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Mois d'Octobre 2005
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Volume 42, Issue S1 (October 2005) Supplement : 56th Annual Meeting of the American Association for the Study of Liver Diseases.
Pas d'abstract en ligne
Copyright © 2005 by the American Association for the Study of Liver Diseases. All rights reserved.
Table of Contents for October 2005 • Volume 129 • Number 4
Clinicalalimentary tract
Projected National Impact of Colorectal Cancer Screening on Clinical and Economic Outcomes and Health Services Demand, 14 September 2005
Ladabaum U, Song K
Background & Aims: Colorectal cancer (CRC) screening is effective and cost-effective, but the potential national impact of widespread screening is uncertain. It is controversial whether screening colonoscopy can be offered widely and how emerging tests may impact health services demand. Our aim was to produce integrated, comprehensive estimates of the impact of widespread screening on national clinical and economic outcomes and health services demand. Methods: We used a Markov model and census data to estimate the national consequences of screening 75% of the US population with conventional and emerging strategies. Results: Screening decreased CRC incidence by 17%54% to as few as 66,000 cases per year and CRC mortality by 28%60% to as few as 23,000 deaths per year. With no screening, total annual national CRC-related expenditures were $8.4 billion. With screening, expenditures for CRC care decreased by $1.5$4.4 billion but total expenditures increased to $9.2$15.4 billion. Screening colonoscopy every 10 years required 8.1 million colonoscopies per year including surveillance, with other strategies requiring 17%58% as many colonoscopies. With improved screening uptake, total colonoscopy demand increased in general, even assuming substantial use of virtual colonoscopy. Conclusions: Despite savings in CRC care, widespread screening is unlikely to be cost saving and may increase national expenditures by $0.8$2.8 billion per year with conventional tests. The current national endoscopic capacity, as recently estimated, may be adequate to support widespread use of screening colonoscopy in the steady state. The impact of emerging tests on colonoscopy demand will depend on the extent to which they replace screening colonoscopy or increase screening uptake in the population.
Comparing Risks and Benefits of Colorectal Cancer Screening in Elderly Patients, 14 September 2005
Ko CW, Sonnenberg A
Background & Aims: In patients with limited life expectancy, the risks of colorectal cancer screening may outweigh the benefits. The aim of this study was to quantify risks and benefits of different screening strategies in elderly patients with varying life expectancies. Methods: We examined risks and benefits of screening in patients aged 7094 years with differing health status using 3 strategies: annual fecal occult blood tests, flexible sigmoidoscopy every 5 years, or colonoscopy every 10 years. We compared the number needed to screen to prevent one cancer-related death and the number needed to encounter one screening-related complication for different strategies. Results: The potential benefit from screening varied widely with age, life expectancy, and screening modality. One cancer-related death would be prevented by screening 42 healthy men aged 7074 years with colonoscopy, 178 healthy women aged 7074 years with fecal occult blood tests, 431 women aged 7579 years in poor health with colonoscopy, or 945 men aged 8084 years in average health with fecal occult blood tests. Colonoscopy screening had the greatest benefit but the highest risk of complications. The potential for screening-related complications was greater than estimated benefit in some population subgroups aged 70 years and older. At all ages and life expectancies, the potential reduction in mortality from screening outweighed the risk of colonoscopy-related death. Conclusions: The potential benefits and risks of screening vary in elderly patients of different life expectancies. For any individual patient, the potential for harm from screening must be weighed against the likelihood of benefit, especially with shorter life expectancy.
National Adherence to Evidence-Based Guidelines for the Prescription of Nonsteroidal Anti-Inflammatory Drugs
Abraham NS, ElSerag HB, Johnson ML, Hartman C, Richardson P, Ray WA, Smalley W
Background & Aims: Our objective was to assess adherence to evidence-based guidelines by providers of the Department of Veterans Affairs nationwide. Methods: This was a cross-sectional study among veterans prescribed a nonsteroidal anti-inflammatory drug (NSAID) from January 1, 2002, to December 31, 2002. Prescription data were linked to inpatient and outpatient medical records and death files. The population was characterized as high risk based on the following: age 65 years or older, concurrent corticosteroid or anticoagulant use, history of peptic ulcer, and high average daily dose of NSAIDs. Adherence was defined as the prescription of a traditional NSAID with gastroprotection or a coxib in high-risk NSAID users. Univariate and multivariate analyses assessed the potential predictors of adherence. Results: Three hundred three thousand seven hundred eighty-seven met our definition of high risk. Most (97.3%) were male; 55.6% were white, 9.6% black, and 34.8% of other/unknown race. Age 65 years or older was the largest high-risk subset (87.1%). Overall, only 27.2% of high-risk veterans (n = 82,766) were prescribed an adherent strategy. Among veterans with at least 2 risk factors, adherence was 39.7%; among those with 3 risk factors, adherence was 41.8%. Predictors of adherence included history of upper gastrointestinal events, anticoagulant use, rheumatologic disease, high Deyo comorbidity index score, use of low-dose salicylates, and concurrent corticosteroid use. Predictors of nonadherence included prescriptions ≥90 days and high average daily dose of NSAIDs. Conclusions: Adherence to evidence-based guidelines for safe prescription of NSAIDs in the Department of Veterans Affairs is low (27.2%). The likelihood of adherence is further decreased if veterans are prescribed NSAIDs for ≥90 days.
