Circulating Elastin Fragments Are Not Affected by Hepatic, Renal and Hemodynamic Changes, But Reflect Survival in Cirrhosis with TIPS.

BACKGROUND AND AIMS: Progressive fibrosis increases hepatic resistance and causes portal hypertension with complications. During progressive fibrosis remodeling and deposition of collagens and elastin occur. Elastin remodeling is crucially involved in fibrosis progression in animal models and human data. This study investigated the association of circulating elastin with the clinical outcome in cirrhotic patients with severe portal hypertension receiving transjugular intrahepatic porto-systemic shunt (TIPS). METHODS: We analyzed portal and hepatic venous samples of 110 cirrhotic patients obtained at TIPS insertion and 2 weeks later. The circulating levels of elastin fragments (ELM) were determined using specific monoclonal ELISA. The relationship of ELM with clinical short-time follow-up and long-term outcome was investigated. RESULTS: Circulating levels of ELM showed a gradient across the liver before TIPS with higher levels in the hepatic vein. Interestingly, the circulating ELM levels remained unchanged after TIPS. The circulating levels of ELM in portal and hepatic veins correlated with platelet counts and inversely with serum sodium. Hepatic venous levels of ELM were higher in CHILD C compared to CHILD A and B and were associated with the presence of ascites. Patients with high levels of ELM in the hepatic veins before TIPS showed poorer survival. In multivariate analysis ELM levels in the hepatic veins and MELD were independent predictors of mortality in these patients. CONCLUSION: This study demonstrated that circulating levels of ELM are not associated with hemodynamic changes, but might reflect fibrosis remodeling and predict survival in patients with severe portal hypertension receiving TIPS independently of MELD.

Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis.

BACKGROUND & AIMS: Toll-like receptor (TLR) 2 and nucleotide-binding oligomerisation domain (NOD) 2 recognize distinct pathogen-associated molecular patterns (PAMS) on the cell surface and in the cytoplasm, respectively. Since they may contribute to susceptibility to spontaneous bacterial peritonitis (SBP), we studied the effects of TLR2 gene variants on susceptibility for SBP in relation to the previously reported NOD2 alleles. METHODS: Overall, 150 patients with liver cirrhosis and ascites were genotyped for TLR2 gene variants -16934 (rs4696480), Arg753Gln (rs5743708), Pro631His (rs5743704) and the TLR2 GT microsatellite polymorphism in intron 2. Patients were monitored for SBP over two years. TLR2 SNPs were identified by hybridization probe assays on a LightCycler system. Numbers of GT repeats were determined with an ABI310 sequencer and Genescan Analysis 2.1 software. RESULTS: Fifty two patients (35%) had SBP. Unlike the TLR2 Arg753Gln and Pro631His mutations, SBP was significantly more frequent in patients with the TLR2 -16934 TT genotype (38.5% vs. 15.3%; p = 0.002) and in carriers with two long tandem GT repeat alleles (>20) (53.8% vs. 25.5%; p = 0.001). A multivariate analysis confirmed TLR2 GT microsatellite polymorphism (OR = 3.8, p = 0.002) and NOD2 variants (OR = 3.3, p = 0.011) as independent predictors of SBP, and the simultaneous presence of both risk factors indicated a particularly high risk for SBP (OR = 11.3, p = 0.00002). CONCLUSIONS: Analogous to NOD2 risk variants, TLR2 polymorphisms indicate increased susceptibility toward SBP in cirrhotic patients with ascites, and the combination of the TLR2 GT microsatellite polymorphism with at least one NOD2 risk variant enables improved identification of patients with a high risk for SBP.

Feasibility and safety of long-term photodynamic therapy (PDT) in the palliative treatment of patients with hilar cholangiocarcinoma.

