Increase in mortality rate of liver transplant candidates residing in specific geographic areas: analysis of UNOS data.

We sought to evaluate survival of liver transplant candidates living in geographic areas with limited access to specialized transplant centers (TxC). We analyzed survival outcome among candidates listed for liver transplant in United Network of Organ Sharing (UNOS) Region 4 from 2004 to 2010. Candidates were stratified into three groups according to the distance from the patient's residence to the closest hospital with a liver transplant program: Group 1 (Gr 1) <30 miles (m), Group 2 (Gr 2) 30-60 m and Group 3 (Gr 3) >60 m. Of the 5673 patients included in the study, 49% resided >30 m from a TxC. Eight percent of the cohort experienced death or dropped out of the list due to medical condition deterioration, with worse outcomes for Gr 2 and Gr 3 (8.5% and 9.9%, respectively, vs. 6.5% for Gr 1 [p < 0.001]). Among patients with a MELD score <20, mortality was higher in Gr 2 and Gr 3 compared to Gr 1 (p < 0.001). We conclude that for Region 4, the mortality risk in patients living >30 m from a TxC is higher. We suggest that the variable "distance from a TxC" should be used to improve the estimate of the mortality risk for patients on the waiting list.

Roux-en-Y gastric bypass for recurrent nonalcoholic steatohepatitis in liver transplant recipients with morbid obesity.

BACKGROUND: Severe obesity is common before and after liver transplantation and has been associated with significant morbidity and mortality. Furthermore, it may cause graft dysfunction through the development of recurrent nonalcoholic steatohepatitis. METHODS: We performed Roux-en-Y gastric bypass in two morbidly obese patients who had undergone liver transplantation and had graft dysfunction secondary to recurrent nonalcoholic steatohepatitis. RESULTS: Both patients demonstrated dramatic weight loss and had normalization of liver enzymes, lipids, and glucose levels. Repeated liver biopsy showed regression of steatosis. CONCLUSIONS: Roux-en-Y gastric bypass can be successfully performed in liver transplant recipients with morbid obesity and may lead to weight loss, correction of metabolic abnormalities, and regression of hepatic dysfunction secondary to recurrent steatosis.

Immune response to influenza vaccine in adult liver transplant recipients.

Influenza virus infection may cause significant complications in liver transplant recipients, and whether vaccination is effective in these patients is controversial. We performed a study to assess the immune response to influenza vaccine in liver transplant recipients and patients with cirrhosis compared with healthy controls. Liver transplant recipients (n = 20), patients with compensated cirrhosis awaiting transplantation (n = 14), and healthy volunteers (n = 9) were administered the standard dose of the 1999 to 2000 inactivated trivalent vaccine (A/Bejing/262/95[H1N1]; A/Sidney/5/97[H3N2]; B/Yamanashi/166/98). Antibody responses to each component of the vaccine were measured at baseline and after 6 weeks by hemagglutination inhibition. Vaccination was well tolerated, and no major side effects were observed. A significant postvaccination increase in antibody titer to all 3 vaccine components was obtained in all groups. However, liver transplant recipients had significantly lower postvaccination geometric mean titers and geometric mean increases to the H3N2 component compared with patients with cirrhosis and controls. The rate of seroconversion to H3N2 after vaccination was also significantly lower in liver transplant recipients (15% v. 89%). We conclude that liver transplant recipients have a significantly impaired immune response to the influenza vaccine, and some patients may remain unprotected from influenza infection after vaccination. Further studies of modified protocols of influenza vaccination for these patients are recommended.

An open-label pilot trial of cladibrine (2-cholordeoxyadenosine) in patients with primary sclerosing cholangitis.

Cladribine (2-chlorodeoxyadenosine) is a nucleoside analog with specific antilymphocytic activity that has been used in patients with a variety of lymphoid malignancies and autoimmune diseases. Primary sclerosing cholangitis (PSC) is a chronic hepatic autoimmune disorder of unknown etiology, thought to be mediated by biliary autoreactive cytotoxic lymphocytes. Because cladribine is an effective antilymphocytic drug, it may have potential disease-modifying activity in patients with PSC. We studied four patients with stages I and II PSC in an open-label pilot trial of 6 months' duration and 2 years' follow-up. Drugs were administered at 0.1 mg/kg/d subcutaneously for 5 days per monthly cycle for a total of 3 cycles. Patients evaluation included monthly liver panel test, cell count and lymphocytes subset, symptom severity score, posttreatment liver biopsy, and endoscopic retrograde cholangiopancreatography at 6 months and 2 years. All patients had a significant decrease in peripheral total lymphocyte (1,629 +/- 462 to 426 +/- 57; p < 0.01) and CD4 cell count (782 +/- 200 to 144 +/- 21; p < 0.05) with consequent decrease of CD4:CD8 ratio (3.82 +/- 1.96 to 1.84 +/- 0.69; p = 0.09). This was associated with a quantifiable decrease in the hepatic inflammatory infiltrate on liver biopsy. No significant changes were found in symptom scores, liver panel tests, or cholangiograms. The drug was well-tolerated and two of four patients reported remission of their inflammatory bowel disease symptoms. Cladribine decreases the hepatic lymphocytic inflammatory infiltrate in early-stage PSC, which did not translate into any short-term symptomatic, biochemical, or radiologic improvements. Further studies with long-term follow-up are needed to assess if this anti-inflammatory effect can modify the progression of disease.

