Saira A. Khaderi

Long-term follow-up of portopulmonary hypertension patients after liver transplantation

Portopulmonary hypertension (POPH) occurs in 5.3% to 8.5% of patients with advanced liver disease. The rate of survival in the absence of orthotopic liver transplantation (OLT) is reportedly 38% at 3 years and 28% at 5 years. Moderate to severe POPH [mean pulmonary artery pressure (MPAP) ≥ 35 mm Hg] is associated with a perioperative mortality rate of 50%. Single‐center series have demonstrated the feasibility and short‐term efficacy of OLT after POPH is controlled with vasodilators, but long‐term outcomes have not been reported. Our aim was to determine graft and patient survival rates and the effects of OLT on pulmonary hypertension (PHT) in patients undergoing transplantation for POPH at our center. Four hundred eighty‐eight adult patients underwent transplantation between June 2004 and January 2011, and 7 underwent transplantation for POPH after their MPAP was reduced to ≤35 mm Hg with vasodilators. These 7 patients included 3 men and 4 women with ages ranging from 39 to 54 years at the time of OLT. All patients received IV EPO or inhaled EPO during the perioperative period, and all were weaned off EPO over the course of 3 days to 8 months. Both the graft and patient survival rates were 85.7% after a median follow‐up of 7.8 years. One patient had recurrent hepatitis C virus cirrhosis and recurrent POPH and died from multiorgan failure unrelated to PHT. Four of the remaining 6 patients required oral vasodilator therapy for persistent PHT. Only 2 of the 7 patients (4.4 and 8.5 years after OLT) did not have PHT. In conclusion, patients with POPH responsive to vasodilator therapy may have excellent long‐term graft and patient survival after OLT. Despite the alleviation of portal hypertension by OLT, most patients have persistent or recurrent PHT that can be controlled with oral vasodilators. Liver Transpl 20:724‐727, 2014.

Model for end‐stage liver disease limbo, model for end‐stage liver disease purgatory, and the dilemma of treating hepatitis C in patients awaiting liver transplantation

The increasing effectiveness of oral regimens to treat hepatitis C has raised questions about their role in treating patients with decompensated cirrhosis, especially those awaiting orthotopic liver transplantation (OLT). In this issue of Liver Transplantation, Modi et al. describe their experience treating patients with decompensated (Child-Pugh B or C) cirrhosis. Their results mirror those of 2 other recent articles, ie, sustained virological response (SVR) rates are fairly good, although not as good as in patients with compensated cirrhosis, and adverse events are rare. The decision to treat seems incontrovertible; hepatitis C virus (HCV) infection confers no advantage on the patient, with most patients in these 3 studies experiencing improvement in their clinical status with SVR. In addition, 2 recent reports confirm that SVR is associated with reductions in all-cause and liver-related mortality, decreased need for liver transplantation, improved portal pressure, and lower frequency of hepatocellular carcinoma (HCC). Finally, patients with hepatitis C have worse longterm outcomes after OLT when compared to matched controls, reflecting graft injury due to HCV infection. An issue is the wisdom of HCV treatment in liver transplant candidates with high Model for End-Stage Liver Disease (MELD) scores who are actively listed for OLT. Indeed, the decision to treat high-MELD patients has been cast by some as a dilemma. A number of experts have voiced concern that listed patients may improve by a few MELD points, thus falling below the range for liver transplantation while not achieving acceptable health. This situation has been termed “MELD limbo” or “MELD purgatory,” both references to Catholic doctrine. Limbo is the border between heaven and hell where souls, though not condemned to punishment, are deprived of entrance into heaven. Purgatory is an intermediate state after physical death in which souls destined for heaven undergo purification so as to achieve the holiness necessary to enter heaven. Were one to have the option, purgatory seems like a better choice. We might reasonably ask which of these options, if any, accurately describes patients who are awaiting OLT? If the threat of MELD limbo/purgatory is to be used as the rationale to withhold antiviral therapy, we must review the evidence. In the 3 trials quoted above, enrollment was based on Child-Pugh score, a valid measure of decompensated cirrhosis, but not the criterion used for organ allocation in the United States. In fact, very few patients with MELD scores over 20 were reported (4 by Modi et al. and 1 by Charlton et al.), and only 1 of the 4 with MELD > 20 in the Modi et al. article achieved SVR. Because most large centers in the United States transplant patients at MELD scores significantly above 20, published

Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma

BACKGROUND & AIMS: Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. The authors investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC. METHODS: We performed a case–control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls) from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC. RESULTS: The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% confidence interval [CI], 0.32–0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5 ± 0.9 years) vs nonusers (mean 59.2 ± 1.1 years; P = .001) and the reduced risk of HCC among long‐term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20–0.63). Users of estrogen also had a reduced risk for hepatitis‐associated HCC: AOR for users, 4.37 (95% CI, 1.67–11.44) vs AOR for nonusers, 17.60 (95% CI, 3.88–79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40–0.77; P = .01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7–41.3 months) and 24.1 months for nonusers (95% CI, 19.02–29.30 months; P = .008). CONCLUSION: In a case–control study of women with HCC vs female control subjects at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor.

Hepatitis C in the pediatric population: transmission, natural history, treatment and liver transplantation.

The number of children affected by the hepatitis C virus (HCV) in the United States is estimated to be between 23000 to 46000. The projected medical cost for children with HCV in the United States is

Survival Outcomes Following Pediatric Liver Transplantation (Pedi-SOFT) Score: A Novel Predictive Index

199-366 million over the next decade. The implementation of routine screening of blood supply has virtually eliminated transmission via transfusion and vertical transmission is now the most common mode of infection in children. Infections acquired during infancy are more likely to spontaneously resolve and fibrosis of the liver tends to increase with age suggesting slow progressive histologic injury. Anti-viral treatment may be warranted in children with persistently elevated liver enzymes or with significant fibrosis on liver biopsy. Current standard of care includes weekly pegylated interferon and ribavirin twice daily. Predictors of high sustained viral response include genotype 2 and 3 and low viral load in children with genotype 1 (< 600000 IU/mL). Phase 1 and 2 trials with triple therapy (interferon, ribavirin, and a protease inhibitor) are ongoing. Triple therapy is associated with a significantly higher rate of sustained virologic response (> 90%). Only 34 pediatric patients were transplanted with hepatitis C between January 2008 and April 2013. The majority of pediatric patients were born prior to universal screening of blood products and, as of June 2013, there are only two pediatric patients awaiting liver transplantation for end-stage liver disease secondary to hepatitis C. Pediatric survival rates post-transplant are excellent but graft survivals are noticeably reduced compared to adults (73.73% for pediatric patients at one year compared to 87.69% in adult patients). New safe and effective antiviral therapies for recurrent HCV should help increase graft survival.

Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo

A prognostic index to predict survival after liver transplantation could address several clinical needs. Here, we devised a scoring system that predicts recipient survival after pediatric liver transplantation. We used univariate and multivariate analysis on 4565 pediatric liver transplant recipients data and identified independent recipient and donor risk factors for posttransplant mortality at 3 months. Multiple imputation was used to account for missing variables. We identified five factors as significant predictors of recipient mortality after pediatric liver transplantation: two previous transplants (OR 5.88, CI 2.88–12.01), one previous transplant (OR 2.54, CI 1.75–3.68), life support (OR 3.68, CI 2.39–5.67), renal insufficiency (OR 2.66, CI 1.84–3.84), recipient weight under 6 kilograms (OR 1.67, CI 1.12–2.36) and cadaveric technical variant allograft (OR 1.38, CI 1.03–1.83). The Survival Outcomes Following Pediatric Liver Transplant score assigns weighted risk points to each of these factors in a scoring system to predict 3‐month recipient survival after liver transplantation with a C‐statistic of 0.74. Although quite accurate when compared with other posttransplant survival models, we would not advocate individual clinical application of the index.

Role of liver transplantation in the management of hepatoblastoma in the pediatric population

Background & Aims: Caspase‐mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan‐caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non‐alcoholic steatohepatitis (NASH). Methods: We performed a multicenter study of 86 patients with cirrhosis (Child‐Pugh class A or B; mean score, 6.9; 38% with alcohol‐associated cirrhosis, 29% with HCV‐associated cirrhosis, and 23% with NASH) and model for end‐stage liver disease (MELD) scores of 11–18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open‐label Emricasan (25 mg) twice‐daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK‐18) at month 3. Results: Seventy‐four patients completed the 3‐month study period (40 given Emricasan and 34 given placebo); 69 patients received open‐label Emricasan for 3 months afterward. At the 3‐month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child‐Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, –0.2882 to –0.0866) and total bilirubin (95% CI, –1.5069 to –0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child‐Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full‐length CK‐18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK‐18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasans effects were generally maintained or increased after 6 months of treatment. Conclusions: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child‐Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.