BACKGROUND AND AIM: PDT is an important palliative option for patients with unresectable extrahepatic cholangiocarcinoma (CC). However, the results published to date reported on studies with no more than 6 (mostly up to 4) PDT procedures. Furthermore, the clinical experience of PDT in combination with chemotherapy is limited. The purpose of this retrospective analysis was to evaluate the feasibility and safety of multiple (4 to 14) settings of PDT, combined with biliary drainage, and (in some cases) with chemotherapy. - METHODS: Ten patients with unresectable extrahepatic CC were treated with biliary stenting and at least 4 PDT procedures in our department between 10/2005 and 08/2010. - RESULTS: Ten patients (male/female = 5/5), mean age 68.8 years (range, 54 - 81 years) who received at least 4 PDT procedures were analyzed. All patients underwent endoscopic biliary drainage. Nine patients received metallic stents and one patient a plastic stent. In 4 patients (40%) bilateral metal stenting (JoStent SelfX®) was performed. The mean number of PDT sessions was 7.9 ± 3.9 (range: 4 - 14). Eight patients had elevated bilirubin levels with a mean bilirubin at admission of 9.9 ± 11.3 mg/dL, which had decreased to an average minimum of 1.2 ± 0.9 mg/dL after 3 months. No severe toxicity was noted. Two patients received concomitant chemotherapy (GEMCIS as 1st line, GEMOX plus cetuximab as 2nd line). The median overall survival has not been reached, whereas the estimated survival of all patients was 47.6 months, 95% CI 25.9 - 48.1. - CONCLUSION: Long-term PDT in patients with extrahepatic CC is feasible and effective and is accompanied - at least in this cohort- by a survival time of more than 2 years.

Progression of liver fibrosis in HIV/HCV genotype 1 co-infected patients is related to the T allele of the rs12979860 polymorphism of the IL28B gene.

OBJECTIVE: HIV/HCV co-infection is characterised by accelerated progression of liver disease. Recently, the rs12979860 C/T polymorphism in the IL28B gene has been linked to progression towards cirrhosis in HCV mono-infected patients and to treatment response of HCV-infection in HIV/HCV co-infected patients. Our aim was to clarify by non-invasive techniques if this polymorphism affects fibrosis progression in HIV/HCV co-infection. METHODS: In a cross-sectional design, liver stiffness (transient elastography), surrogate markers of liver fibrosis (APRI and FIB-4 scores) and rs12979860 genotypes were analysed in 84 HCV/HIV co-infected patients. IL28B genotypes were determined by real-time PCR using a light cycler. In 56 HIV/HCV co-infected patients we also studied progression of fibrosis in relation to rs12979860 C/T genotypes over two years. RESULTS: 82% of the patients were on HAART (74% without detectable HI viremia) and 67% were haemophiliacs, respectively. HCV genotype 1 was present in 62%. Cross-sectional median liver stiffness was 7.4 kPa and correlated with APRI and FIB-4 scores (r = 0.6 each, p < 0.001). Frequencies of IL28B genotypes were: CC 50%, CT 43% and TT 7%. In the cross-sectional analysis liver stiffness values were not different between the various IL28B-genotypes. Upon follow-up under HAART carriers of a C allele did not show further progression, while liver stiffness significantly increased in HIV/HCV co-infected patients with the T allele (p = 0.047). CONCLUSION: Although progression of liver fibrosis was low under HAART in our cohort, progression was more pronounced in HIV/HCV genotype 1 co-infected patients with the T allele.

Cancer risk in HIV-infected individuals on HAART is largely attributed to oncogenic infections and state of immunocompetence.

OBJECTIVES: To estimate the cancer risk of HIV-infected patients in the HAART era with respect to a general reference population and to determine risk factors for malignancy. METHODS: Long term (1996-2009) cancer incidence of the Bonn single centre HIV cohort was compared to the incidence of the reference population of Saarland using standardized incidence ratios (SIR). Poisson regression analysis was used to identify predictors of cancer risk. RESULTS: 1,476 patients entered the cohort, enabling 8,772 person years of observation. 121 tumours in 114 patients, 7 in-situ and 114 invasive cancers, were identified. Malignancies associated with infectious agents such as Kaposi sarcoma (SIRs: male: 5,683; female: 277), non-Hodgkin lymphoma (SIRs male: 35; female: 18), anal cancer (SIRs male: 88; female: 115) as well a cervical carcinoma (SIR female: 4) and Hodgkin?s disease (SIR male: 39) and liver cancer (SIR male: 18) were substantially more frequent in HIV-infected patients than in the general population (p< 0.001, each), whereas all other types of cancer were not increased. Poisson regression identified HAART (incidence rate ratio IRR (95% CI): 0.28 (0.19-0.41), p<0.001), CD4 count (IRR per 100 cells/µl increase: 0.66 (0.57-0.76), p<0.001), hepatitis B (IRR: 2.15 (1.10-4.20), p = 0.046) and age (IRR per 10 year increase: 1.23 (1.03 - 1.46), p = 0.023) as independent predictors for the occurrence of any type of cancer. CONCLUSIONS: HAART and preserved CD4 cells preferentially reduce the risk of malignancies associated with oncogenic infections.

