Transmission of hepatitis C in a pharmacologic study.

OBJECTIVE: To describe an outbreak of hepatitis C in a clinical research study. DESIGN: Observational study. SETTING: Tertiary-care hospital. PATIENTS: Healthcare workers who volunteered to be subjects in a study of the metabolic effects of inhaled and oral corticosteroids who were unwittingly exposed to hepatitis C virus (HCV). METHODS: Epidemiological investigation and serological analyses. RESULTS: One chronic carrier of HCV was identified. Four fellow workers volunteering in the studies became infected with HCV, with 96% homology among strains. There was no evidence of spread from infected healthcare workers to patients on whom they had performed arterial punctures (2 of 214 positive, unrelated to each other and to the outbreak strain). CONCLUSION: Infection control standards in clinical research must be maintained vigorously to prevent transmission of blood-borne pathogens such as HCV.

Unusual presentation of primary sclerosing cholangitis.

A 23-year-old man presenting with acute pancreatitis and autoimmune hemolytic anemia was diagnosed with primary sclerosing cholangitis (PSC) without evidence of ulcerative colitis. This constellation of rare associations constitutes a unique mode of presentation of PSC. Within two years he also developed ankylosing spondylitis with sacroiliitis. Disordered immune regulation as a major factor in the mechanism of injury in PSC is supported by its increased association with other immunologically mediated disorders, most notably ulcerative colitis. Autoimmune hemolytic anemia, however, has been reported to be associated with PSC on only two occasions, and ankylosing spondylitis in the absence of ulcerative colitis is also unusual. In addition, the presentation of PSC with acute pancreatitis has rarely been described. This patient presented with several unusual features of PSC.

Viruses and immune reactions in the liver.

The immunopathology of hepatitis B and delta virus infections of the liver are reviewed. It is clear there are several antigen/antibody systems of importance in acute and chronic HBV infection. Antibodies to HBs, HB core/HBe and antibodies to Dane specific determinants are involved in virus neutralisation. Elimination of virus infected hepatocytes is dependent on recognition of viral determinants in association with HLA proteins on the infected hepatocytes by cytotoxic T cells. The HLA protein display is modulated by exposure to interferon and may regulate the cytotoxic T cell and NK lytic processes. During chronic HBV infection there is evidence of failure of interferon activation of the infected liver cells so that viral protein synthesis is not decreased and there is no enhancement of HLA protein display. These complex interactions between the virus and the immune system determine the heterogeneity of the clinical syndromes seen in patients infected with this agent. The delta virus replicates only in patients with co-existent HBV infection. The agent is cytopathic and therefore always produces liver disease. When there is delta virus superinfection in a carrier of chronic HBV, there is an acceleration of the rate of progression of the liver disease. The presence of delta infection results in IgM and IgG anti-delta responses.

Diagnosis and management of hepatocellular carcinoma: results of a consensus meeting of The Ottawa Hospital Cancer Centre.

Hepatocellular carcinoma (HCC) is an uncommon tumour, but its incidence is increasing in Canada and elsewhere. Currently, there are no Canadian recommendations for diagnosis and treatment of hcc, and possible options may have regional limitations. A consensus symposium was held in the Ottawa region to consider current diagnostic and management options for hcc. These recommendations were developed: Diagnosis-with adequate imaging, a biopsy is not required pre-surgery, but is required before the start of systemic therapy; lesions smaller than 1 cm should be followed and not biopsied; repeat biopsies should be core tissue biopsies; magnetic resonance imaging is preferred, but triphasic computed tomography imaging can be useful. Resection-recommended for localized HCC. Radiofrequency ablation-recommended for unresectable or non-transplantable HCC; should not be performed in the presence of ascites. Trans-arterial chemoembolization (TACE)-doxorubicin with lipiodol is the agent of choice; trans-catheter embolization is an alternative for patients if TACE is not tolerated or is contraindicated. Medical management-first-line sorafenib should be considered the standard of care. Transplantation-suitable patients meeting Milan criteria should be assessed for a graft regardless of other treatments offered. The authors feel that the recommendations from this consensus symposium may be of interest to other regions in Canada.

Vitamin D status and measures of cognitive function in healthy older European adults.

