Waist-to-hip ratio but not body mass index predicts liver cirrhosis in women.

BACKGROUND: Being overweight can lead to fatty liver and end-stage liver disease. In men, higher body mass index is associated with higher risk of developing liver cirrhosis. The extent of association between overweight and liver cirrhosis in women is not fully elucidated. AIMS: This study aimed to investigate the association between overweight and liver cirrhosis in women, taking into account different measures of adipose tissue distribution. METHODS: A cohort of 1462 middle-aged women was followed over 40 years. Cases of liver cirrhosis were identified by linkage to Hospital Discharge and Death Certificate registries. The hazard ratios for different anthropometric measures and liver cirrhosis were obtained by Cox proportional hazard regression, using propensity score methods to adjust for important confounders. RESULTS: During 48,062 person-years of follow-up, 11 cases of liver cirrhosis were identified. The incidence rate in women with waist-to-hip ratio ≥ 0.8 was 131.8 (48.1-287.0), compared to 12.0 (3.9-28.1) in women with a lower ratio. A waist-to-hip ratio ≥ 0.8 was associated with an increased risk of liver cirrhosis, the hazard ratio being 5.8 (95% confidence interval 1.6-21.4). No association between body mass index and liver cirrhosis was found and the hazard ratio for body mass index >25 was 1.8 (0.5-5.8). CONCLUSION: In women, an unfavorable adipose tissue distribution is more important for development of liver cirrhosis than total body fat per se. When assessing the risk for development of liver cirrhosis in women, waist-to-hip ratio is a better predictor than body mass index.

Pregnancy and childbirth in women with autoimmune hepatitis is safe, even in compensated cirrhosis.

INTRODUCTION: Autoimmune hepatitis (AIH) is a liver disease that primarily affects women. Many become ill during childbearing age, and medication can be lifelong. Few studies exist on pregnancy outcome in women with AIH. Objectives The aim was to assess the outcome of women with AIH and their children during pregnancy and postpartum. MATERIALS AND METHODS: Sixty-four women from a well-characterised cohort with AIH filled out a questionnaire with information about their disease, miscarriage/abortion, pregnancies and potential birth defects in 2012. In 2004, 106 women answered the same questionnaire and their results were analysed along with the new questionnaires. RESULTS: One hundred and thirty-eight women have completed the questionnaire and 100 children have been born by 58 women. Fifty-seven women (41%) had cirrhosis. In 84% of the pregnancies, the AIH was stable or milder, 32% had an increase in activity postpartum. The proportion of preterm births (before week 38) was 22%, caesarean sections 17%, malformations 3%, and two children died. Twenty-three women with cirrhosis had children after diagnosis of cirrhosis but without more complications than for non-cirrhotic mothers. However, they did have a higher prevalence of caesarean sections. CONCLUSION: Pregnancy and childbirth in AIH appear to be safe for both child and mother, even in women with compensated liver cirrhosis.

Hepatocellular and extrahepatic cancer in patients with autoimmune hepatitis--a long-term follow-up study in 634 Swedish patients.

OBJECTIVES: Cirrhosis is a well-known risk factor for hepatocellular cancer, but the true risk in autoimmune hepatitis (AIH) is scarcely studied. Other cancers may arise after prolonged use of immune-modulating drugs. The aim of this study was to investigate the cancer risk in a large cohort of AIH patients. MATERIAL AND METHODS: Six hundred and thirty-four Swedish patients in a well-defined cohort were matched to the Cause of Death Registry and the Cancer Registry. Standard incidence ratios were calculated by relating the incidences in the cohort to an age-matched material from the Swedish background population. RESULTS: A higher overall incidence of malignancies than the background population was found, counting from the date of diagnosis (standard incidence ratio (SIR) 2.08, 95% CI 1.68-2.55). The highest risk was found for hepatocellular carcinoma (HCC). We found 10 cases (4.0%) in 248 patients with cirrhosis, which gives an incidence rate of 0.3%. Standard incidence ratio for developing hepatobiliary cancer was 54.55 (95% CI 19.92-99.99). HCC only occurred in cirrhotic patients. There was also an increased risk for non-melanoma skin cancer (SIR 9.87, 95% CI 6.26-14.81). CONCLUSION: A slightly enhanced risk for malignancies in general compared to the background population was found. The risk of hepatobiliary cancer was increased, but the annual risk over the observational period was well under the postulated 1.5% when surveillance in cirrhotic patients is considered to be cost-effective.

