Crispin Musumba

CYP2C19*17 Gain‐of‐Function Polymorphism Is Associated With Peptic Ulcer Disease

Single‐nucleotide polymorphisms (SNPs) in the CYP2C gene cluster have been extensively investigated as predisposing factors for nonsteroidal anti‐inflammatory drug (NSAID)‐induced peptic ulcer disease (PUD) or upper gastrointestinal bleeding (UGIB). However, results have been inconclusive owing to different study designs, limited genotyping strategies, and small sample sizes. We investigated whether eight functional SNPs in the CYP2C family of genes—CYP2C8*3 (rs11572080 and rs10509681), CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17—are associated with PUD in 1,239 Caucasian patients. Logistic regression analysis showed that only CYP2C19*17 was associated with PUD (odds ratio additive model: 1.47 (95% confidence interval (CI) 1.12 to 1.92); P = 0.005; R2 16%), but not UGIB, independent of NSAID use or Helicobacter pylori infection. PUD distribution varied (P = 0.024) according to CYP2C19*17 genotype: *1/*1, 490 (64.3%); *1/*17, 304 (71.7%); and *17/*17, 31 (73.8%). CYP2C19*17, a gain‐of‐function polymorphism, is associated with PUD irrespective of etiology.

Changing Trends in Peptic Ulcer Disease: The Rise of NSAID-Induced and Fall of Helicobacter pylori-Induced Ulcers

Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori are the main causes of peptic ulcer disease (PUD). Data from the UK from 1997 to 2005 indicated that the aetiology is slowly changing as the prevalence of H pylori and use of non-aspirin NSAIDs (NANSAIDs) has been decreasing while the use of low-dose aspirin (LDA; ≤325 mg/day) has been increasing. Methods In order to investigate these changing trends, subjects who presented with endoscopically confirmed PUD at Royal Liverpool Hospital between July 2005 and June 2010 were identified from the endoscopy database and recruited either prospectively or retrospectively. Recruits were interviewed using a structured questionnaire and GPs were contacted to capture data missing from case-notes. Patients were categorised as either NSAID users (those on NSAIDs within 2 weeks) or non-users (those not on NSAIDs within 3 months of endoscopy). Upper GI bleeding (UGIB) was defined as haematemesis, melaena or anaemia (haemoglobin drop ≤2g/dl) and/or endoscopic stigmata of recent bleeding. H pylori status was determined by the rapid urease test and/or histology, or serology (IgG, ELISA) where these were negative or not done. Results Of the 389 patients enrolled, 220 (57%) were using NSAIDs and 169 (43%) were non-users. 29% of the whole cohort were taking LDA alone. 57% of the patients were 65 years or above, comprising 66% of NSAID users and 41% of non-users, with mean ages of 67 and 60 (SD 13.5 vs16) years, respectively. The mean age of those using LDA alone was 70 (SD 10.6) years. H pylori was positive in 41% of ulcers (46% DU, 33% GU). Amongst NSAID users, 51% were on LDA, 30% on NANSAIDS, 15% on both LDA and NANSAIDs and 4% on high dose aspirin. NSAID users had more GU (59% vs. 45%, p=0.006), fewer DU (31% vs 48%, p=0.001) and were less likely to be H pylori positive (34% vs. 49%, p=0.005); there was no difference in gender (% males 50 vs. 56, p=0.318) or prevalence of UGIB (22% vs 20%, p=0.697) between the two groups. Compared to NANSAID users, LDA users were more likely to be H pylori positive (43% vs. 23%, p=0.003) with a similar prevalence of UGIB (21% vs. 20%, p=0.987). 22% of patients with PUD were neither using NSAIDs nor H pylori positive. Conclusion NSAIDs, particularly LDA, were the commonest cause of PUD in this cohort, especially in those over 65 years. Our findings are compatible with the steady decline in the prevalence of H pylori -positive PUD and increase in non-NSAID non- H pylori PUD over recent years. LDA users were older and more likely to be H pylori positive compared to those using NANSAIDs; the significance of this in terms of ulcer pathogenesis needs further study.

