Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence.

BACKGROUND & AIMS: Recurrence of primary biliary cirrhosis (PBC) after liver transplantation (LT) is not rare and can occasionally lead to severe graft dysfunction and retransplantation. Ursodeoxycholic acid (UDCA) is a safe and effective treatment for PBC. However, whether preventive administration of UDCA after LT could lower the incidence of PBC recurrence is unknown. METHODS: Patients transplanted for PBC in five French and Swiss centers from 1988 to 2010 were included. Most patients from a single center received UDCA (10-15 mg/kg/d) preventively. Recurrence of PBC was histologically defined from biopsies routinely performed at 1, 5, 10, and 15 years of follow-up, and at any time when clinically indicated. RESULTS: A total of 90 patients with a 1-year minimum follow-up were studied retrospectively, including 19 (21%) patients receiving preventive UDCA. The mean follow-up was 12 years. Recurrence was diagnosed in 48 (53%) patients. The recurrence rates at 5, 10, and 15 years were 27%, 47%, and 61%, respectively. In a multivariate proportional hazards model adjusted for potential confounders and risk factors, preventive UDCA was the only factor affecting the risk of recurrence significantly (HR=0.32; 95% CI: 0.11-0.91). The 5, 10, and 15-year rates of recurrence were 11%, 21%, and 40%, respectively, under preventive UDCA, and 32%, 53%, and 70%, respectively, without preventive UDCA. Seven patients with recurrence (15%) progressed to cirrhosis, requiring retransplantation in one. However, neither recurrence nor preventive UDCA had a significant impact on survival. CONCLUSIONS: Preventive treatment with UDCA reduces the risk of PBC recurrence after LT.

[Extra-hepatic morbidity and mortality related to hepatitis C virus infection]. / Morbidité et mortalité extra-hépatiques associées a l'infection par le virus de l'hépatite C.

In addition to liver-related complications, HCV infection is associated with extra-hepatic manifestations. Patients have an increased risk of developing insulin resistance or type II diabetes. HCV infection is also associated with cryoglobulinemia which manifests itself with skin lesions, renal failure, or peripheral nervous system involvement. The risk of developing non-Hodgkin lymphoma, typically derived from B cells, is also increased. Patients may present with symptoms of CNS involvement. The association with cardiovascular events is likely but not proven with certainty. In some cases, the management of extra-hepatic manifestations of HCV will require antiviral therapy.

Clinical significance of the CCR5delta32 allele in hepatitis C.

BACKGROUND: The CCR5 receptor, expressed on Th1 cells, may influence clinical outcomes of HCV infection. We explored a possible link between a CCR5 32-base deletion (CCR5delta32), resulting in the expression of a non-functioning receptor, and clinical outcomes of HCV infection. METHODS: CCR5 and HCV-related phenotypes were analysed in 1,290 chronically infected patients and 160 patients with spontaneous clearance. RESULTS: Carriage of the CCR5delta32 allele was observed in 11% of spontaneous clearers compared to 17% of chronically infected patients (OR = 0.59, 95% CI interval 0.35-0.99, P = 0.047). Carriage of this allele also tended to be observed more frequently among patients with liver inflammation (19%) compared to those without inflammation (15%, OR = 1.38, 95% CI interval 0.99-1.95, P = 0.06). The CCR5delta32 was not associated with sustained virological response (P = 0.6), fibrosis stage (P = 0.8), or fibrosis progression rate (P = 0.4). CONCLUSIONS: The CCR5delta32 allele appears to be associated with a decreased rate of spontaneous HCV eradication, but not with hepatitis progression or response to antiviral therapy.

Identifying risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a case-control study.