Moderate hyperkalemia in hospitalized patients with cirrhotic ascites indicates a poor prognosis.

OBJECTIVE: Development of ascites in patients with liver cirrhosis is an ominous sign with a poor outcome. A liver transplantation must be considered, and it then becomes important to know if there are any factors indicating a worsened prognosis. MATERIAL AND METHODS: We used official registers for a follow-up study of at least 5 years considering the prognosis of 155 prospectively recruited in-patients with cirrhotic ascites from medical units at nine Swedish university hospitals. All patients had undergone at least one diagnostic ascites tap, and had initially been questioned about background factors and physically examined according to a standardized case record form, followed by sampling of blood, urine, and ascites. RESULTS: Death occurred within 1 year after inclusion in 53% of the cases, and was primarily liver-related in 70%. In a multivariable analysis, the two ordinary variables that showed the strongest correlation with risk of death were serum potassium and abdominal tenderness. All 22 patients with a serum potassium concentration of at least 4.8 mmol/L (maximum 5.8 mmol/L) died within 1 year after inclusion. Potassium concentration was related to renal function and potassium-saving drugs. CONCLUSION: This follow-up study of a prospectively recruited cohort of in-patients with cirrhotic ascites confirms their poor prognosis. Awareness of an elevated serum potassium value, which would reflect a threatened renal function, seems essential, because it may offer a simple way to identify cases with the worst prognosis. An area for further research should be to explore the significance of including serum potassium in prognostic models.

The specialty clinical pharmacology needs to be examined separately to guarantee a sufficient level of knowledge in medical students.

PURPOSE: In medical schools small specialties like clinical pharmacology may be integrated in courses covering larger specialties and examined concomitantly. The results of a pilot study suggested that this approach would have negative consequences on the knowledge gained in clinical pharmacology with integration of this speciality in the course of internal medicine and concomitant examination. The aim of the present study was to assess in more detail whether students' presumed tendency to study selectively influences approval (the pass mark), a surrogate marker of the knowledge gained. METHODS: A written examination for the integrated course in clinical pharmacology and internal medicine in Gothenburg, Sweden, was specifically designed in 2008 to evaluate the research question. The examination consisted of 50 short answer questions, of which five focused on clinical pharmacology (maximum score 10) and 45 were on internal medicine (maximum score 90). The cut-off level for approval (pass mark) was 60 %. RESULTS: Of the 81 students who wrote the examination, 73 (90.1 %) passed the examination as a whole. When the questions in clinical pharmacology were assessed separately, 62 (76.5 %) students passed the cut-off level of 60 %; the corresponding proportion of students achieving the cut-off level for questions on internal medicine was 90.1 %. There was a significant correlation between the results of the two specialties (p < 0.001), but the questions on clinical pharmacology generated lower scores (p < 0.001). The correlation coefficient between the results of two randomly chosen questions for clinical pharmacology was greater than that of two randomly chosen questions in internal medicine (p < 0.001). CONCLUSIONS: Our results confirm that a small specialty like clinical pharmacology may need to be examined separately in order to guarantee a sufficient level of knowledge among students.

Overweight and hypertriglyceridemia are risk factors for liver cirrhosis in middle-aged Swedish men.

OBJECTIVE: Hyperlipidemia, overweight, insulin resistance and hypertension are associated with non-alcoholic fatty liver disease. The knowledge about these conditions as etiologic factors in liver cirrhosis is, however, limited. In this study, we examined the relation between overweight and hypertriglyceridemia, and development of liver cirrhosis in a general population. MATERIAL AND METHODS: An epidemiological, longitudinal study was conducted involving men at the age of 50 with 40 years of follow-up. Baseline data were collected in 1963 and 1967. Cases of liver cirrhosis were identified by searching the Swedish Hospital Discharge Register and death certificates of the Central Bureau of Statistics. The independent effect of BMI, triglyceride levels and alcohol habits for cirrhosis of the liver was calculated by using multiple logistic regression analysis. RESULTS: Elevated BMI and triglycerides were significant independent risk factors for the development of liver cirrhosis (OR 1.27 and 1.99, respectively, p < 0.01). CONCLUSIONS: Overweight and hypertriglyceridemia are independent risk factors for liver cirrhosis in Swedish men.

Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population.

