The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Social and Financial Outcomes of Living Liver Donation: A Prospective Investigation Within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2).

Because results from single-center (mostly kidney) donor studies demonstrate interpersonal relationship and financial strains for some donors, we conducted a liver donor study involving nine centers within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2) consortium. Among other initiatives, A2ALL-2 examined the nature of these outcomes following donation. Using validated measures, donors were prospectively surveyed before donation and at 3, 6, 12, and 24 mo after donation. Repeated-measures regression models were used to examine social relationship and financial outcomes over time and to identify relevant predictors. Of 297 eligible donors, 271 (91%) consented and were interviewed at least once. Relationship changes were positive overall across postdonation time points, with nearly one-third reporting improved donor family and spousal or partner relationships and >50% reporting improved recipient relationships. The majority of donors, however, reported cumulative out-of-pocket medical and nonmedical expenses, which were judged burdensome by 44% of donors. Lower income predicted burdensome donation costs. Those who anticipated financial concerns and who held nonprofessional positions before donation were more likely to experience adverse financial outcomes. These data support the need for initiatives to reduce financial burden.

Psychological Outcomes of Living Liver Donors From a Multicenter Prospective Study: Results From the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2).

Although single-center and cross-sectional studies have suggested a modest impact of liver donation on donor psychological well-being, few studies have assessed these outcomes prospectively among a large cohort. We conducted one of the largest, prospective, multicenter studies of psychological outcomes in living liver donors within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2) consortium. In total, 271 (91%) of 297 eligible donors were interviewed at least once before donation and at 3, 6, 12, and 24 mo after donation using validated measures. We found that living liver donors reported low rates of major depressive (0-3%), alcohol abuse (2-5%), and anxiety syndromes (2-3%) at any given assessment in their first 2 years after donation. Between 4.7% and 9.6% of donors reported impaired mental well-being at various time points. We identified significant predictors for donors' perceptions of being better people and experiencing psychological growth following donation, including age, sex, relationship to recipient, ambivalence and motivation regarding donation, and feeling that donation would make life more worthwhile. Our results highlight the need for close psychosocial monitoring for those donors whose recipients died (n=27); some of those donors experienced guilt and concerns about responsibility. Careful screening and targeted, data-driven follow-up hold promise for optimizing psychological outcomes following this procedure for potentially vulnerable donors.

Heparin-induced hepatotoxicity.

Heparin-induced hepatotoxicity is well described in the literature, but rarely recognized clinically. Two cases were recently encountered. In the first case, elevated aminotransferase levels occurred after four days of heparin therapy. In the second case, enzyme levels increased after only 8 h of heparin treatment. To the authors' knowledge, this short time interval between the administration of heparin and liver enzyme elevations has not been described. The objective of this report is to increase the clinical awareness of this interesting and under-recognized biochemical observation.

Use of interferon for prevention of hepatocellular carcinoma in cirrhotic patients with hepatitis B or hepatitis C virus infection.

The incidence of hepatocellular carcinoma in North America is increasing. Current debate focuses on whether interferon administered to cirrhotic patients-with or without biochemical or virologic response-delays or prevents cancer of the liver. Review of the literature revealed several studies that showed improvement in or delay in progression of histologic fibrosis in patients with hepatitis C virus (HCV) infection. In patients with hepatitis B virus (HBV) infection, conversion to the nonreplicative stage may be associated with histologic improvement. However, only 11 studies (6 of HCV, 3 of HBV, and 2 of HCV and HBV) compared development of hepatocellular carcinoma in interferon-treated patients with cirrhosis and cirrhotic patients who were not treated with interferon. Although no firm statistical conclusions could be drawn, the literature suggests that interferon therapy may prevent hepatocellular carcinoma in patients with cirrhosis, particularly those infected with HCV. Interferon treatment cannot be recommended for all persons with cirrhosis and HBV or HCV infection because the current evidence is only suggestive. Long-term randomized, controlled trials may provide definitive data; however, it will be difficult, if not impossible, to conduct such trials because of the improved efficacy of combination therapy with interferon and ribavirin in patients with chronic HCV infection and the development of new therapies for patients with HBV infection.

Fatal fulminant hepatic failure due to cyproterone acetate.

Cyproterone acetate is a normally well-tolerated drug that is used widely for the treatment of prostatic carcinoma. Liver toxicity due to its use is not well known. We describe two cases of fatal fulminant hepatitis related to the use of cyproterone acetate.

Specific in vitro association between the hepatitis C viral genome and core protein.

Little is known about the molecular interactions required for hepatitis C virion assembly. The 5' noncoding region (5'NCR) of the RNA genome is highly conserved and has extensive secondary structure. The highly basic core protein is rich in arginine and lysine residues. We postulate that a specific interaction between these structures may be important for virion assembly. Using an RNA gel mobility shift assay, a specific interaction has been demonstrated between the RNA of the 5'NCR and recombinant core protein. Proteins from other regions of the virus do not interact with the viral RNA. The interaction is inhibited competitively by unlabelled sense polarity RNA, but antisense 5'NCR RNA and nonspecific RNAs compete only at much higher concentrations. These data suggest that there is a specific interaction between the 5'NCR of the hepatitis C virus (HCV) genome and HCV core protein. This interaction may be important for the specific encapsidation of the viral genome during HCV replication.

Presence of viral replicative intermediates in the liver and serum of patients infected with hepatitis C virus.

