Search

Background Tacrolimus is metabolized by members of the cytochrome p450 3A subfamily, and its bioavailability depends also on P-glycoprotein. We have observed that some patients admitted for infection presented with increased tacrolimus trough levels (TLs). The aim of the study was to assess the impact of infection on tacrolimus TLs and to determine the factors involved in TL fluctuations. Methods This retrospective cohort study included patients transplanted with a kidney between 2009 and 2011 who were hospitalized for an acute infection. Tacrolimus TLs and dosages were recorded before hospitalization, at admission, and 1 month after discharge. Increased levels of tacolimus were defined as TL 25% higher on admission than those recorded at the last visit before hospitalization. Results Seventy-seven patients were hospitalized 138 times for infection. More than two thirds of first hospitalizations occurred during the first post-transplant year. Causes of hospitalization were urinary (33%), cytomegalovirus (27%), digestive (15%), and pulmonary (12%) infections. Thirty-five percent of kidney transplant recipients had increased tacrolimus TLs (27/77 patients) in 24% of the hospitalizations (34/138). In 34 hospitalizations occurring in 27 patients, TL at admission was ≥25% compared with the last visit before admission. Comparing these 34 hospitalizations with the other 104, no significant differences were noted, except for a greater fraction of digestive infections in the group with elevated tacrolimus TLs, independent of diarrhea occurrence. Conclusions Up to 35% of kidney transplant recipients admitted for acute infection present with high tacrolimus TLs, requiring a dose reduction. How acute infection precisely affects metabolism and bioavailability of tacrolimus remains to be investigated.

Background: Cyst infection is one of the complications of autosomal dominant polycystic kidney disease and polycystic liver disease. The diagnosis is typically made on a mix of clinical, laboratory and imaging abnormalities but the importance of individual items is uncertain. We aimed to perform a Delphi survey amongst physicians to achieve consensus on diagnostic criteria. Methods: We retrieved diagnostic items from the literature and conducted physician and patient interviews. All items were combined to create the online questionnaire. Participants rated each item during 3 consecutive rounds. Items were rated for diagnostic helpfulness for hepatic and renal cyst infection on a 9-point scale with anchors, from extremely unimportant (n = 1) to extremely important (n = 9). We determined consensus with the disagreement index. The median rating of each item was calculated and categorized into inappropriate (≤3.4), uncertain (3.5-6.4) or appropriate (≥6.5). By combining all items that reached an appropriate consensus rating, we developed a diagnostic algorithm based on expert consensus. Results: We invited 58 physicians to participate in the survey. In total, 35 (60%) responded to round 1 of which 91% (n = 32) and 86% (n = 30) responded to round 2 and 3, respectively. The final panel included 23 nephrologists, 5 hepatologists, a nuclear medicine specialist and an infectious disease physician from 11 countries (male 67%, mean age 47 ± 11 years, median clinical experience 21 years). The panel rated the diagnostic helpfulness of 59 potential items. Ultimately, 22 hepatic and 26 renal items were rated appropriate, including positive blood cultures and fluorodeoxyglucose positron-emission CT imaging. Ultrasonography and absence of intracystic bleeding were amongst those deemed uncertain or inappropriate. Subsequently, by combining items rated appropriate, we developed a clinical tool to diagnose hepatic and renal cyst infection. Conclusions: We identified diagnostic items for hepatic and renal cyst infection and developed an expert-based diagnostic algorithm, which may aid physicians in the diagnostic work-up. A prospective study is necessary to validate this algorithm.

