Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.

BACKGROUND: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. METHODS: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. FINDINGS: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 µmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 µmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 µmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001). INTERPRETATION: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 µmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. FUNDING: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.

TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis.

Previous large-scale genetic studies identified single nucleotide polymorphisms (SNPs) of the TM6SF2 and MBOAT7 genes as risk factors for alcoholic liver cirrhosis and non-alcoholic fatty liver disease. In this study, we tried to evaluate the association between TM6SF2 variant rs58542926 and MBOAT7 variant rs641738 and the risk of hepatic fibrosis or liver cirrhosis of different etiology. In parallel, we also aimed to evaluate whether these two SNPs modify the effects of the PNPLA3 rs738409 risk variant for the development of hepatic fibrosis and liver cirrhosis. The study was conducted at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, and included 334 patients with liver cirrhosis, 128 patients with liver fibrosis, and 550 controls. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Overall, TM6SF2 rs58542926 as well as MBOAT7 rs641738 were not linked to hepatic fibrosis, alcohol or hepatitis C virus induced liver cirrhosis in an Eastern European population. These genetic variations also did not mediate the effect of PNPLA3 rs738409 SNP for liver developing liver fibrosis or liver cirrhosis.

Association of HFE gene C282Y and H63D mutations with liver cirrhosis in the Lithuanian population.

BACKGROUND AND OBJECTIVE: Liver cirrhosis is the end-stage disease of chronic liver injury. Due to differences in the natural course of chronic liver diseases, identification of genetic factors that influence individual outcomes is warranted. HFE-linked hereditary hemochromatosis (HH) predisposes disease progression to cirrhosis; however, the role of heterozygous C282Y or H63D mutations in the development of cirrhosis in the presence of other etiological factors is still debated. The aim of this study was to determine the association between heterozygous C282Y and H63D mutations and non-HH liver cirrhosis in Lithuanian population. MATERIALS AND METHODS: The patient cohort consisted of 209 individuals. Diagnosis of cirrhosis was confirmed by clinical, laboratory parameters, liver biopsy, and radiological imaging. Control samples were obtained from 1005 randomly selected unrelated healthy individuals. HFE gene mutations were determined using the PCR-RFLP method. RESULTS: The most common causes of cirrhosis were hepatitis C (33.9%), hepatitis B (13.6%), and alcohol (25.8%). C282Y allele was associated with the presence of cirrhosis (OR=2.07; P=0.005); this was also observed under recessive model for C282Y (OR=2.06, P=0.008). The prevalence of C282Y allele was higher in cirrhotic men than in controls (7.0% vs. 2.8%, P=0.002). The carriage of H63D risk allele (OR=1.54; P=0.02), heterozygous C282Y/wt and homozygous H63D/H63D genotypes were associated with liver cirrhosis in males (OR=2.48, P=0.008, and OR=4.13, P=0.005, respectively). CONCLUSIONS: Heterozygous C282Y mutation of the HFE gene was associated with liver cirrhosis in the Lithuanian population. In gender-related analysis, heterozygous C282Y and homozygous H63D mutations were linked to liver cirrhosis in men, not in women.

Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis.

BACKGROUND & AIMS: We performed a meta-analysis to evaluate the effects of ursodeoxycholic acid (UDCA) on pruritus, liver test results, and outcomes of babies born to women with intrahepatic cholestasis of pregnancy (ICP). METHODS: We performed a systematic review of 9 published, randomized controlled trials (3 double blinded) that compared the effects of UDCA to other drugs, placebo, or no specific treatment (controls) in patients with ICP. We analyzed data from 454 patients: 207 received only UDCA, 70 received only placebo, 42 received cholestyramine, 36 received dexamethasone for 1 week and then placebo for 2 weeks, 65 received S-adenosyl-methionine, and 34 received no specific treatment. To achieve consistency among end points, a standard questionnaire was sent to all corresponding authors. For each end point, we performed pooled analysis that compared the effects of UDCA with those of all controls and UDCA with those of placebos. RESULTS: In pooled analyses that compared UDCA with all controls, UDCA was associated with total resolution of pruritus (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.07-0.74; P < .01), reduced pruritis (OR, 0.27; 95% CI, 0.13-0.55; P < .0001), normalization of serum levels of alanine aminotransferase (ALT) (OR, 0.23; 95% CI, 0.10-0.50; P < .001), decreased serum level of ALT (OR, 0.24; 95% CI, 0.11-0.52; P < .0001), reduced serum levels of bile acids (OR, 0.37; 95% CI, 0.19-0.75; P < .001), fewer premature births (OR, 0.44; 95% CI, 0.24-0.79; P < .01), reduced fetal distress (OR, 0.46; 95% CI, 0.25-0.86; P < .01), less frequent respiratory distress syndrome (OR, 0.30; 95% CI, 0.12-0.74; P < .01), and fewer neonates in the intensive care unit (OR, 0.49; 95% CI, 0.25-0.98; P = .046). In pooled analyses that compared the effects of UDCA with placebo, UDCA reduced pruritus (OR, 0.21; 95% CI, 0.07-0.62; P < .01), normalized (OR, 0.18; 95% CI, 0.06-0.52; P < .001) or decreased serum levels of ALT (OR, 0.12; 95% CI, 0.05-0.31; P < .0001), and reduced serum levels of bile acids (OR, 0.30; 95% CI, 0.12-0.73; P < .01). CONCLUSIONS: Based on a meta-analysis, UDCA is effective in reducing pruritus and improving liver test results in patients with ICP; UDCA therapy might also benefit fetal outcomes.