Acute variceal bleeding in a man with coeliac disease

A 49-year-old man presented with a 1-week history of melaena, lethargy and dizziness. He had been diagnosed with coeliac disease (CD) 1 year earlier, following referral for haematology review due to splenomegaly and pancytopenia. Physical examination revealed pallor and splenomegaly. He reported strict adherence with gluten-free diet, and no weight loss. Laboratory tests showed haemoglobin concentration of 6.2 g/dl, platelet count of 63×109/l, urea 9.3 mmol/l, aspartate transaminase 49 μ/l, alanine transaminase 38 μ/l, normal alkaline phosphatase, albumin 34 g/l, IgA anti-tissue transglutaminase antibodies 7.3 μ/ml (normal <7), and normal clotting profile. Chronic liver disease screen was negative, and thrombophilia screen showed slightly elevated IgM anticardiolipin antibodies (aCL). …

Persistent severe gastrointestinal bleeding in a man with metastatic somatostatinoma

A 50-year-old man with known metastatic pancreatic somatostatinoma was admitted with a 1-day history of haematemesis, melaena and haematochezia. Following an initial diagnosis 14 years earlier, he underwent distal pancreatectomy and splenectomy, followed by lateral hepatectomy a year later for residual hepatic disease, as well as biliary stenting for malignant obstructive jaundice. He was subsequently started on sunitinib, and his disease had remained stable before this presentation. At admission, he was haemodynamically stable, with haemoglobin concentration of 6.2 g/dl and platelet count of 126×109/l. Other blood tests were unremarkable. Oesophagogastroduodenoscopy revealed a large amount of blood in the stomach, portal hypertensive gastropathy and multiple gastric and duodenal varices, but no active bleeding from these or the biliary stent. …

Multicystic Pancreas on Endoscopic Ultrasound Imaging: Worth Thinking Outside the ‘Box’ (Pancreas)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Bilal Hameed, Uma Mahadevan, and Kay Washington, Section Editors 61 62 63 64 Multicystic Pancreas on Endoscopic Ultrasound Imaging: Worth Thinking Outside the ‘Box’ (Pancreas) 65 66 67 68 Wai See Ma, Hadi Moattar, and Crispin Musumba

A Man Presenting With Severe Postprandial Epigastric Pain, Jaundice, and Pyrexia: More Than the Usual Suspects?

Question: A 50-yearold man presented with a 2-week history of intermittent epigastric pain. His pain typically started 1–2 hours after a meal and lasted for 10 minutes, with associated nausea and vomiting. On the day of admission, the pain had become severe and continuous (lasting 2 hours), exacerbated by lying flat, with accompanying jaundice and rigors. On examination, he was icteric and pyrexial (39.2°C), with tenderness in the epigastrium and normal bowel sounds. Bloods tests revealed a hemoglobin count of 13.0 g/dL, leukocytosis (13 109/L), neutrophilia (13.0 109/L), elevated C-reactive protein (161 mg/L), alanine transaminase 424 U/L, alkaline phosphatase 230 U/L, gamma-glutamyl transpeptidase 579 U/L, bilirubin 77 mmol/L, albumin 32 g/L, glucose 7.4 mmol/L, amylase 375 U/L (normal, 150), and normal lipid profile and calcium levels. Liver ultrasonography was unremarkable. Abdominal computed tomography (CT) scan was done (Figure A). He was treated conservatively initially with intravenous morphine for pain relief and commenced on a course of intravenous antibiotics, with good clinical improvement. After improvement of his blood tests, he was discharged a week after admission, and had a magnetic resonance cholangiopancreatography (Figure B) performed as an outpatient. What do the CT and magnetic resonance cholangiopancreatography images show? What is the likely diagnosis and pathogenetic mechanisms? Look on page 468 for the answer and see the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

PWE-165 CYP2C19*17 gain of function mutation is associated with peptic ulcer disease

