Gastroenterology

This Month in Gastroenterology

Jan Tack, John M. Carethers — 2010-07-26

Celiac disease is a well-recognized cause of malabsorptive diarrhea, which responds to a strict, gluten-free diet. Untreated symptomatic celiac disease is associated with substantial morbidity and increased mortality. The availability of noninvasive, serologic testing has revealed a higher prevalence of asymptomatic or minimally symptomatic celiac disease than previously appreciated. The impact of undiagnosed, and therefore untreated, celiac disease on morbidity or mortality is currently uncertain.

Rapid Test for Antibodies to Hepatitis C Virus Approved by the US Food and Drug Administration

Les Lang — 2010-07-20

The US Food and Drug Administration (FDA) announced approval on June 25 of the first rapid blood test for antibodies to the hepatitis C virus (HCV) for individuals ≥15 years old. It is the only rapid, point-of-care test for the detection of antibodies to the HCV in venous whole blood specimens to gain FDA approval.

Automated Telephone Reminders Increase Colon Cancer Screenings

Les Lang — 2010-07-20

Simple, automated telephone reminders can increase colorectal cancer (CRC) screening rates by 30%, according to a Kaiser Permanente Center for Health Research study funded by the National Cancer Institute that appears in the July edition of Medical Care.

National Oceanic and Atmospheric Administration, US Food and Drug Administration Continue Ramping up Efforts to Ensure Safety of Gulf of Mexico Seafood

Les Lang — 2010-07-20

In a joint announcement June 14, 2010, the National Oceanic and Atmospheric Administration (NOAA) and the US Food and Drug Administration (FDA) said they are taking additional steps to enhance inspection measures designed to ensure that seafood from the Gulf of Mexico reaching America's tables is safe to eat.

Early Transjugular Intrahepatic Portosystemic Shunt for Acute Variceal Bleeding Lowers Treatment Failure and Mortality

Les Lang — 2010-07-20

A study published in The New England Journal of Medicine finds that early rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS) for cirrhosis patients who are hospitalized for acute variceal bleeding could significantly lower treatment failure and mortality.

Intraductal Papillary Mucinous Neoplasms of the Pancreas

Carlos Fernández–del Castillo, N. Volkan Adsay — 2010-07-20

See related article, Shirts BH et al, on page 812 in CGH.

Gastroenterology: A Year of Growth and Change

Erin C. Dubnansky, Anil K. Rustgi — 2010-07-26

The past 12 months have been an incredible period of growth and change for Gastroenterology. Perhaps most significantly, the impact factor increased for the second year in a row, up to 12.9 from its 2008 value of 12.6. This new impact factor has once again secured Gastroenterology's position as the number one journal in the category of gastroenterology and hepatology, of which there are now 65 journals. Gastroenterology not only excels in its subspecialty, but it is also recognized as a premiere biomedical journal, ranking in the top 1% of the nearly 7500 journals in biomedicine. Gastroenterology's climbing impact factor and sustained position as the leading journal in the field is a testament to our commitment to publishing only the highest quality clinical and basic science. Additionally, our content is highly topical and of immediate interest to GI investigators, as evidenced by the journal's immediacy index—the average number of times that an article published in a specific year is cited over the course of that same year. Gastroenterology's immediacy index is among the highest in the field at 2.528.

Chronic Cough and Gastroesophageal Reflux Disease: New Twists to the Riddle

Peter J. Kahrilas — 2010-07-26

See “Acoustic cough—reflux associations in chronic cough: potential triggers and mechanisms,” by Smith JA, Decalmer S, Kelsall A, et al, on page 754.

Caught in the Akt: Regulation of Wnt Signaling in the Intestine

Eric C. Anderson, Melissa H. Wong — 2010-07-26

See “Phosphoinositide 3-kinase signaling mediates β-catenin activation in intestinal epithelial stem and progenitor cells in colitis,” by Lee G, Goretsky T, Managlia E, et al, on page 869.

Epithelial-to-Mesenchymal Transition in Liver Fibrosis: Dead or Alive?

Yury Popov, Detlef Schuppan — 2010-08-05

See “Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice,” by Scholten D, Österreicher CH, Scholten A, et al, on page 987.

Durable Correction of Inherited Metabolic Liver Disorders Requires Preventing Transgene Off-Targeting From Gene Therapy Vectors: The Value of MicroRNAs

Gloria Gonzalez–Aseguinolaza, Jesus Prieto — 2010-07-23

See “Lentiviral vectors that express UGT1A1 in liver and contain miR-142 target sequences normalize hyperbilirubinemia in Gunn rats,” by Schmitt F, Remy S, Dariel A, et al, on page 999.

Cadaveric Hepatocytes Repopulate Diseased Livers: Life After Death

David C. Hay — 2010-07-26

See “Therapeutic liver reconstitution with murine cells isolated long after death,” by Erker L, Azuma H, Lee AY, et al, on page 1019.

A Man With Dyspnea and Hepatomegaly

Hsing-Feng Lee, Ching-Liang Lu, Full-Young Chang — 2010-07-26

Question: A 55-year-old man presented with progressive dyspnea on exertion for the past month. He denied any previous systemic disease. On physical examination, an engorged jugular vein without basal rales in bilateral lung and hepatomegaly was noted. Blood tests for cell count and biochemistry were normal. A chest x-ray showed extreme volume reduction in the right lung field (). Plain abdominal radiography revealed a huge mass in right upper abdomen with leftward shift of bowel gas pattern (). What is the most likely diagnosis?

Abdominal Pain in a Young Man With Severe Hypertension

Aparna Singhal, Guy E. Torstenson, Joseph A. Gagliardi — 2010-08-06

Question: A 35-year-old African-American man presented to the emergency department with a history of non radiating epigastric pain that developed abruptly after a meal 4 days prior, which had acutely worsened for the past 2 hours. The patient's pain worsened after food ingestion and straightening up and was alleviated by leaning forward. The pain was not relieved by antacids or acetaminophen. His laboratory studies showed elevated amylase at 194 U/L and slight elevation of aspartate aminotransferase at 56 U/L and slight leukocytosis at 11 100 μ/L, with normal lipase levels. The patient's past medical history was significant for essential hypertension; however, the patient was not on medications for 6 months. After his emergency department evaluation, the patient was diagnosed as having gastritis with uncontrolled hypertension and was discharged home on antihypertensives and antihistaminics. However, he did not take his prescribed medications owing to fear of worsening of pain.

A Man With Loose Stool and Periumbilical Pain

Hsing-Feng Lee, Ching-Liang Lu, Full-Young Chang — 2010-07-26

Question: A 36-year-old man presented with loose stool passage and periumbilical pain off and on for 3 months. On examination, well-demarcated purpuric papules and plaques were noted on his extremities. Blood tests for cell count and biochemistry were normal. Occult blood without pus cells was noted in stool. Colonoscopy revealed multiple hemorrhagic, raised, plaque-like erythematous lesions diffusely scattered along the entire colon (). What is the most likely diagnosis?

A Rare Cause of Upper Gastrointestinal Bleeding

Wei-Yi Lei, Chien-Lin Chen, Andy Shau-Bin Chou — 2010-08-06

Question: An 84-year-old man with a past medical history of prostate cancer and duodenal ulcer presented with right upper quadrant pain, hematochezia, and postural hypotension. Physical examination disclosed pale conjunctiva, abdominal distension, and right upper quadrant tenderness. Laboratory tests were unremarkable except for anemia (hemoglobin, 9.6 mg/dL). He underwent an upper gastrointestinal endoscopy, which demonstrated an ulcer at the first part of the duodenum with a protruding mass in the base but no active bleeding (). In the next 2 days, intermittent episodes of tarry stools continued. He also had the development of hypotension which responded to fluid resuscitation. His hemoglobin fell to 6.2 mg/dL. On repeat endoscopy, active bleeding from the same lesion was found. Hemostasis was obtained by clipping and epinephrine injection. Abdominal computed tomography was performed ().

Lower Gastrointestinal Bleeding in a Patient With a History of Breast Cancer

Josué Barahona-Garrido, Gustavo López-Arce, Sergio Criales — 2010-08-06

Question: A 43-year-old woman with history of breast cancer successfully treated with surgery and chemotherapy in 2003 was admitted because of hematochezia. The patient was well until 1 month ago, when she presented intermittent episodes of abdominal pain and vomiting. An abdominal mass in the right upper quadrant and in the pelvis was evident by palpation. Blood tests showed hemoglobin of 9 g/dL; white blood cells count and platelet count were within normal ranges.. Bilirubin and transaminases were also normal. Alkaline phosphatase was 216 IU/L; γ-glutamyltransferase, 323 IU/L; and albumin, 2.5 g/dL. Abdominal computed tomography showed centripetal-enhanced, hypodense tumors in the liver and ileum (). On colonoscopy, deformation of the ileocecal valve did not allow the evaluation of the ileum; therefore, surgery was performed. Grossly, there were a bleeding, dark-red tumor in the ileum and another 2 in the liver.

