Brendan M. McGuire

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure

Objective:The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure. Summary Background Data:In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. Methods:A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. Results:For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048). Conclusions:This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.

Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis

Extracorporeal albumin dialysis (ECAD) may improve severe hepatic encephalopathy (HE) in patients with advanced cirrhosis via the removal of protein or non–protein‐bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety, and tolerability of ECAD using molecular adsorbent recirculating system (MARS) was conducted in such patients. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for 6 hours for 5 days or until the patient had a 2‐grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the 2 groups. A total of 70 subjects [median age, 53; 56% male; 56% HE grade 3; 44% HE grade 4; median model for end‐stage liver disease (MELD) 32 (11–50) and CPT 13 (10–15)] were enrolled in 8 tertiary centers. Patients were randomized to ECAD + SMT (n = 39) or SMT alone (n = 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (P = 0.044) and was reached faster and more frequently than in the SMT group (P = 0.045). Subjects receiving ECAD tolerated treatment well with no unexpected adverse events. Conclusion: The use of ECAD may be associated with an earlier and more frequent improvement of HE (grade 3/4). Because this 5‐day study was not designed to examine the impact of MARS on survival, a full assessment of the role of albumin dialysis awaits the results of additional controlled trials. (HEPATOLOGY 2007.)

Intensive care of patients with acute liver failure: Recommendations of the U.S. Acute Liver Failure Study Group

Objective:To provide a uniform platform from which to study acute liver failure, the U.S. Acute Liver Failure Study Group has sought to standardize the management of patients with acute liver failure within participating centers. Methods:In areas where consensus could not be reached because of divergent practices and a paucity of studies in acute liver failure patients, additional information was gleaned from the intensive care literature and literature on the management of intracranial hypertension in non-acute liver failure patients. Experts in diverse fields were included in the development of a standard study-wide management protocol. Measurements and Main Results:Intracranial pressure monitoring is recommended in patients with advanced hepatic encephalopathy who are awaiting orthotopic liver transplantation. At an intracranial pressure of ≥25 mm Hg, osmotic therapy should be instituted with intravenous mannitol boluses. Patients with acute liver failure should be maintained in a mildly hyperosmotic state to minimize cerebral edema. Accordingly, serum sodium should be maintained at least within high normal limits, but hypertonic saline administered to 145–155 mmol/L may be considered in patients with intracranial hypertension refractory to mannitol. Data are insufficient to recommend further therapy in patients who fail osmotherapy, although the induction of moderate hypothermia appears to be promising as a bridge to orthotopic liver transplantation. Empirical broad-spectrum antibiotics should be administered to any patient with acute liver failure who develops signs of the systemic inflammatory response syndrome, or unexplained progression to higher grades of encephalopathy. Other recommendations encompassing specific hematologic, renal, pulmonary, and endocrine complications of acute liver failure patients are provided, including their management during and after orthotopic liver transplantation. Conclusions:The present consensus details the intensive care management of patients with acute liver failure. Such guidelines may be useful not only for the management of individual patients with acute liver failure, but also to improve the uniformity of practices across academic centers for the purpose of collaborative studies.

Influence of Hepatic Encephalopathy on Health-Related Quality of Life in Patients with Cirrhosis

Cirrhosis is associated with decrements in health-related quality of life (HRQOL), but the specific effects of encephalopathy, especially subclinical, on quality of life are incompletely understood. Therefore, the aim of our study was to define the effects of encephalopathy on specific domains of HRQOL in a sample of patients with advanced liver disease. The sample consisted of 160 patients with cirrhosis presenting for liver transplantation evaluation. Health-related quality of life was measured with the Short Form-36 questionnaire. Clinical, demographic, and laboratory data were collected. The presence and degree of encephalopathy was ascertained clinically and by the use of the Reitan trail test. HRQOL scores were compared according to liver disease severity and to the presence and degree of encephalopathy. In addition, scores were compared to US population norms. Data were obtained from 148 patients. Compared to the US general population, the physical and mental component summary scores were lower in patients with cirrhosis. Among patients with cirrhosis, there were no significant differences in the physical and mental component summary scores according to age, gender, ethnicity, and etiology (hepatocellular versus/ cholestatic and HCV versus non-HCV). Increasing severity of liver disease (based on the Child-Pugh score), a history of hospitalizations, and a history of ascites were associated with decreased physical component summary scores but not mental component summary scores. Patients with encephalopathy (overt and subclinical) had decreased physical and mental component summary scores compared to patients without encephalopathy. Compared to patients without encephalopathy, those with subclinical encephalopathy had a lower mental component summary score. In conclusion, cirrhosis is associated with a decreased HRQOL, especially at advanced stages. Increased severity of liver disease is associated with decreased physical aspects of quality of life. Overt hepatic encephalopathy negatively affects both physical and mental aspects of quality of life, whereas subclinical encephalopathy affects mainly the mental aspects, independently of liver disease severity.