[Early detection of colonic cancer in the National Cancer Program--present status and recommendations]. / Darmkrebsfrüherkennung im Nationalen Krebsplan--Aktueller Stand und Empfehlungen für die Weiterentwicklung.

The National Cancer Programme of the German Federal Administration aims to assess the present status of the national fight against cancer in Germany. Experts in their field have analysed the present target-performance comparison in different working groups dealing with topics from cancer prevention to follow-up and have developed recommendations as to how improvements in the various fields of cancer care may be achieved and mainly how these imrpovements may be implemented in day-to-day cancer care. The working group "Advancement of Colon Cancer Screening, Early Detection and Prevention" proposes the establishment of regulatory proposals for a nationwide, population-based, postal invitational process and, according to Pilot-Projects in Bavaria and Baden-Wuerttemberg, to evaluate the essential recommendations in data protection, logistics, documentation and financing. There are already several programmes in preparation--for example, the Saarland Offensive, based on the results of the KolosSal-Study.

Correlation of transient elastography with APRI and FIB-4 in a cohort of patients with congenital bleeding disorders and HCV or HIV/HCV coinfection.

SUMMARY: Patients with inherited bleeding disorders frequently suffer from chronic hepatitis C virus (HCV) mono- or human immunodeficiency virus (HIV)/HCV coinfection. Non-invasive markers for liver fibrosis are warranted for these patients. We tested a large cohort of haemophilic patients with HCV mono- or HIV/HCV coinfection for correlation of transient elastography (TE) with two simple surrogate markers of liver fibrosis and for differences in fibrosis stages according to these markers. We prospectively enrolled HCV-positive patients with congenital bleeding disorders with or without HIV coinfection. Liver function tests and platelet counts were determined and TE was performed. Aspartate aminotransferase-to-platelet ratio index (APRI) and a simple index called FIB-4 were calculated and results were correlated with TE. A total number of 174 patients were included (23% HCV, 36% HIV/HCV coinfected, 33% with cleared HCV and 8% with ongoing HIV but cleared HCV). TE correlated significantly with APRI and FIB-4 (r = 0.60; P < 0.001 and r = 0.54; P < 0.001 respectively). This correlation was pronounced in patients with ongoing HCV infection (r = 0.67; P < 0.001 and r = 0.60; P < 0.001). Prediction of advanced fibrosis resulted in concordance rates >80% with combinations of TE plus APRI and APRI plus FIB-4. HIV/HCV coinfected patients did not present with advanced fibrosis stages when compared with HCV-monoinfected patients. Combinations of two non-invasive markers may significantly reduce the number of liver biopsies in patients with bleeding disorders and advanced liver fibrosis. Furthermore, our data support previous studies that observed a favourable outcome in patients with HIV/HCV and a preserved immune function in times of highly active antiretroviral therapy.

Transient elastography discloses identical distribution of liver fibrosis in chronic hepatitis C between HIV-negative and HIV-positive patients on HAART.

OBJECTIVE: Progressive immunodeficiency associated with HIV-infection leads to a progressive course of liver disease in HIV/HCV-co-infected patients. Highly active antiretroviral therapy (HAART) efficiently restores and preserves immune functions and has recently been demonstrated to also result in reduced liver-related mortality in HIV/HCV-co-infected patients. METHODS: To analyse differences in current liver fibrosis as a possible effect of HAART on fibrosis progression we assessed hepatic fibrosis by transient elastography in a cross-sectional comparison between HCV-mono-infected and HIV/HCV-co-infected patients presenting at our outpatient department in 2007. RESULTS: Overall, we did not find any difference in the distribution of liver stiffness between mono- (n = 84) and double-infected (n = 57) patients (14.4 kPa (10.8-18.2) versus 12.4 kPa (9.1 - 16.1), mean (95%-CI)). However, in the 8 HIV+ patients with CD4 counts < 200/microl liver stiffness was markedly greater (18.4 kPa (0.8 - 36.0)) than in HIV+ patients with preserved immunity (11.5 kPa (8.4-15.0)). CONCLUSIONS: These findings are in line with other data that show an improved prognosis of chronic hepatitis C in HIV+ patients under effective HAART, and may be a hint that fibrosis progression in well-treated HIV+ patients will no longer be different from that in HCV-mono-infected patients.

