A retrospective study on the safety, diagnostic yield, and therapeutic effects of endoscopic unroofing for small gastric subepithelial tumors.

BACKGROUND AND AIMS: Accurate diagnosis of small gastric subepithelial tumors (SETs) is essential to assess their malignant potential. Endoscopic unroofing has been reported to yield sufficient tissue samples for histologic evaluation. This study aimed to evaluate the safety, diagnostic yield, and potential therapeutic effects of this technique over time. METHODS: This retrospective analysis of prospectively collected clinical data identified patients who underwent endoscopic unroofing at the Medical University of Vienna from January 2003 to December 2012. Demographic data, indications for endoscopic unroofing, intraprocedural adverse events, hospital stay, histologic results, and follow-up procedures were reviewed. RESULTS: A total of 14 patients (7 men; 7 women; median age, 70 years; range, 51-95 years) underwent endoscopic unroofing of 14 gastric SETs with a mean diameter of 26 ± 13 mm at EUS. In 9 of 14 cases, endoscopic unroofing was done exclusively for diagnostic purposes; in the remaining cases, it was performed with therapeutic intent because of bleeding from the gastric SETs. Unroofing was technically successful in 13 of 14 cases and revealed 8 cases of GI stromal tumor (GIST) and 1 case each of leiomyoma, fibroid polyp, glomus tumor, pancreatic rest, and nondiagnostic material at histology. Intraprocedural bleeding was the only adverse event (4 cases) and could be managed endoscopically. A follow-up EUS was available (median, 8 months) for 10 of the 14 patients. Notably, most patients showed complete regression of their gastric SETs after unroofing (on white light and EUS), including the glomus tumor, the leiomyoma, and 6 of the 8 cases of GIST. CONCLUSIONS: Endoscopic unroofing was safe and had a very favorable diagnostic yield in this study. Unexpectedly, it led to complete regression in most gastric SETs. Although it is not an oncologically curative treatment, endoscopic unroofing can be a valuable option to treat local adverse events in patients unfit for surgical therapy. (Clinical trial registration number: NCT02587923.).

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).

Musculoskeletal disease burden of hereditary hemochromatosis.

OBJECTIVE: To determine the prevalence, clinical picture, and disease burden of arthritis in patients with hereditary hemochromatosis. METHODS: In this cross-sectional observational study of 199 patients with hemochromatosis and iron overload, demographic and disease-specific variables, genotype, and organ involvement were recorded. The prevalence, intensity, and localization of joint pain were assessed, and a complete rheumatologic investigation was performed. Radiographs of the hands, knees, and ankles were scored for joint space narrowing, erosions, osteophytes, and chondrocalcinosis. In addition, the number and type of joint replacement surgeries were recorded. RESULTS: Joint pain was reported by 72.4% of the patients. Their mean ± SD age at the time of the initial joint symptoms was 45.8 ± 13.2 years. If joint pain was present, it preceded the diagnosis of hemochromatosis by a mean ± SD of 9.0 ± 10.7 years. Bony enlargement was observed in 65.8% of the patients, whereas synovitis was less common (13.6%). Joint space narrowing and osteophytes as well as chondrocalcinosis of the wrist and knee joints were frequent radiographic features of hemochromatosis. Joint replacement surgery was common, with 32 patients (16.1%) undergoing total joint replacement surgery due to severe OA. The mean ± SD age of these patients was 58.3 ± 10.4 years at time of joint replacement surgery. Female sex, metacarpophalangeal joint involvement, and the presence of chondrocalcinosis were associated with a higher risk of early joint failure (i.e., the need for joint replacement surgery). CONCLUSION: Arthritis is a frequent, early, and severe symptom of hemochromatosis. Disease is not confined to involvement of the metacarpophalangeal joints and often leads to severe damage requiring the replacement of joints.

Validation of a radiographic scoring system for haemochromatosis arthropathy.