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.)

Brief Communication: Glomerulonephritis in Patients with Hepatitis C Cirrhosis Undergoing Liver Transplantation

Context We do not know why some patients infected with hepatitis C virus (HCV) develop renal failure after liver transplantation. Contribution This case series describes 30 patients who had kidney biopsies during liver engraftment for HCV-induced cirrhosis. Twenty-five had immune-complex glomerulonephritis. Of these, 10 had normal serum creatinine levels, urinalysis results, and urinary protein excretion and none had blood or kidney cryoglobulins. Cautions Investigators did not study clinical outcomes after transplantation. Implications Clinically silent immune-complex glomerulonephritis occurs in patients with end-stage HCV-induced cirrhosis. We do not yet know whether it can lead to renal failure after liver transplantation. The Editors Chronic infection with hepatitis C virus (HCV) substantially impacts health care in the United States; currently, it affects approximately 2.7 million persons (1, 2). Accompanying extrahepatic syndromes may include glomerulonephritis (3, 4). Transplantation is a life-saving procedure for patients with end-stage cirrhosis; this disease accounts for 30% to 50% of the liver transplant surgeries performed annually in the United States. Compared with HCV-negative transplant recipients, HCV-positive recipients have an increased risk for renal failure after engraftment (5), perhaps because of glomerular renal disease. However, it is unclear whether such disease is present at engraftment or develops later. We performed the current study to determine whether HCV-infected patients have substantial renal injury at liver transplantation. Methods Patients From January 2004 through June 2005, 48 HCV antibodypositive adults underwent deceased-donor liver transplantation at the University of Alabama at Birmingham. We enrolled all 37 patients who provided written informed consent and met the following inclusion criteria: age older than 18 years; positive results for HCV antibody on second-generation enzyme-linked immunosorbent assay; circulating HCV RNA; and cirrhosis documented by history, liver biopsy, or abdominal imaging. Patients were excluded if they had previous organ transplantation, concomitant renal transplantation, ABO-incompatible liver, or seropositivity for hepatitis B virus or HIV. The Institutional Review Board for Human Use at the University of Alabama at Birmingham approved this study. Study Procedures Within 6 months of expected liver transplantation, medical history was recorded, physical examination was performed, and blood and urine samples were collected. Blood studies included serum creatinine and albumin, blood urea nitrogen, cryoglobulins (University of Alabama Hospital laboratory [6], assay repeated 9 days later), rheumatoid factor (Behring RapiTex RF slide latex agglutination, Newark, New Jersey), complement component 3 (C3) and complement component 4 (C4) (nephelometry assay, Beckman Array 360 Protein System, Beckman Instruments, Fullerton, California), 50% hemolytic complement (CH50) assay (University of Alabama Hospital laboratory) (7), HCV RNA by polymerase chain reaction (Cobas TaqMan HCV test, Roche Diagnostics, Branchburg, New Jersey), and HCV genotype (GeneAmp 9700 thermal cycler, Applied Biosystems, Foster City, California). Clean-catch urine samples were collected for all patients except the 2 with hepatorenal syndrome, who had indwelling bladder catheters. We defined elevated serum creatinine level as at least 124 mol/L (1.4 mg/dL) in men or at least 115 mol/L (1.3 mg/dL) in women, pathologic proteinuria as urine protein of at least 1+ on dipstick urinalysis or a urinary proteincreatinine ratio greater than 0.3, and hematuria as urine blood of at least 1+ on dipstick urinalysis or more than 2 erythrocytes per high-power field in a resuspended sediment. During liver transplantation, a kidney biopsy specimen was obtained with a Bard Max-Core Disposable Biopsy Instrument (Bard, Covington, Georgia) after reperfusion of the hepatic allograft if there was no clinical coagulopathy. Two-micron sections were processed for routine light microscopy. Direct immunofluorescence studies used polyclonal antibodies for IgA, IgG, IgM, and C3 and C1q components of complement. One-micron sections were used for ultrastructural studies. Role of the Funding Source Roche Pharmaceuticals, Inc., provided funding for this study. The authors independently designed, wrote, and conducted the study; collected and analyzed the data; and prepared and approved the manuscript. Results Patients Renal biopsy was not performed in 7 patients because of ongoing coagulopathy (n= 6) or inadequate tissue (n= 1); these patients were excluded from further analysis. Of the 20 men and 10 women in the analysis, 25 were white, 4 were African American, and 1 was Hispanic. Mean age at transplantation was 53 years (SD, 8); ages ranged from 41 to 73 years. Twelve patients had a history of hypertension, and 6 had diabetes mellitus. Thirteen patients