Randomised clinical trial: the safety and efficacy of long-acting octreotide in patients with portal hypertension.

BACKGROUND: It remains unclear whether a long-acting preparation of octreotide (Sandostatin LAR) can be safely used for portal hypertension in patients with compensated cirrhosis. AIM: To determine the safety and efficacy of LAR among patients with Child Pugh Class A or B cirrhosis and small oesophageal varices. METHODS: A randomised, double-blind, placebo-controlled study was conducted in 39 patients with cirrhosis and small oesophageal varices. Safety was based on frequency and severity of adverse events. Efficacy was determined by hepatic vein pressure gradient (HVPG) measured at baseline and day 84 following administration of LAR 10 mg (n = 15), 30 mg (n = 10) or saline (n = 14). Fasting and postprandial portal blood flow (PBF), superior mesenteric artery pulsatility index (SMA-PI), glucagon and octreotide levels were measured. An intention-to-treat analysis was performed. RESULTS: Four patients in the LAR 30 group (40%) withdrew from the study due to serious adverse events. No patient in the LAR 10 or control group had serious adverse events. There was no statistically significant decrease between HVPG at day 84 and baseline with LAR 30 mg (11.8 ± 2.3 mmHg vs. 14.1 ± 3.2), LAR 10 mg (15.3 ± 4.8 mmHg vs. 15.1 ± 3.8), or saline (13.3 ± 3.8 mmHg vs. 15.1 ± 4.3) (P = 0.26). Neither PBF, SMA-PI nor plasma glucagon levels were significantly decreased from baseline (P = 0.56). CONCLUSIONS: The absence of significant haemodynamic benefit, as well as the high frequency of severe adverse events associated with use of LAR, do not support the use of this agent in the treatment of portal hypertension.

[Improved performance in endurance sports through acupuncture]. / Verbesserung der Leistungsfähigkeit durch Akupunktur im Ausdauersport.

In many years of experience in treating athletes with acupuncture, I often had the impression that athletes in endurance sports showed improved performances after such treatments. In order to scientifically verify these impressions, I performed a field test with three groups of runners of different performance levels preparing for a marathon. The first group was given acupuncture, the second a placebo, with the third being the control group. After their maximum pulse rates were recorded, the runners were asked to run 5000m four times in 4 weeks at 75 % of their maximum pulse rate. Their pulse rates were measured for each runner at the finish of the run, and subsequently, one, two and five minutes after the run. Based on these data, the complexity factor (running time multiplied by the respective pulse rate) was calculated for all four recorded pulse rates for each run and each runner. All groups showed statistically significant enhancements in their running times and their complexity factors, but in the case of the runners treated with acupuncture, the improvements were highly significant. Therefore, the field test proves that acupuncture has a significant impact on the performance of the athletes in endurance sports.

Risk factors for the presence of varices in cirrhotic patients without a history of variceal hemorrhage.

BACKGROUND: Current medical management dictates that all cirrhotic patients without a history of variceal hemorrhage undergo endoscopic screening to detect large varices. However, referral for endoscopic screening of only patients at highest risk for varices may be most cost-effective. The aim of this case-control study was to identify clinical, laboratory, and radiologic findings that predict the presence of varices in patients with cirrhosis. METHODS: Three hundred patients without a history of variceal hemorrhage underwent upper endoscopy as part of an evaluation before liver transplantation. Cases defined as the presence of any varices and cases defined as the presence of large varices were used for examining the risks associated with finding varices on upper endoscopy. Logistic regression was performed to evaluate associations between the presence of varices and patient characteristics. RESULTS: Platelet count and Child-Pugh class were independent risk factors for the presence of any varices and the presence of large varices. For the presence of any varices, a platelet count of 90 x 10(3)/microL or less (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.4-4.0) and advanced Child-Pugh class (OR, 3.0; 95% CI, 1.6-5.6) were independent risk factors. For large varices, a platelet count of 80 x 10(3)/microL or less (OR, 2.3; 95% CI, 1.4-3.9) and advanced Child-Pugh class (OR, 2.8; 95% CI, 1.3-5.8) were independent risk factors associated with varices. CONCLUSIONS: Low platelet count and advanced Child-Pugh class were associated with the presence of any varices and with large varices. These factors allow identification of a subgroup of cirrhotic patients who would benefit most from referral for endoscopic screening for varices.

EUS in cirrhotic patients with and without prior variceal hemorrhage in comparison with noncirrhotic control subjects.