BACKGROUND/OBJECTIVES: Data from human studies that have investigated the association between vitamin D status and cognitive function in elderly adults are conflicting. The objective of this study was to assess vitamin D status (reflected by serum 25-hydroxyvitamin D (25(OH)D)) in older European subjects (n=387; aged 55-87 years) and examine its association with measures of cognitive function. SUBJECTS/METHODS: Serum 25(OH)D was assessed using enzyme-linked immunosorbent assay, whereas measures of cognitive function were assessed using a comprehensive Cambridge Neuropsychological Testing Automated Battery (CANTAB). RESULTS: In all, 12, 36 and 64% of subjects had serum 25(OH)D concentrations <30, <50 and <80 nmol/l, respectively, throughout the year. Serum 25(OH)D was significantly and inversely correlated with four assessments within the spatial working memory (SWM) test parameter (SWM between errors (r=-0.166; P=0.003); SWM between errors 8 boxes (r=-0.134; P=0.038); SWM strategy (r=-0.246; P<0.0001); and SWM total errors (r=-0.174; P<0.003)). When subjects were stratified on the basis of tertiles (T) of serum 25(OH)D (<47.6 (T(1)); 47.6-85.8 (T(2)); and >85.8 (T(3)) nmol/l), fewer errors in SWM test scores occurred in subjects in the third T when compared with the first T (P<0.05-0.084). Stratification by sex showed that these differences between tertiles strengthened (P<0.001-0.043) in the females, but the differences were not significant (P>0.6) in males. CONCLUSIONS: Vitamin D insufficiency, but not deficiency, is widespread in the older population of several European countries. Low vitamin D status was associated with a reduced capacity for SWM, particularly in women.

Liver disease in general practice.

A wide spectrum of liver disease is seen in general practice. For the most part, asymptomatic increases in transaminase may be followed for several months, but the treatable conditions described should be ruled out early on. It is essential do diagnose as promptly as possible Wilson's disease, hemochromatosis, autoimmune heaptitis, and hepatitis B. Drugs are a frequent cause of wild transaminitis. Heavy alcohol consumption as a cause of liver disease must always be suspected, but may be difficult to prove.

Urticaria and acute hepatitis A virus infection.

Urticaria has been described only rarely in patients with hepatitis A virus infection, although its association with acute hepatitis B virus infection is well recognized. A young male homosexual presented with hepatitis and urticaria, which proved to be an acute hepatitis A virus infection. In one study of a foodborne outbreak of hepatitis A virus, 2/130 patients developed hives. A few other isolated cases of presumed hepatitis A virus infection and urticaria have been reported, but this is the first detailed description of a serologically proven hepatitis A virus infection associated with the development of urticaria, in which no other risk factor could be implicated.

Interferon therapy is effective in treatment of hepatitis B-induced polyarthritis.

A patient with acute hepatitis B developed significant polyarthritis. After 10 months of observation he had not cleared the virus and continued to have symptomatic joint problems, with migratory polyarthralgia, tenosynovitis of the left wrist, and a large knee effusion. Hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels were measured in the synovial fluid and were found to be virtually identical to serum levels, indicating the potential infectivity of this fluid. The patient was treated with 14 weeks of thrice-weekly lymphoblastoid interferon and cleared all markers of viral replication. The arthritis resolved with the disappearance of measurable HBsAg. Interferon may be effective therapy for this disorder.

Lymphoblastoid and recombinant alpha-A interferon therapy of chronic hepatitis B virus infection. The Royal Free Hospital experience.

Lymphoblastoid interferon (Wellferon), a combination of at least 8 alpha-interferons, has been shown to be effective therapy in male chronic carriers of HBV infection, resulting in the loss of HBeAg and HBV-DNA in 50% of those treated. However, 0/8 women (5 Chinese) treated in this trial responded to treatment. Patients with higher ASTs, CAH on biopsy and a history of acute hepatitis are more likely to respond to treatment. Recombinant alpha-A interferon has not been as successful in our particular group of patients. However, this may be explained by the observation that most of these patients are asymptomatic, homosexuals and have lower transaminases, less histological inflammation and a higher percentage of HTLV-III antibody positivity than the Wellferon group. In the HTLV-III-negative group of HBV carriers, the response to recombinant alpha-A interferon is similar to that achieved with lymphoblastoid interferon.