BACKGROUND: Central pontine and extrapontine myelinolysis (CPEPM) is a rare but potentially fatal complication after orthotopic liver transplantation (OLT). The aim of this study was to identify risk factors for development of CPEPM after OLT and to assess patient outcome. METHODS: We reviewed the clinical data of 1,378 patients who underwent OLT between 1987 and 2009 in Geneva, Switzerland and Edmonton, Canada. Nineteen patients (1.4 %) developed CPEPM. We compared their characteristics with control patients, matched by age, gender, date of OLT, and MELD score. RESULTS: The 19 patients with CPEPM (7F, mean age 52.1 ± 2 years) had a mean MELD score of 26 ± 2.2. Before OLT, patients who develop CPEPM presented more frequently low (<130 mmol/l; p < 0.04) and very low (<125 mmol/l; p < 0.009) sodium than controls. In patients developing CPEPM, the number of platelet units and fresh frozen plasma transfused during surgery was higher (p = 0.05 and 0.047), hemorrhagic complications were more frequent after OLT (p = 0.049), and variations of sodium before and after OLT were higher (p = 0.023). The association of >2 of these conditions were strongly associated with CPEPM (p = 0.00015). Mortality at 1 year of patients developing CPEPM was higher (63 vs. 13 %, p < 0.0001). CONCLUSIONS: High MELD score patients undergoing OLT, receiving massive perfusions of Na-rich products, experiencing surgery-related hemorrhagic complication and important fluctuations of Na are at risk of developing CPEPM. Therefore careful monitoring of natremia in the perioperative period and use of water-free perfusion in case of massive blood-products transfusion are critical points of this patient management.

Use of glasgow-blatchford bleeding score reduces hospital stay duration and costs for patients with low-risk upper GI bleeding.

BACKGROUND AND STUDY AIMS: Upper gastrointestinal (UGI) bleeding is a frequent cause of hospitalization. Its severity may be assessed before endoscopy using the Glasgow-Blatchford Bleeding Score (GBS), a score validated to identify patients requiring clinical intervention. The aim of this study was to assess whether the GBS was effective for shortening hospital stay and reducing costs in patients with an UGI bleeding predicted at low risk of requiring clinical intervention. PATIENTS AND METHODS: Consecutive outpatients presenting with UGI bleeding at our hospital were prospectively included. In the observational study phase, UGI endoscopy was performed in all patients according to routine clinical practice. In the interventional study phase, patients with a GBS of 0 were discharged with an appointment for an outpatient UGI endoscopy. All patients had follow-up at 7 and 30 days. Need for clinical intervention was defined as performance of endoscopic hemostasis, blood transfusion or surgery. Results Two-hundred and eight patients were included, 104 in each study phase; complete follow-up was obtained in 201 patients. GBS varied from 0 to 18, with 15 (14 %) and 11 (11 %) patients having a GBS of 0 in the observational and interventional study phase, respectively. For patients with a GBS of 0, hospital stay was shorter (6 versus 19 h, P < 0.01), and costs were lower (845 EUR versus 1272 EUR, P = 0.002) in the interventional versus the observational study phase. For patients with a GBS > 0, hospital stay duration did not significantly differ between study phases (189 versus 207 h, P = 0.726). No adverse event was observed in the patients sent home with a GBS of 0 during the interventional study phase. Conclusions Implementing the GBS as a tool for triage of hospital outpatients who present with UGI bleeding allowed us to identify those who could safely be discharged for ambulatory management. Implementing this change in the hospital strategy significantly shortened hospital stay and decreased management costs.

Assessment of sexual function and conjugal satisfaction prior to and after liver transplantation.

BACKGROUND: The aims of this study were to assess sexual function and conjugal satisfaction in patients prior to and after liver transplantation, and in comparison to healthy individuals. MATERIAL AND METHODS: A cross-sectional cohort questionnaire assessment was performed in adult liver recipients, including the International Index of Erectile Function (IIEF) for men or the Female Sexual Function Index (FSFI) for women. Conjugal satisfaction was assessed with the Locke-Wallace Marital Adjustment Test. Waitlist candidates and age-matched healthy individuals were used as controls. RESULTS: Questionnaires of 136 patients were assessed (45 women/91 men, mean age: 57 ± 11 years). Overall, sexual function improved after transplantation (male: p=0.065 and female: p=0.072), but remained lower than in aged-matched healthy individuals. The post-transplant level of conjugal satisfaction was stable and similar to healthy controls in men, but improved significantly in women (p=0.008), with higher levels than in healthy subjects (p=0.05). CONCLUSIONS: The present study shows that sexual function improves after transplantation, yet not to the level of healthy controls. It also demonstrates, for the first time, that post-transplant conjugal satisfaction is at least similar to the one of healthy controls.

