Giuseppe Realdi

Natural history and prognostic factors for chronic hepatitis type B.

One hundred and five hepatitis B surface antigen (HBsAg) positive patients presenting with chronic persistent hepatitis (n = 46) or chronic active hepatitis without cirrhosis (n = 59) were followed longitudinally for one to 16 years (mean 5.5 years) and underwent follow up biopsy. During a mean histological follow up of 3.7 years, active cirrhosis developed in 21 (20%) patients one to 13 years after entry to the study with a calculated annual incidence of 5.9%. The probability of evolution to cirrhosis was significantly higher in patients with chronic active hepatitis and bridging hepatic necrosis than in those with moderate chronic active hepatitis or chronic persistent hepatitis (p less than 0.0001). Cox multiple regression analysis showed that the following three variables independently implied poor prognosis: older age, presence of bridging hepatic necrosis, and persistence of hepatitis B virus DNA in serum (p less than 0.0001). These findings indicate that patients with severe chronic active hepatitis and persistent hepatitis B virus replication are at very high risk of rapid progression to cirrhosis.

Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study

A multicenter longitudinal study was performed to assess the survival of hepatitis B surface antigen positive compensated cirrhosis, primarily in relation to hepatitis B virus replication and hepatitis delta virus infection, and to construct a prognostic index based on entry characteristics. This cohort study involved nine university medical centers in Europe. Three hundred and sixty-six Caucasian HBsAg positive patients with cirrhosis who had never had clinical manifestations of hepatic decompensation were enrolled and followed for a mean period of 72 months (6 to 202 months). Inclusion criteria were biopsy-proven cirrhosis, information on serum hepatitis B e antigen and antibody to hepatitis D virus at the time of diagnosis and absence of complications of cirrhosis. At entry 35% of the patients were HBeAg positive, 48% of the patients tested were HBV-DNA positive and 20% anti-HDV positive. Death occurred in 84 (23%) patients, mainly due to liver failure (45 cases) or hepatocellular carcinoma (23 cases). The cumulative probability of survival was 84% and 68% at 5 and 10 years, respectively. Coxs regression analysis identified six variables that independently correlated with survival: age, albumin, platelets, splenomegaly, bilirubin and HBeAg positivity at time of diagnosis. According to the contribution of each of these factors to the final model, a prognostic index was constructed that allows calculation of the estimated survival probability. No difference in survival of hepatitis D virus infected and uninfected patients was observed. Termination of hepatitis B virus replication and/or biochemical remission during follow up correlated with a highly significant better survival. These data show that in compensated cirrhosis B, hepatitis B virus replication, age and indirect indicators of poor hepatic reserve and established portal hypertension significantly worsen the clinical course of the disease, whereas hepatitis D virus infection does not influence the prognosis. The highly significant improvement in life expectancy following cessation of hepatitis B virus replication and biochemical remission favors antiviral therapy in those patients with a guarded prognosis, as estimated by a prognostic index.

Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B

BACKGROUND The effect of hepatitis delta virus (HDV) infection on the clinical course of cirrhosis type B is poorly defined. AIMS To investigate the impact of HDV status on morbidity and mortality in cirrhosis type B. PATIENTS/METHODS Retrospective cohort study of 200 Western European patients with compensated cirrhosis type B followed for a median period of 6.6 years. RESULTS At diagnosis, 20% of patients had antibodies to HDV (anti-HDV); median age was lower in anti-HDV positive cirrhotics (34 v 48 years respectively). Kaplan-Meier five year probability of hepatocellular carcinoma (HCC) was 6, 10, and 9% in anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive cirrhotics respectively; the corresponding figures for decompensation were 22, 16, and 19% and for survival they were 92, 89, and 83% respectively. Cox regression analysis identified age, albumin concentration, γ-globulin concentration, and HDV status as significant independent prognostic variables. After adjustment for clinical and serological differences at baseline, the risk (95% confidence interval) for HCC, decompensation, and mortality was increased by a factor of 3.2 (1.0 to 10), 2.2 (0.8 to 5.7), and 2.0 (0.7 to 5.7) respectively in anti-HDV positive relative to HDV negative cirrhotic patients. The adjusted estimated five year risk for HCC was 13, 4, and 2% for anti-HDV positive/HBeAg negative, anti-HDV negative/HBeAg negative, and anti-HDV negative/HBeAg positive cirrhotics respectively; the corresponding figures for decompensation were 18, 8, and 14% and for survival 90, 95, and 93% respectively. CONCLUSIONS HDV infection increases the risk for HCC threefold and for mortality twofold in patients with cirrhosis type B.