A Necrotic Liver Mass

Seth Sweetser, Lewis R. Roberts, Fabiola Medeiros — 2010-08-06

Question: A 54-year-old woman presented with a mass in the upper abdomen that had gradually increased in size over the past 3 months. Initially, she did not seek medical attention because she did not like doctors. Her past medical history was unremarkable, with no family history of liver disease, regular alcohol consumption, use of intravenous drugs, or having received a blood transfusion. She was postmenopausal. A screening colonoscopy, mammogram, and Papanicolaou smear had recently been performed and were normal. Worsening abdominal swelling and the onset of bilateral lower extremity prompted evaluation.

Colonic Opacification in a Patient With End-Stage Kidney Disease

Ulrich Hofmann, Meinrad Beer — 2010-08-06

Question: A 66-year-old woman with end-stage chronic kidney disease undergoing peritoneal dialysis for several years presented to the emergency department with diffuse abdominal pain. Physical examination revealed moderate diffuse abdominal tenderness. Routine laboratory evaluation revealed no seminal findings. Her medication consisted of aspirin, amlodipine, carvedilol, dihydralazine, lanthanum carbonate, l-thyroxine, simvastatin, erythropoietin, and torasemide. Microscopy of the peritoneal fluid excluded peritonitis. Abdomen radiography displayed gastric distention but did not reveal signs of free abdominal air (). Peculiarly, the radiograph showed radio-opaque material within the colon without former application of oral or rectal contrast agent.

Vomiting and Painful Abdomen in Dementia

Alexey Surov, Frank Mannes, Curd Behrmann — 2010-08-06

Question: A 47-year-old man with a known history of dementia was admitted to our emergency department because of nausea and vomiting. Communication with the patient was impossible owing to his mental status. According to the nursing personnel, there was no history of trauma, and the patient did not receive any drugs.

Biomarker and Drug Discovery for Gastroenterology Through Translational Bioinformatics

Joel T. Dudley, Atul J. Butte — 2010-07-20

Mandates from federal funding agencies to refocus research toward translational medicine and heightened expectations of patients have put substantial pressure on clinicians to serve active and critical roles in the translational process. Although the clinician scientist is well-poised to interpret and synthesize knowledge discoveries in genomic, molecular, and clinical sciences into improved patient outcomes, the landscape of modern data-driven molecular medicine has come to be profoundly unaccommodating to those best poised to explore it.

Role of Somatostatins in Gastroenteropancreatic Neuroendocrine Tumor Development and Therapy

Kjell E. Öberg, Jean–Claude Reubi, Dik J. Kwekkeboom, Eric P. Krenning — 2010-07-15

The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G protein–coupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs.

Acoustic Cough—Reflux Associations in Chronic Cough: Potential Triggers and Mechanisms

2010-06-21

Background & Aims: Central sensitization is thought to play a role in chronic cough and might explain the temporal association between cough and gastroesophageal reflux (GOR) in patients in whom non-GOR causes have been excluded. Using our novel simultaneous acoustic cough recording and impedance/pH monitoring technique, we aimed to explore this further by assessing such temporal associations and their relationship to the acidity, duration, and proximal extent of reflux and the presence of erosive disease and cough reflex sensitivity in unselected patients (ie, including non-GOR causes) with chronic cough.Methods: Twenty-four hour ambulatory acoustic cough monitoring with simultaneous impedance/pH recording was carried out in 71 unselected patients with chronic cough, aged 51–64 years (47 female). In addition, all patients underwent cough reflex sensitivity testing to citric acid, and 66 patients underwent gastroscopy. Temporal associations between cough and reflux were expressed using the symptom association probability.Results: Seventy percent of patients exhibited temporal associations, with 48% having a positive symptom association probability (SAPR-C) for cough preceded by reflux (mainly distal), 56% a positive symptom association probability (SAPC-R (2 min)) for reflux preceded by cough, and 32% both. Moreover, SAPR-C positive patients had a more sensitive cough reflex (P = .03) but similar esophageal reflux exposure and erosive disease, together with similar prevalence of extraesophageal causes of cough compared with SAPR-C negative patients. Reflux immediately following cough was rare.Conclusions: Cough temporally associates with reflux irrespective of proposed diagnoses, may be self-perpetuating in some patients, and is likely to be driven by central processes.

Morbidity and Mortality Among Older Individuals With Undiagnosed Celiac Disease

2010-05-31

Background & Aims: Outcomes of undiagnosed celiac disease (CD) are unclear. We evaluated the morbidity and mortality of undiagnosed CD in a population-based sample of individuals 50 years of age and older.Methods: Stored sera from a population-based sample of 16,886 Olmsted County, Minnesota, residents 50 years of age and older were tested for CD based on analysis of tissue transglutaminase and endomysial antibodies. A nested case-control study compared serologically defined subjects with CD with age- and sex-matched, seronegative controls. Medical records were reviewed for comorbid conditions.Results: We identified 129 (0.8%) subjects with undiagnosed CD in a cohort of 16,847 older adults. A total of 127 undiagnosed cases (49% men; median age, 63.0 y) and 254 matched controls were included in a systematic evaluation for more than 100 potentially coexisting conditions. Subjects with undiagnosed CD had increased rates of osteoporosis and hypothyroidism, as well as lower body mass index and levels of cholesterol and ferritin. Overall survival was not associated with CD status. During a median follow-up period of 10.3 years after serum samples were collected, 20 cases but no controls were diagnosed with CD (15.2% Kaplan–Meier estimate at 10 years).Conclusions: With the exception of reduced bone health, older adults with undiagnosed CD had limited comorbidity and no increase in mortality compared with controls. Some subjects were diagnosed with CD within a decade of serum collection, indicating that although most cases of undiagnosed CD are clinically silent, some result in symptoms. Undiagnosed CD can confer benefits and liabilities to older individuals.

Reduced Expression of FOXP3 and Regulatory T-Cell Function in Severe Forms of Early-onset Autoimmune Enteropathy

2010-06-09

Background & Aims: Little is known about the pathophysiology of early onset forms of autoimmune enteropathy (AIE). AIE has been associated with mutations in FOXP3—a transcription factor that controls regulatory T-cell development and function. We analyzed the molecular basis of neonatal or early postnatal AIE using clinical, genetic, and functional immunological studies.Methods: Gastroenterological and immunological features were analyzed in 9 boys and 2 girls with AIE that began within the first 5 months of life. FOXP3 and IL2RA were genotyped in peripheral blood monocytes. FOXP3 messenger RNA and protein expression were analyzed using reverse-transcription polymerase chain reaction, flow cytometry, and confocal immunofluorescence of CD4+ T cells. Regulatory T-cell function (CD4+CD25+) was assayed in coculture systems.Results: AIE associated with extraintestinal autoimmunity was severe and life-threatening; all patients required total parenteral nutrition. Regulatory T cells from 7 patients had altered function and FOXP3 mutations that resulted in lost or reduced FOXP3 protein expression; 2 infants had reduced regulatory T-cell activity and reduced levels of FOXP3 protein, although we did not detect mutations in FOXP3 coding region, poly-A site, or promoter region (called FOXP3-dependent AIE). Two patients had a normal number of regulatory T cells that expressed normal levels of FOXP3 protein and normal regulatory activity in in vitro coculture assays (called FOXP3-independent AIE). No mutations in IL2RA were found.Conclusions: Most cases of AIE are associated with alterations in regulatory T-cell function; some, but not all, cases have mutations that affect FOXP3 expression levels. Further studies are needed to identify mechanisms of AIE pathogenesis.

Inflammatory Bowel Disease Is a Risk Factor for Recurrent Venous Thromboembolism

2010-05-24

Background & Aims: Patients with inflammatory bowel disease (IBD) are at increased risk of a first venous thromboembolism (VTE), yet their risk of recurrent VTE is unknown. We performed a cohort study to determine the risk for recurrent VTE among patients with IBD compared with subjects without IBD.Methods: We assessed 2811 patients with IBD for a history of VTE, recruited from outpatient clinics at 14 referral centers (June 2006–December 2008). Patients with VTE before a diagnosis of IBD or those not confirmed to have VTE, cancer, or a VTE other than deep vein thrombosis or pulmonary embolism, were excluded. Recurrence rates were compared with 1255 prospectively followed patients without IBD that had a first unprovoked VTE (not triggered by trauma, surgery, or pregnancy). The primary end point was symptomatic, objectively confirmed, recurrent VTE after discontinuation of anticoagulation therapy after a first VTE.Results: Overall, of 116 IBD patients who had a history of first VTE, 86 were unprovoked. The probability of recurrence 5 years after discontinuation of anticoagulation therapy was higher among patients with IBD than patients without IBD (33.4%; 95% confidence interval [CI]: 21.8–45.0 vs 21.7%; 95% CI: 18.8–24.6; P = .01). After adjustment for potential confounders, IBD was an independent risk factor of recurrence (hazard ratio = 2.5; 95% CI: 1.4–4.2; P = .001).Conclusions: Patients with IBD are at an increased risk of recurrent VTE compared to patients without IBD.

