Cardiac index and hepatopulmonary syndrome in liver transplantation candidates: The pulmonary vascular complications of liver disease study.

BACKGROUND AND AIMS: Hepatopulmonary syndrome (HPS) and a hyperdynamic circulation are common complications of advanced liver disease, but the relationship between HPS and cardiac index (CI) is poorly understood. We sought to compare CI in patients with and without HPS and to assess the relationship between CI and symptoms, quality of life, gas exchange, and exercise capacity among liver transplantation (LT) candidates. We performed a cross-sectional analysis within the Pulmonary Vascular Complications of Liver Disease 2 study, a multicenter prospective cohort study of patients being evaluated for LT. We excluded patients with obstructive or restrictive lung disease, intracardiac shunting, and portopulmonary hypertension. We included 214 patients (81 with HPS and 133 controls without HPS). Compared with controls, patients with HPS had a higher CI (least square mean 3.2 L/min/m 2 , 95% CI 3.1-3.4 vs. 2.8 L/min/m 2 , 95% CI 2.7-3.0, p < 0.001) after adjustment for age, sex, Model for End-stage Liver Disease-Sodium (MELD-Na) score and beta-blocker use, and a lower systemic vascular resistance. Among all LT candidates, CI was correlated with oxygenation (Alveolar-arterial oxygen gradient r =0.27, p < 0.001), intrapulmonary vasodilatation severity ( p < 0.001), and biomarkers of angiogenesis. Higher CI was independently associated with dyspnea and worse functional class and physical quality of life after adjusting for age, sex, MELD-Na, beta-blocker use, and HPS status. HPS was associated with a higher CI among LT candidates. Independent of HPS, higher CI was associated with increased dyspnea and worse functional class, quality of life, and arterial oxygenation.

Six-Minute walk distance predicts outcomes in liver transplant candidates.

A 6-minute walk test is a simple tool for assessing submaximal exercise capacity. We sought to determine whether a 6-minute walk distance (6MWD) predicts outcomes in patients with cirrhosis. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study that enrolled adults with portal hypertension during liver transplantation evaluation. We excluded subjects with an incident or prevalent portopulmonary hypertension. The 6-minute walk test was performed using standardized methods. Cox proportional hazards modeling and multivariable linear regression analysis were performed to determine the relationship between baseline 6MWD and outcomes. The study sample included 352 subjects. The mean 6MWD was 391±101 m. For each 50-meter decrease in 6MWD, there was a 25% increase in the risk of death (HR 1.25, 95% CI [1.11, 1.41], p < 0.001) after adjustment for age, gender, body mass index, MELD-Na, and liver transplant as a time-varying covariate. In a multistate model, each 50-meter decrease in 6MWD was associated with an increased risk of death before the liver transplant ( p < 0.001) but not after the transplant. 6MWD was similar to MELD-Na in discriminating mortality. Each 50-meter decrease in 6MWD was associated with an increase in all-cause ( p < 0.001) and transplant-free hospitalizations ( p < 0.001) in multivariable models for time-to-recurrent events. Shorter 6MWD was associated with worse Short Form-36 physical ( p < 0.001) and mental component scores ( p = 0.05). In conclusion, shorter 6MWD is associated with an increased risk of death, hospitalizations, and worse quality of life in patients evaluated for liver transplantation. The 6-minute walk distance may be a useful adjunct for risk assessment in patients undergoing liver transplant evaluation.

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.

BACKGROUND: Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. METHODS: The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. RESULTS: We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) versus 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. CONCLUSION: Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Prevalence and Impact of Restrictive Lung Disease in Liver Transplant Candidates.

