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Preeclampsia is a multisystem disorder and the leading cause of severe morbidity and death in pregnancy. Liver involvement in preeclampsia ranges from elevated liver enzyme levels to hepatic infarction or rupture. Endothelial dysfunction leads to changes in blood flow and congestion and may be involved in the pathophysiology of preeclampsia. Changes in splanchnic blood flow and portal congestion can lead to altered liver stiffness. Transient elastography is a noninvasive, ultrasound-based technique that measures organ stiffness and steatosis and is therefore widely used in clinical hepatology. Previous studies reported elevated liver stiffness and liver steatosis, as measured by transient elastography, in women with preeclampsia.This study followed changes in liver stiffness and steatosis, as measured by transient elastography, from the antepartum period to 1-week postpartum among women with preeclampsia compared with healthy controls and evaluated the association between preeclampsia severity and transient elastography results.This prospective cohort study was conducted from 2017 through 2021. The study group comprised women with preeclampsia, and the control group comprised healthy pregnant women hospitalized for other reasons. All the participants underwent transient elastography either on diagnosis of preeclampsia (study group) or on hospital admission (control group) and again in the postpartum period. Liver stiffness measurements are expressed in kilopascals (kPa) in the range of 2.5 to 75 kPa, and liver steatosis is expressed by controlled attenuation parameter in the range of 100 to 400 dB/m.The study group comprised 36 women and the control group 37. Liver stiffness scores were significantly elevated in the study when compared with the control group, both in the antepartum period (P.001) and the postpartum period (P=.025). Liver stiffness scores decreased significantly after delivery in the study and control groups (P.001 and P=.002, respectively). Liver steatosis scores were higher in the study group than in the control group both in the antepartum and postpartum periods (P.001 and P.02, respectively). In the multivariable analysis, the diagnosis of preeclampsia correlated with higher antepartum liver stiffness scores (P=.005). For the study group, postpartum liver stiffness and liver steatosis scores were increased among those with vs those without severe features of preeclampsia (P=.03 and P=.04, respectively) CONCLUSION: Reductions in liver stiffness and steatosis from the antepartum to the postpartum period were documented in both the preeclampsia and control groups. However, both these measures were higher in the preeclampsia group and correlated with preeclampsia severity. Larger studies may be able to determine whether transient elastography can predict the severity of preeclampsia or other related metabolic conditions that correlate with chronic hypertension.

Objectives : Intrahepatic cholestasis of pregnancy (ICP) is charachterized by pruritis and elevated serum bile acids (BA) and is associated with adverse obstetrical outcomes. ICP etiology is poorly understood and its incidence varies with ethnicity and geographical distribution. Objectives: Explore the prevalence and characteristics of ICP in the different Northern Israeli ethnic groups and compare maternal and perinatal outcomes according to disease severity. Material and methods: Single-center retrospective study. Women who were diagnosed with ICP based on clinical presentation and elevated fasting BA (≥ 10 μmol/L) were included. Disease incidence, maternal and neonatal complications were explored according to ethnic subgroups analysis and obstetrical complications were examined according to disease severity. Results : The incidence of ICP in the study population was 0.58%. Higher ICP incidence was found in our cohort compared with other reports arising from Central Israel (p < 0.001). The Christian patients had a higher incidence of ICP (1.1%) and preeclampsia (23.1%). A higher rate of neonatal intensive care unit (NICU) admissions was found in the Arab Muslim and Christian groups compared with the Jewish and Druze groups (p = 0.007). A higher rate of preeclampsia was found in the severe (BA ≥ 40 μmol/L) ICP group (p < 0.001). Patients in the severe ICP group had earlier gestational age at delivery (37 versus 38.14 weeks, p < 0.001). Birth weight was significantly lower in the severe ICP group (p = 0.018). Conclusions : The incidence of ICP at our institution was 0.58%, which is higher compared with previous reported Israeli incidence. Higher ICP and preeclampsia incidence were found among Arab Christian patients.