The Risk of Missed Gastroesophageal Cancer Diagnoses in Users and Nonusers of Antisecretory Medication, 14 September 2005
Lassen A, Hallas J, Schaffalitzky de Muckadell OB
Background & Aims: Some patients with early gastroesophageal cancer may appear to “heal” because of antisecretory medication, but the risk of a missed diagnosis is unknown. The aim of the study was to estimate the incidence of gastroesophageal cancer with or without pre-endoscopic treatment with antisecretory medication. Methods: We extracted data on use of endoscopies, gastroesophageal cancer diagnoses, death, migration, and use of antisecretory medication (H2 blockers and proton pump inhibitors) from 5 population-based registries covering 19742002. We included all citizens in Funen County (population, 470,000) who between 1993 and 2002 were investigated by endoscopy for the first time. The patients were followed up until death, emigration, or the end of the study period. Results: Among 27,829 patients with a first endoscopy (mean age, 56 years; 48% male, 115,804 person-years of follow-up), 461 had gastroesophageal cancer diagnosed at the first endoscopy and 52 were diagnosed during a median follow-up of 2.7 years after the first endoscopy. The incidence during follow-up was similar to the background population (standardized incidence ratio, 1.24; 95% confidence interval, 0.811.91), increased with age, and was higher in male patients. The incidence of gastroesophageal cancer during follow-up was 46 per 100,000 person-years in users of antisecretory medication the last 180 days before the first endoscopy compared with 44 per 100,000 person-years in nonusers (age and sex standardized difference, 4 per 100,000 person-years; 95% confidence interval, ?14 to 22). Conclusions: Very few cancers are missed at endoscopy. The risk seems similar in users and nonusers of antisecretory medication before endoscopy.
Clinicalliver, pancreas, and biliary tract
Pancreatic Cancer Proteome: The Proteins That Underlie Invasion, Metastasis, and Immunologic Escape
Chen R, Yi EC, Donohoe S, Pan S, Eng J, Cooke K, Crispin DA, Lane Z, Goodlett DR, Bronner MP, Aebersold R, Brentnall TA
Background & Aims: Pancreatic cancer is a highly lethal disease that has seen little headway in diagnosis and treatment for the past few decades. The effective treatment of pancreatic cancer is critically relying on the diagnosis of the disease at an early stage, which still remains challenging. New experimental approaches, such as quantitative proteomics, have shown great potential for the study of cancer and have opened new opportunities to investigate crucial events underlying pancreatic tumorigenesis and to exploit this knowledge for early detection and better intervention. Methods: To systematically study protein expression in pancreatic cancer, we used isotope-coded affinity tag technology and tandem mass spectrometry to perform quantitative proteomic profiling of pancreatic cancer tissues and normal pancreas. Results: A total of 656 proteins were identified and quantified in 2 pancreatic cancer samples, of which 151 were differentially expressed in cancer by at least 2-fold. This study revealed numerous proteins that are newly discovered to be associated with pancreatic cancer, providing candidates for future early diagnosis biomarkers and targets for therapy. Several differentially expressed proteins were further validated by tissue microarray immunohistochemistry. Many of the differentially expressed proteins identified are involved in protein-driven interactions between the ductal epithelium and the extracellular matrix that orchestrate tumor growth, migration, angiogenesis, invasion, metastasis, and immunologic escape. Conclusions: Our study is the first application of isotope-coded affinity tag technology for proteomic analysis of human cancer tissue and has shown the value of this technology in identifying differentially expressed proteins in cancer.
A Dose-Ranging Study of the Efficacy and Tolerability of Entecavir in Lamivudine-Refractory Chronic Hepatitis B Patients, 14 September 2005
Chang T, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, Pastore G, Bacon BR, Poynard T, Joshi S, Klesczewski KS, Thiry A, Rose RE, Colonno RJ, Hindes RG
Background & Aims: Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients. Methods: Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment for ≥24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks. Results: At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P < .0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P < .01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log10 copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log10 copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group). Conclusions: In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population.
Basicalimentary tract
Inhibition of Hydrogen Sulfide Generation Contributes to Gastric Injury Caused by Anti-Inflammatory Nonsteroidal Drugs, 14 September 2005
Fiorucci S, Antonelli E, Distrutti E, Rizzo G, Mencarelli A, Orlandi S, Zanardo R, Renga B, Di Sante M, Morelli A, Cirino G, Wallace JL
Background & Aims: Hydrogen sulfide (H2S), an endogenous gaseous mediator that causes vasodilation, is generated in mammalian tissues by cystathionine ?-synthase (CBS) and cystathionine-?-lyase (CSE). Here, we have investigated the role of H2S in a rodent model of nonsteroidal anti-inflammatory drug (NSAID) gastropathy. Methods: Rats were given acetyl salycilic acid (ASA) or an NSAID alone or in combination with NaHS, an H2S donor, and killed 3 hours later. Gastric blood flow was measured by laser-Doppler flowmetry, whereas intravital microscopy was used to quantify adhesion of leukocytes to mesenteric postcapillary endothelium. Results: At a dose of 100 ?mol/kg, NaHS attenuated by 60%70% the gastric mucosal injury, and tumor necrosis factor (TNF)-?, intercellular adhesion molecule (ICAM)-1, and lymphocyte function-associated antigen (LFA)-1 mRNA up-regulation induced by NSAIDs (P < .05) NaHS administration prevented the associated reduction of gastric mucosal blood flow (P < .05) and reduced ASA-induced leukocyte adherence in mesenteric venules. NaHS did not affect suppression of prostaglandin E2 (PGE2) synthesis by NSAIDs. Glibenclamide, a KATP channel inhibitor, and DL-propargylglycine, a CSE inhibitor, exacerbated, whereas pinacidil, a KATP opener, attenuated gastric injury caused by ASA. Exposure to NSAIDs reduced H2S formation and CSE expression (mRNA and protein) and activity by 60%70%. By promoter deletion and mutation analysis, an Sp1 consensus site was identified in the CSE promoter. Exposure to NSAIDs inhibits Sp1 binding to its promoter and abrogates CSE expression in HEK-293 cells transfected with a vector containing the core CSE promoter. Exposure to NSAIDs inhibits Sp1 and ERK phosphorylation. Conclusions: These data establish a physiologic role for H2S in regulating the gastric microcirculation and identify CSE as a novel target for ASA/NSAIDs.
