Chronic Persistent Hepatitis Research Articles

Evaluation of Liver Grafts from Hepatitis C Positive Donors for Hepatitis C Positive Recipients.

370 End-stage liver disease secondary to hepatitis C induced cirrhosis is now the most frequent indication for liver transplant. Additionally, the disparity between patients needing transplant and graft availability is becoming greater. In an effort to increase the number of transplantable organs, we have begun a prospective study to evaluate the outcome of hepatitis C positive (HC+) hepatic allografts used for transplantation into hepatitis C RNA-positive recipients. Methods: All patients listed from September 1995 to November 1998 with end-stage liver disease secondary to hepatitis C were evaluated with a qualitative hepatitis C RNA-PCR. Those patients who tested positive for hepatitis C RNA were eligible for transplantation with a liver graft from either a HC+ or negative (HC−) donor. In addition to standard criteria, livers from HC+ donors were used if they had a normal gross appearance at the time of procurement. A protocol biopsy was taken from the HC+ liver at the time of procurement and was masked from the transplant surgeon. Graft function was evaluated by laboratory analysis at specific time intervals according to the post-transplant protocol. Actuarial graft and patient survivals are expressed at one year for recipients of HC+ and HC− grafts. Results: Seventy-seven liver transplants were performed in sixty-three HC+ recipients. Eight patients received a HC+ positive graft and 55 received a HC− graft as a primary transplant. Six protocol biopsies were available for review. All HC+ graft protocol biopsy specimens demonstrated chronic persistent hepatitis; one biopsy demonstrated portal fibrosis on permanent special stained specimen. Delayed or primary non-function occurred in three of the HC− grafts (5%) and none of the HC+ grafts (p=NS). Three recipients of HC+ graft recipients underwent retransplantation (37%) compared to nine of the HC− graft recipients (16%), (p=NS). One-year patient and graft survivals between HC+ and HC− recipients were not significantly different 73% vs. 76% and 60% vs. 69%, respectively. Conclusions: Our results suggest that grossly normal appearing, HC+ donors may be an acceptable source for liver grafts in patients awaiting liver transplantation for end-stage liver disease secondary to hepatitis C cirrhosis.

Clinical usefulness of serum tissue inhibitor of metalloproteinases (TIMP)-2 assay in patients with chronic liver disease in comparison with serum TIMP-1

Tissue inhibitors of metalloproteinases (TIMPs) are involved in liver fibrosis through impaired matrix degradation. Previous studies showed that the serum level of TIMP-1 was increased in patients with chronic liver disease, reflecting the liver TIMP-1 level, and that it is useful for assessing liver fibrosis. An enzyme immunoassay for TIMP-2 is now available. In this study, we examined the clinical usefulness of this serum TIMP-2 test for liver fibrosis in patients with chronic liver disease, in comparison with the serum TIMP-1 test. The serum TIMP-2 concentration was 61±13 ng/ml in healthy controls ( n=32), and 18% higher in the group of chronic active hepatitis (CAH) patients ( n=34), 64% higher in the liver cirrhosis (LC) group ( n=33) and 44% higher in the hepatocellular carcinoma (HCC) group ( n=61), and similar to the control level in the chronic persistent hepatitis (CPH) group ( n=23). In contrast, the serum TIMP-1 concentration was 155±17 ng/ml in the healthy controls, 18% higher in CPH, 35% in CAH, 63% higher in LC and 92% higher in HCC. The serum TIMP-2 level was related to the histological degrees of both periportal necrosis and liver fibrosis, as well as to the serum TIMP-1 level. However, the relationships for TIMP-2 were weaker compared to those of serum TIMP-1. These results suggest that compared to the serum TIMP-1 level, changes in the serum TIMP-2 level in chronic liver disease are less liver-specific, and the serum TIMP-2 level is less useful in the assessment of liver fibrosis in chronic liver disease.