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Background Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions. Methods In a multicentre cohort study ( n=308), NS3 or NS5B sequencing ( n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure. Results GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations. Conclusions NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.

In 2013 the Israeli Ministry of Health appointed a public committee to examine the policy of placing an age limitation on candidates listed for organ transplantation. The committee rejected the use of an age limit criterion for listing candidates for transplantation and recommended to abolish it. However, opinions differed regarding the use of recipients’ age in shaping a fair organ allocation policy. The committee's recommendations were adopted and put into force as of April 2014. This article unfolds the committee deliberations on accommodating values of formal equality for optimising the use of organ transplantation.

The objective of this study was to address the hepatic effects of acute alcohol consumption in obesity by simulating an alcohol binge in genetically obese fa/fa rats compared with lean Fa/? rats.Ethanol 4 g/kg or saline was administered by gavage every 12 hours for 3 days.Plasma alcohol levels were similar in both groups. Binge ethanol exposure caused liver injury in obese fa/fa but not in lean Fa/? rats, as assessed by alanine aminotransferase and HE staining. Obesity impaired the antioxidant defense because basal levels of glutathione, glutamate cysteine ligase modulatory subunit, catalase, glutathione reductase, and superoxide dismutase were lower in fa/fa compared with Fa/? rats; the ethanol binge further decreased these antioxidants in fa/fa rats and also decreased glutathione peroxidase activity. Nonesterified fatty acids and lipid peroxidation were increased after ethanol treatment in fa/fa rats. Cytochrome P450 2E1 was down-regulated in fa/fa compared with Fa/? rats; however, the ethanol binge increased cytochrome P450 2E1 in both genotypes. Adenosine triphosphate decreased and uncoupling protein 2 increased in fa/fa rats treated with ethanol. 3-Nitrotyrosine protein adducts were detected only in fa/fa rats treated with ethanol, and this was accompanied by an induction of inducible nitric oxide synthase. Ethanol binge increased caspase-3 and caspase-8 activity, the expression of Fas ligand, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling in fa/fa rats.These data indicate that binge drinking increases apoptosis and liver injury in obese rats more than in lean controls and suggest that the injury may involve oxidative and nitrosative damage.

Janus kinase-2 (JAK2) is mutated in a high proportion of patients with polycythemia vera and in a smaller number with essential thrombocythemia and primary myelofibrosis. Mutated JAK2 is an important diagnostic marker for myeloproliferative neoplasm (MPN) and may also play a major role in the pathogenesis of MPN.To evaluate the prevalence of mutated JAK2 (JAK2-V617F) among patients with major intraabdominal vein thrombosis who had normal blood counts at diagnosis of the initial event.The medical records of patients who presented with a major intraabdominal venous thrombosis and normal peripheral blood counts were obtained. JAK2-V617F mutation status was determined by real-time polymerase chain reaction.Twenty-two patients were available for this analysis and 9 (41%) were found to have JAK2-V617F. Patients with positive JAK2-V617F were younger and had more frequent clinical splenomegaly than those with wild-type JAK2.A high proportion of patients presenting with "idiopathic" major intraabdominal vein thrombosis and normal blood counts carry JAK2-V617F. We recommend searching for the mutation in this clinical setting to detect patients with occult MPN.