?-Catenin Interacts With the FUS Proto-oncogene Product and Regulates Pre-mRNA Splicing, 14 September 2005
Sato S, Idogawa M, Honda K, Fujii G, Kawashima H, Takekuma K, Hoshika A, Hirohashi S, Yamada T
Background & Aims: ?-Catenin is a downstream effector of the Wnt signaling pathway and is believed to exert its oncogenic function by activating T-cell factor (TCF)/lymphoid enhancer factor (LEF) family transcriptional factors. However, it is still uncertain whether the diverse effects of ?-catenin are caused solely by aberrant gene transactivation. In this study, we used a proteomics approach to obtain further insight into the functional properties of nuclear ?-catenin. Methods: The protein assembly of a native ?-catenin-containing complex in nuclear extracts from a colorectal cancer cell line, DLD-1, was identified using immunoprecipitation and mass spectrometry. Results: ?-Catenin physically interacted with fusion (FUS)/translocated in liposarcoma (TLS) and various RNA-binding proteins. The expression of FUS/TLS was closely associated with the accumulation of ?-catenin and with the undifferentiated status of intestinal epithelial cells. The transient transfection of FUS suppressed ?-catenin-evoked gene transactivation of TCF/LEF, and ?-catenin transfection affected the splicing pattern of the E1A minigene and induced a novel splicing variant of estrogen receptor (ER)-? exerting a dominant-negative activity. Conclusions: Human cancer expresses a large variety of alternatively spliced messenger RNA (mRNA), but the precise molecular mechanisms responsible for cancer-related alternative splicing are largely unknown. In this study, we demonstrated the interaction of ?-catenin with FUS/TLS and other RNA-binding proteins involved in the regulation of pre-mRNA splicing. Certain mRNA splicing abbreviations seen in human cancers may be induced by the activation of the Wnt signaling pathway.
CXCR4 Expression Increases Liver and Lung Metastasis in a Mouse Model of Pancreatic Cancer, 14 September 2005
Saur D, Seidler B, Schneider G, Algül H, Beck R, SenekowitschSchmidtke R, Schwaiger M, Schmid RM
Background & Aims: Expression of the Gi-protein-coupled chemokine receptor CXCR4 has recently been linked to increased proliferation, invasion, and migration of human pancreatic cancer cell lines. However, the relevance of CXCR4 for organ-specific pancreatic cancer metastasis in vivo remains unclear. Here, we have studied the role of CXCR4 in vivo using noninvasive imaging of targeted metastasis in a mouse model of pancreatic cancer. Methods: Functional expression of the chemokine receptors CXCR4 and CCR7 was achieved by stable transfection of murine TD-2 pancreatic cancer cells and analyzed by flow cytometry, calcium flux, migration, and proliferation assays. The metastatic potential of the different stable TD-2 cell clones was assessed by tail vein metastatic assays in nude mice using in vivo bioluminescent imaging. Results: Native TD-2 cells display very low abundant CXCR4 and CCR7 expression and show poor metastatic potential after tail vein injection. To study the role of CXCR4 in pancreatic cancer metastasis, we selected stable TD-2 cell clones with similar CXCR4 expression levels as human pancreatic cancer cell lines derived from metastatic lesions. CXCR4, but not CCR7, expression dramatically increased the in vivo metastatic potential of TD-2 cells, resulting in liver and lung metastasis in nude mice. Systemic administration of the selective CXCR4 inhibitor AMD 3100 effectively blocked the enhanced metastatic potential of CXCR4-expressing pancreatic cancer cells. Conclusions: These results indicate that CXCR4 expression mediates organ-specific metastasis of pancreatic cancer cells and provide preclinical evidence that blockade of the CXCL12/CXCR4 axis is a target for antimetastatic therapy.
Basicliver, pancreas, and biliary tract
Extracellular Cleavage of E-Cadherin by Leukocyte Elastase During Acute Experimental Pancreatitis in Rats
Mayerle J, Schnekenburger J, Krüger B, Kellermann J, Ruthenbürger M, Weiss F U, Nalli A, Domschke W, Lerch MM
Background & Aims: Cadherins play an important role in cell-cell contact formation at adherens junctions. During the course of acute pancreatitis, adherens junctions are known to dissociatea requirement for the interstitial accumulation of fluid and inflammatory cellsbut the underlying mechanism is unknown. Methods: Acute pancreatitis was induced in rats by supramaximal cerulein infusion. The pancreas and lungs were either homogenized for protein analysis or fixed for morphology. Protein sequencing was used to identify proteolytic cleavage sites and freshly prepared acini for ex vivo studies with recombinant proteases. Results were confirmed in vivo by treating experimental pancreatitis animals with specific protease inhibitors. Results: A 15-kilodalton smaller variant of E-cadherin was detected in the pancreas within 60 minutes of pancreatitis, was found to be the product of E-cadherin cleavage at amino acid 394 in the extracellular domain that controls cell-contact formation, and was consistent with E-cadherin cleavage by leukocyte elastase. Employing cell culture and ex vivo acini leukocyte elastase was confirmed to cleave E-cadherin at the identified position, followed by dissociation of cell contacts and the internalization of cleaved E-cadherin to the cytosol. Inhibition of leukocyte elastase in vivo prevented E-cadherin cleavage during pancreatitis and reduced leukocyte transmigration into the pancreas. Conclusions: These data provide evidence that polymorphonuclear leukocyte elastase is involved in, and required for, the dissociation of cell-cell contacts at adherens junctions, the extracellular cleavage of E-cadherin, and, ultimately, the transmigration of leukocytes into the epithelial tissue during the initial phase of experimental pancreatitis.
Case report
Stimulated Active Potassium Secretion in a Patient With Colonic Pseudo-Obstruction: A New Mechanism of Secretory Diarrhea, 14 September 2005
van Dinter Jr TG, Fuerst FC, Richardson CT, Santa Ana CA, Polter DE, Fordtran JS, Binder HJ
Background & Aims: Secretory diarrhea is caused by inhibition of intestinal active sodium absorption and stimulation of active chloride secretion. The resulting increase in fecal sodium salts causes an isotonic increase in fecal water output. Abnormalities in potassium transport are not known to be a cause of secretory diarrhea. The aim of our report is to describe a patient with secretory diarrhea that was mediated by excess intestinal secretion of potassium. Methods: A 78-year-old woman developed colonic pseudo-obstruction, complicated by severe diarrhea and hypokalemia. Her stools were collected quantitatively on 11 occasions and analyzed for electrolyte concentrations. Rectosigmoid potential difference was measured. Results: The diarrheal fluid had a very high potassium concentration (130170 mEq/L) and a very low sodium concentration (415 mEq/L). Stool potassium losses were as high as 256 mEq/day (normal, 9 mEq/day), and fecal sodium losses were never higher than 13 mEq/day. Potential difference between colonic lumen and a peripheral reference electrode was ?14 mV (lumen side negative). Conclusions: Fecal potassium salts were the exclusive driving force for severe secretory diarrhea in a patient with colonic pseudo-obstruction. The high fecal output of potassium was due to stimulation of active colonic potassium secretion, possibly because of changes in autonomic nervous system activity and distention of the colon in association with colonic pseudo-obstruction. The extremely low fecal excretion of sodium indicates that active sodium absorption was not inhibited. This case study reveals an ion transport mechanism of secretory diarrhea that has not been previously appreciated.
