Membranous nephropathy related to hepatitis B virus in adults

BACKGROUND. The natural course of adult hepatitis B virus (HBV)-related membranous nephropathy in areas where HBV infection is endemic (characterized by vertical and horizontal transmission of HBV in early childhood) has not been fully defined. METHODS. We evaluated the clinical features, pathological findings, serologic profiles, therapeutic responses, and prognoses of 21 patients with adult-onset HBV-related membranous nephropathy. The patients were followed for a mean of 60 months (range, 12 to 108). Only patients with evidence of glomerular capillary deposition of hepatitis B e antigen (HBeAg) in a renal-biopsy specimen were included. RESULTS. The clinical features and serologic studies suggested that the patients had acquired chronic HBV infection in early childhood; moreover, other causes of membranous nephropathy had been excluded. All were seropositive for hepatitis B surface antigen and had high titers of antibody to hepatitis B core antigen at first clinical presentation. HBeAg was detected in the serum of 17 patients (81 percent), yet only 3 had even slightly increased plasma alanine aminotransferase levels. The clinical response to therapy with interferon alfa was disappointing; only one of the five patients treated had a complete remission with seroconversion to antibody to HBeAg. Contrary to reports of studies in children, spontaneous remission of the nephrotic syndrome or proteinuria was uncommon in the adults with HBV-related membranous nephropathy whom we studied. Proteinuria and HBV antigenemia persisted in untreated patients. During the follow-up period, 29 percent of the patients had progressive renal failure and 10 percent required maintenance dialysis therapy. CONCLUSIONS. The course of HBV-related membranous nephropathy in adults in areas where HBV is endemic is not benign. Regardless of treatment, the disease has a slowly but relentlessly progressive clinical course in approximately one third of patients.     

Hepatitis B virus, hepatitis A virus and persistently elevated aminotransferases in hemophiliacs

To determine the exposure to hepatitis A and hepatitis B viruses (HAV, HBV) following intravenous replacement therapy in patients with classic hemophilia and to assess the role of these viruses in persistently elevated aminotransferases, sera were studied from 136 patients from 9 months to 67 years of age were transfused with either single-donor cryoprecipitate (CRYO) or Antihemophilic Factor Concentrate (AHF) for periods ranging from a few months to 15 years. Serologic evidence of past or present infection with HBV was detected in 90% of all 136 patients and in 85% of those 34 patients 10 years of age or younger. Sixty-four percent of those with serologic markers of hepatitis B had high titers of antibody to the hepatitis B surface antigen and low titers of antibody to the hepatitis B core antigen. These findings are consistent with the known high frequency of early exposure to HBV in hemophiliacs receiving replacement therapy and with recovery from these hepatitis B infections. Sixteen percent of these patients had persistently elevated aminotransferase levels; HBV could not be implicated as the cause of the enzyme elevations in most of these cases.     

Enzyme-linked immunosorbent assay for detection of immunoglobulin M antibody to hepatitis B core antigen.

An enzyme-linked immunosorbent assay for detection of specific immunoglobulin M (IgM) antibodies against the core antigen of the hepatitis B virus (anti-HBc IgM) is described. The interference of IgM rheumatoid factor was evaluated quantitatively. In the anti-HBc IgM test, the rheumatoid factor gave false-positive results when the concentration exceeded 20 IU/ml. The rheumatoid-positive sera were disclosed by a control and retested for anti-HBc IgM after absorption of rheumatoid factor with latex particles aggregated with human IgG. In five of seven selected patients with acute hepatitis B followed to biochemical and clinical recovery, anti-HBc IgM was present transiently until antibodies against hepatitis B surface antigen (anti-HBs) appeared. Two patients had persistent anti-HBc IgM during the follow-up period. Four patients with hepatitis B surface antigenemia and progression to chronic liver disease did not clear their anti-HBc IgM in the period of observation (11 to 24 months). Anti-HBc IgM could not be demonstrated in 223 of 225 Danish blood donors. The two donors found positive for anti-HBc IgM also had anti-HBs. Twenty patients with acute A or non-A non-B hepatitis were negative for anti-HBc IgM. The enzyme-linked immunosorbent assay for anti-HBc IgM described here has a high specificity and sensitivity. The diagnostic relevance needs further evaluation, including quantitation of anti-HBc IgM, but the results presented indicate that anti-HBc IgM may be helpful in differentiating between prior and recent or ongoing hepatitis B infection.     