Kidney transplant recipients (KTR) are subjected to immunosuppressive therapy that can enhance hepatitis B and C virus replication, leading to cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to assess the prevalence and outcome of HCC in KTR. Case-control study. Patients with chronic HBV and/or HCV infection who underwent kidney transplantation between 1976 and 2011 and subsequently developed HCC were compared to a control group of patients with chronic HBV and/or HCV infection, matched for gender and age at HCC diagnosis, who did not receive kidney transplantation. Among 2944 KTR, 330 had hepatitis B and/or C. Fourteen developed HCC, a period prevalence of 4.2%. Age at HCC diagnosis was 52.6 ± 6.5 years (53.5 ± 5.7 in controls, P=.76). Time between transplantation and HCC diagnosis was 16.7 ± 2.7 years. Six HCCs were related to HBV, six to HCV and two to co-infection with HBV and HCV. Immunosuppressive therapy was comparable in HBV, HCV and HBV+HCV patients. At diagnosis, 71% of patients met Milan criteria (65% in the control group, P=.4). Alpha-fetoprotein levels, tumour characteristics and treatment modalities were comparable between both groups. Patient survival 2 years after HCC diagnosis was 28% in KTR, compared to 68% in controls (P=.024). Survival after HCC diagnosis is significantly worse in KTR compared to nontransplanted patients with HBV and/or HCV. Prevention is crucial and should be based on viral eradication/suppression before or after transplantation.

Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984-2007, nine (1.1%) of 824 adult LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4x), and/or a diffuse tumor localization (3x) and/or a refractory hormonal syndrome (5x). Median post-LT patient survival is 60.9 months (range 4.8-119). One-, 3- and 5-year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5 years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease-free at 78, 84 and 96 months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo- and adjuvant surgical as well as medical treatment. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.

The diagnosis of hepatic cyst infection is difficult in patients with autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that carbohydrate antigen 19-9 (CA 19-9), secreted by the biliary epithelium lining the cysts, is overproduced in the case of cyst infection. In this report, we describe 3 patients with ADPKD with hepatic cyst infection, all with functioning kidney transplants, who had markedly increased serum CA 19-9 levels. Furthermore, CA 19-9 level was extremely increased in cystic fluid obtained in 2 of these individuals. Corresponding with clinical improvement, there was a marked decrease in serum CA 19-9 level in all 3 patients. To assess the potential applicability of these findings, serum CA 19-9 was measured in asymptomatic patients with ADPKD with known liver cysts and in controls without ADPKD. Although serum CA 19-9 levels were significantly higher in asymptomatic patients with ADPKD than in controls, they were markedly increased in patients with cyst infection compared with either asymptomatic ADPKD patients or controls. Immunostaining for CA 19-9 showed strong positivity in biliary tree epithelia and cysts of polycystic livers from patients with ADPKD that appeared more intense than in normal livers. Although further study is necessary, these data suggest that serum CA 19-9 level is markedly increased during liver cyst infection in kidney transplant recipients with ADPKD and has potential utility as a diagnostic marker.

Fatigue is one of the most common non-specific symptoms associated with several disease states including liver diseases. Recently, it was reported that levels of progesterone metabolites such as allopregnanolone (3alpha,5alpha-tetrahydroprogesterone; 3alpha,5alpha-THP) and isopregnanolone (3beta,5alpha-THP) were increased in plasma of patients with chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases. We evaluated fatigue scores and plasma levels of five progesterone metabolites in 16 patients with primary biliary cirrhosis (PBC), 12 patients with chronic hepatitis C (CHC) and 11 age-matched controls. The fatigue impact scale (FIS) ratio was significantly increased (P < 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3alpha,5alpha-THP and pregnanolone (3alpha,5beta-THP) were significantly increased in PBC and CHC patients. The other progesterone metabolites, i.e. 3beta,5alpha-THP, 3beta,5beta-THP and 3alpha,5alpha-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3alpha,5alpha-THP and 3alpha,5beta-THP were found to be significantly higher in patients with fatigue (P < 0.05), while those of patients without fatigue were not significantly different from controls. Both 3alpha,5alpha-THP and 3alpha,5beta-THP are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood-brain barrier. The present preliminary findings suggest that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases.

