With the implementation of the model for end-stage liver disease (MELD), refractory ascites, a known predictor of mortality in cirrhosis, was removed as a criterion for liver allocation. Because ...ascites is associated with low serum sodium, we evaluated serum sodium as an independent predictor of mortality in patients with cirrhosis who were listed for liver transplantation and whether the addition of serum sodium to MELD was superior to MELD alone. This is a single-center retrospective cohort of all adult patients with cirrhosis listed for transplantation from February 27, 2002, to December 26, 2003. Listing laboratories were those nearest the listing date +/-2 months. Of the 513 patients meeting inclusion criteria, 341 were still listed, while 172 were removed from the list (105 for transplantation, 56 for death, 11 for other reasons). The median serum sodium and MELD scores were 137 mEq/L (range, 110-155) and 15 (range, 6-51), respectively, at listing. Median follow-up was 201 (range, 1-662) days. The risk of death with serum sodium <126 mEq/L at listing or while listed was increased, with hazard ratios of 7.8 (P < .001) and 6.3 (P < .001), respectively, and the association was independent of MELD. The c-statistics of receiver operating characteristic curves for predicting mortality at 3 months based upon listing MELD with and without listing serum sodium were 0.883 and 0.897, respectively, and at 6 months were 0.871 and 0.905, respectively. In conclusion, serum sodium <126 mEq/L at listing or while listed for transplantation is a strong independent predictor of mortality. Addition of serum sodium to MELD increases the ability to predict 3- and 6-month mortality in patients with cirrhosis.
Long thought to be just a simple pipe involved in the delivery of bile from hepatocytes to the gallbladder and intestine, bile ducts are now regarded as highly dynamic structures consisting of cell ...populations involved in formation, transport and modification of bile by both secretory and absorptive processes. In fact, both bile and biliary epithelium appear to have active immunologic roles in both innate and adaptive immune responses. These roles are becoming increasingly clear as techniques have been developed allowing for the study of bile and biliary epithelial cells (BECs) in mucosal immunity. Bile is actively involved in the transport of immunoglobulin to the intestine, while BECs secrete chemokines and cytokines and serve to localize the immune response by expressing critical cell adhesion molecules. Evidence suggests that BECs may also function as professional antigen‐presenting cells (APC) and, in the process, contribute to the modulation of inflammatory reactions. Bile ducts and, in particular, BECs, are the primary site of damage in several immunologically mediated liver diseases. Progress in these important areas has been rapid and forms the basis of this review.
In patients with hepatocellular carcinoma (HCC) exceeding conventional (T2) criteria for orthotopic liver transplantation (OLT), the feasibility and outcome following loco‐regional therapy intended ...for tumor downstaging to meet T2 criteria for OLT are unknown. In this first prospective study on downstaging of HCC prior to OLT, the eligibility criteria for enrollment into a downstaging protocol included 1 lesion >5 cm and ≤8 cm, 2 or 3 lesions at least 1 >3 cm but ≤5 cm with total tumor diameter of ≤8 cm, or 4 or 5 nodules all ≤3 cm with total tumor diameter ≤8 cm. Patients were eligible for living‐donor liver transplantation (LDLT) if tumors were downstaged to within proposed University of California, San Francisco (UCSF) criteria.13 A minimum follow‐up period of 3 months after downstaging was required before cadaveric OLT or LDLT, with imaging studies meeting criteria for successful downstaging. Among the 30 patients enrolled, 21 (70%) met criteria for successful downstaging, including 16 (53%) who had subsequently received OLT (2 with LDLT), and 9 patients (30%) were classified as treatment failures. In the explant of 16 patients who underwent OLT, 7 had complete tumor necrosis, 7 met T2 criteria, but 2 exceeded T2 criteria. No HCC recurrence was observed after a median follow‐up of 16 months after OLT. The Kaplan‐Meier intention‐to‐treat survival was 89.3 and 81.8% at 1 and 2 yr, respectively. In conclusion, successful tumor downstaging can be achieved in the majority of carefully selected patients, but longer follow‐up is needed to further access the risk of HCC recurrence after OLT. (Liver Transpl 2005;11:1505–1514.)
