Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

BACKGROUND AND AIMS: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. APPROACH AND RESULTS: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. CONCLUSIONS: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

[Use of specific antidotes in DOAC-associated severe gastrointestinal bleeding - an expert consensus - Antagonozation of direct oral anticoagulants in gastrointestinal hemorrhages]. / Einsatz von spezifischen Antidots bei DOAK-assoziierter schwerer gastrointestinaler Blutung ­ ein Expertenkonsensus.

Gastrointestinal (GI) bleeding is one of the most common complications associated with the use of direct oral anticoagulants (DOAC). Clear algorithms exist for the emergency measures in (suspected) GI bleeding, including assessing the medication history regarding anti-platelet drugs and anticoagulants as well as simple coagulation tests during pre-endoscopic management. Platelet transfusions, fresh frozen plasma (FFP), or prothrombin complex concentrate (4F-PCC) are commonly used for optimizing the coagulation status. For severe bleeding under the thrombin inhibitor dabigatran, idarucizumab is available, and for bleeding under the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa is available as specific antidotes for DOAC antagonization. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures including emergency endoscopy. Antagonization of oral anticoagulants should be considered for severe gastrointestinal bleeding in the following situations: (1) refractory hemorrhagic shock, (2) endoscopically unstoppable bleeding, or (3) nonavoidable delays until emergency endoscopy for life-threatening bleeding. After successful (endoscopic) hemostasis, anticoagulation (DOACs, vitamin K antagonist, heparin) should be resumed timely (i.e. usually within a week), taking into account individual bleeding and thromboembolic risk.

One-year follow-up of the CAPSID randomized trial for high-dose convalescent plasma in severe COVID-19 patients.

BACKGROUNDResults of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported, but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP.METHODSOf 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP donors (n = 113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTSThe median follow-up of patients was 396 days, and the estimated 1-year survival was 78.7% in the CCP group and 60.2% in the control (P = 0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared with the control group (91.5% versus 60.2%, P = 0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase in neutralizing antibodies after vaccination between the CCP and control groups.CONCLUSIONThe trial demonstrated a trend toward better outcome in the CCP group without reaching statistical significance. A predefined subgroup analysis showed a significantly better outcome (long-term survival, time to discharge from ICU, and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared with the control group. A substantial long-term disease burden remains after severe COVID-19.Trial registrationEudraCT 2020-001310-38 and ClinicalTrials.gov NCT04433910.FundingBundesministerium für Gesundheit (German Federal Ministry of Health).

Cytokine levels associated with favorable clinical outcome in the CAPSID randomized trial of convalescent plasma in patients with severe COVID-19.

Objectives: To determine the profile of cytokines in patients with severe COVID-19 who were enrolled in a trial of COVID-19 convalescent plasma (CCP). Methods: Patients were randomized to receive standard treatment and 3 CCP units or standard treatment alone (CAPSID trial, ClinicalTrials.gov NCT04433910). The primary outcome was a dichotomous composite outcome (survival and no longer severe COVID-19 on day 21). Time to clinical improvement was a key secondary endpoint. The concentrations of 27 cytokines were measured (baseline, day 7). We analyzed the change and the correlation between serum cytokine levels over time in different subgroups and the prediction of outcome in receiver operating characteristics (ROC) analyses and in multivariate models. Results: The majority of cytokines showed significant changes from baseline to day 7. Some were strongly correlated amongst each other (at baseline the cluster IL-1ß, IL-2, IL-6, IL-8, G-CSF, MIP-1α, the cluster PDGF-BB, RANTES or the cluster IL-4, IL-17, Eotaxin, bFGF, TNF-α). The correlation matrix substantially changed from baseline to day 7. The heatmaps of the absolute values of the correlation matrix indicated an association of CCP treatment and clinical outcome with the cytokine pattern. Low levels of IP-10, IFN-γ, MCP-1 and IL-1ß on day 0 were predictive of treatment success in a ROC analysis. In multivariate models, low levels of IL-1ß, IFN-γ and MCP-1 on day 0 were significantly associated with both treatment success and shorter time to clinical improvement. Low levels of IP-10, IL-1RA, IL-6, MCP-1 and IFN-γ on day 7 and high levels of IL-9, PDGF and RANTES on day 7 were predictive of treatment success in ROC analyses. Low levels of IP-10, MCP-1 and high levels of RANTES, on day 7 were associated with both treatment success and shorter time to clinical improvement in multivariate models. Conclusion: This analysis demonstrates a considerable dynamic of cytokines over time, which is influenced by both treatment and clinical course of COVID-19. Levels of IL-1ß and MCP-1 at baseline and MCP-1, IP-10 and RANTES on day 7 were associated with a favorable outcome across several endpoints. These cytokines should be included in future trials for further evaluation as predictive factors.