Clinical and experimental study on treatment of chronic hepatitis B with Yanggan Aoping Mixture

Objective: To assess the efficacy of Yanggan Aoping Mixture ( Open image in new window , YGAPM) in treating hepatitis B.Methods: Patients suffered from chronic hepatitis B were treated with YGAPM. Observe their short- and long-term efficacy and the change of serum hepatitis B virus marker. In experiment, the effects of YGAPM in treating rat’s liver injury as well as HBV-infected tree shrew and duck HBV-infected ducks were observed.Results: In 79 cases of chronic persistent hepatitis, the markedly effective rate was 60.76%, and further raised to 70.00% in follow-up study in 40 cases. In 73 cases of chronic active hepatitis, the markedly effective rate was 60.27%, and further raised to 62.50% in 32 follow-up cases. In the treatment group, 85 of the 119 cases (71.43%) with HBeAg-positive were converted to negative. Whereas in the control group, only 40 of 89 HBeAg-positive cases (44. 94%) were converted to negative,P < 0. 01. Results of experimental study showed that negative conversion rate of tree shrew infected with HBV marker was raised, while the duck HBV DNA in infected duck blood was inhibited. Those compared with the control group separately, the difference was markedly significant.Conclusion: YGAPM is an effective drug in treating chronic hepatitis B, and it could effectively convert the marker to negative.

A comparison between previous and present histo-logic assessments of chronic hepatitis C viral infec-tions in humans

AIM:To compare the previously employed classification of liver histology (minimal,chronic persistent hepatitis, chronic active hepatitis and cirrhosis) with a new classification recently described by sheuer et al (activity grade and fibrosis stage) in percutaneous liver biopsies from patients with chronic hepatitis C viral infections.METHODS:Liver biopsies from 79 untreated patients were reviewed. Anti-HCV testing had been performed by ELISA and confirmed by a recombinant immunoblot assay.With respect to the new classification, all the specimens were evaluated using the Knodell score for activity.RESULTS:A good correlation was revealed between the previous and more recent histologic classifica-tions in patients with abnormal liver enzyme tests. However, in 13/15 (87%) of patients with normal aminotransferase values, changes were consistent with chronic persistent hepatitis whereas normal activity and no fibrosis were demonstrated by the Sheuer classifica-tion.CONCLUSION:The old classification is more often mislead-ing but correlates well with the new classification and thereby permits comparisons between historically clinical studies.

A review of virus infections of cataceans and the potential impact of morbilliviruses, poxviruses and papillomaviruses on host population dynamics.

Viruses belonging to 9 families have been detected in cetaceans. We critically review the clinical features, pathology and epidemiology of the diseases they cause. Cetacean morbillivirus (family Paramyxoviridae) induces a serious disease with a high mortality rate and persists in several populations. It may have long-term effects on the dynamics of cetacean populations either as enzootic infection or recurrent epizootics. The latter presumably have the more profound impact due to removal of sexually mature individuals. Members of the family Poxviridae infect several species of odontocetes, resulting in ring and tattoo skin lesions. Although poxviruses apparently do not induce a high mortality, circumstancial evidence suggests they may be lethal in young animals lacking protective immunity, and thus may negatively affect net recruitment. Papillomaviruses (family Papovaviridae) cause genital warts in at least 3 species of cetaceans. In 10% of male Burmeister's porpoises Phocoena spinipinnis from Peru, lesions were sufficiently severe to at least hamper, if not impede, copulation. Members of the families Herpesviridae, Orthomyxoviridae and Rhabdoviridae were demonstrated in cetaceans suffering serious illnesses, but with the exception of a 'porpoise herpesvirus' their causative role is still tentative. Herpes-like viruses and caliciviruses (Caliciviridae) give rise to cutaneous diseases in Monodontidae and Delphinidae. Antibodies to several serotypes of caliciviruses were found in odontocetes and mysticetes. An unrecognized Hepadnaviridae was detected by serology in a captive Pacific white-sided dolphin Lagenorhynchus obliquidens with chronic persistent hepatitis. Adenoviruses (Adenoviridae) were isolated from the intestinal tracts of mysticeti and a beluga Delphinapterus leucas but were not associated with any pathologies. We discuss the potential impact of Paramyxoviridae, Poxviridae and Papovaviridae on the dynamics of several odontocete populations.