BACKGROUND: Arthropathy is one of the earliest and most common manifestations of hereditary haemochromatosis with a significant impact on quality of life. Although its radiographic features are well known, there is no assessment tool for their evaluation. OBJECTIVE: To develop and validate a novel scoring system for the evaluation of radiographic features of haemochromatosis arthropathy. METHODS: A dichotomous scoring system assessing four radiographic features of haemochromatosis arthropathy and a 4-grade scale reflecting severity of radiographic change have been developed. Standard radiographs (hand, wrist, knee and ankle) of 170 subjects (116 male, 54 female) with genetically confirmed haemochromatosis and laboratory signs of iron overload were assessed by three readers and construct validity, feasibility and cross-sectional reliability (intrareader and inter-reader) were assessed. RESULTS: Intrareader and inter-reader reliability as assessed by percentage pairwise agreement and Cohen's weighed κ were good to excellent for most features and locations evaluated. Radiographic scores correlated well with clinical parameters (bony swollen joint count, hand function and physician's global health assessment; Pearson's correlation, r²=0.18-0.62, p<0.0001). A complete set of radiographs took 3.4 ± 1.2 (mean ± SD) min to be assessed. An atlas of characteristic radiographic features was compiled. CONCLUSION: A feasible and reliable radiological assessment tool for the evaluation of haemochromatosis arthropathy has been validated and an atlas of characteristic radiographic features provided.

Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy.

BACKGROUND & AIMS: Oral Silibinin (SIL) is widely used for treatment of hepatitis C, but its efficacy is unclear. Substantially higher doses can be administered intravenously (IV). METHODS: Pedigreed nonresponders to full-dose pegylated (Peg)-interferon/ribavirin (PegIFN/RBV) were studied. First, 16 patients received 10 mg/kg/day SIL IV (Legalon Sil; Madaus, Köln, Germany) for 7 days. In a subsequent dose-finding study, 20 patients received 5, 10, 15, or 20 mg/kg/day SIL for 14 days. In both protocols, PegIFN alpha-2a/RBV were started on day 8. Viral load was determined daily. RESULTS: Unexpectedly, in the first study, HCV-RNA declined on IV SIL by 1.32 +/- 0.55 log (mean +/- SD), P < .001 but increased again in spite of PegIFN/RBV after the infusion period. The viral load decrease was dose dependent (log drop after 7 days SIL: 0.55 +/- 0.5 [5 mg/kg, n = 3], 1.41 +/- 0.59 [10 mg/kg, n = 19], 2.11 +/- 1.34 [15 mg/kg, n = 5], and 3.02 +/- 1.01 [20 mg/kg, n = 9]; P < .001), decreased further after 7 days combined SIL/PegIFN/RBV (1.63 +/- 0.78 [5 mg/kg, n = 3], 4.16 +/- 1.28 [10 mg/kg, n = 3], 3.69 +/- 1.29 [15 mg/kg, n = 5], and 4.85 +/- 0.89 [20 mg/kg, n = 9]; P < .001), and became undetectable in 7 patients on 15 or 20 mg/kg SIL, at week 12. Beside mild gastrointestinal symptoms, IV SIL monotherapy was well tolerated. CONCLUSIONS: IV SIL is well tolerated and shows a substantial antiviral effect against HCV in nonresponders.

Prevalence of Helicobacter pylori and its CagA subtypes in gastric cancer and duodenal ulcer at an Austrian tertiary referral center over 25 years.

BACKGROUND AND AIMS: The prevalence of Helicobacter pylori (H. pylori) tends to be lower in Western countries such as central Europe compared with Asia. The virulence of H. pylori is influenced by its subtype composition, most importantly by the presence or absence of different types of cytotoxin-associated gene A(CagA). This study aimed to assess the prevalence of H. pylori and its respective CagA phenotype in a large retrospective cohort of patients with gastric cancer or duodenal ulcer at a Western tertiary referral institution. METHODS: H. pylori positive gastric biopsy samples from patients diagnosed with the afore mentioned diseases within the past 25 years were re-evaluated by histology for H. pylori and status of gastritis. Confirmed H. pylori positive cases were processed for immunohistochemistry (IHC) for H. pylori,CagA, and EastAsiantype CagA. RESULTS: The prevalence of H. pylori positive gastric biopsy samples decreased from 20.7% to 2.3% within the study period. Among the gastric cancer patients, the H. pylori positive rate was 16.6%, and didn't show significant changes over time (p = 0.38). Contrary, the H. pylori positive rate of duodenal ulcer decreased significantlyfrom 40% to 5% (p = 0.01). Within H. pylori positive groups ofboth diseases, CagA was highly detected at IHC (86% and 78%, respectively). Except for a few patients originating from East Asian countries, all CagA detected in this study were of Western type. CONCLUSION: In this first Western investigation on the chronological prevalence of H. pylori and its most relevant subtypes, Western type of CagA was highly detected in two important index diseases of the pathogen. This raises further questions about the virulence of this subtype.

