Chemoprophylaxis with isoniazid in liver transplant recipients.

A patient receiving a liver graft needs to be treated with immunosuppressive drugs to avoid rejection. These kinds of drugs predispose the patient to the reactivation of latent infections such as tuberculosis (TB). Therefore, it is necessary to establish treatment regimens to prevent this. We retrospectively analyzed all consecutive patients undergoing liver transplantation (LT) at our center between January 1, 2000 and December 31, 2010. Latent tuberculosis infections (LTBIs) were diagnosed with positive tuberculin skin test results. After LT, infected patients were treated with isoniazid for 6 months; the treatment began soon after transplantation, and the patients were followed until the end of the study. During this period, 53 patients had LTBI data. All these patients were treated with isoniazid after LT. The median observation period after LT was 52 months (range = 12-129 months). No cases of TB reactivation were reported during follow-up. Only 4 patients presented alterations in liver enzymes related to this treatment, and they showed clear improvement after the treatment was stopped. None of these patients showed severe graft dysfunction. In conclusion, preventive isoniazid appears to be a safe drug for use in LTBI patients after LT. The treatment may be established just after LT without important graft dysfunction or severe consequences for the patient.

Influence of aquaporin-1 gene polymorphism on water retention in liver cirrhosis.

UNLABELLED: Water retention is a major clinical problem in patients with liver cirrhosis. The factors that predispose to water retention are poorly understood but may involve genetic factors. Recent research suggests that renal aquaporins may be a pathophysiological factor involved in this condition. Aquaporin-1 (AQP1) is expressed in the proximal tubule and aquaporin-2 (AQP2) in the renal collecting duct cells. The aim of our study was to investigate the distribution of single nucleotide polymorphisms (SNPs) of AQP1: rs1049305 (C/G) and AQP2: rs3741559 (A/G) and rs467323 (C/T) in 100 cirrhotic patients with ascites and to analyze their relationship with dilutional hyponatremia. METHODS: Genomic DNA was extracted from peripheral blood. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman SNP Genotyping Assays. The possible influence of rs1049305 (C/G) in AQP1 gene expression was evaluated by luciferase assays in vitro. RESULTS: The allelic frequencies of the AQP1 gene were the following: CC = 15%; CG = 49%; GG = 36%. Patients with CC genotype had significantly lower plasma sodium concentration than those with CG or GG genotype. Luciferase assays showed that the rs1049305 (C/G) in the AQP1 gene functionally affected the expression level in vitro. In addition, we did not find any relationship between AQP2 SNPs observed and plasma sodium concentration. CONCLUSIONS: Our results suggest that the rs1049305 (C/G, UTR3) AQP1 polymorphism could be involved in the genetic susceptibility to develop water retention in patients with liver cirrhosis.

Increased bactericidal/permeability increasing protein in patients with cirrhosis.

BACKGROUND: High levels of endotoxin in patients with cirrhosis are thought to be responsible for the activation of tumour necrosis factor-alpha (TNF)-alpha-mediated pro-inflammatory pathways involved in haemodynamic alterations. Bactericidal/permeability increasing protein (BPI) is a protein found in neutrophils with endotoxin-binding and neutralization capacity. It is not known whether defective BPI production or release is present in cirrhosis. AIMS: We investigated the levels of BPI in cirrhotic patients and its relation to other endotoxin-binding proteins and inflammatory markers. METHODS: Plasmatic levels of BPI, lipopolysaccharide-binding protein, soluble CD14, TNF-alpha and BPI mRNA expression in neutrophils were determined in 130 patients and 30 healthy controls. The capacity of patients' plasma to inhibit lipopolysaccharide (LPS)-mediated TNF-alpha production by monocytes from healthy donors was assessed in vitro. RESULTS: Patients with cirrhosis exhibited an increase in BPI mRNA and plasma level of BPI when compared with healthy controls (P<0.05). Child C group displayed the highest frequency of patients with a high concentration of BPI. A positive correlation was found between TNF-alpha and plasma levels of BPI (P<0.01). High levels of BPI in plasma were able to significantly reduce in vitro TNF-alpha release by monocytes after a challenge with LPS (8.54 +/- 1.04 vs. 10.44 +/- 0.85 pg/ml, P=0.028). CONCLUSION: BPI is increased in cirrhotic patients, especially in those with more severe liver disease. The amount of BPI in the plasma correlated with the TNF-alpha level and was able to reduce LPS-mediated TNF production by monocytes. BPI possibly plays a regulatory role by antagonizing the pro-inflammatory mechanisms mediated by TNF-alpha.