NK cell isolation from liver biopsies: phenotypic and functional analysis of low cell numbers by flow cytometry.

Natural killer (NK) cells are considered to play a critical role in liver disease. However, the available numbers of intrahepatic lymphocytes (IHL) derived from liver biopsies (LB) for ex vivo analysis of intrahepatic NK cells is very limited; and the isolation method may hamper not only yields and viability, but also phenotype and function of IHL. The aim of the present study was therefore to (1) refine and evaluate the cell yields and viability of a modified isolation protocol from standard size needle LB; and (2) to test the effects of mechanical dissociation and enzymatic tissue digestion, as well as the analysis of very low cell numbers, on the phenotype and function of intrahepatic NK cells. Peripheral blood mononuclear cells (PBMC) and IHL, freshly isolated from the peripheral blood, LB (n = 11) or partial liver resections (n = 5), were used for phenotypic analysis by flow cytometry. NK cell function, i.e., degranulation and cytokine production, was determined by staining of CD107a and intracellular IFN-γ following in vitro stimulation. The mean weight of the LB specimens was 9.1 mg, and a mean number of 7,364 IHL/mg were obtained with a viability of >90%. Exposure of IHL and PBMC to 0.5 mg/ml collagenase IV and 0.02 mg/ml DNase I for 30 min did affect neither the viability, NK cell function, nor the percentages of CD56(+), NKp46(+), and CD16(+) NK cells, whereas the level of CD56 surface expression was reduced. The phenotype of LB-derived NK cells was reliably characterized by acquiring as few as 2,500 IHL per tube for flow cytometry. The functional assay of intrahepatic NK cells was miniaturized by culturing as few as 25,000 IHL in 25 µl (10(6)/ml) using 96-well V-bottom plates with IL-2 and IL-12 overnight, followed by a 4 h stimulation with K562 cells at a NK:K562 ratio of 1:1. In summary, we report reliable phenotypic and functional analyses of small numbers of intrahepatic NK cells isolated from LB specimens providing us with a tool to better address the emerging role of human NK cell immunobiology in liver diseases.

Good long-term outcome of Budd-Chiari syndrome with a step-wise management.

UNLABELLED: Budd-Chiari syndrome (BCS) is a rare, life-threatening disease caused by obstruction of hepatic venous outflow. The aim of the study was to assess long-term outcome and identify prognostic factors in BCS patients managed by a step-wise approach using anticoagulation, angioplasty/thrombolysis, transjugular intrahepatic portosystemic shunting (TIPS), and orthotopic liver transplantation (OLT). We reviewed long-term data on 157 patients previously included by the European Network for Vascular Disorders of the Liver, a multicenter prospective study of newly diagnosed BCS patients in nine European countries. Patients were followed for a median of 50 months (range, 0.1-74.0). During the study, 88 patients (56%) received at least one invasive intervention (22 patients angioplasty/thrombolysis, 62 TIPS, and 20 OLT) and 36 (22.9%) died. Most interventions and/or deaths occurred in the first 2 years after diagnosis. The Rotterdam score was excellent in predicting intervention-free survival, and no other variable could significantly improve its prognostic ability. Moreover, BCS-TIPS prognostic index (PI) score (based on international normalized ratio, bilirubin, and age) was strongly associated with survival and had a discriminative capacity, which was superior to the Rotterdam score. CONCLUSIONS: The current study confirms, in a large cohort of patients with BCS recruited over a short period, that a step-wise treatment approach provides good long-term survival. In addition, the study validates the Rotterdam score for predicting intervention-free survival and the BCS-TIPS PI score for predicting survival.

Factors predicting survival after post-transplant hepatocellular carcinoma recurrence.