Microarrays and other new technologies
A Comparative Analysis by SAGE of Gene Expression Profiles of Barrett’s Esophagus, Normal Squamous Esophagus, and Gastric Cardia, 14 September 2005
van Baal JWPM, Milano F, Rygiel AM, Bergman JJGHM, Rosmolen WD, van Deventer SJH, Wang KK, Peppelenbosch MP, Krishnadath KK
Background & Aims: The metaplastic process in which the normal squamous epithelium of the distal esophagus is replaced by columnar-lined epithelium, known as Barrett’s esophagus (BE), is poorly understood. The aim of this study was to define, analyze, and compare transcription profiles of BE, normal cardia epithelium, and squamous epithelium to gain more insight into the process of metaplasia and to identify uniquely expressed genes in these epithelia. Methods: Serial analysis of gene expression was applied for obtaining transcription libraries of biopsy specimens taken from a BE-affected patient with intestinal type of metaplasia and from normal squamous and gastric cardia epithelia. Validation of results by reverse-transcription polymerase chain reaction and immunoblotting was performed using tissues of 20 patients with BE. Results: More than 120,000 tags were sequenced. Between BE and squamous 776, and between BE and gastric cardia 534 tags were significantly differentially expressed (P < .05, pairwise comparison). In contrast, squamous compared with gastric cardia epithelia showed significant differential expression of 1316 tags. The most up-regulated genes in BE compared with squamous epithelium were trefoil factors, annexin A10, and galectin-4. Each of the epithelia showed a unique cytokeratin expression profile. Conclusions: This study provides a comparison of the transcriptomes of BE, squamous epithelium, and gastric cardia epithelium. BE proves to be an incompletely differentiated type of epithelium that shows similarities to both normal squamous and gastric cardia epithelia. In addition, several uniquely expressed genes are identified. These results are a major advancement in understanding the process of metaplasia that leads to BE.
Special reports and review
Uncovered Transjugular Intrahepatic Portosystemic Shunt for Refractory Ascites: A Meta-Analysis, 14 September 2005
D’Amico G, Luca A, Morabito A, Miraglia R, D’amico M
Background & Aims: Several trials showed that uncovered transjugular intrahepatic portosystemic shunt (TIPS) is superior to paracentesis for the control of refractory ascites. However, the results for encephalopathy and mortality were not consistent across trials. We performed a systematic review of randomized controlled trials of TIPS for refractory ascites to assess the overall treatment effects and to explore potential reasons of heterogeneity. Methods: Pertinent studies were retrieved trough MEDLINE (19682004), EMBASE (19862004), the Cochrane Library (2004;4), and reference lists of key articles. Outcome measures were recurrence of ascites, encephalopathy, and mortality. Metaregression analysis was used to explore heterogeneity. Results: Five trials were identified including 330 patients. Successful TIPS placement ranged from 77% to 100% and portosystemic pressure gradient reduction ranged from 6.0 to 14.0 mm Hg. Metaregression analysis showed that bilirubin levels and successful TIPS placement rates were associated significantly with logodds ratio for death after TIPS, explained heterogeneity of trials for mortality, and suggested an outlier trial. After exclusion of the outlier trial, pooled odds ratios for recurrence of ascites with TIPS was .14 (confidence interval, .07.27), for encephalopathy was 2.26 (confidence interval, 1.353.76), and for mortality was .74 (confidence interval, .401.37), without any significant heterogeneity. Conclusions: Uncovered TIPS is significantly better than paracentesis for control of refractory ascites. Although it increases encephalopathy, it also is associated with a trend toward improvement of survival. Future TIPS trials should select patients on the basis of bilirubin levels and predictors of the risk for post-TIPS encephalopathy, and assess costs and quality of life.
Celiac Disease: Caught Between a Rock and a Hard Place, 14 September 2005
Koning F
Celiac disease (CD) is an intestinal disorder caused by an intolerance to gluten, proteins in wheat. CD is an HLA-associated disease: virtually all patients express HLA-DQ2 or HLA-DQ8. Recent work has shown that these disease-predisposing HLA-DQ molecules bind enzymatically modified gluten peptides and these HLA-DQ peptide complexes trigger inflammatory T-cell responses in the small intestine that lead to disease. In addition, gluten induces innate immune responses that contribute to the tissue damage that is characteristic for CD. Thus, CD patients are caught between a rock and a hard place: the disease is caused by a combination of adaptive and innate immune responses that both are triggered by gluten. These findings explain the disease-inducing properties of gluten and provide valuable clues for the development of alternative treatment modalities for patients. They also may be of relevance for our understanding of other multifactorial disorders including IBD and HLA-associated autoimmune diseases.
Copyright © 2001-2005 by the American Gastroenterological Association. All rights reserved.
Table of Contents for October 2005 (Vol. 43, Issue 4)
Viral Hepatitis
Outcome in a hepatitis C (genotype 1b) single source outbreak in Germanya 25-year multicenter study, 31 May 2005
Wiese M, Grüngreiff K, Güthoff W, Lafrenz M, Oesen U, Porst H, for the East German Hepatitis C Study Group
pages 590-598
Background/Aims
The natural course of the hepatitis C virus genotype 1b (HCV-1b) infection is still unclear but important for therapeutic decisions. There are few unbiased long-term follow-up studies with known dates of infection.
Methods
Between August 1978 and March 1979, 14 HCV-1b contaminated batches of anti-D immunoglobulin had been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany. We reexamined 1980 women, representing 70% of the total cohort of 15 centers.
