Forde, Kimberly A.

Patients with chronic liver disease commonly have abnormal lung function; however, the impact of smoking on outcomes in these patients is unknown. We hypothesized current or past smoking would be associated with worse survival in patients with advanced liver disease. The Pulmonary Vascular Complications in Liver Disease Study 2 (PVCLD2) was a prospective cohort of patients with advanced liver disease undergoing evaluation for liver transplantation (LT). Patients were classified by self-report as a “non-smoker,” “past smoker,” or “current smoker.” We used Cox proportional hazards models and Fine-Gray models with LT as a competing risk. Models were adjusted for age, sex, body mass index, race, family income, liver disease etiology, and Model for End-Stage Liver Disease-Sodium score. Of the 410 patients included, most (65%) were male and the mean age at enrollment was 56.5 years. One hundred sixty (39%) patients were nonsmokers, 183 (45%) were past smokers, and 67 (16%) were current smokers. In total, 151 (37%) patients received an LT, and 88 (20%) patients died. When compared to nonsmokers, current smokers had a 2.17-fold increase in risk of death overall (95% CI: 1.12–4.18, p = 0.02). There was a 7% increase in overall risk of death for every 5 pack-years increase (95% CI: 1.01–1.13, p = 0.02). With LT as a competing risk, the subdistributional HR of current smokers versus nonsmokers for death was 2.45 (95% CI: 1.31–4.60, p = 0.005). In this model, past smokers displayed a nonsignificant increase in the risk of death compared to nonsmokers (subdistributional HR: 1.58, 95% CI: 0.91–2.72, p = 0.10). Patients with advanced liver disease undergoing evaluation for LT who smoke have an increased risk of death. Smoking cessation could lead to improved overall survival with or without LT.

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/m2, 95% CI 3.1–3.4 vs. 2.8 L/min/m2, 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.

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.

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.

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.