recombinant 2b to Group C and leukocyte to Group D. The results showed that the best response was achieved using natural IFN. Statistical evaluation of the predictive factors was carried out using bivariate and multivariate analysis. IFN-alpha was associated with different response rates for viral and biochemical remission at the end of the treatment and at the end of 12 months' follow-up period. Therefore, the type of IFN administered may influence the response to therapy and important independent single predictive factors of response should be taken into account. The type of IFN used may determine how well the disease is controlled.

Rapid evolution of chronic viral hepatitis into hepatocellular carcinoma after beta-interferon treatment.

A 62-year-old man, affected by Chronic Active Hepatitis (discovered in 1993) and treated with interferon, referred to our department with increased abdominal volume, persistent abdominal pain, continuous-remittent fever and jaundice. CT scan of the liver revealed a hypodense, not capsulated, infiltrative, solid formation in the right lobe. US guided biopsy showed multinucleated giant cells, with eosinophilic cytoplasm and pleomorphism of the nuclei, arranged in several thick trabecula lined by endothelial cells or formed bile containing acini. In our case, the rapid evolution of chronic viral hepatitis towards HCC calls for a careful evaluation of the role of IFN therapy, since this drug is widely used in chronic liver diseases.

Efficacy of different schedules in the management of chronic hepatitis C with interferon-alpha.

The best results in terms of clinical remission in chronic hepatitis C are achieved by interferon (IFN)-alpha treatment. We studied 255 patients affected by chronic hepatitis C infection (HCV) and divided into 3 groups. A different IFN-alpha therapeutic schedule was adopted in each group: A) 3 million units (MU) three times per week for 6 months; B) 3 MU three times per week for 12 months; C) 6 MU three times per week for 6 months. A sustained biohumoural and virological remission was observed in only 14.5% of the patients included in group A, in 21.6% of the patients included in group B and in 8% of the patients included in group C. The adoption of more aggressive therapeutic regimens did not offer an improvement in response or patient compliance. At present, the long term efficacy of treatment may be evaluated on the basis of both biochemical and virological data.

Interferon, cortisone, and antivirals in the treatment of chronic viral hepatitis: a review of 30 years of therapy.

Over the last 30 years many approaches have been adopted to treat chronic hepatitis. We conducted a meta-analysis to assess the efficacy of various types of treatments. We selected 4 studies of cortisone in chronic hepatitis B; 21 trials of interferon treatment, 6 in chronic hepatitis B, 10 in chronic hepatitis C, and 5 in chronic hepatitis D; and 5 of combined cortisone and interferon treatment in chronic hepatitis B. The Mantel-Haenszel-Peto method was applied to extrapolated data. We completed the study by analyzing four studies of cortisone treatment of chronic hepatitis C, two of cortisone plus interferon alpha (IFN-alpha) for chronic hepatitis C, and antiviral therapy for hepatitis B, C, and D. Trials administering cortisone for chronic hepatitis B had an overall OR of 0.29 (CI 0.12-0.73). No virologic remissions were observed in patients with hepatitis C receiving prednisone, even if those with features of autoimmunity achieved a biohumoral sustained response. Overall ORs in the trials were were as follows: IFN for chronic hepatitis B, 0.27 (CI 0.17-0.46); IFN for chronic hepatitis C, 0.3 (CI 0.21-0.44); IFN for chronic hepatitis D, 0.16 (CI 0.06-0.47); and cortisone plus interferon for chronic hepatitis B, 0.25 (CI 0.15-0.41). Sustained response rates of chronic hepatitis C ranged from 15-24.2%. The only encouraging results were obtained by antivirals. To date the lack of a specific antiviral drug makes it uncertain as to the preferred agent for this disease.

Serum interleukin 6 concentrations in chronic hepatitis C patients before and after interferon-alpha treatment.

IFN-alpha represents the treatment of choice in chronic hepatitis C. It acts directly on the cells infected by the virus and indirectly via the cytokine network. We studied the behavior of interleukin 6 (IL-6), a cytokine that is particularly active in the liver and considered an index of liver inflammation and necrosis, in order to evaluate the relationships between IFN-alpha administration and serum levels of this cytokine. Our study series was composed of 60 patients (32 males, 28 females, mean age 53.03 +/- 12.7 years) affected by chronic hepatitis C and 24 healthy controls (14 males, 13 females, mean age 45.8 +/- 5.9 years). We determined serum IL-6 concentrations before and after 3,000,000 IU of IFN-alpha t.i.w./6 months in the former and compared them with levels observed in the controls. Pre- and post-treatment serum IL-6 levels were higher in chronic hepatitis patients and correlated with HAI score and HCV RNA prior to treatment. Diversely, this correlation was less significant after completion of the treatment. Furthermore, IL-6 concentrations depended on the type of response to treatment, i.e. they decreased in complete responders, while increased in partial and non-responders. Our data indicate that IL-6 concentrations, before treatment, are expression of viral-induced inflammation and that, after treatment, may be increased by the action of IFN-alpha treatment.

