Rising hospital admissions for alcohol-related cirrhosis and the impact of sex and comorbidity - a data linkage study.

OBJECTIVES: International studies have shown shifting demographic data and rising hospitalizations for alcohol-related cirrhosis (ARC), with a paucity of data from Australia. We examined hospitalizations, mortality and demographic data for people admitted with ARC over the last decade in Queensland, Australia. STUDY DESIGN: Data linkage study. METHODS: A retrospective analysis of adults hospitalized with ARC during 2008-2019 was performed using state-wide admissions data. International Classification of Diseases, 10th revision, codes identified admissions with the principal diagnosis of ARC based on validated algorithms. Comorbidity was assessed using the Charlson Comorbidity Index. RESULTS: A total of 7152 individuals had 24,342 hospital admissions with ARC (16,388 were for ARC). There was a predominance of males (72.6%) and age ≥50 years (80.4%) at index admission. Females were admitted at a significantly younger age than men (59% of women and 43% of men were aged <60 years, P < 0.001). Comorbidities were common, with 45.1% of people having at least one comorbidity. More than half (54.6%) of the patients died over the study period (median follow-up time was 5.1 years; interquartile range 2.4-8.6). Women had significantly lower mortality, with 47.6% (95% confidence interval [CI] 45.0-50.2) probability of 5-year survival, compared with 40.1% (95% CI 38.5-41.6) in men. In multivariable analysis, this was attributable to significantly lower age and comorbidity burden in women. Significantly lower survival was seen in people with higher comorbidity burden. Overall, the number of admissions for ARC increased 2.2-fold from 869 admissions in 2008 to 1932 in 2019. CONCLUSIONS: Hospital admissions for ARC have risen substantially in the last decade. Females were admitted at a younger age, with fewer comorbidities and had lower mortality compared with males. The association between greater comorbidity burden and higher mortality has important clinical implications, as comorbidity-directed interventions may reduce mortality.

A discrete choice experiment to elicit preferences for a chronic disease screening programme in Queensland, Australia.

OBJECTIVE: Patient-centred care, increasingly highlighted in healthcare strategies, necessitates understanding public preferences for healthcare service attributes. We aimed to understand the preferences of the Australian population regarding the attributes of chronic disease screening programmes. STUDY DESIGN: The preferences were elicited using the discrete choice experiment (DCE) methodology. METHODS: A DCE was administered to a sample of the Australian general population. Respondents were asked to make choices, each offering two hypothetical screening scenarios defined by screening conduct, quality and accuracy of the test results, cost to the patient, wait time and source of information. Data were analysed using a panel mixed multinomial logit model. RESULTS: A strong preference for highly accurate screening tests and nurse-led screenings at local health clinics was evident. They expressed disutility for waiting time and out-of-pocket costs but were indifferent about the source of information. Their preference for a nurse-led programme was highlighted by the fact that they were willing to pay $81 and $88 to get a nurse-led programme when they were offered a general practitioner-led and a specialist-led programme, respectively. Furthermore, they were willing to pay $32 to reduce a week of waiting time and $205 for a 95% accurate test compared to a 75% accurate test. Preferences remained consistent irrespective of the respondent's place of residence. CONCLUSIONS: Our findings highlight the importance of diagnostic test accuracy and nurse-led service delivery in chronic disease screening programmes. These insights could guide the development of patient-centric services by enhancing test accuracy, reducing waiting times and promoting nurse-led care models.

Liver-related mortality in countries of the developed world: an ecological study approach to explain the variability.