[Rendu-Osler disease with hepatic involvement: first transplant in Spain]. / Enfermedad de Rendu-Osler con afectación hepática: primer trasplante en España.

BACKGROUND AND OBJECTIVE: Rendu-Osler's disease (RO) is a rare systemic vascular disorder due to a fibrovascular dysplasia in the endothelium of vessels. Recurrent epistaxis is the main clinical manifestation, but arteriovenous malformations (AVMs) can involve many organs, including the liver. Hepatic involvement can develop refractory heart failure due to large shunts between the hepatic veins and the hepatic artery. Embolization and hepatic artery ligation have also demonstrated to reduce cardiac output in RO, but these therapeutic options have significant morbidity and complications such as necrosis or liver failure. CASE REPORT: We report the case of a 48 years old woman diagnosed in 1987 with RO and significant hepatic involvement, with multiple fistulas between veins and hepatic artery. In the following years she developed progressive heart failure that limited her quality of life. RESULTS: She was admitted on more times with heart failure and her dyspnea worsened progressively up to NYHA IV. At this time, an echocardiograph control showed an output cardiac about 10.6l/min. On December 2004, although the medical treatment, the worsening of the patient went on, so we finally decided to conduct a liver transplant that resolved the symptoms and the hyperdynamic circulation. Despite the fact that liver transplant has become without doubt into the best treatment for these patients in the last years. CONCLUSIONS: This is the first one done in Spain. There are different therapies available for these patients, but the indications for transplantation are greater each day, mainly due to the risks of the other options. Currently the stated guidelines are heart failure and portal hypertension refractory to medical treatment. So in these situations, liver transplantation should be proposed in the early stages of the disease and may be the only viable option.

[Pruritus associated with cholestasis]. / Prurito asociado a colestasis.

Pruritus is commonly associated with cholestatic disorders and shows wide interindividual variability. The presence of skin lesions due to scratching and the application of a visual analogue scale are useful for clinical evaluation. Although the pathophysiology of this entity is not well understood, advances have recently been made in understanding of the pruritoceptive neural pathway, which shares certain similarities with the nociceptive pathway, although there are other distinguishing characteristics such as the action of a specific neurotransmitter, GPR, on the first synapsis at the posterior horn of the spinal cord. Amongst the modulator systems of the pruritoceptive pathway is the action of the endogenous opioids. An increase of these opioids in cholestatic situations is the most widely accepted hypothesis for pruritus in these patients. Some treatments have proven efficacy in randomized clinical trials in patients with cholestatic disorders, such as anion exchange resins, rifampicin, opioid antagonists and ursodeoxycholic acid; the latter is especially useful in intrahepatic cholestasis of pregnancy.

Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation.

Interleukin-23 (IL-23) and T helper 17 (Th17) cells have been cast as major players in autoimmunity, but their role in transplantation immunity remains to be specified. The aim of our study was to investigate the time course of serum levels of IL-23 and IL-17 during hepatic allograft rejection. Serum levels of IL-23 and IL-17 were determined in 20 healthy subjects and 50 hepatic transplant recipients. These patients were divided into 2 groups: group I was composed of 15 patients with acute rejection, and group II was composed of 35 patients without acute rejection. Samples were collected on days 1 and 7 after liver transplantation and on the day of liver biopsy. The concentrations of IL-23 were similar for the rejection group and nonrejection group at early postoperative times. We observed a significant increase in serum IL-23 levels in the rejection group when a diagnosis of acute rejection had been established. Similarly to IL-23, at the diagnosis of acute rejection, the concentration of IL-17 was significantly higher in the rejection group versus the nonrejection group. The whole transplant group, including those with stable graft function, had higher serum levels of IL-23 and IL-17 than the controls during the entire postoperative period. In conclusion, IL-23 and IL-17 are up-regulated during acute hepatic rejection. These findings suggest a role for Th17 cells in human liver allograft rejection.

[Adult-onset Still's disease with liver failure requiring liver transplantation]. / Enfermedad de Still del adulto con desarrollo de insuficiencia hepática que precisa trasplante hepático.

We present the case of a 23-year-old man with fever of unknown origin, who developed acute liver failure 2 months after symptom onset, requiring an urgent liver transplantation. The diagnosis of adult-onset Still's disease was established after the reappearance of symptoms after transplantation, and high doses of corticosteroids were used to control disease activity. Subsequently, given the impossibility of tapering the steroid dose, interleukin-1 receptor blocking treatment was started with satisfactory outcome. We also review the published literature.

Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis.

BACKGROUND: Some lines of evidence suggest that endotoxin may induce non-alcoholic steatohepatitis (NASH) in a background of fatty liver. However, a clear association between increased endotoxemia and development of steatohepatitis in obese patients has not been confirmed. We aim to assess the endotoxemic state of patients with non-alcoholic fatty liver disease (NAFLD) and its relationship with the liver expression of TNF-alpha and the presence of NASH. METHODS: Prospective study comprising 40 patients with morbid obesity who were diagnosed with NAFLD. Blood samples and liver biopsies were collected. Endotoxemia was assessed by the evaluation of circulating level of LPS-binding protein (LBP). Plasma levels of LBP and TNF-alpha were assessed by ELISA. The expression of TNF-alpha in liver tissue was evaluated by real-time PCR. Histological examination was performed to evaluate the presence of steatosis or NASH. RESULTS: Levels of LBP were increased in obese patients with NAFLD. In addition, plasma level of LBP was increased in patients with steatohepatitis (14.2 +/- 3.9 microg/mL) when compared with patients with simple steatosis (11.5 +/- 3.2 microg/mL), P=0.041. The TNF-alpha mRNA expression in liver tissue was significantly higher in patients with NASH. This increment correlated with the rise in plasma levels of LBP (r=0.412, P=0.036). CONCLUSION: NAFLD patients have elevated plasma levels of LBP and they are further increased in patients with NASH. This increase is related to a rise in TNF-alpha gene expression in the hepatic tissue which supports a role for endotoxemia in the development of steatohepatitis in obese patients.

Non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) is characterized by an excessive accumulation of fatty acids and triglycerides within the cytoplasm of the hepatocytes of non-alcohol users. The natural history varies according to the initial histological diagnosis. A current consideration is that cryptogenic cirrhosis may be representative of a late stage of non-alcoholic steatohepatitis (NASH), which has lost its features of necroinflammatory activity and steatosis in up to 80% of patients. Since NASH is able to progress to cirrhosis, hepatocellular carcinoma (HCC) development may be an end-stage of this disease. We report below two clinical cases of patients diagnosed with NASH who developed HCC. The relationship between NAFLD and HCC is reviewed.

Etiologies and outcomes of acute liver failure in a spanish community.

Previous retrospective study (1992 to 2000) performed in Spain showed that drug toxicity, viral hepatitis, and indeterminate etiology were the most prevalent causes of acute liver failure (ALF). In the last decade, there is no information about ALF in our country. For these reasons we analyze retrospectively, in a ten-year period (2000 to 2010), the presumed causes, clinical characteristics, course, and outcome of ALF in a Spanish community. Causes of ALF were indeterminate in 4 patients (24%), acute hepatitis B infection in 4 patients (24%), drug or toxic reactions in 4 patients (24%), including one case of acetaminophen overdose, followed by miscellaneous causes. The overall short-term survival (6 weeks after admission) was 65%. Liver transplantation was performed in 11 patients with a survival of 82%. Despite fulfilling criteria, 2 patients were not transplanted because of contraindications; they both died. In summary, acute hepatitis B and indeterminate cause are still being the most frequent causes of ALF in our region, and patients with ALF have an excellent chance of survival after emergency liver transplantation. Acetaminophen overdose still represents a very rare cause of ALF in our community.

Osteoprotegerin and receptor activator of nuclear factor-kappaB ligand system in the early post-operative period of liver transplantation.

