Publications by authors named "Liane Rabinowich"

22 Publications

  • Page 1 of 1

Prevalence of bleeding and thrombosis in critically ill patients with chronic liver disease.

Thromb Haemost 2021 Oct 12. Epub 2021 Oct 12.

Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom of Great Britain and Northern Ireland.

Introduction: Haemorrhage and venous thromboembolism (VTE) are recognised complications of chronic liver disease (CLD), but their prevalence and risk factors in critically ill patients is uncertain.

Patients And Methods: We studied a retrospective cohort of patients with CLD non-electively admitted to a specialist intensive care unit determining the prevalence and timing of major bleeding and VTE (early, present on admission/diagnosed within 48h; later diagnosed >48h post ICU admission). Associations with baseline clinical and laboratory characteristics, multi-organ failure (MOF), blood product administration and mortality were explored. Odds ratios (OR) and 95% CIs were calculated using logistic regression.

Results: Of 623 patients with median age 52, bleeding (>48 hours after admission) occurred in 87 (14%) patients. Bleeding was associated with greater illness severity and increased mortality. Gastrointestinal bleeding accounted for 72% of events, secondary to portal hypertension in >90%. Procedure-related bleeding was uncommon. VTE occurred in 125 (20%) patients: Early VTE in 80 (13%) and involving the portal vein (PVT) in 85%. Later VTE affected 45 (7.2%) patients. Hepatocellular Carcinoma (HCC) and non-alcoholic liver disease were independently associated with early VTE (OR 2.79, (95% CI 1.5 -5.2) and 2.32, (1.4 -3.9) respectively), and HCC, sepsis and cryoprecipitate use with late VTE (OR 2.45, (1.11-5.43), 2.26 (1.2-4.3) and 2.60 (1.3-5.1).

Conclusion: VTE was prevalent on admission to critical care and less commonly developed later. Bleeding was associated with MOF and increased mortality. Severe MOF was not associated with an increased rate of VTE which was linked with HCC, and specific etiologies of CLD.
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http://dx.doi.org/10.1055/a-1667-7293DOI Listing
October 2021

Effectiveness of SARS-Cov-2 vaccination in liver transplanted patients: time for comprehensive data analysis.

J Hepatol 2021 Oct 8. Epub 2021 Oct 8.

Organ Transplantation Unit, Division of Surgery, Tel-Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Liver Unit, Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

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http://dx.doi.org/10.1016/j.jhep.2021.09.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498774PMC
October 2021

Kidney transplant recipients vaccinated before transplantation maintain superior humoral response to SARS-CoV-2 vaccine.

Clin Transplant 2021 Sep 10:e14478. Epub 2021 Sep 10.

Organ Transplantation Unit, Tel-Aviv Medical Center Tel-Aviv, Israel and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Majority of transplant recipients did not develop an appreciable humoral response following SARS-CoV-2 vaccine, in contrast to dialysis patients and healthy individuals. We analyzed the serologic response to BNT162b2 (Pfizer-BioNTech) vaccine in a cohort of 19 kidney transplant recipients, vaccinated prior to transplantation, compare to 109 recipients vaccinated after transplantation, and to 39 healthcare workers, by determining the level of anti-spike antibodies after transplantation. All controls and 17 of 19 (90%) of recipients vaccinated before transplant were seropositive, while only 49 of 109 (45%) recipients vaccinated post-transplant had positive serology (P < .001). Median anti-spike IgG in the group of kidney transplant recipients vaccinated after transplantation (10.7 AU/ml, [IQR 0-62.5]) was lower than the patients vaccinated before transplantation (66.2 AU/ml [21.6-138]), which was significantly lower than in the controls (156 AU/ml [99.7-215.5]). Negative humoral response was associated with vaccination post transplantation (odds ratio 22.4), older age (OR = 1.04), and longer time on dialysis (OR = 1.02), while higher lymphocyte count at time of vaccination was protective (OR = .52). Our findings of sustained superior humoral response to SARS-CoV-2 vaccine in kidney transplant recipients vaccinated prior to transplantation strongly support the recommendations of SARS-CoV-2 vaccination of transplant candidates, especially those younger than 60 years.
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http://dx.doi.org/10.1111/ctr.14478DOI Listing
September 2021

Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients.