HCV genotypes in Northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients

Background/Aims: Hepatitis C virus (HCV) easily undergoes genomic changes, thus accounting for the presence of different genotypes, with different geographic distributions and different outcomes of chronic hepatitis. Type 1b is frequently found in advanced diseases; however, since this genotype is the most prevalent in older patients, the association with advanced age and severity of the disease is confounding. The aim of this study was to assess changes in the prevalence of HCV genotypes by surveying a large population of chronic hepatitis C patients in Northern Italy, and to assess if the high prevalence of genotye 1b in older patients with advanced diseases simply reflects the duration of HCV infection, rather than intrinsic biological properties of HCV. Methods: We studied 1368 HCV-RNA positive patients, with histologically proven chronic hepatitis. Drug addiction, blood transfusions and sporadically acquired infections represented the risk factors Results: Genotype 1b, the most prevalent isolate, and genotype 2a were associated with older age, cirrhosis, sporadically-acquired infections and blood transfusion, while types 1a, 3a, and 4 were associated with younger age, chronic persistent hepatitis and drug addiction. Patients with a history of transfusion were divided into four groups depending on the period of transfusion. The prevalence of genotype 1b decreased with time. Type 3a appeared only after 1979. Conclusions: The severity of chronic hepatitis C could be related more to the duration of the infection rather than to the intrinsic pathogenicity of HCV genotypes

Hepatitis in haemophilia.

Hepatitis in haemophilia.

De novo hepatitis C in children after liver transplantation.

We describe the incidence, results of interferon therapy, and outcome of hepatitis C virus (HCV) hepatitis occurring de novo after pediatric orthotopic liver transplantation (OLT). Of children undergoing OLT between 1984 and September 1996, 321 children survived for more than 1 year. Of these, 13 (4.0%) developed previously undiagnosed HCV disease, as suggested by HCV antibody testing and HCV polymerase chain reaction and confirmed by liver biopsy. Of the 117 children who received transplants before HCV screening of blood products or donors, 10.2% developed de novo HCV disease. The mean age at diagnosis of HCV hepatitis was 13.2+/-5.0 years, and the mean time to diagnosis after OLT was 8.1 years (range, 4-11 years). The mean alanine aminotransferase (ALT) level at diagnosis was 108 IU/ml, and the liver biopsy specimen showed chronic active or chronic persistent hepatitis in 11 children, cirrhosis in 1 child, and nonspecific changes in 1 child. Twelve children were treated with interferon-2alpha; children who weighed > or =20 kg received 3 x 10(6) units every other day, and those who weighed <20 kg received 1.5 x 10(6) units every other day. Four patients developed rapidly progressive liver failure while receiving interferon therapy and required urgent re-transplantation. Three of the four children again developed histologic evidence of recurrent HCV 4-6 months after the second OLT, and all three subsequently died of HCV-induced liver failure. One patient remains alive and well with no evidence of HCV recurrence and a negative HCV RNA. Of the remaining eight children treated with interferon, only two have had a sustained response (normal ALT) and one is now HCV RNA negative. HCV RNA levels did not correlate with outcome or disease severity. HCV antibody levels were unreliable, with two patients having negative HCV antibody but a positive HCV RNA at diagnosis. Six patients were able to be genotyped: four were la and two were 1b. Overall mortality for de novo HCV hepatitis was 23%. Seventy-five percent of children who received a second transplant for HCV hepatitis had early histologic recurrence that led to liver failure and death. Interferon therapy resulted in a sustained improvement in ALT in only 15% of children. The time to onset and progression of clinical disease both in the original graft and the retransplant graft were accelerated compared with nonimmunosuppressed individuals.