Non-HLA-linked hemochromatosis in a Chinese woman.

A 55 year-old Chinese woman is described with severe iron overload similar in degree and distribution to that seen in hereditary hemochromatosis in the Caucasian population. Autopsy findings confirmed severe iron overload in the liver, pancreas, skin, heart, and endocrine organs. Hepatic iron concentration was 482 mumol/g with a hepatic iron index of 8.8. There was no history of thalassemia, transfusions, or alcohol abuse. Pedigree analysis revealed two HLA identical brothers that had no clinical or biochemical evidence of iron overload. This case is an unusual example of severe iron overload in a non-Caucasian kindred and may represent a non-HLA-linked form of iron overload.

Clinical and epidemiologic characteristics of hepatitis C in a gastroenterology/hepatology practice in Ottawa.

OBJECTIVE: To examine the clinical and epidemiologic features of hepatitis C virus (HCV) infection in a gastroenterology/hepatology practice in Ottawa. DESIGN: Retrospective chart review. PATIENTS: Sixty-three consecutive patients found to be anti-HCV positive. Their charts were analysed with respect to risk factors, history of hepatitis, serum aspartate aminotransferase (AST) levels and the presence of hepatitis B markers. The long-term sexual partners of 29 patients agreed to undergo HCV antibody testing. RESULTS: Of the patients 48 (76%) had been exposed to HCV parenterally: 27 used intravenous drugs, and 21 had received blood or blood products. Eleven patients did not have any known risk factor (sporadic infection), but eight of them had lived in countries where hepatitis C may be more prevalent; the other three had locally acquired infection. The mean serum AST level at the first visit was 140 (normally less than 40) IU/L. At least one hepatitis B marker was identified in 33% of the patients. None of the sexual partners who were tested were anti-HCV positive. CONCLUSION: Most cases of hepatitis C in Ottawa are acquired through parenteral exposure; sexual transmission is rare. Sporadic infection in the Ottawa region is rare but may be more common in people from countries with a higher prevalence rate of hepatitis C. Most cases of hepatitis C are asymptomatic.

Diclofenac induced hepatitis. 3 cases with features of autoimmune chronic active hepatitis.

Diclofenac is a frequently prescribed nonsteroidal antiinflammatory drug (NSAID). Significant hepatotoxicity related to diclofenac may be more common than previously recognized, as three patients with diclofenac-associated hepatitis were seen by one clinician in a single year. All patients were ANA positive during the hepatitis and had histologic features of chronic active hepatitis. Two had been inappropriately treated with corticosteroids. The third patient presented more acutely with jaundice and symptoms of hepatitis. Two of the patients developed the same hepatic reaction when rechallenged with diclofenac. The third patient was changed to tiaprofenic acid, a NSAID of the same family, and redeveloped evidence of hepatotoxicity. All three were subsequently able to take naproxen without liver dysfunction. Diclofenac-induced liver disease may be misdiagnosed. Twenty-six cases of significant hepatic reactions to diclofenac have been previously reported in the literature and are reviewed. Such hepatic reactions to diclofenac and related NSAIDs may be commoner than realized. Introduction of a NSAID of another class appears to be safe.

Detection of hepatitis B virus DNA in the serum of Canadian hepatitis B surface antigen negative, anti-HBc positive individuals, using the polymerase chain reaction.

Continuing hepatitis B virus (HBV) infection is normally associated with the presence of hepatitis B surface antigen (HBsAg) in the serum. In spite of sensitive screening assays for HBsAg, rare cases of post-transfusion HBV infection are still observed. Antibody to hepatitis B core antigen (anti-HBc) often indicates remote HBV infection but DNA hybridisation and more sensitive polymerase chain reaction (PCR) assays have demonstrated that some HBsAg negative individuals, positive for anti-HBc, have continuing HBV replication. To determine the incidence of ongoing HBV infection in a Canadian HBsAg negative, anti-HBc positive population we studied three groups with this combination of HBV markers: Group A, 36 patients referred for investigation of raised serum aminotransferases; Group B, 21 Canadian Red Cross blood donors; Group C, seven vaccinees in an Ottawa Health Care Student hepatitis B vaccination programme. The PCR was carried out using a nested PCR reaction with primers specific for the pre-core region of HBV. Seven of 36 (19%) patients in Group A had detectable HBV DNA whereas none of Group B or C were positive. This data indicates that in some HBsAg negative patients with ongoing hepatic inflammation, continuing HBV replication may persist. This was not observed in any healthy blood donors or health care students investigated. Larger studies are required, but this data would suggest that, in Canada, the addition of anti-HBc testing for all blood donors for detection of low level HBV replication would not be indicated.