A multicenter prospective study on the diagnostic performance of a new liquid rapid urease test for the diagnosis of Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori (H. pylori) causes a diversity of gastric diseases. Rapid urease tests (RUT) are well established for the point-of-care, invasive diagnosis of H. pylori infection. The study aimed to evaluate the diagnostic performance of a new liquid RUT, the preOx-HUT, within a prospective cohort of treatment-naïve patients. METHODS: The multicenter prospective clinical trial was conducted at nine Austrian centers for gastrointestinal endoscopy. Patients referred for a diagnostic upper gastrointestinal endoscopy underwent gastric biopsy sampling for routine histological evaluation, and in parallel, the preOx-HUT. Histology served as reference standard to evaluate the diagnostic performance of the preOx-HUT. RESULTS: From January 2015 to January 2016, a total of 183 consecutive patients (54 males and 129 females, median age 50 years) were included. Endoscopy revealed pathological findings in 149/183 cases (81%), which were mostly gastritis (59%) and gastro-esophageal reflux disease (27%). H. pylori infection was detected by histology in 41/183 (22%) cases. In relation to histology, the preOx-HUT had a sensitivity of 85%, a specificity of 94%, a positive predictive value of 80% and a negative predictive value of 96%. Performance of preOx-HUT was not affected significantly by concomitant PPI-use as present in 15% of cases (P = 0.73). CONCLUSIONS: This was the first study evaluating the preOx-HUT in a prospective, multicenter clinical setting. We found a high diagnostic accuracy for the point-of-care, invasive diagnostic test of H. pylori infection. Hence, this test may be a valuable diagnostic adjunct to the clinical presentation of patients with suspected H. pylori infection. Trial registration number EK 1548/2014, Name of registry: Register der Ethikkommission der Medizinischen Universität Wien, URL of registry: https://ekmeduniwien.at/core/catalog/2012/, Date of registration: 24.09.2014, Date of enrolment of the first participant to the trial: 15.01.2015.

Austrian Joint ÖGGH-ÖGIR-ÖGHO-ASSO position statement on the use of transarterial chemoembolization (TACE) in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) is one of the most frequently applied standard treatments for this disease. The role for TACE is fairly well defined within the most widely used treatment algorithm for HCC, die Barcelona Clinic Liver Cancer (BCLC) staging system and treatment algorithm. But no general treatment algorithm will go into the technical details of any procedure and several patients will not fit ideally into the patient groups predefined in BCLC or any other treatment algorithm. Furthermore, indications and contraindications sometimes are viewed differently by the various medical specialties involved in taking care of such patients. We present here the joint expert position statement of the Austrian Societies of Gastroenterology and Hepatology (ÖGGH), Interventional Radiology (ÖGIR), Hematology and Oncology (ÖGHO), and Surgical Oncology (ASSO) on the technical aspects, indications, and contraindication for the use of TACE in the management of HCC.

Clinical characteristics of patients with hepatocellular carcinoma in Austria - is there a need for a structured screening program?