Results
After application of the contaminated anti-D, 93% of the recipients developed an acute hepatitis C. After 25 years, 86% of the 1833 affected women still tested positive for hepatitis C virus antibodies and 46% for HCV RNA. Only nine (0.5%) had overt liver cirrhosis, 30 women (1.5%) developed precirrhotic stages and one HCC was diagnosed. Ten (0.5%) died of HCV related complications, half of these related to additional comorbidity. In the last 5 years, a continuous, but low increase of fibrotic scores was observed.
Conclusions
Young women without comorbidity may clear HCV (1b) infection in more than half of the cases, or develop mild chronic hepatitis C. We confirmed the low risk of progression to cirrhosis in this cohort within 25 years.
A follow-up study to determine the value of liver biopsy and need for antiviral therapy for hepatitis C virus carriers with persistently normal serum aminotransferase, 31 May 2005
Okanoue T, Makiyama A, Nakayama M, Sumida Y, Mitsuyoshi H, Nakajima T, Yasui K, Minami M, Itoh Y
pages 599-605
Background/Aims
Long-term follow-up study was performed to identify the candidates for antiviral therapy for hepatitis C virus (HCV) infection among carriers with persistently normal aminotransferase (ALT≤30U/L) levels (PNAL).
Methods
One hundred and twenty-nine HCV carriers with PNAL who underwent liver biopsy and had platelet count over 150,000/?l were entered and 69 were followed for over 5 years. Thirty-five patients underwent serial liver biopsies. Serum ferritin and thioredoxin levels were also determined.
Results
Seventeen patients had normal liver histology, 10 had moderate chronic hepatitis and the remainder 102 had mild hepatitis. Serum ferritin and thioredoxin levels were normal. The mean follow-up period for the 69 patients was 8.5 years. Of these 69 patients, 10 had persistently normal ALT levels (group A), 39 had transient elevation of ALT (group B), and 20 changed to symptomatic chronic hepatitis (group C). The rate of progression of fibrosis for groups A, B, and C were 0.05, 0.04, and 0.08, respectively. Hepatocellular carcinoma was not diagnosed in any of the patients.
Conclusions
Around 90% of HCV carriers with PNAL have normal to mild liver histology. This long-term follow-up study demonstrated that 30% of such carriers became candidates for antiviral therapy within 5 years.
Differential contribution of hepatitis C virus NS5A and core proteins to the induction of oxidative and nitrosative stress in human hepatocyte-derived cells, 27 June 2005
García-Mediavilla MV, Sánchez-Campos S, González-Pérez P, Gómez-Gonzalo M, Majano PL, López-Cabrera M, Clemente G, García-Monzón C, González-Gallego J
pages 606-613
Background/Aims
We aimed to explore the effects of hepatitis C virus (HCV) core and NS5A proteins on reactive oxygen (ROS) and nitrogen species (RNS) formation and on gene expression profile of iNOS in human hepatocyte-derived cells.
Methods
Production of ROS and RNS and nitrotyrosine residues accumulation were determined by flow cytometry and fluorescent microscopy as well as by Western blot, respectively, in NS5A- and core-transfected cells. Northern blot, Western blot, real-time PCR, and luciferase assays were used to assess iNOS gene expression in both transfectants.
Results
Cytokine-activated NS5A- and core-transfected cells induced ROS and RNS production but an earlier and more marked increase was observed in NS5A-expressing cells. Superoxide production was also augmented, showing a similar temporal pattern of appearance in both NS5A- and core-transfected cells. Although both NS5A and core HCV proteins were able to up-regulate iNOS gene expression, accompanied by a nitrotyrosine-containing proteins accumulation, an earlier iNOS overexpression was observed in NS5A-expressing cells, suggesting a different time course of iNOS activation pattern for core and NS5A HCV proteins.
Conclusions
Our results indicate a differential contribution of both HCV proteins to oxidative and nitrosative stress generation.
Cognitive function in hepatitis C patients with advanced fibrosis enrolled in the HALT-C trial, 31 May 2005
Fontana RJ, Bieliauskas LA, Back-Madruga C, Lindsay KL, Kronfol Z, Lok AS, Padmanabhan L, the HALT-C Trial Group
pages 614-622
Background/Aims
Prior studies have demonstrated neuropsychological abnormalities in chronic hepatitis C (CHC) patients even with mild fibrosis. The aim of this study was to determine the frequency, type, and severity of cognitive impairment in a large group of CHC patients with advanced fibrosis.
Methods
Ten validated neuropsychological tests were administered to 201 CHC patients. Standard scores for individual tests were calculated using normative population data that controlled for age, gender, and/or education. Lifetime psychiatric history, alcohol consumption, and mood status were also determined.
Results
33% of patients met criteria for cognitive impairment (i.e. standard score <40 on at least 4 tests). Mild impairment in verbal recall and working memory were noted with other domains remaining intact. Liver disease severity and lifetime psychiatric/substance abuse history did not correlate with group mean cognitive test results or the presence of cognitive impairment. In contrast, IQ and depression scores were significant and independent predictors of cognitive impairment (ROC=0.84).
Conclusions
33% of patients entering the HALT-C trial have evidence of a mild, non-focal subcortical processing deficit which was highly correlated with IQ, education, and occupation. Future studies of cognitive function in CHC patients should control for general cognitive ability.
Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C, 4 July 2005
Asahina Y, Izumi N, Enomoto N, Uchihara M, Kurosaki M, Onuki Y, Nishimura Y, Ueda K, Tsuchiya K, Nakanishi H, Kitamura T, Miyake S
pages 623-629
Background/Aims
To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy.
Methods
Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated.
Results
Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P<0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9?10?2/site/year and 1.3?10?2/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60?10?2/site/year and 0.24?10?2/site/year, P=0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n=10) than in non-responders (8.8?10?2/site/year vs. 0.38?10?2/site/year, P=0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs.
Conclusions
Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy.
Cirrhosis and its Complications
Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: Results of a pilot randomized controlled clinical trial, 31 May 2005
Conchillo M, de Knegt RJ, Payeras M, Quiroga J, Sangro B, Herrero JI, Castilla-Cortazar I, Frystyk J, Flyvbjerg A, Yoshizawa C, Jansen PLM, Scharschmidt B, Prieto J
pages 630-636
Background/Aims
Insulin-like growth factor I (IGF-I) is an anabolic hormone synthesized in the liver whose levels decrease sharply in liver cirrhosis.