Symptomatic anti-HBe positive chronic hepatitis B in Taiwan with special reference to persistent HBV replication and HDV superinfection

Ninety-four patients, who were admitted with symptoms of liver disease and found to be positive for hepatitis B surface antigen and antibody to hepatitis B e antigen (anti-HBe), were examined for hepatitis B virus (HBV) DNA in serum and immunoglobulin antibody to hepatitis B core antigen and liver biopsies were stained for hepatic hepatitis B core antigen. Of 94 patients, 34 (36%) had evidence of HBV replication and 35 (37%) evidence of hepatitis D virus (HDV) superinfection. Most of the latter two groups of patients (greater than 70%) had evidence of chronic active hepatitis or active cirrhosis in their liver biopsies. The majority of these patients (greater than 80%) also had high levels of serum alanine aminotransferase (greater than 200 U/L) during the acute stage of their illness, and suffered from prolonged hepatic inflammation (greater than 1 year). Many of the patients (59%) also experienced frequent (1-6 episodes) relapsing exacerbations during a two-year follow-up period. Thus, persistent replication or reactivation of HBV and HDV superinfection were the two major causes of clinical exacerbations in anti-HBe-positive chronic HBV carriers in Taiwan, and also played an important role in the progression of their liver diseases and unfavorable outcomes.     

Assay of hepatitis B viras genome titers in sera of infected subjects

A method for quantitative standardization of the DNA hybridization assay for hepatitis B virus (HBV) DNA protein complex in serum is described. This method was used to determine the titer of HBV DNA in various groups of subjects with HB surface antigen (HBsAg) in order to ascertain its accuracy as an index of infectivity. The method's detection limit was 10⁵ genome equivalents or 0.3 pg DNA per ml. Titers of 5×10⁷ to 5×10⁸ genome equivalents per ml were found to be typical for persistent massive viremia, which occurred more frequently in symptomatic (30 of 48) than in asymptomatic (24 of 72) carriers positive for HBe antigen (HBeAg). Moderate viremia (10s⁵–5×10⁷) was usually found in patients eliminating the virus from the blood. Patients with resolving acute hepatitis B were frequently positive at the onset (18 of 26) with moderate titers, but became negative within several weeks. In 11 patients who developed chronic hepatitis B, titers increased until typical massive viremia was evident. Whereas healthy HBsAg carriers with anti-HBe always had negative genome titers (144 of 144), symptomatic carriers with anti-HBe often had moderate genome titers (9 of 30). It is recommended that genome titers be monitored in HBeAg-positive and in symptomatic anti-HBe positive virus carriers in order to distinguish between virus carriers with high (>5×10⁷), moderate (10⁵–5×10⁷) and low (<10⁵) infectivity.     

Antibodies to single stranded DNA: A diagnostic aid in chronic hepatitis b virus infections

Serial determinations of titers of binding antibodies to single stranded DNA were performed over a period of three years in 43 type B hepatitis patients with persisting HB_sAg who had either developed chronic hepatitis or were asymptomatic carriers. Patients with histopathological diagnosis of chronic active or chronic persistent hepatitis, with or without clinical symptoms, showed high titers of anti-DNA throughout the course of the disease, whereas in most of these patients the serum alanine transaminase and bilirubin levels fluctuated widely and were often normal; in such cases the elevation of anti-DNA was frequently the only positive sign present. On the other hand anti-DNA titers were within the normal range in chronic asymptomatic HB_sAg carriers who showed no histopathological or biochemical changes. Anti-DNA determinations are proposed as a reliable diagnostic aid to supplement current procedures for assessment of the disease status during the course of chronic hepatitis B virus infections.     

Antibody to hepatitis B surface antigen in haemophiliacs on long-term therapy with Scottish factor VIII.

