Raj Satyanarayana

Donor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C

Background. The use of liver allografts from an older donor (OD) (age >50 years) is a widespread strategy to manage the disparity between supply and demand of organs for liver transplantation. This study determines the effect of OD allografts on fibrosis progression and graft survival after liver transplantation in patients with and without infection caused by hepatitis C virus (HCV). Methods. All patients undergoing liver transplantation at our center from March 1998 to December 2001 were analyzed. Protocol liver biopsies were performed at 1, 16, and 52 weeks after transplantation and yearly thereafter. One liver pathologist scored all biopsy specimens for modified hepatic activity index (0–18) and fibrosis (0–6). Results. A total of 402 patients (167 with HCV and 235 without HCV) underwent liver transplantation during the study period. Among patients with HCV, baseline characteristics of OD recipients were similar to younger donor (YD) (age <50 years) recipients. In patients with HCV, graft survival was shorter in OD graft recipients than in YD recipients (P <0.001). In patients without HCV, graft survival was independent of donor age. In patients with HCV, a fibrosis score of 3 or greater was present in 17% of OD recipients at 4 months and in 26% at 12 months after transplantation, compared with 8% of YD recipients at 4 months and 13% at 12 months (P <0.001). Conclusions. Liver transplantation with OD grafts is associated with rapid progression of fibrosis and decreased graft survival in patients with HCV, but not in patients without HCV. OD grafts should be considered preferentially for patients without HCV.

Liver Transplantation Using Controlled Donation After Cardiac Death Donors: An Analysis of a Large Single-Center Experience

The use of donation after cardiac death (DCD) donors may provide a valuable source of organs for liver transplantation. Concerns regarding primary nonfunction (PNF) and intrahepatic biliary stricture (IHBSs) have limited the enthusiasm for their use. A retrospective analysis of 1436 consecutive deceased donor liver transplants performed between December 1998 and October 2006 was conducted. These included 108 DCD liver transplants, which were compared to 1328 transplants performed with organs from donors meeting the criteria for donation after brain death (DBD). The median follow‐up was 48 months. The 1‐, 3‐, and 5‐year patient survival and graft survival for DCD donors were 91.5%, 88.1%, and 88.1% and 79.3%, 74.5%, and 71.0%, respectively. The 1‐, 3‐, and 5‐year patient survival and graft survival for DBD donors were 87.3%, 81.1%, and 77.2% and 81.6%, 74.7%, and 69.1%, respectively. Patient survival and graft survival were not significantly different between DCD donors less than 60 years old, DCD donors greater than 60 years old, and DBD donors. Causes of graft loss included IHBSs (n = 9), PNF (n = 4), recurrent hepatitis C virus (n = 4), hepatic artery thrombosis (n = 1), rejection (n = 2), and patient death (n = 13). Contrary to previously published data, excellent long‐term patient survival and graft survival can be obtained with DCD allografts, and in our experience, they are equivalent to those obtained from DBD allografts. Liver Transpl 15: 1028–1035, 2009.

Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis.

Background Autoimmune hepatitis (AIH) is an immune mediated chronic liver disease with a prevalence of 17 cases/100,000. Resistance to the standard treatment of AIH (prednisone and azathioprine) occurs in 15% to 20%. There is currently no standard treatment of patients with steroid refractory AIH. Goals Determine the efficacy of tacrolimus in the treatment of steroid refractory AIH. Methods This is a retrospective study evaluating the efficacy of Tacrolimus in the treatment of steroid refractory AIH. Results Between October 1998 and February 2002, 11 patients with steroid refractory AIH were treated with tacrolimus. Mean age was 63 years. Median duration of steroid treatment before starting tacrolimus was 9 months. Median duration of tacrolimus treatment was 25 months. Median follow-up period was 16 months. Median baseline ALT, AST were 77 U/L and 68 U/L and became 21 U/L and 32 U/L respectively at end of follow-up (P = 0.005 and 0.01 respectively). Significant weight reduction was seen in all patients (P = 0.02). Tacrolimus treatment was safe and well tolerated. Conclusion Use of low dose tacrolimus led to successful biochemical and histologic remission and weaning off prednisone in patients with steroid refractory AIH. This data supports further studies in evaluating the use of tacrolimus in the treatment of AIH.

Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

In our previous work, including analysis of more than 10,000 sera from control patients and patients with a variety of liver diseases, we have demonstrated that with the use of recombinant autoantigens, antimitochondrial autoantibodies (AMAs) are only found in primary biliary cirrhosis (PBC) and that a positive AMA is virtually pathognomonic of either PBC or future development of PBC. Although the mechanisms leading to the generation of AMA are enigmatic, we have postulated that xenobiotic‐induced and/or oxidative modification of mitochondrial autoantigens is a critical step leading to loss of tolerance. This thesis suggests that a severe liver oxidant injury would lead to AMA production. We analyzed 217 serum samples from 69 patients with acute liver failure (ALF) collected up to 24 months post‐ALF, compared with controls, for titer and reactivity with the E2 subunits of pyruvate dehydrogenase, branched chain 2‐oxo‐acid dehydrogenase, and 2‐oxo‐glutarate dehydrogenase. AMAs were detected in 28/69 (40.6%) ALF patients with reactivity found against all of the major mitochondrial autoantigens. In addition, and as further controls, sera were analyzed for autoantibodies to gp210, Sp100, centromere, chromatin, soluble liver antigen, tissue transglutaminase, and deaminated gliadin peptides; the most frequently detected nonmitochondrial autoantibody was against tissue transglutaminase (57.1% of ALF patients). Conclusion: The strikingly high frequency of AMAs in ALF supports the thesis that oxidative stress‐induced liver damage may lead to AMA induction. The rapid disappearance of AMAs in these patients provides further support for the contention that PBC pathogenesis requires additional factors, including genetic susceptibility. (HEPATOLOGY 2007.)

Steroid use in acute liver failure

Drug‐induced and indeterminate acute liver failure (ALF) might be due to an autoimmune‐like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug‐induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug‐induced ALF patients in the Acute Liver Failure Study Group from 1998‐2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug‐induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (>40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH < 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. Conclusion: Corticosteroids did not improve overall survival or SS in drug‐induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores. (Hepatology 2014;59:612–621)

Detection and diagnosis of herpes simplex virus infection in adults with acute liver failure.

Disseminated herpes simplex virus (HSV) infection may lead to acute liver failure (ALF) and the need for emergency liver transplantation (LT). The primary aim of this study was to determine the utility of HSV serological testing and HSV DNA testing by polymerase chain reaction (PCR) in the diagnosis and management of indeterminate, pregnancy‐related, and known HSV‐related ALF. Stored sera obtained on study day 1 or 2 from patients enrolled in the United States ALF Study Group with indeterminate (n = 51), pregnancy‐related (n = 12), and HSV‐related (n = 4) ALF were screened for HSV DNA by PCR and serology. While 7 of the indeterminate and pregnant patients had positive anti‐HSV immunoglobulin M, none had detectable HSV DNA. The 4 known HSV cases all had high‐titer HSV DNA on presentation (range: 3.5 to 36 × 108 copies/mL). Two HSV patients underwent LT but developed posttransplant extrahepatic HSV infection despite suppression of HSV DNA with acyclovir treatment, and one of them eventually died. The 2 other fulminant HSV patients died within 48 hours of presentation. In conclusion, serum HSV DNA indicative of occult HSV infection was not detected in 51 indeterminate and 12 pregnancy‐related ALF patients. The 4 patients with known HSV‐related ALF all had high HSV DNA levels at presentation, and despite the rapid use of antiviral therapy and emergency LT, substantial morbidity and mortality were encountered, highlighting the poor prognosis with severe disseminated HSV infection. Liver Transpl 14:1498–1504, 2008.

Detection of anti‐isoniazid and anti–cytochrome P450 antibodies in patients with isoniazid‐induced liver failure

Isoniazid (INH)‐induced hepatotoxicity remains one of the most common causes of drug‐induced idiosyncratic liver injury and liver failure. This form of liver injury is not believed to be immune‐mediated because it is not usually associated with fever or rash, does not recur more rapidly on rechallenge, and previous studies have failed to identify anti‐INH antibodies (Abs). In this study, we found Abs present in sera of 15 of 19 cases of INH‐induced liver failure. Anti‐INH Abs were present in 8 sera; 11 had anti–cytochrome P450 (CYP)2E1 Abs, 14 had Abs against CYP2E1 modified by INH, 14 had anti‐CYP3A4 antibodies, and 10 had anti‐CYP2C9 Abs. INH was found to form covalent adducts with CYP2E1, CYP3A4, and CYP2C9. None of these Abs were detected in sera from INH‐treated controls without significant liver injury. The presence of a range of antidrug and autoAbs has been observed in other drug‐induced liver injury that is presumed to be immune mediated. Conclusion: These data provide strong evidence that INH induces an immune response that causes INH‐induced liver injury. (Hepatology 2014;59:1084–1093)

Long-term outcomes of donation after cardiac death liver allografts from a single center.