We investigated the prevalence of spirometric restriction in liver transplantation (LT) candidates and the clinical impacts of restriction. We performed a cross-sectional study within the Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) study, a multicenter prospective cohort study of patients being evaluated for LT. Patients with obstructive lung disease or missing spirometry or chest imaging were excluded. Patients with and without restriction, defined as a forced vital capacity (FVC) <70% predicted, were compared. Restriction prevalence was 18.4% (63/343). Higher Model for End-Stage Liver Disease-sodium score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.11; P = 0.007), the presence of pleural effusions (OR, 3.59; 95% CI, 1.96-6.58; P < 0.001), and a history of ascites (OR, 2.59; 95% CI, 1.26-5.33; P = 0.01) were associated with the presence of restriction, though one-third with restriction had neither pleural effusions nor ascites. In multivariate analysis, restriction was significantly and independently associated with lower 6-minute walk distances (least squares mean, 342.0 [95% CI, 316.6-367.4] m versus 395.7 [95% CI, 381.2-410.2] m; P < 0.001), dyspnea (OR, 2.69; 95% CI, 1.46-4.95; P = 0.002), and lower physical component summary Short Form 36 scores indicating worse quality of life (least squares mean, 34.1 [95% CI, 31.5-36.7] versus 38.2 [95% CI, 36.6-39.7]; P = 0.004). Lower FVC percent predicted was associated with an increased risk of death (hazard ratio, 1.16; 95% CI, 1.04-1.27 per 10-point decrease in FVC percent predicted; P = 0.01). Restriction and abnormal lung function are common in LT candidates; can be present in the absence of an obvious cause, such as pleural effusions or ascites; and is associated with worse exercise capacity, quality of life, and survival.

Pulse Oximetry Is Insensitive for Detection of Hepatopulmonary Syndrome in Patients Evaluated for Liver Transplantation.

Screening for hepatopulmonary syndrome (HPS) using pulse oximetry is recommended in liver transplant (LT) candidates because mortality is increased, independently of the severity of the oxygenation defect. LT exception points may be afforded to those with HPS and severe hypoxemia. We assessed the screening characteristics of pulse oximetry for HPS. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study of adults undergoing their first LT evaluation. Patients underwent protocolized assessment of oxygen saturation by pulse oximetry (SpO2 ), arterial blood gas, spirometry, and contrast-enhanced echocardiography (CE). HPS was defined as an alveolar-arterial gradient ≥15 mm Hg (≥20 mm Hg if age >64 years), intrapulmonary vascular dilatation on CE, and absence of lung disease. The study sample included 363 patients. Of these, 75 (20.7%; 95% confidence interval [CI], 16.6%-25.2%) met the criteria for HPS. The area under the receiver operating characteristic curve (or c-statistic) for SpO2 in discriminating HPS was 0.59 (95% CI, 0.51-0.66). An SpO2 <96%, recommended by practice guidelines as a threshold to require further testing, had low sensitivity (28%; 95% CI, 18%-28%). The c-statistic of SpO2 in discriminating HPS with a partial pressure of oxygen (PaO2 ) <60 mm Hg (eligible for LT exception points) was 0.76 (95% CI, 0.46-1.00). An SpO2 cutoff of <96% had higher sensitivity for detecting HPS with PaO2 <60 mm Hg (71%; 95% CI, 38%-100%) but was still inadequate. Conclusion: Pulse oximetry is not sufficiently sensitive to screen for HPS in LT candidates. Arterial blood gas and CE are required in LT candidates for diagnosis of HPS.

Incidence, determinants and outcomes of pregnancy-associated hepatitis B flares: A regional hospital-based cohort study.

BACKGROUND & AIMS: There is limited knowledge about hepatitis B virus (HBV) flare among pregnant women. We evaluated the incidence, determinants and outcomes of HBV flare in a multicultural cohort of pregnant HBV-infected women in the United States. METHODS: We performed a retrospective cohort study of pregnant hepatitis B surface antigen-positive women cared for at hospital-based clinics of 4 medical centres in Southeastern Pennsylvania from 2006 to 2015. The main outcome was incident HBV flare (alanine aminotransferase [ALT] ≥2 times upper limit of normal) during pregnancy or within 6 months after delivery. Among patients with flare, we determined development of jaundice (total bilirubin ≥2.5 mg/dL) and hepatic decompensation. Multivariable logistic regression was used to estimate odds ratios (ORs) of HBV flare for risk factors of interest, including timing of flare (during pregnancy versus post-delivery), nulliparity, younger age, HBV e antigen (HBeAg) status, and lack of anti-HBV therapy. RESULTS: Among 310 pregnant predominantly African HBV-infected women with 388 pregnancies, the incidence of HBV flare was 14% (95% CI, 10-18%) during pregnancy and 16% (95% CI, 11-24%) post-delivery. Jaundice developed in 12% and hepatic decompensation in 2%. Positive HBeAg was associated with HBV flare (OR, 2.55; 95% CI, 1.04-6.20). HBV DNA was measured in 55% of patients, and only 50% were referred for HBV specialty care. CONCLUSIONS: Pregnancy-associated hepatitis B flare occurred in 14% during pregnancy and 16% post-delivery and rarely led to hepatic decompensation. Positive HBeAg was the main risk factor identified. Women did not have adequate HBV monitoring or follow-up during pregnancy.