Inhibition of neuropilin-1 by RNA-interference and its angiostatic potential in the treatment of hepatocellular carcinoma.

Neuropilin-1 (Nrp1) was recently described as a novel receptor for the pro-angiogenic molecule vascular endothelial growth factor (VEGF), indicating a role in tumor angiogenesis and tumor progression. Recent data confirm this assumption by demonstrating that some tumor and endothelial cells express Nrp1. Therefore, we wanted to investigate the potential role of Nrp1-knockdown on hepatoma and endothelial cell function in vitro and tumor growth in vivo. Nrp1 knockdown in SVEC4 - 10 and Hepa129 cells and its influence on signal transduction (MAPK pP38, pAKT, pERK1 / 2) was analyzed by Western blot. Effects on endothelial tube formation were assayed in an in vitro and in vivo matrigel assay. In vivo, effects of siRNA-Nrp1 were analyzed in a subcutaneous hepatoma model. To verify effects on endothelial and tumor cells in vivo, immunohistochemistry for proliferation, apoptosis and endothelial vessels was performed. LightCycler and Western blot analysis showed efficient inhibition of gene expression in SVEC4 - 10 and Hepa129 cells following siRNA-Nrp1 transfection. Signal transduction pathways were not influenced after siRNA-Nrp1 treatment compared to the controls. Endothelial tube formation was reduced by 59 % and 94 % in vitro and in vivo compared to controls, corresponding to reduced VCAM expression. Subcutaneous tumor growth was not influenced after siRNA treatment. Intratumoral proliferation was not altered after treatment with siRNA-Nrp1, whereas microvessel density and apoptosis were reduced after treatment with siRNA-Nrp1 compared to siRNA-Ctrl. In conclusion, inhibition of Nrp1 expression led to strong anti-endothelial effects, whereas tumor cells and tumor growth were not affected.

[Heterozygous alpha-1-antitrypsin deficiency (PiMZ): risk factor in the development of primary liver carcinoma in non-cirrhotic liver?]. / Heterozygoter Alpha-1-Antitrypsin-Mangel (PiMZ): Risikofaktor zur Entwicklung eines hepatozellulären Karzinoms in der nicht zirrhotischen Leber?

Here we report on a patient with a primary hepatocellular carcinoma in a non-cirrhotic liver, in whom heterozygosity for an AAT-deficiency allele was found (PiMZ). Based on this observation and the current literature, the possible mechanisms for an eventual contribution of a heterozygosity of a heterozygous AAT-deficiency for a hepatocellular carcinoma are discussed. Alpha-1-antitrypsin (AAT)-deficiency (Laurell-Eriksson syndrome) is a genetic disorder, in which individuals who are homozygous for a deficiency allele are at an increased lifetime risk for pulmonary emphysema, liver cirrhosis, and primary hepatocellular carcinoma. It has been controversially discussed whether the heterozygous form (PiMZ) is also associated with an increased risk for liver diseases. Hepatocarcinogenesis for AAT-deficiency is probably based on a series of toxic events. Precipitation of AAT aggregates in hepatocytes is the initial step. These accumulate in the endoplasmic reticulum and cannot be eliminated from all hepatocytes by proteasomal and non-proteasomal mechanisms. AAT aggregates induce proinflammatory pathways and may be a stimulus for hepatocarcinogenesis. This hypothesis is based mostly on studies of individuals homozygous for a deficiency allele (PiZZ). The mechanism may also play a role in heterozygous patients. Since not all patients with precipitates of AAT-aggregates are develop a hepatocellular carcinoma related comorbidities such as chronic hepatitis B, C, chronic alcohol abuse, or so far unknown genetic and environmental factors may be crucial.

Combination of bilateral metal stenting and trans-stent photodynamic therapy for palliative treatment of hilar cholangiocarcinoma.