J Hepatol 2021 08 21;75(2):435-438. Epub 2021 Apr 21.

Organ Transplantation Unit, Division of Surgery, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Liver Unit, Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background & Aims: Two SARS-CoV-2 mRNA vaccines were approved to prevent COVID-19 infection, with reported vaccine efficacy of 95%. Liver transplant (LT) recipients are at risk of lower vaccine immunogenicity and were not included in the registration trials. We assessed vaccine immunogenicity and safety in this special population.

Methods: LT recipients followed at the Tel-Aviv Sourasky Medical Center and healthy volunteers were tested for SARS-CoV-2 IgG antibodies directed against the Spike-protein (S) and Nucleocapsid-protein (N) 10-20 days after receiving the second Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine dose. Information regarding vaccine side effects and clinical data was collected from patients and medical records.

Results: Eighty LT recipients were enrolled. Mean age was 60 years and 30% were female. Twenty-five healthy volunteer controls were younger (mean age 52.7 years, p = 0.013) and mostly female (68%, p = 0.002). All participants were negative for IgG N-protein serology, indicating immunity did not result from prior COVID-19 infection. All controls were positive for IgG S-protein serology. Immunogenicity among LT recipients was significantly lower with positive serology in only 47.5% (p <0.001). Antibody titer was also significantly lower in this group (mean 95.41 AU/ml vs. 200.5 AU/ml in controls, p <0.001). Predictors for negative response among LT recipients were older age, lower estimated glomerular filtration rate, and treatment with high dose steroids and mycophenolate mofetil. No serious adverse events were reported in either group.

Conclusion: LT recipients developed substantially lower immunological response to the Pfizer-BioNTech SARS-CoV-2 mRNA-based vaccine. Factors influencing serological antibody responses include age, renal function and immunosuppressive medications. The findings require re-evaluation of vaccine regimens in this population.

Lay Summary: The Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine elicited substantially inferior immunity in liver transplant recipients. Less than half of the patients developed sufficient levels of antibodies against the virus, and in those who were positive, average antibody levels were 2x less compared to healthy controls. Factors predicting non-response were older age, renal function and immunosuppressive medications.
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http://dx.doi.org/10.1016/j.jhep.2021.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058047PMC
August 2021

Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus.

Am J Transplant 2021 08 7;21(8):2719-2726. Epub 2021 May 7.

Organ Transplantation Unit, Sackler Faculty of Medicine, Tel-Aviv Medical Center, Tel-Aviv University, Tel-Aviv, Israel.

COVID-19 is associated with increased morbidity and mortality in transplant recipients. There are no efficacy data available regarding these patients with any of the available SARS-CoV-2 vaccines. We analyzed the humoral response following full vaccination with the BNT162b2 (Pfizer-BioNTech) in 136 kidney transplant recipients, and compared it to 25 controls. In order to exclude prior exposure to the virus, only participants with negative serology to SARS-CoV-2 nucleocapsid protein were included. All controls developed a positive response to spike protein, while only 51 of 136 transplant recipients (37.5%) had positive serology (p < .001). Mean IgG anti-spike level was higher in the controls (31.05 [41.8] vs. 200.5 [65.1] AU/mL, study vs. control, respectively, p < .001). Variables associated with null humoral response were older age (odds ratio 1.66 [95% confidence interval 1.17-2.69]), high-dose corticosteroids in the last 12 months (1.3 [1.09-1.86]), maintenance with triple immunosuppression (1.43 [1.06-2.15]), and regimen that includes mycophenolate (1.47 [1.26-2.27]). There was a similar rate of side effects between controls and recipients, and no correlation was found between the presence of symptoms and seroconversion. Our findings suggest that most kidney transplant recipients remain at high risk for COVID-19 despite vaccination. Further studies regarding possible measures to increase recipient's response to vaccination are required.
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http://dx.doi.org/10.1111/ajt.16615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250589PMC
August 2021

Nutritional Evaluation and Treatment of the Cirrhotic Patient.

Clin Liver Dis 2021 05;25(2):373-392

Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, 6 Weizmann Street, Tel Aviv 6423906, Israel; Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 39040, Tel Aviv 6997801, Israel.