BACKGROUND Aristolochic acids (AA) are nephrotoxic and carcinogenic. The aim of this study was to assess the long-term outcome of patients with AA nephropathy (AAN) after kidney transplantation. METHODS Observational study. Patients' characteristics, long-term surveillance and follow-up data, patient and graft survival, as well as outcomes with respect to rejection, cardiovascular complications, infections, and cancers with a focus on urothelial carcinomas, are reported. RESULTS Twenty patients transplanted for AAN were included. All were submitted to prophylactic bilateral ureteronephrectomy and annual surveillance of the bladder. Median duration of posttransplant follow-up was 12.5 (3-19) years. Time from diagnosis of AAN to renal replacement therapy was relatively short (1 [0-15] years). Immunosuppression consisted of a triple therapy in the majority of patients. Nineteen patients had upper urinary tract multifocal atypia. Eleven patients presented with urothelial carcinomas of the upper tract; 2 of them with additional bladder urothelial carcinomas. Of these 2 patients, one required radical cystectomy. One patient developed a hepatocarcinoma. Patient survival was 100% in AAN patients at 5, 10, and 15 years after transplantation. Graft survival at 5, 10, and 15 years was 95%, 83%, and 75%. CONCLUSIONS Despite a high prevalence of urothelial carcinoma and the risk of bladder carcinoma, the long-term patient and kidney graft survival is excellent in patients with AAN, provided that prophylactic bilateral ureteronephrectomy and lifelong surveillance of the bladder are performed.

Treatment options for advanced hepatocellular carcinoma (HCC) remain limited. Recently, octreotide has been proposed for therapy, although its efficacy remains controversial. Thus, the aim of this open-label pilot study was to evaluate the response of HCC to long-acting octreotide (Sandostatin LAR). Thirty patients were enrolled for this prospective 2-year trial. Initially, patients were given short acting octreotide to ensure drug tolerability. Thereafter, patients received long-acting octreotide 30 mg IM every 4 to 6 weeks. Measurable disease was assessed at 3-month intervals. Five of 30 patients were unable to tolerate the test dose, and 1 patient was reevaluated and underwent hepatic resection. The remaining 24 patients, who received long-acting octreotide, all had advanced stage of disease with multifocal-massive morphology (67%), vascular thrombosis (63%), or extrahepatic spread (17%), but well compensated liver disease. The treatment was well tolerated, except for diarrhea. Median time to tumor progression was 3.6 months, and median survival was 5.1 months. Seven patients (29%) had stable disease (median duration of 8.0 months) with 2 patients demonstrating disease stability for 24 months. In conclusion, although occasional patients appear to have stable disease on long-acting octreotide therapy, overall the beneficial response in terms of time to tumor progression and survival is limited.

Several studies have linked centrilobular necrosis (CN) to acute cellular rejection (ACR) following liver transplantation. However, it may be difficult to establish the diagnosis of ACR when the classic portal features are absent. The aim of the present study was to identify specific features that would help to recognize ACR in biopsies with CN. One hundred and forty liver biopsies with CN were identified from 97 patients who underwent liver transplantation. The following histopathologic features were assessed: CN, steatosis, lobular inflammation, cholestasis, endothelialitis, and fibrosis. CN was graded semiquantitatively. A number of clinical and biochemical parameters were also recorded. Biopsies with CN were assessed for the presence or absence of ACR and divided into two groups accordingly. The associations of the biochemical, pathologic, and clinical features with ACR were assessed using a multivariate logistic regression model. The outcomes of patients with and without rejection were compared using the Cox proportional hazards regression model. Seventy-four biopsies (52.9%) showed evidence of ACR, and 52 patients (53.6%) had evidence of ACR at the first biopsy with CN. The multivariate analysis showed the presence of cholestasis, lobular inflammation, the ALT level, and time since liver transplantation to be independent predictors of the presence of ACR in biopsies with CN. Patients with ACR on their first biopsy with CN were significantly more likely to experience graft loss compared with patients without ACR. In conclusion, the presence of cholestasis and lobular inflammation on biopsies with CN appeared helpful in predicting its association with ACR. (Liver Transpl 2004;10:480–487.)