A review of the efficacy of adenine arabinoside and lymphoblastoid interferon in the Royal Free Hospital studies of hepatitis B virus carrier treatment: identification of factors influencing response rates.

We have reviewed the results of treating over 100 HBV carriers with adenine arabinoside, adenine arabinoside monophosphate and lymphoblastoid interferon. In the homosexual group of carriers, adenine arabinoside and its monophosphate have no value. However in this group, lymphoblastoid interferon will produce a response in over 50% of cases. This lack of effectiveness of adenine arabinoside monophosphate in this group may stem from its immunosuppressant properties. In heterosexual carriers both adenine arabinoside monophosphate and lymphoblastoid interferons are effective in approximately 50% to 60% of cases. However, the response rate is different in the various racial groups. Northern European and Mediterranean people appear to respond whereas those from the Far East do not. This may reflect the fact that there are at least two mechanisms by which the chronic carrier state may arise. In 5% to 10% of adults, a relative deficiency of alpha interferon production exists, and this defect is found in the majority of HBV carriers in Western Europe. In these, interferon acts as a replacement therapy and excellent results may be obtained if the patient is treated early in the course of the disease. It would appear that as the duration of the infection increases, the virus may integrate into interferon-reactive consensus sites and prevent the cell from responding to interferon. In patients infected at birth, transplacental anti-HBc appears to modulate the immune response and, along with immaturity of the immune system at this age, results in failure to lyse infected cells. These patients do not benefit from interferon treatment: some form of immune manipulation is required.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphoblastoid interferon therapy of chronic HBV infection. A comparison of 12 vs. 24 weeks of thrice weekly treatment.

This study set out to examine the relative effectiveness and tolerability of 12- versus 24-week courses of thrice weekly intramuscular lymphoblastoid interferon in the treatment of hepatitis B 'e' antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection, and to identify pretreatment factors predicting the outcome of therapy. Twenty patients were randomised to each treatment group. Treatment was associated with clearance of HBeAg and HBV-DNA in 59% of the 32 male patients, whereas none of the eight women responded (48% overall response rate). This response rate in males is at least three times the recorded spontaneous seroconversion rates in this population. Most of the women (5/8) were of Oriental origin and had minimal disease, factors that may have influenced response. The longer course was poorly tolerated and was therefore no more effective: eight of 20 patients withdrew because of side-effects. Variables associated with response included high AST (aspartate transaminase), short duration of disease and previous history of acute hepatitis. A response to antiviral therapy was accompanied by clinical and biochemical evidence of improvement in liver disease.

Identification of factors influencing response rate to antiviral therapy of chronic hepatitis B virus infection. A review of the efficacy of adenine arabinoside and lymphoblastoid interferon in the Royal Free Hospital studies.

We have reviewed the results of treating over 100 HBV carriers with adenine arabinoside, adenine arabinoside monophosphate and lymphoblastoid interferon. In the homosexual group of carriers, adenine arabinoside and its monophosphate have no value. However, in this group, lymphoblastoid interferon will produce a response in over 50% of cases. The lack of effectiveness of adenine arabinoside monophosphate in this group may stem from its immunosuppressant properties. In heterosexual carriers both adenine arabinoside monophosphate and lymphoblastoid interferon are effective in approximately 50-60% of cases. However, the response rate is different in the various racial groups. Northern European and Mediterranean people appear to respond whereas those from the Far East do not. This may reflect the fact that there are at least 2 mechanisms by which the chronic carrier state may arise. In 5-10% of adults, a relative deficiency of alpha-interferon production exists and this defect is found in the majority of HBV carriers in Western Europe. In these, interferon acts as a replacement therapy and excellent results may be obtained if the patient is treated early in the course of the disease. It would appear that as the duration of the infection increases, the virus may integrate into interferon-reactive consensus sites and prevent the cell from responding to interferon. In patients infected at birth, transplacental anti-HBc appears to modulate the immune response and along with immaturity of the immune system at this age, results in failure to lyse infected cells. These patients do not benefit from interferon treatment: some form of immune manipulation is required.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-ribosomal P antibodies in systemic lupus erythematosus: a case-control study correlating hepatic and renal disease.

