Anne M. Larson

Acetaminophen‐induced acute liver failure: Results of a United States multicenter, prospective study

Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen‐induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6‐year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen‐related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra‐strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic‐containing compounds. Eighty‐one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant‐free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high‐risk use settings is recommended. (HEPATOLOGY 2005;42:1364–1372.)

Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.

BACKGROUND & AIMS N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure. METHODS In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation. RESULTS A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I-II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III-IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031). CONCLUSIONS Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.

Depression, fatigue, and functional disability in patients with chronic hepatitis C

OBJECTIVE To examine the extent to which fatigue and functional disability correlate with severity of depressive symptoms in patients with chronic hepatitis C. METHODS Fifty patients with chronic hepatitis C were evaluated using structured psychiatric interviews and standardized rating instruments. RESULTS Fourteen (28%) of patients had current depressive disorders. Depressed and nondepressed patients did not differ with regard to demographics or hepatic disease severity. Severity of depressive symptoms was highly correlated with fatigue severity while measures of hepatic disease severity, interferon treatment, and severity of comorbid medical illness were not. Severity of depressive symptoms was associated with functional disability and somatization. CONCLUSIONS Disability and fatigue are more closely related to depression severity than to hepatic disease severity. Antidepressant treatment trials in patients with hepatitis C are indicated to determine whether improvement in depressive symptoms leads to improvement in fatigue and functioning.

Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy

Monitoring of intracranial pressure (ICP) in acute liver failure (ALF) is controversial as a result of the reported complication risk (∼20%) and limited therapeutic options for intracranial hypertension. Using prospectively collected information from 332 patients with ALF and severe encephalopathy, we evaluated a recent experience with ICP monitoring in the 24 centers constituting the U.S. ALF Study Group. Special attention was given to the rate of complications, changes in management, and outcome after liver transplantation (LT). ICP monitoring was used in 92 patients (28% of the cohort), but the frequency of monitoring differed between centers (P < 0.001). ICP monitoring was strongly associated with the indication of LT (P < 0.001). A survey performed in a subset of 58 patients with ICP monitoring revealed intracranial hemorrhage in 10.3% of the cohort, half of the complications being incidental radiological findings. However, intracranial bleeding could have contributed to the demise of 2 patients. In subjects listed for LT, ICP monitoring was associated with a higher proportion of subjects receiving vasopressors and ICP‐related medications. The 30‐day survival post‐LT was similar in both monitored and nonmonitored groups (85% vs. 85%). In conclusion, the risk of intracranial hemorrhage following ICP monitoring may have decreased in the last decade, but major complications are still present. In the absence of ICP monitoring, however, patients listed for LT appear to be treated less aggressively for intracranial hypertension. In view of the high 30‐day survival rate after LT, future studies of the impact of intracranial hypertension should also focus on long‐term neurological recovery from ALF. (Liver Transpl 2005;11:1581–1589.)

Introduction to the revised American Association for the Study of Liver Diseases position paper on acute liver failure 2011

The diagnosis of ALF hinges on identifying that the patient has an acute insult and is encephalopathic. Imaging in recent years has suggested “cirrhosis,” but this is often an overcall by radiology, because a regenerating massively necrotic liver will give the same nodular profile as cirrhosis.1 It is vital to promptly get viral hepatitis serologies, including A-E as well as autoimmune serologies, because these often seem to be neglected at the initial presentation. Fulminant Wilsons disease can be diagnosed most effectively not by waiting for copper levels (too slow to obtain) or by obtaining ceruloplasmin levels (low in half of all ALF patients, regardless of etiology), but by simply looking for the more readily available bilirubin level (very high) and alkaline phosphatase (ALP; very low), such that the bilirubin/ALP ratio exceeds 2.0. 2 The availability of an assay that measures acetaminophen adducts has been used for several years as a research tool and has improved our clinical recognition of acetaminophen cases when the diagnosis is obscured by patient denial or encephalopathy. 3 Any patient with very high aminotransferases and low bilirubin on admission with ALF very likely has acetaminophen overdose, with the one possible exception being those patients who enter with ischemic injury. Obtaining autoantibodies should be routine and a low threshold for biopsy in patients with indeterminate ALF should be standard, given that autoimmune hepatitis may be the largest category of indeterminate, after unrecognized acetaminophen poisoning. 4