LKM-positive autoimmune hepatitis in the western United States: a case series.

OBJECTIVE: LKM-positive, or type 2, autoimmune hepatitis is characterized by the presence of antibodies directed against liver-kidney microsomes (LKM1). Although described frequently in southern Europe and the Mediterranean, this subtype of autoimmune liver disease seems to be extremely rare in northern Europe and in the United States. We report here five cases of LKM-positive autoimmune hepatitis that were seen at our center in the period 1989-1999. METHODS: We reviewed the medical records of all patients with the diagnosis of AIH in our institution during the period 1989-1999, and found that five patients had type 2 AIH. All patients were female; four of five were young, and four of five presented with overt cirrhosis. RESULTS: One patient died, one underwent liver transplantation and two are currently awaiting liver transplantation. Response to conventional immunosuppressive therapy was poor and two patients required treatment with cyclosporine and tacrolimus respectively. Four of five patients had at least one associated autoimmune disorder, including IgE-induced IgA deficiency, idiopathic thrombocytopenic purpura (ITP), and arthritis. HLA class II DR4 was present in two patients. CONCLUSIONS: LKM-positive autoimmune hepatitis seems to be a subset of autoimmune hepatitis with distinct clinical features; although rare, it is occasionally encountered in the western United States. Prompt diagnosis and appropriate immunosuppressive treatment are recommended, as well as early referral to transplantation centers. Clinicians should be aware of this condition in the setting of young female patients with unexplained severe liver disease.

Influenza infection in patients before and after liver transplantation.

Infection with influenza virus poses specific problems in pediatric and adult liver transplant recipients, both before and after liver transplantation. These include a higher rate of pulmonary and extrapulmonary complications, development of rejection with graft dysfunction, prolonged shedding of influenza virus, and increased drug-resistance. Hepatic decompensation may occur during influenza infection in patients with cirrhosis. Current prophylaxis includes yearly vaccination with trivalent inactivated vaccine. Appropriate diagnosis and prompt treatment of any upper respiratory infections are indicated in these patients. In this review, we describe a case of influenza viral pneumonia in an adult liver transplant recipient, review basic and clinical aspects of influenza infection in this patient population, and discuss current modes of prevention and treatment in detail.

Pulmonary infarction after liver transplant and previous hepatopulmonary syndrome.

We describe the case of a 36-year-old woman with previous hepatopulmonary syndrome in which a focal pulmonary lesion developed after liver transplantation. Thoracoscopic resection showed a pulmonary infarction of the superior segment of the right lower lobe. The patient recovered and had no further thrombotic events after 2 years of follow-up. The pulmonary vascular changes observed during hepatopulmonary syndrome may predispose patients to the development of pulmonary infarction.

Hepatic decompensation in patients with cirrhosis during infection with influenza A.

BACKGROUND: Patients with chronic liver disease can develop hepatic decompensation during systemic infections. Although gram-negative and gram-positive bacteria are well recognized as causes of decompensation, the effect of influenza virus infection on patients with chronic liver disease is poorly documented. METHODS: Retrospective analysis of patients with positive viral cultures who were seen at a liver transplantation clinic in a tertiary care referral center during the 1997-1998 influenza A (H3N2) epidemic in San Diego, Calif. RESULTS: Three patients with end-stage liver disease (1 with Wilson disease and 2 with alcoholic liver disease) developed hepatic decompensation and required hospitalization during infection with influenza A. Two patients had biochemical and clinical evidence of hepatic decompensation, including ascites, hepatic encephalopathy, and peripheral edema, and the third had acute hepatocellular damage, with elevated levels of aminotransferases. Viral hepatitis serologic test results, acetaminophen levels, drug and alcohol screening findings, and bacterial and fungal cultures were negative in all 3 patients. Hepatic decompensation resolved without the need for transplantation in the 2 patients with liver failure, and all patients recovered to their baseline liver function levels within 1 month of onset of acute illness. CONCLUSIONS: Influenza A infection can cause hepatic decompensation and hospitalization in patients having cirrhosis or who are awaiting liver transplantation. Effective prevention with vaccination and early recognition and treatment of influenza are strongly recommended in these individuals.