Renal involvement in hepatitis C infection: Cryoglobulinemic glomerulonephritis

Patient 1. A 49-year-old man reported recurrent episodes of arthralgia, purpura, and abdominal colic over 2 years. He was transferred to the San Carlo Hospital in Milan from another hospital, where he had been admitted because of fever, abdominal pain, purpura and edema of the legs, slightly increased serum creatinine (1.5 mg/dl), nephrotic-range proteinuria (4–5 g/day), and positive serum cryoglobulins (cryocrit 1%). On admission to San Carlo Hospital, the proteinuria was still in the nephrotic range, with reduced total serum proteins (4.9 g/dl), and the cryocrit was 11%, with mixed cryoglobulins characterized as IgG-IgM. Serum C4 was almost undetectable, with C3 moderately reduced; ALT was 57 U/liter. Hepatomegaly was present, and a liver biopsy disclosed mild active chronic hepatitis. Markers for HBV were negative, while anti-HCV antibodies were detected a posteriori in the stored serum. His blood pressure was markedly elevated, and severe retinal lesions (grade 3 hypertensive retinopathy) were present.

Evidence for in vivo peroxynitrite production in human chronic hepatitis

During inflammation nitric oxide reacts at near diffusion limited rates with superoxide to form the strong oxidant peroxynitrite. Nitration on the ortho position is a major product of peroxynitrite attack on proteins. In the present study we investigated whether immunohistochemical detection of nitrotyrosine (footprint of peroxynitrite) can be associated with human hepatitis. Paraffin-embedded liver tissue biopsies from patients with chronic active hepatitis, chronic active hepatitis plus cirrhosis and chronic persistent hepatitis exhibit significant specific immunostaining with the antibody to nitrotyrosine. Positive staining was found in 57% and 72% of tissue specimens from patients with chronic hepatitis and cirrhosis, respectively. Immunohistochemical staining of nitrotyrosine residues was found in the hepatocytes and Kuppffer cells of the necrotic area. The presence of nitrotyrosine indicates that oxidants derived from nitric oxide such as peroxynitrite are generated in human hepatitis and may be involved in its pathogenesis.

Hepititis C and renal transplantation: The controversy continues

Hepatitis C virus (HCV) infection, the leading cause of posttransplant liver disease, has recently been recognized as one of the major causes of morbidity and mortality in renal transplantation. Most HCV antibody-positive recipients acquire HCV infection before or at the time of transplantation. The prevalence of HCV among patients with end-stage renal disease (ESRD) undergoing dialysis is reported between 12% to 85%, depending on the techniques used such as antibody and RNA assays [1‐ 4]. It has been shown that HCV is transmissible by organ transplantation [5, 6]. In recipients of kidneys from HCV antibody positive donors, 57 to 96% were tested positive for HCV RNA by polymerase chain reaction (PCR) and 0 to 55% developed post-transplantation liver disease [7]. There have been controversial reports on the long-term effects of HCV infection on graft and patient survival in kidney transplant recipients. In this issue of Kidney International, Pereira and colleagues analyze the impact of HCV infection on survival of kidney transplant and ESRD patients [8]. They report that the presence of HCV infection was associated with an increased risk of death in patients referred for renal transplantation, and the effect of transplantation was similar in anti-HCV positive and negative patients. They conclude that anti-HCV positive status is not a contraindication for renal transplantation, which has a beneficial effect on long-term survival in anti-HCV positive patients. The report by Pereira and associates provides new fuel to the controversy as to how HCV infection alters outcomes in ESRD and transplant population [8]. Two important infection-related outcomes are described by the authors: the relationship of infection to chronic liver disease and to transplant outcome. There have been other reports of progressive liver disease in HCVinfected renal allograft recipients. A study by Morales et al demonstrated that more than 50% of HCV positive renal transplant recipients exhibited a severe pattern including cirrhosis, chronic active hepatitis and chronic persistent hepatitis in liver biopsies indicating the seriousness of HCV infection [9]. Older age at transplant, female sex, and morphologic diagnosis of advanced chronic hepatitis were found to be associated with histologic progression to cirrhosis [10]. On the other hand, several other groups have described the absence of dire consequences of HCV infection on patient and graft survival in renal allograft recipients [11, 12]. A group of HCV-infected ESRD patients (N 5 14) was prospectively followed for up to two years with pretransplant liver biopsies, and virologic and biochemical parameters post-transplant [11]. All patients did well with functioning grafts despite enhanced viral replication and mild increase in liver enzymes. Haem and colleagues followed 62 HCV positive renal transplant recipients with liver biopsies for a mean of 72 months (range 36 to 108 months) [12]. Although they found a 42% incidence of chronic active hepatitis, patient and graft survival were not significantly different from HCV negative recipients. At our institution, we found that, despite a predisposition to post-transplant liver disease in recipients with pre-existing HCV infection, overall patient and graft survival were similar in long-term follow up (median follow-up 9 years) in the HCV positive and HCV negative recipients [12]. Irrespective of the antibody status, the outcome was poor in patients with associated liver disease. Less controversial has been the variant impact of HCV infection on patient outcomes related to forms of renal replacement. Similar to the report by Pereira et al, in a study by Knoll and colleagues, HCV-positive renal transplant recipients had a better survival compared with HCV-positive patients who were acceptable candidates for transplantation but were on dialysis [14]. The importance of these studies lies in using a cohort of dialysis patients for outcome comparison very similar to the transplant group as they were on the transplant waiting list, reducing the possibility that differences discerned were merely a consequence of selection bias. The continuing controversy of the impact of HCV infection on the transplant recipient demands further study and analysis by examining such issues as variant viral strains or geographic differences, and improving our understanding of HCV related liver disease. Nevertheless, the report by Pereira and his colleagues supports the conclusion that transplantation is the preferred mode of renal replacement therapy for HCV positive patients with end-stage renal disease [8].

Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis.

Primary haemophagocytic lymphohistiocytosis (HLH) is a fatal childhood disorder. The diagnosis is difficult to establish, clinically as well as histopathologically, and it is markedly underdiagnosed. Because of these difficulties, we wanted to elucidate the histopathological findings in population-based patient material. The post-mortem findings in 27 children with primary HLH diagnosed in Sweden between 1971 and 1986 was reviewed. Twelve of these patients had an affected sibling and three additional children had parental consanguinity. Some of the children showed generalized disease, whereas in others only one or a few organs were affected. The major histological alteration was an accumulation of primarily lymphocytes, but also of histiocytes, some of which exhibited evidence of haemophagocytosis. The haemophagocytic activity may be difficult to detect if there are pronounced post-mortem changes, particularly in the spleen, and it is therefore preferable to perform the autopsy as soon as possible after death in order to minimize autolysis. Haemophagocytosis was most commonly observed in the spleen (17/24), the lymph nodes (17/23) and the bone marrow (9/23), indicating that a negative bone marrow examination does not rule out this diagnosis. Three additional patients had discrete signs of haemophagocytosis in the bone marrow. In the spleen, the lymph nodes and the bone marrow, lymphocytic depletion, pronounced in some cases, could be observed, even without prior treatment with steroids or cytostatics. In the liver, most of the patients demonstrated an infiltration of lymphocytes into the portal tracts similar to that seen in chronic persistent hepatitis (22/27), a finding which is uncommon in infancy and therefore suggestive of the diagnosis HLH. Other organs involved included the thymus, lungs intestine, pancreas, kidney, heart and striated muscle. The diagnosis of HLH must be based on clinical, histological and additional laboratory findings. A negative bone marrow examination is common. Previous treatment with steroids and/or cytostatic drugs may attenuate or even eliminate the typical histological findings. Liver findings similar to those in chronic persistent hepatitis are common.

Impact of hepatitis C virus duration and hepatitis C virus genotypes on renal transplant patients: correlation with clinicopathological features.