Long-term follow-up of non-A, non-B (type C) post-transfusion hepatitis.

Abstract One hundred and thirty-five patients who developed non-A, non-B post-transfusion hepatitis mostly after cardiac surgery, were followed for a mean (±S.D.) of 90±41 months (range: 13–180) to evaluate clinical and histological outcome. Thirty-one cases resolved within 12 months, while 104 (77%) progressed to chronicity. Twenty-one of 65 (32%) biopsied patients developed cirrhosis at the end of the follow-up, and one further progressed to hepatocellular carcinoma. One patient had a complete histological remission (1%). The remaining cases had chronic active (37%), chronic persistent (27%) or chronic lobular hepatitis (3%). About half of the cases with cirrhosis developed portal hypertension, and three of these died due to esophageal varices hemorrhage, one due to liver failure, and one due to hepatocellular carcinoma. Out of 26 patients with the initial histologic diagnosis of chronic hepatitis that were rebiopsied during follow-up, 13 (50%) progressed to cirrhosis. These patients were significantly older than patients who did not develop cirrhosis (mean age 57 and 45 years respectively; p During acute hepatitis anti-HCV was positive in all but one of the 114 patients tested. Percentages were similar for patients who recovered (95%) and those who developed chronic hepatitis (100%). However, during follow-up, 71% of the 1st generation and 21% of the 2nd generation ELISA test patients with acute resolved hepatitis became anti-HCV negative, while the same figures in chronic cases were only 8.5% ( p p =0.012). This suggests a correlation between anti-HCV antibody activity, hepatitis C virus replication, and the development of chronic liver disease.

Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: A cohort study of 297 patients

OBJECTIVE:The aim of this study was to compare the prognosis of patients with hepatitis B surface antigen(HBsAg) positive and those with antibody to hepatitis C (anti-HCV) positive cirrhosis.METHODS:This was a retrospective cohort study of 297 untreated Western European patients with compensated viral cirrhosis (Child class A; 161 patients with hepatitis type B and 136 with type C) who were followed for a median period of 6.6 yr.RESULTS:At diagnosis, median age was lower (48 vs 58 yr, respectively) in HBsAg-positive cirrhotic patients. The Kaplan-Meier 5-yr probability of hepatocellular carcinoma (HCC) was 9% and 10% in HBsAg and anti-HCV-positive cirrhotic patients, respectively; the corresponding figures for decompensation unrelated to HCC were 16% and 28% and for survival were 86% and 84%, respectively. After adjustment for clinical and serological differences at baseline, the relative risk (95% CI) for HCC, decompensation and mortality was 1.53 (CI = 0.81–2.89), 0.59 (CI = 0.37–0.94), and 1.44 (CI = 0.85–2.46) respectively, in HBsAg-positive patients compared with anti-HCV-positive cirrhotic patients. Among HBsAg-positive cirrhotic patients, the relative risk for HCC, decompensation, and mortality was 0.89 (CI = 0.30–2.63), 4.05 (CI = 1.09–15.1), and 5.9 (CI = 1.64–21.3), respectively, in HBV-DNA positive (HBeAg positive or negative) compared with HBV-DNA negative (HBeAg negative) patients at entry.CONCLUSIONS:Patients with HBV infection may present with cirrhosis about 10 yr earlier than those with HCV infection. HCV infection tends to be associated with a higher risk of decompensation, but these data should take into consideration the heterogeneity of HBV-related cirrhosis in terms of viremia levels and risk of hepatic failure. Survival shows no significant differences according to HBV or HCV etiology in Western European cirrhotic patients.

Long-term follow-up of acute and chronic non-A, non-B post-transfusion hepatitis: evidence of progression to liver cirrhosis.