Endoscopic biliary drainage is the mainstay of palliative treatment in patients with unresectable malignant hilar biliary obstruction. While self-expandable metal stents have shown significant advantages in distal tumors, bilateral hilar stenting is technically demanding. Moreover, ingrowth is a significant problem in uncovered stents. We evaluated the feasibility and efficacy of endoscopic bilateral JoStent SelfX deployment in patients with proximal malignant biliary obstruction in combination with photodynamic therapy (PDT) and/or chemotherapy. Twenty-one consecutive patients with malignant hilar biliary strictures were treated with transpapillary bilateral insertion of JoStentSelfX metal stents. Additional PDT was applied in 8 patients (PDT plus chemotherapy n = 4, only PDT n = 4). Solely chemotherapy was performed in 5 patients. Mean (+/- SD) stent patency was 173.9 +/- 201.8 days. The median estimated survival was 12.3 months (95 % CI: 8.5; 15.9). PDT was safely and efficaciously performed after endoscopic stent deployment (1.8 +/- 1.1 sessions/patient). There was a trend towards a longer stent patency in patients receiving additional therapy (202.2 +/- 197.6 vs. 128 vs. 213.2 days; p = 0.38). Furthermore, we observed a significantly longer survival in this cohort (16.5 [12.2; 20.1] vs. 12.3 [1.9; 8.5] months, p < 0.005). Additional therapy had no significant impact on cumulative hospitalization time (16.3 +/- 15.8 vs. 14.4 +/- 22.5 days; p = 0.54). Bilateral insertion of Jostent SelfX in patients with proximal cholangiocarcinoma is feasible and effective and can be safely combined with trans-stent photodynamic therapy.

Vascular hyporesponsiveness to angiotensin II in rats with CCl(4)-induced liver cirrhosis.

BACKGROUND: Portal hypertension is triggered by vasodilation due to impaired contraction of extrahepatic vessels. Angiotensin II type 1 (AT(1)) receptor-induced vasocontraction is mediated by G proteins and may be desensitized by recruitment of beta-arrestin-2 to the receptor. In this study, we analysed the interaction of AT(1) receptors with beta-arrestin-2 in the context of vascular hypocontractility in rats with CCl(4)-induced cirrhosis. METHODS: Micronodular liver cirrhosis in rats (n = 15) was induced by regular CCl(4) exposure. Age-matched rats (n = 15) served as controls. Contractility of aortic rings was measured by myography. Protein expressions and phosphorylations were assessed by Western blot analysis, and AT(1) receptor interaction with beta-arrestin-2 by co-immunoprecipitation. RESULTS: Aortic rings from CCl(4) rats were hypocontractile to angiotensin II independent of nitric oxide synthases (Nomega-nitro-l-arginine methyl ester 200 microM). Expression of the AT(1) receptor, Galpha(q/11) and the contraction-mediating effector Rho kinase was similar in aortas from both groups. Expression and AT(1) receptor binding of beta-arrestin-2 were up-regulated in aortas from CCl(4) rats. Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of beta-arrestin-2 in aortas from noncirrhotic rats, but no further interaction of AT(1) receptors with beta-arrestin-2 was found in aortas from CCl(4) rats. While angiotensin II stimulation resulted in Rho kinase activation in aortas from noncirrhotic rats but not in aortas from CCl(4) rats, extracellular signal-regulated kinase activation in response to angiotensin II was observed in aortas from both groups. CONCLUSIONS: Vascular hyporesponsiveness to angiotensin II in CCl(4) rats is due to enhanced interaction of the AT(1) receptor with beta-arrestin-2 and consecutively changed receptor function.

Keratin 18 provides resistance to Fas-mediated liver failure in mice.

BACKGROUND: Keratins are intermediate filament proteins of epithelial cells with pivotal functions for cell integrity. They comprise keratins 18 [K18] and 8 [K8] in hepatocytes. Keratins are of major importance for an intact cellular microarchitecture and have protective functions in human liver diseases. In mice, K8 has been demonstrated to protect against Fas-antibody-induced liver failure by direct interaction with apoptotic regulators, while the role of K18 remains unresolved. MATERIALS AND METHODS: We analysed effects of K18 deficiency on Fas-induced liver failure in mice. We determined survival and analysed induction of apoptosis after injection of the agonistic Fas antibody Jo2 into K18(-/-) and wild-type control mice by TUNEL assay and fluorometrically analysed caspase-3, -8 and -9 activities 1, 2 and 3 h after Jo2 injection. RESULTS: In K18(-/-) mice, survival of Fas-antibody treated mice was significantly shorter than that of wild-type controls (P = 0.02). However, shortened survival of K18(-/-) mice was caused by increased hepatic damage but was not correlated to enhanced induction of apoptotic pathways, as neither numbers of TUNEL positive apoptotic cells nor activities of caspases-3, -8 and -9 differed between K18(-/-) and K18(+/+) mice at any point of time. CONCLUSION: K18(-/-) mice are significantly more susceptible to Fas-antibody-induced liver failure. The cytoprotective effect of K18 is not explained by a differential activation of caspases-3, -8 and -9, suggesting that K18 does not directly interfere with apoptotic regulators. Importantly, however, K18 exerts significant protective functions by other mechanisms.

Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening.

BACKGROUND AND STUDY AIMS: Individuals carrying germline mutations in one of the genes responsible for hereditary nonpolyposis colon cancer (HNPCC) have a lifetime risk of up to 80 % of developing colorectal cancer. As there is evidence for a higher incidence of flat adenomatous precursors and because an accelerated adenoma-carcinoma sequence has been postulated for these patients, early detection of these lesions is essential. It was the aim of the present study to assess the detection rate of polypoid lesions by comparing chromocolonoscopy with standard white light colonoscopy and narrow-band imaging (NBI) colonoscopy. PATIENTS AND METHODS: 109 patients were included (98 with a functionally relevant mutation in a mismatch repair gene, 11 fulfilling the strict Amsterdam criteria). In 47 patients, standard colonoscopy was followed by chromocolonoscopy with indigo carmine. In 62 patients, NBI was performed first followed by chromocolonoscopy. RESULTS: A total of 128 hyperplastic and 52 adenomatous lesions were detected. In the first series, 0.5 lesions/patient were identified by standard colonoscopy and 1.5 lesions/patient by chromocolonoscopy ( P < 0.001). In the second series, 0.7 lesions/patient were detected by NBI colonoscopy and 1.8 lesions/patient by chromocolonoscopy ( P = 0.01). At least one adenoma was detected in 15 % of patients by both standard and NBI colonoscopy compared with 28 % of patients by chromocolonoscopy. CONCLUSION: According to this study, chromocolonoscopy detects significantly more hyperplastic and, in particular, adenomatous lesions than standard white light colonoscopy or NBI.

Association of the c.3972C>T variant of the multidrug resistance-associated protein 2 Gene (MRP2/ABCC2) with susceptibility to bile duct cancer.

BACKGROUND: Multidrug resistance-associated protein 2 (MRP2/ABCC2) is one of the ATP-binding cassette (ABC) transporters expressed on the apical membrane of hepatocytes and cholangiocytes. ABCC2 plays an important role in the biliary clearance of endogenous and exogenous toxic compounds. Recently, the ABCC2 variant c.3972C>T in exon 28 has been shown to be associated with hepatocellular carcinoma risk. Our aim was to assess the role of this ABCC2 variant on cholangiocarcinoma susceptibility. METHODS: Prospectively, we recruited 60 cholangiocarcinoma patients and 73 healthy controls of Caucasian origin. The c.3972C>T polymorphism was genotyped using solution-phase hybridization reactions with 5'-nuclease and fluorescence detection (TaqMan assays). RESULTS: Allele frequencies were in Hardy-Weinberg equilibrium (p > 0.05). The c.3972T allele was significantly more frequent in patients with cholangiocarcinoma (39.2%) compared to healthy controls (26.0%, p = 0.022), resulting in an odds ratio (OR) of 1.83 (95% CI = 1.09-3.08). Armitage's trend test showed a significant association between genotypes and cancer susceptibility (p = 0.026, OR = 1.95). CONCLUSIONS: We describe a novel association between the common ABCC2 variant c.3972C>T and cholangiocarcinoma risk. Further studies are warranted to replicate our findings in different populations and to elucidate the mechanisms of this observation.

Coinheritance of hereditary spherocytosis and reversibility of cirrhosis in a young female patient with hereditary hemochromatosis.