Prevalence of C282Y, H63D, and S65C mutations in hereditary HFE-hemochromatosis gene in Lithuanian population.

HFE-hemochromatosis is a common autosomal recessive disease caused by HFE gene mutations and characterized as iron overload and failure of different organs. The aim of this study was to determine the prevalence of C282Y (c.845 G>A), H63D (c.187 C>G), and S65C (c.193A>T) alleles of HFE gene in the Lithuanian population. One thousand and eleven healthy blood donors of Lithuanian nationality were examined in four different ethnic Lithuanian regions to determine HFE gene alleles and genotype frequencies. The samples of DNA were analyzed for the presence of restriction fragment length polymorphism and validated by DNA sequencing. Among 1,011 blood donors tested, the frequency of C282Y, H63D, and S65C alleles were 2.6%, 15.9%, and 1.9%, respectively. One third of the tested subjects (n = 336) had at least one of the C282Y or H63D HFE gene mutations. The screening of Lithuanian blood donors has detected 13 (1.3%) subjects with a genotype C282Y/C282Y or C282Y/H63D responsible for the development of HFE-hemochromatosis. The prevalence of C282Y mutation was significantly higher among the inhabitants of Zemaitija (Somogitia) at the Baltic Sea area (5.9%) in comparison to the regions of continental part of Lithuania (2.4% in Dzukija, 2.3% in Aukstaitija, and 2% in Suvalkija, p < 0.05). These data support the hypothesis that the p.C282Y mutation originated from Scandinavia and spread with the Vikings along the Baltic Sea coast. The first epidemiological investigation of HFE gene mutations in ethnic Lithuanians showed that the frequencies of H63D, C282Y, and S65C of HFE gene alleles are similar to the other North-Eastern Europeans, especially in the Baltic region (Estonia, Latvia), Poland, and part of Russia (Moscow region).

Lysophosphatidic acid is a potential mediator of cholestatic pruritus.

BACKGROUND & AIMS: Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons. METHODS: Cytosolic free calcium ([Ca(2+)](i)) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca(2+)](i)-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device. RESULTS: Transient increases in neuronal [Ca(2+)](i) induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca(2+)](i) agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P < .0001) and cholestatic patients with versus without pruritus (P < .0001). Autotaxin activity correlated with intensity of pruritus (P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or mu-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal. CONCLUSIONS: We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

BACKGROUND: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. METHODS: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 µmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. FINDINGS: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016). INTERPRETATION: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. FUNDING: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.

SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis.