Hepatitis C virus (HCV) is a positive-polarity, single-stranded RNA virus, distantly related to the pestivirus and flavivirus genera. These viruses replicate through the formation of a minus-strand RNA intermediate, which encodes the positive-strand genome, which is subsequently encapsidated, enveloped, and released from infected cells. Minus-strand RNA is not found in the mature, circulating virions of flaviviruses. In an attempt to study the relative amounts of viral plus and minus strand in the liver and serum of HCV-infected individuals, we have developed a technique to amplify specifically each of the viral strands using a modified reverse transcriptase/polymerase chain reaction protocol on extracted RNA. Liver tumor and nontumor tissue from a patient with C-100-3 antibody was analyzed using this technique. In both cases, viral plus and minus strands were detected, although the plus-strand signal was several fold stronger than minus-strand signal by Southern hybridization. Sera from 11 C-100-3 antibody-positive patients with abnormal serum AIT levels were similarly analyzed. In all cases viral plus strand was detected, and in 10 of 11 cases viral minus strand was detected. The minus-strand signal was always much weaker than the plus-strand signal and the ratio of plus strand to minus strand varied among patients. No correlation was found between the level of minus strand detected or its ratio to plus strand with the level of serum transaminases or any other clinical parameter.

Acute hepatitis in Crigler-Najjar syndrome.

We describe a 23-yr-old man with congenital unconjugated hyperbilirubinemia secondary to uridine diphosphate glucuronosyltransferase deficiency, and who cannot readily be classified as type I or type II Crigler-Najjar syndrome. After an episode of kernicterus in childhood he was treated with phenobarbital with a resultant marked decrease in his serum bilirubin concentration. Herein we describe his course after developing acute hepatitis secondary to infectious mononucleosis. He was treated acutely with plasmapheresis with prevention of any neurological sequelae despite having previously suffered from kernicterus.

Effects of adenine arabinoside on serum and intrahepatic replicative forms of duck hepatitis B virus in chronic infection.

Adenine arabinoside is an antiviral agent which has been used in a number of clinical studies for the treatment of chronic infections with hepatitis B virus. In order to better understand its effects and mode of action, we treated ducks chronically infected with duck hepatitis B virus with a 2-week course and monitored the effects of the drug on viral replication by studying duck hepatitis B virus DNA in liver and serum using molecular biological techniques. We found the drug to be effective in ducks only at much higher doses than those used in humans. At high doses, adenine arabinoside had a dose-related inhibitory effect on viral replication during treatment, but there was a rapid return toward baseline values soon after the cessation of treatment. The supercoiled form of viral DNA was found to be most resistant to adenine arabinoside therapy, and the drug had a disproportionate inhibitory effect on viral plus (noncoding) strand synthesis. We conclude that adenine arabinoside likely exerts its effect in hepadna virus infections predominantly through inhibition of viral DNA polymerase. On the basis of our current study and previous trials in hepatitis B virus-infected patients, we predict that adenine arabinoside will not efficiently eliminate viral replication in chronic hepadna virus infection, when used as the sole therapeutic modality. Adenine arabinoside may have a role to play as an adjunct to immunomodulation or interferon therapy in chronic hepatitis B virus infection in man.

Foscarnet decreases serum and liver duck hepatitis B virus DNA in chronically infected ducks.

Foscarnet (trisodium phosphonoformate) is a new antiviral compound with in vitro inhibitory effects against the DNA polymerases of hepadna viruses. To study the effects of the drug in chronic hepadna virus infection, we treated ducks chronically infected with duck hepatitis B virus for 10 days with either low-dose foscarnet (50 mg/kg i.p. b.i.d.), high-dose foscarnet (250 mg/kg i.p. b.i.d.), or sterile water injections. Serum duck hepatitis B virus DNA and intrahepatic replicative forms of the virus were measured using molecular biological techniques with both a double-stranded radiolabeled DNA probe and a plus-strand (noncoding) specific RNA probe. We found a dose-related decrease in serum and intrahepatic duck hepatitis B virus DNA during treatment, with a rapid return toward baseline values after the cessation of treatment. There was a disproportionate decrease in the plus strand of viral DNA with treatment. We conclude that foscarnet exerts its effect in hepadna virus infection through inhibition of viral DNA polymerase. Further study is necessary to determine whether foscarnet, by itself or in combination with other treatment modalities, has a role to play in the treatment of chronic hepatitis B infections in humans.

Effects of adenine arabinoside and corticosteroid on replication of duck hepatitis B virus DNA in the liver.

Adenine arabinoside (Ara-A) therapy and abrupt withdrawal of corticosteroids have both been used in the treatment of chronic infections due to hepatitis B virus (HBV). In order to better understand the effects and mechanism of action of these treatments, we treated ducks chronically infected with duck hepatitis B virus (DHBV) with different dosage regimens of the two therapies. We measured endogenous DNA polymerase activity and used sensitive molecular biological techniques to monitor serum and intrahepatic viral replicative forms during and after drug treatment. Ara-A had a transient, dose related inhibitory effect on DHBV replication. Viral plus strand synthesis was disproportionately affected. Following the cessation of Ara-A treatment markers of viral replication returned to their baseline values. We conclude that Ara-A exerts its effect through inhibition of viral DNA polymerase. Corticosteroid treatment results in an increase in DHBV replication, but steroid withdrawal results in a short-lived transient decrease in markers of viral replication to below pretreatment values. Our results suggest that steroid withdrawal decreases hepadna virus replication through a mechanisms of immune modulation. On the basis of these results and previous trials in HBV infected patients, we predict that neither agent will efficiently eliminate viral replication in chronic hepadna virus infection when used as the sole therapeutic modality. We suggest that the differences in the mechanisms of action of Ara-A treatment and corticosteroid withdrawal be exploited, and the use of combination therapy be explored.