Susceptibility Genetic Variants Associated With Colorectal Cancer Risk Correlate With Cancer Phenotype

2010-06-02

Background & Aims: Ten common low-penetrant genetic variants have been consistently associated with colorectal cancer (CRC) risk; little is known about the correlation between these variants and CRC phenotype. Characterization of such a correlation would improve CRC management and prevention programs. We assessed the association between these genetic variants and CRC phenotype in patients and modeled pairwise combinations to detect epistasis.Methods: The validation population corresponded to a prospective, multicenter, population-based cohort (EPICOLON I) of 1096 patients with newly diagnosed CRC. The replication set was an independent, prospective, multicenter Spanish cohort (EPICOLON II) of 895 patients with newly diagnosed CRC. For individual single nucleotide polymorphism (SNP) association analyses, a multivariate method using logistic regression was applied in EPICOLON I and subsequently prospectively validated in EPICOLON II. Interactions between SNPs were assessed using the likelihood ratio test.Results: Validated results confirmed that the C allele on 8q23.3 (rs16892766) was significantly associated with advanced-stage tumors (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.15–1.90; P value = 4.9 × 10−3). The G allele on 8q24.21 (rs6983267) was more common in patients with a familial history of CRC (OR, 2.02; 95% CI, 1.35–3.03; P value = 3.9 × 10−4). The combination of rs6983267 on 8q24.21 and rs9929218 on 16q22.2 was associated with a history of colorectal adenoma (carriers of GG and AA, respectively; OR, 2.28; 95% CI, 1.32–3.93; P = 5.0 × 10−4).Conclusions: CRC susceptibility variants at 8q23.3, 8q24.21, and 16q22.2 appear to be associated with cancer phenotype. These findings might be used to develop screening and surveillance strategies.

Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

2010-06-09

Background & Aims: Combination of polyamine and prostaglandin E2 (PGE2)–synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients who received polypectomies. We studied effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that modify their efficacy.Methods: We analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III chemoprevention trial of DFMO/sulindac.Results: In the group that received DFMO/sulindac, spermidine-to-spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < .001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 vs 0.15 nmol/mg protein; P < .001) but rebounded between 12 and 36 months (0.15 vs 0.36 nmol/mg protein; P = .001). PGE2 levels did not change, although aspirin use was significantly associated with lower baseline levels of PGE2. No significant associations were observed between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high PGE2 at baseline; none of these subjects, versus 39% of those given placebo, developed CRA (P < .001). Efficacy was lowest in subjects with high Spd:Spm and low PGE2 at baseline; 28% developed CRA, compared with 36% of patients given placebo (P = .563).Conclusions: A combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. No relationship was found between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention.

Preoperative Colorectal Neoplasia Increases Risk for Pouch Neoplasia in Patients With Restorative Proctocolectomy

2010-06-09

Background & Aims: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has substantially reduced the risk for ulcerative colitis (UC)–associated dysplasia or cancer (neoplasia). We characterized features, risk factors, and outcomes of pouch neoplasia in patients with inflammatory bowel disease in a historical cohort study.Methods: A total of 3203 patients with a preoperative diagnosis of inflammatory bowel disease underwent restorative proctocolectomy with IPAA from 1984 to 2009 at the Cleveland Clinic. Demographic, clinical, and endoscopic data were reviewed and samples were examined by histological analyses. Univariable and Cox regression analyses were performed.Results: Cumulative incidences for pouch neoplasia at 5, 10, 15, 20, and 25 years were 0.9%, 1.3%, 1.9%, 4.2%, and 5.1%, respectively. Thirty-eight patients (1.19%) had pouch neoplasia, including 11 (0.36%) with adenocarcinoma of the pouch and/or the anal-transitional zone (ATZ), 1 (0.03%) with pouch lymphoma, 3 with squamous cell cancer of the ATZ, and 23 with dysplasia (0.72%). In the Cox model, the risk factor associated with pouch neoplasia was a preoperative diagnosis of UC-associated cancer or dysplasia, with adjusted hazard ratios of 13.43 (95% confidence interval: 3.96−45.53; P < .001) and 3.62 (95% confidence interval: 1.59−8.23; P = .002), respectively. Mucosectomy did not protect against pouch neoplasia.Conclusions: Risk for neoplasia in patients with UC and IPAA is small and not eliminated by colectomy or mucosectomy. A preoperative diagnosis of dysplasia or cancer of colon or rectum is a risk factor for pouch dysplasia or adenocarcinoma.

Organ Failure and Infection of Pancreatic Necrosis as Determinants of Mortality in Patients With Acute Pancreatitis

2010-06-10

Background & Aims: There is no consistency between the individual studies in the literature on whether organ failure (OF) or infected pancreatic necrosis (IPN) is the main determinant of severity in acute pancreatitis. We aimed to statistically aggregate the available data and determine the pooled influence of OF and IPN on mortality in patients with acute pancreatitis.Methods: The search for relevant observational studies was undertaken in the MEDLINE, EMBASE, and Scopus electronic databases, as well as in the proceedings of major gastroenterology meetings. The summary estimates are presented as relative risk (RR) and 95% confidence interval (CI).Results: Fourteen studies comprising 1478 patients with acute pancreatitis were meta-analyzed. A total of 600 patients developed OF and 179 of them died (mortality, 30%); 314 patients developed IPN and 102 of them died (mortality, 32%). In a stratified analysis, patients with OF and IPN had a significantly higher risk of death in comparison with patients with OF and no IPN (RR = 1.94; 95% CI: 1.32−2.85; P = .0007) and in comparison with patients with IPN and no OF (RR = 2.65; 95% CI: 1.30−5.40; P = .0007).Conclusions: In patients with acute pancreatitis, the absolute influence of OF and IPN on mortality is comparable and thus the presence of either indicates severe disease. The relative risk of mortality doubles when OF and IPN are both present and indicates extremely severe disease or critical acute pancreatitis.

An IL28B Polymorphism Determines Treatment Response of Hepatitis C Virus Genotype 2 or 3 Patients Who Do Not Achieve a Rapid Virologic Response

2010-06-04

Background & Aims: Polymorphisms in the region of the interleukin (IL)-28B gene on chromosome 19 have been associated with peginterferon-alfa–induced clearance of genotype 1 hepatitis C virus (HCV); there are no data for patients with genotype 2 or 3 HCV. We evaluated the effects of IL-28B polymorphisms on response to treatment with peginterferon and ribavirin in a well-characterized cohort of genotype 2/3 patients.Methods: DNA was analyzed from 268 patients (Caucasian: genotype 2, 213; genotype 3, 55). Patients were randomly assigned to groups that received standard duration (24 wk; n = 68) or variable durations of therapy. Patients who received variable durations (VD) and had a rapid virologic response (RVR) were treated for 12 weeks (VD12; n = 122); those without an RVR were treated for 24 weeks (VD24; n = 78). IL-28B genotypes (rs12979860) were analyzed for association with treatment response.Results: The frequencies of the IL-28B genotypes were as follows: CC, 37%; CT, 48%; and TT, 15%; 82% of patients with the CC genotype achieved a sustained virologic response (SVR), compared with 75% with the CT and 58% with the TT genotypes (P = .0046). Differences between IL-28B genotypes were greatest among patients who failed to attain RVR (VD24 SVR rates: CC, 87%; CT, 67%; and TT, 29%; P = .0002). Among patients with RVRs (61%), the IL-28B genotype was not associated with SVR (>70% for all IL-28B genotypes). In a multivariable logistic regression model, IL-28B genotype predicted SVR (odds ratio, 1.76; 95% confidence interval, 1.16–2.7).Conclusions: An IL-28B polymorphism was associated with an SVR in patients infected with genotype 2/3 HCV who did not achieve a RVR. Analysis of IL-28B genotype might be used to guide treatment for these patients.

Keratin Variants Predispose to Acute Liver Failure and Adverse Outcome: Race and Ethnic Associations

2010-06-09

Background & Aims: Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the overrepresentation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans.Methods: We analyzed the entire coding regions of KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49% acetaminophen-related) and 2 control groups (African-American [n = 245] and previously analyzed white [n = 727] subjects).Results: Forty-five ALF patients had significant amino-acid-altering K8/K18 variants, including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (P < .001). We found increased frequency of variants in white ALF patients (9.1%) versus controls (3.7%) (P = .01). K8 R341H was more common in white (P = .01) and G434S was more common in African-American (P = .02) ALF patients versus controls. White patients with K8/K18 variants were less likely to survive ALF without transplantation (P = .02). K8 A333A and G434S variants associated exclusively with African Americans (23% combined frequency in African American but none in white controls; P < .0001), while overall, K18 variants were more common in non-white liver-disease subjects compared to whites (2.8% vs 0.6%, respectively; P = .008).Conclusions: KRT8 and KRT18 are important susceptibility genes for ALF development. Presence of K8/K18 variants predisposes to adverse ALF outcome, and some variants segregate with unique ethnic and race backgrounds.

