Rajasekhar Tanikella

Pilot study of pentoxifylline in hepatopulmonary syndrome

Hepatopulmonary syndrome (HPS) results when chronic liver disease or portal hypertension causes intrapulmonary microvascular dilatation with hypoxemia. In experimental HPS, tumor necrosis factor alpha (TNF‐α) overproduction contributes to vasodilatation, which is improved by pentoxifylline, a TNF‐α inhibitor. The effectiveness of pentoxifylline in humans is unknown. The aim of this open‐label, single‐arm clinical trial was to assess the efficacy and tolerability of pentoxifylline in patients with cirrhosis and advanced HPS undergoing liver transplantation evaluation. Nine adults with cirrhosis and moderate to severe HPS were enrolled. All patients had an initial 2‐week titration to a target dose of pentoxifylline of 400 mg by mouth every 8 hours, which was continued for 6 weeks. Baseline and follow‐up arterial blood gases and TNF‐α levels were evaluated. Adverse effects and tolerability were assessed. The 9 patients had a mean age of 55 ± 10 years, and 67% were female. The most common causes of cirrhosis were hepatitis C virus and alcohol (55%). The mean Model for End‐Stage Liver Disease score was 11 (range, 6‐19), and patients had advanced hypoxemia [mean partial pressure of arterial oxygen (PaO2) = 54 ± 12 mm Hg, mean alveolar‐arterial oxygen gradient (A‐a PaO2) = 57 ± 15 mm Hg]. Of the 9 patients enrolled, follow‐up blood gases were done in 7. There was no significant change in PaO2 (P = 0.3) or A‐a PaO2 (P = 0.3) with treatment. Pentoxifylline was poorly tolerated. Nausea (100%) and vomiting (56%) were the predominant side effects, and only a single patient was able to complete full‐dose therapy. Treatment with pentoxifylline did not improve arterial oxygenation in advanced HPS, and tolerance was limited by gastrointestinal toxicity. Liver Transpl 14:1199–1203, 2008.

Health-related quality of life and survival in liver transplant candidates†

Health‐related quality of life (HRQOL) is an important measure of the effects of chronic liver disease in affected patients that helps guide interventions to improve well‐being. However, the relationship between HRQOL and survival in liver transplant candidates remains unclear. We examined whether the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores from the Short Form 36 (SF‐36) Health Survey were associated with survival in liver transplant candidates. We administered the SF‐36 questionnaire (version 2.0) to patients in the Pulmonary Vascular Complications of Liver Disease study, a multicenter prospective cohort of patients evaluated for liver transplantation in 7 academic centers in the United States between 2003 and 2006. Cox proportional hazards models were used with death as the primary outcome and adjustment for liver transplantation as a time‐varying covariate. The mean age of the 252 participants was 54 ± 10 years, 64% were male, and 94% were white. During the 422 person years of follow‐up, 147 patients (58%) were listed, 75 patients (30%) underwent transplantation, 49 patients (19%) died, and 3 patients were lost to follow‐up. Lower baseline PCS scores were associated with an increased mortality rate despite adjustments for age, gender, Model for End‐Stage Liver Disease score, and liver transplantation (P for the trend = 0.0001). The MCS score was not associated with mortality (P for the trend = 0.53). In conclusion, PCS significantly predicts survival in liver transplant candidates, and interventions directed toward improving the physical status may be helpful in improving outcomes in liver transplant candidates. Liver Transpl 16:238–245, 2010.

Endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis: Testing the current guidelines

BACKGROUND Current guidelines include an algorithm for predicting choledocholithiasis. Presence of any very strong predictor or both strong predictors confers a high (>50%) probability of choledocholithiasis. Absence of predictors confers low risk (<10%) of choledocholithiasis. Other combinations have an intermediate risk of choledocholithiasis. AIM Determine accuracy of the proposed algorithm in predicting choledocholithiasis. METHODS Retrospective analysis of all endoscopic retrograde cholangiopancreatographies performed for suspected choledocholithiasis in 3 years in a Tertiary care hospital and a community hospital serviced by The University of Texas Health Science Center at Houston Division of Gastroenterology. Application of the guidelines, and comparing results to endoscopic retrograde cholangiopancreatography findings. RESULTS A total of 1080 endoscopic retrograde cholangiopancreatographies were performed; 521 for choledocholithiasis. Most patients were Hispanic and female. Univariate analysis: presence of any very strong predictor and both strong predictors had an OR for choledocholithiasis of 3.30 and 2.36 respectively. Multivariate analysis: odds of choledocholithiasis with any very strong predictor was 2.87, and both strong predictors 3.24. Choledocholithiasis was present in 71.5%, and 41% of patients with high, and intermediate risk respectively. CONCLUSION This study confirms the utility of clinical predictors for the diagnosis of choledocholithiasis. All of the very strong predictors and one of the strong predictors increased the odds of choledocholithiasis. Patients with high risk for choledocholithiasis had a probability of 79% of choledocholithiasis. Sensitivity and specificity of current predictors are too low to obviate the possible need of non-invasive tests to confirm or exclude choledocholithiasis in all risk groups.

