Ayse L. Mindikoglu

Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease

Nonalcoholic steatohepatitis (NASH) is becoming a common cause of liver cirrhosis requiring liver transplantation (LT). Cardiovascular complications related to metabolic syndrome and NASH recurrence in the transplanted liver may affect the outcome of LT in these patients. We compared the outcomes of LT for NASH cirrhosis and alcoholic cirrhosis (ETOH) in a large transplant center. A retrospective chart review was performed for all patients who underwent LT for cryptogenic cirrhosis with the NASH phenotype (the NASH group) or ETOH (the ETOH group) at the University of Miami from January 1997 to January 2007. There was no significant difference in survival between the NASH and ETOH groups, despite a trend toward lower survival in the former (P = 0.1699). Sepsis was the leading cause of posttransplant death in both groups, and it was followed by cardiovascular causes in the NASH group (26% versus 7% in the ETOH group, P = 0.21) and malignancies in the ETOH group (29% versus 0% in the NASH group, P = 0.024). Recurrent steatohepatitis (33% versus 0%, P < 0.0001) and acute rejection (41% versus 23%, P < 0.023) were significantly more frequent in the NASH group than in the ETOH group. There was no difference in graft failure between the groups (24% in the NASH group versus 18% in the ETOH group, P = 0.3973). In conclusion, despite a numerical trend favoring the ETOH group, there were no statistically significant differences in posttransplant survival and cardiovascular mortality between the NASH and ETOH groups. Acute rejection and recurrent steatohepatitis were significantly more frequent in the NASH group but did not lead to higher rates of retransplantation. Liver Transpl 15:1814–1820, 2009.

Outcome of Liver Transplantation for Drug- Induced Acute Liver Failure in the United States: Analysis of the United Network for Organ Sharing Database

Acute liver failure (ALF) is an uncommon but potentially lethal drug‐related adverse effect that often leads to liver transplantation (LT) or death. A retrospective cohort study was performed with the United Network for Organ Sharing Standard Transplant Analysis and Research files. Recipients who underwent LT for drug‐induced acute liver failure (DIALF) from 1987 through 2006 were analyzed. A total of 661 patients transplanted for DIALF were included in the analysis. The 4 leading implicated drug groups were acetaminophen (n = 265; 40%), antituberculosis drugs (n = 50; 8%), antiepileptics (n = 46; 7%), and antibiotics (n = 39; 6%). One‐year estimated survival probabilities were 76%, 82%, 52%, 82%, and 79% for acetaminophen, antituberculosis drugs, antiepileptics, antibiotics, and others, respectively. The lower rate of survival among those exposed to antiepileptics was observed mainly in children. Of the 22 patients less than 18 years old who had ALF due to antiepileptics, 73% died within the first year. The difference in overall survival between acetaminophen‐related and non–acetaminophen‐related ALF was not statistically significant. Patients with acetaminophen‐related ALF required dialysis prior to LT at a significantly higher rate than all other drug groups (27% versus 3%‐10%, P < 0.0001). According to Cox proportional hazards regression analysis, the independent pretransplant predictors of death after LT were being on life support, DIALF due to antiepileptic drugs at age less than 18, and elevated serum creatinine. In conclusion, the leading drug groups causing LT due to DIALF in the United States were acetaminophen, antituberculosis drugs, antiepileptics, and antibiotics. Children who had ALF due to antiepileptics had a substantially higher risk of death after LT in comparison with other drugs. Patients transplanted for acetaminophen‐related ALF required dialysis at a significantly higher rate. Being on life support, DIALF due to antiepileptics (at age less than 18), and elevated serum creatinine were independent pretransplant predictors of poor survival after LT for DIALF. Liver Transpl 15:719–729, 2009.

Impact of human immunodeficiency virus on survival after liver transplantation: analysis of United Network for Organ Sharing database.

Background. The outcome of liver transplantation (LT) in patients infected with human immunodeficiency virus (HIV) has been a matter of controversy. Methods. A retrospective cohort study was performed to assess the impact of HIV on LT survival by using United Network for Organ Sharing registry Standard Transplant Analysis and Research files. Results. A total of 138 HIV(+) and 30,520 HIV(−) patients who were ≥18 years old and underwent LT during the highly active antiretroviral therapy era (starting January 1, 1997) in the United States were included. Among all HIV(+) patients, the estimated 2-year survival probability was lower (70%) than among non-HIV patients (81%). This excess risk appeared entirely among those with coinfections, that is, HIV with hepatitis B virus or hepatitis C virus (HCV), as none of the 24 HIV-infected patients who did not have hepatitis B virus or HCV died during an average of 1.2 years of follow-up per person. Among HCV(+) patients, those with HIV coinfection had significantly lower survival rates than patients without HIV (P=0.006). Controlling for age, coinfection, Model for End-Stage Liver Disease scores, and other potential confounders in a proportional hazards regression analysis, HIV(+) patients had a hazard ratio of 1.41 (P=0.14, 95% confidence interval: 0.90–2.22) for mortality after LT. Conclusion. HIV(+) patients without HCV coinfection seemed to have good prognosis, whereas patients who had HIV/HCV coinfection had poor outcomes, which were significantly worse than that seen in those with HCV alone.