Blood-Based Targeted Metabolomics Discriminate Patients with Alcoholic Liver Cirrhosis from Those with Non-Cirrhotic Liver Damage: An Explorative Study.

BACKGROUND: Early detection of liver cirrhosis is crucial for secondary prevention of complications. However, noninvasive blood-based patient monitoring tools are lacking. In this explorative study, we conducted a targeted metabolomic analysis in order to identify possible serum markers indicating alcoholic liver cirrhosis (aLiC) with or without hepatocellular carcinoma (HCC). METHODS: Venous blood of 30 individuals was collected: healthy controls ("Con", n = 12), patients with aLiC without and with HCC ("aLiC": n = 6 and "aLiC + HCC": n = 6), and patients with other liver diseases ("oLiD": n = 6). A targeted metabolomic analysis was conducted using the AbsoluteIDQ® p180 Kit (Biocrates Life Sciences®, Innsbruck, Austria). Statistical analysis was performed by applying a one-way ANOVA on all subgroups followed by a t test for pairwise comparison of subgroups and logistic regression analysis. RESULTS: ANOVA revealed 29 metabolites that significantly discriminate between the different cohorts. Among these analytes, 25 were significantly altered in Con versus aLiC, as indicated by t test, most importantly SM C18:1 (p < 0.001), SM C20:2 (p = 0.001), SM (OH) C22:2 (p < 0.001), lysoPC a C20:4 (p < 0.001), and PC aa C36:5 (p < 0.001). To a similar extent, the metabolites discriminated also between the oLiD and aLiC but less between the Con or oLiD and aLiC + HCC cohorts. Most of these analytes were either lyso- and phosphatidylcholines or sphingomyelins. Results were not significant for comparison of Con versus oLiD and aLiC versus aLiC + HCC. CONCLUSION: Decreased lyso- and phosphatidylcholine as well as sphingomyelin species in venous blood could help to detect liver cirrhosis in patients with non-cirrhotic liver disease.

Results of the CAPSID randomized trial for high-dose convalescent plasma in patients with severe COVID-19.

BACKGROUNDCOVID-19 convalescent plasma (CCP) has been considered a treatment option for COVID-19. This trial assessed the efficacy of a neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment.METHODSPatients (n = 105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21.ResultsThe primary outcome occurred in 43.4% of patients in the CCP group and 32.7% in the control group (P = 0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (P = 0.27). The median time to discharge from the hospital was 31 days in the CCP group and 51 days in the control group (P = 0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies, the primary outcome occurred in 56.0% of the patients (vs. 32.1%), with significantly shorter intervals to clinical improvement (20 vs. 66 days, P < 0.05) and to hospital discharge (21 vs. 51 days, P = 0.03) and better survival (day-60 probability of survival 91.6% vs. 68.1%, P = 0.02) in comparison with the control group.ConclusionCCP added to standard treatment was not associated with a significant improvement in the primary and secondary outcomes. A predefined subgroup analysis showed a significant benefit of CCP among patients who received a larger amount of neutralizing antibodies.Trial registrationClinicalTrials.gov NCT04433910.FundingBundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802.

Effect of ET-A blockade on portal pressure and hepatic arterial perfusion in patients with cirrhosis: A proof of concept study.

BACKGROUND/AIM: Endothelin causes vasoconstriction via the endothelin-A receptor (ET-A) in the intrahepatic circulation in cirrhosis and its increase leads to portal hypertension. The aim of the study was to investigate the acute effect of a selective ET-A antagonist in patients with portal hypertension and cirrhosis. METHODS: Proof-of-concept study with two different substudies: (a) local intrahepatic administration of the ET-A antagonist BQ 123 and (b) systemic oral administration of the ET-A antagonist Ambrisentan. Portal pressure was determined by hepatic venous pressure gradient (HVPG, both substudies) and hepatic arterial blood flow (HABF) by intra-arterial Doppler measurements (substudy 1) before and under the ET-A antagonist. Systemic haemodynamic parameters were measured in substudy 2. RESULTS: Twelve patients (Child-Pugh [CP] B/C n = 7/5) were included in substudy 1 and 14 patients (CP A/B/C n = 4/6/4) in substudy 2. The relative decrease in HVPG was -12.5% (IQR: -40% to 0%; P = .05) in substudy 1 and -5.0% (IQR: -11.5% to 0%; P = .01) in substudy 2. Substudy 1 revealed higher decrease in HVPG in CP B patients. HABF increased significantly and patients without portal pressure decrease showed a higher increase of HABF. Substudy 2 showed a slight decrease in the mean arterial pressure without changes of other systemic haemodynamic parameters. CONCLUSION: Administration of a selective ET-A antagonist decreases the portal pressure in cirrhotic patients. This decrease was higher in CP B patients and the non-responders showed a higher increase in hepatic arterial flow. Selective ET-A antagonists might be a future treatment option in patients with portal hypertension.

