The majority of patients with acute liver failure (ALF) die waiting for orthotopic liver transplantation (OLT). No other treatment modality is shown to improve survival. This study was conducted to assess the safety and feasibility of hepatocyte transplantation (HT) and subsequent engraftment and function of donor cells. Functional and structural integrity of cryopreserved and thawed human hepatocytes were assessed by their morphological characteristics, induction of P-4501A1 transcription, and survival in vivo by xenotransplantation into rats. Five patients with severe ALF underwent intrasplenic (4 patients) and/or intrahepatic (2 patients) HT through angiography under cyclosporine immunosuppression. All patients had grade III to IV encephalopathy and factor V levels less than 0.5 U/mL, were ventilator and dialysis dependent, and were not OLT candidates. Three of the 5 patients who survived 48 hours after HT had substantial improvement in encephalopathy scores, arterial ammonia levels, and prothrombin times. Clinical improvement was paralleled by an increase in aminopyrine and caffeine clearances. All 3 patients lived substantially longer than expected based on clinical experience after HT (12, 28, and 52 days) but eventually died. Postmortem examination showed the presence of transplanted hepatocytes in liver and spleen by light microscopy and fluorescent in situ hybridization (FISH). Cryopreserved and thawed human hepatocytes can be transplanted into recipients with ALF with some acceptable but definite complications. Engraftment of donor hepatocytes was proven by histological examination and FISH by both transjugular biopsy and at autopsy. Improvement in brain edema, encephalopathy grade, and clearance of antipyrine and caffeine suggested function, albeit with a 24- to 72-hour delay posttransplantation.

A Sengstaken-Blakemore (SB) tube, when used approximately, still has a place in the management of acute variceal bleeding. Due to a number of reported complications from the misplacement of this tube, an x-ray localization before full inflation of the gastric balloon is recommended as the standard of care. Here, we report a new technique of SB tube placement with endoscopic confirmation in three patients. This technique is easy, accurate, and can be performed in any unit where a patient with variceal bleeding can be managed. Because it cuts down on the need for an x-ray or ultrasound confirmation, this technique may well become the "standard of care" among the practicing gastroenterologists.

Alterations in cerebral blood flow (CBF) are implicated in the etiology of portal-systemic encephalopathy. We hypothesized that CO2 reactivity of the cerebral circulation may be impaired in subjects with chronic liver disease (CLD) who also had subclinical portal-systemic encephalopathy (SPSE). We compared the relationship between PETCO2 and cerebral blood flow velocity in 10 patients with CLD with those of 10 healthy control subjects. Middle cerebral artery mean blood flow velocity (MCAMFV) was measured using transcranial Doppler during rest, hyperventilation, and hypoventilation. The degree of SPSE was quantified by using psychometric testing. Patients with CLD had poorer psychometric test scores compared with control subjects. Patients with CLD had lower PETCO2, MCAMFV, and blood pressure values and higher heart rates, differing from control subjects in all ventilation states. However, CO2 reactivity, the rate of change in MCAMFV to changes in ventilation (expressed as percent change in CBF velocity per mm Hg change in PETCO2) was similar for both groups (4.6% +/- 0.6% vs 4.2% +/- 0.5% for patients with CLD versus control subjects, P = 0.15). Implications: Psychometric test scores in patients with chronic liver disease revealed subclinical impairment compared with control subjects. Transcranial Doppler measurements of middle cerebral artery blood flow with varying PETCO2 were conducted, but the CO2 response of patients with liver disease was within the range of control subjects. (Anesth Analg 1998;86:1005-9)

Hepatic venoocclusive disease (VOD) is an often fatal disease which can occur during the first 100 days following bone marrow transplantation (BMT).To date multiple factors have been implicated; however, there is no clear cut study to identify the patients at increased risk before and after BMT.Thus, to identify the potential high risk groups and factors predisposing to VOD, we retrospectively reviewed the charts of patients who had BMT between 1990-96 at MD Anderson Cancer Center.Methods: In this case-control study patients' previous chemotherapy, medical and surgical history as well as hospital course, biochemical and histological data 100 days after BMT were extensively evaluated.Baltimore Clinical Diagnostic Criteria were applied to diagnose VOD within 21 days after BMT (Bilirubin _> 2 mg/dL, new onset ascites, 5% gain above admission weight, hepatomegaly and right upper quadrant pain) In addition to hyperbilirubinemia, presence of 2 out of 3 events was considered as diagnostic for VOD.Multiple stepwise logistic regression analysis was done and p<0.05 was considered as statistically significant.Results: There were 19 VOD patients and 99 controls who were age, gender and race matched.Use of pain medications, cyclosporin-A and methotrexate and presence of renal failure were the only significant independent risk factors for VOD (Table 1).

