Santiago J. Munoz

A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis

One hundred fifty-one patients with primary biliary cirrhosis (PBC) grouped into four strata based on entry serum bilirubin ( or +2 (strata 3 and 4). Histology was favorably affected by ursodiol in patients in strata 1 and 2 but not in strata 3 and 4. Ursodiol enrichment in fasting bile obtained at the conclusion of the trail was approximately 40% and comparable in all strata. Thus, differences in ursodiol enrichment of the bile acid pool do not explain better responses of laboratory tests and histology found in patients with less advanced PBC. Patients treated will ursodiol tended to develop a treatment failure less frequently that those who received placebo, particularly in strata 1 and 2 (ursodiol 42%, placebo 60%, P = .078). Development of severe symptoms (fatigue/pruritus) and doubling of serum bilirubin were reduced significantly in ursodiol-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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.)

Molecular mimicry in primary biliary cirrhosis. Evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2.

Sera from patients with primary biliary cirrhosis (PBC) react with enzymes of the 2-oxo dehydrogenase pathways, particularly PDC-E2. These enzymes are present in all nucleated cells, yet autoimmune damage is confined to biliary epithelial cells. Using a panel of eight mouse monoclonal antibodies and a human combinatorial antibody specific for PDC-E2, we examined by indirect immunofluorescence and confocal microscopy sections of liver from patients with PBC, progressive sclerosing cholangitis, and hepatocarcinoma. The monoclonal antibodies gave typical mitochondrial immunofluorescence on biliary epithelium and on hepatocytes from patients with either PBC, progressive sclerosing cholangitis, or hepatocarcinoma. However, one of eight mouse monoclonal antibodies (C355.1) and the human combinatorial antibody reacted with great intensity and specificity with the luminal region of biliary epithelial cells from patients with PBC. Simultaneous examination of these sections with an antiisotype reagent for human IgA revealed high IgA staining in the luminal region of biliary epithelial cells in patients with PBC. IgG and IgA antibodies to PDC-E2 were detected in the bile of patients with PBC but not normal controls. We believe that this data may be interpreted as indicating that a molecule cross-reactive with PDC-E2 is expressed at high levels in the luminal region of biliary epithelial cells in PBC.

Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders

Summary Background Retroviruses have been implicated in the aetiology of various autoimmune diseases. We used immunoblots as a surrogate test to find out whether retroviruses play a part in the development of primary biliary cirrhosis. Methods We did western blot tests for HIV-1 and the human intracisternal A-type particle (HIAP), on serum samples from 77 patients with primary biliary cirrhosis, 126 patients with chronic liver disease, 48 patients with systemic lupus erythematosus, and 25 healthy volunteers. Findings HIV-1 p24 gag seroreactivity was found in 27 (35%) of 77 patients with primary biliary cirrhosis, 14 (29%) of 48 patients with systemic lupus erythematosus, 14 (50%) of 28 patients with chronic viral hepatitis, and nine (39%) of 23 patients with either primary sclerosing cholangitis or biliary atresia, compared with only one (4%) of 24 patients with alcohol-related liver disease or α 1 -antitrypsin-deficiency liver disease, and only one (4%) of 25 healthy volunteers (p=0·003). Western blot reactivity to more than two HIAP proteins was found in 37 (51%) of patients with primary biliary cirrhosis, in 28 (58%) of patients with systemic lupus erythematosus, in 15 (20%) of patients with chronic viral hepatitis, and in four (17%) of those with other biliary diseases. None of the 23 patients with either alcohol-related liver disease or α 1 -antitrypsin deficiency, and only one of the healthy controls showed the same reactivity to HIAP proteins (p Interpretation The HIV-1 and HIAP antibody reactivity found in patients with primary biliary cirrhosis and other biliary disorders may be attributable either to an autoimmune response to antigenically related cellular proteins or to an immune response to uncharacterised viral proteins that share antigenic determinants with these retroviruses.

Controlled non-heart-beating donor liver transplantation : A successful single center experience, with topic update