Abstract:  Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non‐heart‐beating or donation after cardiac death (DCD) are encouraging. However, long‐term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow‐up >4.5 years. During 1998–2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart‐beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non‐function and biliary complications as compared with SCD and ECD. The overall one‐, two‐, and five‐yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long‐term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

Context Whether changes have occurred in the causes of acute liver failure (ALF), its management, or the survival of patients with the condition (with or without liver transplantation) is not known. Contribution This large cohort study found that despite similar causes and severity of ALF among patients referred to specialty centers from 1998 to 2013, the proportion of patients listed for liver transplantation decreased and survival improved among those who did not receive a transplant as well as those who did. Implication More study is warranted to better understand the specific changes in care that may have led to improved survival of patients with ALF. Acute liver failure (ALF) is defined as severe liver injury with rapid onset that results in hepatic encephalopathy (HE) and coagulopathy in persons without preexisting liver disease. The principal causes of ALF include acetaminophen (N-acetyl-p-aminophenol [APAP]) overdose, ischemic and pregnancy-associated liver injury, acute infection with hepatitis A or B virus, drug-induced liver injury, autoimmune hepatitis, BuddChiari syndrome, and Wilson disease (1, 2). For some causes, such as APAP toxicity, outcomes are favorable and transplant-free survival (TFS) approaches 70%, whereas other causes have unfavorable outcomes, including a much lower likelihood (<30%) of recovery without liver transplantation (2). One-year survival after emergency liver transplantation in patients with ALF in the United States and Europe is reportedly good but is lower than among patients with cirrhosis who receive a transplant (3). Patients with ALF often deteriorate rapidly and therefore receive the most urgent ranking (status 1) in the United Network for Organ Sharing transplantation system. Treatment of ALF in the intensive care unit is largely supportive and includes ventilator and vasopressor support for respiratory and/or circulatory failure, renal replacement therapy, plasma and blood transfusions, antibiotics, and measures to decrease intracranial pressure (46). N-acetylcysteine is used to treat APAP overdose and has shown efficacy in patients with ALF not due to APAP toxicity, particularly those referred early and having only mild HE (7). However, few disease-specific or general treatments are available that yield improved outcomes. In this study, our aim was to update the U.S. experience with ALF at specialized liver disease and transplant centers since the last published overview by the Acute Liver Failure Study Group (ALFSG) in 2002 (2). This group initiated its registry in January 1998 to better characterize the causes, clinical features, and outcomes of this super-orphan condition and aimed to enroll cases prospectively from participating liver transplant centers across North America. Accordingly, we analyzed data on all patients with ALF enrolled between 1998 and 2013, focusing on whether clinical features or outcomes of the ALF syndrome have changed over time. In addition, we sought to determine the relationship between ALF causes and rates of TFS and whether utilization of liver transplantation changed in the 16-year observation period. Methods Study Population From 1 January 1998 through 31 December 2013, adult patients were consecutively enrolled in the ALFSG registry (2) from 31 U.S. academic liver centers (of which only 5 legacy sites participated continuously throughout the 16-year period). All enrolled patients had both coagulopathy (international normalized ratio [INR] 1.5) and any grade of HE (as clinically defined by the classic West Haven criteria [8]) within 26 weeks of the first symptoms and had no evidence of significant chronic liver disease, especially cirrhosis. Patients for whom prior liver transplantation failed (due to primary graft nonfunction or other causes) were excluded. During the 16-year period, the number of sites participating, their geographic locations, and the number of cases contributed per site varied depending on each sites ability to continually identify and enroll patients over time (Appendix Figure 1). Appendix Figure 1. Site enrollment over time. Patients were usually admitted to intensive care units; 82.4% were hospitalized before transfer to the referral tertiary care study site, and the remainder were admitted directly to the study site. All were screened for inclusion according to the ALF criteria defined earlier. Written informed consent was obtained from the legal next of kin. A log of screen failures and consent refusal was maintained. All centers complied with local institutional review board requirements. Data Management and Integrity At enrollment into the study, we prospectively collected patient demographic characteristics (age, sex, race, and ethnicity); a complete medical history, including the timing of the first symptom of ill health, onset of jaundice and HE, and the number of days between the first symptom, hospital admission, transfer to the study site (where relevant), and enrollment in the study; and clinical features, including blood pressure and need for vasopressor support, mechanical ventilation, and renal replacement therapy, which allowed calculation of the systemic inflammatory response syndrome (SIRS) score (9). We also collected standard liver and metabolic test results and clinical data daily for up to 7 days, as well as serologic and other tests to determine the cause. All data were managed and housed on a central server at the Medical University of South Carolina. A data query system and periodic monitoring are in place to manage data integrity. In addition, ALFSG leadership conducted annual visits to clinical sites to verify data and ensure compliance with study procedures. Statistical Analysis Statistical analyses were performed using SAS, version 9.4 (SAS Institute). Missing values were not replaced or estimated. Patients with missing data were excluded from the respective analyses for those variables, and patients who were lost to follow-up before 21 days were excluded from the study. Descriptive statistics were used to characterize the demographic and other clinical variables. Categorical variables were compared using the chi-square test or the Fisher exact test (the latter when expected cell counts were <5). Medians were reported with interquartile ranges (IQRs) and were compared with the Wilcoxon rank-sum test. Survival and transplant outcomes at 21 days after study enrollment were classified as TFS (survival without liver transplantation), liver transplantation, or death (2). Outcomes were also determined at 1 and 2 years after study enrollment, but these data were less complete than the 21-day outcome data. Survival rates over time were assessed descriptively at the individual-site level to verify that changes in TFS were not affected by varying accrual of patients from different sites. Treatment utilization and survival and transplant outcomes were analyzed over time annually for trends and were also stratified into two 8-year periods: early (1998 to 2005) and later (2006 to 2013). Trends over time were analyzed using the CochranArmitage test. A significance level of less than 0.05 was used for all comparisons. Role of the Funding Source This study was funded by the National Institutes of Health. The funding source had no direct role in the design, conduct, or reporting of the study. Results Demographic Characteristics and Comorbidities During the 16-year study, 2070 patients (median age, 39.0 years [IQR, 29.0 to 52.0 years]) were enrolled in the ALFSG registry. Over the same interval, there were 660 confirmed ALF screen failures (286 due to failure to meet inclusion criteria, 212 for whom consent could not be obtained, and 162 for other reasons). Among enrolled patients, 69.3% were women and 76.4% were white (Table 1). Patients did not differ in sex, race, or ethnicity between the two 8-year periods but were significantly older and heavier in the later period. Prevalence of hypertension, heart disease, diabetes, psychiatric illness, and substance dependency all increased significantly between the early and later periods, whereas prevalence of renal disease did not. Table 1. Demographic Characteristics, Comorbidities, Clinical Severity, and Causes at Admission Causes and Clinical Severity of ALF The percentage of enrollment as a reflection of the most common causes of ALF did not change during the two 8-year periods. Hepatotoxicity due to APAP accounted for almost half the cases of ALF for the entire 16-year period (Table 1), with the highest annual prevalence (53.0%) occurring in 2013. Unintentional APAP overdoses (those in which patients took excessive medication over several days for such ailments as pain, malaise, or fever [10, 11]) were more common than intentional (suicidal) overdoses. Hepatitis A virus infection was significantly less evident during the later period (9 cases [0.8%]) than the early period (28 cases [2.8%]) (P< 0.001). Hepatic ischemia and autoimmune hepatitis increased modestly, whereas hepatitis B virus infection, drug-induced liver injury, Wilson disease, and BuddChiari syndrome were less frequently noted. Patients entered either the primary or the referral (study) site more rapidly after initial symptom onset in the later period (2.0 days [IQR, 0.0 to 8.0 days]) than the early period (3.0 days [IQR, 1.0 to 14.0 days]) (P< 0.001) (Table 1). However, the corresponding interval between symptom onset and HE onset was 4.0 days in both the early (IQR, 1.0 to 15.0 days) and later (IQR, 1.0 to 12.0 days) periods, and time from onset of jaundice to enrollment also was unchanged (3.0 days in each period [IQRs, 1.0 to 12.0 and 1.0 to 10.0 days, respectively]). Most patients with ALF were severely ill at study enrollment, with nearly 50% having grade 3 or 4 (that is, deep) HE throughout. Biochemical liver test results varied widely but indicated severe illness in most patients (Appendix Table 1). Appendix Table 1. Laboratory Values at Study Enrollment Laboratory Tests fo