The hepatorenal syndrome (HRS) is related to vasoconstriction of the renal cortex induced by systemic hypovolemia that follows splanchnic vasodilatation as the primary event in the cascade of hemodynamic changes associated with portal hypertension. We evaluated the effects of octreotide, a splanchnic vasoconstrictor, on HRS in cirrhotic patients. We compared the effects of octreotide infusion (50 microg/h) to placebo using a randomized, double-blind, cross-over design over 2, 4-day periods. Nineteen patients were included, and 14 patients could complete the 2 phases of the study (group 1: placebo first; n = 8 and group 2: octreotide first; n = 6) The end point of the study was to evaluate improvement in renal function as defined by a 20% decrease in serum creatinine value after a 4-day treatment as compared with baseline. In all the patients, a normal central venous pressure was maintained by daily intravenous administration of 2 units of albumin. The 2 groups were similar with regard to demographic data and liver and kidney function parameters at baseline. Improvement in renal function was observed in 2 patients after the placebo and 1 patient after octreotide infusion in group 1 and in 2 patients after octreotide infusion and 1 patient after placebo in group 2 (P = not significant). In addition, treatment with octreotide infusion did not result in significant changes in creatinine clearance, daily urinary sodium, plasma renin activity, plasma aldosterone and glucagon levels, or renal and mesenteric artery resistance indices as measured by Doppler ultrasonography. In conclusion, the present study demonstrates that, under our experimental conditions, octreotide infusion combined with albumin is not effective for the treatment of HRS in cirrhotic patients.

Hepatocellular carcinoma (HCC) accounts for approximately 6% of all human cancers. It represents the fifth most common cancer and the third most frequent cause of cancer death worldwide. In the United States, the overall incidence is 2.4 per 100,000 persons per year. The incidence of HCC in the United States has been growing during the past two decades, and the age-specific incidence of this cancer has progressively shifted toward younger people. This is most likely related to the increased prevalence of hepatitis C virus– related cirrhosis. Several risk factors are associated with HCC.1 Hepatitis B virus (HBV) is the most frequent underlying cause worldwide. About 85% of HCC cases occur in eastern and southeastern Asia and sub-Saharan Africa, where chronic HBV infection is endemic, and about 80% of the cases in these locations have been associated with chronic hepatitis B. Between 70% and 90% of HBV-related HCC develop in patients with cirrhosis. There is also a strong causal association between hepatitis C virus (HCV) infection and HCC. Indeed, HCV-related HCC has now become a clinical problem that most gastroenterologists encounter in their practice. Almost all HCVrelated HCCs occur among patients with cirrhosis. Other risk factors for HCC include alcohol abuse, which can act synergistically with HCV to promote liver carcinogenesis; cirrhosis that results from any cause (the magnitude of the HCC risk being greater when it is associated with a viral origin); inherited metabolic disorders such as hemochromatosis, tyrosinemia, and glycogen storage disease; and dietary aflatoxin exposure. In the United States, chronic viral hepatitides account for no more than 30%– 40% of reported cases of HCC. Men are 2 to 4 times more frequently affected by HCC than are women.

Previous experience with OLT for hilar CCA has been discouraging, and survival was dismal. This study demonstrates that carefully selected patients with unresectable hilar CCA can achieve long-term survival after OLT. The survival rate obtained with this protocol (5-year actuarial survival of 87%) is comparable with the overall survival rate of liver-transplant recipients at the authors' institution. In comparison, the best survival rate after OLT for hilar CCA reported in the literature is 64.8% at 5 years in a subset of nine patients with negative lymph nodes. In the absence of a control group, it is difficult to assess with certainty the role of a combination of chemotherapy and radiotherapy, but in some patients it seems to prevent or slow progression of the disease while waiting for an available organ. Treatment-related morbidity, although significant, is not prohibitive. Nevertheless, a considerable proportion of treated patients ultimately was found to have advanced disease precluding transplantation. This finding confirms the importance of the staging laparotomy as an essential component of the protocol.