BACKGROUND: Liver-related mortality varies across developed nations. AIM: To assess the relative role of various risk factors in relation to liver-related mortality in an ecological study approach. METHODS: Data for liver-related mortality, prevalence data for hepatitis B and C, human immunodeficiency virus (HIV), alcohol consumption per capita, Type 2 Diabetes mellitus (T2DM), overweight and obesity were extracted from peer-reviewed publications or WHO databases for different developed countries. As potential other risk-modifying factors, purchase power parity (PPP)-adjusted gross domestic product (GDP) per capita and health expenditure per capita were assessed. As an environmental 'hygiene factor', we also assessed the effect of the prevalence of Helicobacter pylori. Only countries with a PPP-adjusted GDP greater than $20 000 and valid information for at least 8 risk modifiers were included. Univariate and multivariate analyses were utilised to quantify the contribution to the variability in liver-related mortality. RESULTS: The proportion of chronic liver diseases (CLD)-related mortality ranged from 0.73-2.40% [mean 1.56%, 95% CI (1.43-1.69)] of all deaths. Univariately, CLD-related mortality was significantly associated with Hepatitis B prevalence, alcohol consumption, PPP-adjusted GDP (all P < 0.05) and potentially H. pylori prevalence (P = 0.055). Other investigated factors, including hepatitis C, did not yield significance. Backward elimination suggested hepatitis B, alcohol consumption and PPP-adjusted GDP as risk factors (explaining 66.3% of the variability). CONCLUSION: Hepatitis B infection, alcohol consumption and GDP, but not hepatitis C or other factors, explain most of the variance of liver-related mortality.

Patterns of service utilisation within Australian hepatology clinics: high prevalence of advanced liver disease.

BACKGROUND: Liver diseases in Australia are estimated to affect 6 million people with a societal cost of $51 billion annually. Information about utilisation of specialist hepatology care is critical in informing policy makers about the requirements for delivery of hepatology-related healthcare. AIMS: This study examined the aetiology and severity of liver disease seen in a tertiary hospital hepatology clinic, as well as the resource utilisation patterns. METHODS: A longitudinal cohort study included consecutive patients booked in hepatology outpatient clinics during a 3-month period. Subsequent outpatient appointments for these patients over the following 12 months were then recorded. RESULTS: During the initial 3-month period, 1471 appointments were scheduled with a hepatologist, 1136 of which were attended. Twenty-one per cent of patients were 'new cases'. Hepatitis B virus (HBV) was the most common disease aetiology for new cases (37%). Advanced disease at presentation varied between aetiology; only 5% of HBV cases had advanced liver disease at presentation, in contrast with HCV, NAFLD and ALD, in which advanced disease was identified at presentation in 31%, 46% and 72% of cases, respectively. Most patients (83%) attended multiple hepatology appointments, and a range of referral patterns for procedures, investigations and other specialty assessments were observed. CONCLUSIONS: There is a high prevalence of HBV in new case referrals. Patients with HCV infection, NAFLD and ALD have a high prevalence of advanced liver disease at referral, requiring ongoing surveillance for development of decompensated liver disease and liver cancer. These findings that describe the patterns of health service utilisation among patients with liver disease provide useful information for planning sustainable health service provision for this clinical population.

Burden of decompensated cirrhosis and ascites on hospital services in a tertiary care facility: time for change?

BACKGROUND: Ascites, the most frequent complication of cirrhosis, is associated with poor prognosis and reduced quality of life. Recurrent hospital admissions are common and often unplanned, resulting in increased use of hospital services. AIMS: To examine use of hospital services by patients with cirrhosis and ascites requiring paracentesis, and to investigate factors associated with early unplanned readmission. METHODS: A retrospective review of the medical chart and clinical databases was performed for patients who underwent paracentesis between October 2011 and October 2012. Clinical parameters at index admission were compared between patients with and without early unplanned hospital readmissions. RESULTS: The 41 patients requiring paracentesis had 127 hospital admissions, 1164 occupied bed days and 733 medical imaging services. Most admissions (80.3%) were for management of ascites, of which 41.2% were unplanned. Of those eligible, 69.7% were readmitted and 42.4% had an early unplanned readmission. Twelve patients died and nine developed spontaneous bacterial peritonitis. Of those eligible for readmission, more patients died (P = 0.008) and/or developed spontaneous bacterial peritonitis (P = 0.027) if they had an early unplanned readmission during the study period. Markers of liver disease, as well as haemoglobin (P = 0.029), haematocrit (P = 0.024) and previous heavy alcohol use (P = 0.021) at index admission, were associated with early unplanned readmission. CONCLUSION: Patients with cirrhosis and ascites comprise a small population who account for substantial use of hospital services. Markers of disease severity may identify patients at increased risk of early readmission. Alternative models of care should be considered to reduce unplanned hospital admissions, healthcare costs and pressure on emergency services.