Fatty livers of obese fa/fa rats are vulnerable to injury when challenged by insults such as endotoxin, ischemia-reperfusion or acute ethanol treatment. The objective of this study was to evaluate whether a high-fat diet can act as a "second hit" and cause progression to liver injury in obese fa/fa rats compared with lean Fa/? rats. Accordingly, obese fa/fa rats and their lean littermates were fed a diet low in fat (12% of total calories) or a diet with 60% calories as lard for 8 weeks. Hyperglycemia and steatohepatitis occurred in the fa/fa rats fed the high-fat diet. This was accompanied by liver injury as assessed by alanine aminotransferase, hematoxilin and eosin staining, increased TNFalpha and stellate cell-derived TGFbeta, collagen deposition, and up-regulation of alpha-smooth muscle actin. Active MMP13 decreased in fa/fa rats independently of the diet, and TIMP1 expression increased with the high-fat diet, especially in fa/fa rats. Although UCP2 expression was higher in fa/fa rats regardless of the diet, minor changes in ATP levels were observed. Oxidative stress occurred in the fa/fa rats fed the high-fat diet as lipid peroxidation and protein carbonyls were elevated, while glutathione and antioxidant enzymes were very low. Expression and activity of cytochrome P450 2E1 and xanthine oxidase activity were down-regulated in fa/fa compared with Fa/? rats, and no effect was seen by the high-fat diet. However, NADPH oxidase activity increased 2.5-fold in fa/fa rats fed with the high-fat diet. In summary, a high-fat diet induces liver injury in fa/fa rats leading to periportal fibrosis. A role for oxidative stress is suggested via increased NADPH oxidase activity, lipid peroxidation, protein carbonyl formation, and low antioxidant defense.

Background: Cognitive disturbances are relatively common in patients with liver disease. High protein load precipitates hepatic encephalopathy in cirrhotic patients. Minimal hepatic encephalopathy (MHE) is a prevalent neurocognitive complication of cirrhosis. Objective: Because the influence of nutritional factors on the progression of cognitive impairment has not been explored in depth, this study aimed to investigate the effect on cognition of acute metabolic changes induced by breakfast consumption. Design: Twenty-one subjects (10 women) with Child A cirrhosis and 21 age- and sex-matched healthy controls were enrolled. Patients and controls were divided into 2 groups: those receiving a breakfast of 500 kcal and 21 g protein and those receiving no breakfast. Serum ammonia concentrations and cognitive functions were studied (Mindstreams; NeuroTrax, Fresh Meadows, NY) before and 2 h after breakfast. A mixed model was used to analyze the data. Results: At baseline, cirrhotic patients had significantly lower total scores and significantly lower subscores (P , 0.015 global cognitive score) in 4 of 7 cognitive categories, which is indicative of MHE. Patients with hyperammonemia (.85 lg/dL) scored significantly lower for attention than did patients with normal serum ammonia concentrations (P , 0.003). After 2 h, MHE patients and controls responded differently to breakfast consumption with regard to attention and executive functions (P , 0.003 and P , 0.04, respectively). Although patients’ scores improved after breakfast consumption, despite an increase in serum ammonia, healthy controls who continued to fast performed better. Conclusions: Chronic hyperammonemia may negatively affect attention. Eating breakfast improves attention and executive functions of patients with MHE. Prolonged periods of starvation may be partly responsible for these changes. This trial was registered at clinicaltrials. gov as NCT01083446. Am J Clin Nutr 2010;92:137‐40.

Objective The purpose of this study was to describe and evaluate the sonographic and color Doppler features of tumorlike biliary and venous changes in patients with cavernous transformation of the portal vein (CTPV). Methods The sonographic studies of 24 patients with CTPV were reviewed. Sonographic evaluation of the biliary system included measurement of intrahepatic and extrahepatic biliary duct caliber changes and common bile duct (CBD) wall thickening and character. Color Doppler features of the portoportal collateral circulation at various locations (intrahepatic, periportal, gallbladder, pancreatic, and gastric regions) were carefully evaluated. Results Biliary abnormalities were detected in 13 (54%) of 24 patients with CTPV. All 13 patients (100%) had intrahepatic biliary dilatation; 11 patients (85%) had CBD abnormalities: diffuse CBD wall thickening causing diffuse narrowing of the true lumen in 7 (54%) and CBD dilatation proximal to the focal area of narrowing due to pericholedochal compressing venous collaterals in 4 (30%). A tumorlike solid mass appeared on the gray scale images of 2 patients (8%): 1 at the porta hepatis and the other at the pancreatic head level. Color Doppler imaging evaluation showed venous-type flow, suggesting a bulk of varicosities. Conclusions Portoportal collaterals in patients with CTPV may alter the biliary and venous systems, causing biliary wall thickening, stenosis, intrahepatic and extrahepatic dilatation, and pseudotumors. Detailed sonographic and color Doppler imaging assessment can show and facilitate the correct diagnosis of those changes, thus avoiding the need for a more invasive modality such as endoscopic retrograde cholangiopancreatography or a more expensive investigation such as magnetic resonance cholangiopancreatography.