OBJECTIVE: The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. PATIENTS AND METHODS: 373 patients with hemochromatosis detected through routine health check-ups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 ± 5.8 years. The degree of liver fibrosis and survival were analyzed. RESULTS: Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. CONCLUSION: Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation.

Characterisation and utility of thiopurine methyltransferase and thiopurine metabolite measurements in autoimmune hepatitis.

BACKGROUND & AIMS: Corticosteroids alone or in conjunction with azathioprine (AZA) is the standard treatment in autoimmune hepatitis (AiH). Individual variations in thiopurine (TP) metabolism may affect both drug efficacy and toxicity. Our aim was to investigate the utility of thiopurine methyltransferase (TPMT) as well as thioguanine nucleotide (TGN) and methylthioinosine monophosphate (meTIMP) metabolite measurements with regard to clinical outcome. METHODS: Two hundred thirty-eight patients with AiH were included in this cross-sectional study. TPMT status was assessed in all patients, while TGN and meTIMP were measured in patients with ongoing TP medication. Clinical outcome was evaluated by liver tests and the ability to withdraw steroids. RESULTS: TPMT genotyping (n=229) revealed 207 (90.4%) wild-type and 22 heterozygous patients. One hundred forty-three patients had ongoing TP therapy with AZA (n=134) or mercaptopurine (MP; n=9); response was judged as complete response (CR) in 113 patients and partial response (PR) in 30 patients. Both TP dose (1.64 vs 1.19 mg/kg; p=0.012) and TPMT activity (14.3 vs 13.5; p=0.05) were higher in PR, resulting in similar TGN levels (PR: 121 pmol/8 x 10(8) red blood cells [RBC]; CR: 113 pmol/8 x 10(8) RBC; p=0.33) but higher meTIMP levels in PR (1350 vs 400 pmol/8 x 10(8) RBC; p=0.004). Patients able to withdraw steroids or who were using 5 mg prednisolone daily were treated with lower TP doses than patients on higher steroid doses (1.15 vs 1.18 vs 1.82 mg/kg; p<0.001). CONCLUSIONS: TP metabolite measurements are of clinical value in AiH patients who do not respond to standard TP treatment and for the identification of a shifted metabolism, which may demand an alternative treatment strategy.

Increased mortality risk in patients with phenotypic hereditary hemochromatosis but not in their first-degree relatives.

BACKGROUND & AIMS: Hereditary hemochromatosis (HH) is an autosomal-recessive disorder characterized by iron overload. Relatives of HH patients were screened and those with HH-associated mutations and an increased iron load were identified. However, little is known about their mortality or strategies for their management. We assessed mortality among Swedish patients with HH and their first-degree relatives using health and census registers. METHODS: We performed a matched population-based cohort study of 3832 patients with HH and their 14,496 first-degree relatives using data collected from 1990 through 2007. Mortality data from these groups were compared with that of 38,969 population controls and their 143,349 first-degree relatives using Cox regression analyses. RESULTS: Patients identified on the basis of hospitalization with HH had an increased risk (relative risk [RR]) for death (RR, 2.45; 95% confidence interval [CI], 2.27-2.64; 857 deaths). Patients identified through other means had a mortality risk that was lower than those identified in the hospital but higher than controls (RR, 1.15; 95% CI, 1.00-1.33; 216 deaths). Their first-degree relatives had only a marginally increased mortality risk (RR, 1.05; 95% CI, 1.01-1.10); this RR was similar to that of patients' spouses (RR, 1.09; 95% CI, 0.86-1.38; 82 deaths). Patients with HH who also had a family history of HH did not have an increased mortality risk compared with other groups (RR, 1.05; 95% CI, 0.67-1.62; 21 deaths). CONCLUSIONS: Patients with HH have a modestly increased mortality risk compared with controls. The mortality of relatives is increased marginally compared with controls, and is similar among biological and nonbiological relatives.

Characteristics and long-term outcome of patients with autoimmune hepatitis related to the initial treatment response.