BACKGROUND: Endoscopic ultrasound (EUS) was used to evaluate cirrhotic patients with and without prior variceal hemorrhage. The findings were compared with those of EUS in noncirrhotic control subjects to determine EUS features indicative of cirrhosis and of a risk for variceal hemorrhage. METHODS: Patients with cirrhosis undergoing indicated endoscopic screening for varices or surveillance after endoscopic therapy for variceal hemorrhage were studied and compared with healthy noncirrhotic control patients undergoing EUS for benign conditions. RESULTS: Sixty-six cirrhotic patients (31 with prior hemorrhage) and 32 control patients were studied. Nonhemorrhage cirrhotic patients had more severe liver disease by Child's class (p = 0.02) and less beta-adrenergic blocker usage (p < 0.0001). Paraesophageal varices were detected in 97% of cirrhotic patients and 3% of control patients (p < 0.001) and were a more sensitive predictor of cirrhosis than varices at endoscopy (74%, p < 0.0001). Azygos vein and thoracic duct diameters, and gastric mucosa and submucosa thickness were greater for cirrhotic than control patients (p < 0.001). More hemorrhage patients had large (5 mm or greater) paraesophageal varices (odds ratio 3.1: 95% CI [1.1, 8.3]; p < 0.05) and paragastric varices (odds ratio 3.7: 95% CI [1.3, 10.2]; p = 0.01). Paraesophageal varix size correlated with ascites (p = 0.03) and, for nonhemorrhage patients, with Child's class (p < 0.01). CONCLUSIONS: Paraesophageal and paragastric varices correlate with the presence and severity of liver disease and portal hypertension. These data support the hypothesis that large paraesophageal and paragastric varices (5 mm or greater) may be risk factors for variceal hemorrhage, an observation that merits further prospective study. Cirrhosis causes dilation of the azygos vein and thoracic duct and thickening of gastric mucosa and submucosa.

Association of fungal infection and increased mortality in liver transplant recipients.

BACKGROUND: Invasive fungal infection is associated with increased morbidity and mortality following orthotopic liver transplantation (OLTx). Understanding the risk factors associated with fungal infection may facilitate identification of high-risk patients and guide appropriate initiation of antifungal therapy. OBJECTIVES: The aim of this study was to determine the incidence of fungal infections, identify the most common fungal pathogens, and determine the risk factors associated with fungal infections and mortality in OLTx recipients. METHODS: Medical records from 96 consecutive OLTx in 90 American veterans (88 males, 2 females; mean age 48 years, range 32 to 67) performed from January 1994 to December 1997 were retrospectively reviewed for fungal infection in the first 120 days after transplantation. Infection was defined by positive cultures from either blood, urine (<105 CFU/mL), cerebrospinal or peritoneal fluid, and/or deep tissue specimens. Superficial fungal infection and asymptomatic colonization were excluded from study. All patients received cyclosporine, azathioprine, and prednisone as maintenance immunosuppressive therapy. Fungal prophylaxis consisted of oral clotrimazole (10 mg) troches, five times per day during the study period. RESULTS: Thirty-five patients (38%) had documented infection with one or more fungal pathogens, including Candida albicans (25 of 35; 71%), C torulopsis (7 of 35; 20%), C tropicalis (2 of 35; 6%), non-C albicans (2 of 35; 6%), Aspergillus fumigatus (4 of 35; 11%), and Cryptococcus neoformans (1 of 35; 3%). The crude survival for cases with or without fungal infection was 68% and 87%, respectively (P <0.0001). The median intensive care unit stay and overall duration of hospitalization were significantly longer for patients with fungal infection (P <0.01). The mean time interval from transplantation to the development of fungal infection was 15 days (range 4 to 77) with a mean survival time from fungal infection to death of 21 days (range 3 to 64). Fungal infections occurred significantly more often in patients with renal insufficiency (serum creatinine >2.5 mg/dL), biliary/vascular complications, and retransplantation. CONCLUSIONS: Fungal infections were associated with increased morbidity and mortality following OLTx, with Candida albicans being the most common pathogen. Treatment strategies involving antifungal prophylaxis for high-risk patients and earlier initiation of antifungal therapy in cases of presumed infection are warranted.

A combined X-ray and NMR study of borate esters of furanoidic cis-1,2-diols.