Methods
We conducted a randomized double-blind placebo-controlled clinical trial to evaluate the effect of subcutaneous administration of IGF-I (20?g/kg/day with dose escalation to 50100?g/kg/day) for 4 months in patients with alcoholic or primary biliary cirrhosis (PBC) and subnormal IGF-I levels. Eight alcoholics and one PBC entered the placebo group and seven alcoholics and two PBC the treatment group. Biochemistry, body composition, muscle mass and strength, and resting energy expenditure (REE) were evaluated.
Results
Total serum IGF-I and IGF-I/IGFBP-3 ratio (a surrogate marker of IGF-I biovailability) increased in the treatment group but IGF-I values still remained below normal limits in the treated patients. No differences were observed in body composition, muscle strength or muscle mass between groups. However, IGF-I therapy increased significantly serum albumin (P=0.038) and this improvement correlated positively with variation of IGF-I/IGFBP-3 ratio. IGF-I treatment also tended to increase REE (P=0.085); this difference was significant (P=0.049) in the subgroup of alcoholic patients.
Conclusions
A short course of IGF-I increased albumin levels and tended to improve energy metabolism in liver cirrhosis. These findings warrant larger clinical trials to assess the clinical benefit of IGF-I in cirrhotic patients.
Prolonged QTc interval in mild portal hypertensive cirrhosis, 16 June 2005
Ytting H, Henriksen JH, Fuglsang S, Bendtsen F, Møller S
pages 637-644
Background/Aims
The QTc interval is prolonged in a substantial fraction of patients with cirrhosis, thus indicating delayed repolarisation. However, no information is available in mild portal hypertensive patients. We therefore determined the QTc interval in cirrhotic patients with hepatic venous pressure gradient (HVPG)<12mmHg.
Methods
Forty-four patients with cirrhosis and HVPG<12mmHg underwent a haemodynamic study. They were compared with 36 cirrhotic patients with clinically significant portal hypertension (HVPG≥12mmHg) and controls without liver disease.
Results
The fraction with prolonged QTc interval (>0.440s1/2) was similar in the two cirrhotic groups (49 vs 50%, ns) and significantly above that of the controls (5%, P<0.005). QTc was normal in patients with normal HVPG. Likewise, mean QTc was 0.449 and 0.447s1/2 in the two cirrhotic groups (ns), values which are significantly above that of the controls (0.410s1/2, P<0.01). In the mild portal hypertensive group, the QTc interval was inversely related to indicators of liver function, such as indocyanine green clearance (r=?0.34, P<0.02).
Conclusions
Delayed repolarisation of the myocardium already occurs in a substantial fraction of patients with cirrhosis with only a mild increase in portal pressure. The prolonged QTc interval may be related to liver dysfunction and to the presence of portal hypertension.
Liver Failure, Growth and Cancer
Doxorubicin coupled to lactosaminated albumin inhibits the growth of hepatocellular carcinomas induced in rats by diethylnitrosamine, 16 May 2005
Fiume L, Bolondi L, Busi C, Chieco P, Kratz F, Lanza M, Mattioli A, Di Stefano G
pages 645-652
Background/Aims
The hepatocyte receptor for asialoglycoproteins internalizes galactosyl terminating macromolecules which can be used as hepatotropic drug carriers. Since this receptor is also expressed on the cells of well differentiated human hepatocellular carcinomas (HCCs), we studied whether conjugation of doxorubicin (DOXO) with lactosaminated human albumin (L-HSA) increases the drug efficacy on HCCs induced in rats by diethylnitrosamine (DENA).
Methods
DENA was given in the drinking water for 8 weeks. One week after the last day of DENA administration, animals were randomly assigned to three groups. Each group was administered with either saline, free or coupled DOXO (1?g/g). Rats received 4 weekly intravenous injections. One week after the last administration, rats were killed and HCC development was evaluated by counting the tumor nodules on the surface of hepatic lobes.
Results
In rats treated with L-HSA coupled DOXO the number of neoplastic nodules was significantly lower (P<0.05) than that counted in animals injected with saline or with free DOXO. Coupled DOXO did not decrease body rat weight, which was markedly reduced by the free drug.
Conclusions
Conjugation with L-HSA increased the antineoplastic efficacy and decreased the systemic toxicity of DOXO administered to rats with HCCs produced by DENA.
Celecoxib, a cyclooxygenase-2 inhibitor, prevents induction of liver preneoplastic lesions in rats, 6 May 2005
Márquez-Rosado L, Trejo-Solís MC, García-Cuéllar CM, Villa-Treviño S
pages 653-660
Background/Aims
Several studies suggest that cyclooxygenase-2 (COX-2) inhibitors are chemopreventive agents against colon, breast and skin cancer. In this study, we evaluated the chemopreventive effect of celecoxib, a specific COX-2 inhibitor, on the development of liver preneoplastic lesions in rats.
Methods
Male SpragueDawley rats were fed during 5 weeks either a control or an experimental diet containing 1500ppm celecoxib on a medium-term hepatocarcinogenesis protocol. Livers were collected and evaluated by histological and biochemical assays.
Results
A reduction by 80 and 90% both in the number and size of altered hepatic foci was observed in the group treated with celecoxib during hepatocarcinogenesis treatment, respectively. No evidence of apoptosis was observed in our present study, however, the expression of the proliferation markers such as PCNA and Ki-67 was drastically reduced. Interestingly, neither COX-2 expression nor prostaglandin-E2 (PGE2) production were altered by the hepatocarcinogenic treatment or celecoxib treatment. Finally, celecoxib inhibited the translocation of Rel A/p65 to the nucleus with significant effect on stability of the repressor I?B-?.
Conclusions
This is the first demonstration that a specific COX-2 inhibitor, celecoxib, possesses striking chemopreventive activity, inhibiting preneoplastic lesions during hepatocarcinogenesis in vivo, suggesting that celecoxib effects are mediated by PGE2-independent mechanisms.
Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics, 16 May 2005
Huether A, Höpfner M, Sutter AP, Schuppan D, Scherübl H
pages 661-669
Background/Aims
Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. In light of the very poor 5-year-survival new therapeutic approaches are urgently needed. Recently, evidence has been accumulated that the epidermal growth factor receptor (EGFR) is a promising target for cancer therapy. Several reports indicate that EGFRs are expressed frequently in HCC, most likely contributing to the aggressive growth characteristics of these tumors.
Methods
Erlotinib, an inhibitor of EGFR-tyrosine kinase, potently suppresses the growth of various tumors, but its effect on HCC remains to be explored. We therefore studied the antineoplastic potency of erlotinib in human HCC cells (Huh-7 and HepG2 cell lines).
Results
We show that erlotinib inhibited HCC growth in a time- and dose-dependent manner. Moreover erlotinib treatment induced apoptosis and resulted in a dose-dependent arrest at the G1/S checkpoint of the cell cycle. Combining erlotinib with doxorubicin or docetaxel or SN-38 resulted in additive or even synergistic antiproliferative effects.
Conclusions
Our data demonstrate that in human HCC cells the inhibition of EGFR-tyrosine kinase by erlotinib induces growth inhibition, apoptosis and cell cycle arrest. Additionally, erlotinib enhances the antineoplastic activity of conventional cytostatic drugs. Thus, inhibiting EGFR-tyrosine kinase appears to be a promising treatment strategy in HCC.
Neutralization of tumor necrosis factor abrogates hepatic failure induced by ?-galactosylceramide without attenuating its antitumor effect in aged mice, 3 May 2005
Inui T, Nakashima H, Habu Y, Nakagawa R, Fukasawa M, Kinoshita M, Shinomiya N, Seki S
pages 670-678
Background/Aims
The functions of mouse liver NK1.1+ T (NKT) cells stimulated with ?-galactosylceramide (?-GalCer) are enhanced age dependently, and the antitumor and anti-metastatic effect in the liver is dependent on IFN-?. However, hepatic injury is independent of IFN-? and Fas/Fas-ligand dependent. The aim of this study is to investigate how tumor necrosis factor is involved in the ?-GalCer-mediated immune phenomena.
Methods
C57BL/6 mice were intraperitoneally treated with anti-TNF antibody 1h before ?-GalCer injection, and Fas-ligand expression of NKT cells, the serum ALT levels and histopathological findings of the liver, kidney and lung and mortality after ?-GalCer injection were evaluated. IFN-? production and antitumor immunity in the liver after the intravenous injection of EL-4 cells were also assessed.
Results
Serum TNF levels after ?-GalCer injection increased age dependently in mice. Anti-TNF Ab reduced Fas-ligand (Fas-L) expression of NKT cells while it completely inhibited organ injuries induced by ?-GalCer and thereby reduced the mortality of old mice, whereas it did not affect the IFN-? production from NKT cells, the antitumor immunity in the liver nor the mouse survival after EL-4 injection.
Conclusions
NKT cells activated by ?-galactosylceramide participated in either antitumor immunity or hepatic injury using IFN-? and TNF/Fas-L, respectively.
Induction of endoplasmic reticulum stress and apoptosis by a marine prostanoid in human hepatocellular carcinoma, 18 May 2005
Chiang PC, Chien CL, Pan SL, Chen WP, Teng CM, Shen YC, Guh JH
pages 679-686
Background/Aims
Hepatocellular carcinoma is a very common malignancy and is highly chemoresistant to currently available chemotherapeutic agents. We isolated a marine prostanoid, bromovulone III, from soft coral Clavularia viridis and found that it displayed effective anti-tumor activity in human hepatocellular carcinoma. The anti-tumor mechanism has been delineated in this study.
Methods
Anti-tumor efficacy and apoptotic cell death were examined by sulforhodamine B and Hoechst 33342 assays. Rhodamine 123 was used to measure the change of mitochondrial membrane potential. Immunoprecipitation and Western blotting detect the involvement of several apoptosis-related proteins. Electron microscopic examination detects the morphological change of mitochondria and endoplasmic reticulum (ER).
Results
Bromovulone III primarily induced mitochondria-related activation of caspase-9 and -3 in several tumor types, such as prostate cancer PC-3 and acute promyelocytic leukemia HL-60 cells. However, it primarily induced the activation of m-calpain, caspase-12, and transcription factor CHOP/GADD153 in hepatocellular carcinoma Hep3B cells, suggesting the involvement of ER stress. Furthermore, a secondary mitochondrial swelling and depolarization of mitochondrial membrane potential were subsequently triggered after ER stress, suggesting the crosstalk between ER and mitochondria.
Conclusions
It is suggested that bromovulone III induces apoptosis in Hep3B cells through a mechanism that induces ER stress and leads to activation of CHOP/GADD153 and caspase-12.
Deficient Stat3 DNA-binding is associated with high Pias3 expression and a positive anti-apoptotic balance in human end-stage alcoholic and hepatitis C cirrhosis, 31 May 2005
Stärkel P, De Saeger C, Leclercq I, Strain A, Horsmans Y
pages 687-695
Background/Aims
In vitro and animal data suggest that alcohol and hepatitis C virus (HCV) proteins might interfere with Stat3 signaling, a potential regulator of liver cell apoptosis and proliferation.
Methods
We assessed Stat3 expression, activity and the apoptotic-proliferation balance in end-stage HCV and alcoholic liver disease (ALD) in man. Explanted livers of HCV and ALD patients were compared to normal and primary biliary cirrhosis (PBC) livers.
Results
Although Stat3 expression and phosphorylation was not altered in HCV and ALD cirrhosis, Stat3 DNA-binding was not detected in all ALD and most HCV samples. Deficient Stat3 DNA-binding was associated with high Pias3 expression, but not with increased Socs3 levels. Bcl-2 was up-regulated in HCV and ALD together with decreased Caspase3 activity. Compared to base-line cell proliferation in normal donor livers, HCV cirrhosis showed a marked reduction in cyclin D1 and PCNA, whereas both markers were only slightly reduced in ALD.
