Impact of bariatric surgery on neural food processing and cognition: an fMRI study.

INTRODUCTION: The Roux-en-Y gastric bypass (RYGB) is one of the most widely used techniques for bariatric surgery. After RYGB, weight loss up to 50%-70% of excess body weight, improvement of insulin-resistance, changes in food preferences and improvements in cognitive performance have been reported. This protocol describes a longitudinal study of the neural correlates associated with food-processing and cognitive performance in patients with morbid obesity before and after RYGB relative to lean controls. METHODS AND ANALYSIS: This study is a pre-post case-control experiment. Using functional MRI, the neural responses to food stimuli and a working memory task will be compared between 25 patients with obesity, pre and post RYGB, and a matched, lean control group. Resting state fMRI will be measured to investigate functional brain connectivity. Baseline measurements for both groups will take place 4 weeks prior to RYGB and 12 months after RYGB. The effects of RYGB on peptide tyrosine tyrosine and glucagon-like polypeptide-1 will also be determined. ETHICS AND DISSEMINATION: The project has received ethical approval by the local medical ethics committee of the Carl-von-Ossietzky University of Oldenburg, Germany (registration: 2017-073). Results will be published in a peer-reviewed journal as original research and on international conferences. TRIAL REGISTRATION NUMBER: DRKS00012495; Pre-results.

Photodynamic therapy with polyhematoporphyrin for malignant biliary obstruction: A nationwide retrospective study of 150 consecutive applications.

BACKGROUND: Photodynamic therapy (PDT) is a palliative treatment for malignant biliary obstruction. OBJECTIVE: The objective of this article is to assess the feasibility and safety of this technique. METHODS: In this nationwide, retrospective study of prospectively collected clinical data, all patients treated with PDT using polyhematoporphyrin in Austria from March 2004 to May 2013 were included. Feasibility, adverse events, stent patency and mortality rates were investigated. RESULTS: Eighty-eight patients (54 male, 34 female, median age 69 years) underwent 150 PDT procedures at seven Austrian referral centers for biliary endoscopy. The predominant underlying disease was Klatskin tumor (79/88). All PDT procedures were feasible without technical issues. Cholangitis was the most frequent adverse event (21/88). Stent patency was 246 days (95% CI 203-289) median and was significantly longer for metal than for plastic stents (269 vs. 62 days, p < 0.01). The median survival was 12.4 months (95% CI 9.7-14.9 m) calculated from first PDT and 15.6 months (95% CI 12.3-18.7 m) calculated from initial diagnosis. In patients suffering from biliary tract cancer, Cox regression revealed the number of PDT treatment sessions as the only independent predictor of survival at a multivariate analysis (p = 0.048). CONCLUSION: PDT using polyhematoporphyrin was feasible and safe in this nationwide analysis. Survival data suggest a benefit of PDT in this unselected real-life patient population. Prospective trials comparing PDT to other palliative treatments will help to define its role in the management of malignant biliary obstruction. The study is registered at ClinicalTrials.gov number: NCT02504957.

CCBE1 mutation causing sclerosing cholangitis: Expanding the spectrum of lymphedema-cholestasis syndrome.

A 52-year old patient presented with lymphedema, protein loosing enteropathy, and sclerosing cholangitis and was diagnosed with lymphedema cholestasis syndrome (LCS). Cholangioscopy revealed dilated lymphatic vessels obstructing the bile duct and compound heterozygosity for collagen and calcium-binding epidermal growth factor domain-containing protein 1 (CCBE1) mutations was identified defining a novel type of LCS. (Hepatology 2017;66:286-288).

Choice of High-Dose Intravenous Iron Preparation Determines Hypophosphatemia Risk.