The aim of this study was to assess the impact of fatigue on the quality of life of patients with chronic hepatitis C (CHC) and to examine its relationship with various parameters of the disease, including viral load. The Fatigue Impact Scale (FIS), a self-report questionnaire, was applied to 92 patients with CHC, and the results were compared to those of an age-matched cohort of 213 healthy blood donors. Fatigue was frequent and disabling, being present in 67% of CHC patients, and the FIS was significantly increased in CHC patients compared to the healthy controls. Fatigue severity was not correlated with the activity of the disease or with the level of viremia. The FIS proved to be a valuable tool to assess this symptom. It should be of help for better evaluation of the clinical spectrum of the disease and should be included in trials assessing the efficacy of therapeutic interventions.

Liver transplantation is associated with a number of neurological complications. We herein report a case of chronic inflammatory demyelinating polyneuropathy associated with the use of sirolimus-based immunosuppression. The patient was treated by converting the immunosuppression from sirolimus to cyclosporine and by a short course of oral steroids. Following this, we observed almost complete clinical and electrophysiologic resolution of this syndrome. We believe that this is the first described case of such a complication occurring in association with sirolimus. This immunosuppressive agent can, therefore, lead to neurological complications similar to the ones that have been observed with calcineurin inhibitors.

Summary Background Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. Methods In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. Findings 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4–2·8]) than placebo (1·4 months [1·4–1·5]; hazard ratio [HR] 0·64, 90% CI 0·43–0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4–8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4–1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19–0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. Interpretation Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. Funding ArQule, Daiichi Sankyo (Daiichi Sankyo Group).

Cyst infection is a diagnostic challenge in patients with autosomal dominant polycystic kidney disease (ADPKD) because of the lack of specific manifestations and limitations of conventional imaging procedures. Still, recent clinical observations and series have highlighted common criteria for this condition. Cyst infection is diagnosed if confirmed by cyst fluid analysis showing bacteria and neutrophils, and as a probable diagnosis if all four of the following criteria are concomitantly met: temperature of >38°C for >3 days, loin or liver tenderness, C-reactive protein plasma level of >5 mg/dL and no evidence for intracystic bleeding on computed tomography (CT). In addition, the elevation of serum carbohydrate antigen 19-9 (CA19-9) has been proposed as a biomarker for hepatic cyst infection. Positron-emission tomography after intravenous injection of 18-fluorodeoxyglucose, combined with CT, proved superior to radiological imaging techniques for the identification and localization of kidney and liver pyocyst. This review summarizes the attributes and limitations of these recent clinical, biological and imaging advances in the diagnosis of cyst infection in patients with ADPKD.

BACKGROUND: Limited data is available on the risk of hepatitis B virus (HBV) reactivation in patients with resolved infection undergoing kidney transplantation. It is generally thought that this risk is negligible. OBJECTIVES: To evaluate the incidence of HBV reactivation in such patients, and the potential risk factors for reactivation. STUDY DESIGN: Retrospective cohort study including 93 patients transplanted with a kidney between 1995 and 2007 who had evidence of resolved HBV infection (HBsAg negative, anti-HBc positive, anti-HBs positive or negative, and normal liver enzymes). HBV reactivation was defined as HBsAg reversion with HBV DNA>2000 IU/mL. RESULTS: Six patients experienced HBsAg reversion followed by HBV reactivation, 3 within the first post-transplant year. Immunosuppression regimen was similar in patients with and without reactivation. Among patients with reactivation only one was positive for anti-HBs antibodies at time of transplantation; these were progressively lost before reactivation. The odds ratio for reactivation in patients without anti-HBs antibodies at transplantation compared to those with anti-HBs antibodies was 26 (95% CI [2.8-240.5], p=0.0012). In patients with anti-HBs antibody titer above 100 IU/L, no reactivation was observed. CONCLUSIONS: Reactivation rate of resolved hepatitis B is not negligible in patients without anti-HBs antibodies at transplantation. We suggest monitoring of liver tests and HBV serology including HBsAg and anti-HBs antibodies after transplantation as well as vaccination pre- and post-transplantation in all patients, including those with resolved hepatitis B, aiming at maintaining anti-HBs antibody level above 100 IU/L.