Serum beta2-microglobulin in chronic hepatitis C.

beta2-Microglobulin (beta2-MG) plays a key role in influencing the immune response to viral infections as it is an integrating part of the main histocompatibility system (HLA). We attempted to evaluate the changes in class I HLA antigens by comparing the serum beta2-MG behavior in a group of patients affected by chronic hepatitis C with that observed in a group of healthy controls. Our study revealed that the patients presented higher serum beta2-MG levels than healthy controls (P = 0.0003). beta2-MG levels were correlated with duration and degree of the disease. Furthermore, there was a statistically significant correlation between beta2-MG and HCV RNA levels, while no correlations were observed between serum beta2-MG levels and HCV genotypes. The increment in serum beta2-MG values accompanying the progression of liver disease may be an expression of augmented production rather than altered excretion.

Elevation of interleukin 6 levels in patients with chronic hepatitis due to hepatitis C virus.

Interleukin 6 (IL-6) is a pleiotropic cytokine produced by a wide variety of lymphoid and non-lymphoid tissues. We studied the relationship between IL-6 and the liver in an attempt to elucidate this cytokine's role in hepatitis C-induced liver inflammation. We investigated the behavior of serum IL-6 in 25 patients with chronic hepatitis C (divided into three groups depending on severity) and in 27 healthy controls. Our results showed a significant elevation (P < 0.0001) in serum IL-6 levels in the patients with chronic hepatitis C, correlated with the histological activity index (HAI) and their HCV-RNA serum levels. This rise may represent the expression of the hepatitis C virus-induced inflammatory state.

Decrease of interferon gamma serum levels in patients with chronic hepatitis C.

Cytokines can play a crucial role in defending the organism from viral infections. One of these, interferon gamma (IFN-gamma), possesses marked immunomodulating activity. As cell immunity seems to be involved in chronic hepatitis C virus (HCV), study of the events regulated by IFN-gamma may be useful in evaluating the host's immunological response. We studied 63 patients (36 males, 27 females) affected by chronic HCV and 28 (14 males, 14 females) healthy controls. IFN-gamma concentrations were significantly lower in the former, and were positively correlated with the histological activity index, suggesting that low IFN-gamma values play a part in determining chronicity. We believe they may be an unfavorable factor and may be useful in detecting patients who are not capable of eradicating the virus.

Interleukin-6 in hepatitis C cirrhosis.

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in numerous diseases but the correlation between liver fibrosis and IL-6 role is not clear. We studied IL-6 levels in 50 HCVAb+ patients with liver cirrhosis (grouped into A, B and C, Child classes) and in 27 healthy control subjects. IL-6 serum levels were significantly increased in the former (p < 0.005) suggesting that IL-6 stimulates and sustains liver fibrosis. In cirrhotic subjects, the rise in IL-6 serum levels is due to impaired hepatic clearance of this cytokine, while its production remains steady.

[Erythropoietin in hepatocellular carcinoma]. / L'érythropoïétine dans le carcinome hépatocellulaire.

Hemopoietic alterations may occur during tumoral diseases, determining anemia. In most cases, serum EPO levels were lower than normal values. Hepatocellular carcinoma (HCC), one of the most frequent malignancies world-wide, is often characterized by mild anemia and increased serum EPO levels. We studied 30 HCC patients and 20 healthy subjects. We found that HCC patients presented higher serum EPO levels than healthy controls. In HCC patients, there was a significant inverse correlation between serum EPO levels and red blood cell count or hemoglobin levels. We postulated that the elevated serum EPO levels observed in these patients may be due to reduced hepatic clearance of EPO, and to the influence of cytokine-mediated inflammatory factors.

A meta-analysis of interferon-alpha treatment of hepatitis D virus infection.

The severity of chronic hepatitis D infection and its unfavorable progress necessiate research into drugs and protocols capable of changing the natural history of the disease. Over the last few years interferon (IFN)-alpha has been the drug of choice in the management of this infection. We assessed its long-term efficacy by analyzing 5 controlled and 10 uncontrolled trials conducted between 1987 and 1994. The Mantel-Haenszel-Peto method was used in the former to perform statistical analysis. The odds ratio (0.16, confidence interval 0.058-0.476) confirmed the efficacy of IFN-alpha, even if the coefficient was not significant because of the limited number of spontaneous remissions in the trials. Although IFN treatment is fully beneficial in only a small number of patients with chronic hepatitis D infection, at present it is the only available agent.