Crystals of K[B(AnErytH(-2)2] x 2 H2O (AnEryt = 1,4-anhydroerythritol) form from aqueous alkaline solutions containing a double molar amount of diol over borate. The spiro-type monoanions are the main borate species in the mother liquors of crystallisation according to 11B and 13C NMR spectroscopy. Ribofuranosides form analogous borate esters using their 1,4-anhydroerythritol core. Crystals of Na[B(Me beta-D-Ribf 2,3H(-2))2] x 2 H2O were grown from alkaline methyl beta-D-ribofuranoside solutions that had attacked boron-containing Duran vessels. NMR spectra show closely resembling borate-ester speciation in solutions of diols with the 1,4-anhydroerythritol core--1,4-anhydroerythritol itself, methyl beta-D-ribofuranoside and guanosine.

Cost of treating an episode of variceal bleeding in a VA setting.

OBJECTIVES: The specific aims of this study were to develop a demographic description of a sample of patients presenting with bleeding esophageal varices and determine the direct health care costs of variceal bleeding. METHODS: This was a retrospective evaluation of patients who underwent esophagogastroduodenoscopy at the Portland VA Medical Center between January 1993 and May 1997. Data sources included both electronic databases and patient medical charts. The primary unit of analysis was an episode of care, defined as an index bleed plus 6 months of follow-up or death, whichever came first. RESULTS: The total inpatient direct cost was $1,566,904 and outpatient direct cost was $104,611, for a total of $1,671,515 for 100 bleeding episodes in 79 patients. Episodes of care for patients receiving < or =2 units of packed red blood cells were approximately a third as costly as those receiving >2 units of packed red blood cells (n = 17, $6,470 and n = 83, $17,553). The difference in costs was statistically significant (p < 0.05), and primarily attributable to hospital bed costs. CONCLUSIONS: There is a substantial financial burden associated with this illness, primarily attributable to inpatient costs. In addition to severity of bleeding, Child's class, endoscopic findings, and the timing of pharmacological therapy seem to influence the overall cost of managing esophageal varices.

Acute liver failure associated with prolonged use of bromfenac leading to liver transplantation. The Acute Liver Failure Study Group.

Bromfenac, a nonnarcotic analgesic nonsteroidal anti-inflammatory drug, was associated with reversible, minor elevations in serum aminotransferase levels during clinical trials. The aim of this study is to describe the clinical, laboratory, and histological features of 4 patients with severe bromfenac hepatotoxicity identified at 3 tertiary care centers participating in the US Acute Liver Failure Study Group. Bromfenac was administered for chronic musculoskeletal disorders to 4 women in therapeutic doses of 25 to 100 mg/d for a minimum of 90 days. All patients reported a prodrome of malaise and fatigue and presented with severe, symptomatic hepatocellular injury with associated hypoprothrombinemia. None of the subjects had underlying liver or kidney disease, and there was no evidence of a hypersensitivity reaction. Other identifiable causes of acute liver failure were uniformly excluded. Despite supportive measures, all the subjects developed progressive liver failure over 5 to 37 days, leading to emergency liver transplantation in 3 patients and death in 1 patient while awaiting transplantation. Extensive confluent parenchymal necrosis that appeared to begin in the central zones and was accompanied by a predominantly lymphocytic infiltrate was noted in all the livers examined. Nodular regeneration was seen in the 2 patients with a more protracted clinical course. Administration of therapeutic doses of bromfenac for greater than 90 days was associated with the development of acute liver failure leading to liver transplantation or death in 4 adult women. The poor outcomes observed in this series, coupled with the inability to identify individuals at risk for severe, idiosyncratic bromfenac hepatotoxicity, preclude further use of bromfenac in the medical community.

Factors predicting the presence of esophageal or gastric varices in patients with advanced liver disease.

OBJECTIVE: Recently it has been recommended that all cirrhotic patients without previous variceal hemorrhage undergo endoscopic screening to detect varices and that those with large varices should be treated with beta-blockers (American College of Gastroenterology guidelines). However, endoscopic screening only of patients at highest risk for varices may be the most cost effective. METHODS: Ninety-eight patients without a history of variceal hemorrhage underwent esophagogastroduodenoscopy as part of a liver transplant evaluation. Univariate/multivariate analysis was used to evaluate associations between the presence of varices and patient characteristics including etiology of liver disease, Child-Pugh class, physical findings (spider angiomata, splenomegaly, and ascites), encephalopathy, laboratory parameters (prothrombin time, albumin, bilirubin, BUN, creatinine, and platelets), and abdominal ultrasound findings (portal vein diameter/flow, splenomegaly, and ascites). RESULTS: The causes of cirrhosis among the 67 men and 31 women (mean age, 48 yr) included 28% Hepatitis C/alcoholism, 25% Hepatitis C, 13% alcoholism, 9% primary sclerosing cholangitis/primary biliary cirrhosis, 9% cryptogenic, 6% Hepatitis B, 1% Hepatitis B and C, and 9% other. Patients were Child-Pugh class A 34%, B 51%, and C 15%. Endoscopic findings included esophageal varices in 68% of patients (30% were large), gastric varices in 15%, and portal hypertensive gastropathy in 58%. Platelet count <88,000 was the only parameter identified by univariate/multivariate analysis (p < 0.05) as associated with the presence of large esophageal varices (odds ratio 5.5; 95% confidence interval 1.8-20.6) or gastric varices (odds ratio 5; 95% confidence interval 1.4-23). CONCLUSIONS: Platelet count <88,000 is associated with the presence of esophagogastric varices. A large prospective study is needed to verify and validate these findings and may allow identification of a group of patients who would most benefit from endoscopic screening for varices.