The aim of this study was to evaluate the long-term impact of chronic hepatitis C virus (HCV) infection on the liver in renal transplant patients. We studied 78 patients for whom at least one posttransplant liver biopsy (LB) was available and for whom the duration of HCV infection was precisely defined. The LB were graded according to a histological activity index, i.e., the Knodell score, divided into the activity score and the fibrosis score. They were also classified as either normal or showing evidence of chronic persistent hepatitis, chronic active hepatitis (CAH), or cirrhosis. The study comprised 7 HCV-positive/hepatitis B surface antigen-positive patients (group 1); 4 HCV-positive/RNA-negative patients (group 2); and 67 HCV-positive/RNA-positive patients (group 3). The three groups were comparable according to demographic data and baseline immunosuppression. The median time from transplantation to LB was 38 months (range, 10-306 months). At that time, alanine aminotransferase (ALT) levels had increased in 71.4%, 0%, and 42% of patients from groups 1, 2, and 3, respectively (P=0.07). The total Knodell score showed significantly more severe lesions in group 1 patients (6.2+/-3.2) than in group 2 (1+/-1.2) or in group 3 (4.6+/-2.4) patients (P=0.007). The Knodell score also showed that the fibrosis score was significantly higher in group 1 (2.3+/-1.6) than in group 2 (0) or in group 3 (0.9+/-1.1) patients (P=0.007). Overall, there were 28 cases of CAH (36%) and 4 cases of cirrhosis (5%). We did not observe any correlation between liver histology and characteristics of HCV infection or the type of chronic immunosuppression (double-drug versus triple-drug therapy). However, liver histology (total Knodell score) and the activity score were significantly correlated with ALT levels. Multivariate analysis did identify (i) four independent variables that could explain the degree of liver fibrosis-the sex of the patient, the number of blood units received before transplantation, increased ALT levels at the time of LB, and the occurrence of at least one acute rejection episode (thus the receipt of methylprednisolone pulses); and (ii) two independent variables associated with the occurrence of CAH-the number of blood units before transplantation and increased ALT levels at the time of LB. This study showed that renal transplant patients infected by HCV for more than 10 years, with a mean posttransplant follow-up of more than 5 years, showed more severe liver lesions when coinfected by hepatitis B virus. Overall, we observed only four cases of cirrhosis (5%) and evidence of histological CAH lesions in 36% of the patients.

Influence of a history of gastrectomy for gastric cancer on serum hyaluronan concentration in normal individuals and patients with chronic liver disease

Recently, we detected elevated concentrations of serum hyaluronan in patients with chronic persistent hepatitis who had a history of gastrectomy combined with lymphadenectomy for early gastric cancer. We hypothesized that the operation itself might have altered the serum hyaluronan concentration. To test this hypothesis, we measured the serum hyaluronan concentrations in normal individuals and patients with chronic liver disease with or without a history of gastrectomy for gastric cancer. We found that gastrectomy results in increase of serum hyaluronan concentration in healthy individuals and in patients with chronic persistent hepatitis, but not in patients with chronic active hepatitis and liver cirrhosis. In clinical interpretation of serum hyaluronan values, it is important to check the history of gastrectomy for gastric cancer.

Influence of the transmission route and disease duration in the histopathology of chronic hepatitis C: a study of 101 patients.

Different studies have demonstrated that factors such as transmission route, disease duration and age at the time of infection can influence the histological evolution of chronic hepatitis by the hepatitis C virus (HCV). The aim of this study was to determine if epidemiological factors such as disease duration and transmission route influence the severity of the histological lesions of patients with chronic hepatitis by HCV. A prospective study. The hepatic biopsies of 101 patients diagnosed with chronic hepatitis by HCV were studied. The patients were divided into three groups according to transmission mode: (1) post-transfusional (n = 28), (2) associated with the use of drugs by parenteral route or intravenous drug use (n = 28), and (3) sporadic hepatitis (n = 45). We found more severe forms of hepatopathy in post-transfusional hepatitis and sporadic groups than in the intravenous drug user group of patients. The disease evolution time was significantly higher in patients diagnosed as having chronic active hepatitis with or without cirrhosis (13.8 +/- 9 years) than in patients with chronic persistent hepatitis (8 +/- 4 years), P < 0.01. We found a significant correlation between the evolution time of the infection by HCV and the Histology Activity Index (P < 0.01). The multivariate analysis showed that only the transmission route and the disease evolution time are predictive variables of Histology Activity Index in chronic hepatitis C. These results suggest that the post-transfusional and sporadic transmission routes and a greater evolution time of the disease are epidemiological variables that are associated with the presence of more severe histological lesions in chronic hepatitis C.