had received interferon- therapy for at least 3 months, but none had resolution of viremia. Two participants with the hepatorenal syndrome at engraftment required continuous low-flow hemodialysis. Laboratory Data The mean interval between pretransplantation laboratory testing and surgery was 21 days (SD, 47), ranging from 0 to 192 days. Mean Model for End-stage Liver Disease score, including the exemption for hepatoma, was 25 (SD, 6); the range was 16 to 40. Thirteen patients had a normal renal laboratory profile (normal serum creatinine level, no pathologic proteinuria, and no hematuria) (Table 1). Mean serum creatinine level in 28 patients without the hepatorenal syndrome was 112 mol/L (SD, 46) (1.27 mg/dL [SD, 0.52]); values ranged from 44 to 265 mol/L (0.5 to 3.0 mg/dL). Mean HCV RNA viral load was 320000 IU/mL (SD, 440000); genotype was type 1 in 23 of 28 patients tested. Cryoglobulinemia was not detected in the 20 patients tested. Level of C3 was low in 18 of 24 patients, C4 level was low in 7 of 24 patients, and CH50 level was low in 18 of 23 patients. Results of tests for rheumatoid factor were positive in 10 of 24 patients. Table 1. Baseline Demographic and Clinical Characteristics and Renal Biopsy Findings of the 30 Patients, Grouped by Renal Biopsy Diagnosis Renal Biopsy With 1 exception, biopsy specimens contained 10 to 40 (mean, 22) glomeruli. Global glomerulosclerosis was relatively mild; 4 specimens showed more than 20% obsolete glomeruli. Three specimens contained a single segmental sclerotic lesion, and 1 specimen contained 2. Twenty-nine kidney biopsy specimens showed mesangial proliferation by light microscopy with immunofluorescence staining for immunoglobulins, complement, or both (Table 1). However, 4 of these specimens had no deposits by electron microscopy: One showed focal segmental glomerulosclerosis, and 3 were diagnosed as minor glomerular abnormalities in the absence of well-defined, electron-dense deposits. The 1 specimen that appeared normal on immunofluorescence and electron microscopy contained only 3 glomeruli. No specimen showed features of cryoglobulins. Twelve specimens were classified as membranoproliferative glomerulonephritis (MPGN) type 1 but did not show lobular accentuation and marked endocapillary hypercellularity, both of which are common in idiopathic MPGN type 1. Instead, mild to moderate mesangial hypercellularity was observed, with focal duplication of glomerular basement membranes. Another unusual feature was the pattern of immunofluorescence staining. Ten specimens showed staining for all reagents; 1 lacked staining for only IgA and another for only C3. Electron microscopy demonstrated mesangial interposition with subendothelial and mesangial deposits. Three specimens contained occasional subepithelial deposits. Thirteen other biopsy specimens showed an immune-complex glomerulonephritis of 2 patterns. Seven exhibited IgA nephropathy; none had mesangial interposition, but 4 had subendothelial deposits. Six other specimens demonstrated mesangial glomerulonephritis with proliferation of mesangial cells and variable increases in mesangial matrix without mesangial interposition. Immunofluorescence staining for IgA was less intense than that for IgG or IgM; electron microscopy confirmed mesangial deposits. Correlation of Renal Biopsy Findings with Clinical and Laboratory Data Age, ethnicity, and sex appeared similar among the patients grouped by histologic diagnosis. Frequency of diabetes mellitus, hypertension, previous alcohol use, hepatocellular carcinoma, HCV genotype, treatment with interferon-, and viral load did not differ substantially among groups. Levels of C3, C4, and CH50 tended to be lower in patients with MPGN type 1. Eighteen patients had no evidence of renal injury by urinary testing, including 15 with immune-complex glomerulonephritis; of these, 10 had a normal serum creatinine level and, thus, a normal renal laboratory profile (Figure). Patients with MPGN type 1 were most likely to have a clinical renal abnormality (Tables 1 and 2). Figure. Features of glomeruli in a kidney biopsy specimen from a 49-year-old white man with mesangial glomerulonephritis. A B C D E F Table 2. Pretransplantation Laboratory Characteristics of 25 Patients with Hepatitis C Infection and Immune-Complex Glomerulonephritis at Liver Transplantation Discussion An immune-complex glomerulonephritis, characterized by IgA deposits and some mesangial hypercellularity, was very common in patients with end-stage cirrhosis due to chronic HCV infection. Three types of disease were observed: MPGN type 1, IgA nephropathy, and mesangial glomerulonephritis. These distinctive patterns were not associated with any demographic variable tested. The immunoglobulin staining in MPGN type 1 differed from that in patients with idiopathic MPGN; IgA was much more frequent (8). Cryoglobulins, often found in HCV-infected patients with MPGN (9), were not detected, even in rheumatoid factorpositive patients with urinary abnormalities. Subendothelial depos

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.)