BACKGROUND: Ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) are increasingly used because they allow correction of severe iron deficiency in a single infusion. A transient decrease in serum phosphate concentrations is a frequent side effect of FCM. AIM: To characterize this adverse event and search for its predictors in a gastroenterology clinic patient cohort. METHODS: Electronic medical records of patients attending the University Hospital of Innsbruck were searched for the keywords ferric carboxymaltose or iron isomaltoside. Eighty-one patients with documented administration of FCM or IIM with plasma phosphate concentrations before and after treatment were included. RESULTS: The prevalence of hypophosphatemia (<0.8 mmol/L) increased from 11% to 32.1% after treatment with i.v. iron. The hypophosphatemia risk was greater after FCM (45.5%) compared with IIM (4%). Severe hypophosphatemia (<0.6 mmol/L) occurred exclusively after FCM (32.7%). The odds for hypophosphatemia after i.v. iron treatment were independently determined by baseline phosphate and the choice of i.v. iron preparation (FCM vs. IIM-OR = 20.8; 95% CI, 2.6-166; p = 0.004). The median time with hypophosphatemia was 41 days, but prolonged hypophosphatemia of ≥ 2 months was documented in 13 of 17 patients in whom follow-up was available. A significant increase in the phosphaturic hormone intact FGF-23 in hypophosphatemic patients shows that this adverse event is caused by FCM-induced hormone dysregulation. CONCLUSION: Treatment with FCM is associated with a high risk of developing severe and prolonged hypophosphatemia and should therefore be monitored. Hypophosphatemia risk appears to be substantially lower with IIM.

Indications for liver transplantation in adults : Recommendations of the Austrian Society for Gastroenterology and Hepatology (ÖGGH) in cooperation with the Austrian Society for Transplantation, Transfusion and Genetics (ATX).

Liver transplantation has emerged as an established and well-accepted therapeutic option for patients with acute and chronic liver failure and hepatocellular carcinoma. The disproportion between recipients and donors is still an ongoing problem that has only been solved partially over the last centuries. For several patients no life-saving organs can be distributed. Therefore, objective and internationally established recommendations regarding indication and organ allocation are imperative. The aim of this article is to establish evidence-based recommendations regarding the evaluation and assessment of adult candidates for liver transplantation. This publication is the first Austrian consensus paper issued and approved by the Austrian Society of Gastroenterology and Hepatology in cooperation with the Austrian Society of Transplantation, Infusion and Genetics.

Excellent post-transplant survival in patients with intermediate stage hepatocellular carcinoma responding to neoadjuvant therapy.

BACKGROUND & AIMS: Current treatment guidelines preclude liver transplantation for patients with BCLC B (intermediate stage) HCC, and expanding transplantation criteria for selected patients beyond early stage HCC remains controversial. The aim of this study was to determine stage-dependent HCC recurrence and overall survival rates in transplant recipients and the impact of response to neoadjuvant treatment on outcome. METHODS: The CT/MRI scans of patients who underwent liver transplantation for HCC at our transplant centre during a time period of 12 years were reviewed by two radiologists to assess tumour stage and response to neoadjuvant treatment according to mRECIST. RESULTS: Of 174 HCC patients, 48 (28%) were BCLC intermediate stage. Neoadjuvant treatment was performed in 94% of patients. When patients were stratified according to tumour stage, no significant difference in overall survival was observed between very early or early and intermediate stage. When stratified according to treatment response, patients with complete response had a 5-year overall survival of 87%, which was significantly higher than in patients with progressive disease (62%, P = 0.02). HCC recurrence in intermediate stage patients without disease progression after neoadjuvant treatment was equal to that in patients with very early or early stage HCC. Tumour grading, histological and radiological evidence of vascular invasion, but not tumour stage were identified as independent risk factors for HCC recurrence. CONCLUSIONS: Liver transplantation may be an option for selected patients with BCLC intermediate stage HCC and complete response after neoadjuvant treatment because of excellent long-term survival and low recurrence rates.

Impaired hepcidin expression in alpha-1-antitrypsin deficiency associated with iron overload and progressive liver disease.

Liver disease due to alpha-1-antitrypsin deficiency (A1ATD) is associated with hepatic iron overload in a subgroup of patients. The underlying cause for this association is unknown. The aim of the present study was to define the genetics of this correlation and the effect of alpha-1-antitrypsin (A1AT) on the expression of the iron hormone hepcidin. Full exome and candidate gene sequencing were carried out in a family with A1ATD and hepatic iron overload. Regulation of hepcidin expression by A1AT was studied in primary murine hepatocytes. Cells co-transfected with hemojuvelin (HJV) and matriptase-2 (MT-2) were used as a model to investigate the molecular mechanism of this regulation. Observed familial clustering of hepatic iron overload with A1ATD suggests a genetic cause, but genotypes known to be associated with hemochromatosis were absent. Individuals homozygous for the A1AT Z-allele with environmental or genetic risk factors such as steatosis or heterozygosity for the HAMP non-sense mutation p.Arg59* presented with severe hepatic siderosis. In hepatocytes, A1AT induced hepcidin mRNA expression in a dose-dependent manner. Experiments in overexpressing cells show that A1AT reduces cleavage of the hepcidin inducing bone morphogenetic protein co-receptor HJV via inhibition of the membrane-bound serine protease MT-2. The acute-phase protein A1AT is an inducer of hepcidin expression. Through this mechanism, A1ATD could be a trigger of hepatic iron overload in genetically predisposed individuals or patients with environmental risk factors for hepatic siderosis.