BACKGROUND AND AIMS: Two single nucleotide polymorphisms (SNPs) in SERPINA1 (Pi*Z rs28929474 and Pi*S rs17580) are risk factors for developing liver cirrhosis. A recent study identified a common SNP in HSD17B13 (rs72613567) that conferred protection from chronic liver disease. The aim of the present study was to test these associations in a cohort of Lithuanian patients with liver fibrosis or cirrhosis. METHODS: The study included 302 patients with cirrhosis, 127 patients with liver fibrosis (METAVIR stages I-III) and 548 controls, all from Lithuania. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Adjusted p value of ≤ 0.016 was considered significant. RESULTS: Genotype distributions of SERPINA1 and HSD17B13 SNPs were in Hardy-Weinberg equilibrium. SERPINA1 Pi*Z was not associated with liver fibrosis or cirrhosis. HSD17B13 rs10433937 (in high linkage disequilibrium with rs72613567; r 2 =0.96) also showed no overall association with liver disease, but the GG- genotype was associated with reduced risk of liver fibrosis (aOR 0.37, p=0.03). SERPINA1 Pi*S was associated with higher risk of developing hepatic fibrosis (aOR 3.42, p=0.001) and cirrhosis (aOR 2.59, p=0.02). CONCLUSIONS: We found that SERPINA1 Pi*S variant conferred an increased risk of developing liver fibrosis, while SERPINA1 Pi*Z and HSD17B13 rs10433937 were not associated with liver fibrosis or cirrhosis of different aetiology.

Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICP.

Liver diseases unique to pregnancy.

The aim of this review article is to improve knowledge of the liver disease in pregnancy. The article summarizes the results of own experience and the recent reviews of liver disorders unique to pregnancy. Abnormalities in liver tests occur in 3% of pregnancies with causes ranging from self-limiting to rapidly fatal. In Kaunas University of Medicine Hospital, a retrospective analysis disclosed a rate of 0.52% of liver diseases in 16252 pregnant women over a 5-year period. Several liver diseases occur only during pregnancy and are considered to be associated with the pregnant state. The liver disorders unique to pregnancy have characteristic clinical features and timing of onset. Hyperemesis gravidarum occurs in the first trimester, intrahepatic cholestasis of pregnancy in the second or third trimester, preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, and acute fatty liver of pregnancy usually in the third trimester. The disorders of late pregnancy - preeclampsia, HELLP syndrome, and acute fatty liver of pregnancy - may progress to severe liver dysfunction. The correct diagnosis is critical, as any delay can result in morbidity or mortality of both the mother and fetus. Early delivery and advances in supportive management are the only available option for improving the prognosis.

Predictors of premature delivery in patients with intrahepatic cholestasis of pregnancy.

AIM: To evaluate the predictive value of clinical symptoms and biochemical parameters for prematurity in intrahepatic cholestasis of pregnancy (ICP). METHODS: Sixty symptomatic patients with ICP were included in this retrospective analysis. Preterm delivery was defined as delivery before 37 wk gestation. Predictors of preterm delivery were disclosed by binary multivariate logistic regression analysis. RESULTS: Mean time of delivery was 38.1 +/- 1.7 wk. No stillbirths occurred. Premature delivery was observed in eight (13.3%) patients. Total fasting serum bile acids were higher (47.8 +/- 15.2 vs 41.0 +/- 10.0 mumol/L, P < 0.05), and pruritus tended to start earlier (29.0 +/- 3.9 vs 31.6 +/- 3.3 wk, P = 0.057) in patients with premature delivery when compared to those with term delivery. Binary multivariate logistic regression analysis revealed that early onset of pruritus (OR 1.70, 95% CI 1.23-2.95, P = 0.038) and serum bile acid (OR 2.13, 95% CI 1.13-3.25, P = 0.013) were independent predictors of preterm delivery. CONCLUSION: Early onset of pruritus and high levels of serum bile acids predict preterm delivery in ICP, and define a subgroup of patients at risk for poor neonatal outcome.

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population.

BACKGROUND AND AIMS: Genome-wide association studies have revealed an association between the risk of developing liver fibrosis or cirrhosis and the single nucleotide polymorphisms (SNPs) of the PNPLA3, RNF7, MERTK and PCSK7 genes. We aimed to validate these results in an Eastern European population. METHODS: We evaluated the associations between the PNPLA3 (rs738409), RNF7 (rs16851720), MERTK (rs4374383) and PCSK7 (rs236918) variants and liver fibrosis and cirrhosis in a series of consecutive patients recruited at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, during the period 2012-2015. The study included 317 individuals with liver cirrhosis, 154 individuals with liver fibrosis, and 498 controls. The studied SNPs were determined using RT-PCR TaqMan assays. RESULTS: MERTK and PCSK7 SNPs were not associated with liver fibrosis or cirrhosis. The PNPLA3 SNP rs738409 was associated with a higher risk of developing liver fibrosis (aOR: 1.65, P=0.001) and cirrhosis (aOR: 1.92, P=5.57*10-7). PNPLA3 genotypes were also associated with higher risk of developing liver fibrosis and cirrhosis in dominant (aOR: 1.98, P=2.20*10-5; aOR: 1.67, P=0.008, respectively) and recessive (aOR: 3.94, P=5.16*10-5; aOR: 3.02, P=0.003, respectively) models. RNF7 rs16851720 was associated with liver cirrhosis comparing CC vs. AA + CA genotypes (aOR: 0.26, P=0.020). CONCLUSION: Our study showed that PNPLA3 rs738409 and RNF7 rs16851720 confer an increased risk of developing liver fibrosis and cirrhosis in this Eastern European population, while the MERTK and PCSK7 SNPs are not associated with these conditions.