Diarrhea in the International Traveler.

International travelers to developing countries have a 40% risk of developing a diarrheal illness, usually acute and occasionally chronic. Preventive measures, including diet and lifestyle modifications, are highly recommended but may not be sufficient. Prophylaxis with bismuth subsalicylate or an antimicrobial should be considered in travelers with immunodeficiencies, co-morbid conditions, achlorhydria, or those who cannot afford a loss of time. Oral rehydration is the primary goal of therapy. Bismuth-subsalicylate is a first-line agent for treatment of milder cases with less than three watery bowel movements per day and prominent nausea. Use of an antibiotic is indicated for more severe cases or in the presence of fever, dysentery, or severe dehydration. A short course of a quinolone is highly effective, safe and well tolerated. Antimicrobial resistance among enteropathogens is growing and appropriate therapeutic modifications should be considered according to specific geographic areas. Metronidazole may be empirically added in those cases that do not respond to quinolones. Specific guidelines for particular pathogens are highlighted.

Gastrointestinal hemorrhage in patients with systemic sclerosis and CREST syndrome.

OBJECTIVES: Systemic sclerosis (SSc) and calcinosis, Raynaud's phenomenon, esophageal disease, sclerodactyly, telangiectasia (CREST) syndrome present distinctive microvasculature lesions that are thought to be responsible for tissue damage and disease progression. Involvement of the gastrointestinal tract may lead to the occurrence of profuse hemorrhage. We performed a study to assess the incidence and characteristics of gastrointestinal hemorrhage in a large group of patients with SSc and CREST syndrome. METHODS: We reviewed the medical records of 144 patients with SSc/CREST seen at our institution during the period 1985-1996. Endoscopic findings and clinical data were correlated. Data are expressed as means +/- SD. RESULTS: Twenty-two of 144 (15.2%) patients had at least one episode of gastrointestinal hemorrhage (16 women, 6 men; mean age, 59.4 +/- 17.6 yr). Eight patients (8/22; 36%) had multiple episodes and four (4/22; 18%) required chronic transfusion therapy. Mucosal telangiectasias were the most common cause of bleeding (9/22; 40.9%), followed by peptic ulcer disease (7/22; 31.8%) and erosive gastritis (3/22; 13.6%). Bleeding telangiectasias occurred in the entire gastrointestinal tract, including oral cavity (n = 1), esophagus (n = 1), stomach (n = 3), duodenum (n = 1), ileum (n = 1), cecum (n = 2), and colon (n = 2). Mortality was 22.7% in patients with gastrointestinal bleeding, compared with 7.3% in patients without bleeding. CONCLUSIONS: Patients with SSc/CREST syndrome are at risk of developing severe gastrointestinal hemorrhage. This complication is associated with frequent hospitalization, blood transfusions, and increased mortality. Mucosal telangiectasias are the most common source of bleeding. Appropriate endoscopic intervention is recommended in evaluating and preventing bleeding in patients with SSc/CREST.

Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells.

BACKGROUND: Proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) play an important role in the blood-brain barrier breakdown present in several neurological diseases including multiple sclerosis and AIDS. However, the specific effects of these cytokines on central nervous system-derived endothelial cells (CNS-EC) is not fully understood. In this study the effects of TNF-alpha and IL-6 were tested on different permeability mechanisms of CNS-EC. METHODS: Central nervous system endothelial cells were isolated from human brain and retina and cultured in vitro in a transwell system. Fluid-phase endocytosis and transcytosis, absorptive-mediated endocytosis, and ammonia diffusion were measured with specific methods. Endothelial cells were studied with electron microscopy for the ultrastructural effects of cytokine stimulation. RESULTS: Fluid-phase endocytosis and transcytosis were significantly increased by TNF-alpha and IL-6. This effect was dose dependent and reversible. The ammonia diffusion rate was also significantly increased by TNF-alpha. Absorptive-mediated endocytosis was not enhanced by TNF-alpha. Ultrastructural analysis of cytokine-treated CNS-EC confirmed the alterations in permeability showing an increase in endocytotic activity and a decrease in tight junctions. CONCLUSIONS: The proinflammatory cytokines IL-6 and TNF-alpha induce specific changes in the morphology and permeability of CNS-EC. These alterations can be important in many diseases characterized by increased cytokine production.