The Effect of Multi-Parametric Magnetic Resonance Imaging in Standard of Care for Nonalcoholic Fatty Liver Disease: Protocol for a Randomized Control Trial.

BACKGROUND: The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and the more aggressive subtype, nonalcoholic steatohepatitis (NASH), is a global public health concern. Left untreated, NAFLD/NASH can lead to cirrhosis, liver failure, and death. The current standard for diagnosing and staging liver disease is a liver biopsy, which is costly, invasive, and carries risk for the patient. Therefore, there is a growing need for a reliable, feasible, and cost-effective, noninvasive diagnostic tool for these conditions. LiverMultiScan is one such promising tool that uses multi-parametric magnetic resonance imaging (mpMRI) to characterize liver tissue and to aid in the diagnosis and monitoring of liver diseases of various etiologies. OBJECTIVE: The primary objective of this trial (RADIcAL1) is to evaluate the cost-effectiveness of the introduction of LiverMultiScan as a standardized diagnostic test for liver disease in comparison to standard care for NAFLD, in different EU territories. METHODS: RADIcAL1 is a multi-center randomized control trial with 2 arms conducted in 4 European territories (13 sites, from across Germany, Netherlands, Portugal, and the United Kingdom). In total, 1072 adult patients with suspected fatty liver disease will be randomized to be treated according to the result of the mpMRI in the intervention arm, so that further diagnostic evaluation is recommended only when values for metrics of liver fat or fibro-inflammation are elevated. Patients in the control arm will be treated as per center guidelines for standard of care. The primary outcome for this trial is to compare the difference in the proportion of patients with suspected NAFLD incurring liver-related hospital consultations or liver biopsies between the study arms, from the date of randomization to the end of the study follow-up. Secondary outcomes include patient feedback from a patient satisfaction questionnaire, at baseline and all follow-up visits to the end of the study, and time, from randomization to diagnosis by the physician, as recorded at the final follow-up visit. RESULTS: This trial is currently open for recruitment. The anticipated completion date for the study is December 2020. CONCLUSIONS: This randomized controlled trial will provide the evidence to accelerate decision making regarding the inclusion of mpMRI-based tools in existing NAFLD/NASH clinical care. RADIcAL1 is among the first and largest European health economic studies of imaging technologies for fatty liver disease. Strengths of the trial include a high-quality research design and an in-depth assessment of the implementation of the cost-effectiveness of the mpMRI diagnostic. If effective, the trial may highlight the health economic burden on tertiary-referral hepatology clinics imposed by unnecessary consultations and invasive diagnostic investigations, and demonstrate that including LiverMultiScan as a NAFLD diagnostic test may be cost-effective compared to liver-related hospital consultations or liver biopsies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03289897 https://clinicaltrials.gov/ct2/show/NCT03289897. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/19189.

[Updated S2k-Guideline "Complications of liver cirrhosis". German Society of Gastroenterology (DGVS)]. / Aktualisierte S2k-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) "Komplikationen der Leberzirrhose".

This guideline provides evidence-based key recommendations for diagnosis and therapy of complications of liver cirrhosis and upgrades the 2011 version. An interdisciplinary team of medical experts and patient support groups developed the guideline following the AWMF recommendations for evidence based consensus guidelines. New chapters concerning diagnosis and therapy of hepatic encephalopathy were added.

Early Detection of Colorectal Cancer: a Multi-Center Pre-Clinical Case Cohort Study for Validation of a Combined DNA Stool Test.