Mesenteric vein thrombosis (MVT) is a rare cause of intestinal ischemia. Because of its nonspecific symptoms, diagnosis is often delayed. We describe a patient with liver cirrhosis who developed acute MVT while waiting for liver transplantation. Surgical intervention carried a high risk because of her underlying cirrhosis. Mesenteric venous thrombectomy and thrombolysis were performed with an AngioJet (Possis Medical, Minneapolis, MN) thrombectomy device and streptokinase infusion through transjugular route. The patient subsequently received an orthotopic liver transplant. We also present a review of the literature about the occurrence and treatment options for MVT.

The nuroose of this study was to evaluate the feasibility of a novel type of antiviral therapy based on prenylation inhibition.Prenylation is a form of sitespecific lipid modification of proteins.Large delta antigen of hepatitis delta virus (HDV) was the first viral protein shown to undergo prenylation, but numerous other viruses may also have prenylated proteins.Abolishing large delta antigen prenylation by genetic mutation of its prenylation site prevents assembly of HDV virus-like particles.We therefore wished to test t h__ge hypothesis that pharmacologic inhibition of large delta antigen prenylation can prevent HDV assembly.Methods: First, we created a cell culture model of HDV assembly.Second, we tested the effect of a prenylation inhibitor, BZA-5B, on large delta antigen prenylation in reticulocyte lysates.Finally, we then tested the effect of BZA-5B on HDV virus-like particle production in the cell culture model.Results: HDV virus-like particles were assembled and released into the media of our cell culture model.BZA-5B was shown to be a potent inhibitor of large delta antigen prenylation in vitro at micromolar concentrations.When tested in our cell culture model, BZA-5B was also shown to specifically inhibit the prenylation-dependent production of HDV virus-like particles in a dosedependent manner.By 50 micromolar BZA-5B, no particles could be detected.Controls for non-specific inhibition of protein synthesis and secretion showed essentially no effect of BZA-5B.We conclude: BZA-5B is an effective inhibitor of large delta antigen prenylation.The prenylation-inhibiting activity of BZA-5B can abolish HDV virus-like particle production.Prenylation inhibitors, like BZA-5B, represent a novel class of potential antiviral agents for use against HDV and similarly prenylated viruses.

We report a case of fulminant hepatic failure in a 55-yr-old man due to Budd-Chiari syndrome in the setting of polycythemia rubra vera. The patient presented with acute hepatic failure, which rapidly progressed to grade IV hepatic encephalopathy. Placement of a transjugular intrahepatic portosystemic shunt resulted in marked improvement of the encephalopathy and stabilized the liver failure. Subsequently, he underwent successful nonemergent orthotopic liver transplantation. Transjugular intrahepatic portosystemic shunt placement is a safe, effective, therapeutic option to bridge patients with fulminant Budd-Chiari to liver transplantation.

We report the case of a 41-yr-old male with chronic hepatitis C who developed severe thrombocytopenia on interferon alfa-n3 therapy. The patient was enrolled in a multi-center trial of interferon alfa-n3 in the treatment of chronic hepatitis C. In the 10th wk of therapy, he presented with gingival bleeding and a petechial rash. Complete blood count demonstrated WBC 5,800/mm3. Hgb 16.3 g/dl, Hct 45.5%, and platelet count 6,000/mm3. Interferon was withdrawn, and he was admitted to intensive care and was treated with platelet transfusion, intravenous steroids, and intravenous immunoglobulin. His platelet counts returned to 157,000/mm3 in 7 days and remained normal on a tapering dose of prednisone. Bone marrow biopsy/aspirate demonstrated numerous megakaryocytes. Stored plasma was negative for development of specific high-titer anti-platelet antibody. We suggest that the clinical findings and response to therapy are consistent with interferon-induced idiopathic thrombocytopenic purpura.

Cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile salt synthesis from cholesterol is a P450 enzyme (CYP7A). Its expression and activity are regulated by bile salts, cholesterol, hormones and a circadian modulator. Here we define the hepatocytes contributing to the expression of the rat CYP7A gene during its in vivo circadian variation. The diurnal expression of the CYP7A messenger RNA (mRNA) was studied by in situ hybridization and correlated with the diurnal rate of CYP7A gene transcription and mRNA expression. At 10 AM, the time of lowest mRNA expression and gene transcription rate, only four to five hepatocytes, located close to the hepatic venules (''perivenular''), contained the CYP7A mRNA At 10 PM, the time of highest mRNA expression and fastest in vitro transcription rate, approximately one half of the hepatocytes (still in a ''perivenular'' location) contained the cholesterol 7 alpha-hydroxylase mRNA. In addition, the measured half-life of the CYP7A mRNA was shorter at 10 AM than at 10 PM suggesting that posttranscriptional mechanisms also contributed to the observed circadian differences. Therefore, the basal transcription rate of the CYP7A gene is maintained by four to five ''perivenular'' hepatocytes. During the circadian variation, the rate of gene transcription increases in these ''perivenular'' hepatocytes, but in addition, there is recruitment of other more proximal hepatocytes to transcribe the gene. It is proposed here that the response of specific hepatocytes to the various modulators of CYP7A gene expression is dependent on the relative position of these hepatocytes within the liver cell plate.