In a double-blind trial of streptokinase for acute myocardial infarction, 219 consecutive patients presenting with infarction within four hours (mean, 3.0 +/- 0.8) of the onset of chest pain were ...randomly assigned to treatment with streptokinase (1.5 million units) or placebo, given intravenously over 30 minutes. The primary end point of the study was left ventricular function in patients with first infarctions. Patients who could undergo beta-blockade also received intravenous propranolol. Heparin (for 48 hours) and a combination of low-dose aspirin and dipyridamole were administered to both groups until cineangiography was performed at three weeks. In the patients with first infarctions treated with streptokinase, the left ventricular ejection fraction was 6 percentage points higher (streptokinase vs. placebo, 59 +/- 10.5 vs. 53 +/- 13.5 percent; P less than 0.005), with benefit to patients with either anterior infarction (57 +/- 11.9 vs. 49 +/- 15.9 percent; P less than 0.05) or inferior infarction (60 +/- 9.1 vs. 55 +/- 11.3 percent; P less than 0.05). Left ventricular function was improved regardless of whether concomitant propranolol was given. Survival (at 30 days) was improved with streptokinase: 2 deaths occurred among 79 patients who received this drug, as compared with 12 deaths among 93 patients who received placebo (2.5 vs. 12.9 percent, P = 0.012). Rates of reinfarction (streptokinase vs. placebo, 3 vs. 1 percent) and requirements for surgery or angioplasty (7 vs. 5 percent) were similar in the two groups. We conclude that administration of intravenous streptokinase (1.5 million units) to patients with a first myocardial infarction results in improved left ventricular function and short-term survival.
Nuclear receptors which interact with the retinoid X receptor are involved in the regulation of epidermal differentiation and development. We have recently shown that activators of the peroxisome ...proliferator-activated receptor and of the farnesoid X-activated receptor accelerate epidermal barrier maturation in fetal rat skin in vitro. In this study we asked whether cutaneous development in utero was affected by peroxisome proliferator-activated receptor or farnesoid X-activated receptor activators, or by an activator of another retinoid X receptor partner, liver X receptor. Activators of the peroxisome proliferator-activated receptor (clofibrate or linoleic acid), farnesoid X-activated receptor (farnesol or juvenile hormone III), or liver X receptor (22R-hydroxycholesterol), were injected into the amniotic fluid of fetal rats on gestational day 17. Fetal epidermal barrier function and morphology was assessed on day 19. Whereas vehicle-treated fetal rats displayed no measurable barrier (transepidermal water loss > 10 mg per cm2 per h), a measurable barrier was induced by the intra-amniotic administration of all activators tested (transepidermal water loss range 4.0-8.5 mg per cm2 per h). By light microscopy, control pups lacked a well-defined stratum corneum, whereas a distinct stratum corneum and a thickened stratum granulosum were present in treated pups. By electron microscopy, the extracellular spaces of the stratum corneum in control pups revealed a paucity of mature lamellar unit structures, whereas these structures filled the stratum corneum interstices in treated pups. Additionally, protein and mRNA levels of loricrin and filaggrin, two structural proteins of stratum corneum, were increased in treated epidermis, as were the activities of two lipid catabolic enzymes critical to stratum corneum function, beta-glucocerebrosidase and steroid sulfatase. Finally, peroxisome proliferator-activated receptor-alpha and -delta and liver X receptor-alpha and -beta mRNAs were detected in fetal epidermis by reverse transcriptase-polymerase chain reaction and northern analyses. The presence of these receptors and the ability of their activators to stimulate epidermal barrier and stratum corneum development suggest a physiologic role for peroxisome proliferator-activated receptor and liver X receptor and their endogenous ligands in the regulation of cutaneous development.
In registration trials, zafirlukast, an asthma medication, caused asymptomatic elevated aminotransferase levels in up to 5% of participants. Until now, however, no cases of severe hepatitis ...attributed to zafirlukast have been reported.
To report the clinical characteristics of three patients with severe hepatitis due to zafirlukast.
Case report.
One community hospital and two university hospitals.
Three middle-aged women taking zafirlukast, 20 mg twice per day.
Discontinuation of zafirlukast therapy in three patients, steroid therapy in two patients, and orthotopic liver transplantation in one patient.
Serum aminotransferase and bilirubin levels, standard blood tests for causes of hepatitis other than drug toxicity, and liver biopsy in two patients.
Patient 1 recovered spontaneously, had a severe relapse after inadvertent rechallenge with the medication, and ultimately made a complete recovery. Patient 2 developed subfulminant hepatic failure and required liver transplantation. Patient 3 developed severe hepatitis that improved after treatment with corticosteroids. Liver tissue was available from two patients and showed histologic changes commonly associated with drug reactions.