BACKGROUND: Although colonoscopy-based screening has proven to be highly effective in detecting colorectal cancer (CRC), participation rates remain disappointing. Development of CRC is associated with a number of genetic or somatic mutations. New, non-invasive stool tests are currently being developed based on the detection of these alterations. We investigated if a non-invasive stool assay can offer sufficient sensitivity and specificity to supplement colonoscopy-based screening. METHODS: We compared a combined stool assay, which incorporates fecal occult blood testing (FOBT), quantification of human DNA (hDNA) as well as detection of genetic mutations of KRAS and BRAF (Combined DNA stool assay), with commercially available FOBT and M2-PK tests in a multi-centric six-armed pre-clinical case cohort study. Seven hundred thirty-four patients were recruited prior to elective/screening colonoscopy or prior to surgery in case of a recent CRC diagnosis. According to clinical assessment and colonoscopy/histology results, the following groups were assigned: controls, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hyperplastic polyps, adenomas, and CRC. Finally, 566 out of 734 patients (77.1%) were screened for CRC and overall gut status via colonoscopy, FOBT, M2-PK, with combined FOBT/M2-PK and the Combined DNA stool assay as described here. RESULTS: All sensitivities and specificities are measured against histologically confirmed results by colonoscopy. Confirmed sensitivities for detecting colorectal cancer were 68% with FOBT, 83% with M2-PK, 90% with combined FOBT and M2-PK, and 85% with the Combined DNA stool assay. Specificities were 96% with FOBT, 61% with M2-PK, 62% with combined FOBT and M2-PK, and 92% with the Combined DNA stool assay in the control group with no pathological findings during colonoscopy. CONCLUSIONS: The Combined DNA stool assay detects CRC with a significantly higher Youden Index than the other reviewed non-invasive screening options. The results also suggest that the Combined DNA stool assay represents a reliable assay for detecting colorectal cancer, sufficient to be recommended as a supplement to colonoscopy screening.

Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model.

In patients, acute kidney injury (AKI) is often due to haemodynamic impairment associated with hepatic decompensation following extended liver surgery. Mesenchymal stem cells (MSCs) supported tissue protection in a variety of acute and chronic diseases, and might hence ameliorate AKI induced by extended liver resection. Here, 70% liver resection was performed in male pigs. MSCs were infused through a central venous catheter and haemodynamic parameters as well as markers of acute kidney damage were monitored under intensive care conditions for 24 h post-surgery. Cytokine profiles were established to anticipate the MSCs' potential mode of action. After extended liver resection, hyperdynamic circulation, associated with hyponatraemia, hyperkalaemia, an increase in serum aldosterone and low urine production developed. These signs of hepatorenal dysfunction and haemodynamic impairment were corrected by MSC treatment. MSCs elevated PDGF levels in the serum, possibly contributing to circulatory homeostasis. Another 14 cytokines were increased in the kidney, most of which are known to support tissue regeneration. In conclusion, MSCs supported kidney and liver function after extended liver resection. They probably acted through paracrine mechanisms improving haemodynamics and tissue homeostasis. They might thus provide a promising strategy to prevent acute kidney injury in the context of post-surgery acute liver failure.

High Prognostic Value of Mini-Laparoscopy for Advanced Liver Disease-Related Complications in Patients with HCV Infection.

BACKGROUND/AIM: The assessment of advanced chronic liver disease (ACLD) is a prerequisite for therapy and surveillance in patients with chronic hepatitis C infection. Mini-laparoscopy-assisted liver biopsies facilitate both histological and macroscopical evaluation of liver fibrosis. This study is aimed at investigating the prognostic significance of the laparoscopic assessment for the cumulative incidence of ACLD-related events. PATIENTS AND METHODS: We performed a single center, retrospective analysis of 94 patients with either macroscopically or/and microscopically assessed advanced fibrosis/cirrhosis caused by chronic hepatitis C infection. The patients' data, the respective laboratory results, and follow-up period were evaluated in the outpatient clinic. RESULTS: The group with both macro- and microscopic diagnosed ACLD showed a significantly higher number of decompensating events (n = 7) compared with the other 2 groups (n = 0 in the group with only histological and n = 1 in the group with only laparoscopic diagnosis of advanced liver disease). The results were not affected by the successful treatment of the hepatitis C virus. In the Cox-regression analysis, the spleen size (>120 mm) was significantly associated with the incidence of ACLD-related events. CONCLUSIONS: Assessment of ACLD in chronic hepatitis C by mini-laparoscopy-assisted liver biopsies may facilitate the selection of patients with a poor prognosis, irrespective of achieving a sustained virological response following treatment. Follow-up of these patients should be intensified to treat decompensation early.

Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study.

BACKGROUND & AIMS: No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib. METHODS: Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat. RESULTS: 57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival. CONCLUSIONS: The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications. LAY SUMMARY: No established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib. CLINICAL TRIAL REGISTRATION: The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.

Coffee consumption protects against progression in liver cirrhosis and increases long-term survival after liver transplantation.