Malnutrition and sarcopenia that lead to functional deterioration, frailty, and increased risk for complications and mortality are common in cirrhosis. Sarcopenic obesity, which is associated with worse outcomes than either condition alone, may be overlooked. Lifestyle intervention aiming for moderate weight reduction can be offered to obese compensated cirrhotic patients, with diet consisting of reduced caloric intake, achieved by reduction of carbohydrate and fat intake, while maintaining high protein intake. Dietary and moderate exercise interventions in patients with cirrhosis are beneficial. Cirrhotic patients with malnutrition should have nutritional counseling, and all patients should be encouraged to avoid a sedentary lifestyle.
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http://dx.doi.org/10.1016/j.cld.2021.01.007DOI Listing
May 2021

Hepatitis C related cognitive impairment: Impact of viral and host factors and response to therapy.

J Viral Hepat 2021 06 8;28(6):870-877. Epub 2021 Mar 8.

Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Chronic hepatitis C virus (HCV) infection is associated with cognitive impairment via several suggested mechanisms including direct neurotoxicity and minimal hepatic encephalopathy. The prevalence of HCV-related cognitive impairment and whether it is reversed by anti-viral therapy is unknown. We aimed to assess predictors and reversibility of cognitive impairment of HCV-infected patients after successful treatment. Consecutive HCV patients treated during the EMERALD study (AbbVie 3D regimen for protease inhibitors failure) underwent neuropsychological (number connection test A [NCTA] and digital symbol test [DST]) and neurophysiological (critical flicker frequency [CFF]) tests at baseline and at 12 weeks post-treatment. Patient self-reported outcomes (PROs) were prospectively collected. Patients with a history of hepatic encephalopathy were excluded. Thirty-two patients underwent the cognitive tests at baseline. Seven of them had abnormal CFF test findings. Twenty-five (25/32, 78%) patients had repeated evaluations 3 months post-treatment. High viral loads were significantly associated with abnormal CFF across fibrosis levels (area under the ROC curve 0.817). CFF results significantly improved following viral eradication, from 40.9 (interquartile range 38.6-42.9) at baseline to 41.5 (39.8-44), p = .042, at follow-up. Both NCTA and DST results improved, but not significantly. There was improvement in the PROs of general health perception and vitality. The NCTA and DST results were more significantly associated with PROs than CFF. This prospective interventional study showed greater cognitive impairment in HCV patients with high viral load and demonstrated partial reversibility of HCV neurotoxicity and subsequent improvement in PROs following treatment.
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http://dx.doi.org/10.1111/jvh.13492DOI Listing
June 2021

Clinical features and evolution of bacterial infection-related acute-on-chronic liver failure.

J Hepatol 2021 02 8;74(2):330-339. Epub 2020 Aug 8.

Department of Internal Medicine IV, Jena University Hospital, Jena, Germany; Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.

Background & Aims: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital.

Methods: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death.

Results: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p <0.001). Spontaneous bacterial peritonitis, pneumonia or infections caused by extensively drug resistant (XDR) bacteria were more frequently associated with ACLF development. More patients with ACLF had a positive quick sequential organ failure assessment score and septic shock, resulting in a lower infection resolution rate (all p <0.001).

Conclusions: Bacterial infections, especially with XDR organisms, are associated with the highest risk of ACLF development, accounting for almost half of cases globally. Geographic differences result in variable epidemiology and clinical outcomes.

Lay Summary: Bacterial infections can trigger a sudden deterioration in an otherwise stable cirrhotic patient, a condition known as acute-on-chronic liver failure or ACLF. This study has found that the development of ACLF following bacterial infection occurs most commonly in the Indian subcontinent and less so in Southern Europe. The common infections that can trigger ACLF include infection of the abdominal fluid, known as spontaneous bacterial peritonitis, pneumonia and by bacteria that are resistant to multiple antibiotics. Patients who develop ACLF following a bacterial infection have high death rates and are frequently unable to clear the infection.
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http://dx.doi.org/10.1016/j.jhep.2020.07.046DOI Listing
February 2021

Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay.