Tacrolimus (FK506) and mycophenolate mofetil combination therapy versus tacrolimus in adult liver transplantation

BACKGROUND Mycophenolate mofetil (MMF) prolongs allograft survival in experimental animals, prevents acute rejection in humans, and has recently been approved for use in renal transplantation in combination with cyclosporine. Tacrolimus (Prograf) has been shown to be effective for the prevention and treatment of allograft rejection in liver transplantation. However, there has been limited experience with the combination of tacrolimus and MMF in liver transplantation. METHODS This retrospective pilot study examined the results in 130 primary, consecutive, adult liver transplants under two separate immunosuppressive protocols. Patients in the study group received MMF (1 g p.o. b.i.d.), tacrolimus (0.1 mg/kg p.o. b.i.d.), and a standard steroid taper. MMF was also tapered and then discontinued within 3 months of transplantation. A historical control received tacrolimus (0.15 mg/kg p.o. b.i.d.) and the same steroid taper. RESULTS Pretransplant demographics, including creatinine, were not significantly different between the groups. The 6-month patient and graft survivals of 96.3% (control) versus 92.0% (study) were not significantly different. The incidence of acute rejection was 45.0% in the control group versus 26.0% in the study group (P = 0.03). The study group had a lower incidence of rejection (mean episodes/patient +/- SEM): 0.28+/-0.07 vs. 0.61+/-0.10 (P = 0.007). All of the study group members responded to high-dose steroids. In the control group, three patients required monoclonal antibody therapy and two patients required the addition of MMF. The incidence of cytomegalovirus was similar in the study group and the control group (13.8% vs. 10.0%, P = NS). Early renal function was better preserved in the tacrolimus/MMF group (mean creatinine +/- SEM): 1.09 mg/dl +/- 0.05 vs. 1.51 mg/dl +/- 0.08 at 30 days, P = 0.0001. The study design required dosing with less tacrolimus (mean mg/day +/- SEM), which was achieved at 1 week (23.2+/-0.7 vs. 13.5+/-0.5); 1 month (18.7+/-0.8 vs. 11.4+/-0.5); 3 months (14.5+/-0.6 vs. 9+/-0.5); and 6 months (11.6+/-0.6 vs. 8.2+/-0.6); P = 0.0001, for all time points. CONCLUSION Combination therapy with tacrolimus and MMF may significantly reduce the incidence of acute liver allograft rejection, allow a significant reduction in tacrolimus dosage, and decrease the incidence of nephrotoxicity. Long-term analysis will be necessary to assess any increased risk of opportunistic infections.

Liver transplantation for erythropoietic protoporphyria liver disease

In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post‐transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13‐56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15‐29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5‐year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival. (Liver Transpl 2005;11:1590–1596.)

Viral hepatitis-related acute liver failure.

OBJECTIVES: Viral hepatitis has previously been the major cause of acute liver failure (ALF) in the United States. We aimed to determine the incidence of viral hepatitis-related ALF and to compare the outcome and clinical and biochemical variables in patients with hepatitis A and B. METHODS: A total of 354 patients with ALF from multiple centers were screened for possible acute viral etiology. RESULTS: Forty-three patients (12.1% of all ALF cases) had acute viral hepatitis: hepatitis A (n = 16), hepatitis B (n = 26), and herpes simplex virus infection (n = 1). There was no difference between groups with regard to age, gender, body mass index, admission or peak coma grade, symptom duration, admission mean arterial pressure, temperature, or biochemical liver tests, creatinine, arterial pH, or rate of infections. Platelet count was significantly higher in hepatitis A patients than in hepatitis B patients. The transplantation-free (spontaneous) survival rate was significantly higher for hepatitis A patients (69%) than for hepatitis B patients (19%, p = 0.007), whereas the liver transplantation rate was higher in hepatitis B patients (62%) than in hepatitis A patients (19%, p = 0.017). Spontaneous survivors had significantly higher mean arterial pressure, higher platelet count, and lower AST/ALT ratio than patients who did not survive spontaneously. CONCLUSIONS: Viral hepatitis now comprises only one-eighth of all ALF cases in the United States. The marked difference in spontaneous survival between hepatitis A and B cannot be explained by the severity of hepatic dysfunction on admission but may rather be an inherent feature of the infections or a bias toward transplanting patients with hepatitis B.