BACKGROUND: Therapeutic options to treat progression of end-stage liver disease (ESLD) or improve long-term survival after liver transplantation remain scarce. We investigated the impact of coffee consumption under these conditions. METHODS: We recorded coffee consumption habits of 379 patients with ESLD awaiting liver transplantation and 260 patients after liver transplantation. Survival was analyzed based on coffee intake. RESULTS: One hundred ninety-five patients with ESLD consumed coffee on a daily basis, while 184 patients did not. Actuarial survival was impaired (P = 0.041) in non-coffee drinkers (40.4 ± 4.3 months, 95% confidence interval [CI]: 32.0-48.9) compared with coffee drinkers (54.9 ± 5.5 months, 95% CI: 44.0-65.7). In subgroup analysis, the survival of patients with alcoholic liver disease (ALD; P = 0.020) and primary sclerosing cholangitis (PSC; P = 0.017) was increased with coffee intake while unaffected in patients with chronic viral hepatitis (P = 0.517) or other liver disease entities (P = 0.652). Multivariate analysis showed that coffee consumption of PSC and ALD patients retained as an independent risk factor (odds ratio [OR]: 1.94; 95% CI: 1.15-3.28; P = 0.013) along with MELD score (OR: 1.13; 95% CI: 1.09-1.17; P = 0.000). Following liver transplantation, long-term survival was longer in coffee drinkers (coffee: 61.8 ± 2.0 months, 95% CI: 57.9-65.8) than non-drinkers (52.3 ± 3.5 months, 95% CI: 45.4-59.3; P = 0.001). CONCLUSIONS: Coffee consumption delayed disease progression in ALD and PSC patients with ESLD and increased long-term survival after liver transplantation. We conclude that regular coffee intake might be recommended for these patients.

Association of serum zinc levels with liver function and survival in patients awaiting liver transplantation.

PURPOSE: Zinc is an important trace element with catalytic and defensive functions. We assessed the impact of zinc deficiency in patients with end-stage liver disease awaiting liver transplantation. METHODS: Serum zinc levels were measured at the time of evaluation for liver transplantation (n = 368). Patients were dichotomized in two groups based on low and normal zinc serum levels. RESULTS: Serum zinc levels are tightly associated with liver function as patients with low zinc levels (n = 226) had a higher Model for End-Stage Liver Disease (MELD) score (15.0 [5.0-40.0]) than patients with normal zinc (n = 142) levels (9.0 [6.0-34.0]; p < 0.00). Multivariate analysis demonstrated that serum zinc levels function as an independent predictor of hepatic decompensation (hydropic decompensation: odds ratio [OR] 0.82; 95% confidence interval [CI] 0.70-0.96; p = 0.015; hepatic encephalopathy: OR 0.80; 95% CI 0.71-0.90; p = 0.000; spontaneous bacterial peritonitis: OR 0.85; 95% CI 0.72-1.00; p = 0.047; hepatorenal syndrome: OR 0.83; 95% CI 0.72-0.95; p = 0.011). Actuarial survival free of liver transplantation was reduced for low-zinc patients (26.7 ± 4.0 months; 95% CI 18.8-34.6) compared to patients with normal zinc levels (30.9 ± 3.0 months; 95% CI 24.9-36.9; p = 0.008). Reduction of zinc levels for patients on the transplantation list resulted in a 28.3-fold increased risk of death/liver transplantation (95% CI 3.2-244.8, p < 0.001). CONCLUSIONS: Serum zinc levels are associated with reduced survival in end-stage liver disease patients. Whether or not zinc supplementation might be beneficial for patients on a liver transplantation list requires further study.

Prevention of Rebleeding From Esophageal Varices in Patients With Cirrhosis Receiving Small-Diameter Stents Versus Hemodynamically Controlled Medical Therapy.

BACKGROUND & AIMS: Patients with cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective randomized trial to compare the prevention of rebleeding in patients given a small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. METHODS: We performed an open-label study of patients with cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were assigned randomly more than 5 days after variceal hemorrhage to groups given a small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) (8 mm; n = 90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n = 95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with an adequate reduction in HVPG (responders) remained on the drugs whereas nonresponders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary end point was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the Short Form-36 health survey) were secondary outcome measures. RESULTS: A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 years (7%) than in the medical group (26%) (P = .002). A slightly higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; P = .05). Rebleeding occurred in 6 of 23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in nonresponders who received variceal band ligation (31%) (P = .06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up evaluation, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. CONCLUSIONS: Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.