A pilot study of the CY-1899 T-cell vaccine in subjects chronically infected with hepatitis B virus. The CY1899 T Cell Vaccine Study Group.

Clinical observations suggest that eradication of the hepatitis B virus (HBV) is immune-mediated. Vigorous cytotoxic T lymphocyte (CTL) activity directed at HLA class I-bound viral epitopes are detected during acute hepatitis B, but not in chronic hepatitis B carriers. A CTL epitope derived from the hepatitis B core protein amino acids 18-27 has been incorporated into a vaccine also comprised of a T-helper cell epitope and 2 palmitic acid residues (CY-1899). The aim of this study was to determine whether repeated doses of CY-1899 given to patients with chronic hepatitis B could initiate in vivo CTL activity and viral clearance. Patients with chronic hepatitis B received up to 4 doses (ranging from 0.05 mg to 15 mg) 6 weeks apart. Following vaccination, patients were monitored for hepatitis B surface antigen and "e" status, HBV-DNA levels, liver biochemistry, CTL activity, and any adverse events. Ninety patients with chronic hepatitis B infection received CY-1899. Mean CTL responses were all low but were maximal following vaccination with 5 mg CY-1899. Peak CTL responses never exceeded 10 lytic units (LU) regardless of vaccine dose, this value being well below that seen following resolution of acute hepatitis B. No significant changes in liver biochemistry or viral serology were observed during follow-up. No serious adverse events were noted. Administration of the single-epitope vaccine, CY-1899, initiated CTL activity, but of a magnitude lower than that observed during spontaneous HBV clearance. This low-level CTL activity was not associated with viral clearance.

Vancomycin-resistant Enterococcus in liver transplant patients.

BACKGROUND: Vancomycin-resistant Enterococcus (VRE) infection is emerging in the transplant population, and there is no effective antibiotic therapy available. The aims of this retrospective review were to (1) investigate the outcome of and (2) identify common characteristics associated with VRE infection and colonization in orthotopic liver transplant (OLTx) candidates. METHODS: From October 1994 through September 1998, 126 isolates of VRE were identified in 42 of 234 OLTx recipients and 5 OLTx candidates who did not proceed to transplantation. Data were collected by patient chart review or from a computerized hospital database. RESULTS: The 1-year mortality rate with VRE infection was 82%, and with VRE colonization, 7%. This mortality rate contrasts with a 14% 1-year mortality for non-VRE transplant patients (P <0.01, infected patients and colonized patients). Characteristics of VRE colonized and infected patients included recent prior vancomycin (87%), coinfection by other microbial pathogens (74%), recent prior susceptible enterococcal infection (72%), concurrent fungal infection (62%), additional post-OLTx laparotomies (47%), and renal failure (Cr >2.5 mg/dL or need for dialysis; 43%). Biliary complications were seen in 52% of post-OLTx VRE-infected or VRE-colonized patients (versus 22% in non-VRE transplant patients, P <0.05). CONCLUSION: VRE infection is associated with a very high mortality rate after liver transplantation. The incidence of biliary complications prior to VRE isolation is very high in VRE-infected and VRE-colonized patients. The most common characteristics of VRE patients were recent prior vancomycin use, recent prior susceptible enterococcal infection, coinfection with other microbial pathogens, and concurrent fungal infection. With no proven effective antimicrobial therapy for VRE, stringent infection control measures, including strict and limited use of vancomycin, must be practiced.

Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients.