Genetic Covariance Between γ-Glutamyl Transpeptidase and Fatty Liver Risk Factors: Role of β2-Adrenergic Receptor Genetic Variation in Twins

2010-06-10

Background & Aims: Plasma levels of γ-glutamyl transpeptidase (GGT) are associated with risk factors for nonalcoholic fatty liver disease (NAFLD), such as dyslipidemia, insulin resistance (IR), and hypertension. Limited data exist on whether there is genetic covariance between plasma levels of GGT and NAFLD risk factors. Variants of β2-adrenergic receptor gene (ADRB2) have been associated with dyslipidemia, IR, and hypertension, but its effect on GGT secretion is not known. We estimated the heritability of GGT using a twin-study design and examined the genetic covariance between GGT levels, IR, hypertension, levels of low-density lipoproteins and triglycerides, and ADRB2 variants.Methods: We studied phenotypes of 362 twins; the heritabilities of increased GGT activity and genetic covariance with NAFLD risk factors were estimated by variance-component methodology. ADRB2 genotype associations with plasma GGT activity were examined using generalized estimating equations to account for intra-twinship correlations.Results: GGT activity was heritable at 49% ± 8% of the twin cohort and had significant covariance with IR; insulin, triglyceride, and uric acid levels; and diastolic blood pressure. In generalized estimating equation models, the most common haplotype of ADRB2 was significantly associated with plasma GGT activity. Five single nucleotide polymorphisms in ADRB2 were associated with levels of GGT; ADRB2 haplotypes displayed pleiotropic effects on GGT and triglyceride levels.Conclusions: In a twin study, GGT shared genetic codetermination with traits of metabolic syndrome. The ADRB2 gene had pleiotropic effects on plasma levels of GGT and triglycerides, indicating linked pathways (eg, adrenergic) between genetic susceptibility to NAFLD and metabolic syndrome.

Fatty Acid Metabolism in the Liver, Measured by Positron Emission Tomography, Is Increased in Obese Individuals

2010-05-31

Background & Aims: Hepatic lipotoxicity results from and contributes to obesity-related disorders. It is a challenge to study human metabolism of fatty acids (FAs) in the liver. We combined 11C-palmitate imaging by positron emission tomography (PET) with compartmental modeling to determine rates of hepatic FA uptake, oxidation, and storage, as well as triglyceride release in pigs and human beings.Methods: Anesthetized pigs underwent 11C-palmitate PET imaging during fasting (n = 3) or euglycemic hyperinsulinemia (n = 3). Metabolic products of FAs were measured in arterial, portal, and hepatic venous blood. The imaging methodology then was tested in 15 human subjects (8 obese subjects); plasma 11C-palmitate kinetic analyses were used to quantify systemic and visceral lipolysis.Results: In pigs, PET-derived and corresponding measured FA fluxes (FA uptake, esterification, and triglyceride FA release) did not differ and were correlated with each other. In human beings, obese subjects had increased hepatic FA oxidation compared with controls (mean ± standard error of the mean, 0.16 ± 0.01 vs 0.08 ± 0.01 μmol/min/mL; P = .0007); FA uptake and esterification rates did not differ between obese subjects and controls. Liver FA oxidation correlated with plasma insulin levels (r = 0.61, P = .016), adipose tissue (r = 0.58, P = .024), and systemic insulin resistance (r = 0.62, P = .015). Hepatic FA esterification correlated with the systemic release of FA into plasma (r = 0.71, P = .003).Conclusions: PET imaging can be used to measure FA metabolism in the liver. By using this technology, we found that obese individuals have increased hepatic oxidation of FA, in the context of adipose tissue insulin resistance, and increased FA flux from visceral fat. FA flux from visceral fat is proportional with the mass of the corresponding depot.

Glucagon-Like Peptide-2 Receptor Modulates Islet Adaptation to Metabolic Stress in the ob/ob Mouse

2010-05-24

Background & Aims: Glucagon-like peptide-2 (GLP-2) is a gut hormone that increases gut growth, reduces mucosal cell death, and augments mesenteric blood flow and nutrient absorption. Exogenous GLP-2(1-33) also stimulates glucagon secretion and enhances gut barrier function with implications for susceptibility to systemic inflammation and subsequent metabolic dysregulation. We examined the importance of GLP-2 receptor (GLP-2R) signaling for glucose homeostasis in multiple models of metabolic stress, diabetes, and obesity.Methods: Body weight, islet function, glucose tolerance, and islet histology were studied in wild-type, high-fat fed, lean diabetic, Glp2r−/− and ob/ob:Glp2r−/− mice.Results: GLP-2 did not stimulate glucagon secretion from isolated pancreatic islets in vitro, and exogenous GLP-2 had no effect on the glucagon response to insulin-induced hypoglycemia in vivo. Glp2r−/− mice exhibit no change in glycemia, and plasma glucagon levels were similar in Glp2r−/− and Glp2r+/+ mice after hypoglycemia or after oral or intraperitoneal glucose challenge. Moreover, glucose homeostasis was comparable in Glp2r−/− and Glp2r+/+ mice fed a high-fat diet for 5 months or after induction of streptozotocin-induced diabetes. In contrast, loss of the GLP-2R leads to increased glucagon secretion and α-cell mass, impaired intraperitoneal glucose tolerance and hyperglycemia, reduced β-cell mass, and decreased islet proliferation in ob/ob:Glp2r−/− mice.Conclusions: Our results show that, although the GLP-2R is not critical for the stimulation or suppression of glucagon secretion or glucose homeostasis in normal or lean diabetic mice, elimination of GLP-2R signaling in obese mice impairs the normal islet adaptive response required to maintain glucose homeostasis.

Phosphoinositide 3-Kinase Signaling Mediates β-Catenin Activation in Intestinal Epithelial Stem and Progenitor Cells in Colitis

2010-05-24

Background & Aims: Mechanisms responsible for crypt architectural distortion in chronic ulcerative colitis (CUC) are not well understood. Data indicate that serine/threonine protein kinase Akt (Akt) signaling cooperates with Wingless (Wnt) to activate β-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-β-catenin552). We investigated whether phosphoinositide 3-kinase (PI3K) is required for Akt-mediated activation of β-catenin during intestinal inflammation.Methods: The class IA subunit of PI3K was conditionally deleted from intestinal epithelial cells in mice named I-pik3r1KO. Acute inflammation was induced in mice and intestines were analyzed by biochemical and histologic methods. The effects of chemically blocking PI3K in colitic interleukin-10−/− mice were examined. Biopsy samples from patients were examined.Results: Compared with wild-type, I-pik3r1KO mice had reduced T-cell–mediated Akt and β-catenin signaling in intestinal stem and progenitor cells and limited crypt epithelial proliferation. Biochemical analyses indicated that PI3K–Akt signaling increased nuclear total β-catenin and P-β-catenin552 levels and reduced N-terminal β-catenin phosphorylation, which is associated with degradation. PI3K inhibition in interleukin-10−/− mice impaired colitis-induced epithelial Akt and β-catenin activation, reduced progenitor cell expansion, and prevented dysplasia. Human samples had increased numbers of progenitor cells with P-β-catenin552 throughout expanded crypts and increased messenger RNA expression of β-catenin target genes in CUC, colitis-associated cancer, tubular adenomas, and sporadic colorectal cancer, compared with control samples.Conclusions: PI3K–Akt signaling cooperates with Wnt to increase β-catenin signaling during inflammation. PI3K-induced and Akt-mediated β-catenin signaling are required for progenitor cell activation during the progression from CUC to CAC; these factors might be used as biomarkers of dysplastic transformation in the colon.

Imbalance of NKp44+NKp46− and NKp44−NKp46+ Natural Killer Cells in the Intestinal Mucosa of Patients With Crohn's Disease

2010-05-31

Background & Aims: Mucosal natural killer (NK) cells that produce interleukin (IL)-22 mediate intestinal homeostasis and inflammation in mice. However, their role in the pathogenesis of human inflammatory bowel diseases (IBDs) is not known. We investigated intestinal NK cells in intestinal mucosa samples of patients with Crohn's disease (CD).Methods: We isolated lamina propria NK cells from intestinal mucosal samples of patients with IBD and subjects without IBD (controls) and analyzed expression patterns of cell surface molecules and cytokine production. Interactions between lamina propria NK cells and intestinal macrophages were examined.Results: In intestinal mucosa samples from controls, NKp44 and NKp46 were expressed differentially on CD3−CD56+ NK cells, NKp44+NKp46− (NKp44+) NK cells expressed CD127 and the transcription factor retinoic acid-related orphan receptor C (RORC) and produced IL-22 whereas NKp44−NKp46+ (NKp46+) NK cells did not express CD127 or RORC and produced interferon (IFN)-γ. NKp46+ NK cells were predominant in intestinal mucosa of patients with CD compared with controls or patients with ulcerative colitis. Upon interaction with intestinal inflammatory macrophages NKp46+, NK cells from patients with CD were activated via IL-23 and produced IFN-γ; this activation required cell-to-cell contact.Conclusions: The balance of NKp44+/NKp46+ NK cells is disrupted in intestinal mucosa of patients with CD. NKp46+ NK cells might mediate the pathogenesis of CD by producing IFN-γ.

