Biomedical subjects
Publications and source records attributed to S I Strasser.
Hepatocellular carcinoma, frequently associated with chronic viral hepatitis, is the fourth most common cancer worldwide. The incidence in Western countries is rising rapidly. Recent developments in diagnostic imaging allow for identification of small lesions amenable to curative therapy. Effective therapy of advanced hepatocellular carcinoma remains a major clinical problem.
OBJECTIVE: Severe GI bleeding after hematopoietic cell transplantation is commonly due to lesions that are unusual in nontransplant patients. The frequency of GI bleeding appears to have decreased over the last decade, but the reasons have not been readily apparent. We sought to determine the incidence of severe bleeding during two time periods, to describe the causes and outcomes of bleeding, and to analyze the reasons behind an apparent decline in severe bleeding over the decade covered. METHODS: During 1986-1987 and 1996-1997, we followed all patients with and without severe bleeding at our institution, a marrow transplant center. RESULTS: Over this decade, the incidence of severe bleeding declined from 50/467 (10.7%) to 15/635 (2.4%) (p < 0.0001). Overall mortality from intestinal bleeding declined from 3.6% to 0.9% (p = 0.002), but mortality in those with bleeding remained high (34% vs 40%). The onset (day 42 vs 47) and platelet counts (35,994 vs 37,600/microl) were similar, but the sites and causes of bleeding were different. During 1986-1987, 27/50 patients bled from multiple GI sites, viral and fungal ulcers, or graft-versus-host disease (GVHD). Over the decade, bleeding from GVHD had decreased 80% (p < 0.0001), and bleeding from viral (p < 0.0001) and fungal (p = 0.023) ulcers almost disappeared. CONCLUSIONS: The incidence of severe GI bleeding has declined significantly over the last decade because of prevention of viral and fungal infections and severe acute GVHD. However, severe bleeding after transplant remains a highly morbid event, particularly among patients with GVHD.
BACKGROUND: Hepatitis C virus (HCV) infection is a significant problem in the Australian community. Over the past few years, the number of patients with diagnosed hepatitis C has increased greatly. The aims of the present study were to define the clinical features of a large group of patients with chronic HCV infection and to examine changes occurring in the referral base and epidemiological characteristics of this group since analysis of the first 342 patients in 1994. METHODS: The study included 1,546 consecutive anti-HCV-positive patients who had been referred to St Vincent's Hospital from January 1990 to June 1998. Clinical and laboratory data were collected on all patients. RESULTS: Referrals from general practitioners increased from 31% to 70% of all patients between 1990-1993 and 1994-1998. A history of injecting drug use (IDU) was present in 64% of the patients. While 89% of the IDU group was Australasian born, 49% of those in the sporadic group were born overseas. Cirrhosis was found in 18% of biopsied patients. Age, infection duration, age at infection, Mediterranean or Asian origin and a history of transfusion or lack of HCV risk factors were associated with cirrhosis on univariate analysis. Patient age was the only independent predictor of cirrhosis. CONCLUSION: The majority of patients with HCV are diagnosed in general practice. A risk factor for infection is identified in 82% of patients. While our reported prevalence of cirrhosis may be an overestimate of that in the overall HCV community, the ultimate disease burden is likely to be significant.
Chronic graft-versus-host disease (GVHD) of the liver usually presents as an indolent cholestatic disease in patients with skin, mouth, and eye involvement. We observed 14 patients in whom chronic GVHD of the liver presented with marked elevations of serum aminotransferases, clinically resembling acute viral hepatitis. Onset of liver dysfunction was at 294 days (range, 74-747 days) after allogeneic hematopoietic cell transplantation and coincided with a recent cessation or taper of immunosuppressive drugs. Median peak serum alanine transaminase (ALT) was 1,640 U/L (698-2,565 U/L), and median bilirubin was 12.3 mg/dL (0.9-55.9 mg/dL). All biopsies showed characteristic features of GVHD with damaged and degenerative small bile ducts. Other features included a marked lobular hepatitis, moderate to marked amounts of hepatocyte unrest, sinusoidal inflammation with perivenular necroinflammatory foci, and many acidophilic bodies scattered throughout the lobule. When high-dose immunosuppressive therapy was instituted soon after presentation, progressive improvement and eventual normalization of liver enzymes and bilirubin levels were observed. However, in cases in which the diagnosis was not made and therapy was delayed, a progressive cholestatic picture emerged with histologic evidence of loss of small bile ducts and portal fibrosis. We conclude that a distinct syndrome of chronic liver GVHD presenting as an acute hepatitis can be recognized in a patient at risk who is receiving no, or minimal, immunosuppressive medications. Liver biopsy is necessary to exclude viral causes of liver dysfunction and to confirm characteristic abnormalities of small bile ducts. Institution of high-dose immunosuppression can prevent progressive bile duct destruction and effect resolution of jaundice if given early.