Single-center outcomes of combined heart and liver transplantation in the failing Fontan.

Long-term outcomes of the Fontan operation include Fontan failure and liver disease. Combined heart-liver transplantation (CHLT) is an option for select patients although limited data exist on this strategy. A retrospective review of Fontan patients 18 years or older referred for cardiac transplant evaluation between 2000 and 2013 at the Hospital of the University of Pennsylvania was performed. All patients were considered for potential CHLT. Clinical variables such as demographics, perioperative factors, and short-term outcomes were reviewed. Of 17 referrals for cardiac transplantation, seven Fontan patients underwent CHLT. All patients who underwent CHLT had either advanced fibrosis or cirrhosis on liver biopsy. There were no perioperative deaths. The most common postoperative morbidity was acute kidney injury. Short-term complications include one episode of acute liver rejection but no cardiac rejection greater than 1R. CHLT is an acceptable therapeutic option for patients with failing Fontan physiology who exhibit concomitant advanced liver fibrosis. However, optimal patient selection is currently undefined, and long-term outcomes are not known.

Portal Hypertension: An Underestimated Entity?

OBJECTIVE: The aim of this study is to evaluate portal hypertension as an independent risk factor in general surgical procedures. BACKGROUND: Data on the impact of portal hypertension in general surgical outcomes has been limited. Published literature has focused mainly on its effect in liver surgery. The Child Pugh score and Model for End Stage Liver Disease are utilized for surgical risk assessment in liver disease but they do not accurately reflect degree of portal hypertension. METHODS: From 2005 to 2012, patients with esophageal varices (EV) in the National Surgical Quality Improvement Program (NSQIP) formed the portal hypertension cohort, and were case matched to patients without esophageal varices (NEV) based on sex, age, surgery type, and year of operation. Thirty day mortality and morbidity were analyzed using generalized estimating equations for binary outcomes. EV patients were also dichotomized by Model for End Stage Liver Disease (MELD) score (≤15 vs >15) and compared with NEV patients. RESULTS: One thousand five hundred and seventy-four EV patients were matched to 3148 NEV patients. In multivariable analysis, EV patients had a 3.01 higher odds of 30 day mortality (P < 0.001) and 1.28 higher odds of complications (P < 0.001) compared with NEV patients. EV patients with MELD >15 had 4.64 higher odds of death within 30 days (P < 0.001) and had 1.75 higher odds of complications within 30 days (P < 0.001) compared with NEV patients; EV patients with MELD 15 or less had 1.95 higher odds of 30 day mortality (P < 0.001) compared with NEV patients. CONCLUSIONS: Portal hypertension is associated with a significant mortality and morbidity risk in general surgery, and should not be underestimated even in patients with MELD 15 or less where the early mortality risk remained significant.

Impact of the hepatopulmonary syndrome MELD exception policy on outcomes of patients after liver transplantation: an analysis of the UNOS database.

BACKGROUND & AIMS: Patients with hepatopulmonary syndrome (HPS) are prioritized for liver transplantation (given exception points) due to their high pre- and post-transplantation mortality. However, few studies have evaluated the outcomes of these patients. METHODS: We performed a retrospective cohort study using data submitted to the United Network for Organ Sharing in a study of the effects of room-air oxygenation on pre- and post-transplantation outcomes of patients with HPS. We identified thresholds associated with post-transplantation survival using cubic spline analysis and compared overall survival times of patients with and without HPS. RESULTS: From 2002 through 2012, nine hundred and seventy-three patients on the liver transplant waitlist received HPS exception points. There was no association between oxygenation and waitlist mortality among patients with HPS exception points. Transplant recipients with more severe hypoxemia had increased risk of death after liver transplantation. Rates of 3-year unadjusted post-transplantation survival were 84% for patients with PaO2 of 44.1-54.0 mm Hg vs 68% for those with PaO2 ≤ 44.0 mm Hg. In multivariable Cox models, transplant recipients with an initial room-air PaO2 ≤ 44.0 mm Hg had significant increases in post-transplantation mortality (hazard ratio = 1.58; 95% confidence interval [CI]: 1.15-2.18) compared with those with a PaO2 of 44.1-54.0 mm Hg. Overall mortality was significantly lower among waitlist candidates with HPS exception points than those without (hazard ratio = 0.82; 95% CI: 0.70-0.96), possibly because patients with HPS have a reduced risk of pre-transplantation mortality and similar rate of post-transplantation survival. CONCLUSIONS: Although there was no association between pre-transplantation oxygenation and waitlist survival in patients with HPS Model for End-Stage Liver Disease exception points, a pre-transplantation room-air PaO2 ≤ 44.0 mm Hg was associated with increased post-transplantation mortality. HPS Model for End-Stage Liver Disease exception patients had lower overall mortality compared with others awaiting liver transplantation, suggesting that the appropriateness of the HPS exception policy should be reassessed.