Assessment of alcohol histories obtained from patients with liver disease: opportunities to improve early intervention.

BACKGROUND: Alcohol is an important primary and comorbid cause of liver injury in patients referred for investigation and management of liver disease. Early assessment and documentation of alcohol consumption is therefore essential, and recommended in both general practice and hospital settings. AIMS: To determine the extent and accuracy of documentation of alcohol consumption in patients referred for evaluation of liver disease. METHODS: Patients were interviewed using a structured questionnaire. The medical records of all patients interviewed were reviewed to obtain information from the referral letter and the hepatology consultations. RESULTS: Eighty-three patients were surveyed. Only 14 referrals had an informative alcohol history, despite 27 patients admitting risky alcohol consumption at the initial hepatology consultation. Ninety per cent of initial consultations had an informative alcohol history documented, whereas only 56% of patients attending a follow-up appointment had informative documentation. Assessment of alcohol consumption was comparable between the hepatology consultation and the structured questionnaire, but four subjects had substantially different alcohol histories. Alcohol Use Disorders Identification Test identified all patients reporting harmful alcohol consumption on the questionnaire. CONCLUSIONS: Hazardous alcohol use is prevalent in subjects attending hepatology clinics, but informative alcohol histories, which are crucial to patient management, are rarely documented in referrals. Screening tools improve documentation and accuracy of alcohol histories, and their use by general practitioners and hospital clinicians would improve detection rates of hazardous drinking and allow earlier intervention. Systematic use of screening tools in hepatology clinics will provide opportunities for education and reinforce recommendations to reduce hazardous or harmful alcohol consumption.

Awareness and opinions of non-alcoholic fatty liver disease by hospital specialists.

BACKGROUND/AIM: Subjects with metabolic risk factors for non-alcoholic fatty liver disease (NAFLD) are commonly seen by hospital specialists other than gastroenterologists/hepatologists. The aim of this study was to assess the awareness of NAFLD and opinions regarding management among non-hepatologists at two major tertiary hospitals in Brisbane. METHODS: A face-to-face questionnaire assessing current beliefs and practices regarding NAFLD was administered to specialists and specialists-in-training across six specialties (internal medicine, cardiology/cardiac surgery, endocrinology, thoracic medicine, rheumatology and nephrology). RESULTS: One hundred clinicians were surveyed with 99% returning completed questionnaires (>89% questions answered). The majority of respondents (75%) believe the prevalence of NAFLD in the general population to be ≤ 10%, although two-thirds feel that its incidence will rise markedly. The vast majority (>90%) appreciate that traditional cardiovascular risk factors (obesity, hypertriglyceridaemia and diabetes) are risk factors for NAFLD and acknowledge that these are common in non-hepatology patients. Despite this, most believe that NAFLD is uncommon in their own patients (89% indicated a prevalence ≤ 30%). The vast majority (93%) agree that non-alcoholic steatohepatitis (NASH) is associated with increased overall mortality, but 60% also believe that simple steatosis confers increased liver-related mortality. Most (74%) agree that a diagnosis of NASH cannot be made using liver enzymes, but 67% support 6-monthly liver function tests as the most effective way to monitor progression of NAFLD. Most respondents (71%) make no referrals to hepatology for suspected NAFLD. CONCLUSIONS: Non-hepatologists appreciate the seriousness of NAFLD but appear to underestimate its prevalence, especially among their own patients despite known risk factors. Attitudes regarding simple steatosis versus NASH and appropriate monitoring of suspected NAFLD suggest that more can be done to improve the understanding of this disease among non-hepatologists. This has implications for targeting 'at-risk' populations and appropriate referral of patients to hepatology clinics.

Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1.