Thirty-five patients with haemophilia A were studied clinically and serologically between 1971-2 and 1975-6 for evidence of hepatitis B infection. One patient suffered from clinical hepatitis B, and a further eight patients showed antibody responses to hepatitis B surface antigen (HBsAg) consistent with exposure to HBsAg during this period. No evidence for HBsAg exposure was found in 14 patients, while the remaining 12 patients had high titres of antibody to HBsAg at both times and no inferences could be drawn about HBsAg exposure. All patients had received exclusively replacement factor VIII material prepared locally from HBsAg-screened voluntary Scottish blood donations. From the details of the therapy given we calculated that the rate of HBsAg seroconversion in these patients represented about 0.3 HBsAg-containing donations/1000 donations.     

Hepatitis D virus antibody in HBsAg-positive and HBsAg-negative substance abusers with chronic liver disease

The hepatitis D virus (HDV; previously called the "delta agent") is a defective organism which can replicate only in the presence of the hepatitis B virus (HBV). We tested the serum of 95 substance abusers, all of whom had sufficient evidence of chronic liver disease to warrant a liver biopsy, for hepatitis D virus antibody (anti-HDV). Anti-HDV was detected in five of eight hepatitis B surface antigen (HBsAg)-positive patients and 12 of 87 (14%) HBsAg-negative patients. Antibody to the hepatitis B core antigen (anti-HBc) was the sole hepatitis B marker in eight of the 12 (67%) anti-HDV-positive, HBsAg-negative patients but in only 14 of 75 (19%) anti-HDV-negative, HBsAg-negative patients (P less than 0.005). None of the anti-HDV-positive, HBsAg-negative patients had detectable IgM anti-HBc in the serum or hepatitis D antigen in liver tissue, and they had similar clinical features and liver biopsy diagnoses to HBsAg-negative patients without anti-HDV. We conclude that anti-HDV in HBsAg-negative substance abusers reflects infection with HDV and HBV in the distant past and does not indicate more severe liver disease than that seen in HBsAg-negative patients without anti-HDV.     

The role of circulating hepatitis B antigen/antibody immune complexes in the pathogenesis of vascular and hepatic manifestations in polyarteritis nodosa

To investigate further the role of hepatitis B antigen (HBs Ag) and specific immune complexes in polyarteritis, sera from 55 histologically confirmed cases were tested for the presence of hepatitis B antigen-associated particles and hepatitis B-antibody (anti HBs) by solid phase radio-immunoassay, electron microscopy, and passive haemagglutination. Results of these findings have been correlated with the clinical course of the disease.HBs Ag was detected in 30 patients (54.5%) and anti HBs in 13/45 (28%). Subtyping in 20 patients revealed that 11 were Y and 9 D. Thirty-seven cases (69%) demonstrated either HBs Ag or anti HBs and 5/45 (11%) had both. Electron microscopic examination showed 20 nm spherical and tubular particles in sera of 20/27 patients with 42 nm particles in 11 cases and clumped particles in 12 (60%).No correlation was found between detection of immune complexes and liver disease whereas the presence of coexisting hepatitis B antigen and antibody or aggregated particles was restricted to cases of active vasculitis. Seroconversion or the presence of hepatitis B antibody alone was associated with improved prognosis. Circulating hepatitis B antigen antibody complexes may be responsible for vasculitis or polyarteritis but do not appear to be pathogenic for the liver.     

Persistence of serum antibody to hepatitis B core antigen.

The purpose of the present study was to measure the amount of antibody to hepatitis B core antigen (anti-HBc) in different populations by the immunoelectroosmophoresis method. High titers of anti-HBc, up to 1/4,096, were found in the acute stage of hepatitis B virus infections and in the chronic carrier state of hepatitis B surface antigen. In cases of acute hepatitis the anti-HBc titers gradually declined to low levels but persisted for the observation time of 5 to 6 years. Individuals positive for antibodies to hepatitis B surface and core antigens selected from a Swedish "normal" population showed still lower anti-HBc titers, indicating that the hepatitis B infection had occurred earlier. The anti-HBc titers in sera drawn at intervals of 4 years from a group of hemophilia patients may indicate previous infection with replicating hepatitis B virus rather than immunization with noninfectious hepatitis B core antigen material.     