Indian Hedgehog Regulates Intestinal Stem Cell Fate Through Epithelial−Mesenchymal Interactions During Development

2010-06-14

Background & Aims: Intestinal stem cells (ISCs) are regulated by the mesenchymal environment via physical interaction and diffusible factors. We examined the role of Indian hedgehog (Ihh) in mesenchymal organization and the mechanisms by which perturbations in epithelial−mesenchymal interactions affect ISC fate.Methods: We generated mice with intestinal epithelial-specific disruption of Ihh. Gross and microscopic anatomical changes were determined using histologic, immunohistochemical, and in situ hybridization analyses. Molecular mechanisms were elucidated by expression profiling and in vitro analyses.Results: Deletion of intestinal epithelial Ihh disrupted the intestinal mesenchymal architecture, demonstrated by loss of the muscularis mucosae, deterioration of the extracellular matrix, and reductions in numbers of crypt myofibroblasts. Concurrently, the epithelial compartment had increased Wnt signaling, disturbed crypt polarity and architecture, defective enterocyte differentiation, and increased and ectopic proliferation that was accompanied by increased numbers of ISCs. Mechanistic studies revealed that Hh inhibition deregulates bone morphogenetic protein signaling, increases matrix metalloproteinase levels, and disrupts extracellular matrix proteins, fostering a proliferative environment for ISCs and progenitor cells.Conclusions: Ihh regulates ISC self-renewal and differentiation. Intestinal epithelial Ihh signals to the mesenchymal compartment to regulate formation and proliferation of mesenchymal cells, which in turn affect epithelial proliferation and differentiation. These findings provide a basis for analyses of the role of the muscularis mucosae in ISC regulation.

Nucleotide-Binding Oligomerization Domain-2 Inhibits Toll-Like Receptor-4 Signaling in the Intestinal Epithelium

2010-05-24

Background & Aims: Factors that regulate enterocyte apoptosis in necrotizing enterocolitis (NEC) remain incompletely understood, although Toll-like receptor-4 (TLR4) signaling in enterocytes plays a major role. Nucleotide-binding oligomerization domain-2 (NOD2) is an immune receptor that regulates other branches of the immune system, although its effects on TLR4 in enterocytes and its role in NEC remain unknown. We now hypothesize that activation of NOD2 in the newborn intestine inhibits TLR4, and that failure of NOD2 signaling leads to NEC through increased TLR4-mediated enterocyte apoptosis.Methods: The effects of NOD2 on enterocyte TLR4 signaling and intestinal injury and repair were assessed in enterocytes lacking TLR4 or NOD2, in mice with intestinal-specific wild-type or dominant-negative TLR4 or NOD2, and in mice with NEC. A protein array was performed on NOD2-activated enterocytes to identify novel effector molecules involved.Results: TLR4 activation caused apoptosis in newborn but not adult small intestine or colon, and its intestinal expression was influenced by NOD2. NOD2 activation inhibited TLR4 in enterocytes, but not macrophages, and reversed the effects of TLR4 on intestinal mucosal injury and repair. Protection from TLR4-induced enterocyte apoptosis by NOD2 required a novel pathway linking NOD2 with the apoptosis mediator second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI (SMAC-DIABLO), both in vitro and in vivo. Strikingly, activation of NOD2 reduced SMAC-DIABLO expression, attenuated the extent of enterocyte apoptosis, and reduced the severity of NEC.Conclusions: These findings reveal a novel inhibitory interaction between TLR4 and NOD2 signaling in enterocytes leading to the regulation of enterocyte apoptosis and suggest a therapeutic role for NOD2 in the protection of intestinal diseases such as NEC.

Atonal Homolog 1 Is Required for Growth and Differentiation Effects of Notch/γ-Secretase Inhibitors on Normal and Cancerous Intestinal Epithelial Cells

Avedis Kazanjian, Taeko Noah, Douglas Brown, Jarred Burkart, Noah F. Shroyer — 2010-06-02

Background & Aims: The atonal homolog 1 (Atoh1) transcription factor is required for intestinal secretory (goblet, Paneth, enteroendocrine) cell differentiation. Notch/γ-secretase inhibitors (GSIs) block proliferation and induce secretory cell differentiation in the intestine. We used genetic analyses of mice to determine whether Atoh1 mediates the effects of GSIs in normal and cancerous intestinal epithelia.Methods: We studied mice with intestine-specific disruption of Atoh1 (Atoh1Δintestine), the adenomatosis polyposis coli (APC)min mutation, both mutations (Atoh1Δintestine; APCmin), or littermate controls; mice were given GSI or vehicle. Colorectal cancer (CRC) cell lines were treated with GSI or vehicle and with small hairpin RNAs to reduce ATOH1. Differentiation and homeostasis were assessed by protein, RNA, and histologic analyses.Results: GSIs failed to induce secretory cell differentiation or apoptosis or decrease proliferation of Atoh1-null progenitor cells, compared with wild-type cells. Exposure of APCmin adenomas to GSIs decreased proliferation and increased secretory cell numbers in an Atoh1-dependent manner. In CRC cells treated with GSI, ATOH1 levels were correlated inversely with proliferation. ATOH1 was required for secretory cell gene expression in cell lines and in mice.Conclusions: ATOH1 is required for all effects of GSIs in intestinal crypts and adenomas; Notch has no unique function in intestinal progenitors and cancer cells other than to regulate ATOH1 expression. Reducing ATOH1 activity might mitigate intestinal toxicity from systemic GSI therapy for nonintestinal diseases. Among gastrointestinal malignancies, ATOH1 mediates the effects of GSIs, so ATOH1 expression levels might predict responses to these inhibitors. We propose that only the subset of CRCs that retain ATOH1 expression will respond to GSIs.

F-box and WD Repeat Domain-Containing 7 Regulates Intestinal Cell Lineage Commitment and Is a Haploinsufficient Tumor Suppressor

2010-06-04

Background & Aims: The E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (Fbw7) degrades several proto-oncogenes including c-Myc, cyclinE, Notch1, and c-Jun. Fbw7 is the fourth most frequently mutated gene in human colorectal carcinomas and has recently been described as a poor prognosis marker in human colorectal carcinoma; however, the molecular mechanism underlying fbw7 mutations in intestinal tumor suppression is unclear.Methods: To address the role of fbw7 in intestinal homeostasis and tumorigenesis, we generated conditional knock-out mice lacking fbw7 in the intestine and evaluated the effect of fbw7 absence in normal intestinal homeostasis and in adenomatous polyposis coli-mediated tumorigenesis. In parallel, we analyzed a cohort of human tumors bearing mutations in fbw7.Results: Fbw7 was found to be highly expressed in the transit-amplifying progenitor cell compartment, and its deletion resulted in impaired goblet cell differentiation and accumulation of highly proliferating progenitor cells. This function of Fbw7 was mirrored during tumor formation because absence of Fbw7 increased proliferation and decreased differentiation of tumors triggered by aberrant Wnt signalling. Fbw7 exhibited haploinsufficiency for intestinal tumor suppression. Biallelic fbw7 inactivation increased cellular proliferation in physiologic and pathologic conditions in a c-Jun-dependent manner. Increased Notch activity was also observed in human tumors carrying heterozygous fbw7 mutations, suggesting that fbw7 haploinsufficiency for antagonizing Notch activity is conserved between human and murine cancers.Conclusions: Fbw7 regulates intestinal biology and tumorigenesis by controlling the abundance of different substrates in a dose-dependent fashion, providing a molecular explanation for the heterozygous mutations of fbw7 observed in human colorectal carcinoma.

Kitlow Stem Cells Cause Resistance to Kit/Platelet-Derived Growth Factor α Inhibitors in Murine Gastrointestinal Stromal Tumors

2010-06-04

Background & Aims: Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating stem cell factor receptor (Kit) or platelet-derived growth factor receptor α (Pdgfra) mutations. Kit/Pdgfra inhibitors such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kitlow ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST.Methods: Isolated KitlowCd44+Cd34+ cells were characterized after serial cloning. The tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The KitlowCd44+Cd34+ cells' responsiveness to Kit activation and blockade was studied by enumerating them in KitK641E mice (a GIST model), in mice with defective Kit signaling, and pharmacologically.Results: Single isolated KitlowCd44+Cd34+ cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The KitlowCd44+Cd34+ cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In KitK641E mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer stem, cell-targeting drug salinomycin blocked the proliferation of KitlowCd44+Cd34+ cells and increased their sensitivity to imatinib.Conclusions: KitlowCd44+Cd34+ progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is caused by the native ICC stem cells' lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.

Monoclonal Anti-Claudin 1 Antibodies Prevent Hepatitis C Virus Infection of Primary Human Hepatocytes

2010-06-02

Background & Aims: Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. The tight junction protein claudin-1 (CLDN1) has been shown to be required for entry of HCV into the cell.Methods: Using genetic immunization, we produced 6 monoclonal antibodies against the host entry factor CLDN1. The effects of antibodies on HCV infection were analyzed in human cell lines and primary human hepatocytes.Results: Competition and binding studies demonstrated that antibodies interacted with conformational epitopes of the first extracellular loop of CLDN1; binding of these antibodies required the motif W(30)-GLW(51)-C(54)-C(64) and residues in the N-terminal third of CLDN1. The monoclonal antibodies against CLDN1 efficiently inhibited infection by HCV of all major genotypes as well as highly variable HCV quasispecies isolated from individual patients. Furthermore, antibodies efficiently blocked cell entry of highly infectious escape variants of HCV that were resistant to neutralizing antibodies.Conclusions: Monoclonal antibodies against the HCV entry factor CLDN1 might be used to prevent HCV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.