Liver Transplantation-Associated Lung Cancer: Comparison of Clinical Parameters and Outcomes.

BACKGROUND: The incidence of lung cancer (LC) is increased in patients with a history of liver transplantation (LT). The purpose of our study was to compare the clinical characteristics and outcomes of patients with postliver transplantation LC (PLTLC) with cohorts of patients with "transplant-naive" LC, and LT patients without LC. PATIENTS AND METHODS: All the patients who had undergone LT or had been diagnosed with LC from 1987 to 2012 were included in the present analysis. The PLTLC cohort was compared with a LT cohort (n = 725) and the local LC registry (n = 2803). The standardized incidence ratios (SIRs) were computed in the classic manner after adjustment for sex, age, and year of follow-up. RESULTS: Within the LT cohort, 22 patients (5 women) developed PLTLC (2.3%). The SIR for LC in LT recipients was 4.4 in the women and 2.6 in the men. The PLTLC cohort was older at LT (58.4 vs. 53.3 years; P = .028). Also, 90.5% of the PLTLC group had a history of smoking; 8 patients (42.1%) had had LC detected by annual routine lung cancer screening. The median post-LT survival was significantly inferior in the PLTLC cohort (117.1 vs. 182.6 months; P = .041). The median overall survival (OS), starting from the diagnosis of LC, was similar in the PLTLC and LC cohort (14.7 vs. 15.1 months; P = .519). CONCLUSION: The incidence of LC is significantly increased in the LT population. Therefore, LC screening might be an option for LT patients with a history of smoking. The prognosis of LC does not seem to be impaired by LT, suggesting a minor effect of LT on OS in patients with lung cancer.

How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma.

BACKGROUND & AIMS: We aimed to establish an objective point score to guide the decision for the first treatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). METHODS: 277 patients diagnosed with HCC and treated with transarterial treatments between 1/2002 and 12/2011 at the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the impact of baseline liver function and tumour load on overall survival (OS, log-rank test) and developed a point score (STATE-score: Selection for TrAnsarterial chemoembolisation TrEatment) in the training-cohort (n=131, Vienna) by using a stepwise Cox regression model. The STATE-score was externally validated in an independent validation cohort (n=146, Innsbruck) and thereafter combined with the Assessment for Retreatment with TACE (ART)-score to identify patients who are (un)suitable for TACE. RESULTS: The STATE-score starts with the serum-albumin level (g/L), which is reduced by 12 points each, if the tumour load exceeds the up-to-7 criteria and/or C-reactive protein (CRP) levels are ⩾1 mg/dl (maximum reduction: 24 points). The STATE-score differentiated 2 groups (<18, ⩾18 points) with distinct prognosis (median OS: 5.3 vs. 19.5 months; p<0.001) and a lower STATE-score was associated with short-term harm and increased mortality after TACE-1 (39% vs. 14% p<0.001). Sequential use of the STATE and the ART-score (START-strategy) identified the most (un)suitable patients for TACE. Results were confirmed in the external validation-cohort and were independent from recently proposed baseline selection tools. CONCLUSION: The STATE-score identifies patients who are (un)suitable for the first TACE. The START-strategy identified the best candidates for multiple TACE sessions.

Impact of D181V and A69T on the function of ferroportin as an iron export pump and hepcidin receptor.

