Liver transplantation for refractory hepatic hydrothorax is associated with a greater survival benefit compared to other complications of cirrhosis.

Hepatic hydrothorax (HH) is a significant complication of cirrhosis associated with increased mortality. Liver transplantation (LT) remains the best treatment modality. We aim to assess predictors of mortality and the survival benefit of LT in patients with HH. A prospectively maintained cohort of adult patients with cirrhosis, being evaluated for LT at our institution, was retrospectively reviewed from 2015 to 2020. The primary outcome was death or LT. Cox proportional hazard regression identified associations between covariates and death. We calculated the years saved due to LT by comparing patients who were on the waiting list with patients who received an LT. This was done by calculating the area under the Kaplan-Meier curve. Censoring occurred at the time of the last follow-up or death. Patients with refractory HH had the lowest median survival of only 0.26 years. Within the HH group, having a refractory HH group was significantly associated with an increased risk of mortality (HR 1.73; 95% CI 1.06-2.81; p -value 0.03). Refractory HH was also significantly associated with mortality when evaluated in the entire cohort and after adjusting for other covariates (HR 1.48, 95% CI 1.03-2.11; p -value 0.03). Patients with refractory HH had the highest 1-year survival benefit with LT (0.48 y), followed by patients with non-refractory HH (0.28 y), then patients with other complications of cirrhosis (0.19 y). In this large study evaluating the prognostic impact of HH on patients with cirrhosis, refractory HH was an independent predictor of mortality. LT provides an additional survival benefit to patients with HH compared with those without HH.

Hepatic hydrothorax is not associated with increased complications or poor survival after liver transplantation.

BACKGROUND: Hepatic hydrothorax (HH) is associated with a poor prognosis. Liver transplant (LT) is the best treatment modality. We aim to assess post-LT morbidity and mortality in patients with cirrhosis and HH. RESEARCH DESIGN AND METHODS: Adult patients with cirrhosis, who underwent LT at our institution from 2015 to 2020, were retrospectively reviewed. Baseline data was obtained at the time of LT. Patients were followed from baseline until the last follow-up or death. Censoring occurred at the time of the last follow-up or death, whichever occurred earlier. Cumulative incidence of outcomes was determined by the Kaplan-Meier method. Short-term post-operative complications were compared between both groups as well. RESULTS: 428 patients had a LT, of which 72 (16.8%) had HH. Most of the baseline characteristics were similar between patients with and without HH; however, patients in the HH group had a higher proportion of pre-operative history of ascites and hepatic encephalopathy. Pre-operative HH was not significantly associated with post-LT mortality (Hazard ratio 1.12, 95% confidence interval 0.54-2.32; P-value 0.76). Patients had similar short-term post-operative complications between both groups. CONCLUSIONS: LT is an excellent therapeutic option for patients with cirrhosis and HH, with excellent long-term survival without increased morbidity.

Refractory Hepatic Hydrothorax Is an Independent Predictor of Mortality When Compared to Refractory Ascites.

BACKGROUND: Hepatic hydrothorax (HHT) is an uncommon but significant complication of cirrhosis and portal hypertension, associated with a worse prognosis and mortality. Nearly 25% of patients with HHT will have refractory pleural effusion. It is unclear if refractory HHT has a different prognosis compared to refractory ascites. AIMS: We aim to evaluate the prognostic significance of refractory HHT when compared to refractory ascites. METHODS: Forty-seven patients who had refractory HHT in a tertiary care center were identified, and matched, retrospectively, one-to-one by age, gender and MELD-Na with 47 patients with refractory ascites. One-year mortality rate was compared between both groups. Cox proportional hazard regression was used to identify the association between different covariates and primary endpoint. RESULTS: The 1-year mortality was 51.06% in the HHT group compared to 19.15% in the refractory ascites group. The median survival for patients with refractory hepatic hydrothorax was 4.87 months while the median survival for patients with refractory ascites exceeded 1 year. The presence of HHT was statistically significant in predicting the development of 1-year mortality [Hazard Ratio (HR) 4.45, 95% Confidence Interval (CI) 2.25-8.82; P value < 0.001]. Furthermore, refractory HHT remained associated with one-year mortality after adjusting for all other covariates. In a subgroup of patients with MELD-Na ≤ 20, HHT continued to be a significant predictor of one-year mortality (HR 3.30, 95% CI 1.47-7.40; P value 0.004). CONCLUSIONS: Refractory HHT is a significant independent predictor of mortality and offers additional prognostic value.