BACKGROUND: Cyst infection remains a challenging issue in patients with autosomal dominant polycystic kidney disease (ADPKD). In most patients, conventional imaging techniques are inconclusive. Isolated observations suggest that (18)fluorodeoxyglucose (¹⁸FDG) positron-emission computed tomography (PET/CT) might help detect cyst infection in ADPKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Comparative assessment of administrative databases from January 2005 to December 2009 identified 27 PET/CT scans performed in 24 ADPKD patients for suspicion of abdominal infection. Cyst infection was definite if confirmed by cyst fluid analysis. Cyst infection was probable if all four of the following criteria were met: temperature of >38°C for >3 days, loin or liver tenderness, C-reactive protein plasma level of >5 mg/dl, and no CT evidence for intracystic bleeding. Episodes with only two or three criteria were grouped as "fever of unknown origin". RESULTS: Thirteen infectious events in 11 patients met all criteria for kidney (n = 3) or liver (n = 10) cyst infection. CT was contributive in only one patient, whereas PET/CT proved cyst infection in 11 patients (84.6%). In addition, 14 episodes of "fever of unknown origin" in 13 patients were recorded. PET/CT identified the source of infection in nine patients (64.3%), including 2 renal cyst infections. Conversely, PET/CT showed no abnormal ¹⁸FDG uptake in 5 patients, including 2 intracystic bleeding. The median delay between the onset of symptoms and PET/CT procedure was 9 days. CONCLUSIONS: This retrospective series underscores the usefulness of PET/CT to confirm and locate cyst infection and identify alternative sources of abdominal infection in ADPKD patients.

Hepatitis E virus (HEV) infection can evolve to chronic hepatitis in immunocompromised patients leading to rapidly progressive cirrhosis. Proper diagnosis is therefore important, as reducing immunosuppressive therapy can allow clearance of the virus. We report a case of chronic HEV infection in a renal transplant recipient that went undiagnosed for many years, discuss the therapeutic options, and review the current available literature.

Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984-2007, nine (1.1%) of 824 adult LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4x), and/or a diffuse tumor localization (3x) and/or a refractory hormonal syndrome (5x). Median post-LT patient survival is 60.9 months (range 4.8-119). One-, 3- and 5-year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5 years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease-free at 78, 84 and 96 months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo- and adjuvant surgical as well as medical treatment. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.

Primary liver cancer includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, hepatoblastoma, and other rare tumors of mesodermal origin such as angiosarcoma. The terms “primary liver cancer” and “hepatocellular carcinoma” are often used interchangeably in the literature. HCC accounts for 70–85% of primary liver cancers (1), and although intrahepatic cholangiocarcinoma is rare, it accounts for 5–30% of all liver cancers (2). Hepatoblastoma, a rare tumor that occurs only in children, represents approximately 1% of childhood cancers (3). This chapter will focus on HCC; cholangiocarcinoma, hepatoblastoma, and primary malignancies of mesodermal origin that develop in the liver will not be addressed.

Potent immunosuppressive agents make renal transplant recipients at increased risk of infections. Syphilis is a sexually transmitted disease caused by the bacterium Treponema pallidum with varied and often subtle clinical manifestations. If unrecognized, it can have devastating consequences [1]. The incidence of syphilis decreased significantly in the 1940s with the advent of penicillin, with later outbreaks being related to HIV infections, sexual practices and the use of drugs [2]. With the declining prevalence of syphilis, many physicians have become unfamiliar with its clinical presentation. We report a case of secondary syphilis in a renal transplant recipient who presented with systemic signs of illness and a mild hepatitis, in whom diagnosis was delayed until he developed a characteristic cutaneous rash.