Chronic liver disease in Peru: Role of viral hepatitis

The prevalence of antibodies to hepatitis C virus (anti-HCV) was determined in 105 patients with biopsy-proven chronic liver disease and 128 comparison patients without any evidence of liver pathology living in Lima, Peru. Using a second-generation EIA screening and supplemental immunoblot assay, anti-HCV was detected in four of 13 patients with chronic hepatitis, in 11% of 85 patients with cirrhosis, and in none of seven patients with hepatocellular carcinoma. Only two (1.6%) comparison patients without liver disease had anti-HCV. Hepatitis B surface antigen (HBsAg) was found in 23% of patients with chronic hepatitis, 12% of patients with cirrhosis, and three of seven patients with hepatocellular carcinoma. There was no evidence of chronic viral hepatitis or alcohol abuse (reported by one-third of subjects) in 48% of chronic liver disease patients. These preliminary data suggest that among this South American population neither hepatitis B nor hepatitis C infection is the predominate cause of chronic liver disease and that other infectious or environmental factors may be important. © 1994 Wiley-Liss, Inc.     

Accelerated schedule of hepatitis B vaccination in patients with hemophilia

Early development of immunity after hepatitis B vaccination is particularly important for patients such as hemophiliacs, at high risk for acquiring hepatitis B from potentially infectious plasmaderived concentrates. The purpose of this study was to evaluate whether or not protective antibody titers could be achieved quickly and maintained in hemophiliacs by an accelerated vaccination schedule. A yeast-recombinant hepatitis B vaccine (Engerix B, SKF Ritt) was given subcutaneously in the deltoid region and repeated 2 and 6 weeks later to 85 hemophiliacs negative for hepatitis B virus (HBV) markers. After the first 22 patients had been enrolled, a modification of the schedule involving a fourth booster dose 24 weeks after the first dose of vaccine was applied to the next 63 consecutive vaccinees. Fifty-three percent of vaccinees had antibody titers to hepatitis B surface antigen (anti-HBs≥ 10 mlU/ml) by week 6, even though the mean titers of anti-HBs were somewhat lower than those achieved historically in normal individuals. The protection rate had increased to 87% by week 10, one month after the third dose of vaccine, and to 93% by week 24. One year after starting vaccination, the rate for the vaccinees who did not receive the fourth booster dose was 71%, and 96% for those who did receive the fourth dose, with only 2 patients not responding despite the booster dose. It is concluded that even though the accelerated schedule of immunization produced rapidly high rates of protective antibody titers, a booster dose is required to obtain higher titers and provide more persistent immunity.     

Dominant replication of either virus in dual infection with hepatitis viruses B and C

To characterize the state of dual infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), HBV-DNA and HCV-RNA levels were determined by spot hybridization or polymerase chain reaction in the sera of patients who were positive for both hepatitis B surface antigen and HCV antibody. Among 27 patients who showed evidence of double infection, 21 (77.8%) had detectable levels of only either HBV or HCV genome in their sera, 2 (7.4%) showed none of the viral genomes, and 4 (14.8%) had both HBV-DNA and HCV-RNA. In the 4 patients with both HBV-DNA and HCV-RNA, the titers of HCV-RNA or HBV-DNA were lower than those in the patients with HCV-RNA or HBV-DNA alone. In some patients with chronic hepatitis, the viruses appeared to replicate in turn in the course of the disease. These results indicate that the viruses show alternating dominance in replication in most of the patients who have dual infection with HBV and HCV, probably due to interference of the viruses. © 1995 Wiley-Liss, Inc.     

Influence of hepatitis G virus infection on liver disease

The influence of hepatitis G virus (HGV) infection on disease activity in hepatitis C related and unrelated liver disease was investigated in 254 individuals using an EIA polymerase chain reaction assay for HGV. One hundred patients had chronic hepatitis C, 26 primary biliary cirrhosis, and 30 alcoholic liver cirrhosis. In addition, 51 hepatitis B surface antigen (HBsAg)-positive and 47 anti-hepatitis C virus (HCV)-positive blood donors were screened. Hepatitis G virus was detected in 18% of patients with chronic hepatitis C, 13% of patients with alcoholic liver cirrhosis, 11 % of patients with primary biliary cirrhosis, 10% of anti-HCV-positive blood donors, and 2% of HBsAg-positive blood donors. Virus load and alanine aminotransferase (ALT) levels did not differ significantly in patients with HCV alone versus patients coinfected with HCV and HGV. However, mild liver fibrosis correlated with HGV coinfection. Hepatitis G virus did not influence ALT levels or liver damage in liver disease unrelated to viral infection.     