Aorto-duodenal fistula: a rare but serious complication of gastrointestinal hemorrhage. A case report.

A primary aortoduodenal fistula (PADF) is a rare cause of gastrointestinal bleeding that is difficult to diagnose (and sometimes not diagnosed until a laparotomy.) A PADF is associated with high mortality if undiagnosed and untreated (the mortality rate of nearly 100% in the absence of a surgical intervention). While this condition is extremely rare with an incidence rate at autopsy of 0.04% to 0.07%, a secondary ADF occurs much more commonly (the post-operative incidence of 0.5% to 2.3%) and is due to prior aortic surgery and/or the placement of a synthetic aortic graft. It should be considered in any elderly patient who presents with upper gastrointestinal bleeding in the context of a known abdominal aortic aneurysm or without it when no identifiable source of bleeding is found. We present an autopsy case of a 59-year-old man with no history of an abdominal aortic aneurysm who presented with intermittent massive gastrointestinal bleeding. The autopsy revealed a pinhole fistula. It was identified between an atherosclerotic abdominal aortic aneurysm and the lower horizontal part of the duodenum. Our case indicates that the aortoenteric fistula can result in fatal gastrointestinal bleeding. This case is unique in that the fistula formed as a result of a complex atherosclerotic abdominal aorta and a localized necrotizing granulomatous aortitis the etiology of which was not clear.

Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy.

BACKGROUND & AIMS: Treatment of intrahepatic cholestasis of pregnancy with ursodeoxycholic acid appears promising, but data are limited so far. The aim of this randomized study was to evaluate the efficacy and safety of ursodeoxycholic acid in comparison with cholestyramine. METHODS: Eighty-four symptomatic patients with intrahepatic cholestasis of pregnancy were randomized to receive either ursodeoxycholic acid, 8-10 mg/kg body weight daily (n = 42), or cholestyramine, 8 g daily (n = 42), for 14 days. The primary end point was a reduction of pruritus by more than 50% after 14 days of treatment as evaluated by a pruritus score. Secondary end points were outcome of pregnancy, reduction of serum aminotransferase activities and serum bile acid levels, and drug safety. Intention-to-treat analysis was applied. RESULTS: Pruritus was more effectively reduced by ursodeoxycholic acid than cholestyramine (66.6% vs 19.0%, respectively; P < .005). Babies were delivered significantly closer to term by patients treated with ursodeoxycholic acid than those treated with cholestyramine (38.7 +/- 1.7 vs 37.4 +/- 1.5 weeks, respectively, P < .05). Serum alanine and aspartate aminotransferase activities were markedly reduced by 78.5% and 73.8%, respectively, after ursodeoxycholic acid, but by only 21.4%, each, after cholestyramine therapy (P < .01 vs ursodeoxycholic acid). Endogenous serum bile acid levels decreased by 59.5% and 19.0%, respectively (P < .02). Ursodeoxycholic acid, but not cholestyramine was free of adverse effects. CONCLUSIONS: Ursodeoxycholic acid is safe and more effective than cholestyramine in intrahepatic cholestasis of pregnancy.

[Wernicke's encephalopathy induced by hyperemesis gravidarum (case report)]. / Uzsitesusio nesciuju vemimo sukelta Wernicke encefalopatija.

One of the life-threatening complications of hyperemesis gravidarum is Wernicke's encephalopathy, the main etiological factor of which is a lack of thiamine (vitamin B1). Most frequently Wernicke's encephalopathy is found among persons suffering from excessive drinking. The aim of the report was to present a case of Wernicke's encephalopathy induced by hyperemesis gravidarum. The course of the disease, clinical signs, diagnostics, treatment and its results are presented. Also a review of the literature on Wernicke's encephalopathy secondary to hyperemesis gravidarum is introduced.