J Thromb Haemost 2020 04 18;18(4):834-843. Epub 2020 Feb 18.

Institute of Liver Studies, King's College Hospital, London, UK.

Background And Aims: Patients with cirrhosis have a rebalanced hemostasis, often with normal or elevated thrombin-generating (TG) capacity in plasma. Whole blood (WB) TG allows faster determination and, importantly, includes the influence of all circulating blood cells. We aimed to study the TG profile of patients with cirrhosis in WB and in platelet poor plasma.

Methods: Thrombin-generating capacity in WB and plasma were assessed with a near-patient WB-TG assay and the calibrated automated thrombinography assay, respectively. TG assays were tested in presence and absence of thrombomodulin. Conventional coagulation tests were also performed.

Results: Thirty-four patients with cirrhosis and twenty-two controls were analyzed. Compared with controls, patients had substantially deranged results in conventional coagulation tests. Comparable WB-TG capacity (endogenous thrombin potential until peak, ETPp) but significantly lower peak thrombin were found in patients, and these results persisted when thrombomodulin was present. TG of the patients was more resistant to thrombomodulin than controls in both WB and plasma, although the inhibitory effect of thrombomodulin was drastically weaker in WB than in plasma. The peak of WB-TG in patients correlated moderately with their hematocrit and platelet count. Significant correlations were found between TG results in WB and plasma.

Conclusions: The WB-TG assay shows a normal to hypocoagulable state in patients with cirrhosis with a decreased anticoagulant activity of TM compared to plasma-TG. The clinical value of this assay needs further validation.
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http://dx.doi.org/10.1111/jth.14751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186949PMC
April 2020

Chronic schistosomiasis in African immigrants in Israel: Lessons for the non-endemic setting.

Medicine (Baltimore) 2019 Dec;98(52):e18481

Sanz Medical Centre, Laniado Hospital, Netanya.

To study the clinical presentation of Chronic Schistosomiasis (CS) in immigrants from East Africa to Israel and the tests that were useful in confirming the diagnosis.A retrospective study of all medical notes pertaining to hospitalized patients who were immigrants from East Africa with a pathological or microscopic confirmation of CS. Literature review was also conducted focusing on diagnosis of schistosomiasis among immigrants from endemic countries.We identified 32 suspected and 11 confirmed cases of CS. Most of the patients (82%) presented with gastrointestinal symptoms. Sensitivity of stool smear, serology and tissue diagnosis (by histopathology or microscopy) were 14%, 100%, 89%, respectively. Patients have undergone extensive diagnostic evaluation with long hospitalization stays (median 10 days, range 4 to 33 days).CS has multiple presentations and is seen in Israel among refugees from Eritrea and Sudan. Most of the manifestations are gastrointestinal, suggestive of infection with Schistosoma mansoni (S. mansoni). Standard diagnostic techniques used in endemic countries, such as microscopy for ova and parasites were unhelpful, necessitating more advanced procedures like colonoscopic or liver biopsy. We propose a diagnostic algorithm for CS in this patient population in order to make an accurate diagnosis and avoid unnecessary invasive procedures.
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http://dx.doi.org/10.1097/MD.0000000000018481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946286PMC
December 2019

Withholding Treatment From the Dying Patient: The Influence of Medical School on Students' Attitudes.

J Bioeth Inq 2019 Jun 8;16(2):217-225. Epub 2019 Mar 8.

Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben Gurion University of the Negev, 1 Ben-Gurion Boulevard, Israel, P.O.B. 653, Beer-Sheva, Israel.

Purpose: To determine motives and attitudes towards life-sustaining treatments (LSTs) by clinical and preclinical medical students.

Methods: This was a scenario-based questionnaire that presented patients with a limited life expectancy. The survey was distributed among 455 medical students in preclinical and clinical years. Students were asked to rate their willingness to perform LSTs and rank the motives for doing so. The effect of medical education was then investigated after adjustment for age, gender, religion, religiosity, country of origin, and marital status.