Hepatic hydrothorax.

Hepatic hydrothorax is defined as a transudative pleural effusion, usually greater than 500 mL, in patients with portal hypertension without any other underlying primary cardiopulmonary cause. It develops most likely because of diaphragmatic defects that allow for passage of fluid from the peritoneal space to the pleural space. Because of the mechanical constraints of the thoracic cavity, this complication of portal hypertension can be challenging to treat because patients will become symptomatic when as little as 500 mL of fluid is present in the pleural space. Treatments include salt restriction, diuretics, thoracentesis, transjugular intrahepatic portosystemic shunt, video-assisted thoracoscopy, and pleurodesis. It is important to note that a chest tube is not a potential treatment option; a hepatic hydrothorax should not be treated with a chest tube unless there is frank pus in the pleural fluid or a pneumothorax is present. The ultimate treatment is a liver transplant; the development of a hepatic hydrothorax thus warrants a referral to a liver transplant center.

The precarious state of the liver after a Fontan operation: summary of a multidisciplinary symposium.

As the cohort of survivors with the single-ventricle type of congenital heart disease grows, it becomes increasingly evident that the state of chronically elevated venous pressure and decreased cardiac output inherent in the Fontan circulation provides the substrate for a progressive decline in functional status. One organ at great risk is the liver. Wedged between two capillary beds, with the pulmonary venous bed downstream, which typically has no pulsatile energy added in the absence of a functional right ventricle, and the splanchnic bed upstream, which may have compromised inflow due to inherent cardiac output restriction characteristic of the Fontan circulation, the liver exists in a precarious state. This review summarizes a consensus view achieved at a multidisciplinary symposium held at The Children's Hospital of Philadelphia in June 2011. The discussion includes current knowledge concerning the hemodynamic foundations of liver problems, the diagnostic tools available, the unique histopathology of the liver after the Fontan operation, and proposed mechanisms for hepatic fibrosis at the cellular level. At the completion of the symposium, a consensus recommendation was made by the authors' group to pursue a new prospective protocol for clinical evaluation of the liver for all patients in our practice 10 years after the Fontan operation.

Review of Sarcopenia and Testosterone Deficiency With Chronic Liver Disease and Postoperative Liver Transplant Utility of Short-Term Testosterone Replacement Therapy.

OBJECTIVES: Chronic liver disease is often associated with testosterone deficiency. However, testosterone replacement does not improve hepatic function or survival with diseased liver. So far, to our knowledge, testosterone replacement therapy after successful livertransplantforfunctional sarcopenia has not been studied. We had 3 goals: (1) define postoperative functional sarcopenia afterlivertransplant with serum testosterone level; (2) examine the role of short-term testosterone replacement therapy with active in-bed exercise of upper and lower extremity joints; and (3) correlate functional sarcopenia with skeletal muscle index and skeletal muscle density in relation to ascites, pleural effusion subtracted body mass index. MATERIALS AND METHODS: We evaluated 16 liver transplant recipients who had been receiving posttransplanttestosterone replacementtherapy with functional sarcopenia. Preoperative and postoperative demographics and laboratory and radiological data were retrieved; body mass index, skeletal muscle index, and skeletal muscle density were calculated. For this retrospective study, institutional review board approval was obtained before the electronic database was reviewed and analyzed. RESULTS: Mean testosterone level was 28.3 ng/dL (<5% of expected). Twelve patients received 1 dose, and the remaining 4 patients received >1 dose oftestosterone cypionate, 200 mg. Mean hospital stay was 26 days. Seven patients were discharged home, with the remaining patients to a rehabilitation facility or nursing home. One patient died from a cardiac event, and another patient died from recurrent metastatic malignancy. The 1-year and 5-year actuarial patient and graft survival rates were 93.8% and 87.5%, respectively. Overall, 5 patients were sarcopenic by skeletal muscle index, and 6 patients had poor muscle quality by skeletal muscle density. CONCLUSIONS: Testosterone deficiency after liver transplant exists with functional sarcopenia. Two- thirds of such recipients have low skeletal muscle index and/or have low skeletal muscle density. Short- term testosterone replacement therapy with in-bed active exercise provides 5-year patient and graft survival of 87.5%.