Performance of chronic kidney disease epidemiology collaboration creatinine‐cystatin C equation for estimating kidney function in cirrhosis

Conventional creatinine‐based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD‐EPI creatinine‐cystatin C equation (2012) was superior to previous creatinine‐ or cystatin C‐based GFR equations. To evaluate the performance of the CKD‐EPI creatinine‐cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by nonradiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the “bias,” “precision,” and “accuracy” of the new CKD‐EPI creatinine‐cystatin C equation to that of 24‐hour urinary creatinine clearance (CrCl), Cockcroft‐Gault (CG), and previously reported creatinine‐ and/or cystatin C‐based GFR‐estimating equations. Accuracy of CKD‐EPI creatinine‐cystatin C equation as quantified by root mean squared error of difference scores (differences between mGFR and estimated GFR [eGFR] or between mGFR and CrCl, or between mGFR and CG equation for each subject) (RMSE = 23.56) was significantly better than that of CrCl (37.69, P = 0.001), CG (RMSE = 36.12, P = 0.002), and GFR‐estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P = 0.024), CG (P = 0.0001), 4‐variable MDRD (P = 0.027), and CKD‐EPI creatinine 2009 (P = 0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD‐EPI creatinine‐cystatin C equation differed from the mGFR by more than 30%. Conclusion: The diagnostic performance of CKD‐EPI creatinine‐cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis. (Hepatology 2014;59:1532‐1542)

Hepatitis C in the Elderly: Epidemiology, Natural History, and Treatment

Hepatitis C continues to be a major public health problem affecting approximately 3% of the global population. According to the World Health Organization, an estimated 170 million people have chronic hepatitis C. Ten percent to 20% of those who are chronically infected with hepatitis C will progress to cirrhosis and 5% will develop hepatocellular carcinoma. Although the safety and efficacy of hepatitis C therapies have been studied extensively in patients between the ages of 18 and 65, patients who are older than 65 still remain an understudied and difficult-to-treat population. This review discusses the epidemiology, natural history, and treatment of chronic hepatitis C in older adults.

Gender disparity in liver transplant waiting‐list mortality: The importance of kidney function

Previous studies of men and women on the liver transplantation (LT) waiting list, without taking transplantation rates into account, have suggested a higher risk of mortality for women on the waiting list. The objective of this study was to compare men and women with respect to dying within 3 years of registration on the LT waiting list and to take into account both the immediate mortality risks and the transplantation rates. The analysis was based on Organ Procurement and Transplantation Network data for patients with end‐stage liver disease (ESLD) on the waiting list who were registered between February 2002 and August 2009. Competing risk survival analysis was performed to assess the gender disparity in waiting‐list mortality; 42,322 patients and 610,762 person‐months of waiting‐list experience were included in the analysis. The risk of dying within 3 years of listing was 19% and 17% in women and men, respectively (P < 0.0001). Among patients with kidney disease and especially those not on dialysis with an estimated glomerular filtration rate (eGFR) ≥15 and <30 mL/minute/1.73 m2, women had a substantially higher risk of dying on the waiting list within 3 years of registration versus men (26% versus 20%, P = 0.001). This disparity was related to lower transplantation rates in women (transplantation rate ratio = 0.68, P < 0.0001). Controlling for eGFR and other variables related to mortality risk, we found that the overall female‐male disparity disappeared. In conclusion, among patients with ESLD and kidney dysfunction who are not on dialysis, there is a substantial gender disparity in LT waiting‐list mortality. Our analysis suggests as an explanation the fact that women have lower transplantation rates than men in this group. The lower transplantation rates can be explained in part by the fact that Model for End‐Stage Liver Disease scores tend to be lower for women versus men because they are based on serum creatinine rather than the glomerular filtration rate. Liver Transpl 16:1147–1157, 2010.

Use of activated recombinant human factor VII (rhFVIIa) for colonic polypectomies in patients with cirrhosis and coagulopathy.