The model for end-stage liver disease is the best available predictor of waiting list mortality among liver transplant candidates.To validate the applicability of MELD in Israel.All candidates awaiting liver transplantation in our institution were followed prospectively since 2002. We measured the concordance (c-statistic) equivalent to the area under the receiver operating characteristic curve in order to assess the predictive power of MELD. Other independent mortality risk factors were identified by a separate multivariate analysis. Mortality rates within different MELD and Child-Pugh-Turcotte scores were compared to the original (United States) MELD data.Of 86 patients listed for transplantation, 40 were transplanted (36 in Israel and 4 abroad). Of the other 46 patients, 24 are alive and still listed, and 22 died (25%, approximately 7%/year). The area under the ROC curve for MELD score was 0.79 (0.83 USA) compared to a CPT score of 0.71 (0.76 USA). High MELD scores, occurrence of spontaneous bacterial peritonitis, and diagnosis of hepatocellular carcinoma were independent risk factors of mortality. Death rates per mid-MELD score (20-29) were significantly higher than the USA results.MELD is valid in Israel and superior to CPT in predicting waiting list mortality. Although longer waiting time due to organ scarcity is a key factor, death rates in the mid-range (10-29) MELD groups indicate further audit of the care of patients with end-stage liver disease.

Retransplantation (re-LT) of patients with recurrent hepatitis C virus (HCV) carries significant morbidity and mortality, negatively impacting on an already scarce donor allograft pool. In this study, we investigated the outcome of allografts and patients after re-LT due to recurrent HCV. Between 1989 and 2002, 47 patients were retransplanted at our institution due to HCV-related graft failure. Clinical HCV recurrence after re-LT was diagnosed when patients had acute liver enzyme elevation correlated with histological recurrence. The independent influence of these variables on survival was tested using Cox regression model. Chi-squared tests were used to examine the influence of individual demographic and pre/perioperative variables on recurrence. Thirty-one (66%) patients died after re-LT (median 2.2 months). Donor age >60, clinical HCV recurrence, and graft failure due to cirrhosis were significant risk factors for mortality (risk ratios of 3.6, 3.3, and 2.4, respectively). Pre-LT MELD score was lower among survivors (22± 5 vs. 27± 8). Following re-LT, 38 patients had at least one biopsy due to acute liver dysfunction; 19 of them (50%) had recurrence within the first 3 months. High-dose solumedrol was correlated with early recurrence. No association was found between time of recurrence after the first LT and time of recurrence after re-LT. In conclusion, patients with cirrhosis due to recurrent HCV undergoing re-LT have an extremely high mortality rate; older allografts should be avoided in retransplanting these patients. The timing of clinical recurrence after initial liver transplantation is not predictive of the timing of recurrence after re-LT. Patients experiencing early graft failure due to accelerated forms of HCV should not be denied re-LT with the expectation that a similar disease course will occur after re-LT. (Liver Transpl 2005;11:1567–1573.)