Excellent outcomes with liver transplantation in hepatopulmonary syndrome across pre-transplant PaO2 spectrum.

BACKGROUND & AIMS: Significantly worse survival has been reported in patients with hepatopulmonary syndrome (HPS) and partial pressure of arterial oxygen (PaO2) <45 mmHg undergoing liver transplantation. Long-term pre- and post-transplant outcomes based on degree of hypoxaemia were re-examined. METHODS: A retrospective analysis of 1,152 HPS candidates listed with an approved HPS model for end-stage liver disease (MELD) exception was performed. A Fine and Gray competing risks model was utilised to evaluate pre-transplant outcomes for PaO2 thresholds of <45, 45 to <60, and ≥60 mmHg. Post-transplant survival was analysed using the Kaplan-Meier method. RESULTS: Patients with a PaO2 <45 mmHg were significantly more likely to undergo transplantation (hazard ratio [HR] 1.51; 95% CI 1.12-2.03), whereas patients with higher MELD scores had lower hazard of transplant (HR 0.80, 95% CI 0.67-0.95, p = 0.011) and higher hazard of pre-transplant death (HR 2.29, 95% CI 1.55-3.37, p <0.001). Post-transplantation, patients with a PaO2 <45 mmHg had lower survival (p = 0.04) compared with patients with a PaO2 ≥45 to <50 mmHg, with survival curves significantly different at 2.6 years (75% survival compared with 86%) and median survival of 11.5 and 14.1 years, respectively. Cardiac arrest was a more likely (p = 0.025) cause of death for these patients. Cardiac arrest incidence in patients who died with a PaO2 >50 mmHg was 6.2%. CONCLUSIONS: Patients with a PaO2 <45 mmHg had a significantly higher rate of transplantation, and higher calculated MELD scores were associated with significantly higher pre-transplant mortality. Although post-transplant survival was lower in patients with a PaO2 <45 mmHg, the median survival was 11.5 years, and survival curves only became significantly different at 2.6 years. This suggests that patients with HPS do benefit from transplantation up to 2-3 years post-transplant regardless of the severity of pre-transplant hypoxaemia. LAY SUMMARY: A total of 1,152 patients with hepatopulmonary syndrome listed for liver transplant were analysed. Patients with a low PaO2 <45 mmHg had a high likelihood of transplantation. If associated with advanced liver disease, the mortality risk was higher for patients with hepatopulmonary syndrome on the wait list. After liver transplantation, patients with a PaO2 <45 mmHg had a lower survival, but this only became significant after 2.6 years, and the median survival was 11.5 years. This suggests that patients with hepatopulmonary syndrome do benefit from transplantation.

Renal Protective Effect of Everolimus in Liver Transplantation: A Prospective Randomized Open-Label Trial.

Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months. METHODS: This was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson's chi-square test for binary outcomes. Effect size was measured using Cohen's d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test. RESULTS: Each arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months. CONCLUSIONS: EVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.

Incidence of Post-Liver Transplant Hepatic Dysfunction After Sustained Virologic Response Following Direct-Acting Anti-Hepatitis C Therapy.