Here we report a 33-years-old woman with hereditary spherocytosis and hemochromatosis due to homozygosity for the C282Y mutation of the HFE gene. The coinheritance of both conditions led to severe iron overload and liver cirrhosis at young age. The patient was treated by repeated phlebotomy, and reversibility of cirrhosis was documented by transient elastography. This report discusses the pathophysiology of iron accumulation in patients with hemolytic anemia combined with HFE C282Y homozygosity. The case indicates that patients with hematological disorders characterized by increased erythropoetic activity should be screened for HFE mutations.

Renal impairment after liver transplantation - a pilot trial of calcineurin inhibitor-free vs. calcineurin inhibitor sparing immunosuppression in patients with mildly impaired renal function after liver transplantation.

OBJECTIVES: Chronic kidney disease is frequent in patients after orthotopic liver transplantation (OLT) and has impact on survival. Patients receiving calcineurin inhibitors (CNI) are at increased risk to develop impaired renal function. Early CNI reduction and concomitant use of mycophenolat mofetil (MMF) has been shown to improve renal function. METHODS: The aim of this trial was to compare dose-reduced CNI/MMF versus CNI-free MMF/prednisone-based treatment in stable patients after OLT with respect to glomerular filtration rate (GFR). 21 patients (GFR 44.9 ' 9.9 mL/min/1.73m2 measured by 99m-Tc-DTPA-clearance, serum creatinine (SCr) 1.5 ' 0.42 mg/dL) were randomized either to exchange CNI for 10 mg prednisone (group 1; n = 8) or to receive CNI at 25% of the initial dose (group 2; n = 13) each in combination with 1000 mg MMF b.i.d. RESULTS: At month 12 mean SCr (-0.3 ' 0.4 mg/dL, p = 0.031) and GFR improved (8.6 ' 13.1 mL/min/ 1.73m superset2, p = 0.015) in group 2 but remained unchanged in group 1. Main side effects were gastroinstestinal symptoms (14.3%) and infections (4.8%). Two biopsy proven, steroid-responsive rejections occurred. In group 1 mean diastolic blood pressure (BP) increased by 11 ' 22 mmHg (p = 0.03). CONCLUSIONS: Reduced dose CNI in combination with MMF but not CNI-free-immunosuppression leads to improvement of GFR in patients with moderately elevated SCr levels after OLT. Addition of steroids resulted in increased diastolic blood pressure presumably counterbalancing the benefits of CNI withdrawal on renal function.

Mechanisms of extrahepatic vasodilation in portal hypertension.

In liver cirrhosis, abnormal persistent extrahepatic vasodilation leads to hyperdynamic circulatory dysfunction which essentially contributes to portal hypertension. Since portal hypertension is a major factor in the development of complications in cirrhosis, the mechanisms underlying this vasodilation are of paramount interest. Extensive studies performed in cirrhotic patients and animals revealed that this vasodilation is associated on the one hand with enhanced formation of vasodilators, and on the other hand with vascular hyporesponsiveness to vasoconstrictors. The latter phenomenon has been termed "vascular hypocontractility". It is caused by a combination of different mechanisms and factors described in this review.

Beta-trace protein-based equations for calculation of GFR in renal transplant recipients.

Recently, we showed that serum beta-trace protein (BTP) is an alternative marker of glomerular filtration rate (GFR) in renal transplant recipients (RTR). We have now developed three BTP-based GFR formulae derived by multiple regression analyses from the patients who had participated in that study. Currently, we validated the diagnostic performance of these BTP-formulae in 102 consecutive RTR who underwent a technetium diethylenetriamine pentaacetic acid (DTPA) clearance for GFR measurement in comparison to the re-expressed Modification of Diet in Renal Disease (MDRD) equation and a recently proposed BTP-based equation (referred to as 'White equation'). The best-performing BTP formula was found to be: GFR = 89.85 x BTP(-0.5541)x urea(-0.3018). This equation estimated true GFR virtually without bias (+0.43 mL/min/1.73 m(2), not significant [NS]), while a small, but significant, overestimation was seen for the MDRD formula (+3.43 mL/min/1.73 m(2), p = 0.003). Precision and accuracies within 50% of true GFR (93.1% and 88.2%, respectively) tended to be higher for the BTP formula, but the differences did not reach significance. The White equation overestimated the true GFR by 9.43 mL/min/1.73 m(2)(p = 0.001), and was inferior with respect to precision and 50% accuracy (79.4%). BTP-based GFR calculations are reliable, and may serve as an alternative to the re-expressed MDRD equation.