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Item Admission plasma uromodulin and the risk of acute kidney injury in hospitalized patients with cirrhosis: a pilot study(American Physiological Society, 2019-10-01) Patidar, Kavish R.; Garimella, Pranav S.; Macedo, Etienne; Slaven, James E.; Ghabril, Marwan S.; Weber, Regina E.; Anderson, Melissa; Orman, Eric S.; Nephew, Lauren D.; Desai, Archita P.; Chalasani, Naga; El-Achkar, Tarek M.; Medicine, School of MedicineAcute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis. Uromodulin, a protein uniquely produced by the kidney and released both in the urine and circulation, has been shown to regulate AKI and is linked to tubular reserve. Although low levels of urine uromodulin are associated with AKI after cardiac surgery, it is unclear whether circulating uromodulin can stratify the risk of AKI, particularly in a susceptible population such as hospitalized patients with cirrhosis. Thus, we investigated whether plasma uromodulin measured at the time of admission is associated with subsequent hospital-acquired AKI (defined by a rise in serum creatinine >0.3mg/dL within 48 h or ≥ 1.5 times baseline) in patients with cirrhosis. A total of 98 patients [mean age 54 yr, Model for Endstage Liver Disease Sodium (MELD-Na) score 19, and baseline creatinine of 0.95 mg/dL] were included, of which 13% (n = 13) developed AKI. Median uromodulin levels were significantly lower in patients who developed AKI compared with patients who did not (9.30 vs. 13.35 ng/mL, P = 0.02). After adjusting for age, sex, diabetes, hypertension, albumin, and MELD-Na score as covariates on multivariable logistic regression, uromodulin was independently associated with AKI [odd ratios of 1.19 (95% confidence interval 1.02, 1.37; P = 0.02)]. Lower uromodulin levels on admission are associated with increased odds of subsequent AKI in hospitalized patients with cirrhosis. Further studies are needed to better understand the role of uromodulin in the pathogenesis and as a predictive biomarker of AKI in this population. NEW & NOTEWORTHY In this study, we found that admission plasma uromodulin levels are significantly lower in patients who developed subsequent acute kidney injury (AKI) during their hospital stay compared with patients who did not. Additionally, uromodulin is independently associated with AKI development after adjusting for clinically relevant parameters such as age, sex, diabetes, hypertension, severity of cirrhosis, and kidney function. To our knowledge, this is the first study linking plasma uromodulin with AKI development in patients with cirrhosis.Item Cost Effectiveness of Different Strategies for Detecting Cirrhosis in Patients With Non-alcoholic Fatty Liver Disease Based on United States Health Care System(Elsevier, 2020) Vilar-Gomez, Eduardo; Lou, Zhouyang; Kong, Nan; Vuppalanchi, Raj; Imperiale, Thomas F.; Chalasani, Naga; Medicine, School of MedicineBackground & Aims Several strategies are available for detecting cirrhosis in patients with non-alcoholic fatty liver disease (NAFLD), but their cost effectiveness is not clear. We developed a decision model to quantify the accuracy and costs of 9 single or combination strategies, including 3 noninvasive tests (fibrosis-4 [FIB-4], vibration controlled transient elastography [VCTE], and magnetic resonance elastography [MRE]) and liver biopsy, for detection of cirrhosis in patients with NAFLD. Methods Data on diagnostic accuracy, costs, adverse events, and cirrhosis outcomes over a 5-y period were obtained from publications. The diagnostic accuracy, per-patient cost per correct diagnosis of cirrhosis, and incremental cost-effectiveness ratios (ICER) were calculated for each strategy for base cirrhosis prevalence values of 0.27%, 2%, and 4%. Results The combination of the FIB-4 and VCTE identified patients with cirrhosis in NAFLD populations with a 0.27%, 2%, and 4% prevalence of cirrhosis with the lowest cost per person ($401, $690, and $1024, respectively) and highest diagnostic accuracy (89.3%, 88.5%, and 87.5% respectively). The combination of FIB-4 and MRE ranked second in cost per person ($491, $781, and $1114, respectively) and diagnostic accuracy (92.4%, 91.6%, 90.6%, respectively). Compared to the combination of FIB-4 and VCTE (least costly), the ICERs were lower for the combination of FIB-4 and MRE ($2864, $2918, and $2921) than the combination of FIB-4 and liver biopsy ($4454, $5156, and $5956) at the cirrhosis prevalence values tested. When goal was to avoid liver biopsy, FIB-4+VCTE and FIB-4+MRE had similar diagnostic accuracies, ranging from 87.5% to 89.3% and 90.6% to 92.4% for cirrhosis diagnosis, although FIB-4+MRE had a slightly higher cost. Conclusions In our cost effectiveness analysis based on United States health care system, we found that