BACKGROUND: We investigated the differences in clinical presentation of patients with hepatocellular carcinoma (HCC) at the time of diagnosis, before and after the publication of the European Association for the study of the Liver (EASL) guidelines of HCC management and screening. METHODS: Between 1991 and 2009, 907 patients were diagnosed with HCC at our department of which 850 were included in this study. Data regarding demography, liver function and tumor stage at the time of diagnosis were retrospectively collected. Differences in clinical characteristics and overall survival (OS) were compared before (period 1) and after (period 2) the publication of the EASL guidelines in 2001. RESULTS: In period 2, patients were more likely to be overweight (BMI: 26.1 vs. 27.5, p = 0.003), suffered more often from diabetes (25.4 vs. 37.3%, p = 0.001) and nonalcoholic steatohepatitis (NASH) (0.7 vs. 5.1%, p < 0.001). Alcoholic liver disease replaced viral hepatitis as the main etiology but not in the increasing number of patients with migration background where viral hepatitis (76.3%) remained the predominant etiology. No change in liver function and tumor stages at the time of HCC diagnosis was observed. Most patients presented with advanced incurable HCC. However, the median OS of all HCC patients increased in period 2 (7 vs. 14 months, p < 0.001) suggesting improvements of palliative therapy. CONCLUSIONS: Patients with HCC are still predominantly diagnosed at incurable tumor stages, despite explicit European screening guidelines existing since 9 years. The implementation of a HCC surveillance program for cirrhotic patients in Austria seems to be warranted.

Impact of hypoxic hepatitis on mortality in the intensive care unit.

PURPOSE: Hypoxic hepatitis (HH) is a form of hepatic injury following arterial hypoxemia, ischemia, and passive congestion of the liver. We investigated the incidence and the prognostic implications of HH in the medical intensive care unit (ICU). METHODS: A total of 1,066 consecutive ICU admissions at three medical ICUs of a university hospital were included in this prospective cohort study. All patients were screened prospectively for the presence of HH according to established criteria. Independent risk factors of mortality in this cohort of critically ill patients were identified by a multivariate Poisson regression model. RESULTS: A total of 118 admissions (11%) had HH during their ICU stay. These patients had different baseline characteristics, longer median ICU stay (8 vs. 6 days, p < 0.001), and decreased ICU survival (43 vs. 83%, p < 0.001). The crude mortality rate ratio of admissions with HH was 4.62 (95% CI 3.63-5.86, p < 0.001). Regression analysis demonstrated strong mortality risk for admissions with HH requiring vasopressor therapy (adjusted rate ratio 4.91; 95% CI 2.51-9.60, p < 0.001), whereas HH was not significantly associated with mortality in admissions without vasopressor therapy (adjusted rate ratio 1.79, 95% CI 0.52-6.23, p = 0.359). CONCLUSIONS: Hypoxic hepatitis (HH) occurs frequently in the medical ICU. The presence of HH is a strong risk factor for mortality in the ICU in patients requiring vasopressor therapy.

Hereditary hemochromatosis as a risk factor for joint replacement surgery.

OBJECTIVE: Hemochromatosis is an inherited disease with iron overload and joint involvement resembling osteoarthritis. To determine the rate of joint replacement surgery in patients with hemochromatosis, we performed a cross-sectional cohort study. METHODS: A total of 199 individuals with hereditary hemochromatosis were included. The prevalence of joint replacement surgery in hip, knee, and ankle joints because of secondary osteoarthritis was assessed. Data were compared with 917 healthy subjects from the population-based Bruneck study. RESULTS: A total of 32 of 199 individuals with hemochromatosis received joint replacement surgery with a total number of 52 joints replaced. Compared with expected rates in healthy individuals, patients with hemochromatosis had a significantly higher risk for joint replacement surgery (odds ratio 9.0; confidence interval, 4.6-17.4). Joint replacement occurred significantly earlier in life in patients with hemochromatosis; 21.9% of the patients with hemochromatosis and 1.7% of healthy individuals required joint replacement before the age of 50 years (P=.0027). Moreover, patients with hemochromatosis were more likely to require multiple joint replacements (8.5%) than the control group (expected rate 0.3%; P=.0001). CONCLUSION: Hemochromatosis is a risk factor for joint replacement surgery because of severe secondary osteoarthritis.

Octreotide treatment of patients with hepatocellular carcinoma--a retrospective single centre controlled study.