Spontaneous bacterial empyema: a tertiary care center experience and a systematic review.

BACKGROUND: Spontaneous bacterial empyema (SBE) is an infection of a preexisting hepatic hydrothorax (HH). We aim to describe the experience in managing SBE in a liver transplant (LT) referral center and assessing the incidence and mortality rates of SBE after conducting a systematic review. METHODS: 992 patients with cirrhosis were retrospectively reviewed from 2015 to 2020. SBE was diagnosed by (i) positive microbiological culture and polymorphonuclear leukocyte count >250 cells/µL or (ii) negative microbiological culture, compatible clinical course, and polymorphonuclear count >500 cells/µL in pleural fluid. Furthermore, we conducted a comprehensive literature search of MEDLINE, EMBASE, and Google Scholar for studies evaluating SBE. RESULTS: Twelve patients (10.4%) had spontaneous bacterial empyema out of 115 patients with HH. Five patients underwent LT, 6 had died, and 1 did not get transplanted and was alive throughout the duration of follow-up. Ten studies were included in the systematic review. Pooled incidence in patients with HH was 19.03%. Only 20.69% of the patients received a LT. Pooled mortality rate was 46.45%, with only 3.45% of the patients dying post-transplant. CONCLUSION: SBE is a severe complication of cirrhosis and HH. LT may provide a survival benefit. Thus, patients should be considered for early transplant.

Probiotics in Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Cirrhosis.

With the growing epidemic of obesity, the incidence of both nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH) is increasing. The intestinal microbiota differs between individuals who are obese or have normal body mass indices. Animal studies have shown increased intestinal permeability in NAFL, NASH, and cirrhosis. This increases the risk of oxidative and inflammatory injury to the liver from intestinal microbacteria. It may also increase the risk of fatty acid injury and fatty deposition. Bacterial translocation is associated with increased portal hypertension and hepatic encephalopathy in cirrhosis. By preventing bacterial adhesion and translocation, probiotics may have a role in the management of patients with NAFL, NASH, and cirrhosis. Multiple small studies have suggested that probiotics improve some of the clinical markers of activity in patients with NAFL and NASH. Controlled studies have also shown improved outcomes in patients with cirrhosis who were treated with probiotics.

Recommendations for Probiotic Use--2015 Update: Proceedings and Consensus Opinion.

This paper describes the consensus opinion of the participants in the 4th Triennial Yale/Harvard Workshop on Probiotic Recommendations. The recommendations update those of the first 3 meetings that were published in 2006, 2008, and 2011. Recommendations for the use of probiotics in necrotizing enterocolitis, childhood diarrhea, inflammatory bowel disease, irritable bowel syndrome and Clostridium difficile diarrhea are reviewed. In addition, we have added recommendations for liver disease for the first time. As in previous publications, the recommendations are given as A, B, or C ratings.

ST Elevation Myocardial Infarction Mortality Among Patients With Liver Cirrhosis: A Nationwide Analysis Across a Decade.

BACKGROUND: Mortality from ST elevation myocardial infarction (STEMI) is decreasing nationwide, but no report to date examined STEMI mortality among patients with cirrhosis. GOALS: Determine mortality rates and investigate possible disparities in cardiovascular interventions for patients with and without cirrhosis admitted with STEMI across a decade using a national database. STUDY: We included all urgent/emergent admissions with STEMI to acute care hospitals across the United States in 1999 and 2009. Exclusion criteria were age less than 18 years or prior liver transplantation. Confounders were accounted for using multivariable regression analyses. RESULTS: A total of 325,857 and 182,491 patients with STEMI were included in 1999 and 2009, respectively, 741 and 541 of whom had cirrhosis, respectively. In-hospital mortality rate was 31% and 11% for patients with and without cirrhosis in 1999, and 17% and 9% in 2009. The adjusted mortality odds ratio was 2.54 (1.52 to 4.24) in 1999 and 1.45 (0.73 to 2.86) in 2009. Stent placement rate was 11% and 26% for patients with and without cirrhosis in 1999, and increased to 47% and 61% in 2009, respectively. Thrombolytic medication injection rate was 3% and 10% for patients with and without cirrhosis in 1999, and 0% and 2% in 2009, respectively. Coronary artery bypass graft surgery rate was 3% and 9% for patients with and without cirrhosis in 1999, and was 6% and 7% in 2009, respectively. CONCLUSIONS: STEMI mortality in patients with cirrhosis is higher compared with patients without cirrhosis. However, this mortality difference declined from 1999 to 2009, likely because of higher coronary artery stent utilization for patients with cirrhosis.