OBJECTIVES: Newly developed, direct-acting antiviral therapy is effective in over 90% of cases to eradicate hepatitis C virus infection. Direct-acting antiviral therapy is also effective in liver transplant recipients with recurrent hepatitis C virus infection. However, hepatic function after sustained virologic response in transplant recipients is unknown. Here, we aimed to uncover the incidence of hepatic dysfunction in this patient group at our center. MATERIALS AND METHODS: Our study included 40 consecutive (January 2014 to February 2016) and compliant posttransplant recipients who achieved sustained viral response from direct-acting antiviral therapy. Patients were investigated for incidence and causes of hepatic dysfunction. RESULTS: In our patient group, 4 (10%) experienced hepatic dysfunction with stable baseline immunosuppression, with 2 having drastic increases in alanine aminotransferase at 15 and 32 weeks after direct-acting antiviral therapy. Biopsies showed hepatitis, and both patients were treated with hydrocortisone, which increased their baseline immunosuppression. The 3rd patient had an increase in bilirubin at 21 weeks posttherapy, with biopsy showing macrovascular steatosis. The 4th patient had a rapid increase in bilirubin at 7 weeks after direct-acting antiviral therapy, with biopsy showing significant duct loss. CONCLUSIONS: During the study period, 10% of patients experienced hepatic dysfunction after sustained viral response. Presumed causative factors included partial immune reconstitution and nonalcoholic fatty liver disease.

Insulin resistance and microalbuminuria are associated with microvascular disease in patients with cirrhosis.

Cardiovascular (CV) disease has a significant impact on post-liver transplantation (LT) survival. Finding surrogate markers for occult CV disease would improve CV assessment in the LT evaluation. This study was designed to determine the prevalence of microvascular disease (MVD) and the utility of both microalbuminuria and the homeostatic model for insulin resistance (HOMA-IR) for assessing the presence of MVD in potential LT recipients. In this study, we examined the prevalence of MVD in 72 diabetics and 71 nondiabetics; both groups were matched for age, sex, race, and etiology of cirrhosis while awaiting LT. We prospectively collected data including fasting serum insulin and glucose levels, urine creatinine and microalbumin, and macrovascular and microvascular complications. MVD was present in 58 (40.5%) patients; MVD was more common in diabetics (n = 45, 62.5%) than nondiabetics (n = 13, 18.3%). The presence of diabetes mellitus (DM; P = 0.03), insulin use (P = 0.002), and duration (months) of DM (85.3 +/- 96.1 versus 22.1 +/- 46.3, P < 0.0001), hypertension (51.3 +/- 101.5 versus 22.7 +/- 58.2, P = 0.03), and hypertriglyceridemia (7.2 +/- 17.4 versus 3.8 +/- 18.5, P = 0.04) were associated with MVD. Significant microalbuminuria had a sensitivity of 85%, a specificity of 100%, and a positive predictive value of 100% for the presence of MVD. HOMA-IR also was associated with MVD (P = 0.0001). In conclusion, at our center, 62.5% of DM patients and 18% of non-DM patients awaiting LT have MVD. Patients with DM, significant microalbuminuria, or an elevated HOMA-IR should undergo rigorous CV assessment prior to LT.

Is there increased risk of hepatocellular carcinoma recurrence in liver transplant patients with direct-acting antiviral therapy?

BACKGROUND: Recently, a controversy has emerged: is the rate of recurrence of hepatocellular carcinoma (HCC) higher following treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapy? However, the risk of HCC recurrence has not been studied in liver transplant (LTx) recipients who received DAA therapy. The aim of the present study is to compare the rate of HCC recurrence in LTx recipients who did or did not receive DAA therapy. PATIENTS AND METHODS: Sixty-three patients received LTx with HCC. Twenty-seven (42.9%) with HCV received DAA therapy (Group A), 20 (31.7%) with HCV did not receive DAA therapy (Group B), and 16 (25.4%) did not have HCV (Group C). RESULTS: In group A, three (11%), in group B, one (5%), and in group C, none had recurrence of HCC. Actuarial 4-year recurrence-free survival was 88.9, 95, and 100% in group A, B, and C, respectively (p = 0.37). Group A was subdivided into two groups for comparison with Group B: A1 included five patients who had end of treatment response (ETR) without sustained virological response (SVR), and A2 included 20 patients who achieved SVR. Three patients from A1 had HCC recurrence and no patients from A2 had HCC recurrence. (p = 0.0038; group A1, A2, and B). CONCLUSIONS: The rate of HCC recurrence in LTx patients with DAA therapy was significantly higher with ETR, without SVR, after DAA therapy compared to patients with SVR or patients who did not receive DAA therapy. LTx recipients with HCC receiving DAA therapy requires further studies.