Electrophysiological alterations in hepatic encephalopathy detected by brain mapping.

Analogical electroencephalogram has been used to study electric alterations in the brain during liver encephalopathy. We adopted digital technique brain mapping to study the electric background activity in the brain and to evaluate the diagnostic and prognosis usefulness of this technique compared with the methods routinely used in this disease. We studied 18 patients with liver cirrhosis and varying degrees of liver encephalopathy and 7 healthy control subjects to assess correlation between the severity of encephalopathy and abnormal electric activity in the brain, and to detect the main differences between the brain mapping findings obtained in the two groups. The findings revealed an overall reduction in the rhythm, increased amplitude and anomalous distribution of the waveforms in the cirrhotic patients. Although similar results have already been reported, brain mapping furnished prompt and more easily visualised findings. Moreover, brain mapping facilitated detailed analysis of wave amplitude, frequency and topographic location indicating that this technique is a valid tool in diagnosing brain disorders.

Mapped auditory evoked potentials before and after interferon treatment.

Neurotoxicity induced by interferon (IFN) is revealed by neurobehavioral changes, such as irritability, somnolence, lack of motivation, and delayed ideation. As these side effects persist throughout IFN-alpha treatment, we studied cerebral mapped auditory evoked potentials (MAEP) in 20 hepatitis C virus antibody (HCV Ab)-positive chronic active hepatitis patients before and after administration of leukocyte IFN-alpha (i.m. 3,000,000 IU). Some of the main components of MAEP, such as morphology, latency, and power spectra, were altered before IFN injection. These parameters changed 7 h after administration as revealed by increased quality and quantity of acoustic signal reaching the brain cortex and appearance of physiologic waves in patients with mild/intermediate liver disease. These effects revealed 48 h after IFN administration.

[Role of interleukin 6 in hepatocellular carcinoma]. / Rôle de l'interleukine 6 dans le carcinome hépatocellulaire.

Interleukin 6 (IL-6) is a pleiotropic cytokine which possesses a broad spectrum of action in diverse pathological conditions. It is mainly produced and metabolised in the liver where it carries out one of its best known actions in the mediation of the acute phase response. We studied its behaviour in hepatocellular carcinoma to evaluate its clinical prognostic role. We determined serum IL-6 concentrations in 39 patients with hepatocarcinoma (27 males and 12 females) and 25 healthy controls (15 males and ten females). Our results showed a significant increase in serum IL-6 concentrations in hepatocarcinoma subjects compared with controls (P < 0.005) and an elevated positive correlation (r = 0.616) between IL-6 and size of the hepatocarcinoma. Our study demonstrated that IL-6 is able to influence hepatocarcinoma progression by acting as an autocrine tumoral growth factor and depleting immune surveillance.

Erythropoietin in healthy elderly subjects.

The effects of aging on erythropoiesis and the factors regulating it are not well known. Erythropoietin (Epo) is a specific growth factor for the erythroid line and is mainly produced by the kidney. As data on the effects of aging on Epo are discordant we studied serum Epo concentrations in a group of apparently healthy subjects divided into age classes in order to evaluate age-related modifications and correlations with hemoglobin (Hb) and red blood cells (RBC). Our results revealed that Epo values were correlated with age. Epo was higher in the over 65 years age classes than observed in control subjects. We believe that the elevated Epo values in the latter age class may be required to maintain Hb and RBC within normal range.

Lipoprotein(a) in cirrhosis. A new index of liver functions?

Over the last few years, lipoprotein(a) [Lp(a)] levels have been investigated because clinical studies have related it to increased cardiovascular and cerebrovascular risk. Although it is known that serum Lp(a) concentrations are controlled genetically, little is known about its metabolism. We studied changes in the lipid profile and Lp(a) values in 57 patients (34 males and 23 females) affected by cirrhosis of the liver subdivided into Child's classes in order to assess whether this lipoprotein is sensitive to reduced liver protein synthesis. The patients presented with low total cholesterol, normal HDL-cholesterol (HDL-c), LDL-cholesterol (LDL-c), triglycerides, apoprotein A1 (Apo-A1) and apoprotein B100 (Apo-B100) concentrations, while Lp(a) concentrations seemed elevated. Grouping the patients into Child's classes revealed that all the lipid parameters investigated reduced as the disease progressed. Lp(a) reduced significantly between Child's Classes I and II and seems to be correlated with the severity of cirrhosis and the clinical worsening of the patients' conditions. These findings suggest that Lp(a) is not only an index of atherosclerosis risk, but also plays a role in monitoring liver functions.