The role of central nervous system endothelial cell activation in the pathogenesis of hepatic encephalopathy.

I propose that central nervous system endothelial cells are directly or indirectly responsible for the brain pathology in hepatic encephalopathy, and that this damage to the central nervous system is mediated by specific cytokines and nitric oxide which activate endothelial cells and thereby alter their cell functions. Liver diseases are conditions characterized by high circulating levels of cytokines, namely interleukin-1, interleukin-6 and tumor necrosis factor. Interactions between these cytokines and central nervous system endothelial cells may trigger a cascade of events including enhanced blood-brain barrier permeability, brain edema, astrocyte alterations and gliosis. Cytokine-induced production of nitrogen reactive molecules by endothelial cells themselves may also lead to further cellular damage and neuronal dysfunction. This hypothesis may explain several characteristics of hepatic encephalopathy including reversibility, disease progression and clinical features. It also suggests potential ways of intervention.

A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB1016) in chronic active hepatitis.

In order to assess the liver protective activity and the antioxidant properties of a new silybin complex (IdB1016), we carried out a short-term pilot study on 20 patients with chronic active hepatitis (CAH), randomly assigned to 240 mg of silybin b.i.d. (10 patients, 4 m/6 f, mean age: 50 years) or placebo (10 patients, 2 m/8 f, mean age: 55 years). Blood samples were collected before and after 7 days of treatment for liver function tests (LFTs), malonaldehyde (MDA) as an index of lipid peroxidation, and copper (Cu) and zinc (Zn), two trace elements involved in protecting cells against free radical-mediated lipid peroxidation. In the treated group, there was a statistically significant reduction of mean (+/- SEM) serum concentrations of aspartate aminotransferase (AST) from 88.0 (+/- 13.3) to 65.9 (+/- 7.5) u/l, (p < 0.01), of alanine aminotransferase (ALT) from 115.9 (+/- 12.9) to 82.5 (+/- 10.6) u/l (p < 0.01), of gamma-glutamyltranspeptidase (gamma-GT) from 51.4 (+/- 9.3) to 41.3 (+/- 4.2) u/l (p < 0.02) and of total bilirubin (TB) from 0.76 (+/- 0.08) to 0.53 (+/- 0.04) mg/dl (p < 0.05). Alkaline phosphatase (AP) fell slightly from 143.4 (+/- 6.4) to 137.5 (+/- 7.8) u/l. There were no significant changes in MDA, Cu or Zn serum concentrations. These results show that IdB1016 may improve LFTs related to hepatocellular necrosis and/or increases membrane permeability in patients affected by CAH.

Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis.

The effects of human recombinant interleukin-1 receptor antagonist (IL-1ra) on inflammation, tissue damage, and production of inflammatory mediators in rabbit formalin-immune complex colitis were examined. Treatment of rabbits with intravenous administration of IL-1ra before and periodically throughout the first 43 hours after the induction of colitis (total 7 doses) suppressed inflammation and tissue damage in a dose-related manner. Maximum inhibition of inflammatory index (from 3.0 +/- 0.3 to 0.8 +/- 0.3, P less than 0.001), edema (from 2.3 +/- 0.2 to 0.6 +/- 0.2, P less than 0.001), percent of mucosal necrosis (from 44% +/- 7% to 7% +/- 3%, P less than 0.02) and myeloperoxidase (MPO) activity (from 4.9 +/- 1.0 U/g to 1.0 +/- 0.3 U/g, P less than 0.001) occurred with the dose of 5 mg/kg. Colonic prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, measured in rectal dialysates by specific radioimmunoassays, was also dose dependently suppressed (from 1124 +/- 319 pg/mL to 190 +/- 75 pg/mL, P less than 0.001 and 568 +/- 192 pg/mL to 92 +/- 51 pg/mL, P less than 0.001, respectively, at 5 mg/kg). In contrast, colonic IL-1 alpha tissue levels measured by a specific radioimmunoassay after tissue extraction were similar in all groups. When only two doses of IL-1ra, 10 minutes before and 3 hours after the induction of colitis were given, there was no longer an inhibitory effect on inflammation or production of inflammatory mediators. However, delaying the initial IL-1ra treatment 3 hours after the induction of colitis (total 6 doses) was effective in reducing inflammatory index (by 60%), MPO activity (by 79%), PGE2 (by 62%), and LTB4 (by 72%) whereas colonic IL-1 alpha levels were unchanged compared with vehicle-treated animals. These studies show the ability of human recombinant IL-1 receptor antagonist to suppress the proinflammatory activity of IL-1 produced in the colon during the induction and progression of rabbit immune complex colitis.