BACKGROUND: Interferon alpha (IFN-alpha) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. OBJECTIVES: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-alpha therapy and to determine hepatic expression of factors inhibiting IFN-alpha signalling in obese and non-obese subjects with chronic HCV. METHODS: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-alpha or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. RESULTS: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p < 0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index > or = 30 kg/m2 (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). CONCLUSIONS: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-alpha.

A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C.

BACKGROUND: There is increasing interest in the influence of host genetic factors on hepatic fibrosis, and whether genetic markers can reliably identify subjects at risk of developing severe disease. We hypothesised that hepatitis C virus (HCV) infected subjects with progressive fibrosis, classified using strict criteria based on histology at biopsy in addition to disease duration would be more likely to inherit several genetic polymorphisms associated with disease progression compared with subjects with a low rate of disease progression. METHODS: We examined polymorphisms in eight genes that have been reported to have an association with hepatic fibrosis. RESULTS: Associations between polymorphisms in six genes and more rapidly progressing fibrosis were observed, with individual adjusted odds ratios ranging from 2.1 to 4.5. The relationship between rapidly progressing fibrosis and possession of > or =3, > or =4, or > or =5 progression associated alleles was determined and the adjusted odds ratios increased with increasing number of progression associated alleles (9.1, 15.5, and 24.1, respectively). Using logistic regression analysis, a predictive equation was developed and tested using a second cohort of patients with rapidly progressing fibrosis. The predictive equation correctly classified 80% of patients in this second cohort. CONCLUSIONS: This approach may allow determination of a genetic profile predictive of rapid disease progression in HCV and identify patients warranting more aggressive therapeutic management.

CCR5-Delta32 mutation is strongly associated with primary sclerosing cholangitis.

CCR5 plays a key role in the distribution of CD45RO+ T cells and contributes to generation of a T helper 1 immune response. CCR5-Delta32 is a 32-bp deletion associated with significant reduction in cell surface expression of the receptor. We investigated the role of CCR5-Delta32 on susceptibility to ulcerative colitis (UC), Crohn's disease (CD) and primary sclerosing cholangitis (PSC). Genotype and allelic association analyses were performed in 162 patients with UC, 131 with CD, 71 with PSC and 419 matched controls. There was a significant difference in CCR5 genotype (OR 2.27, P=0.003) between patients with sclerosing cholangitis and controls. Similarly, CCR5-Delta32 allele frequency was significantly higher in sclerosing cholangitis (17.6%) compared to controls (9.9%, OR 2.47, P=0.007) and inflammatory bowel disease patients without sclerosing cholangitis (11.3%, OR 1.9, P=0.027). There were no significant differences in CCR5 genotype or allele frequency between those with either UC or CD and controls. Genotypes with the CCR5-Delta32 variant were increased in patients with severe liver disease defined by portal hypertension and/or transplantation (45%) compared to those with mild liver disease (21%, OR 3.17, P=0.03). The CCR5-Delta32 mutation may influence disease susceptibility and severity in patients with PSC.

Nonalcoholic fatty liver disease: is all the fat bad?

Nonalcoholic fatty liver disease is now a major cause of liver disease in developed countries, largely as a result of an epidemic of obesity, diabetes and sedentary lifestyles. This has resulted in raised clinical awareness and diagnostic refinement. The entity encompasses several histologic patterns from benign steatosis to nonalcoholic steatohepatitis, the latter having a significant risk of progressive fibrosis and the development of cirrhosis. Laboratory tests and imaging are not able to distinguish steatosis from steatohepatitis, which requires liver biopsy. However following an assessment of several risk factors, patients can be stratified for the potential risk of fibrosis, allowing the rational use of liver biopsy. This review will describe the various patterns of nonalcoholic fatty liver disease and relate this to disease pathogenesis and progression. Strategies for management, including experimental interventions, will be discussed.

Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life.