Results: Preclinical students had a significantly higher willingness to perform LSTs in all cases. This was observed in all treatments offered in cases of a metastatic oncologic patient and an otherwise healthy man after a traumatic brain injury (TBI). In the case of an elderly woman on long-term care, preclinical students had higher willingness to supply vasopressors but not perform an intubation, feed with a nasogastric tube, or treat with a continuous positive air-pressure ventilator. Both preclinical and clinical students had high willingness to perform resuscitation on a twelve-year-old boy with a TBI. Differences in motivation factors were also seen.

Discussion: Preclinical students had a greater willingness to treat compared to clinical students in all cases and with most medical treatments offered. This is attributed mainly to changes along the medical curriculum. Changes in reasons for supplying LSTs were also documented.
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http://dx.doi.org/10.1007/s11673-019-09897-2DOI Listing
June 2019

Update on the management of acute liver failure.

Curr Opin Crit Care 2019 04;25(2):157-164

Liver Intensive Therapy Unit, Institute of Liver Studies, King's College Hospital, Denmark Hill, London, UK.

Purpose Of Review: This review describes the current intensive care management of acute liver failure (ALF) and the latest evidence for emerging therapies.

Recent Findings: Mortality from ALF continues to improve and in some cases, medical therapy can negate the need for liver transplantation because of protocolized management in specialist centres. Liver transplantation remains the cornerstone of management for poor prognosis ALF. The reduced use of blood products in ALF reflects growing evidence of balanced haemostasis in severe liver disease. Prophylactic therapeutic hypothermia is no longer recommended for neuroprotection. In cases not suitable for liver transplantation, high-volume plasma exchange (HVP) has potential benefit, although further research on the optimal timing and dosing is needed. Although sepsis remains an important complication in ALF, the use of prophylactic antimicrobials is being questioned in the era of emerging bacterial resistance.

Summary: ICU management of ALF has improved such that liver transplantation is not required in some cases. HVP has emerged as a potential therapy for patients who may not be good liver transplantation candidates. Nevertheless in suitable patients with poor prognosis liver transplantation remains the optimal therapy.
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http://dx.doi.org/10.1097/MCC.0000000000000583DOI Listing
April 2019

Epidemiology and Effects of Bacterial Infections in Patients With Cirrhosis Worldwide.

Gastroenterology 2019 Apr 13;156(5):1368-1380.e10. Epub 2018 Dec 13.

Division of Gastroenterology/Hepatology, University of Miami, Miami, Florida.

Background & Aims: Bacterial infections are common and life-threatening in patients with cirrhosis. Little is known about the epidemiology of bacterial infections in different regions. We performed a multicenter prospective intercontinental study to assess the prevalence and outcomes of bacterial and fungal infections in patients with cirrhosis.

Methods: We collected data from 1302 hospitalized patients with cirrhosis and bacterial or fungal infections at 46 centers (15 in Asia, 15 in Europe, 11 in South America, and 5 in North America) from October 2015 through September 2016. We obtained demographic, clinical, microbiology, and treatment data at time of diagnosis of infection and during hospitalization. Patients were followed until death, liver transplantation, or discharge.

Results: The global prevalence of multidrug-resistant (MDR) bacteria was 34% (95% confidence interval 31%-37%). The prevalence of MDR bacteria differed significantly among geographic areas, with the greatest prevalence in Asia. Independent risk factors for infection with MDR bacteria were infection in Asia (particularly in India), use of antibiotics in the 3 months before hospitalization, prior health care exposure, and site of infection. Infections caused by MDR bacteria were associated with a lower rate of resolution of infection, a higher incidence of shock and new organ failures, and higher in-hospital mortality than those caused by non-MDR bacteria. Administration of adequate empirical antibiotic treatment was independently associated with improved in-hospital and 28-day survival.

Conclusions: In a worldwide study of hospitalized patients, we found a high prevalence of infection with MDR bacteria in patients with cirrhosis. Differences in the prevalence of MDR bacterial infections in different global regions indicate the need for different empirical antibiotic strategies in different continents and countries. While we await new antibiotics, effort should be made to decrease the spread of MDR bacteria in patients with cirrhosis.
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http://dx.doi.org/10.1053/j.gastro.2018.12.005DOI Listing
April 2019

Clinical management of acute liver failure: Results of an international multi-center survey.