The impact of left ventricular hypertrophy on survival in candidates for liver transplantation

Left ventricular hypertrophy (LVH) occurs in 12% to 30% of patients with cirrhosis; however, its prognostic significance is not well studied. We assessed the association of LVH with survival in patients undergoing a liver transplantation (LT) evaluation. We performed a multicenter cohort study of patients undergoing an evaluation for LT. LVH was defined with transthoracic echocardiography. The outcome of interest was all‐cause mortality. LVH was present in 138 of 485 patients (28%). Patients with LVH were older, more likely to be male and African American, and were more likely to have hypertension. Three hundred forty‐five patients did not undergo transplantation (212 declined, and 133 were waiting): 36 of 110 patients with LVH (33%) died, whereas 57 of 235 patients without LVH (24%) died (P = 0.23). After LT, 8 of 28 patients with LVH (29%) died over the course of 3 years, whereas 9 of 112 patients without LVH (8%) died (P = 0.007). This finding was independent of conventional risk factors for LVH, and all deaths for patients with LVH occurred within 9 months of LT. No clinical or demographic characteristics were associated with mortality among LVH patients. In conclusion, the presence of LVH is associated with an early increase in mortality after LT, and this is independent of conventional risk factors for LVH. Further studies are needed to confirm these findings and identify factors associated with mortality after transplantation to improve outcomes. Liver Transpl 20:705‐712, 2014.

Hepatopulmonary syndrome and liver transplantation: Who, when, and where?†‡

H epatopulmonary syndrome (HPS) is a relatively common pulmonary vascular complication of cirrhosis and/or portal hypertension (PH) found in 5%-32% of patients evaluated for liver transplantation (LT). It is characterized by pulmonary microvascular dilatation and remodeling, which result in impaired oxygenation in the absence of marked intrinsic cardiopulmonary disease. The range in observed frequency of HPS is influenced by what level of gas exchange abnormality is used to define the presence of the syndrome. The European Respiratory Society (ERS) consensus definition establishes an alveolar-arterial oxygen gradient (AaPO2) 15 mmHg (age >64 years including 20 mmHg) as abnormal and further delineates severity into mild (partial pressure of oxygen [PaO2] 80 mmHg), moderate (PaO2 60-<80 mmHg), severe (PaO2 50-<60 mmHg), or very severe (PaO2 <50 mmHg). There has been a focus on patients with severe HPS with regards to the Model for End-Stage Liver Disease (MELD) exception for LT based on data that both preand postoperative mortality are increased in this group, relative to nonHPS patients without cirrhosis. However, the only multicenter prospective study found that the increased mortality in HPS, relative to non-HPS, occurred across the spectrum of oxygenation abnormalities, suggesting that factors other than severity of hypoxemia influence outcome. Medical therapy for HPS has generally been ineffective, although a number of promising targets have been identified, including the endothelin system, nitric oxide synthase, tumor necrosis factor alpha, and angiogenesis. Currently, LT is the only successful treatment for HPS and typically results in complete resolution of gas exchange impairment. However, the effect of institution of the MELD exception policy for severe HPS on wait-list and post-transplant mortality remains incompletely defined. An analysis of the United Network for Organ Sharing (UNOS) database in 2008 suggested that wait-list survival was better and post-transplant survival similar between HPS exception patients and non-HPS patients. Unfortunately, the UNOS database does not include data on pulmonary parameters and many patients did not undergo HPS screening, making it difficult to be sure which patients had HPS and to define the severity of the process. Against this backdrop, Iyer et al report on a followup retrospective analysis of outcomes in the largest single-center cohort of HPS patients. One hundred and six patients with HPS evaluated at the Mayo Clinic from 1986 through 2010 were included and outcomes were compared before and after the institution of MELD exception for HPS (January 1, 2002). There are three major findings of the study: (1) Long-term outcomes in patients transplanted for HPS are excellent; (2) there has been a trend toward improved postLT outcomes since the inception of the MELD exception for HPS; and (3) transplant outcomes are similar between HPS and non-HPS patients. These findings strongly support employing LT as a therapy for HPS and suggest that the current MELD exception policy may have contributed to the goal of improving LT outcomes in HPS. A closer look at the results of the study provides some additional insights. First, based on the survival curves, the trend in improved post-LT survival among HPS patients in the MELD exception era appears most prominent in the early postoperative period. This finding corroborates observations from other groups suggesting that post-LT survival in HPS is improving. Whether these outcomes reflect the application of the MELD exception for HPS and prevention of deterioration of hypoxemia, advancement in surgical techniques, or improved perioperative management of HPS are unclear. The observation in the current study that many patients had very severe hypoxemia and that the degree of hypoxemia and intrapulmonary shunting did not influence post-LT Abbreviations: AaPO2, alveolar-arterial oxygen gradient; ERS, European Respiratory Society; HPS, hepatopulmonary syndrome; LT, liver transplantation; MELD, Model for End-stage Liver Disease; PaO2, partial pressure of oxygen; PH, portal hypertension; UNOS, United Network for Organ Sharing Address reprint requests to: Michael B. Fallon, M.D., Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Medical School at Houston, 6431 Fannin Street, MSB 4.234, Houston, TX 77030. E-mail: Michael. B. Fallon@uth.tmc.edu; fax: 713-704-6616. Copyright VC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26367 Potential conflict of interest: Nothing to report.