Patients receiving zafirlukast may develop severe liver injury and should be observed for signs and symptoms of hepatitis.
A major obstacle for orthotopic liver transplantation (OLT) as treatment for hepatocellular carcinoma (HCC) is tumor growth resulting in dropout from the waiting list for OLT. There is a paucity of ...data on survival according to intention-to-treat analysis and the rate of dropout from the waiting list for OLT among patients with HCC. To further evaluate these issues, we analyzed the outcome of 46 consecutive patients with HCC listed for OLT between January 1998 and January 2001. Exclusion criteria for OLT were tumor size greater than 5 cm for one to three lesions or four lesions or greater of any size. Twenty-one patients underwent OLT. There were 11 dropouts because of tumor progression and six deaths, including three deaths after dropout. Kaplan-Meier 1- and 2-year intention-to-treat survival rates were 91.7% and 72.6%, respectively. Monthly dropout rates were 0% from 0 to 3 months, 1.5% from 3 to 6 months, 1.0% from 6 to 9 months, 4.9% from 9 to 12 months, and 5.6% from 12 to 15 months. One dropout occurred beyond 15 months among 4 patients remaining at risk. Cumulative probabilities for dropout at 6, 12, and 24 months were 7.3%, 25.3%, and 43.6%, respectively. Predictors for dropout included two or three tumor nodules or a solitary lesion greater than 3 cm at initial presentation and previous hepatic resection. Our results support recent changes in the scheme of organ allocation aimed at reducing the dropout rate and improving outcome for patients with HCC awaiting OLT. (Liver Transpl 2002;8:873-883.)
Menopause induces a loss of bone as a result of estrogen deficiency. Despite pharmaceutical options for the treatment of osteopenia and osteoporosis, many aging women use dietary supplements with ...estrogenic activity to prevent bone loss and other menopausal-related symptoms. Such supplements are yet to be tested for efficacy against a Food and Drug Administration (FDA) approved medication for menopausal bone loss such as zoledronic acid (ZA). The postmenopausal rat model was used to investigate the efficacy of various synergistic phytochemical blends mixed into the diet for 16 weeks. Retired-breeder, Fischer 344 rats were randomly assigned to sham or ovariectomy surgery and 4 treatment groups: ZA; genistein supplementation; and a low dose and high dose blend of genistein, resveratrol, and quercetin. Ovariectomy resulted in a loss of both trabecular and cortical bone which was prevented with ZA. The phytochemical blends tested were unable to reverse these losses. Despite the lack of effectiveness in preventing bone loss, a significant dose-response trend was observed in the phytochemical-rich diets in bone adipocyte number compared to ovariectomized control rats. Data from this study indicate that estrogenic phytochemicals are not as efficacious as ZA in preventing menopausal-related bone loss but may have beneficial effects on bone marrow adiposity in rats.
We previously proposed modified staging criteria for predicting acceptable outcome after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). These were solitary tumor ≤6.5 cm, ...or three or fewer nodules with the largest lesion ≤4.5 cm and total tumor diameter ≤8 cm, without gross vascular invasion (University of California, San Francisco UCSF criteria). In this study, we further evaluated the performance of the Milan criteria (solitary tumor ≤5 cm, or three or fewer lesions none >3 cm), the UCSF criteria, and the Pittsburgh modified tumor-node-metastasis (TNM) criteria. Pathologic HCC staging according to each set of criteria was performed in 70 patients. The difference in survival when comparing 24 patients with HCC exceeding Milan criteria versus 46 patients meeting Milan criteria did not reach statistical significance (HR, 2.0; P = .12). Using our definition for acceptable 2-year survival to be ≥70%, the 14 patients (20%) meeting UCSF criteria but exceeding Milan criteria had a 2-year survival of 86% (95% CI, 54% to 96%). Survival for Pittsburgh stage I, II, and IIIA patients as a group was significantly better than for stages IIIB and IVA patients combined (HR, 4.2; P = .007), and similar to survival for patients meeting UCSF criteria. Advanced tumor exceeding UCSF criteria served reasonably well as a surrogate marker for poorly differentiated grade and microvascular invasion. In conclusion, our analyses suggest that UCSF criteria better predict acceptable posttransplant outcome than Milan criteria. UCSF criteria confer a different advantage over Pittsburgh criteria, which require information on microvascular invasion that is difficult to ascertain preoperatively without the attendant risk of biopsy. (Liver Transpl 2002;8:765-774.)
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