World J Gastroenterol 2016 Sep;22(33):7595-603

Liane Rabinowich, Oren Shibolet, Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center and Tel-Aviv University, Tel-Aviv 64239, Israel.

Aim: To assess the practice of caring for acute liver failure (ALF) patients in varying geographic locations and medical centers.

Methods: Members of the European Acute Liver Failure Consortium completed an 88-item questionnaire detailing management of ALF. Responses from 22 transplantation centers in 11 countries were analyzed, treating between 300 and 500 ALF cases and performing over 100 liver transplants (LT) for ALF annually. The questions pertained to details of the institution and their clinical activity, standards of care, referral and admission, ward- based care versus intensive care unit (ICU) as well as questions regarding liver transplantation - including criteria, limitations, and perceived performance. Clinical data was also collected from 13 centres over a 3 mo period.

Results: The interval between referral and admission of ALF patients to specialized units was usually less than 24 h and once admitted, treatment was provided by a multidisciplinary team. Principles of care of patients with ALF were similar among centers, particularly in relation to recognition of severity and care of the more critically ill. Centers exhibited similarities in thresholds for ICU admission and management of severe hepatic encephalopathy. Over 80% of centers administered n-acetyl-cysteine to ICU patients for non-paracetamol-related ALF. There was significant divergence in the use of prophylactic antibiotics and anti-fungals, lactulose, nutritional support and imaging investigations in admitted patients and in the monitoring and treatment of intra-cranial pressure (ICP). ICP monitoring was employed in 12 centers, with the most common indications being papilledema and renal failure. Most patients listed for transplantation underwent surgery within an average waiting time of 1-2 d. Over a period of 3 mo clinical data from 85 ALF patients was collected. Overall patient survival at 90-d was 76%. Thirty six percent of patients underwent emergency LT, with a 90% post transplant survival to hospital discharge, 42% survived with medical management alone.

Conclusion: Alongside similarities in principles of care of ALF patients, major areas of divergence were present in key areas of diagnosis, monitoring, treatment and decision to transplant.
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http://dx.doi.org/10.3748/wjg.v22.i33.7595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011673PMC
September 2016

Response to The relationship between serum uric acid levels and NAFLD.

Liver Int 2016 05;36(5):769-70

Medical Division, Maccabi Healthcare Services, Tel Aviv, Israel.

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http://dx.doi.org/10.1111/liv.13101DOI Listing
May 2016

Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease.

Biomed Res Int 2015 26;2015:168905. Epub 2015 Jul 26.

Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center, 6423906 Tel Aviv, Israel.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI). The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial β-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.
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http://dx.doi.org/10.1155/2015/168905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529891PMC
May 2016

The association between the serum levels of uric acid and alanine aminotransferase in a population-based cohort.

Liver Int 2015 Nov 23;35(11):2408-15. Epub 2015 Apr 23.

Medical Division, Maccabi Healthcare Services, Tel Aviv, Israel.

Background & Aims: Elevated serum uric acid levels reflect and also cause both oxidative stress and insulin resistance and are frequently observed in patients with the metabolic syndrome. A strong association exists between the metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Therefore, we aimed to test the association between uric acid and elevated alanine aminotransferase (ALT), as a surrogate for NAFLD, using real-world data.

Methods: Data used for the cross-sectional study were obtained from Maccabi Healthcare System, a 2-million member health maintenance organization in Israel. The population consisted of individuals aged 20-60 years who underwent blood tests for ALT and uric acid between 1997 and 2012. Individuals with secondary liver disease, celiac, and inflammatory bowel-disease were excluded. Subgroup analysis was performed in subjects who were given the diagnosis of fatty liver in their medical records (n = 2628).

Results: The study population included 82,608 people (32.5% men, mean age 43.91 ± 10.15 years). There was a significant positive dose-response association between serum uric acid levels and the rate of elevated serum ALT (P for trend <0.001). In multivariable model, controlling for potential confounders, the association between uric acid and elevated ALT persisted (OR = 2.10, 95% CI 1.93-2.29, for the fourth quartile vs. the first). This association was maintained in all categories of gender and BMI. Similar results were observed among patients diagnosed with fatty liver (OR = 1.77, 1.22-2.57).