BACKGROUND: Although factors associated with an increased risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC) have been extensively studied, the history of patients with a post-transplant recurrence is poorly known. METHODS: Patients experiencing a post-transplant HCC recurrence from 1996 to 2011 in two transplant programs were included. Demographic, transplant, and post-recurrence variables were assessed. RESULTS: Thirty patients experienced an HCC recurrence-22 men and 8 women with a mean age of 55 ± 6 years. Sixteen (53 %) were outside the Milan criteria at the time of transplantation. Most recurrences (60 %) appeared within the first 18 months after transplantation, ranging between 1.7 and 109 months (median 14.2 months). Mean post-recurrence survival was 33 ± 31 months. On univariate analysis, total tumor volume (TTV; p = 0.047), microvascular invasion (p = 0.011), and time from transplant to recurrence (p = 0.001) predicted post-recurrence survival. On multivariate analysis, both time from transplant to recurrence (p = 0.001) and history of rejection (p = 0.043), but not the location of the recurrence or the type of recurrence treatment, predicted post-recurrence survival. CONCLUSION: This study suggests that patients with early post-transplant HCC recurrence have worse outcomes. Those with a history of graft rejection have better survivals, possibly due to more active anti-cancer immunity.

Demographics and outcomes of severe herpes simplex virus hepatitis: a registry-based study.

BACKGROUND & AIMS: Herpes simplex virus hepatitis is a rare, but severe disease, thus far only documented by case reports and short series. The present study was based on the SRTR registry, and included all listed patients for liver transplantation from 1985 to 2009 with a diagnosis of HSV hepatitis. METHODS: We assessed demographics and outcome of all listed patients, and further conducted a case-control study, matching each transplanted patient with 10 controls. Matching criteria included: transplant status, MELD score ±5, transplant date ±6 months, and age at transplant ±5 years. During the study period, 30 patients were listed for HSV hepatitis. Of the 30 listed patients, seven recovered spontaneously and five died, prior to transplantation. The remaining 10 children and eight adults were transplanted. RESULTS: The chance of recovery was significantly higher in children than in adults (7/19 vs. 0/11, p=0.02). In children, survival was similar between HSV patients and the matched controls (5-year survival: 69% vs. 64%, p=0.89). Conversely, survival was poor in adult HSV (5-year survival: 38% vs. 65%, p=0.006), with 62% of them dying within the first 12 months. All three reported post-transplant deaths in children were independent from HSV. Among the seven adult post-transplant deaths, four were related to infection (bacterial, fungal, or viral). CONCLUSIONS: Children listed for HSV hepatitis have a significantly better survival than adults both prior and after liver transplantation. While HSV fulminant hepatitis is an appropriate indication for liver transplantation in children, it should only be performed in selected adult patients in otherwise good condition.

Tolerability of everolimus-based immunosuppression in maintenance liver transplant recipients.

BACKGROUND: The aim of this study was to evaluate the tolerability of the conversion from calcineurin inhibitor (CNI) to everolimus (ERL) in maintenance liver transplant (LT) recipients. METHODS: From January 2005 to March 2008, ERL was introduced after LT as maintenance immunosuppressive therapy because of (i) de novo or recurrent cancer after LT, (ii) pre-existing liver carcinoma on the liver explant or (iii) CNI toxicity. CNI dosage was progressively reduced until discontinuation. RESULTS: The study population included 94 patients, of mean age 57 ± 10. The mean delay between LT and ERL introduction was 5 ± 5 yr. After a mean follow-up of 12 ± 7 months, 70% of the patients did present at least one side effect. The mean trough level of ERL was 6 µg/L at the end of follow-up. Main side effects included hyperlipidemia (37%), dermatitis (19%), mucositis (15%), and proteinuria (18%). Biopsy-proven acute rejection occurred in 9% of patients. Global ERL discontinuation rate was 21% (16% because of side effects). CONCLUSIONS: The results of our experience indicate that conversion to ERL is associated with adverse effects in 70% of patients leading to drug discontinuation in 16% (and amenable to dose reduction in the remainders). Longer follow-up periods are necessary to capture the impact of ERL fully on renal function and survival in cancer patients.

Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study.

UNLABELLED: Current recommendations for early anticoagulation in acute portal vein thrombosis unrelated to cirrhosis or malignancy are based on limited evidence. The aim of this study was to prospectively assess the risk factors, outcome, and prognosis in patients managed according to these recommendations. We enrolled 102 patients with acute thrombosis of the portal vein, or its left or right branch. Laboratory investigations for prothrombotic factors were centralized. Thrombus extension and recanalization were assessed by expert radiologists. A local risk factor was identified in 21% of patients, and one or several general prothrombotic conditions in 52%. Anticoagulation was given to 95 patients. After a median of 234 days, the portal vein and its left or right branch were patent in 39% of anticoagulated patients (versus 13% initially), the splenic vein in 80% (versus 57% initially), and the superior mesenteric vein in 73% (versus 42% initially). Failure to recanalize the portal vein was independently related to the presence of ascites (hazard ratio 3.8, 95% confidence interval 1.3-11.1) and an occluded splenic vein (hazard ratio 3.5, 95% confidence interval 1.4-8.9). Gastrointestinal bleeding and intestinal infarction occurred in nine and two patients, respectively. Two patients died from causes unrelated to thrombosis or anticoagulation therapy. CONCLUSION: Recanalization occurs in one-third of patients receiving early anticoagulation for acute portal vein thrombosis, whereas thrombus extension, intestinal infarction, severe bleeding, and death are rare. Alternative therapy should be considered when ascites and splenic vein obstruction are present.

Non-alcoholic fatty liver disease in liver transplant recipients: another story of "seed and soil".

OBJECTIVES: Fatty liver disease is a potential long-term complication of liver transplantation (LT). We therefore aimed to determine the prevalence and risk factors of liver steatosis in a large population of adult post-LT patients. METHODS: We evaluated the clinical, biological, histological, and evolutive features of patients with a diagnosis of steatosis made at liver biopsy examination during post-LT follow-up. Risk factors were analyzed by univariate and multivariate analysis. RESULTS: In total, 1,596 liver biopsies from 599 patients were available. Recurrent liver disease was present in 178 patients. A histological diagnosis of steatosis was made in 131 (31.1%) of the remaining 421 patients (51.1% had normal liver tests): 53% had grade 1, 31% grade 2, and 16% grade 3 steatosis. Perisinusoidal fibrosis was present in 38 patients (29.0%). Histological lesions were consistent with the diagnosis of non-alcoholic steatohepatitis (NASH) in 5 patients (3.8%). At the end of follow-up, cirrhosis or extensive fibrosis was observed in 3 patients (2.25%). Multivariate analysis showed that seven factors (post-LT obesity, tacrolimus-based regimen, diabetes mellitus, hyperlipidemia, arterial hypertension, alcoholic cirrhosis as primary indication for LT, and pre-transplant liver graft steatosis) were risk factors for post-LT steatosis. When zero, one, two, three, four, five, and six factors were present, steatosis occurred in 6.0, 12.0, 22.1, 29.9, 65.5, 81.5, and 100.0%, respectively. CONCLUSIONS: Liver steatosis is a frequent late complication of LT; its development depends on a combination of host and graft factors. LT is therefore an interesting model to study the natural history and the determinants of liver steatosis.

Etiology, management, and outcome of the Budd-Chiari syndrome.

