Iris Liou

Natural history of nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as one of the most common chronic liver diseases. The natural history of this liver disease remains unclear due to its indolent nature, the paucity of prospective studies, and the lack of consensus regarding the various forms of this disorder. Based on retrospective studies, it appears that the histologic features of NAFLD may be important determinants of the clinical course of this disease; patients with nonalcoholic steatohepatitis (NASH) appear to have a higher likelihood of progression to cirrhosis. There is an increased risk of hepatocellular carcinoma and end-stage liver disease among patients with NASH-related cirrhosis and those with cryptogenic cirrhosis, which likely represents a late stage of NAFLD. Recurrence of NASH has been described among patients who have undergone liver transplantation for NASH-related end-stage liver disease.

Role of Liver Transplantation in Acute Liver Failure

Orthotopic liver transplantation is employed as salvage therapy for individuals who are unable to recover from acute liver failure. Prognostic models are helpful but not entirely accurate in predicting those who will eventually require liver transplantation. There are specific criteria for United Network for Organ Sharing category 1a (urgent) listing of these patients. Unfortunately, clinical deterioration develops rapidly and many require removal from the waiting list prior to transplantation. With advances in critical care management and surgical technique, 1-year post-transplant survival rates have improved to 60 to 80%. Alternatives to conventional orthotopic liver transplantation include living donor liver transplantation, ABO-incompatible grafts, and auxiliary liver transplantation. There are many ethical and psychosocial issues inherent to transplanting these sick patients due to the urgent nature of acute liver failure. Fortunately, the long-term survival and quality of life in these transplant recipients is good.

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)

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

Proteome and computational analyses reveal new insights into the mechanisms of hepatitis C virus-mediated liver disease posttransplantation

Liver transplant tissues offer the unique opportunity to model the longitudinal protein abundance changes occurring during hepatitis C virus (HCV)‐associated liver disease progression in vivo. In this study, our goal was to identify molecular signatures, and potential key regulatory proteins, representative of the processes influencing early progression to fibrosis. We performed global protein profiling analyses on 24 liver biopsy specimens obtained from 15 HCV+ liver transplant recipients at 6 and/or 12 months posttransplantation. Differentially regulated proteins associated with early progression to fibrosis were identified by analysis of the area under the receiver operating characteristic curve. Analysis of serum metabolites was performed on samples obtained from an independent cohort of 60 HCV+ liver transplant patients. Computational modeling approaches were applied to identify potential key regulatory proteins of liver fibrogenesis. Among 4,324 proteins identified, 250 exhibited significant differential regulation in patients with rapidly progressive fibrosis. Patients with rapid fibrosis progression exhibited enrichment in differentially regulated proteins associated with various immune, hepatoprotective, and fibrogenic processes. The observed increase in proinflammatory activity and impairment in antioxidant defenses suggests that patients who develop significant liver injury experience elevated oxidative stresses. This was supported by an independent study demonstrating the altered abundance of oxidative stress‐associated serum metabolites in patients who develop severe liver injury. Computational modeling approaches further highlight a potentially important link between HCV‐associated oxidative stress and epigenetic regulatory mechanisms impacting on liver fibrogenesis. Conclusion: Our proteome and metabolome analyses provide new insights into the role for increased oxidative stress in the rapid fibrosis progression observed in HCV+ liver transplant recipients. These findings may prove useful in prognostic applications for predicting early progression to fibrosis. (HEPATOLOGY 2012;56:28–38)

Two‐year outcomes in initial survivors with acute liver failure: results from a prospective, multicentre study

The long‐term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known. The aim of this study was to provide an overview of the 2‐year clinical outcomes among initial survivors and liver transplant (LT) recipients that were alive 3 weeks after enrolment in the Acute Liver Failure Study Group (ALFSG).

Micro‐RNA‐122 levels in acute liver failure and chronic hepatitis C

MicroRNA‐122 (miR‐122) is the foremost liver‐related micro‐RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR‐122 are elevated in chronic‐HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR‐122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen‐induced, 15 other etiologies), 39 chronic‐HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV–HCV co‐infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR‐122 and hgDNA levels measured before and throughout treatment. Serum miR‐122 levels were elevated approximately 100‐fold in both acute liver failure and chronic‐HCV sera as compared to controls (P < 0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic‐HCV and controls (P < 0.001). Subgroup analysis showed that chronic‐HCV sera with normal aminotransferase levels showed elevated miR‐122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR‐122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic‐HCV patients have very elevated serum miR‐122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR‐122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic‐HCV to explain the exaggerated circulating levels of miR‐122 observed. J. Med. Virol. 86:1507–1514, 2014.