Serum hepatitis B virus-DNA in chronic hepatitis B and delta infection

Hepatitis B-associated delta agent, a defective RNA virus requiring helper functions of hepatitis B virus (HBV), has been shown to interfere with HBV replication. Low titers of serum hepatitis B surface antigen, absence of hepatitis B e antigen, and low levels of stainable hepatitis B core antigen in liver cells usually seen in chronic delta infection are indirect evidences of such an interference. Measurement of serum HBV-DNA by hybridization with phosphorus 32-labeled HBV-clone DNA is the most sensitive method currently available to detect HBV replication. Using this method, we found that only two of 13 patients with chronic delta infection showed serum HBV-DNA positivity in comparison with seven of 14 patients who had chronic hepatitis B without delta infection. These two groups were matched for hepatitis B e antigen status and liver histopathology. Thus, we report direct evidence of delta agent interfering with the replication of the helper (HBV) virus.     

Blood levels of TT virus following immune stimulation with influenza or hepatitis B vaccine

Torque Teno virus (TTV) has been demonstrated to be present persistently in the blood of healthy individuals without evidence that it causes any disease process. The levels of TTV vary in patients co-infected with other viruses and there has been considerable speculation as to whether TTV contributes to pathogenesis by other viruses or if the varying levels might be related to immune activation in the host. In the present study, the load of TTV was examined in plasma and peripheral blood mononuclear cells (PBMCs) following immunization of subjects with either influenza (a recall antigen) or hepatitis B virus (HBV) (a new antigenic exposure). The results overall did not indicate a significant change in TTV titers over a 90 day observation period; however, when TTV genogroup was taken into consideration there was an increase in viral load in plasma at some time points for subjects persistently infected with genogroup 3. While this was observed in both influenza and HBV immunized subjects, the effect was more profound in HBV vaccination. Thus, it appears that exposure to a new antigen rather than a recall antigen may stimulate TTV replication more effectively. The data further suggest that investigating the interactions between TTV and its host might require to examine specifically each TTV genogroup separately in order to determine if certain TTV types have any role in disease pathogenesis.     

Seroepidemiological investigation of patients and family contacts in an epidemic of hepatitis A.

Serial blood and faecal samples were collected from patients and family contacts during an outbreak of hepatitis A in a village and tested by a solid-phase competitive type radioimmunoassay for hepatitis A antigen and hepatitis A antibody. The amount and duration of excretion of hepatitis A antigen was correlated with the severity of the illness. In 2 severe clinical cases, hepatitis A antigen was demonstrated in faecal extracts 11 days before the onset of jaundice and continuing for 10 days thereafter, with maximum shedding during the late incubation period. Faecal antigen was demonstrated in low concentrations for only 2 days in a patient with mild disease and in a person with subclinical infection. There was an inverse correlation between the incidence of infection and prevalence of hepatitis A antibody and age. Of 24 infections, 19 (79%) occurred in persons in the age group 0 to 20 years, a group in which only 6% of individuals had pre-existing antibody. Hepatitis A antibody was present in the serum of 3 persons in low titres of 1:20 to 1:40 on the day jaundice developed. The antibody titres increased very rapidly during the following 2 weeks of illness and slowly during the following months, reaching titres of 1:900 to 1:3500. In a separate study, a mean antibody titre of 1:591 was found in 13 patients, 12 years after clinical hepatitis A with jaundice.     