OBJECTIVES: Autoimmune hepatitis (AIH) is a liver disease which, if untreated, may lead to liver cirrhosis and hepatic failure. Limited data exist regarding factors predicting the long-term outcome. The aims of this study were to investigate symptoms at presentation, prognostic features, management and treatment in relation to long-term outcome of AIH. MATERIAL AND METHODS: A cohort of 473 Swedish patients with AIH was characterized regarding initial symptoms and signs, factors predicting death and future need for liver transplantation. Survival and causes of death were retrieved from Swedish national registers. RESULTS: At diagnosis, fatigue was a predominant symptom (69%), 47% of the patients were jaundiced and 30% had liver cirrhosis. Another 10% developed cirrhosis during follow-up. Markedly elevated alanine aminotransferase levels at presentation were correlated with a better outcome. A high international normalized ratio (INR) at diagnosis was the only risk factor predicting a need for later liver transplantation. Histological cirrhosis, decompensation and non-response to initial treatment were all factors that correlated with a worse outcome. Overall life expectancy was generally favourable. However, most deaths were liver-related, e.g. liver failure, shock and gastrointestinal bleeding. CONCLUSIONS: Cirrhosis at diagnosis, a non-response to initial immune-suppressive treatment or elevated INR values were associated with worse outcome and a need for later liver transplantation. In contrast, an acute hepatitis-like onset with intact synthetic capacity indicated a good response to treatment and favourable long-term prognosis. Lifetime maintenance therapy is most often required.

Budd-Chiari syndrome in Sweden: epidemiology, clinical characteristics and survival - an 18-year experience.

BACKGROUND: The exact incidence and prevalence of Budd-Chiari syndrome (BCS) is unknown in the general population. Published reports differ in terms of the clinical characteristics, effects of therapy and survival. AIMS: To investigate the epidemiology, clinical presentation and survival in patients with BCS. METHODS: Retrospective multicentre study in Sweden reviewing the medical records of all patients with BCS 1986-2003, identified from the computerised diagnosis database of 11 hospitals, including all university hospitals and liver transplantation centres. RESULTS: Forty-three patients with BCS were identified, of whom nine (21%) had concomitant portal vein thrombosis. The mean age-standardised incidence and prevalence rates in 1990-2001 were calculated to be 0.8 per million per year and 1.4 per million inhabitants respectively. Myeloproliferative disorders (38%), thrombophilic factors (31%) and oral contraceptives (30%) were common aetiological factors. Two or more risk factors were present in 44%. In 23%, no risk factor was evident. The median follow-up time was 2.7 years. Seventy-two percent were on anticoagulant therapy during follow-up. Transjugular intrahepatic portosystemic shunting, surgical shunting procedures and liver transplantation were performed in 4, 6 and 18 patients respectively. Nineteen patients died. The overall transplantation-free survival at 1, 5 and 10 years was 47, 28 and 17% respectively. CONCLUSIONS: Budd-Chiari syndrome is a rare disorder; the mean age-standardised incidence and prevalence rates in Sweden in 1990-2001 were calculated to be 0.8 per million per year and 1.4 per million inhabitants respectively. The presence of a myeloproliferative disorder was a common aetiological factor in our cohort and about half of the patients had a multifactorial aetiology. The transplantation-free survival was poor.

Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study.

OBJECTIVE: Autoimmune hepatitis (AIH) is a chronic liver disease, which if untreated can lead to cirrhosis and hepatic failure. The aim of the study was to investigate the incidence, prevalence, diagnostic tradition and clinical initial presentation of AIH. MATERIAL AND METHODS: Analyses were performed in 473 patients identified as having probable or definite AIH. RESULTS: The incidence of AIH was 0.85/100,000 (95% CI 0.69-1.01) inhabitants, which is somewhat lower than reported previously. The point prevalence amounted to 10.7/100,000 (95% CI 8.8-13.1), and 76% of the cases were females. The age-related incidence curve was bimodal but men were found to have only one incidence peak in the late teens, whereas women had a peak after menopause. AIH was presented as a spectrum of clinical settings from detected "en passant" to acute liver failure. Almost 30% of patients already had liver cirrhosis at diagnosis. Autoantibodies indicative of AIH type 1 were found in 79% of cases. Other concomitant autoimmune diseases were frequently found (49%). CONCLUSIONS: The incidence and prevalence figures confirm that AIH is a fairly uncommon disease in the Swedish population. Symptoms at presentation were unspecific, but almost half of the patients were jaundiced, with around 30% having liver cirrhosis. The majority of Swedish AIH patients had AIH type 1.