Ischemic cholangiopathy following liver transplantation from donation after cardiac death donors

The use of donation after cardiac death (DCD) donor hepatic allografts is becoming more widespread; however, there have been published reports of increased graft failure from specific complications associated with this type of allograft. The complication of ischemic cholangiopathy (IC) has been reported to occur more frequently after the use of DCD hepatic allografts. We report the results of 52 liver transplants from DCD donors and the factors that influenced the development of IC. We conducted a retrospective review of all DCD and donation after brain death (DBD) donor liver recipients from September 2003 through December 2006 at a single institution. Survival and complication rates were compared between the 2 groups. The Cox proportional hazards model was then used to identify recipient and donor factors that predict the development of IC in the DCD group. There was no difference in 1‐year patient or graft survival rates between the 2 groups. There was no incidence of primary nonfunction from the DCD allografts. Hepatic artery complications and anastomotic bile duct complications were comparable in the 2 groups. There was, however, an increased risk for the development of IC in the DCD group (13.7% versus 1%, P = 0.001). Donor weight >100 kg and total ischemia times ≥9 hours, in donors older than 50 years of age, predicted the development of IC in the DCD group. In conclusion, there is a higher incidence of IC in recipients receiving DCD donor livers; however, patient and graft outcomes with DCD donors remain comparable to those with DBD donors. Careful donor selection may improve utilization of these grafts. Liver Transpl 14:604–610, 2008.

Screening for Wilson Disease in Acute Liver Failure: A Comparison of Currently Available Diagnostic Tests

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF‐WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 μg/dL in all ALF‐WD patients measured (13/16), but were also elevated in non‐WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conclusion: Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF‐WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD. (HEPATOLOGY 2008.)

Prospective Characterization of Full-Length Hepatitis C Virus NS5A Quasispecies during Induction and Combination Antiviral Therapy

ABSTRACT The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein has been controversially implicated in the inherent resistance of HCV to interferon (IFN) antiviral therapy in clinical studies. In this study, the relationship between NS5A mutations and selection pressures before and during antiviral therapy and virologic response to therapy were investigated. Full-length NS5A clones were sequenced from 20 HCV genotype 1-infected patients in a prospective, randomized clinical trial of IFN induction (daily) therapy and IFN plus ribavirin combination therapy. Pretreatment NS5A nucleotide and amino acid phylogenies did not correlate with clinical IFN responses and domains involved in NS5A functions in vitro were all well conserved before and during treatment. A consensus IFN sensitivity-determining region (ISDR237–276) sequence associated with IFN resistance was not found, although the presence of Ala245 within the ISDR was associated with nonresponse to treatment in genotype 1a-infected patients (P < 0.01). There were more mutations in the 26 amino acids downstream of the ISDR required for PKR binding in pretreatment isolates from responders versus nonresponders in both HCV-1a- and HCV-1b-infected patients (P < 0.05). In HCV-1a patients, more amino acid changes were observed in isolates from IFN-sensitive patients (P < 0.001), and the mutations appeared to be concentrated in two variable regions in the C terminus of NS5A, that corresponded to the previously described V3 region and a new variable region, 310 to 330. Selection of pretreatment minor V3 quasispecies was observed within the first 2 to 6 weeks of therapy in responders but not nonresponders, whereas the ISDR and PKR binding domains did not change in either patient response group. These data suggest that host-mediated selective pressures act primarily on the C terminus of NS5A and that NS5A can perturb or evade the IFN-induced antiviral response using sequences outside of the putative ISDR. Mechanistic studies are needed to address the role of the C terminus of NS5A in HCV replication and antiviral resistance.