BACKGROUND AND AIM: Obesity is a risk factor for progression of fibrosis in chronic liver diseases such as non-alcoholic fatty liver disease and hepatitis C. The aim of this study was to investigate the longer term effect of weight loss on liver biochemistry, serum insulin levels, and quality of life in overweight patients with liver disease and the effect of subsequent weight maintenance or regain. PATIENTS: Thirty one patients completed a 15 month diet and exercise intervention. RESULTS: On completion of the intervention, 21 patients (68%) had achieved and maintained weight loss with a mean reduction of 9.4 (4.0)% body weight. Improvements in serum alanine aminotransferase (ALT) levels were correlated with the amount of weight loss (r = 0.35, p = 0.04). In patients who maintained weight loss, mean ALT levels at 15 months remained significantly lower than values at enrollment (p = 0.004), while in regainers (n = 10), mean ALT levels at 15 months were no different to values at enrollment (p = 0.79). Improvements in fasting serum insulin levels were also correlated with weight loss (r = 0.46, p = 0.04), and subsequent weight maintenance sustained this improvement. Quality of life was significantly improved after weight loss. Weight maintainers sustained recommended levels of physical activity and had higher fasting insulin levels (p = 0.03) at enrollment than weight regainers. CONCLUSION: In summary, these findings demonstrate that maintenance of weight loss and exercise in overweight patients with liver disease results in a sustained improvement in liver enzymes, serum insulin levels, and quality of life. Treatment of overweight patients should form an important component of the management of those with chronic liver disease.

Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C.

BACKGROUND: Steatosis occurs in more than 50% of patients with chronic hepatitis C and is associated with increased hepatic fibrosis. In many of these patients the pathogenesis of steatosis appears to be the same as for patients with non-alcoholic fatty liver disease-that is, related to visceral adiposity and obesity. METHODS: The effect of a three month weight reduction programme on liver biochemistry and metabolic parameters was examined in 19 subjects with steatosis and chronic hepatitis C. Paired liver biopsies were performed in 10 subjects, prior to and 3-6 months following the intervention, to determine the effect of weight loss on liver histology. RESULTS: There was a mean weight loss of 5.9 (3.2) kg and a mean reduction in waist circumference of 9.0 (5.0) cm. In 16 of the 19 patients, serum alanine aminotransferase levels fell progressively with weight loss. Mean fasting insulin fell from 16 (7) to 11 (4) mmol/l (p<0.002). Nine of 10 patients with paired liver biopsies had a reduction in steatosis irrespective of viral genotype. In these subjects the median modified Knodell fibrosis score decreased from 3 to 1 (p=0.04) and activated stellate cells significantly decreased (p<0.004). CONCLUSIONS: Weight loss in patients with chronic hepatitis C may be associated with a reduction in steatosis and abnormal liver enzymes and an improvement in fibrosis, despite the persistence of the virus. Weight reduction may provide an important adjunct treatment strategy for patients with chronic hepatitis C.

First isolation of La Crosse virus from naturally infected Aedes albopictus.

La Crosse (LAC) virus, a California serogroup bunyavirus, is the leading cause of pediatric arboviral encephalitis in the United States and an emerging disease in Tennessee, West Virginia, and North Carolina. Human cases of LAC encephalitis in Tennessee and North Carolina have increased above endemic levels during 1997 to 1999 and may represent an expansion of a new southeastern endemic focus. This report describes the isolation of LAC virus from the exotic mosquito Aedes albopictus. The discovery of LAC virus in wild populations of Ae. albopictus coupled with its expanding distribution in the southeastern United States, suggests that this mosquito may become an important accessory vector, potentially increasing the number of human cases in endemic foci or expanding the range of the disease.

Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis.