BACKGROUND: Studies of treatment with octreotide of patients with hepatocellular carcinoma (HCC) gave conflicting results. We analyzed retrospectively the survival of our patients treated with octreotide monotherapy and compared it to stage-matched patients who received either TACE, multimodal therapy or palliative care. METHODS: 95 patients seen at the department of Gastroenterology and Hepatology, Medical University of Vienna with HCC in BCLC stage A or B, who received either TACE, multimodal therapy, long-acting octreotide or palliative care were reviewed for this retrospective study. RESULTS: Survival rates of patients with BCLC stage B and any "active" treatment (long-acting octreotide, TACE or multimodal therapy) were significantly higher (22.4, 22.0, 35.5 months) compared to patients who received palliative care only (2.9 months). Survival rates of patients with BCLC stage A and "active" treatment (31.4, 37.3, 40.2 months) compared to patients who received only palliative care (15.1 months) did not show statistically significant differences. Octreotide monotherapy showed a similar outcome compared to patients who received TACE or multimodal therapy. CONCLUSION: Survival under octreotide treatment was not different compared to TACE or multimodal therapy and might be a therapeutic option for patients with HCC.

Percutaneous ethanol instillation therapy for hepatocellular carcinoma - a randomized controlled trial.

BACKGROUND AND AIMS: The aim of the study was to compare the clinical outcome of additional percutaneous ethanol instillation (PEI) against no further treatment in patients with hepatocellular carcinoma receiving hormonal treatment with long-acting octreotide. METHODS: In a randomized controlled trial conducted in a tertiary care center, a total of 61 patients with inoperable hepatocellular carcinoma were treated with long-acting octreotide 30 mg i.m. once a month and randomly assigned to receive either PEI (31 patients) or no further treatment (30 patients). RESULTS: Median survival time did not significantly differ between the long-acting octreotide plus PEI group (14 months; 95% CI: 9-28 months) and the long-acting octreotide alone group (22 months; 95% CI: 10-30 months) (logrank test P = 0.9). Similarly, an analysis stratifying for tumor diameter (< 5 cm or 5-8 cm) showed no significant survival differences between PEI or non-PEI treatment (logrank test P = 0.68). Progression-free survival according to RECIST was similar in the two groups (median: 3 months [3-6 months 95% CI] vs. 6 months [3-7 months 95% CI], logrank test P = 0.63). Time of local tumor control did not significantly differ between the two groups (6 months vs. 6 months). The course of alpha-fetoprotein levels and the reported quality of life were similar in the two groups. CONCLUSIONS: The addition of PEI to treatment with long-acting octreotide in patients with hepatocellular carcinoma did not result in better overall survival, longer progression-free survival or longer time of local tumor control.

Tropheryma whipplei in the environment: survey of sewage plant influxes and sewage plant workers.

We studied the prevalence of Tropheryma whipplei in influxes to 46 sewage treatment plants and in stool, mouthwash fluids, and dental plaques of 64 healthy workers in those facilities and 146 disease control patients. T. whipplei was found in sewage water, in stool of healthy individuals, and significantly more often in stool of workers exposed to sewage water.

The combined elevation of tumor markers CA 19-9 and CA 125 in liver disease patients is highly specific for severe liver fibrosis.

Increased tumor markers in patients with liver cirrhosis are often considered to be unspecific. The use of this unspecific elevation to discriminate minimal fibrosis from severe fibrosis has never been explored. We aimed to answer the question, Do tumor markers predict severe liver fibrosis? The study group consisted of 125 patients with alcoholic liver disease, hepatitis B, or hepatitis C with available liver biopsy. Tumor markers CA 19-9, CA 15-3, and CA 125 were determined using routine laboratory methods and correlated with the extent of liver fibrosis. Fibrosis stages 1 and 2 were classified as minimal fibrosis; stages 3 and 4, as severe fibrosis. Tumor markers CA 19-9, CA 125, and CA 15-3 increased with stage of fibrosis. For separating patients with mild fibrosis (F1+F2) from patients with severe fibrosis (F3+F4), CA 19-9 had a sensitivity of 70.5% and a specificity of 88.6, CA 125 had 38.1% and 89.7%, and CA 15-3 had 19.0% and 93.0%, respectively. Logistic regression of a combined score of CA19-9 and CA 125 values revealed that an increase of 1 point of the CA 19-9/CA125 score resulted in a 1.6 times increase in likelihood of the presence of severe fibrosis. The CA 19-9/CA 125 score achieved a similar specificity (97.1% vs. 100%) but a higher sensitivity (42.9% vs. 33.3%) than the widely used cirrhosis discriminant score of Bonacini. A specificity (98.5%) similar to that of the CA 19-9/CA 125 score was reached by the easier determination of the combined elevation of CA 19-9 and CA 125, which had the best positive predictive value, 92.9%. The excellent predictive ability of the combined elevation of CA 19-9 and CA 125 for severe liver fibrosis (F3+F4) was confirmed in an independent group of patients with liver disease. The combined elevation of CA 19-9 and CA 125 is useful for identifying patients with advanced fibrosis or cirrhosis with high specificity. Patients without a combined elevation of CA 19-9 and CA 125 still require histological examination to identify severe fibrosis or cirrhosis.