Cutoff levels of immunoglobulin M antibody against viral core antigen for differentiation of acute, chronic, and past hepatitis B virus infections

The titer of antibody against core antigen of hepatitis B virus in the immunoglobulin M class (IgM anti-HBc) was determined by an IgM capture assay of reduced sensitivity (30 arbitrary units). The distribution of titers among 235 acute hepatitis patients who were hepatitis B surface antigen (HBsAg) positive suggested that 600 U forms a lower cutoff value for acute hepatitis B. Clinically apparent cases of acute hepatitis with high IgM anti-HBc and without HBsAg were rare (2.6%). Acute, non-B hepatitis in HBsAg carriers was more frequent (9.4%). In chronic hepatitis B, 39% of 174 biopsy-proven cases had moderate titers of 30 to 600 U, whereas healthy HBsAg carriers were rarely (4/84) positive. In mild or inapparent infections without HBsAg, titers were between 50 and 400 U. Thus, sufficiently accurate and sensitive quantitation of IgM anti-HBc allows for differentiation of acute and nonacute hepatitis B virus infection in acute hepatitis, partial differentiation between clinically symptomatic and asymptomatic chronic infections, and identification of recent subclinical infections.     

Risk of post-transfusion infection with the hepatitis delta virus. A multicenter study

Hepatitis delta virus is a defective virus that can replicate only in the presence of hepatitis B virus. To determine the prevalence, circumstances of transmission, and clinical importance of infection with hepatitis delta virus, we obtained data on 262 patients with post-transfusion hepatitis who were positive for the hepatitis B surface antigen (HBsAg) even though they had received blood screened for it. We also studied 94 HBsAg carriers who were receiving repeated blood transfusions for other diseases, and 103 HBsAg carriers with hemophilia who were receiving various forms of coagulation factors. Antibody to hepatitis delta virus was found in 9 of 262 patients (3.5 per cent) with post-transfusion hepatitis, 5 of 234 (2 per cent) with self-limited disease, and 4 of 28 (14.5 per cent) with fulminant disease (P less than 0.05). The absence of IgM antibodies to the hepatitis B core antigen indicated that three of the nine patients with both HBsAg and antibodies to hepatitis delta virus had been carriers of HBsAg at the time of transfusion, and the acute disease represented the combined effects of the two viruses. Antibody to hepatitis delta virus was found in 3 of 94 Italian carriers of HBsAg who were receiving repeated blood transfusions, in none of 24 Brazilian, East German, or Australian hemophiliac carriers infused with clotting factors prepared from single or mini-pool volunteer plasma, and in 27 to 100 per cent of 79 hemophiliac carriers from European and U.S. series who received coagulation factors manufactured from large pools of plasma. We conclude that infection with hepatitis delta virus is likely to be more severe than infection with hepatitis B virus alone and that screening for HBsAg provides a high degree of safety in preventing infection with hepatitis delta virus, but that the risk is considerably greater in patients who are already carriers of HBsAg. We recommend that HBsAg carriers be given only blood derivatives prepared from a single donor or mini-pool donors.     

A prospective study of post-transfusion non-A, non-B (type C) hepatitis following cardiovascular surgery in Taiwan

In an attempt to investigate the incidence and clinical course of non-A, non-B (NANB) hepatitis following blood transfusion in Taiwan, 288 patients who underwent cardiovascular surgery and received blood transfusion were followed prospectively with serum liver aminotransferase levels and viral hepatitis markers for at least six months. None had any past history of liver disease or drug abuse. All blood donors were tested for serum hepatitis B surface antigen and alanine aminotransferase (ALT) (greater than 45 U/L). Thirty-seven (12.8%) patients developed PTH. 34 (91.9%) were considered to be cases of NANB hepatitis, 2 (5.4%) were cytomegalovirus hepatitis, and one (2.7%) was caused by Epstein-Barr virus. No one developed hepatitis B post-transfusion hepatitis (PTH). Of the 34 NANB PTH patients, 15 (44.1%) were asymptomatic, 16 (47.1%) had clinical symptoms, and 9 (26.5%) had serum total bilirubin levels higher than 2 mg/dl. There was no case of fulminant hepatic failure. Of 26 NANB PTH patients who were followed up for more than one year, 15 (57.7%) still had abnormal serum ALT levels. The incubation period of NANB PTH ranged from 2 to 16 (mean 6.1 +/- 3.2) weeks. Of the 37 PTH patients, 32 (86.5%) were found to have anti-HCV seroconversion during one year follow-up period. NANB PTH is as common in Taiwan as in the United States and Japan, and is demonstrated by this study to be due mostly to HCV.