Meta-Analysis of Hepatitis C Virus Vaccine Efficacy in Chimpanzees Indicates an Importance for Structural Proteins

Harel Dahari, Stephen M. Feinstone, Marian E. Major — 2010-06-04

Background & Aims: Studies in patients and chimpanzees that spontaneously cleared hepatitis C virus (HCV) infections demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism about prophylactic HCV vaccines, and several studies were performed in chimpanzees, although most included fewer than 6 animals. To draw meaningful conclusions about the efficacy of HCV vaccines in chimpanzees, we performed statistical analyses of data from previously published studies from different groups.Methods: We performed a meta-analysis that compared parameters among naïve (n = 63), vaccinated (n = 53), and rechallenged (n = 36) animals, including peak RNA titer postchallenge, time points of peak RNA titer, duration of viremia, and proportion of persistent infections.Results: Each vaccination study induced immune responses that were effective in rapidly controlling HCV replication. Levels of induced T-cell responses did not indicate vaccine success. There was no reduction in the rate of HCV persistence in vaccinated animals, compared with naïve animals, when nonstructural proteins were included in the vaccine. Vaccines that contained only structural proteins had clearance rates that were significantly higher than vaccines that contained nonstructural components (P = .015).Conclusions: The inclusion of nonstructural proteins in HCV vaccines might be detrimental to protective immune responses, and/or structural proteins might activate T-cell responses that mediate viral clearance.

Effects and Regulation of Autoreactive CD8+ T Cells in a Transgenic Mouse Model of Autoimmune Hepatitis

Mario Zierden, Elisabeth Kühnen, Margarete Odenthal, Hans-Peter Dienes — 2010-06-02

Background & Aims: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown etiology. Autoreactive T cells are thought to mediate liver injury, but the pathogenesis of AIH is poorly understood because of the lack of suitable animal models. We established a mouse model to investigate liver-specific T-cell responses and assess the effects and regulation of autoreactive CD8+ T cells in the pathogenesis of AIH.Methods: We generated transgenic mice expressing the influenza virus hemagglutinin (HA) autoantigen under control of mouse albumin regulatory elements and α-fetoprotein enhancers (Alb) specifically in the liver (Alb-HA mice); they were crossed with mice that express a specific T-cell receptor (TCR) (CL4-TCR). CL4-TCR transgenic CD8+ T cells were also adoptively transferred into Alb-HA mice. We investigated immunologic mechanisms of CD8+ T cell-induced liver damage and of counteracting peripheral tolerance.Results: The double-transgenic mice (Alb-HA/CL4-TCR) spontaneously developed chronic, autoimmune-mediated hepatitis, characterized by necroinflammatory lesions, hepatic fibrosis, and increased levels of aminotransferase; these features resembled those of AIH. Interestingly, most liver-infiltrating, HA-specific CD8+ T cells had an anergic phenotype; regulatory CD4+CD25+Foxp3+ T cells accumulated in the inflamed liver.Conclusions: The continuous development of a few, HA-specific CD8+ effector T cells is sufficient to induce chronic hepatitis. Peripheral tolerance mechanisms such as induction of T-cell anergy and accumulation of regulatory CD4+CD25+Foxp3+ T cells protect the liver from severe damage. Our mouse model that spontaneously develops chronic autoimmune-mediated hepatitis provides a new tool to investigate autoantigen-specific T-cell responses and regulatory mechanisms involved in the prevention and pathogenesis of AIH.

Genetic Labeling Does Not Detect Epithelial-to-Mesenchymal Transition of Cholangiocytes in Liver Fibrosis in Mice

2010-05-24

Background & Aims: Chronic injury changes the fate of certain cellular populations, inducing epithelial cells to generate fibroblasts by epithelial-to-mesenchymal transition (EMT) and mesenchymal cells to generate epithelial cells by mesenchymal-to-epithelial transition (MET). Although contribution of EMT/MET to embryogenesis, renal fibrosis, and lung fibrosis is well documented, role of EMT/MET in liver fibrosis is unclear. We determined whether cytokeratin-19 positive (K19+) cholangiocytes give rise to myofibroblasts (EMT) and/or whether glial fibrillary acidic protein positive (GFAP+) hepatic stellate cells (HSCs) can express epithelial markers (MET) in response to experimental liver injury.Methods: EMT was studied with Cre-loxP system to map cell fate of K19+ cholangiocytes in K19YFP or fibroblast-specific protein-1 (FSP-1)YFP mice, generated by crossing tamoxifen-inducible K19CreERT mice or FSP-1Cre mice with Rosa26f/f-YFP mice. MET of GFAP+ HSCs was studied in GFAPGFP mice. Mice were subjected to bile duct ligation or CCl4-liver injury, and livers were analyzed for expression of mesodermal and epithelial markers.Results: On Cre-loxP recombination, >40% of genetically labeled K19+ cholangiocytes expressed yellow fluorescent protein (YFP). All mice developed liver fibrosis. However, specific immunostaining of K19YFP cholangiocytes showed no expression of EMT markers α-smooth muscle actin, desmin, or FSP-1. Moreover, cells genetically labeled by FSP-1YFP expression did not coexpress cholangiocyte markers K19 or E-cadherin. Genetically labeled GFAPGFP HSCs did not express epithelial or liver progenitor markers in response to liver injury.Conclusion: EMT of cholangiocytes identified by genetic labeling does not contribute to hepatic fibrosis in mice. Likewise, GFAPCre-labeled HSCs showed no coexpression of epithelial markers, providing no evidence for MET in HSCs in response to fibrogenic liver injury.

Lentiviral Vectors That Express UGT1A1 in Liver and Contain miR-142 Target Sequences Normalize Hyperbilirubinemia in Gunn Rats

2010-05-24

Background & Aims: Crigler–Najjar type 1 (CN-I) is an inherited liver disease caused by an absence of bilirubin–uridine 5′-diphosphate–glucuronosyltransferase (UGT1A1) activity. It results in life-threatening levels of unconjugated bilirubin, and therapeutic options are limited. We used adult Gunn rats (an animal model of the disease) to evaluate the efficiency of lentiviral-based gene therapy to express UGT1A1 in liver.Methods: Gunn rats were given intraportal injections of VSVG-pseudotyped lentiviral vectors that encode UGT1A1 under the control of a liver-specific transthyretin promoter (mTTR.hUGT1A1); this vector does not contain target sequences for miR-142, a microRNA that is expressed specifically in hematopoietic cells. Rats were also injected with the vector mTTR.hUGT1A1.142T, which contains 4 copies of the miR-142 target sequences; its messenger RNA should be degraded in antigen-presenting cells. Bilirubinemia was monitored, and the presence of transduced hepatocytes was analyzed by quantitative polymerase chain reaction. Vector expression was tested in vitro in rat hematopoietic cells.Results: In Gunn rats, bilirubin levels normalized 2 weeks after administration of mTTR.hUGT1A1. However, hyperbilirubinemia resumed 8 weeks after vector administration, concomitant with the induction of an immune response. In contrast, in rats injected with mTTR-UGT1A1.142T, bilirubin levels normalized for up to 6 months and transduced cells were not eliminated.Conclusions: Lentiviral vectors that express UGT1A1 reduce hyperbilirubinemia in immunocompetent Gunn rats for at least 6 months. The immune response against virally expressed UGT1A1 can be circumvented by inclusion of miR-142 target sequences, which reduce vector expression in antigen-presenting cells. This lentiviral-based gene therapy approach might be developed to treat patients with CN-I.

Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

2010-05-24

Background & Aims: Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons.Methods: Cytosolic free calcium ([Ca2+]i) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca2+]i-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device.Results: Transient increases in neuronal [Ca2+]i induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca2+]i agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P < .0001) and cholestatic patients with versus without pruritus (P < .0001). Autotaxin activity correlated with intensity of pruritus (P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or μ-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal.Conclusions: We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.

Therapeutic Liver Reconstitution With Murine Cells Isolated Long After Death

2010-06-04

Background & Aims: Due to the shortage of donor organs, many patients needing liver transplantation cannot receive one. For some liver diseases, hepatocyte transplantation could be a viable alternative, but donor cells currently are procured from the same sources as whole organs, and thus the supply is severely limited.Methods: Here, we investigated the possibility of isolating viable hepatocytes for liver cell therapy from the plentiful source of morgue cadavers. To determine the utility of this approach, cells were isolated from the livers of non–heart-beating cadaveric mice long after death and transplanted into fumarylacetoacetate hydrolase–deficient mice, a model for the human metabolic liver disease hereditary tyrosinemia type I and a stringent in vivo model for hepatic cell transplantation.Results: Surprisingly, complete and therapeutic liver repopulation could be achieved with hepatocytes derived up to 27 hours post mortem.Conclusions: Competitive repopulation experiments showed that cadaveric liver cells had a repopulation capacity similar to freshly isolated hepatocytes. Importantly, viable hepatocytes also could be isolated from cadaveric primate liver (monkey and human) efficiently. These data provide evidence that non–heart-beating donors could be a suitable source of hepatocytes for much longer time periods than previously thought possible.