Background. The critical shortage of transplantable organs necessitates utilization of unconventional donors. We describe a successful experience of controlled non-heart-beating donor (NHBD) liver transplantation. Methods. Controlled NHBDs had catastrophic head injury, prognosis for no meaningful recovery, decision to withdraw life support, and subsequent consent for donation. After stopping mechanical ventilation in the operating room, death determination by a nontransplant caregiver, and rapid aortic cannulation, liver and kidneys were recovered. Results. Controlled NHBDs contributed 5% of hepatic allografts (8/164) from August 1996 through June 1999 (9% in 1998). Sixteen NHBDs afforded 8 livers and 24 kidneys. Liver donors (n=8) were 11–66 years old; half were >50 years old. Premortem alanine aminotransferase was 25–157 U/L. Arrest occurred 3–27 min after stopping ventilation. Perfusion started 3–5 min after incision, and <22 min after hypotension (mean arterial pressure: <50 mmHg). Patient and graft survivals are 100% at 18±12 months follow-up. There was no intraoperative complication, reperfusion syndrome, poor graft function, primary nonfunction, arterial thrombosis, biliary complication, or serious infection. Postoperative day 2 prothrombin time was 13±1 sec. Peak alanine aminotransferase was 980±601 U/L. Intensive care unit and posttransplant lengths of stay were 2±2 and 10±7 days, respectively. Soon after transplantation there was frequent temporary hyperbilirubinemia (five of eight recipients; bilirubin peak: 7–29 mg/dl, 2–3 weeks after transplantation) and rejection (4/8 recipients, <3 weeks after transplantation). Conclusions. NHBDs significantly and safely expanded our donor pool. NHBD surgeons must be capable of rapid procurement. Cautious liberalization of criteria for accepting livers from NHBDs with confounding risk factors is justified. Refined ethics guidelines would broaden approval of NHBDs.

Long-term outcome of controlled, non-heart-beating donor liver transplantation.

Background. Previous reports have established the feasibility of using livers from controlled, non–heart-beating donors (CNHBD) with good immediate graft function. This has been largely borne out of necessity because of the donor shortage. Methods. Retrospective database review for the last 7 years (1995–2002), encompassing 19 patients receiving CNHBD, with follow-up period of 1,000±694 days, median 762 days. Detailed review of recipient characteristics, operative and clinical course, immunosuppression, complications, survival rates, and comparison with the results obtained in patients receiving transplants of allografts procured in standard fashion, from heart-beating donors Results. Kaplan-Meier patient survival rates were 100%, 89.5%, and 83.5% at 30 days, 1, and 2 years, respectively, which is not different from recipients of livers procured from heart-beating cadaveric donors (P=0.74, log-rank test). Five patients died at a mean follow-up time of 492 (range 46–1,103) days. The causes of death were related to secondary sclerosing cholangitis (n=1), cardiac failure (n=1), and sepsis (n=3). Two (10.5%) recipients underwent retransplantation, one for primary graft nonfunction and one because of biliary cast syndrome with cholangitis. Significant preservation damage (ALT>2,000) developed in five patients, but this did not affect survival. The incidence of vascular (15.6% vs. 9.6%, P=0.34) and biliary complications (10.55 vs. 13.8%, P=0.68) was no different than for those recipients receiving standard cadaveric donors. Conclusions. CNHBD safely expands the donor pool with similar long-term results as those obtained in patients receiving organs from brain-dead donors under standard procurement techniques.

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.)

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo‐controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwigs histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6‐8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;42:1184–1193.)

Coagulopathy of Acute Liver Failure

Coagulopathy is an essential component of the acute liver failure (ALF) syndrome and reflects the central role of liver function in hemostasis. ALF is a syndrome characterized by the development of hepatic encephalopathy and coagulopathy within 24 weeks of the onset of acute liver disease. Coagulopathy in this setting is a useful prognostic tool in ALF and a dynamic indicator of the hepatic function. If severe, it can be associated with bleeding and is commonly a major obstacle to the performance of invasive procedures in patients with ALF. This review focuses on the epidemiology, pathophysiology, presentation, evaluation, and management of coagulopathy in ALF.

Alpha-fetoprotein and prognosis in acute liver failure

Serum concentrations of alpha‐fetoprotein (AFP), variably elevated during liver injury, have been suggested to be of prognostic importance in acute liver failure (ALF), higher values being associated with improved outcome. Using a nephelometric assay, we measured AFP in sera obtained on admission from 206 patients prospectively enrolled in the US ALF Study, and on day 3 in 162 of these patients. The AFP ratio was defined as the day 3 AFP concentration divided by that observed on day 1. Median (range) admission serum AFP in all patients was 8.1 (1–1,811) ng/mL and increased to 17.6 (1.1–1,162) ng/mL on day 3 (P < 0.001). Higher absolute levels were not associated with improved outcome. In fact, admission AFP levels were lower in survivors not receiving transplants than in those who died or were transplanted (P < 0.001), whereas there was no difference between the 2 groups on day 3 (P = 0.34). However, a rise in AFP values between day 1 and day 3 indicated a better prognosis: the AFP ratio was 2.2 (0.11–22.1) in spontaneous survivors and 0.87 (0.11–16.4) in nonsurvivors (P < 0.001). An increasing AFP level indicated by an AFP ratio ≥1 was observed in 70 of 98 (71%) survivors, whereas a ratio <1 was observed in 51 of 64 (80%) nonsurvivors. In conclusion, AFP values change dynamically during ALF. In this large prospective study, higher absolute values of AFP did not predict a favorable outcome, but a rising level of AFP over the first 3 hospital days frequently indicated survival. Liver Transpl 12:1776–1781, 2006.