Fulminant Hepatitis A Virus Infection in the United States: Incidence, Prognosis, and Outcomes

Acute liver failure (ALF) due to hepatitis A virus (HAV) infection is an uncommon but potentially lethal illness. The aim of this study was to identify readily available laboratory and clinical features associated with a poor prognosis among ALF patients with HAV infection. The presenting features of 29 adults with anti‐HAV IgM positive ALF enrolled in the ALFSG_between 1998 and 2005 were reviewed. The HAV patients listed for transplantation by UNOS were also reviewed. Acute HAV accounted for 3.1% of patients enrolled in the ALFSG. At 3 weeks follow‐up, 16 had spontaneously recovered (55%), 9 underwent transplantation (31%), and 4 had died (14%). A prognostic model incorporating 4 presenting features (serum ALT <2,600 IU/L, creatinine >2.0 mg/dL, intubation, pressors) had an AUROC for transplant/death of 0.899 which was significantly better than the Kings College criteria (0.623, P = .018) and MELD scores (0.707, P = .0503). Between 1988 and 2005, the frequency of patients requiring liver transplantation for HAV in the UNOS database significantly decreased from 0.7 % to 0.1% (P < .001). In addition, the proportion of HAV cases enrolled in the ALFSG significantly decreased from 5% to 0.8% (P = .007). In conclusion, the frequency of HAV patients enrolling in the ALFSG and being listed for liver transplantation in the United States has declined in parallel. A prognostic index consisting of 4 clinical and laboratory features predicted the likelihood of transplant/death significantly better than other published models suggesting that disease specific prognostic models may be of value in non‐acetaminophen ALF. (HEPATOLOGY 2006;44:1589–1597.)

Troglitazone-induced fulminant hepatic failure

Troglitazone (Rezulin, Parke-Davis, Morris Plains, New Jersey), the first marketed member of a new class of oral agents for type II diabetes mellitus, the thiazolidinediones, has a number of attractive attributes. It reduces insulin resistance and increases insulin-stimulated glucose disposal, resulting in improved glycemic control and decreased insulin requirements in treated patients (1, 2). In addition, it is dosed once a day, is readily absorbed from the gastrointestinal tract, does not induce hypoglycemia, and does not appear to interact with other medications. Because of these attributes, troglitazone has enjoyed widespread use since its introduction in March 1997. In premarketing clinical trials of troglitazone, mild hepatotoxicity identified as reversible elevations of alanine aminotransferase (ALT) greater than three times normal were seen in less than 2% of treated patients (3). However, since the drug was released, several cases of more severe, even fatal, episodes of hepatitis have been reported (4–7). Here we report three cases of apparent troglitazone-induced fulminant liver failure prospectively identified through the Acute Liver Failure Study Group (ALFSG), a consortium of 14 academic medical centers with the purpose of collecting data regarding the etiology, treatment, and outcome of patients with acute liver failure. The cases highlight the potential hepatotoxicity of troglitazone and reinforce the need for close monitoring of all patients taking the drug.The three reported cases demonstrate that troglitazone is an idiosyncratic hepatotoxin that can lead to irreversible liver injury. Thus, troglitazone should be prescribed with caution and should not be used as a first-line agent in the treatment of type II DM when potentially less toxic alternatives are available. It remains to be seen whether the hepatotoxicity associated with troglitazone is a drug-class effect or specific to troglitazone. Other thiazolidinediones currently in clinical trials may be able to provide the therapeutic benefits of troglitazone without significant hepatotoxicity. If troglitazone is used, frequent monitoring of serum aminotransferases and symptoms is mandatory. However, as illustrated by these and other cases reported to date, the onset of troglitazone-induced liver injury is insidious and temporally variable. Thus, the value of close monitoring and when, if ever, it is safe to stop such monitoring are currently unclear.