BACKGROUND: The Budd-Chiari syndrome (BCS) is hepatic venous outflow obstruction. What is known about the syndrome is based on small studies of prevalent cases. OBJECTIVE: To characterize the causes and treatment of incident BCS. DESIGN: Consecutive case series of patients with incident BCS, enrolled from October 2003 to October 2005 and followed until May 2006. SETTING: Academic and nonacademic hospitals in France, Spain, Italy, Great Britain, Germany, Belgium, the Netherlands, Portugal, and Switzerland. PATIENTS: Persons older than 16 years with definite hepatic outflow obstruction diagnosed by imaging. Persons with hepatic outflow obstruction due to heart failure, sinusoidal obstruction syndrome, cancer, or liver transplantation were excluded. MEASUREMENTS: Signs and symptoms; laboratory and imaging findings; diagnosis; treatment; and overall, transplantation-free, and intervention-free survival. RESULTS: 163 incident cases of BCS were identified. Median follow-up was 17 months (range, 0.1 to 31 months). Most patients (84%) had at least 1 thrombotic risk factor, and many (46%) had more than 1; the most common was myeloproliferative disorders (49% of 103 tested patients). Patients were mainly treated with anticoagulation (140 patients [86%]), transjugular intrahepatic portosystemic shunting (56 patients [34%]), or liver transplantation (20 patients [12%]), and 80 patients (49%) were managed noninvasively. Only 3 patients underwent surgical shunting. The survival rate was 87% (95% CI, 82% to 93%) at 1 year and 82% (CI, 75% to 88%) at 2 years. LIMITATION: Treatment was not standardized across all centers, and data on important clinical variables were missing for some patients. CONCLUSION: Most patients with BCS have at least 1 thrombotic risk factor, and many have more than 1; myeloproliferative disorders are most common. One- and 2-year survival rates are good with contemporary management, which includes noninvasive therapies (anticoagulation and diuretics) and invasive techniques. Transjugular intrahepatic portosystemic shunting seems to have replaced surgical shunting as the most common invasive therapeutic procedure. PRIMARY FUNDING SOURCE: Fifth Framework Programme of the European Commission.

Risk of complications after abdominal paracentesis in cirrhotic patients: a prospective study.

BACKGROUND & AIMS: Complications and technical problems of paracentesis in cirrhotic patients are infrequent. However, the severity and the incidence of these events and their risk factors have not been assessed prospectively. METHODS: Cirrhotic patients (n = 171) undergoing paracentesis were included. Of the 515 paracenteses, 8.8% were diagnostic, and 91.2% were therapeutic. Technical features, demographic data, and adverse events during a period of 72 hours after the procedure were examined. RESULTS: Major complications occurred in 1.6% of procedures and included 5 bleedings and 3 infections, resulting in death in 2 cases. Major complications were associated with therapeutic but not diagnostic procedures and tended to be more prevalent in patients with low platelet count (<50 10(9)/L), Child-Pugh stage C, and in alcoholic cirrhosis patients. Technical problems occurred in 5.6%. The most frequent complication was a leak of ascites at the puncture site (5.0%), and in 89.5% there were no complications. CONCLUSIONS: The safety of paracentesis in cirrhotic patients might be decreased if risk factors, which depend on the characteristics of the patient and of the procedure itself, are present.

[Drug induced diarrhea]. / Diarrhée médicamenteuse.

Diarrhea is a frequent adverse event involving the most frequently antibiotics, laxatives and NSAI. Drug induced diarrhea may be acute or chronic. It may be due to expected, dose dependant properties of the drug, to immuno-allergic or bio-genomic mechanisms. Several pathophysiological mechanisms have been described resulting in osmotic, secretory or inflammatory diarrhea, shortened transit time, or malabsorption. Histopathological lesions sometimes associated with drug induced diarrhea are usually non specific and include ulcerations, inflammatory or ischemic lesions, fibrous diaphragms, microscopic colitis and apoptosis. The diagnosis of drug induced diarrhea, sometimes difficult to assess, relies on the absence of other obvious causes and on the rapid disappearance of the symptoms after withdrawal of the suspected drug.

Spontaneous Resolution of Brain Edema in Fulminant Hepatic Failure due to Hepatitis E.

Fulminant hepatic failure is characterized by the presence of hepatic encephalopathy in the setting of acute liver injury that occurs in a noncirrhotic organ. Brain edema is the ultimate complication of advanced hepatic encephalopathy as it often leads to cerebral herniation and death. Thus, the presence of fulminant hepatic failure indicates the need for urgent liver transplantation to prevent death or irreversible brain damage. We report a very unusual evolution of fulminant hepatic failure complicated by brain edema and hepatic coma in a 45-year-old woman admitted with acute viral hepatitis E infection.