A comparison of four types of interferon alpha in the treatment of chronic hepatitis C

Several clinical trials and meta-analyses have shown that the efficacy of interferon (IFN)-alpha in the treatment of chronic hepatitis C is variable, depending on the type of IFN-alpha used. We randomly assigned 220 patients with hepatitis C to receive a 6-month treatment (3 megaunits three times per week) with lymphoblastoid IFN-alpha (group A), recombinant IFN alpha-2a (group B), leukocyte IFN-alpha (group C), or recombinant IFN alpha-2b (group D). The groups were homogeneous with reference to histologic severity of the disease (chronic persistent hepatitis, 21.4%; mild chronic active hepatitis, 28.2%; moderate chronic active hepatitis, 28.6%; and severe chronic active hepatitis, 21.8%). We used common laboratory techniques to detect and assess all serum variables. Liver biopsy was conducted according to Menghini's modified technique, and administration of IFN alpha was conducted according to a double-masked method. A total of 220 patients were enrolled in the study. Ninety-two patients dropped out because of side effects, comorbidity unrelated to the baseline disease, or voluntary termination and 128 patients (32 patients in each group) completed the treatment course and the follow-up period. At the 6-month end point, 14 of 32 patients were completed responders in group A, 13 of 32 in group B, 14 of 32 in group C, and 8 of 32 in group D. After completion of the follow-up period, 10 of 32 patients had a sustained response in group A, 9 of 32 in group B, 10 of 32 in group C, and 8 of 32 in group D. Treatment failure and relapse rates were higher in the patients treated with recombinant alpha IFNs than in patients treated with leukocyte or lymphoblastoid IFN alpha. We observed no relation between the relapse rate and baseline severity of the disease. Among the recombinant IFNs, a major rate of clinical response was observed in patients treated with recombinant IFN alpha-2a. Although leukocyte IFN-alpha and lymphoblastoid IFN-alpha treatments showed an overlapping efficacy in terms of complete or sustained response, the former achieved a lower rate of treatment failure or relapse.

Depressive Symptoms in Adult Coeliac Disease

Background: Psychic symptoms and depression have been reported in coeliac disease (CD). The aim of this study was to explore depression in a large cohort of adult CD patients. Methods: Depressive symptoms were evaluated in 92 adult coeliacs,100 normal controls (NC), and 48 chronic persistent hepatitis (CPH) patients by means of a modified version of the Zung Self-Rating Depression Scale (M-SDS). CD patients were evaluated for the level of knowledge about CD and the compliance with diet. Results: The M-SDS score differentiated CD patients from NC. Age at diagnosis and duration of and compliance with diet did not correlate with depression. Three main factors could be identified with the M-SDS: 'reactiveness', 'pessimism', and 'anhedonic-asthenic'. Conclusion: Depressive symptoms are a feature of CD; they are present to a similar extent in patients with childhood- and adulthood-diagnosed CD. The results underline the relevance of personal psychologic resources, which play a fundamental role in determining and sustaining depression.

The importance of cofactors in the histologic progression of minimal and mild chronic hepatitis C.