BACKGROUND AND AIMS: There is a significant relationship between inheritance of high transforming growth factor (TGF)-beta1 and angiotensinogen-producing genotypes and the development of progressive hepatic fibrosis in patients with chronic hepatitis C. In cardiac and renal fibrosis, TGF-beta1 production may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system. The aim of the present study was to determine the effects of the angiotensin-converting enzyme inhibitor, captopril, on the progression of hepatic fibrosis in the rat bile duct ligation model. METHODS: Rats were treated with captopril (100 mg. kg(-1). day(-1)) commencing 1 or 2 weeks after bile duct ligation. Animals with bile duct ligation only and sham-operated animals served as controls. Four weeks after bile duct ligation, indices of fibrosis were assessed. RESULTS: Captopril treatment significantly reduced hepatic hydroxyproline levels, mean fibrosis score, steady state messenger RNA levels of TGF-beta1 and procollagen alpha1(I), and matrix metalloproteinase 2 and 9 activity. CONCLUSIONS: Captopril significantly attenuates the progression of hepatic fibrosis in the rat bile duct ligation model, and its effectiveness should be studied in human chronic liver diseases associated with progressive fibrosis.

Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation.

BACKGROUND/AIMS: Steatosis is a frequent histological finding in chronic hepatitis C and is associated with increased hepatic fibrosis. METHODS: We studied 80 patients with untreated chronic hepatitis C to determine whether steatosis contributes to fibrosis through a steatohepatitis-like pathway. RESULTS: Fine sinusoidal and/or central vein fibrosis was present in 52 patients (65%). This was typically located in acinar zone 3 and had a chicken-wire appearance similar to that seen in steatohepatitis. A statistically significant relationship was found between subsinusoidal fibrosis and age (r(s) = 0.33, P = 0.003) and grade of steatosis (r(s) = 0.35, P = 0.001). Mean body mass index was higher in patients with focal (28.4 +/- 4.7 kg/m2) or extensive (29.6 +/- 5.9 kg/m2) subsinusoidal fibrosis than in those patients with no subsinusoidal fibrosis (25.5 +/- 3.7 kg/m2). The extent of alpha-smooth muscle actin staining (as a marker of stellate cell activation) correlated with the degree of portal inflammation and the stage of portal fibrosis, but not with the grade of hepatic steatosis. CONCLUSIONS: These findings suggest that in hepatitis C infection, host factors, particularly adiposity, contribute to both steatosis and acinar fibrosis. The implication of these observations is that weight reduction may provide an important therapeutic strategy for patients with chronic hepatitis C.

Role of cytokine gene polymorphisms in acute rejection and renal impairment after liver transplantation.

Although immunosuppressive regimens are effective, rejection occurs in up to 50% of patients after orthotopic liver transplantation (OLT), and there is concern about side effects from long-term therapy. Knowledge of clinical and immunogenetic variables may allow tailoring of immunosuppressive therapy to patients according to their potential risks. We studied the association between transforming growth factor-beta, interleukin-10, and tumor necrosis factor alpha (TNF-alpha) gene polymorphisms and graft rejection and renal impairment in 121 white liver transplant recipients. Clinical variables were collected retrospectively, and creatinine clearance was estimated using the formula of Cockcroft and Gault. Biallelic polymorphisms were detected using polymerase chain reaction-based methods. Thirty-seven of 121 patients (30.6%) developed at least 1 episode of rejection. Multivariate analysis showed that Child-Pugh score (P =.001), immune-mediated liver disease (P =.018), normal pre-OLT creatinine clearance (P =.037), and fewer HLA class 1 mismatches (P =.038) were independently associated with rejection. Renal impairment occurred in 80% of patients and was moderate or severe in 39%. Clinical variables independently associated with renal impairment were female sex (P =.001), pre-OLT renal dysfunction (P =.0001), and a diagnosis of viral hepatitis (P =.0008). There was a significant difference in the frequency of TNF-alpha-308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-alpha-308 polymorphism and graft rejection approached significance (P =.06). Recipient cytokine genotypes do not have a major independent role in graft rejection or renal impairment after OLT. Additional studies of immunogenetic factors require analysis of large numbers of patients with appropriate phenotypic information to avoid population stratification, which may lead to inappropriate conclusions.

Detection of male DNA in the liver of female patients with primary biliary cirrhosis.