BACKGROUND: The precise mechanism that leads to accelerated bone resorption in the early post-transplant period remains unclear. Recent data suggest that osteoprotegerin (OPG) and its ligand receptor activator of nuclear factor-kappaB ligand (RANKL) constitute a novel cytokine system that can influence the function of both bone and immune cells. The aim of our study was to assess OPG and RANKL concentrations in the early post-operative period of liver transplantation. METHODS: Serum OPG and RANKL levels were measured in 30 patients who underwent liver transplantation at 1, 7 and 14 d post-operatively. These values were compared with 22 age- and sex-matched healthy controls. Plasma sodium, creatinine, aspartate-aminotransferase, alanine-amino transferase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, albumin, prothrombin time, tacrolimus and cyclosporine levels were measured in each patient. RESULTS: We found a significant increase in OPG levels in the early post-operative period compared with the control group: day 1 (10.42 pmol/L, range 3.80-17.50 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.0001), day 7 (6.90 pmol/L, range 3.00-15.30 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.0001) and day 14 (5.76 pmol/L, range 2.60-10.70 vs. 3.91 pmol/L, range 1.20-6.60; p = 0.001). Similarly, serum RANKL levels were significantly higher than in the control group in this period, day 1 (0.123 pmol/L, range 0.010-0.420 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.02), day 7 (0.236 pmol/L, range 0.010-0.720 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.0004) and day 14 (0.137 pmol/L, range 0.010-0.520 vs. 0.054 pmol/L, range 0.010-0.300; p = 0.007). No correlation was found between OPG levels and RANKL, ischemic times, liver function tests, albumin, sodium or creatinine concentrations and tacrolimus or cyclosporine levels. CONCLUSIONS: A significant amount of OPG and RANKL is released in the early post-transplant period of liver transplantation. This might be explained by an activation of the immune system caused by the allograft. Therefore, the RANKL/OPG system may be involved in the pathophysiological evolution of transplantation osteoporosis.

Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease.

The aim of this study was to evaluate the rate of alcohol recidivism after orthotopic liver transplantation (OLT) for alcoholic liver disease (ALD) and its influence on the allograft and patient survival, as well as the development of comorbidities and de novo cancers. The study was performed on 54 subjects previously analyzed and transplanted in our center for ALD, whose follow-up was prolonged to a mean of 99.2 (SD 31.7) months (range, 14-155). Medical records were reviewed, and data on alcohol consumption, therapeutic compliance, graft evolution, rejection, infections, comorbidities, rates of de novo malignancies and other clinical events, and survival were collected. Comparisons between groups were performed by the Fisher's exact test, and survival was assessed by the Kaplan-Meier method. Survival curves were compared using the Mantel-Cox statistic. The risk of death resulting from alcohol recidivism was analyzed with a Cox proportional hazards model. Fourteen patients who underwent transplantation for ALD (25.9%) returned to alcohol use between 5.0 and 86.9 months after OLT (median, 47.5). There was no significant association between the presence or absence of alcohol recidivism and the occurrence of graft rejection, infections, associated comorbidities after OLT, or compliance. The 5- and 10-year survival rates for patients with alcohol recidivism were 92.9% and 45.1%, respectively, compared with 92.4% and 85.5%, respectively, for patients without alcohol recidivism. These figures show significantly lower survival rates in recidivistic patients after 10 years (P < 0.01, Mantel-Cox). The fact that patients who resumed alcohol consumption have a worse 10-year survival rate might be attributed to a higher frequency of deaths, primarily from cancer and cardiovascular events.

Osteoprotegerin and RANKL in alcoholic liver cirrhosis.

BACKGROUND/AIMS: The mechanisms leading to osteoporosis in alcoholic liver disease remain poorly understood. Recently identified soluble circulating osteoprotegerin (OPG), is the osteoclastogenesis inhibitory factor. It acts as a decoy receptor for osteoclast activating factor, receptor activator of nuclear factor-kappaB ligand (RANKL), and impairs osteoclast function. The aim of our study was to investigate the OPG/RANKL system in alcoholic cirrhotic patients and their correlation with biochemical marker of bone turnover. PATIENTS AND METHODS: Serum OPG, RANKL, osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX-I), bone alkaline phosphatase activity (bALP), and urinary hydroxyproline were measured in 30 patients with alcoholic cirrhosis, and in 20 age- and sex-matched healthy controls. RESULTS: OPG levels were significantly increased in patients with alcoholic cirrhosis compared with healthy subjects (5.9 pmol/l, range 2.7-9.0 vs 4.1 pmol/l, range 1.2-6.6; P < 0.001). RANKL levels were significantly higher in patients with cirrhosis (0.48 pmol/l, range 0.01-1.34) than in healthy subjects (0.11 pmol/l, range 0.01-0.90). There was a positive correlation between serum OPG and RANKL (r = 0.37; P < 0.001), bALP (r = 0.66; P < 0.001) and urinary hydroxyproline (r = 0.51; P < 0.05) but not with OC and CTX-I. CONCLUSIONS: OPG might partly represent a compensating mechanism to the negative balance of bone remodelling in patients with alcoholic cirrhosis.

Liver transplantation with allografts from hepatitis B core antibody-positive donors: a new approach.