Mutation of keratin 8 in patients with liver disease.

BACKGROUND: Epithelial tissues of the gastrointestinal tract and the liver express predominantly cytokeratin 8 and cytokeratin 18. In vitro experiments and animal studies have demonstrated a protective influence of keratin 8 and keratin 18 against toxic damage of hepatocytes. A specific mutation of keratin 8 (G61C) was found to be a genetic risk factor for the development of cryptogenic liver cirrhosis. The purpose of the present paper was therefore to determine the prevalence of cytokeratin 8 (G61C) and cytokeratin 18 mutations (Y53H) in patients with liver disease. METHODS: Overall 152 patients (male, n = 93, 61%; female, n = 59, 39%) were included in the present study. The 152 patients consisted of 107 patients with liver disease (70.4%; male, n = 71, 66.4%; female, n = 36, 33.6%) and 45 control patients (29.6%; male, n = 22, 48,9%; female, n = 23, 51,1%) without liver disease. Of the patients with liver disease 46 had alcoholic liver disease; 25, chronic hepatitis C; 15, cryptogenic liver disease; and 21, other liver diseases of various etiologies. Cytokeratin 8 and 18 genotypes were specified by polymerase chain reaction (PCR) amplification and direct sequence analysis was used to detect the previously described mutations in cytokeratin 8 (G61C) and in cytokeratin 18 (Y53H). RESULTS: Four out of 152 patients (male n = 2, female n = 2) with a mutation (G61C) in cytokeratin 8 were found. The etiology was alcoholic liver disease (n = 1), cryptogenic liver disease (n = 1) and idiopathic liver disease with minimal changes in liver biopsy (n = 1). Also, one out 45 disease control patients with an adenoma of the colon but without liver disease was found to carry the mutation G61C of cytokeratin 8. Therefore, the mutation G61C in cytokeratin 8 was found in 2.8% of patients with liver disease and in 2.2% of control patients without liver disease. Two of 15 patients (13.3%) with cryptogenic liver disease had the mutation G61C in cytokeratin 8 (P = 0.069 vs patients with non-cryptogenic liver disease). In the 152 patients studied, no mutation in cytokeratin 18 was found. DISCUSSION: The mutation G61C in the cytokeratin 8 gene was found in one patient with alcoholic liver disease and in two patients with liver disease of unknown etiology. Also, one patient without liver disease had the cytokeratin 8 G61C mutation. In summary, the cytokeratin 8 mutation G61C, which has been found to be associated with cryptogenic liver cirrhosis, was also found in the present patient population. However, the clinical relevance is yet to be determined in further investigations.

Exclusion of trisialo-transferrin from carbohydrate-deficient transferrin measurement: advantage in patients with chronic liver disease?