BACKGROUND/AIMS: Primary biliary cirrhosis is a chronic cholestatic liver disease characterized by progressive inflammatory destruction of bile ducts, with eventual hepatic fibrosis and cirrhosis. Since primary biliary cirrhosis affects predominantly middle-aged women and has pathological similarities to hepatic graft-versus-host-disease, we investigated whether fetal cell microchimerism might be involved in the development of this disease. METHODS: The presence of Y-chromosome-specific sequences was analyzed by polymerase chain reaction using peripheral blood mononuclear cells from women with primary biliary cirrhosis (n=18) and healthy (control) women (n=18), and by in situ hybridization of liver biopsy sections from women with primary biliary cirrhosis (n=19) and women with chronic hepatitis C or alcoholic liver disease (n=20). RESULTS: Male cells were detected in liver biopsy specimens of 8 of 19 patients (42%) with primary biliary cirrhosis. Y-chromosome-containing cells were not seen in any of the liver biopsy specimens from women with chronic hepatitis C or alcoholic liver disease. Male cells were detected in peripheral blood mononuclear cells from one healthy control at a level of 1 male cell per 10(6) female cells, but were not detected in peripheral blood mononuclear cells of women with primary biliary cirrhosis. CONCLUSIONS: The presence of male cells in the liver of women with primary biliary cirrhosis raises the possibility that fetal cell microchimerism may be involved in the pathogenesis of this chronic liver disease.

Novel surveillance and cure of a donor-transmitted lymphoma in a renal allograft recipient.

BACKGROUND: In this report we describe a malignant lymphoma of donor origin inadvertently transplanted into two renal allograft recipients, despite standard comprehensive donor screening. The successful clearance of the tumor from both patients and a novel method of surveillance are detailed. METHODS: Initial management consisted of withdrawal of immunosuppression to promote rejection of the allograft and the transplanted tumor in both patients, followed by graft removal. Peripheral blood microchimerism was assessed in both recipients using nested polymerase chain reaction to detect the DYZ3 gene on the Y chromosome (donor male, recipients female). RESULTS: Although microchimerism was detected on day 6 after transplantation and day 1 after explantation, repeat peripheral blood examination at 1, 3, and 6 months after explantation demonstrated no microchimerism. Both patients remain well at 12 months and have been relisted for transplantation. CONCLUSION: Despite inadvertent transplantation of a previously undiagnosed malignancy of donor origin, the recipients' immune response was able to eliminate donor tumor cells after the withdrawal of immunosuppression. Repeated surveillance of peripheral blood from both recipients, using a novel application of the technique of nested polymerase chain reaction to amplify donor DNA, demonstrated no persistence of donor cells, supporting effective eradication of the donor malignancy.

Expression of cytokines and factors modulating apoptosis by human sinusoidal leucocytes.

BACKGROUND/AIMS: Liver sinusoids contain a large population of spontaneously cytotoxic cells (NK cells), CD8+ T cells and macrophages. The physiological role of these leucocytes remains unclear. They may participate in immune surveillance and peripheral tolerance by deleting tumour cells, virus-infected cells and activated T cells as they traffic through the liver. In order to gain further information about the function of these leucocytes within the hepatic sinusoids, we examined their production of immunomodulatory cytokines and apoptosis-related molecules. METHODS: Semi-quantitative polymerase chain reaction and immunohistochemistry were used to determine the spontaneous production of cytokines and apoptosis-related molecules by sinusoidal leucocytes isolated from donor liver preservation solution. RESULTS: In comparison with matched peripheral blood mononuclear cells, sinusoidal leucocytes produced more mRNA for IL-10, IL-15, TNF-alpha, IL-18, IFN-gamma, FasL, perforin and granzyme. IL-4 and IL-12 were not detected and IL-2 was only faintly detected in the liver-derived CD4+ population. Less bcl-2 was expressed in liver-derived CD4+ and CD8+ cells in comparison with matched peripheral blood cell populations. CONCLUSIONS: The cytokines produced spontaneously by sinusoidal leucocytes are consistent with their high level of activation and spontaneous cytotoxicity. Their strong expression of apoptosis-mediating molecules (FasL, perforin, granzyme and TNF-alpha) support a role for these cells in immune surveillance and peripheral tolerance induction.