results from FIB-4, followed by either VCTE, MRE, or liver biopsy, detect cirrhosis in patients with NAFLD with a high level of accuracy and low cost. Compared to FIB-4 + VCTE which was the least costly strategy, FIB-4+MRE had lower ICER than FIB-4+LB.Item Daily Aspirin Use Reduces Risk of Fibrosis Progression in Patients With Nonalcoholic Fatty Liver Disease, Providing New Uses for an Old Drug(Elsevier, 2019) Vilar-Gomez, Eduardo; Chalasani, Naga; Medicine, School of MedicineItem Enhanced Liver Fibrosis Score Can Be Used to Predict Liver-Related Events in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis(Elsevier, 2020) Are, Vijay S.; Vuppalanchi, Raj; Vilar-Gomez, Eduardo; Chalasani, Naga; Medicine, School of MedicineItem Karnofsky performance status predicts outcomes in candidates for simultaneous liver-kidney transplant(Wiley, 2021-02) Shamseddeen, Hani; Pike, Francis; Ghabril, Marwan; Patidar, Kavish R.; Desai, Archita P.; Nephew, Lauren; Anderson, Melissa; Kubal, Chandrashekhar; Chalasani, Naga; Orman, Eric S.; Medicine, School of MedicineKarnofsky performance status (KPS), a measure of physical frailty, predicts pre-transplant and post-transplant outcomes in liver transplantation, but has not been assessed in simultaneous liver–kidney transplantation (SLKT). We examined the association between KPS and outcomes in SLKT waitlist registrants and recipients (2005-2018) in the UNOS database. KPS was categorized into A (able to work), B (able to provide self-care), and C (unable to provide self-care). Cox regression and competing risk analysis were used to assess the association between KPS groups and outcomes. A total of 10,785 patients were waitlisted (KPS: 19% A, 46% B, 35% C), and 5,516 underwent SLKT (12% A, 36% B, 52% C). One-year waitlist mortality was 17%, 22%, and 32% for KPS A, B, and C, respectively. In adjusted competing risk regression, KPS C was associated with increased waitlist mortality (SHR 1.15, 95%CI 1.04-1.28). One-year post-transplant survival was 92%, 91%, and 87% for KPS A, B, and C, respectively. In adjusted Cox regression, KPS C was associated with increased post-transplant mortality (HR 1.32, 95%CI 1.08-1.61). It was also associated with increased liver and kidney graft losses and with hospital length of stay. Frailty, as assessed by KPS, is associated with poor outcomes in SLKT pre- and post-transplant.Item Management of Difficult Cases of Autoimmune Hepatitis(Springer, 2016-02) Lammert, Craig; Loy, Veronica M.; Oshima, Kiyoko; Gawrieh, Samer; Department of Medicine, IU School of MedicineAutoimmune hepatitis (AIH) is a complex autoimmune disease characterized by immune-mediated destruction of hepatic parenchyma which can result in cirrhosis, liver failure, and death. Current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver (EASL) guidelines recommend corticosteroids alone or in combination with azathioprine as first-line treatment strategies. However, a significant proportion of patients may not be able to tolerate or achieve complete biochemical response with these options. In this article, we discuss approaches to these patients and other challenging AIH patient groups such as the asymptomatic, pregnant, elderly, and liver transplant recipients.Item Postoperative Atrial Fibrillation and Flutter in Liver Transplantation: An Important Predictor of Early and Late Morbidity and Mortality(Wiley, 2019) Rachwan, Rayan Jo; Kutkut, Issa; Hathaway, Taylor J.; Timsina, Lava R.; Kubal, Chandrashekhar A.; Lacerda, Marco A.; Ghabril, Marwan S.; Bourdillon, Patrick D.; Mangus, Richard S.; Surgery, School of MedicinePostoperative atrial fibrillation/flutter (POAF) is the most common perioperative arrhythmia and may be particularly problematic after liver transplantation (LT). This study is a single‐center retrospective analysis of POAF to determine its incidence following LT, to identify risk factors, to assess its impact on clinical outcomes, and to summarize management strategies. The records of all patients who underwent LT between 2010 and 2018 were reviewed. Extracted data included pre‐LT demographics and cardiac evaluation, in‐hospital post‐LT cardiac events, early and late complications, and survival. Among 1011 patients, the incidence of post‐LT POAF was 10%. Using binary logistic regression, pre‐LT history of atrial fibrillation was the strongest predictor of POAF (odds ratio [OR], 6.72; 95% confidence interval [CI], 2.00‐22.57; P < 0.001), followed by history of coronary artery disease (CAD; OR, 2.52; 95% CI, 1.10‐5.81; P = 0.03). Cardiac stress testing abnormality and CAD on cardiac catheterization were also associated with higher risk. Median time to POAF onset after LT was 3 days with 72% of cases resolving within 48 hours. POAF patients had greater hospital length of stay, death during the LT