BACKGROUND: Biological markers for chronic alcohol consumption like MCV or gammaGT or carbohydrate deficient transferrin (CDT) are useful, but far from being perfect. In patients with liver disease a reliable marker for chronic alcohol consumption as the underlying etiology is highly needed. Recently, a new ELISA based version of the carbohydrate-deficient-transferrin (CDT-TRISIALO (-)) assay has been developed, which measures asialo-, monosialo- and disialo transferrin, but excludes trisialo- transferrin; that modification suggests higher sensitivity and specificity in detecting recent alcohol consumption in patients. AIMS: The study goal was to evaluate the sensitivity, specificity, positive and negative predicitive value of this new carbohydrate-deficient-transferrin assay (CDT-TRISIALO (-)) in a group of patients with liver disease and to compare the results with that of the established CDT assay (CDT-TRISIALO (+)). PATIENTS AND METHODS: Our study population consisted of 110 consecutive patients (male: n = 80 [72.7 %], female: n = 30 [27.3 %]) with liver disease of the following etiologies: chronic alcohol consumption (n = 51 [46.4 %]; Out of them 30 alcohol abusing patients were assessed by cage = 1 and 21 alcohol dependent patients were assessed by cage = 2, chronic viral hepatitis (n = 33 [30.0 %]) including 25 [22.7 %] patients with chronic hepatitis C infection and 8 [7.3 %] patients with chronic hepatitis B infection), haemochromatosis (n = 4 [3.6 %]), mechanical cholestasis (n = 17 [15.5 %]) and other liver diseases (n = 5 [4.6 %] including autoimmune hepatitis (n = 2) and primary biliary cirrhosis (n = 3)). 27.3 % of our patients (n = 30) had no liver cirrhosis whereas the majority (72.7 %, n = 80) had liver cirrhosis. RESULTS: In our population of liver disease patients the CDT-TRISIALO (-) assay had a sensitivity of 72.7 % and specificity of 58.1 % for recent alcohol consumption at the published cutoff level of 2.6 %. The positive predictive value was 34.0 % and the negative predictive value was 87.8 %. Sensitivity and specificity of the CDT-TRISIALO (+) assay at the recommended cutoff level of 4.7 % were similar, 77.3 % and 49.3 %, respectively. The positive and negative predictive values were 30.9 % and 88.1 %. CDTTRISIALO (+) and CDT-TRISIALO (-) levels increased significantly with higher Child-Pugh stages. CONCLUSION: The newly developed carbohydrate deficient transferrin test (CDT-TRISIALO (-)) is of no advantage as compared to the established assay (CDT-TRISIALO (+)) when used in a patient population with liver disease. In that population, normal CDT-TRISIALO (-) helps to exclude recent alcohol consumption; this results from the high negative predictive value of a normal CDT-TRISIALO (-).

Hepatocellular carcinoma--survival and clinical characteristics in relation to various histologic molecular markers in Western patients.

BACKGROUND: Many genes participate in the regulation of cell proliferation and growth of tumor cells. Altered expression and loss of function of some of these gene products have been found in malignant tumors and correlated with progression and poor prognosis. AIMS: Our aim was to correlate the expression of various molecular histologic markers with tumor characteristics and survival time of patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Tumor tissues of 81 patients with HCC were investigated immunohistochemically for the expression of cellular proliferation markers Mib1 (Ki67) and c-erbB-2 (HER2/neu), cellcycle markers (p53, mdm2 and p21), CD81 (TAPA1), a marker shown to be associated with metastasis, and human leukocyte antigen (HLA)-DR expression, involved in immunological antigen presentation. RESULTS: p21 was expressed in a higher percentage (83.3 vs. 50%, P=0.014) in undifferentiated histological tumor grades (Edmondson Steiner G3 vs. G1/G2). HCC in patients with enlarged lymph nodes expressed HLA-DR in a higher percentage (28.6%) than tumors without lymph node enlargement (5.7%, P=0.006). Patients with distant metastases were less likely to express CD 81 (11.1%) on tumor cells than patients without distant metastases (38.3%, P=0.0335). No other correlation with clinical or tumor characteristics or molecular histologic markers investigated was found. P53 accumulating patients showed a worse survival than patients with tumors p53 non-accumulating (median 4.1 months vs. median 9.3 months, P=0.01798). Neither the expression nor the non-expression of proliferation, cell cycle, immunologic or cell adhesion markers was associated with differences in survival. However, patients with a low expression of cell cycle marker mdm2 survived significantly longer (median 9.4 months) as compared with patients with high expression (median 3.9 months). CONCLUSION: Our results suggest that p53 nuclear accumulation and mdm2 high expression are associated with poor survival in patients withHCC. Furthermore, patients with enlarged lymph nodes had HLA-DR-positive tumors more frequently and patients with distant metastases had tumors with CD81 expression less often.

Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis.

BACKGROUND AND AIMS: The hepatopulmonary syndrome (HPS) has been defined by chronic liver disease, arterial deoxygenation, and widespread intrapulmonary vasodilation. Mortality of patients with HPS is considered to be high, but the effect of HPS on survival in patients with cirrhosis remains unclear. METHODS: A total of 111 patients with cirrhosis were studied prospectively by using transthoracic contrast echocardiography for detection of pulmonary vasodilation, blood gas analysis, and pulmonary function test. Twenty different clinical characteristics and survival times were noted. RESULTS: Twenty-seven patients (24%) had HPS. Their mortality was significantly higher (median survival, 10.6 months) compared with patients without HPS (40.8 mo, P < 0.05), even after adjusting for liver disease severity (2.9 vs. 14.7 months in Child-Pugh class C with [n = 15] and without HPS [n = 35, P < 0.05]; 35.3 vs. 44.5 months in Child-Pugh class B with [n = 7] and without HPS [n = 23, P = NS]), and exclusion of patients who underwent liver transplantation during follow-up (median survival 4.8 vs. 35.2 months, P = 0.005). Causes of death were mainly nonpulmonary and liver-related in the 19 patients with and the 35 patients without HPS who died. In multivariate analysis, HPS was an independent predictor of survival besides age, Child-Pugh class, and blood urea nitrogen. Mortality correlates with severity of HPS. CONCLUSIONS: The presence of HPS independently worsens prognosis of patients with cirrhosis. This should influence patient management and scoring systems and accelerate the evaluation process for liver transplantation.

Liver pathology in compound heterozygous patients for hemochromatosis mutations.

BACKGROUND: While hepatic pathology of homozygous carriers of the C282Y mutation of the HFE haemochromatosis gene is well defined, the impact of the C282Y/H63D compound heterozygous carrier state is unknown. AIMS: To evaluate the range of hepatic pathology in C282Y/H63D compound heterozygous patients. PATIENTS: 25 C282Y/H63D compound heterozygous patients with and without known underlying liver disease underwent liver biopsies for evaluation or abnormal liver tests. Eleven cadaveric liver donors with HFE wild type served as controls. METHODS: Mutations in the HFE gene were detected by polyacrylamide gel electrophoresis (PAGE) separation of digested polymerase chain reaction (PCR)-amplificates. The extent of light microscopic changes of liver architecture were studied on haematoxylin, eosin (H. E.) stains. In addition, the extent and the distribution of iron deposition was graded on Prussian blue-stained sections and hepatic iron was quantified by atom absorption spectroscopy. Serum ferritin concentration and the transferrin saturation index were measured using routine laboratory methods. RESULTS: Patients without underlying liver disease (n = 15): Hepatic inflammation was seen in only 8% but fibrosis was found in 36% of compound heterozygous patients. Eighty six percent of those patients had stainable iron predominantly found in Rappaport's zone 1 and 2, but all had a liver iron-index < 1.9. Transferrin saturation was found elevated in 36% of compound heterozygous patients. Patients with liver fibrosis showed significantly higher ferritin levels than patients without liver fibrosis (1110 ng/mL versus 307 ng/mL, p < 0.05). Patients with underlying disease (n = 10): In compound heterozygous patients, 77% had hepatic inflammation and 88% fibrosis. Stainable iron (44%) was less frequently found than in patients without underlying liver disease. Hepatic iron-index in patients with underlying liver disease was always below 1.17; transferrin saturation was elevated in only 22% of the compound heterozygous patients. Histologic hepatic iron-index was significantly lower in patients with underlying disease (median 0.047) as compared to patients without underlying liver disease (median 0.274, P < 0.05). CONCLUSIONS: The underlying liver disease determines the extent of hepatic pathology seen in livers of compound heterozygous patients. However, considerable histologic fibrosis can also be found in compound heterozygous patients without underlying liver disease.