Hepatitis C virus genotypes in elderly patients with chronic hepatitis C.

The importance of determination of hepatitis C virus (HCV) genotypes and subtypes has been demonstrated not only as epidemiological characteristics, but also as prognostic factors regarding the seriousness of the disease and response to interferon (IFN) in patients with chronic hepatitis C (CHC). Aim of this study was to determine HCV genotypes in a group of elderly patients with CHC, in order to acquire epidemiological data on the prevalence of HCV genotypes in Eastern Sicily, and to evaluate any relationship with the seriousness of the disease and with the response to IFN. The study was carried out on 22 patients with CHC, aged from 65 to 75 years. The prevalence of HCV-RNA subtypes in elderly patients (Group A) was compared with two other groups: Group B aged from 36 to 64 years; and Group C aged from 20 to 35 years. HCV-RNA proved to be positive in 20 of the 22 patients in Group A, and in 100% of these cases the prevalent subtype was 1b; in the other two groups the occurrence of other subtypes was more frequent, especially in the younger ages. In conclusion, the subtype 1b is indigenous in our region and it cannot be proposed as the only prognostic factor for seriousness of the disease and response to IFN, especially in elderly patients.

Chronic hepatitis C in elderly patients: clinical, histological and virological features.

Some clinical, histological and virological features, efficacy and safety of interferon (IFN) therapy were evaluated in elderly patients with chronic hepatitis C (CHC). We enrolled 22 patients aged 65-75 (mean age: 68.3 +/- 3.17 years); 15 males and 7 females. In all cases the hepatitis C virus RNA (HCV-RNA) was determined before, during and after the therapy, and HCV sub-types were established; 15 patients underwent hepatobiopsy. At entry, the duration of disease was: 6 patients 1-3 years, 2 patients 4-10 years, 14 patients 11-30 years; alanine-aminotransferase (ALT) = (3.17 +/- 1.15) x N (N = normal value); aspartate-transaminase (AST) = 2.28 +/- 1.6 x N; gamma-glutamyl-transpeptidase (gGT) = 1.4 +/- 1.1 x N; platelets = 164,000 +/- 66,000/mm(3); histological pattern: 2 mild chronic active hepatitis (CAH), 5 CAH, 2 severe CAM, 6 CAH with liver cirrhosis (LC); histological activity index (HAI) (14 patients) = 11.14 +/- 4.5 (range 5-17); scores according to Scheuer: lobular 2.28 +/- 1.13, portal 2.71 +/- 0.99, fibrosis 2.35 +/-1.33; HCV-RNA +ve: 20 patients, HCV-RNA -ve: 2 patients; HCV-subtypes: 1b 20/20 (100%), 1b+1a 1/20 (5%), 1b+ 2a 1/20 (5%). Treatment was applied to 18 patients, for 3-12 months; 5 received alpha-IFN2a; 5 received alpha-IFN2b, 3 lymphoblastoid IFN, all at a dose of 3 mU thrice per week; 3 patients received 6 mU beta-IFN thrice per week. Therapy over 6 months was applied to 16 patients: Complete response (CR) was observed in 8 patients (50%), one of them was with long-term CR (over 12 months after therapy); 5 have had relapse and 2 patients are still under treatment. Partial response (PR) was observed in 4 patients (25%), no response (NR) in 4 patients (25%). Side effects were moderate and self-limited. Loss of HCV-RNA was shown in some patients with PR and in all patients with CR, but only temporarily.

[Immunologic diseases and hepatitis C virus]. / Maladies immunologiques et virus de l'hépatite C.

Active chronic hepatitis may be associated with various immunologic diseases. In the Mediterranean area and to a lesser extent elsewhere, hepatitis C virus, has often been detected in patients affected by mixed cryoglobulinemia, membranoproliferative glomerulonephritis, polyarteritis nodosa autoimmune type 2b hepatitis, Hashimoto's disease, Sjögren's syndrome and lichen ruber planus. These findings should not be considered fortuitous due to the elevated prevalence of autoantibodies and immunologic abnormalities observed in hepatitis C patients compared with subjects presenting other liver diseases. The pathogenetic evaluation of the association between these immunologic diseases and chronic hepatitis C has led us to suggest that diverse virus C and host induced factors may play a fundamental role in determining these immunologic diseases.

Interferon or hepatitis C virus induced autoimmune aplastic anemia and severe thrombocytopenia? A case report.

We describe a case of aplastic anemia with severe thrombocytopenia in a patient affected by chronic active hepatitis C treated with interferon. The hematologic alterations did not disappear after suspension of interferon or after the ensuing steroid treatment. Administration of cyclosporin markedly improved the hematologic parameters and serum transaminase levels.