Conclusions
End-stage HCV and ALD cirrhosis is characterized by impaired Stat3 DNA-binding possibly through up-regulation of Pias3. Therefore, impaired activation of Stat3 target genes might contribute to disturbed liver regeneration and repair. The attempt in cirrhotic livers to favor anti-apoptotic over pro-apoptotic pathways is not sufficient to compensate for the low cellular proliferation rates.
Molecular and Cell Biology
Induction of anti-proliferative mechanisms in hepatitis B virus producing cells, 3 May 2005
Friedrich B, Wollersheim M, Brandenburg B, Foerste R, Will H, Hildt E
pages 696-703
Background/Aims
Hepatitis B virus (HBV) preferentially replicates in quiescent cells. It was analyzed whether HBV affects cell cycle control.
Methods
The amount of EGF-receptor (EGFR) and the binding capacity for 125I-EGF was determined. Expression of mdm2 and p21 and relevance of p53 for it were analyzed by reporter gene assays and western blotting. Cyclin A/E associated cdk2 activities were determined by immunocomplex assays. Cell proliferation was quantified by measurement of BrdU incorporation.
Results
In HBV producing cells a significant reduction of EGFR expression, diminished 125I-EGF-binding capacity and insensitivity to EGF-stimulation were observed as compared to the control.
Moreover, c-Raf-1-dependent induction of mdm2-P2 and p21cip1/waf1-promoter and elevated amounts of the respective proteins were observed in HBV producing cells. Whereas activation of mdm2-P2-promoter requires p53, activation of p21cip1/waf1-promoter is mediated partially by a p53-independent process. Induction of p21cip1/waf1 is reflected by a reduction of cyclin A associated cdk2 activity and an increase of cyclin E associated cdk2 activity. In accordance with this proliferation rate of HBV-producing hepatocytes is reduced as compared to control cells.
Conclusions
These results describe novel cell-cycle inhibitory functions of HBV that correlate well with the general concept of enhanced HBV replication in quiescent cells.
Interleukin-6 plays a crucial role in the hepatic expression of SOCS3 during acute inflammatory processes in vivo, 16 May 2005
Yang XP, Schaper F, Teubner A, Lammert F, Heinrich PC, Matern S, Siewert E
pages 704-710
Background/Aims
Interleukin-6 is mandatory for liver regeneration after injury and for the hepatic expression of acute phase proteins and cytochrome P450 enzymes during inflammation. Due to its crucial contribution to the maintenance of homeostasis IL-6 signaling is tightly controlled. Suppressor of cytokine signaling (SOCS) 3 is a potent IL-6-induced feedback inhibitor terminating IL-6 signal transduction. However, several signaling pathways converge on SOCS3: SOCS3 can be induced by other mediators in vitro, and it does not exclusively inhibit IL-6 signaling. The individual contribution of each cytokine to the induction of SOCS3 in vivo is unknown.
Methods
Using IL-6-deficient mice we analyzed the role of interleukin-6 for the hepatic SOCS3 expression in response to turpentine and LPS as models of aseptic and bacterial inflammation, respectively.
Results
In wild-type animals, turpentine and LPS elicited strong induction of SOCS3. IL-6-deficient mice, by contrast, showed severely impaired SOCS3 expression in response to both stimuli: turpentine failed to induce SOCS3 mRNA; in LPS-induced inflammation, the early inductive response 60min after LPS injection was absent, and the delayed expression of SOCS3 was markedly reduced. The residual delayed SOCS3 expression in IL-6-deficient mice was abolished in IL-6/TNFR-1 knockout mice.
Conclusions
Our data strongly argue for a crucial role of IL-6 in the hepatic expression of SOCS3 during acute inflammatory processes in vivo. Although other cytokines are capable of inducing SOCS3 their contribution seems to be minor.
Pathways for the regulation of body iron homeostasis in response to experimental iron overload, 16 June 2005
Theurl I, Ludwiczek S, Eller P, Seifert M, Artner E, Brunner P, Weiss G
pages 711-719
Background/Aims
Secondary iron overload is a frequent clinical condition found in association with multiple blood transfusions.
Methods
To gain insight into adaptive changes in the expression of iron genes in duodenum, liver and spleen upon experimental iron overload we studied C57BL/6 mice receiving repetitive daily injections of iron-dextran for up to 5 days.
Results
Iron initially accumulated in spleen macrophages but with subsequent increase in macrophage ferroportin and ferritin expression its content in the spleen decreased while a progressive storage of iron occurred within hepatocytes which was paralleled by a significant increase in hepcidin and hemojuvelin expression. Under these conditions, iron was still absorbed from the duodenal lumen as divalent metal transporter-1 expressions were high, however, most of the absorbed iron was incorporated into duodenal ferritin, while ferroportin expression drastically decreased and iron transfer to the circulation was reduced.
Conclusions
Experimental iron overload results in iron accumulation in macrophages and later in hepatocytes. In parallel, the transfer of iron from the gut to the circulation is diminished which may be referred to interference of hepcidin with ferroportin mediated iron export, thus preventing body iron accumulation.
Cholestasis and Autoimmune Liver Disease
Prohepcidin localises to the Golgi compartment and secretory pathway in hepatocytes, 16 May 2005
Wallace DF, Summerville L, Lusby PE, Subramaniam V N
pages 720-728
Background/Aims
Hepcidin is a liver-expressed peptide which plays an important role in the regulation of iron metabolism. It is a negative regulator of iron absorption and release of iron from cells. The aims of this study were to analyse the expression and localisation of prohepcidin in liver and cell lines.
Methods
We generated antibodies against recombinant mouse prohepcidin and studied its expression in cell lines, primary hepatocytes and livers of normal mice and mice with abnormalities in iron metabolism.
Results
Prohepcidin localised to the secretory pathway, primarily the Golgi apparatus in liver cells and tissues. Hfe and ?2-microglobulin knockout mice have similar levels of prohepcidin protein expression as compared to wild-type mice despite increased iron stores. Sex-linked anaemia mice have iron deficiency and no prohepcidin expression in the liver.
Conclusions
Prohepcidin protein is present in the secretory pathway of liver cells. Despite iron loading, mouse models of haemochromatosis have comparatively normal levels of prohepcidin expression whereas mice with iron deficiency have no prohepcidin expression.
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