OBJECTIVE: The aim of this study was to identify the frequency of fatigue and musculoskeletal pain in hepatitis C compared with other liver diseases. METHODS: Hepatology outpatients were evaluated by questionnaire for musculoskeletal pain and fatigue. Charts were reviewed for diagnoses, aminotransferases, histology, treatment, and presence of hepatitis C by second generation ELISA and/or polymerase chain reaction. The frequency of symptoms in patients with and without hepatitis C were compared. RESULTS: In 239 patients (mean age 46.7 +/- 11.6 yr; 52% male) musculoskeletal pain was present in 70% for 6.7 +/- 8.3 yr and fatigue in 56% for 3.3 +/- 5.1 yr. Backache was the most common complaint (54%), followed by morning stiffness (45%), arthralgia (42%), myalgia (38%), neck pain (33%), pain "all over" (21%), and subjective joint swelling (20%). Diffuse body pain was present in 23% on a pain diagram and was strongly associated with fatigue. There was a significant association between hepatitis C positivity and the presence of musculoskeletal pain (81% of HCV-positive compared with 56% of HCV-negative patients, respectively; p = 0.0001), and fatigue (67% compared with 44%; p = 0.001). Musculoskeletal pain was more frequent among patients with isolated hepatitis C infection than among patients with isolated hepatitis B or alcoholic liver disease (91%, 59%, and 48%, respectively; p = 0.004). Similarly, fatigue was more frequent among patients with isolated hepatitis C than among those with isolated alcoholic liver disease or hepatitis B (66%, 30%, and 29%, respectively; p = 0.004). There was no relationship between musculoskeletal complaints and possible route of acquiring hepatitis C, levels of aminotransferases, liver disease severity on biopsy, or interferon treatment. CONCLUSIONS: Musculoskeletal pain and fatigue are frequent in hepatology clinic attendees, particularly those with hepatitis C and are unrelated to severity of liver disease, route of infection, or interferon therapy.

Prevalence of upper and lower gastrointestinal tract findings in liver transplant candidates undergoing screening endoscopic evaluation.

OBJECTIVE: The incidence of esophageal and gastric varices and portal hypertensive gastropathy (PHG) has been well studied in cirrhotic patients. Because little is known of the prevalence of other upper and lower gastrointestinal tract pathology in pre-liver transplant candidates, we retrospectively studied the prevalence of and factors associated with these findings. METHODS: One hundred and twenty pre-liver transplant candidates underwent esophagogastroduodenoscopy to evaluate for varices, and 71 of them also underwent flexible sigmoidoscopy to screen for colorectal carcinoma. The association of upper and lower GI tract pathology with Child-Pugh Class, etiology of cirrhosis, and signs of portal hypertension, including presence and size of esophageal varices, presence of gastric varices, PHG, ascites, and splenomegaly, was analyzed using univariate and multivariate analysis. RESULTS: Etiology of cirrhosis among 87 men and 33 women (mean age, 52 yr) included 25% hepatitis C, 27% hepatitis C/alcohol, 15% alcohol, 10% primary sclerosing cholangitis/primary biliary cirrhosis, 9% cryptogenic, 8% metabolic, and 6% hepatitis B. Prevalence of Child-Pugh Classes A, B, and C were 34%, 49%, and 17%, respectively; 73% of patients had esophageal varices (23% were large), 62% PHG (23% were severe), and 16% gastric varices. Excluding varices and PHG, endoscopic findings in the upper GI tract (n = 120) included: 13% esophagitis/ulcers, 7.5% gastritis, 8% duodenitis, 2% Barrett's esophagus, 3% duodenal ulcers, and 2% gastric ulcers. Findings in the lower gastrointestinal tract (n = 71) included 21% adenomatous polyps, 21% internal hemorrhoids, 15% diverticulosis, 7% rectal varices, 3% colopathy, and 3% vascular ectasias. Univariate analysis revealed that there was a significant association between rectal varices and severe PHG (p < 0.05). This association was not maintained when multivariate analysis was performed. CONCLUSIONS: Among all the findings, only rectal varices and colopathy were of higher prevalence in the pre-liver transplant population than that reported for the general population. No significant associations were found between these gastrointestinal tract lesions and patient characteristics.

Y-site stability of fosphenytoin and sodium phenobarbital.

Fosphenytoin and sodium phenobarbital in 0.9% sodium chloride injection were analyzed in a simulated Y-site admixture. Each drug was analyzed for stability by high-pressure liquid chromatography (HPLC) from three simulated Y-site samples over an eight-hour period. The HPLC assay results indicate that both fosphenytoin and sodium phenobarbital are stable together at a Y site over an eight-hour period. In addition, there was no change in sample clarity or pH over the same period. The results indicate that, when medically necessary, fosphenytoin and sodium phenobarbital in 0.9% sodium chloride injection can be administered via the same intravenous line.