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Patients who survive hematopoietic cell transplantation (HCT) have multiple risk factors for chronic liver disease, including hepatitis virus infection, iron overload, and chronic graft-versus-host disease (GVHD). We studied 3,721 patients who had survived 1 or more years after HCT at a single center and identified patients with histologic or clinical evidence of cirrhosis. Risk factors for the development of cirrhosis were evaluated and compared with a group of matched control subjects. Cirrhosis was identified in 31 of 3,721 patients surviving 1 or more years after HCT, 23 of 1,850 patients surviving 5 or more years, and in 19 of 860 patients surviving 10 or more years. Cumulative incidence after 10 years was estimated to be 0.6% and after 20 years was 3.8%. The median time from HCT to the diagnosis of cirrhosis was 10.1 years (range, 1.2 to 24.9 years). Twenty-three patients presented with complications of portal hypertension, and 1 presented with hepatocellular carcinoma. Thirteen patients have died from complications of liver disease, and 2 died of other causes. Three patients have undergone orthotopic liver transplantation. Hepatitis C virus infection was present in 25 of 31 (81%) of patients with cirrhosis and in 14 of 31 (45%) of controls (P =.01). Cirrhosis was attibutable to hepatitis C infection in 15 of 16 patients presenting more than 10 years after HCT. There was no difference in the prevalence of acute or chronic GVHD, duration of posttransplant immunosuppression, or posttransplant marrow iron stores between cases and controls. Cirrhosis is an important late complication of hematopoietic cell transplantation and in most cases is due to chronic hepatitis C. Long-term survivors should be evaluated for the presence of abnormal liver function and hepatitis virus infection.
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Before the introduction of routine blood donor screening in 1991, marrow transplant recipients were at significant transfusion-associated risk for infection with hepatitis C virus (HCV). We followed a cohort of 355 patients undergoing transplant in Seattle during 1987 to 1988 to determine (1) the impact of pretransplant HCV infection on the occurrence and severity of venocclusive disease (VOD); (2) the impact of HCV infection on liver dysfunction, other than VOD, occurring between 21 and 60 days after transplantation; and (3) the natural history of post-transplant HCV liver disease with a 10-year follow-up. HCV-RNA status was determined on serum stored before transplant and at day 100 post-transplant. Sixty-two (17%) patients were HCV-RNA positive before transplant, and 113 (32%) were HCV-RNA positive by day 100 post-transplant (or before death). Severe VOD developed in 22 of 46 (48%) evaluable patients with pretransplant HCV infection and in 150 of 229 (14%) evaluable patients without HCV (P <.0001). In multivariable analysis of risk factors for developing VOD, pretransplant HCV infection associated with elevated serum aspartate transaminase (AST) levels predicted the development of severe VOD (relative risk, 9.6; P =.0001). The presence of HCV with normal AST levels before transplant was not a risk factor for severe VOD. Between 21 and 60 days after transplant, HCV-RNA positive-patients had higher AST levels (median 101 U/L), but similar alkaline phosphatase and total bilirubin levels compared with HCV-negative patients, suggesting that cholestatic liver disease (particularly graft-versus-host disease [GVHD]) was not related to HCV infection. An acute flare of hepatitis (AST >10 times the upper limit of normal) developed at a mean of 136 +/- 58 days in 31% of HCV-positive patients; no patients developed fulminant hepatitis. Between 5 and 10 years after transplant, 57% of HCV-positive and 6% of HCV-negative patients had mild to moderate elevations of AST (P <. 0001), but HCV infection was not associated with excess mortality between 3 and 10 years after bone marrow transplantation. In summary, HCV infection with elevated AST levels is a significant risk factor for severe VOD after marrow transplant. However, the decision to proceed to transplantation in HCV-positive patients must balance the absolute risk of death from VOD against the risks of the underlying disease. In long-term survivors, HCV infection is not associated with excess mortality over 10 years of follow-up.
Cholestasis and jaundice are common after hematopoietic cell transplantation and may have multiple causes. Specific disorders that may contribute to cholestasis in this setting include sepsis, hemolysis, cyclosporine administration, drug toxicity, parenteral nutrition, graft versus host disease, viral infection, and extrahepatic obstruction.