Conclusions: Serum uric acid is independently associated with elevated ALT, as a surrogate for NAFLD, and thus may serve as a serum marker for liver damage and should be further investigated as a risk factor for NAFLD.
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http://dx.doi.org/10.1111/liv.12842DOI Listing
November 2015

Sortilin deficiency improves the metabolic phenotype and reduces hepatic steatosis of mice subjected to diet-induced obesity.

J Hepatol 2015 Jan 27;62(1):175-81. Epub 2014 Aug 27.

The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address:

Background & Aims: Sortilin traffics newly synthesized molecules from the trans-Golgi apparatus along secretory pathways to endosomes, lysosomes or to the cell surface. Sortilin trafficking of acid sphingomyelinase (aSMase) may regulate ceramide levels, a major modulator of insulin signalling. We therefore tested whether sortilin deficiency reduces hepatic and adipose tissue aSMase activity, improving insulin sensitivity in diet-induced obesity (DIO).

Methods: DIO in C57BL/6 (WT) and sortilin(-/-) mice was induced by high-fat diet feeding for 10 weeks.

Results: Sortilin(-/-) mice gained less body weight and less visceral fat, despite similar food intake compared to WT type mice and had enhanced glucose uptake in insulin tolerance tests, which was further corroborated by enhanced hepatic pAkt expression. Sortilin deficiency led to attenuated hepatic steatosis, reduced expression of genes involved in lipogenesis, ceramide synthesis and inflammatory cytokine production and reduced activity of ceramide synthase 5/6 (CerS5/6). Sortilin(-/-) mice had reduced hepatic aSMase activity under both steady-state and DIO. Likewise, sortilin(-/-) hepatocytes displayed hypersensitivity to insulin, due to enhanced insulin receptor downstream signalling. In adipose tissue, sortilin(-/-) mice exhibited lower expression of inflammatory cytokines and lower expression and activity of CerS5/6. As in liver, adipose tissue displayed increased insulin signalling, accompanied by attenuated aSMase activity.

Conclusions: Sortilin deficiency induces a beneficial metabolic phenotype in liver and adipose tissue upon DIO, mediated in part by reduced aSMase activity.
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http://dx.doi.org/10.1016/j.jhep.2014.08.030DOI Listing
January 2015

[Refractory ascites following liver transplantation caused by an anastomotic stricture of the portal vein].

Harefuah 2012 Dec;151(12):667-70, 722

Liver Unit, Department of Gastroenterology and Liver Disease Tel-Aviv Sourasky Medical Center and the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

We present a case of a 34-year-old woman who underwent liver transplantation and developed refractory ascites. Following a prolonged work-up she was diagnosed with anastomotic site stricture of the portal vein. The patient underwent percutaneous angioplasty with balloon dilatation and stent placement, with resolution of the ascites. We review the literature and discuss the etiology of posttransplant refractory ascites and its treatment.
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December 2012

Adherence to statins is associated with reduced incidence of idiopathic venous thromboembolism: real-life data from a large healthcare maintenance organisation.

Heart 2012 Dec 4;98(24):1817-21. Epub 2012 Oct 4.

Department of Internal Medicince 'D' and 'E", Tel-Aviv Sourasky Medical Center, Tel-Aviv University, Tel-Aviv, Israel.

Objective: Previous reports on the association between statin use and venous thromboembolism (VTE) did not examine patient adherence to medications, thus their applicability in a real life setting is questionable. Our objective was to investigate the association between the use of statins and incidence of first ever idiopathic VTE.

Design: A retrospective cohort study.

Settings: A large healthcare maintenance organisation.

Patients: Included were statin initiators aged 30 years or older since 2003 who did not have a statin prescription for at least 4 years before that and had at least 18 months follow-up. Excluded were patients with known risk factors for VTE. End of follow-up was defined as the first of the following: leaving Maccabi Healthcare Services, death, VTE or October 27, 2010.

Interventions: Prescription drug purchase data was analysed in order to evaluate the association between statin use and adherence and between VTE prevention.

Main Outcome Measures: VTE diagnosis during follow-up.