Statin use in patients with cirrhosis: a retrospective cohort study.

BACKGROUND: Statins reduce cardiovascular risk. Patients with cirrhosis have decreased hepatic clearance of statins and potentially increased risk for complications. No studies assess mortality in patients with biopsy-confirmed cirrhosis. AIM: Compare mortality in patients with cirrhosis on statins to those not on statins. METHODS: A retrospective cohort study evaluated patients from 1988 to 2011 at Partners Healthcare Hospitals. The Partners Research Patient Data Registry identified patients with biopsy-proven cirrhosis on statins at biopsy and at least 3 months following. Controls were matched 1:2 by age, gender and Child-Pugh class. Decompensation was defined as ascites, jaundice/bilirubin >2.5 mg/dL, and/or hepatic encephalopathy or variceal hemorrhage. Primary outcome was mortality. Secondary outcome was decompensation in baseline-compensated patients. Chi-square and two-way ANOVA testing compared groups. Cox proportional hazards models for mortality controlled for age, Child-Pugh class, diabetes, coronary artery disease, non-alcoholic steatohepatitis and hepatocellular carcinoma. Kaplan-Meier curves graphed mortality. RESULTS: Eighty-one statin users and 162 controls were included. Median follow-up: 36 months in statin users and 30 months in controls. 70.4% of patients were Child-Pugh A. Model for End-Stage Liver Disease (MELD), albumin, varices and beta-blocker use were not significantly different between groups. Statin users had lower mortality on multivariate analysis (HR 0.53, p = 0.01), and Child-Pugh A patients had longer survival on Kaplan-Meier analysis. Cox multivariate analysis for decompensation showed lower risk of decompensation with statins while increased decompensation with low albumin, high MELD score and beta-blocker use. CONCLUSIONS: In patients with cirrhosis, statin therapy is not associated with increased mortality and may delay decompensation.

Hematologic indices improve with eradication of HCV in patients with cirrhosis and predict decompensation.

BACKGROUND: Abnormal hematological indices (HI) are common in cirrhosis from hepatitis C virus (HCV). Eradication of HCV may ameliorate these abnormalities. The objectives of the current study were to assess whether HI improve with HCV eradication and whether they can predict prognosis in patients with cirrhosis during and after completion of antiviral therapy. METHODS: A retrospective cohort study of 153 patients with HCV cirrhosis treated with Peg-interferon and ribavirin was conducted. The primary endpoint was improvement in HI after successful antiviral therapy. The secondary outcome was clinical decompensation during and after completion of antiviral therapy and association with HI. A repeated measures 2-way ANOVA was performed to compare means. Multivariate analysis was used to identify predictors of clinical decompensation. RESULTS: One hundred fifty three patients met study criteria. The rate of sustained virological rate was 26%. Median follow-up was 55 months. Platelet and WBC counts improved with HCV eradication compared to those in whom treatment was unsuccessful (p < 0.05). On univariate analysis, the presence of thrombocytopenia was associated clinical decompensation prior to, on treatment and after completion of therapy. Thrombocytopenia (OR 14.8, p-value <0.001) after completing treatment predicted clinical decompensation when controlled for albumin, MELD and age in multivariate analysis at 6 months after completion of therapy. CONCLUSIONS: Platelet and leukocyte counts improve in patients with cirrhosis who respond to antiviral therapy against HCV. The presence of thrombocytopenia predicts decompensation on treatment and after completion of therapy.

The ability of serum from alpha 1-antitrypsin-deficient patients to inhibit PRT-201, a recombinant human type I pancreatic elastase.

PRT-201 is a recombinant human pancreatic elastase under development as a treatment for blood vessels to promote hemodialysis access patency. Proteases such as elastase are normally inactivated by antiproteases such as alpha 1-antitrypsin. It is unknown if serum from patients with alpha 1-antitrypsin deficiency will inhibit PRT-201 elastase activity. An assay for PRT-201 elastase activity in the presence of serum was developed and validated. PRT-201 elastase activity inhibition curves were developed using serum and also using purified alpha 1-antitrypsin and alpha 2-macroglobulin. Serum from 15 patients with documented alpha 1-antitrypsin deficiency, some of whom were receiving alpha 1-antitrypsin augmentation therapy, and four normal volunteers was analyzed. Serum from normal volunteers and patients with alpha 1-antitrypsin deficiency completely inactivated PRT-201 elastase activity in vitro. In the alpha 1-antitrypsin-deficient patients, the volume of serum necessary to inhibit elastase activity was related to the serum concentration of alpha 1-antitrypsin and augmentation therapy. Purified alpha 1-antitrypsin and alpha 2-macroglobulin were each alone capable of completely inhibiting PRT-201 elastase activity. It is unlikely that the use of PRT-201 will be associated with negative outcomes in patients with alpha 1-antitrypsin deficiency.

Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis develop abnormal hematologic indices (HI) from multiple factors, including hypersplenism. We aimed to analyze the sequence of events and determine whether abnormal HI has prognostic significance. METHODS: We analyzed a database of 213 subjects with compensated cirrhosis without esophageal varices. Subjects were followed for approximately 9 years until the development of varices or variceal bleeding or completion of the study; 84 subjects developed varices. Abnormal HI was defined as anemia at baseline (hemoglobin, < or =13.5 g/dL for men and 11.5 g/dL for women), leukopenia (white blood cell counts, < or =4000/mm3), or thrombocytopenia (platelet counts, < or =150,000/mm3). The primary end points were death or transplant surgery. RESULTS: Most subjects had thrombocytopenia at baseline. Kaplan-Meier analysis showed that leukopenia occurred by 30 months (95% confidence interval, 18.5-53.6), and anemia occurred by 39.6 months (95% confidence interval, 24.1-49.9). Baseline thrombocytopenia (P = .0191) and leukopenia (P = .0383) were predictors of death or transplant, after adjusting for baseline hepatic venous pressure gradient (HVPG), and Child-Pugh scores. After a median of 5 years, a significant difference in death or transplant, mortality, and clinical decompensation was observed in patients who had leukopenia combined with thrombocytopenia at baseline compared with patients with normal HI (P < .0001). HVPG correlated with hemoglobin and white blood cell count (hemoglobin, r = -0.35, P < .0001; white blood cell count, r = -0.31, P < .0001). CONCLUSIONS: Thrombocytopenia is the most common and first abnormal HI to occur in patients with cirrhosis, followed by leukopenia and anemia. A combination of leukopenia and thrombocytopenia at baseline predicted increased morbidity and mortality.

Platelet count is not a predictor of the presence or development of gastroesophageal varices in cirrhosis.

UNLABELLED: Current guidelines recommend esophagogastroduodenoscopy (EGD) in patients with cirrhosis to screen for gastroesophageal varices (GEV). Thrombocytopenia has been proposed as a noninvasive test to predict the presence of GEV. There is no agreement regarding a specific platelet count (PLT) that can reliably predict GEV. The present longitudinal study aims to (1) further investigate the relationship between varices and PLT at the time of endoscopy, (2) investigate whether changes in PLT from the baseline over time can predict the development of GEV, and (3) investigate whether changes in PLT correlate with the hepatic venous pressure gradient (HVPG). A secondary analysis was conducted for 213 subjects with compensated cirrhosis with portal hypertension but without GEV enrolled in a randomized, placebo-controlled, double-blind trial of a nonselective beta-blocker used to prevent GEV. PLTs were obtained every 3 months, and HVPG measurements and EGD were done annually. The PLTs were compared between subjects who did and did not develop GEV. In a median follow-up of 54.9 months, 84 patients developed GEV. PLT was greater than 150,000 in 15% of patients at the development of GEV. A receiver operating curve did not show any PLT with high sensitivity or specificity for the presence of GEV. Subjects with clinically insignificant portal hypertension (HVPG < 10 mm Hg) whose PLT remained greater than 100,000 had a 2-fold reduction in the occurrence of GEV (P = 0.0374). A significant correlation was found between HVPG and PLT at the baseline, year 1, and year 5 (P < 0.0001). CONCLUSION: Cross-sectional or longitudinal evaluations of PLTs are inadequate noninvasive markers for GEV. Patients with mild portal hypertension whose PLT remains greater than 100,000 have significantly less risk of GEV. Although HVPG correlates somewhat with PLT, changes in PLT cannot be used as a surrogate for HVPG changes.

Fulminant hepatic failure secondary to erlotinib.

Erlotinib is a tyrosine kinase inhibitor recently approved by the Food and Drug Administration for the treatment of non-small-cell lung cancer and pancreatic cancer. We report a case of a patient with stage IV non-small-cell lung cancer who died of fulminant hepatic failure as a result of treatment with erlotinib.