admission, and 90‐day and 1‐year mortality. POAF was an independent risk factor for post‐LT mortality (OR, 2.0; 95% CI, 1.3‐3.0; P < 0.01). Amiodarone was administered to 73% of POAF patients with no evidence of increased serum alanine aminotransferase levels. POAF occurred in 10% of post‐LT patients with early onset and rapid resolution in most affected patients. POAF patients, however, had significant morbidity and mortality, suggesting that POAF is an important marker for worse early and late post‐LT outcomes.Item Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension(Wiley, 2019-03) Abraldes, Juan G.; Trebicka, Jonel; Chalasani, Naga; D’Amico, Gennaro; Rockey, Don C.; Shah, Vijay H.; Bosch, Jaime; Garcia-Tsao, Guadalupe; Medicine, School of MedicinePortal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta‐blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.Item Update in the Treatment of the Complications of Cirrhosis(Elsevier, 2023-07) Abradles, Juan G.; Caraceni, Paolo; Ghabril, Marwan; Ghabril, Marwan; Guadalupe , Garcia-Tsao; Medicine, School of MedicineCirrhosis consists of 2 main stages: compensated and decompensated, the latter defined by the development/presence of ascites, variceal hemorrhage, and hepatic encephalopathy. The survival rate is entirely different, depending on the stage. Treatment with nonselective β-blockers prevents decompensation in patients with clinically significant portal hypertension, changing the previous paradigm based on the presence of varices. In patients with acute variceal hemorrhage at high risk of failure with standard treatment (defined as those with a Child-Pugh score of 10-13 or those with a Child-Pugh score of 8-9 with active bleeding at endoscopy), a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) improves the mortality rate and has become the standard of care in many centers. In patients with bleeding from gastrofundal varices, retrograde transvenous obliteration (in those with a gastrorenal shunt) and/or variceal cyanoacrylate injection have emerged as alternatives to TIPS. In patients with ascites, emerging evidence suggests that TIPS might be used earlier, before strict criteria for refractory ascites are met. Long-term albumin use is under assessment for improving the prognosis of patients with uncomplicated ascites and confirmatory studies are ongoing. Hepatorenal syndrome is the least common cause of acute kidney injury in cirrhosis, and first-line treatment is the combination of terlipressin and albumin. Hepatic encephalopathy has a profound impact on the quality of life of patients with cirrhosis. Lactulose and rifaximin are first- and second-line treatments for hepatic encephalopathy, respectively. Newer therapies such as L-ornithine L-aspartate and albumin require further assessment.Item Vitamin E Improves Transplant‐free Survival and Hepatic Decompensation among Patients with NASH and Advanced Fibrosis(AASLD, 2018) Vilar-Gomez, Eduardo; Vuppalanchi, Raj; Gawrieh, Samer; Ghabril, Marwan; Saxena, Romil; Cummings, Oscar W.; Chalasani, Naga; Medicine, School of MedicineVitamin E improves liver histology in non‐diabetic adults with nonalcoholic steatohepatitis (NASH), but its impact on long‐term patient outcomes is unknown. We evaluated whether vitamin E treatment improves clinical outcomes of NASH patients with bridging fibrosis or cirrhosis. Two hundred and thirty‐six patients with biopsy‐proven NASH and bridging fibrosis or cirrhosis seen at Indiana University Medical Center between October 2004, and January 2016 were included. Ninety of them took 800 IU/day of vitamin E for ≥ 2 years (vitamin E users) and were propensity matched to 90 adults who did not take vitamin E (controls) after adjusting for fibrosis severity, age, gender, body mass index, comorbidities and their treatment, LDL cholesterol, liver biochemistries and length of follow‐up on vitamin E. Covariate‐adjusted cox and competing risk regression models were assessed to evaluate association between vitamin E treatment and patient outcomes. The median follow‐up was 5.62 (IQR: 4.3‐7.5) and 5.6 (IQR: 4‐6.9) years for vitamin E users and controls respectively. Vitamin E users had higher adjusted transplant‐free survival (78% vs. 49%, P<.01) and lower rates of hepatic decompensation (37% vs. 62%, P=.04) than controls. After controlling for severity of fibrosis, calendar year of patient enrollment and other potential confounders, vitamin E treatment decreased the risk of death or transplant (adj. HR: 0.30, 95% CI: 0.12‐0.74, P<.01) and hepatic decompensation (adj. sHR: 0.52, 95% CI: 0.28‐0.96, P=.036). These benefits were evident in both diabetics as well as non‐diabetics. Adjusted 10‐year cumulative probability of HCC, vascular events and non‐hepatic cancers were not different between vitamin E exposed and controls.