CD39/ENTPD1 Expression by CD4+Foxp3+ Regulatory T Cells Promotes Hepatic Metastatic Tumor Growth in Mice

2010-05-24

Background & Aims: Adenosine mediates immune suppression and is generated by the ectonucleotidases CD39 (ENTPD1) and CD73 that are expressed on vascular endothelial cells and regulatory T cells (Tregs). Although tumor-infiltrating immune cells include Foxp3+ Tregs, it is not clear whether local adenosine generation by Tregs promotes tumor growth in a CD39-dependent manner. In this study, we have examined the effect of CD39 expression by Tregs on effector immune cell responses to hepatic metastases in vivo.Methods: A model of hepatic metastatic cancer was developed with portal vein infusion of luciferase-expressing melanoma B16/F10 cells and MCA38 colon cancer cells in wild-type (wt) and mutant mice null for Cd39. Chimeric mice were generated by bone marrow transplantation (BMT) using Cd39 null or wt C57BL6 donors and irradiated recipient mice.Results: We demonstrate that hepatic growth of melanoma metastatic tumors was strongly inhibited in mice with Cd39 null vasculature or in wt mice with circulating Cd39 null bone marrow–derived cells. We show functional CD39 expression on CD4+Foxp3+ Tregs suppressed antitumor immunity mediated by natural killer (NK) cells in vitro and in vivo. Finally, inhibition of CD39 activity by polyoxometalate-1, a pharmacologic inhibitor of nucleoside triphosphate diphosphohydrolase activity, significantly inhibited tumor growth (P < .001).Conclusions: CD39 expression on Tregs inhibits NK activity and is permissive for metastatic growth. Pharmacologic or targeted inhibition of CD39 enzymatic activity may find utility as an adjunct therapy for secondary hepatic malignancies.

CD10+ Pancreatic Stellate Cells Enhance the Progression of Pancreatic Cancer

2010-06-07

Background & Aims: Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer by producing extracellular matrix and soluble factors. However, the functional heterogeneity of PSCs has not been identified until now. Detailed characterization of the PSCs in human pancreatic cancer would provide a set of potential targets for stroma-directed therapy.Methods: We isolated PSCs from fresh pancreatic ductal adenocarcinoma tissue and sorted them by flow cytometry according to cell surface expression of CD10, which is a stromal prognostic marker for various tumors. We analyzed the functional differences between CD10+ PSCs and CD10− PSCs.Results: Immunohistochemical analysis showed that the frequency of CD10 expression by PSCs was markedly higher in tumor tissue than in normal tissue (33.7% vs 0%, respectively, P = .028). In pancreatic ductal adenocarcinoma, CD10 expression by PSCs was associated with positive nodal metastases (P = .011) and a shorter survival time (P < .001). In vitro coculture experiments showed that CD10+ PSCs promoted the invasiveness of pancreatic cancer cell lines, SUIT-2 and Panc-1 cells more intensively than CD10− PSCs. CD10+ PSCs significantly increased the tumor growth and invasiveness of SUIT-2 cells in a murine cotransplantation model. CD10+ PSCs secreted higher levels of matrix metalloproteinase 3 than CD10− PSCs, and knockdown of matrix metalloproteinase 3 in cocultured PSCs reduced the invasion of SUIT-2 and Panc-1 cells.Conclusions: CD10+ PSCs enhance the progression of pancreatic cancer cells. CD10+ PSCs may be a candidate for selective therapeutic targeting in the treatment of pancreatic cancer.

Continuing Medical Education Exam 1: Inflammatory Bowel Disease Is a Risk Factor for Recurrent Venous Thromboembolism

2010-07-23

Continuing Medical Education Exam 2: Organ Failure and Infection of Pancreatic Necrosis as Determinants of Mortality in Patients With Acute Pancreatitis

2010-07-23

Report of the AGA Institute Education and Training Committee Task Force on Physician Reentry

Arthur J. Decross, Darrell S. Pardi, Deborah D. Proctor — 2010-09-01

The Council on Medical Education of the American Medical Association (AMA) has requested a study of the issue of physician reentry into clinical practice, in collaboration with the respective specialty societies, the Accreditation Council on Graduate Medical Education (ACGME), the American Board of Medical Specialties (ABMS), and the Federation of State Medical Boards (FSMB).

Transferrin Receptor 1: A Ferritin Receptor as Well?

Daniel F. Wallace, Cameron McDonald, V. Nathan Subramaniam — 2010-08-06

Li L, Fang CJ, Ryan JC, et al. (Department of Medicine, Veterans Administration Medical Center, San Francisco, CA; others). Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci U S A 2010;107:3505–3510.

Probiotics for Ulcerative Colitis … Are The Good Bugs Back?

Shamita B. Shah — 2010-08-06

Sood A, Midha V, Makharia, GK, et al. (Department of Gastroenterology and Medicine, Dayanad Medical College and Hospital, Ludhiana, India; Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India; and Pushpawati Singhania Research Institute, Sheikh Sarai-I, New Delhi, India). The probiotic preparation, VSL#3, induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2009;7:1202–1209.

Reply

2010-07-26

We thank Dr Shah for her appreciation of our study and acceptance of our results. We agree that further, well-designed, randomized, controlled trials are needed to confirm our results. A recent study in adults (Am J Gastroenterol 2010 Jun 1 [Epub ahead of print]) and 2 studies in children (Inflamm Bowel Dis 2009;15:760–768; Am J Gastroenterol 2009;104:437–443) do, however, support our results by demonstrating efficacy of VSL#3 in inducing remission in relapsed ulcerative colitis. The patients in these 3 studies are from outside India, indicating that this probiotic should be effective in all patients with ulcerative colitis, including those from the United States.

Is Lack of “Education” a Mechanism Driving Loss of Tolerance in Crohn's Disease?

Marisol Veny, Azucena Salas, Julian Panes — 2010-08-05

Iliev ID, Spadoni I, Mileti E, et al. (Department of Experimental Oncology, European Institute of Oncology, Milan, Italy). Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells. Gut 2009;58:1481–1489.

Reply

Maria Rescigno, Iliyan D. Iliev — 2010-07-26

Doctors Veny, Salas, and Panes correctly point out that in our reports (Gut 2009;58:1481–1489; Nat Immunol 2005;6:507–514) we have isolated epithelial cells from regions that were not macroscopically involved by the disease, but we cannot rule out that they were not affected by subtle—undetectable—inflammation in the same region or by overt inflammation in adjacent regions. Hence, the reduction in transforming growth factor (TGF)-β, thymic stromal lymphopoietin (TSLP), or ALDH1A1 expression by epithelial cells isolated from tissues of Crohn's disease patients could still be secondary to inflammation.

Infliximab and Azathioprine for Crohn's Disease: A Super-Sonic Combination?

Laurent Peyrin–Biroulet, Silvio Danese — 2010-07-26

Colombel JF, Sandborn WJ, Reinisch W, et al; SONIC Study Group. (Hôpital Claude Huriez and Centre d'Investigation Clinique, Centre Hospitalier Universitaire de Lille, Université Lille Nord de France, Lille, France). Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362:1383–1395.

Robert C. Huebert, Vijay H. Shah — 2010-07-26

Liver resection surgery has become standard of care for a variety of benign and malignant liver conditions. This, along with the increased number of living-donor liver transplantation procedures being performed, requires ongoing improvement in resection techniques. Historically, these procedures were complicated and high-risk endeavors. However, over the past 3 decades, significant improvements in perioperative outcomes have been realized. This is likely owing to advancing imaging technology, better patient selection, and more informed preoperative planning. In The New Liver Anatomy, Ryu and Cho formalize the application of advanced imaging technology to individualized preoperative planning. In the process, they extend our understanding of liver anatomy with some new and innovative concepts.

Daniel Cornett, Patrick Pfau — 2010-07-26

The pancreas is the latest focus of the Curbside Consultation series. This clinically oriented series reviews 49 topics in a question-and-answer format. The book is written not only for gastroenterologists, but also for primary care physicians and trainees looking for a supplement to fine tune their management of pancreatic and biliary disease. The aim of this book is to provide concise answers to informal consultation questions frequently asked among colleagues.

Joel E. Richter — 2010-07-26

Gastroesophageal reflux disease affects 20%–30% of Western populations and is one of the most common diseases of mankind. A subset of these patients present with esophageal chest pain, which can mimic angina. Additional etiologies of this “noncardiac” chest pain may involve esophageal spasms from both circular and longitudinal muscles, inflammatory processes of the esophagus (infections, pill injury, eosinophilic esophagitis), and esophageal hypersensitivity. It is estimated that >500,000 new cases of chronic esophageal chest pain are diagnosed in the United States yearly. The quality of life of these individuals is often severely affected and considerable time and expense invested in seeking medical evaluation and treatment.

Colorectal Cancer Screening: From Perspectives to Reality

Alain Braillon — 2010-07-23

Gellad and Provenzale offered a perfect summary of the public health perspectives for colorectal cancer: Frequency, severity, effectiveness of screening with disparities, not only nationally but also worldwide. However, the 54% participation rate reported for screening in France (see Table 4) is not accurate. Official calls for screening were published as early as 1995 (the results of the two 1996 Lancet papers being available since 1994). However, screening was only implemented in 2003, in only 23 departments out of 100: The mean participation rate for the first intervention was 42%, 5 over 50% (the best was 54%) and 5 below 35%. For the second intervention, generalization to all 100 departments occurred in late 2008; Denis et al recently reported a decreased in participation rate.

Reply

Ziad F. Gellad, Dawn Provenzale — 2010-07-23

In our recently published review, we examined the public health impact of colorectal cancer. Because colorectal cancer is not uniquely an American or a Western phenomenon, we reviewed the available evidence to discuss screening and surveillance programs throughout the world. Our data regarding the compliance rate for screening in France originates from a review by West et al published in 2009. Dr Braillon has insightfully added to this discussion by providing updated figures on participation rates in France. Barriers of language and publication timing unfortunately prevented us from including the references shared by Dr Braillon in our review. We appreciate his contribution.