Mutations in the only known mammalian iron exporter ferroportin cause a rare iron overload disorder termed ferroportin disease. Two distinct clinical phenotypes are caused by different disease mechanisms: mutations in ferroportin either cause loss of iron export function or gain of function due to resistance to hepcidin, the peptide hormone that normally downregulates ferroportin. The aim of the present study was to examine the disease mechanisms of the thus far unclassified A69T and D181V ferroportin mutations. We overexpressed wild-type and mutant ferroportin fused to green fluorescent protein in human embryonic kidney cells and used a (59)Fe-assay, intracellular ferritin concentrations, confocal microscopy and flow cytometry to study iron export function, subcellular localization and the responsiveness to hepcidin. While the A69T ferroportin mutation seems not to affect the iron export function it causes dose-dependent hepcidin resistance. We further found that D181V mutated ferroportin is iron export defective and hepcidin resistant, similar to the loss of function mutations A77D and C367X. This indicates that intact iron export might be necessary for hepcidin-induced downregulation of ferroportin. This hypothesis was investigated by studying the hepcidin response under modulation of iron availability. Incubation of wild-type ferroportin overexpressing cells with holo-transferrin increases the hepcidin effect whereas chelating extracellular ferrous iron causes hepcidin resistance. In this study we present data that postulates to classify the D181V ferroportin mutation as loss of function and the A69T mutation as dose-dependent hepcidin resistant and outline a possible causal link between iron export function and the hepcidin effect.

Holes in gastric mucosa in upper gastrointestinal endoscopy.

Gastritis cystica profunda (GCP) is a rare disease that shows multiple cystic gastric glands dispersed within the submucosa of the stomach. GCP occurs most commonly in patients who have undergone previous gastric surgery and presents as subepithelial tumor or a polypoid lesion. Here, we report the case of GCP in a 79-year-old patient who had undergone Billroth II gastric resection. During upper gastrointestinal endoscopy multiple lesions like tiny holes in the mucosa were observed. Endoscopic ultrasound showed cystic structures in the gastric submucosa. Biopsies finally proved the dispersed mucosal glands in the submucosa, which are pathognomonic for GCP. So far, in all published cases, GCP presented as polypoid lesions with no mucosal damage in upper gastrointestinal endoscopy. It is for the first time that GCP has been diagnosed with cystic lesions connected to the gastric lumen with a porus in each of the cysts.

Distress in primary caregivers and patients listed for liver transplantation.

Orthotopic liver transplantation (LTx) has become a routine procedure in the treatment of end-stage liver disease. During the waiting period for transplantation, the patient's family members are also highly affected. We examined the course of distress and quality of life (QOL) in 47 patients awaiting LTx and distress in 24 caregivers at baseline and in intervals of 4-6 weeks, using The Hospital Anxiety and Depression Scale (HADS) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). All subscales of the EORTC QLQ-C30, except emotional functioning, were lower than normal at baseline. Little change in patients' QOL was observed during the waiting period. In the HADS, there were significantly higher anxiety scores in caregivers than in patients both at baseline and after 1-2 months and the third assessment, with the difference after 3-5 months reaching almost significance. Caregivers' anxiety levels increased significantly. Relatives showed more depression than patients only at month 1-2 and a significant increase in depression from baseline to month 1-2. In patients, depression scores remained relatively stable throughout all visits. Our results emphasize the importance of evaluation of psychic stress especially in relatives during the waiting period for LTx.

The ART-strategy: sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE.

BACKGROUND & AIMS: Recently, we developed the ART score (assessment for re-treatment with TACE) to guide the decision for a second transarterial chemoembolization (TACE-2) in patients with hepatocellular carcinoma (HCC). Patients with an ART score of 0-1.5 points gained benefit from a second TACE session, while patients with an ART score ≥2.5 points did not. Here, we investigated (1) the prognostic significance of the ART score prior to the third (TACE-3) and fourth TACE (TACE-4), and (2) the feasibility of an ART score guided re-treatment strategy by sequential assessment of the ART score in HCC patients treated with multiple TACE sessions. METHODS: 109 patients, diagnosed with intermediate stage HCC and treated with ≥3 TACE sessions between January 1999 and December 2009 at the Medical Universities of Vienna and Innsbruck, were included. The ART score prior to each TACE session was assessed in comparison to the TACE naïve liver. The prognostic performance of the ART score before TACE-3 and 4 was evaluated with and without stratification based on the ART score prior to the respective last intervention. RESULTS: The pre-TACE-3 ART score discriminated two groups with different prognosis and remained a valid predictor of OS independent of Child-Pugh score (5-7 points), CRP-levels and tumor characteristics. Even in patients with an initially beneficial ART score (0-1.5 points) before TACE-2, repeated ART score assessment before TACE-3 identified a subgroup of patients with dismal prognosis (median OS: 27.8 vs. 10.8 months, p<0.001). Similar results were observed when the ART score was applied before TACE-4. CONCLUSIONS: The sequential assessment of the ART score identifies patients with dismal prognosis prior to each TACE session.

Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.

BACKGROUND & AIMS: Impaired binding function of albumin has been demonstrated in end-stage liver disease. This and other functional disturbances of albumin may be related to oxidative stress which is believed to play an important role in the pathogenesis of liver failure as well as sepsis. The aim of the present study was to relate oxidative modification of albumin to loss of albumin binding function in advanced chronic liver failure and in sepsis. METHODS: Patients with decompensated cirrhosis or sepsis and healthy controls were investigated. Three fractions of albumin were separated by chromatography according to the redox state of cysteine-34: non-oxidized human mercaptalbumin, reversibly oxidized human non-mercaptalbumin-1, and irreversibly oxidized human non-mercaptalbumin-2 (HNA2). Binding properties of albumin site II were measured using dansylsarcosine as a ligand. RESULTS: Both in cirrhotic and septic patients, fractions of oxidized albumin were increased and binding capacity for dansylsarcosine was decreased. Mass spectroscopy confirmed specific oxidation of cysteine-34. In cirrhotic patients, dansylsarcosine binding correlated strongly with liver function parameters and moderately with HNA2. Baseline levels of HNA2 accurately predicted 30-day and 90-day survival in cirrhotic patients and this was confirmed in an external validation cohort. CONCLUSIONS: Our results suggest that oxidative damage impairs binding properties of albumin. In advanced liver disease, reduced binding capacity of albumin site II is mainly related to impaired liver function. The plasma level of HNA2 is closely related to survival and may represent a novel biomarker for liver failure.

Alpha-fetoprotein and modified response evaluation criteria in solid tumors progression after locoregional therapy as predictors of hepatocellular cancer recurrence and death after transplantation.

Locoregional therapy (LRT) is being increasingly used for the management of hepatocellular cancer (HCC) in patients listed for liver transplantation (LT). Although several selection criteria have been developed, stratifications of survival according to the pathology of explanted livers and pre-LT LRT are lacking. Radiological progression according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and alpha-fetoprotein (AFP) behavior was reviewed for 306 patients within the Milan criteria (MC-IN) and 116 patients outside the Milan criteria (MC-OUT) who underwent LRT and LT between January 1999 and March 2010. A prospectively collected database originating from 6 collaborating European centers was used for the study. Sixty-one patients (14.5%) developed HCC recurrence. For both MC-IN and MC-OUT patients, an AFP slope > 15 ng/mL/month and mRECIST progression were unique independent risk factors for HCC recurrence and patient death. When the radiological Milan criteria (MC) status was combined with radiological and biological progression, MC-IN and MC-OUT patients without risk factors had similarly excellent 5-year tumor-free and patient survival rates. MC-IN patients with at least 1 risk factor had worse outcomes, and MC-OUT patients with at least 1 risk factor had the poorest survival (P < 0.001). In conclusion, both radiological and biological modifications permit documentation of the response to LRT in patients waiting for LT. According to these 2 parameters, tumor progression significantly increases the risk of recurrence and patient death not only for MC-OUT patients but also for MC-IN patients. The monitoring of both parameters in combination with the initial radiological MC status is an essential element for further refining the selection criteria for potential liver recipients with HCC.