Fatigue is a common debilitating complication of primary biliary cirrhosis (PBC), the pathophysiologic mechanism of which is poorly understood. Recently, the neuroactive steroid dehydroepinadrosterone sulfate (DHEAS) was reported to be implicated in Chronic Fatigue Syndrome in the absence of liver disease. The present study was undertaken to analyse fatigue scores and their relationship with disease severity and circulating levels of DHEAS as well as its precursors DHEA and pregnenolone in PBC patients with (n=15) or without fatigue (n=10) compared to control subjects (n=11). Fatigue was assessed using the fatigue impact scale (FIS) including cognitive, physical and psychosocial subclasses. Steroids were measured by radioimmunoassay or gas chromatography/mass spectrometry. Plasma concentrations of DHEAS were significantly reduced in PBC patients with fatigue as compared to controls, while those of its precursors DHEA and pregnenolone remained within the control range. Plasma levels of DHEAS in PBC patients were significantly correlated with fatigue severity as reflected by total FIS scores including total (rp=-0.42; p=0.018), as well as the cognitive (rp=-0.37; p=0.03), physical (rp=-0.48; p=0.006) and psychosocial (rp=-0.35; p=0.04) subclasses of fatigue scores. No correlation of fatigue scores was observed with indices of liver function. These findings suggest that reduced levels of the neurosteroid DHEAS may contribute to fatigue in patients with PBC; substitutive therapy using DHEAS or its precursor DHEA could be beneficial in the management of fatigue in patients with low levels of DHEAS.

The transjugular intrahepatic portosystemic shunt (TIPS) represents a major advance in the treatment of complications of portal hypertension. It is most commonly used in the management of refractory variceal bleeding, where it can be life-saving. Two other indications have been studied in randomized controlled trials: prevention of variceal rebleeding and refractory cirrhotic ascites. These trials have demonstrated that TIPS is superior to standard therapy but is associated with a higher rate of hepatic encephalopathy and with no improvement in survival. Consequently, TIPS is considered a second-line therapy in these situations. TIPS has also been used successfully in the treatment of hepatic hydrothorax, hepatorenal syndrome, severe portal hypertensive gastropathy, Budd-Chiari syndrome and veno-occlusive disease. Its use in these indications has only been reported in small uncontrolled series. TIPS usefulness is limited by two major problems: shunt dysfunction and hepatic encephalopathy. Shunt dysfunction is frequently responsible for the recurrence of complications of portal hypertension, and requires a surveillance program to monitor shunt patency. The use of polytetrafluoroethylene-covered stents may help prevent this complication.

The transjugular intrahepatic portosystemic shunt (TIPS) is a new nonsurgical therapeutic modality used to treat complications of portal hypertension1, 2. It allows the creation of a communication between one hepatic vein and an intrahepatic branch of the portal vein by using a transjugular approach. The first TIPS implantation was reported in 1989 by Ritcher et al3; it is a hemodynamic equivalent of the small-diameter side-to-side surgical portacaval shunt. This procedure has been widely used all around the world for more than 15 years. After an initial wave of enthusiasm its exact place in the treatment of portal hypertension is now better defined as clinical controlled trials are available for the main potential indications. The major drawbacks of TIPS are stent dysfunction and hepatic encephalopathy, but progress has been made to decrease their clinical impact.