A follow-up liver biopsy was done 9-16 years (mean 12 years) after initial biopsy in 20 untreated Swedish patients infected with hepatitis C (8 men, 12 women; mean age 30 years at initial biopsy) in whom first biopsy had been classified as chronic persistent hepatitis. A significant progression of liver damage was found when using Histology Activity Index (HAI) scoring according to Knodell (p=0.006 for total HAI score; p=0.03 for grading, i.e., sum of HAI components 1, 2, and 3; p=0.01 for staging, i.e., HAI component 4, fibrosis). Fourteen of 20 (70%) patients had increased while 6 had decreased or unchanged HAI scores on follow-up biopsy. Occasional heavy alcohol drinkers (n=6) had an increased follow-up HAI score as compared with nondrinkers (p<0.05). Eight of 14 who deteriorated on follow-up versus 0 of 6 with improved or unchanged liver histology were anti-HBc positive (p=0.04). There was no significant correlation between HCV genotype and prognosis; however, the only two patients with liver cirrhosis on follow-up had genotype 1b. In conclusion, most patients with minimal or mild chronic hepatitis C in the present study had histologic progression on the latest biopsy. Cofactors such as alcohol abuse and exposure to hepatitis B may have a greater influence than HCV alone in determining the rate of deterioration of liver disease.

Association between frequency of amino acid changes in core region of hepatitis B virus (HBV) and the presence of precore mutation in Japanese HBV carriers.

To elucidate the relationship between the frequency of core mutations and precore mutation of hepatitis B virus (HBV) in Japanese HBV carriers, we investigated the nucleotide sequence of the precore/core region of HBV in 26 Japanese HBV carriers [15 who were HBe antigen-negative (HBeAg-) and 11 who were HBeAg-positive (HBeAg+)]. The number of amino acid changes (5.9 +/- 3.8) in the core region of HBV in HBeAg-carriers was significantly greater than that in the HBeAg+ carriers (1.5 +/- 1.0; P < 0.005). The precore stop codon mutation was found in 93.3% of HBeAg-negative HBV carriers, while no precore mutation was found in the HBeAg-positive HBV carriers, suggesting that the frequency of core mutations may be associated with the presence of the precore stop codon mutation. However, there was no significant difference in the frequency of amino acid changes among HBeAg-HBV carriers. The mean number of core amino acid changes of liver cirrhosis patients, chronic active hepatitis patients, chronic persistent hepatitis patients, and asymptomatic carriers were 2.7 +/- 1.5, 6.0 +/- 2.2, 4.7 +/- 1.2, and 8.4 +/- 5.3, respectively. We detected hot spots for core mutations, which showed characteristic localizations and specific substitutions: Gly-87, Leu-97, and Thr-130 were detected exclusively in patients with chronic liver disease with or without HBeAg. To address further the relationship between frequency of core mutations and the presence of the precore stop codon mutation, we investigated the precore/core nucleotide sequence serially along with seroconversion in three patients with chronic hepatitis B in whom the hepatitis either became inactive or remained active after the seroconversion. Emergence of the precore stop codon mutation and a significant increase in core amino-acid changes after seroconversion were noted in all three patients. Our results suggest a close association between the frequency of core amino acid changes and the presence of the precore stop codon mutation; some characteristic core mutations may be associated with the clinical course of chronic hepatitis B in Japanese patients.

Efficacy of interferons in treating children with chronic hepatitis C.

Twenty-two children with chronic hepatitis serologically positive for hepatitis C virus (HCV) were treated with interferon-alpha (IFN-alpha). Liver biopsy showed chronic active hepatitis in 13 and chronic persistent hepatitis in 9 patients. A sustained clearance of HCV was observed in 8/22 children 12 months after the administration of IFN-alpha for 26 weeks, associated with normalization of HCV core antibody. Of these eight patients six had HCV genotype III and two HCV genotype II or IV. Hepatitis relapsed in seven other patients after completion of IFN-alpha with an increase in HCV core antibody titre, five with HCV genotype II, and two with HCV genotype III or IV. A second course of IFN-alpha suppressed the reactivation of HCV in all seven patients. Three of seven responders who relapsed after the first course remained negative for HCV RNA 12 months after their second course of IFN-alpha. However, the remaining four patients with HCV genotype II again relapsed after completing their second course of IFN-alpha. Seven children with the HCV genotype II resistant to IFN, including 8 weeks of IFN-beta administration, and showed no significant reduction in HCV core antibody titre. The genotype of HCV (III) and a reduction in the core antibody titre appear to be useful parameters for predicting the response to IFN-alpha therapy.