Congestive hepatic fibrosis score: a novel histologic assessment of clinical severity

Chronic right heart failure predisposes to hepatic passive congestion and centrizonal necrosis that may lead to hepatic fibrosis (cardiac sclerosis). Although there have been several studies on the histologic features of congestive hepatopathy, there is no available grading system. In this study we developed a novel grading system for congestive hepatic fibrosis. Liver biopsies were examined in patients with chronic heart failure of various etiologies including congenital heart disease, idiopathic cardiomyopathy, ischemic heart disease, and valvular heart disease. The cases with available echocardiography and/or right heart catheterization were included. Cases with other types of underlying chronic liver diseases, alcoholic liver disease, significant steatosis (>20%), malignant neoplasm, and acute heart failure or shock were excluded. After exclusion, 42 cases were included in the study. We herein proposed a novel congestive hepatic fibrosis score and correlated it with the right heart structure and function obtained by echocardiography and/or right heart catheterization. Our results showed that congestive hepatic fibrosis score is well correlated with the right atrial pressure (P for trend <0.001). The presence of portal fibrosis (congestive hepatic fibrosis scores 2 and 3) is associated with significantly higher right atrial pressure than those with no fibrosis (P<0.001) or with centrizonal fibrosis only (P=0.02). Congestive hepatic fibrosis score is also significantly associated with increasing severity of right atrial dilatation (P=0.03) and right ventricular dilatation (P=0.02), indicators for chronic volume and/or pressure overload. Other histopathologic features include sinusoidal dilatation and centrizonal hepatocyte atrophy. In summary, although sinusoidal dilatation and centrizonal fibrosis are the hallmarks of hepatic passive congestion, the presence of portal fibrosis is suggestive of more advanced disease, as it correlates with more severe impairment of right heart function, regardless of the etiologies of right heart failure. Congestive hepatic fibrosis score is a useful indicator of clinical severity.

Management of end-stage liver disease

Patients with cirrhosis who experience hepatic decompensation, such as the development of ascites, SBP, variceal hemorrhage, or hepatic encephalopathy, or who develop HCC, are at a higher risk of mortality. Management should be focused on the prevention of recurrence of complications, and these patients should be referred for consideration of liver transplantation.

An Immunoassay to Rapidly Measure Acetaminophen Protein Adducts Accurately Identifies Patients With Acute Liver Injury or Failure

BACKGROUND & AIMS A rapid and reliable point‐of‐care assay to detect acetaminophen protein adducts in the serum of patients with acute liver injury could improve diagnosis and management. AcetaSTAT is a competitive immunoassay used to measure acetaminophen protein adducts formed by toxic metabolites in serum samples from patients. We compared the accuracy of AcetaSTAT vs high‐pressure liquid chromatography with electrochemical detection (HPLC‐EC; a sensitive and specific quantitative analytic assay) to detect acetaminophen protein adducts. METHODS We collected serum samples from 19 healthy individuals (no liver injury, no recent acetaminophen use), 29 patients without acetaminophen‐associated acute liver injury, and 33 patients with acetaminophen‐associated acute liver injury participating in the Acute Liver Failure Study Group registry. Each serum sample was analyzed by AcetaSTAT (reported as test band amplitude) and HPLC‐EC (the reference standard). We also collected data on patient age, sex, weight, level of alanine aminotransferase on test day and peak values, concentration of acetaminophen, diagnoses (by site investigator and causality review committee), and outcome after 21 days. Differences between groups were analyzed using the Fisher exact test for categoric variables and the Kruskal–Wallis test or rank‐sum test for continuous variables. RESULTS AcetaSTAT discriminated between patients with and without acetaminophen‐associated acute liver injury; the median AcetaSTAT test band amplitude for patients with acetaminophen‐associated acute liver injury was 584 (range, 222–1027) vs 3678 (range, 394–8289) for those without (P < .001). AcetaSTAT identified patients with acetaminophen‐associated acute liver injury with 100% sensitivity, 86.2% specificity, a positive predictive value of 89.2%, and a negative predictive value of 100%. Results from AcetaSTAT were positive in 4 subjects who received a causality review committee diagnosis of non–acetaminophen‐associated acute liver injury; HPLC‐EC and biochemical profiles were consistent with acetaminophen‐associated acute liver injury in 3 of these cases. CONCLUSIONS The competitive immunoassay AcetaSTAT shows a high degree of concordance with HPLC‐EC results in identifying patients with acetaminophen‐associated acute liver injury. This rapid and simple assay could increase early detection of this disorder and aid clinical management.