Transjugular intrahepatic portosystemic shunt patency and the importance of stenosis location in the development of recurrent symptoms.

PURPOSE: To analyze in detail the location and types of stenosis and occlusion that occur after transjugular intrahepatic portosystemic shunt (TIPS) creation and to determine the relative contribution of these various types of TIPS malfunction to recurrent symptoms of variceal bleeding or ascites. MATERIALS AND METHODS: In 116 of 217 patients who underwent TIPS creation between June 1990 and July 1995, follow-up portal venography was performed at 6-month intervals and for symptoms of recurrent variceal bleeding or ascites. RESULTS: Cumulative primary venographic patency by means of Kaplan-Meier survival analysis was 55% at 6 months and 5% at 2 years. Secondary patency was 92% at 2 years. Stenosis or occlusion occurred in 63 of 116 patients (54%). In 20 patients (17%), acute shunt occlusions developed less than 30 days after TIPS creation; in 24 patients (21%), tract abnormalities were detected after 30 days; and in 19 patients (16%), hepatic vein stenoses were detected after 30 days. Abnormalities of the parenchymal tract were more often correlated with recurrent variceal bleeding or ascites than were hepatic vein stenoses (odds ratio, 3.6; P = .02). Ten of 14 patients (71%) with detected biliary fistulas to their TIPS had symptoms, and all patients with biliary fistulas had tract abnormalities. CONCLUSION: Tract stenoses and occlusions were the major cause of symptomatic shunt failure after TIPS creation. Substantial bile duct transections are often associated with tract abnormalities and recurrent symptoms. Although common, hepatic vein stenoses were rarely associated with recurrent symptoms in our patient population.

Liver transplantation for disulfiram-induced hepatic failure.

Fulminant hepatitis is a rare but potentially fatal adverse reaction that may occur after the use of disulfiram. A patient without a known history of liver disease was transplanted for fulminant hepatic failure secondary to disulfiram. A high index of suspicion and aggressive therapeutic approaches are essential for the prompt diagnosis and treatment of disulfiram-induced hepatic failure. The clinical presentation, histopathology, treatment, and all cases of disulfiram-induced hepatic failure reported in the English literature are reviewed. The role of orthotopic liver transplantation in a case of disulfiram-induced hepatic failure is discussed.

Timing and severity of initial hepatitis C recurrence as predictors of long-term liver allograft injury.

BACKGROUND: The majority of patients infected with hepatitis C virus (HCV) undergoing liver transplantation develop evidence of histologic recurrence, and multiple mechanisms are likely poised to affect long-term allograft injury. The purpose of this analysis was to study the hypothesis that histologic and biochemical features at the onset of HCV recurrence predict the long-term evolution of allograft hepatitis. METHODS: We studied 34 consecutive liver transplant recipients with evidence of histologic HCV recurrence and with a minimal histologic follow-up of 1 year (up to 6.2 years; mean: 696+/-83.2 days). Two-hundred and seventy-eight serial allograft biopsies (mean: 6.85+/-0.62 per patient, range: 4-21) were analyzed. The hepatic activity index was utilized to quantitate piecemeal necrosis, intralobular degeneration, portal inflammation, and hepatic fibrosis. The presence of hepatocyte ballooning degeneration and cholestasis was also assessed. RESULTS: Although there was no significant difference with regard to initial hepatic activity index scores between patients who ultimately developed allograft cirrhosis (group 1; n=8) versus those with milder hepatitis (group 2; n=26), the finding of ballooning degeneration/cholestasis was more frequent in the former group (P=0.04). The distribution of HCV genotypes, the mean follow-up after orthotopic liver transplantation, the mean number of allograft biopsy specimens per patient, basal immunosuppression, and incidence of rejection were comparable in both groups. Patients who ultimately developed allograft cirrhosis had significantly higher initial total bilirubin at the onset of histologic recurrence and peak total bilirubin (pT. Bili, the highest value in the ensuing month). Actuarial rates of moderate-to-severe allograft hepatitis were significantly greater in patients with pT. Bili > or = 3.5 mg/dl (P=0.004). Multiple regression analysis identified pT. Bili as the only independent predictor of allograft cirrhosis. CONCLUSIONS: Features at the onset of histologic HCV recurrence predict the natural history of allograft injury; specifically, marked, transient hyperbilirubinemia is associated with the subsequent development of allograft cirrhosis.