Acute portal vein thrombosis (PVT) is a devastating complication of Budd-Chiari syndrome (BCS). Con-servative approach, anticoagulation, systemic or transarterial thrombolysis, and urgent liver transplanta-tion were applied in this scenario but with poor results. We present and discuss an approach to treat BCS complicated by acute PVT. Two young female patients presented with acute liver failure, rapidly pro-gressive tense ascites, renal- and respiratory failure. The diagnosis of chronic BCS complicated by acute PVT was confirmed with ultrasound Doppler. Initial treatment was supportive. Right portal vein local-ization was by transarterial portogram or by computed tomography-guided microcoil placement. Trans-jugular intrahepatic portosystemic shunt (TIPS) was performed and included Wallstents and a Jograft in one case and Viatorr stentgraft that was extended later with a Hemobahn stentgraft in another. Mechan-ical clot removal from the portal system was performed in the primary procedure and in a revision pro-cedure in the following few days. Stents were placed precisely with no extension into the inferior vena cava or deeply into the main portal vein. Patients were fully anticoagulated and patency was assessed by ultrasound Doppler. The procedures were performed on days 5 and 10 following admission. In both cases, successful thrombectomies were reveised and maintained. Partial occlusion of the TIPS and reaccumulation of ascites were reversed with repeated procedure. Both patients were discharged without ascites and normal liver function. In conclusion, urgent TIPS and portal vein thrombectomy via TIPS are emerging therapeutic options that offer a safe and effective treatment to patients with BCS complicated by acute portal vein thrombosis.

Adult-to-adult living donor liver transplantation is becoming an alternative to cadaveric transplantation in urgent and elective settings. Donor selection crucially affects donor safety and recipient outcome.To present our algorithm of urgent and elective donor selection.Urgent selection is expeditious and protocol-based. Elective selection permits a comprehensive process. Both include medical, psychosocial and surgical-anatomic evaluations. Liver volumes and vascular anatomy are evaluated with computerized tomographic angiography. Informed consent is obtained after painstaking explanations. Independent institutional committees review and approve all cases.Between July 2003 and June 2004 we evaluated 43 potential live donors for 12 potential recipients (fulminant hepatic failure, n = 5; chronic end-stage liver disease, n = 6; primary graft non-function, n = 1). Thirty-three candidates (76%) were excluded due to blood type incompatibility (n = 14, 42%), incompatible anatomy (n = 8, 24%)--including problematic volume distribution (n = 2) or vascular anatomy (n = 6)--psychosocial issues (n = 4, 12%), or medical co-morbidity (n = 7, 22%). Five recipients (FHF, n = 4; chronic ESLD, n = 1) were successfully transplanted from living donors. In the acute setting, two patients (FHF, PGNF) died in the absence of an appropriate donor (cadaveric or living donor). In the elective group, one patient died of unexpected variceal bleeding and one received a cadaveric graft just before the planned living donor transplantation was performed. One candidate was transplanted overseas and two cases are scheduled. The ratio of compatibility for donation was 34% (10/29) for blood type-compatible candidates.Donor selection for living donor liver transplantation is a complex, labor-intensive multidisciplinary process. Most exclusions are due to blood type incompatibility or anatomic details. Psychosocial aspects of these donations warrant special attention.

A 37-year-old white woman was infected with the human immunodeficiency virus (HIV) through a blood transfusion which she received during a complicated labour in the Ivory Coast. Three years later, due to a decline in the CD4+ cell counts to 200/ml, zidovudine (AZT) and trimethoprim-cotrimoxazole were administered. A few months later, zalcitabine (ddC) was added, due to the appearance of fever, abdominal pain and weight loss, and a further decline in the CD4+ cell counts down to 15/ml. Despite these measures the patient continued to complain of abdominal pain, which was often exacerbated by food intake. Laboratory studies then showed normal serum amylase and liver enzyme levels. Abdominal ultrasonography (US) and gastroscopy were normal. Due to a suspected role of the antiretroviral drug therapy in inducing the abdominal pain, AZT and ddC were discontinued. Three months later, the patient was admitted because of severe abdominal pain, vomiting and a fever of 38.5°C. On examination, marked epigastric tenderness was noted. Investigation results were as follows: amylase 1120 IU/l, hypocalcaemia (1.52 mmol/l), alkaline phosphate 219 IU/l, and gamma-glutamyl transpeptidase 478 IU/l. US and computed tomography (CT) revealed gall bladder wall thickening, with a dilated common bile duct and no evidence of stones. The pancreas was mildly enlarged and oedematous. A diagnosis of pancreatitis was made, a nasogastric tube …