We examined the degree of hepatic iron overload in patients receiving marrow transplant for hematologic malignancy and evaluated a new method of morphometric analysis of marrow iron content as a means of estimating hepatic iron stores in these patients. The iron content of marrow and liver specimens from 10 consecutive patients who died between 50 and 100 days after transplant was determined by spectrophotometry. Their mean age was 34.9 years (range 10-59). The mean time to death from disease onset was 2.2 years (0.5-8.7). Patients had received 30.2 +/- 17.4 units of red cells during the transplant period and 47.6 +/- 25.9 red cell units from diagnosis to death. The median hepatic iron concentration (HIC) was 4307 microg/g dry weight (range 1832-13120; normal 530-900) and the median hepatic iron index (HIC (micromol/g dry weight/age (years)) was 3.85 (0.76-8.14). The median biochemical marrow iron content was 1999 microg/g dry weight (range 932-3942). Morphometric analysis of the marrow iron content was performed on digital photomicrographs of a single Prussian blue-stained section of marrow. Strong correlations were demonstrated between morphometric marrow iron content and (1) biochemical marrow iron content (r = 0.8, P= 0.006) and (2) biochemical hepatic iron index (r = 0.82, P = 0.004). We conclude that marrow transplant recipients have a high liver iron content at 50-100 days post transplant with the hepatic iron index in the hereditary hemochromatosis range. Computerized morphometric marrow iron determination is a readily available means of estimating hepatic iron stores in these patients.
The acute-phase response is associated with profound effects on oxidative drug metabolism. However, the effects on glucuronidation are poorly characterized. The aim of the present study was to determine the role of mediators of the acute-phase response in the regulation of hepatic uridine diphosphate glucuronosyltransferase (UGT) expression. Family 1 and family 2 UGT isoforms were studied in turpentine-injected rats and in primary hepatocyte cultures exposed to cytokines and/or dexamethasone. In the in vivo model, glucuronidation of p-nitrophenol was unaffected, while testosterone glucuronidation was reduced to 65% of control (P<0.01). In contrast, the mRNA level of UGT1*1 (which metabolizes bilirubin, not phenols) was depressed to 16% of control (P<0.002), while the mRNA level of UGT2B3 (which metabolizes testosterone) was reduced to 53% (P<0.05). In primary hepatocyte culture, dexamethasone treatment resulted in a 3.4-fold induction of UGT1*1 mRNA levels (P<0.001) but only a 1.5-fold induction of UGT2B3 (P=0.1). Interleukin-6 in the presence of dexamethasone resulted in a marked dose-dependent suppression of both UGT1*1 and UGT2B3, although to different degrees. Interleukin-1 had no effect on UGT mRNA levels. Thus, inflammatory mediators, such as cytokines and glucocorticoids, may be important determinants of both oxidative and conjugative drug metabolism by the liver.
PURPOSE: To investigate the role of sex hormones in the regulation of UDP-glucuronosyltransferase (UGT). METHODS: We examined liver from adult, prepubertal, gonadectomised and gonadectomised plus hormone replaced rats of both sexes. Immunohistochemistry and immunoblots were performed using a polyclonal UGT antibody to a number of family 1 and family 2 UGT isoforms. Northern blot analysis was performed utilising cDNA probes to family 1 and family 2 isoforms. RESULTS: Immunohistochemistry demonstrated variations in intensity and distribution of staining in the hormonally manipulated rats. Immunoblots showed variations in individual band intensity between rat groups. Immunoblots using a more specific antibody (anti-17 beta-hydroxysteroid UGT, which recognises UGT2B3 and UGT2B2) demonstrated marked differences between male and female rats and significant alterations after gonadectomy and testosterone replacement in the male rats. In northern analysis, UGT2B3 and 2B1 mRNA were significantly higher in adult males than females, and in prepubertal males compared to prepubertal females. In male rats, gonadectomy resulted in a 45-53% reduction in UGT2B3 and 2B1 levels respectively, which increased significantly with testosterone treatment to greater than normal adult levels. No change in UGT2B3 or 2B1 occurred after gonadectomy in females. In contrast, UGT1*1 mRNA tended to be higher in adult female and prepubertal female rats than in their male counterparts. In females, gonadectomy resulted in significant up-regulation of UGT1*1, while gonadectomy plus oestradiol treatment resulted in markedly reduced levels. UGT1*1 mRNA was not significantly altered by gonadectomy in males. CONCLUSIONS: This study demonstrates the differential effects of sex hormones on the expression of isoforms from the two phylogenetically distinct UGT families.