Information for Authors

2010-09-01

Gastroenterology publishes clinical and basic studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. The types of articles Gastroenterology publishes include original papers, review articles, and special category manuscripts. Manuscripts must be prepared in accordance with the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” developed by the International Committee of Medical Journal Editors (http://www.icmje.org). Gastroenterology is a member of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org.uk).

Cover 1

2010-09-01

Editorial Board

2010-09-01

Information for Authors and Readers

2010-09-01

Gastroenterology is the premiere journal in the field of gastrointestinal disease and is led by an internationally renowned board of editors. As the official journal of the AGA Institute, Gastroenterology delivers up-to-date and authoritative coverage of both basic and clinical gastroenterology and hepatology. Regular features include research and perspectives by leading authorities, reports on the latest technologies for diagnosing and treating digestive diseases, images illustrating important clinical findings, reviews of scholarly media, medical news, meeting summaries, video abstracts, and monthly podcasts. Gastroenterology also bridges the gap between basic and clinical science by publishing comprehensive reviews on important topics such as pancreatitis and liver disease.

Copyright Assignment, Authorship Responsibility, NIH Funding, Financial Disclosure, Institutional Review Board/Animal Care Committee Approval, and Sponsorship

2010-09-01

Copyright Assignment. In consideration of the American Gastroenterological Association (AGA) Institute (the “AGA Institute”) taking action to review and credit the below-identified submission (the “Manuscript”), and for other valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the undersigned authors and/or creators (the “Authors”), jointly and severally, hereby transfer, convey, and assign to the AGA Institute, free and clear of any liens, licenses or encumbrances, the entire right, title, and interest in and to the Manuscript throughout the world, including without limitation in and to any and all copyrights for the Manuscript (including but not limited to rights to copy, publish, excerpt, collect royalties and make derivative works) in print, electronic, Internet, broadcast, and all other forms and media now or hereafter known, and for any and all causes of action heretofore accrued in Authors' favor for infringement of the aforesaid copyrights, to have and to hold the same unto the AGA Institute, its successors and assigns, for and during the existence of the aforesaid copyrights, and all renewals and extensions thereof. At any time and from time to time hereafter, the Authors shall upon the AGA Institute's written request take any and all steps and execute, acknowledge and deliver to the AGA Institute any and all further instruments and assurances necessary or expedient in order to vest the aforesaid copyrights and causes of action more effectively in the AGA Institute. The Authors retain the nonexclusive permission to use all or part of the Manuscript in future works of their own in a noncompeting way, provided proper copyright credit is given to the AGA Institute. Should the AGA Institute finally determine that it will not publish the Manuscript, the AGA Institute agrees to assign its rights therein back to the Authors. (Note: material prepared by employees of the federal government in the course of their official duties may not be copyrightable.)

Gastroenterology

This Month in Gastroenterology

Rapid Test for Antibodies to Hepatitis C Virus Approved by the US Food and Drug Administration

Automated Telephone Reminders Increase Colon Cancer Screenings

National Oceanic and Atmospheric Administration, US Food and Drug Administration Continue Ramping up Efforts to Ensure Safety of Gulf of Mexico Seafood

Early Transjugular Intrahepatic Portosystemic Shunt for Acute Variceal Bleeding Lowers Treatment Failure and Mortality

Intraductal Papillary Mucinous Neoplasms of the Pancreas

Gastroenterology: A Year of Growth and Change

Chronic Cough and Gastroesophageal Reflux Disease: New Twists to the Riddle

Caught in the Akt: Regulation of Wnt Signaling in the Intestine

Epithelial-to-Mesenchymal Transition in Liver Fibrosis: Dead or Alive?

Durable Correction of Inherited Metabolic Liver Disorders Requires Preventing Transgene Off-Targeting From Gene Therapy Vectors: The Value of MicroRNAs

Cadaveric Hepatocytes Repopulate Diseased Livers: Life After Death

A Man With Dyspnea and Hepatomegaly

Abdominal Pain in a Young Man With Severe Hypertension

A Man With Loose Stool and Periumbilical Pain

A Rare Cause of Upper Gastrointestinal Bleeding

Lower Gastrointestinal Bleeding in a Patient With a History of Breast Cancer

A Necrotic Liver Mass

Colonic Opacification in a Patient With End-Stage Kidney Disease

Vomiting and Painful Abdomen in Dementia

Biomarker and Drug Discovery for Gastroenterology Through Translational Bioinformatics

Role of Somatostatins in Gastroenteropancreatic Neuroendocrine Tumor Development and Therapy

Acoustic Cough—Reflux Associations in Chronic Cough: Potential Triggers and Mechanisms

Morbidity and Mortality Among Older Individuals With Undiagnosed Celiac Disease

Reduced Expression of FOXP3 and Regulatory T-Cell Function in Severe Forms of Early-onset Autoimmune Enteropathy

Inflammatory Bowel Disease Is a Risk Factor for Recurrent Venous Thromboembolism

Susceptibility Genetic Variants Associated With Colorectal Cancer Risk Correlate With Cancer Phenotype

Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

Preoperative Colorectal Neoplasia Increases Risk for Pouch Neoplasia in Patients With Restorative Proctocolectomy

Organ Failure and Infection of Pancreatic Necrosis as Determinants of Mortality in Patients With Acute Pancreatitis

An IL28B Polymorphism Determines Treatment Response of Hepatitis C Virus Genotype 2 or 3 Patients Who Do Not Achieve a Rapid Virologic Response

Keratin Variants Predispose to Acute Liver Failure and Adverse Outcome: Race and Ethnic Associations

Genetic Covariance Between γ-Glutamyl Transpeptidase and Fatty Liver Risk Factors: Role of β2-Adrenergic Receptor Genetic Variation in Twins

Fatty Acid Metabolism in the Liver, Measured by Positron Emission Tomography, Is Increased in Obese Individuals

Glucagon-Like Peptide-2 Receptor Modulates Islet Adaptation to Metabolic Stress in the ob/ob Mouse

Phosphoinositide 3-Kinase Signaling Mediates β-Catenin Activation in Intestinal Epithelial Stem and Progenitor Cells in Colitis

Imbalance of NKp44+NKp46− and NKp44−NKp46+ Natural Killer Cells in the Intestinal Mucosa of Patients With Crohn's Disease

Indian Hedgehog Regulates Intestinal Stem Cell Fate Through Epithelial−Mesenchymal Interactions During Development

Nucleotide-Binding Oligomerization Domain-2 Inhibits Toll-Like Receptor-4 Signaling in the Intestinal Epithelium

Atonal Homolog 1 Is Required for Growth and Differentiation Effects of Notch/γ-Secretase Inhibitors on Normal and Cancerous Intestinal Epithelial Cells

F-box and WD Repeat Domain-Containing 7 Regulates Intestinal Cell Lineage Commitment and Is a Haploinsufficient Tumor Suppressor

Kitlow Stem Cells Cause Resistance to Kit/Platelet-Derived Growth Factor α Inhibitors in Murine Gastrointestinal Stromal Tumors

Monoclonal Anti-Claudin 1 Antibodies Prevent Hepatitis C Virus Infection of Primary Human Hepatocytes

Meta-Analysis of Hepatitis C Virus Vaccine Efficacy in Chimpanzees Indicates an Importance for Structural Proteins

Effects and Regulation of Autoreactive CD8+ T Cells in a Transgenic Mouse Model of Autoimmune Hepatitis

Genetic Labeling Does Not Detect Epithelial-to-Mesenchymal Transition of Cholangiocytes in Liver Fibrosis in Mice

Lentiviral Vectors That Express UGT1A1 in Liver and Contain miR-142 Target Sequences Normalize Hyperbilirubinemia in Gunn Rats

Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

Therapeutic Liver Reconstitution With Murine Cells Isolated Long After Death

CD39/ENTPD1 Expression by CD4+Foxp3+ Regulatory T Cells Promotes Hepatic Metastatic Tumor Growth in Mice

CD10+ Pancreatic Stellate Cells Enhance the Progression of Pancreatic Cancer

Continuing Medical Education Exam 1: Inflammatory Bowel Disease Is a Risk Factor for Recurrent Venous Thromboembolism

Continuing Medical Education Exam 2: Organ Failure and Infection of Pancreatic Necrosis as Determinants of Mortality in Patients With Acute Pancreatitis

Report of the AGA Institute Education and Training Committee Task Force on Physician Reentry

Transferrin Receptor 1: A Ferritin Receptor as Well?

Probiotics for Ulcerative Colitis … Are The Good Bugs Back?

Reply

Is Lack of “Education” a Mechanism Driving Loss of Tolerance in Crohn's Disease?

Reply

Infliximab and Azathioprine for Crohn's Disease: A Super-Sonic Combination?

Colorectal Cancer Screening: From Perspectives to Reality

Reply

Information for Authors

Cover 1

Editorial Board

Table of Contents

Information for Authors and Readers

Copyright Assignment, Authorship Responsibility, NIH Funding, Financial Disclosure, Institutional Review Board/Animal Care Committee Approval, and Sponsorship