We report a case-control study of the occurrence of liver and kidney disease in 20 systemic lupus erythematosus (SLE) patients with anti-ribosomal P antibodies and 20 age-, sex-, and race-matched (control group) SLE patients without anti-P antibodies. In the group with anti-P antibodies, 7 patients were found to have had liver disease, compared with only 1 in the control group (P = 0.03), and 14 anti-P (+) patients have had kidney disease, compared with 4 in the control group (P = 0.01). A major serological difference between the groups was an increased prevalence of anti-dsDNA in the anti-P positive group (12/20) vs the control group (4/20), P = 0.02. These statistically significant differences suggest that antibodies to ribosomal P identify a subset of SLE patients at higher risk for liver and kidney involvement, in addition to the previously recognized risk for neuropsychiatric disease.

Early-onset autoimmune hepatitis is associated with a C4A gene deletion.

BACKGROUND: Autoimmune hepatitis is an immunologically mediated disorder with some similarities to systemic lupus erythematosus, including an association with HLA-A1, B8, DR3. This haplotype includes a C4A, 21-OHA gene deletion. Low serum levels of complement and C4 null alleles have been reported in autoimmune hepatitis, but studies have been at the protein level only. METHODS: Twenty-four white patients with autoimmune hepatitis were studied by Southern blots using a C4A gene complementary DNA probe. HLA A, B, and C typing was determined using standard microcytotoxicity assays, and DR and DQ specificities were determined by restriction fragment length polymorphism analysis. RESULTS: Thirteen of 24 patients had the C4A gene deletion compared with 12 of 90 controls. HLA-A1 and B8 were increased in patients with autoimmune hepatitis, as were HLA-DR3 (DR17), Dw24, DQ2. Patients with a C4A gene deletion presented at a younger age than those without the deletion and had significantly lower serum C3 and C4 levels. The C4A gene deletion was associated with HLA-A1, B8, DR3 in all but 1 patient who was HLA-DR3 negative. CONCLUSIONS: A C4A gene deletion is found in patients with autoimmune hepatitis, especially those presenting at a young age. This complement gene deletion may be an important factor in the development of this disease.

Liver fibrosis attributed to lipid lowering medications: two cases.

We identified two cases of chronic active hepatitis with liver fibrosis induced by lipid lowering drugs of the statin and fibrate classes despite regular monitoring of transaminases. There are few reports of clinically significant hepatitis induced by these drugs and even fewer cases of fibrosis. Given the growing use of these drugs, there are implications for monitoring patients on long-term therapy for liver damage.

Immunological studies before and during interferon therapy in chronic HBV infection: identification of factors predicting response.

Lymphoblastoid interferon is effective therapy in some but not all patients with chronic hepatitis B virus infection. To assess whether immunological parameters were predictive of response to interferon therapy, we determined the human leukocyte antigen type, CD4/CD8 ratio, natural killer cell activity, IgM anti-HBc antibody levels and concanavalin A-induced lymphocyte proliferative response in 30 patients before treatment. In addition, to investigate the mechanisms of action of interferon in promoting hepatitis B virus clearance, we serially measured the CD4/CD8 ratios, natural killer activity and lymphocyte proliferative response at wk 4, 8 and 12 of treatment. A beneficial response to therapy was defined as the sustained clearance of HBeAg and serum hepatitis B virus DNA within 1 yr of commencing therapy. Elevated IgM anti-HBc levels were associated with a beneficial response to therapy, but there was no correlation observed between response and pretreatment CD4/CD8 ratio, natural killer activity or lymphocyte proliferative response. Six of seven human leukocyte antigen DR3-positive patients responded. No measurable changes in the immunological parameters studied were observed in the nonresponder group, whereas a significant rise in CD4/CD8 ratio, associated with a fall in peripheral CD8 number and a decline in measurable NK activity, was seen in the responder group. These changes were maximal at the time of hepatitis B virus DNA clearance, which was associated with a transient increase in hepatic inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)