Results: The study population included 127 822 subjects (53 618 females). The follow-up period was comprised of 594 190 patient years, and included 1375 VTE cases and 5-year cumulative incidence rate of 1.15%. Cox regression analysis demonstrated a significantly lower VTE risk of 19% and 22% in the more adherent patient groups, compared to the risk for the lowest adherence group. The simvastatin dose, the most frequently prescribed statin, was negatively associated with the risk of VTE.

Conclusions: In a real life healthcare maintenance organisation setting, better adherence to statins is associated with a reduced risk of first ever idiopathic VTE events.
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http://dx.doi.org/10.1136/heartjnl-2012-302906DOI Listing
December 2012

Dipeptidyl peptidase 4-deficient rats have improved bile secretory function in high fat diet-induced steatosis.

Dig Dis Sci 2013 Jan 24;58(1):172-8. Epub 2012 Aug 24.

The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.

Background/aims: Rodent obesity models have been shown to display impaired bile secretory functions. We have shown that glucagon-like peptide 1 (GLP-1) attenuates hepatic lipogenesis, and in the present study we investigated whether GLP-1 also improves high fat diet-associated cholestatic injury.

Methods: Wild type (WT) and dipeptidyl peptidase 4-deficient rats (DPP4-) with chronic elevated serum levels of active GLP-1 were fed regular chow and a Western diet for 2 months. Primary hepatocytes were used to assess GLP-1 effects on mRNA expression and transcription of genes encoding bile acid synthesis enzymes and transporters.

Results: DPP4- exhibited attenuated liver injury as expressed by lower serum AST and ALT after 2 months of a Western diet. In addition, DPP4- had better insulin sensitivity, lower serum triglycerides, cholesterol and bile acids. Hepatic expression of cyp7A1, the rate limiting enzyme in conversion of cholesterol into bile acids, was strongly attenuated in DPP4- fed with a Western diet. Moreover, hepatic expression of bile transporter, ABCB11, was increased, facilitating a higher rate of bile secretion. Mechanistically, we showed that GLP-1 directly reduced basal and LXR-induced cyp7A1 mRNA expression and suppressed cyp7A1 transcription in transient transfection assays in primary hepatocytes. However, GLP-1 and its analog exendin 4 also induced mRNA expression of bile acid transporter ABCC3 in primary rat hepatocyte cultures.

Conclusions: Our data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function.
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http://dx.doi.org/10.1007/s10620-012-2353-7DOI Listing
January 2013

Mycophenolic acid suppresses human pterygium and normal tenon fibroblast proliferation in vitro.

Br J Ophthalmol 2010 Oct 23;94(10):1373-7. Epub 2010 Aug 23.

Department of Ophthalmology, Hadassah University Hospital, Jerusalem, Israel.

Aims: To investigate whether mycophenolic acid (MPA) exerts antifibrotic effects on pterygium fibroblasts (PFB) with and without stimulation with fibrogenic cytokines, and to compare the efficacy of MPA with mitomycin (MMC) and dexamethasone (DXM) on PFB and tenon fibroblasts (TFB).

Methods: TFB and PFB were obtained from tissue explants during strabismus or pterygium surgery. Proliferation of subconfluent fibroblasts ± basic fibroblast growth factor (bFGF) (10 ng/ml) was assessed by using the (3H) thymidine-incorporation assay. Cell cultures were incubated with MPA, MMC or DXM. Apoptosis was evaluated by quantifying Annexin V and propidium iodide positive cells with flow cytometry.

Results: MPA showed a concentration-dependent inhibition of proliferation of PFB ± bFGF as well as TFB ± bFGF. The antiproliferative effect of MPA was comparable with that of MMC and DXM. Short exposure of PFB to MPA under profibrogenic conditions was significantly inhibitory. No apoptotic effect was found on TFB.

Conclusions: MPA suppressed tenon and pterygium fibroblast proliferation in vitro under basal and profibrogenic conditions. It was comparable with MMC under long-term exposure, but MMC was more suppressive under short-term exposure. MPA may be safer than MMC due to a more specific mechanism of action and lack of cytotoxicity. Further investigation is warranted regarding MPA concentrations that will lead to a potent antiproliferative effect in vivo.
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http://dx.doi.org/10.1136/bjo.2009.177857DOI Listing
October 2010
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