The long-term outcome of non-A, non-B post-transfusion hepatitis was evaluated in 21 patients who developed the illness after open-heart surgery and could be followed thereafter up to five years. Histological chronic sequelae were documented in 13 patients, and consisted of chronic persistent hepatitis in one case, chronic lobular hepatitis in two and chronic active hepatitis in 10, five of whom also developed superimposed cirrhosis. Progression to these chronic states was in most cases symptomless, independently of the severity of liver lesions; one patient, however, died of gastrointestinal bleeding due to cirrhosis of the liver. During follow-up the biochemical pattern of chronic non-A, non-B hepatitis was unique, while striking fluctuations of transaminase levels. Liver histology proved essential to identify the severity of chronic liver lesions, as clinical and biochemical features were uniform and not indicative of it. Our results suggest that cirrhosis may develop, often with an asymptomatic course, in a significant number of patients who do not recover after acute post-transfusion non-A, non-B hepatitis.

Long term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood.

Seventy-six children aged 1-13 years who were known to be positive for hepatitis B surface antigen and hepatitis B e antigen in serum for at least 6 months and who had biopsy-proven chronic hepatitis have been followed longitudinally for 1-12 years (mean, 5 years). Twenty-three of them are now young adults. Eight patients had acute type B hepatitis 12-24 months before entering the study, while 68 patients came to observation during a chronic phase. At the beginning of follow-up, all 76 children were positive in serum for hepatitis B virus DNA, and 44 (58%) had chronic active hepatitis, associated with cirrhosis in two cases. During follow-up, 23 (30%) patients remained hepatitis B e antigen-positive, most with unchanged biochemical and histological features. The other 53 (70%) cases seroconverted to hepatitis B e antibody and cleared hepatitis B virus DNA from serum, including 7 of 8 (87%) patients with acute hepatitis at presentation. After seroconversion, alanine aminotransferase levels normalized in all patients and remained normal in 49 patients (92.5%) throughout a mean observation period of 3 years. Five of these children, including 2 of 7 (29%) with previous acute hepatitis, eventually cleared hepatitis B surface antigen from their sera. Finally, 4 (7.5%) patients experienced a mild increase of alanine aminotransferase levels several months after seroconversion in the absence of hepatitis B virus replication or of delta virus superinfection. Clinical and virological parameters did not significantly differ between patients with or without acute onset; however, seroconversion occurred earlier, and the rate of hepatitis B surface antigen clearance was greater in the former than in the latter group. The present data indicate that approximately two thirds of children with hepatitis B e antigen- and hepatitis B virus DNA-positive chronic hepatitis clear hepatitis B virus DNA from their sera before reaching adulthood. After termination of viral replication, most patients achieve a sustained biochemical remission, suggesting the disappearance of disease activity. Reactivation of virus replication after hepatitis B e antibody seroconversion has never been observed in this series, although mild alanine aminotransferase level abnormalities could be detected in a minority of cases.