The prevalence of colonic polyps in patients with cirrhosis appears to be higher than that of the general population. The current practice for a polypectomy in a coagulopathic cirrhotic patient involves the reversal of the coagulopathy using fresh frozen plasma (FFP) prior to the polypectomy, usually at a second colonoscopy. The use of FFP is associated with many problems, particularly that of volume overload. Here we report four cases with advanced cirrhosis and severe coagulopathy that underwent polypectomies by snare cautery after an intravenous bolus infusion of recombinant human factor VIIa (rhFVIIa). The dose used was 120 microg/kg, which provided normalization of the coagulation parameters for 10-16 hr. The immediate use of rhFVIIa reduced the utilization of resources and enabled the performance of the polypectomies at the initial colonoscopy. No postpolypectomy bleeding was noted. The high cost of the drug is the only obstacle to a wider use of rhFVIIa for this purpose. The cost of the drug, however, is offset substantially by the cost of hospitalization for the administration of FFP, the cost of a second colonoscopy, and the charges associated with a second utilization of the endoscopy suite.

Current Concepts in the Diagnosis and Classification of Renal Dysfunction in Cirrhosis

Background: Renal dysfunction is one of the most common complications of cirrhosis with high morbidity and mortality. Summary: In subjects with cirrhosis, renal dysfunction can present either as a direct consequence of cirrhosis (e.g. hepatorenal syndrome type I and type II) or secondary to etiologies other than cirrhosis (chronic kidney disease due to diabetic nephropathy, prerenal azotemia), or patients with cirrhosis may have renal dysfunction resulting directly from cirrhosis and an underlying chronic kidney disease. Key Messages: Given the challenges in the differential diagnosis of renal dysfunction and insufficient accuracy of serum creatinine and creatinine-based glomerular filtration rate estimating equations in cirrhosis, there is an urgent need for more accurate biomarkers of renal dysfunction in this population. This review will discuss novel concepts for the diagnosis and classification of renal dysfunction in cirrhosis to overcome at least some of the diagnostic and therapeutic challenges. Additionally, a new classification will be proposed for renal dysfunction in cirrhosis.

SlimQuick™ - associated hepatotoxicity in a woman with alpha-1 antitrypsin heterozygosity

Green tea (Camellia sinensis)-associated hepatotoxicity is reported. However, the presence of alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated drug-induced liver injury (DILI) is unknown. A previously healthy woman with alpha-1 antitrypsin MZ phenotype who took SlimQuick™, an herbal supplement containing green tea extract, developed severe hepatotoxicity requiring corticosteroid treatment. Green tea-associated hepatotoxicity is reviewed and alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated DILI is discussed. Liver biopsy demonstrated marked inflammation with necrosis suggestive of toxic injury with diffuse alpha-1 antitrypsin globule deposition on immunostaining. Corticosteroid therapy resulted in rapid clinical improvement. Alpha-1 antitrypsin MZ phenotype may increase vulnerability to herbal hepatotoxicity.

Simultaneous Liver-Kidney Versus Liver Transplantation Alone in Patients with End-Stage Liver Disease and Kidney Dysfunction Not on Dialysis

BACKGROUND Since implementation of the Model for End-stage Liver Disease (MELD), the number of simultaneous liver-kidney transplantations (SLKT) has increased in the United States. However, predictors and survival benefit of SLKT compared to liver transplantation alone (LTA) are not well defined. METHODS Organ Procurement and Transplantation Network data of patients with end-stage liver disease (ESLD) with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) who had not been on dialysis while on the waiting list and underwent liver transplantation between 2002 and 2008 were analyzed. To identify predictors of undergoing SLKT versus LTA, multiple logistic regression analysis was performed. Cox proportional hazards regression analysis was used to assess the association between SLKT and post-liver transplant patient and graft survival. RESULTS The study cohort comprised 5443 patients; 262 (5%) underwent SLKT and 5181 (95%) underwent LTA. Adjusting for potential confounders, patients who underwent SLKT were 34% less likely to die after liver transplantation than those who underwent LTA (hazard ratio [HR] = 0.66, P = .012) and 33% less likely to have liver graft failure than those who underwent LTA (HR = 0.67, P = .010). Among those who underwent SLKT, 1-, 3-, and 5-year kidney graft survival probabilities were 88%, 80%, and 77%, respectively. Black race and diabetes were associated with a higher likelihood of SLKT versus LTA; female sex, a higher eGFR, and higher MELD score reduced the likelihood of SLKT. CONCLUSIONS Among those with ESLD and kidney dysfunction not on dialysis, post-liver transplant patient and liver graft survivals of patients who underwent SLKT were superior to those of patients who underwent LTA. Whether this reflects differences in the two groups that could not be adjusted in survival models or a specific effect of kidney dysfunction cannot be established.