MNGIE Syndrome: Liver Cirrhosis Should Be Ruled Out Prior to Bone Marrow Transplantation.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive mitochondriopathy caused by loss-of-function mutations in the thymidine phosphorylase gene. The disease leads to premature death and is characterized by gastrointestinal dysmotility and cachexia, external ophthalmoplegia, a sensorimotor neuropathy, and leukoencephalopathy. Bone marrow transplantation (BMT) is the only potentially curative treatment that can achieve a sustained biochemical correction of the metabolic imbalances.We report a 23-year-old male homozygous for the c.866A > C, p.Glu289Ala mutation of the TYMP gene, who presented with fatty liver and cachexia. Laboratory examinations were unremarkable except for increased transaminase activities. Grade II fibrosis and steatosis was found in an initial and a follow-up liver biopsy 4 years later. Myeloablative conditioning and BMT was performed 10 years after initial presentation due to the progressive weight loss and polyneuropathy. Pre-transplant liver staging was normal except for an elevated transient elastography of 31.6 kPa. Severe ascites developed after transplantation and liver function deteriorated progressively to liver failure. Despite engraftment on day +15, the patient died on day +18 from liver failure. Autopsy revealed micronodular liver cirrhosis, and postmortem diagnosis of acute-on-chronic liver failure was done.This case illustrates the difficulties and importance of diagnosing liver cirrhosis in MNGIE. Before BMT, patients must be carefully evaluated by transient elastography, liver biopsy, or assessment of hepatic venous pressure gradient. In patients with liver cirrhosis, further studies should evaluate if liver transplantation may be an alternative to BMT. Considerable amounts of thymidine phosphorylase are expressed in liver tissue which may prevent accumulation of toxic metabolites.

The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma.

UNLABELLED: We aimed to establish an objective point score to guide the decision for retreatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). In all, 222 patients diagnosed with HCC and treated with multiple TACE cycles between January 1999 and December 2009 at the Departments of Gastroenterology/Hepatology of the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the effect of the first TACE on parameters of liver function and tumor response and their impact on overall survival (OS, log rank test) and developed a point score (ART score: Assessment for Retreatment with TACE) in the training cohort (n = 107, Vienna) by using a stepwise Cox regression model. The ART score was externally validated in an independent validation cohort (n = 115, Innsbruck). The increase of aspartate aminotransferase (AST) by >25% (hazard ratio [HR] 8.4; P < 0.001), an increase of Child-Pugh score of 1 (HR 2.0) or ≥2 points (HR 4.4) (P < 0.001) from baseline, and the absence of radiologic tumor response (HR 1.7; P = 0.026) remained independent negative prognostic factors for OS and were used to create the ART score. The ART score differentiated two groups (0-1.5 points; ≥2.5 points) with distinct prognosis (median OS: 23.7 versus 6.6 months; P < 0.001) and a higher ART score was associated with major adverse events after the second TACE (P = 0.011). These results were confirmed in the external validation cohort and remained significant irrespective of Child-Pugh stage and the presence of ascites prior the second TACE. CONCLUSION: An ART score of ≥2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessions. (HEPATOLOGY 2013;57:2261-2273).

Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma.

UNLABELLED: We investigated the prognostic value of C-reactive protein (CRP) in patients with hepatocellular carcinoma (HCC) not amenable to surgery. A total of 615 patients diagnosed with HCC not amenable to surgery between April 1999 and December 2009 at the Department of Gastroenterology of the Medical Universities of Vienna and Innsbruck were included. We assessed the optimal CRP cutoff by regression spline analysis and tested its impact on median overall survival (OS) by the Kaplan-Meier method, univariate analysis (log-rank test), and multivariate analysis (Cox proportional hazard regression model) in a training cohort (n = 466, Vienna) and an independent validation cohort (n = 149, Innsbruck). We found a sigmoid-shaped association of CRP and the hazard ratio of death upon regression spline analysis and defined a CRP level <1/≥1 mg/dL as optimal cutoff for further survival assessments. Elevated CRP (≥1 mg/dL) at diagnosis was associated with poor OS (CRP-elevated versus CRP-normal; 4 versus 20 months; P < 0.001) and remained a significant negative predictor for OS upon multivariate analysis (hazard ratio, 1.7; P < 0.001), which was independent of age, Child-Pugh class, tumor characteristics, and treatment allocation. Analyses with respect to Barcelona Clinic Liver Cancer (BCLC) stage and Child-Pugh class supported the relevance of CRP (BCLC-stage C and Child-Pugh A: OS for CRP-elevated versus CRP-normal, 6 versus 14; P < 0.001; BCLC-stage C and Child-Pugh B: OS for CRP-elevated versus CRP-normal, 4 versus 15 months; P < 0.001). The prognostic significance of elevated CRP was reproducible at a second CRP determination timepoint and confirmed in the independent validation cohort. CONCLUSION: Elevated CRP is associated with a dismal prognosis in HCC patients and may become a useful marker for patient selection in HCC management. (HEPATOLOGY 2012).