The enduring shortfall of organ donors has inspired the widespread utilization of hepatic allografts from donors with hepatitis B core antibodies in spite of the potential risk of transmitting hepatitis B virus (HBV) infection to the recipient. Here we report a protocol of naive recipients receiving livers from hepatitis B core antibody-positive donors. From November, 1999 to March, 2002, 77 liver transplantations were performed in 73 patients at our institution, 7 of whom received livers from hepatitis B core antibody-positive donors. All recipients received 10,000 U/d of intravenous HBIg for 7 days and 100 mg/d of lamivudine until we could obtain the HBV-DNA from the donor samples (serum and liver tissue). If the results of the HBV-DNA from the donor samples were positive, the patient would continue with prophylaxis and if they were negative we would finish the combined prophylaxis. After transplantation, HBV serologic markers and HBV-DNA by polymerase chain reaction (PCR) in serum and lymphocytes were tested in the recipients on the seventh, fifteenth, thirtieth, and ninetieth days as well as every 3 months after transplantation. All seven donor organs were negative for HBV-DNA in serum and liver tissue. Thus, we stopped the combined prophylaxis in all recipients (range, 7 to 10 days). None of the 7 patients developed de novo HBV infection over the 3-year study period (range, 9 to 36 months). Our approach is reasonably safe, and it appears to be very effective in the prevention of de novo HBV infection after liver transplantation.

Plasma leptin and TNF-alpha levels in chronic hepatitis C patients and their relationship to hepatic fibrosis.

The aim of this study was to examine the possible relationship between the plasma levels of leptin and tumor necrosis factor (TNF)-alpha and the stage of hepatic fibrosis in a cohort of patients with chronic hepatitis C. Leptin and TNF levels were measured by RIA in 135 patients and in 75 age- and sex-matched controls. Liver disease was evaluated by the stage of fibrosis and the extent of inflammatory infiltrate in the liver biopsy. Leptin levels correlated with BMI values in healthy controls and in patients with chronic hepatitis C (men, r = 0.61, P = 0.0001; women, r = 0.68, P = 0.003). Leptin levels increased as hepatic fibrosis stage progressed both in male and in female patients (P < 0.001); also, TNF levels were higher in patients with an advanced stage of fibrosis (P = 0.006). In these patients, levels of leptin increased according to the progression of the stage of fibrosis; these data suggest that leptin may play a role in the regulation of hepatic fibrosis.

Serum immunological profile in patients with chronic autoimmune cholestasis.

AIM: To compare patients who had biochemical and histological features of chronic autoimmune cholestasis (CAIC) using serological autoantibody profiling. METHODS: Patients (n = 174 CAIC; 79 AMA(-) and 95 AMA(+)) were profiled for the following antibodies: antinuclear antibodies (ANAs), antimitochondrial antibodies (AMAs), antismooth muscle actin (SMA, mainly F-actin), antiperinuclear cytoplasmic neutrophil antibodies (pANCAs), anti-SP100, anti-GP210, anti-M2 (2-oxo-acid dehydrogenase complexes), and antisoluble liver antigen (SLA). Liver specimens were reviewed according to staging, biliary interface activity, lobular hepatitis, granulomas, cholestasis, and florid ductal lesion. RESULTS: In patients who were AMA(-) by indirect immunofluorescence (IIF), 34.6% were positive for anti-M2 by immunoblotting. In 49 definitively AMA(-) patients, 24 (48.9%) showed ANA-primary biliary cirrhosis (PBC)-related antibodies (rim-like, multiple nuclear dots, anti-SP100, or anti-GP210). There were no differences in immunological, biochemical, or histopathological features between IIF-AMA(+) patients and AMA(-) patients with anti-M2 or ANA-PBC-related antibodies. AIH-related autoantibodies were found in 13 patients (7.5%). Patients with AMAs or ANA-PBC-related antibodies had higher IgM levels, whereas patients with antibodies highly specific for AIH had higher AST, bilirubin, and IgG levels, and AIH scores, and higher grades of lobular hepatitis. Overall, three distinct categories of patients were observed: AMA(+) or AMA(-) patients with ANA-PBC-related antibodies; AMA(-) patients with non-PBC-related ANAs; and patients with AIH-related antibodies together with serum PBC markers. CONCLUSION: Since these three groups had immunological, biochemical, and histopathological differences, they ought to be considered as separate clinical subentities rather than as merely AMA(-) or AMA(+) patients with autoimmune cholestasis.