Most patients with hepatocellular carcinoma (HCC) have viral hepatitis, either hepatitis C (HCV) or hepatitis B (HBV). HCV is an RNA virus that does not integrate into the host genome but likely induces HCC through viral protein: for example, host protein interactions or via the inflammatory response to the virus. Eradication of HCV with interferon plus riboviron therapy may help prevent cancer recurrence in selected patients. In contrast to HCV, HBV is an DNA virus that integrates into the host genome, and this integration is believed, in part, to be carcinogenic. HBV is usually classified as replicative (DNA-positive in the serum) or nonreplicative (DNA-negative in the serum). Treatment with nucleoside analogs is indicated in most patients with cirrhotic-stage replicating HBV. Nonreplicative stages of this virus do not merit therapy with these agents.

The aim of this study was to assess the impact of fatigue on the quality of life of patients with chronic hepatitis C (CHC) and to examine its relationship with various parameters of the disease, including viral load. The Fatigue Impact Scale (FIS), a self-report questionnaire, was applied to 92 patients with CHC, and the results were compared to those of an age-matched cohort of 213 healthy blood donors. Fatigue was frequent and disabling, being present in 67% of CHC patients, and the FIS was significantly increased in CHC patients compared to the healthy controls. Fatigue severity was not correlated with the activity of the disease or with the level of viremia. The FIS proved to be a valuable tool to assess this symptom. It should be of help for better evaluation of the clinical spectrum of the disease and should be included in trials assessing the efficacy of therapeutic interventions.

In the present study we evaluated the predictive value of pretransjugular intrahepatic portosystemic shunt (TIPS) portal perfusion as assessed by Doppler ultrasonography for the onset of chronic encephalopathy after TIPS.A total of 231 cirrhotic patients were followed-up prospectively after TIPS placement. The pattern of intrahepatic portal flow was assessed before TIPS. Patients were divided into two groups according to Doppler findings. Group 1 comprised patients with prograde portal flow (n = 200), whereas group 2 comprised those with loss of portal perfusion (hepatofugal or back-and-forth flow or portal vein thrombosis; n = 31). The presence of chronic encephalopathy during a median follow-up of 32 months was prospectively recorded. The prognostic value of the following parameters for the onset of chronic recurrent encephalopathy after TIPS was evaluated: age, presence of encephalopathy before TIPS, alcoholism, Pugh score, and loss of portal perfusion before TIPS. The independent prognostic value of each variable was tested with a multiple logistic regression analysis.The two groups were comparable in terms of age, incidence of prior episodes of hepatic encephalopathy, and portacaval gradient before and after the procedure; however, liver failure was more severe in patients in group 2 (Pugh score: 9.2 +/- 1.9 vs 10.3 +/- 1.7). The 3-yr survival was identical for both groups; 25% of the 200 patients in group 1 developed chronic encephalopathy as compared to 6% of the 31 patients in group 2 (p = 0.03). Multiple logistic regression analysis demonstrated that loss of portal perfusion and age65 yr were the only independent predictors of the onset of post-TIPS chronic encephalopathy (odds ratios 0.24 and 1.98, respectively).Cirrhotic patients with loss of portal perfusion before TIPS were protected against post-TIPS chronic hepatic encephalopathy despite a more severe liver dysfunction at baseline. The only other independent predictive factor for the onset of this complication was age.

A patient who underwent orthotopic liver transplantation for giant cell hepatitis with cirrhosis and in whom giant cell hepatitis recurred twice after orthotopic liver transplantation is reported. He was treated with ribavirin with an excellent result. The literature on this subject is reviewed. This observation clearly confirms the efficacy of ribavirin for the treatment of giant cell hepatitis, thus providing evidence for its viral origin.

Thromboangiitis obliterans characteristically affects small- and medium-sized vessels of the limbs in young smokers. There is some controversy about the existence of visceral localizations of the disease. The case of a patient with a well-established diagnosis of thromboangiitis obliterans who presented with mesenteric ischemia is described and the literature concerning mesenteric involvement in the disease is reviewed.

Umbilical hemorrhage from a cutaneous varix treated by transjugular intrahepatic portosystemic shunt (TIPS)