Abdominal tenderness in ascites patients indicates spontaneous bacterial peritonitis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP), which has been reported to be present in 10-30% of patients with cirrhotic ascites, may easily be overlooked. An important aim of our study was to determine whether there are any clinical signs which, in clinical practice, may predict or exclude SBP. METHODS: We studied 133 patients with cirrhotic ascites from medical units at nine Swedish university hospitals where there had been at least one diagnostic ascites tap with analysis of polymorphonuclear leukocytes in the ascites fluid. The patients had initially been questioned about background factors and physically examined according to a standardized case record form. Samples of blood, urine, and ascites were then drawn for analysis according to a structured schedule. RESULTS: SBP could be excluded in 80% of all the cases and was confirmed in 8% of the 133 patients in the final analysis. Abdominal pain and abdominal tenderness were more common in patients with SBP (p<0.01), but no other physical sign or laboratory test could separate SBP cases from the others. CONCLUSIONS: SBP was present in about one-tenth of the hospitalized patients with cirrhotic ascites in this cohort. Performing repeated physical examinations and paying particular attention to abdominal tenderness may be the best way to become aware of the possible development of this complication.

Clinical features in hepatocellular carcinoma and the impact of autopsy on diagnosis. A study of 530 cases from a low-endemicity area.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) had been one of the malignancies with the highest reported increase of incidence in Sweden, but during the late 20-year period the incidence has been decreasing. The aims of our study were to state the impact of autopsy on diagnosis and to identify clinical characteristics in HCC. METHODOLOGY: This retrospective study was performed in Göteborg, Sweden and included all cases with a diagnosis of liver cancer from a period with a high autopsy frequency (1958-1979). The cases were reevaluated histopathologically and the autopsy records as well as the case files were scrutinized. RESULTS: The majority (63%) of the 530 biopsy verified cases of HCC were diagnosed unexpectedly at autopsy. Cirrhosis of the liver could be established in 71% of the cases, but was diagnosed or at least clinically suspected before the diagnosis of the tumor only in a minority (19%) of all HCC patients. At presentation, malaise (85%), weight loss (78%), anorexia (67%) and hepatomegaly (84%) were common. The median survival time from diagnosis was one month. In most cases (92%) the cause of death was either directly or indirectly related to HCC and/or underlying liver disease such as advanced tumor disease, hepatic failure and gastrointestinal bleeding. Spontaneous rupture of HCC was the cause of death in 17 cases (3%) CONCLUSIONS: In an unselected population in a low incidence area of HCC, most patients have clinically unknown cirrhosis of the liver and present with vague general paramalignant symptoms. HCC has an extremely poor prognosis. Since HCC, in a majority of cases, remains undiagnosed before death, the autopsy has great impact on the diagnosis. This should be considered in interpretation of results from epidemiological studies.

Analysis of carbohydrate-deficient transferrin (CDT) in vitreous humour as a forensic tool for detection of alcohol misuse.

Analysis of carbohydrate-deficient transferrin concentration in vitreous humour (VH-CDT) has recently been demonstrated to be useful for diagnosis of pre-mortal alcohol misuse, but more knowledge considering possible methodological problems is warranted. In a forensic sample we examined the stability of VH-CDT during laboratory handling as well as the possible affection of time-dependent changes of total transferrin concentrations in vitreous humour (VH-Transferrin) in the dead body on VH-CDT as indicator of alcohol misuse. By use of a commercial assay designed for serum analysis (CDTect) it was possible to measure VH-CDT with high precision, and detectable amounts were found in 20 of 21 alcoholics and in two of seven controls. The compound was demonstrated to be stable in vitreous humour during laboratory handling, since the results of the first analysis were well reproducible after 4 months storage of the specimens (rs=0.86, P=0.0002). Transferrin concentrations in vitreous humour (VH-Transferrin) correlated to the estimated time since the individual last time had been alive before the forensic examination (rs=0.57, P<0.005). However, in this small sample the discriminating property of VH-CDT as indicator of alcohol misuse was not decisively affected, whether or not the variables "VH-Transferrin" and "estimated time since the individual last time had been alive" were considered in a multivariate logistic regression analysis (minor change in the beta-coefficient from 0.57 to 0.52, P=0.086). We conclude that CDT is stable in vitreous humour during proper laboratory handling and that detection of VH-CDT is primarily a marker of alcohol misuse before death. However, the results of this study do not exclude that time-dependent changes of VH-Transferrin, possibly affecting VH-CDT, may occur in the dead body. VH-CDT analysis should thus, at present, be restricted to cases with rather short post-mortal time interval.