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In both acute and chronic liver disease in man, elimination of drugs metabolized by the cytochrome P450 (CYP) enzymes is impaired. In contrast, those drugs metabolized by UDP-glucuronosyltransferase (UGT) have a relatively normal elimination. Studies in rats with experimentally induced liver injury also show this relative preservation of glucuronidation. In liver disease, a number of factors, including inflammation, fibrosis and regeneration, may be associated with this differential effect on drug metabolism. Partial hepatectomy provides a model in which to isolate the effects of liver regeneration on drug metabolism. Partial hepatectomy or sham operation was performed in 24 male Sprague-Dawley rats and three rats from each group were studied at days 1, 2, 4 and 6. Comparison between CYP and UGT was made at the protein level using immunohistochemistry and immunoblotting probed with a polyclonal antibody to UGT, identifying both family 1 and family 2 isoforms, and an antibody to the CYP isoform CYP2C11. Steady state messenger RNA levels of four isoforms of UGT were assessed by northern blot analysis. By both immunohistochemistry and immunoblotting, the level of CYP protein decreased from day 2 to 6 after hepatectomy. In contrast, the UGT protein level was not altered by partial hepatectomy. Northern blot analysis of UGT isoforms demonstrated differential regulation of isoforms from the two major families. The UGT family 1 isoforms were initially markedly depressed following partial hepatectomy and then steadily rose over 6 days to greater than the level in controls. In contrast, there was an apparent increase in UGT2B1 mRNA (not significant) on day 2, while UGT2B3 mRNA was maintained over the six days. These results demonstrate that during hepatic regeneration the protein content of total UGT is normal, while CYP2C11 protein is markedly reduced. Northern blot analysis suggests that individual isoforms of UGT are differentially regulated during the regeneration process.
OBJECTIVE: To characterise blood donors with equivocal hepatitis C serological results and to develop an algorithm for their diagnosis and follow-up. DESIGN: Prospective case survey. SUBJECTS AND SETTING: 100 consecutive blood donors referred to the St Vincent's Hospital Liver Clinic, Victoria, with equivocal hepatitis C serological results (positive result for second generation Abbott Enzyme Immunoassay 2.0, but at least one negative result on supplemental testing by first generation Abbott neutralisation assay and Abbott Supplemental Assay for antibody to specific viral antigens). OUTCOME MEASURES: Percutaneous risk factors for hepatitis C exposure, peak serum alanine aminotransferase (ALT) levels, results of alternative immunoassay (Monolisa) and polymerase chain reaction (PCR) to detect hepatitis C viraemia. RESULTS: Thirty subjects had positive results for alternative immunoassay. A risk factor was identified for 32 subjects and was significantly associated (P < 0.01) with positive results for alternative immunoassay (23/32) and PCR (11/32), abnormal ALT levels (7/32), and strong reactivity on initial immunoassay (23/32). Presence of antibodies to both structural and non-structural antigens was also associated with risk factors and positive alternative immunoassay results. CONCLUSIONS: A definitive diagnosis was possible in 87% of subjects. A diagnosis of hepatitis C infection was based on positive alternative immunoassay results together with positive PCR results or presence of a risk factor. Hepatitis C was excluded for 60% of patients. The diagnosis for the remaining 13% remained indeterminate, indicating the need for a definitive diagnostic test for hepatitis C.
OBJECTIVES: To define demographic and epidemiological features of an Australian population with chronic hepatitis C virus (HCV) infection and determine predictors of histological and clinical outcome. DESIGN: Cohort study. PATIENTS AND SETTING: 342 consecutive HCV antibody-positive patients referred to the liver clinic of a major metropolitan general hospital. OUTCOME MEASURES: Demographic data, serial alanine aminotransferase (ALT) levels, full blood count for all patients. Percutaneous liver biopsy in 152 patients (44%). RESULTS: 51% of patients had previously used injecting drugs, 15% had received a blood transfusion and 27% had no definite percutaneous risk factor (sporadic group). The injecting drug users (IDUs) were younger and more likely to have been born in Australia. The sporadic group were older and frequently were born in Mediterranean or Asian countries. A history of excessive alcohol use was common, particularly among IDUs (60%). Of 152 patients who had a liver biopsy, 49 had cirrhosis and 103 had chronic hepatitis. Some patients with a normal ALT level had marked necro-inflammatory activity. On univariate analysis, the presence of cirrhosis correlated with older age (P < 0.0001), lack of an identifiable risk factor (P < 0.001) and birth in a Mediterranean or Asian country (P < 0.0001). On multivariate analysis, the only significant predictor of cirrhosis was age (P < 0.001). Among patients with an identifiable percutaneous risk factor, cirrhosis was seen at a median time of 18 years after first exposure to risk, compared with 13 years in patients with chronic hepatitis (P < 0.01). Patients with clinical evidence of portal hypertension were, on average, 15 years older than those with histological cirrhosis only (P < 0.01). CONCLUSIONS: Injecting drug use is the major risk factor for chronic HCV infection in Australia. In patients with an identifiable risk factor, the most significant factor associated with a biopsy finding of cirrhosis is the time since first exposure to HCV.