EXTRADIGESTIVE MANIFESTATIONS OF HELICOBACTER PYLORI INFECTION: FACT AND FICTION

Helicobacter pylori is a gram-negative , microae rophilic, oxidase -, catalase -, and urease-positive bacte rium, motile by means of a tuft of sheathed ̄ agella at one pole . The bacterium colonize s gastric mucosa and induces a strong in ̄ ammatory response with release of various bacterial and host-de pendent cytotoxic substance s (1). H. pylori infection is the main aetiological factor for gastritis and peptic ulce r. Its eradication is associate d to healing of these diseases and signi® cant reduction of ulcer recurrence and rebleeding (2, 3). Multiple studie s have demonstrated that in ̄ ammation caused by H. pylori infection may contribute to the development of adenocarcinoma of the stomach; moreover, it has been involve d in the deve lopment of low-grade B-ce ll lymphoma of gastric mucosa-associated-lymphoid-tissue (MALT lymphoma) (4). Isolate s of H. pylori can be divided into two major distinct phenotypic groups: type I bacte ria, expre ss the vacuolating cytotoxin (VacA) and the cytotoxinassociate d gene (CagA), type II bacteria do not express VacA and CagA. Such strains show different pathoge nic potential: type I strains, in particular, may induce mucosal damage by stimulating gastric epithe lial cytokine response s and may produce s a varie ty of other factors that determine , directly and indirectly, the local in ̄ ammatory response (5). Therefore , the characte ristics of the infecting strain may in ̄ uence the clinical outcome of the infection. Recently, a potential role of H. pylori infection in several extrainte stinal pathologie s has been sugge sted (Table 1). The postulated role of H. pylori in the pathoge ne sis of extrainte stinal manife stations is based on the facts that: (1) local in ̄ ammation has systemic effects; (2) H. pylori gastric infection is a chronic process lasting for decades, and (3) persistent infection induces a chronic in ̄ ammatory and immune response able to induce lesions both locally and remote to the primary site of infection (1). Various potential causative mechanisms have been propose d for the reported associations between H. pylori infection and extradige stive diseases and can be divided into direct and indirect effects (6). Direct effects of infectious agent on the vascular wall include endothe lial injury or dysfunction related to circulating endotoxins, smooth-muscle prolife ration, and local in ̄ ammation. Indire ct effects are like ly more freque ntly involve d and include production of in ̄ ammatory mediators with proin ̄ ammatory, procoagulant, and atherogenic action; changes in risk factors (lipid pro® le, coagulation, oxydative metabolites), cross-reactive antibodie s, nutrient and vitamin malabsorption, as well as metabolic factors, such as overproduction of ammonia. The aim of this report was to provide a critical review of the available lite rature about extradige stive manife stations of H. pylori infection. Pertinent articles have been identi® ed through a MEDLINE search done using as key words every extradige stive manife station so far linke d to H. pylori infection. Studie s publishe d in English between 1990 and 1997 have been identi® ed and reviewed. We also used the bibliographie s of relevant article s to augment our search in order to identify studies, including abstracts and case reports. Manuscript rece ived June 2, 1998; revised manuscript rece ived October 8, 1998; accepte d October 26, 1998. From the Department of Internal Medicine, University of Sassari, Italy; and VA Medical Center and Baylor College of Medicine , Houston, Texas. Address for reprint requests: Professor Giuseppe Realdi, Istituto di Clinica Medica Gene rale e Terapia Medica, Viale San Pietro, 8, 07100 Sassari, Italy. Digestive Diseases and Sciences, Vol. 44, No. 2 (February 1999), pp. 229 ± 236

Pretreatment Antibiotic Resistance in Helicobacter pylori Infection: Results of Three Randomized Controlled Studies

Background. Although combinations of antibiotics and antisecretory drugs are useful for treatment of Helicobacter pylori infection, treatment failure is common. The aim of this study was to evaluate the relation between pretreatment antibiotic resistance and outcome by using six different treatment regimens for H. pylori infection.

Isolation of Helicobacter pylori From Sheep—Implications for Transmission to Humans

OBJECTIVES:When and how Helicobacter pylori (H. pylori) originally entered the human population as well as how the infection is transmitted in different communities is unknown. We previously showed that Sardinian shepherds had almost a 100% prevalence of H. pylori and that the prevalence was higher than that of their same-household siblings.Aim:To examine whether H. pylori infection might be transmitted from sheep.METHODS:Milk and gastric tissue were cultured and analyzed by PCR amplification using three sets of primers Helicobacter genus–specific 16S rRNA and two sets of primers specific for H. pylori vacA gene.RESULTS:Helicobacter DNA was demonstrated in 60% (38/63) of milk samples and in 30% (6/20) of sheep tissue samples. H. pylori vacA gene was amplified in five of 38 milk samples, and in two of six sheep tissue samples respectively. H. pylori were cultured from sheep milk and tissue samples and confirmed as H. pylori on the basis of colony morphology, positive biochemical reactions, and negative Gram stain. Sequence analysis of 16S rRNA PCR products from these isolates demonstrated 99% identity with H. pylori.CONCLUSIONS:Together, the presence of H. pylori in sheep stomach in the absence of associated gastritis and recovery of H. pylori from sheep milk and gastric tissue suggest that sheep may be a natural host for H. pylori.