Elevated troponin I levels in acute liver failure: Is myocardial injury an integral part of acute liver failure?

Although rare instances of cardiac injury or arrhythmias have been reported in acute liver failure (ALF), overall, the heart is considered to be spared in this condition. Troponin I, a sensitive and specific marker of myocardial injury, may be elevated in patients with sepsis and acute stroke without underlying acute coronary syndrome, indicating unrecognized cardiac injury in these settings. We sought to determine whether subclinical cardiac injury might also occur in acute liver failure. Serum troponin I levels were measured in 187 patients enrolled in the US Acute Liver Failure Study Group registry, and correlated with clinical variables and outcomes. Diagnoses were representative of the larger group of >1000 patients thus far enrolled and included 80 with acetaminophen‐related injury, 26 with viral hepatitis, 19 with ischemic injury, and 62 others. Overall, 74% of patients had elevated troponin I levels (>0.1 ng/ml). Patients with elevated troponin I levels were more likely to have advanced hepatic coma (grades III or IV) or to die (for troponin I levels >0.1 ng/ml, odds ratio 3.88 and 4.69 for advanced coma or death, respectively). Conclusion: In acute liver failure, subclinical myocardial injury appears to occur more commonly than has been recognized, and its pathogenesis in the context of acute liver failure is unclear. Elevated troponin levels are associated with a significant increase in morbidity and mortality. Measurement of troponin I levels may be helpful in patients with acute liver failure, to detect unrecognized myocardial damage and as a marker of unfavorable outcome. (HEPATOLOGY 2007;45:1489–1495.)