Introduction Studies show that single nucleotide polymorphisms (SNPs) in non-steroidal antiinflammatory drug (NSAID)-metabolising enzymes (mainly CYP2C9 and CYP2C8) may predispose NSAID-users to peptic ulcer disease (PUD) or upper gastrointestinal bleeding (UGIB), but results have been inconclusive. Methods We hypothesised that the eight closely-linked clinically important SNPs in the CYP2C family of genes, namely CYP2C8*3 (rs11572080 and rs10509681), CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 predispose to PUD via impaired NSAID metabolism as well as other potentially important mechanisms (eg, metabolism of arachidonic acid (AA) and proton-pump inhibitors-PPIs). Subjects diagnosed with PUD/UGIB at 13 hospitals in the UK between 2005 and 2011 were recruited and interviewed using a structured questionnaire, and categorised as either NSAID-users or non-users. UGIB was defined as haematemesis, melaena or anaemia, and endoscopic stigmata of recent bleeding. H pylori status was ascertained in most subjects. Following extraction of genomic DNA, genotyping was performed by KBioscience Ltd (UK). Logistic regression analysis was used to test for association between each SNP and risk of PUD/UGIB. Interaction terms were introduced to determine whether any observed genetic effects were influenced by factors including type of NSAID, PPI use and gender. Results 1246 white patients were recruited and categorised as follows: 485 (39%) PUD+/NSAID+; 357 (29%) PUD+/NSAID-; 125 (10%) PUD−/NSAID+; 280 (22%) PUD−/NSAID−. Seven SNPs were included in the final analysis (CYP2C19*3 was monomorphic and excluded). All SNPs were in Hardy-Weinberg equilibrium. Logistic regression analysis of cases (PUD+; n=842) and controls (PUD−; n=405), assuming an additive mode of inheritance at each SNP, showed that only CYP2C19*17 was significantly associated with PUD (p=0.006), with suggestion of an allele-dose effect, even on classifying cases as those using only CYP2C9/CYP2C8-substrate NSAIDs (p=0.005). Post-hoc analysis showed no interaction between CYP2C19*17 and NSAID type, PPI use or gender. Subgroup analysis per ulcer type showed CYP2C19*17 was significantly associated with gastric ulcers (p=0.02), while only rs11572080 was associated with duodenal ulcers (p=0.04). No SNPs were associated with UGIB. Conclusion Possession of CYP2C19*17 allele is associated with PUD, especially gastric ulcers, regardless of aetiology. We postulate that this could be through its effect on the metabolism of AA or other endogenous substances, leading to impairment of gastrointestinal mucosal defences. Further studies are needed to correlate the functional consequences of CYP2C19*17 in the pathogenesis of PUD. Competing interests None declared.

Acute abdomen in a woman with celiac disease.

Question: A 53-year-old woman with known celiac disease (CD) for 21 years, vitamin D deficiency, and osteoporosis was admitted with a 2-year history of weight loss, lethargy, and chronic watery diarrhea, which had become more marked in the last 6 months. She reported strict compliance with a gluten-free diet, although a detailed dietary history revealed she was inadvertently taking gluten in her diet in the form of breakfast cereal. On examination, she was malnourished (weight, 36 kg; body mass index, 13.7), with peripheral pitting edema and bilateral peripheral neuropathy to mid-shin level. Laboratory tests showed evidence of malabsorption with a microcytic anemia (hemoglobin, 9.5 g/dL; mean corpuscular volume, 75.9 fL) and reduced folate (2.1 g/L), ron (3.3 mol/L), calcium (2.0 mmol/L), albumin (17 g/L), and creatinine (28 mol/L) levels. Vitamin B12 level was elevated (she as on 3-monthly B12 injections). Vitamin E levels were not measured. Immunoglobulin A antibodies against tissue transglutamiase were not raised. Upper endoscopy 1 week before admission showed nodular duodenal mucosa and histology was consistent ith CD. Two weeks later, she developed an episode of acute severe abdominal pain with a markedly distended, tender, tympanitic bdomen, and absent bowel sounds. The rectum was empty. Computed tomography (CT) of the abdomen showed a round mass in the ight iliac fossa (Figure A). Shortly thereafter, she deteriorated with signs of peritonitis and septic shock. An urgent chest x-ray and bdominal CT showed pneumoperitoneum. An emergency laparotomy was performed which revealed a pinhole perforation in a ondilated, dusky segment of the mid ileum. The rest of the small bowel seemed normal. There was also evidence of a recent sigmoid olvulus. The perforated ileum was excised and a loop ileostomy fashioned. Histology from the ileum is shown (Figure B, C). What is the diagnosis? See the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Conflicts of interest: The authors disclose no conflicts.

Persistent Abdominal Pain and Pyrexia After Combined Radiofrequency Ablation and TACE

Question: A 53-year-old man was admitted with a week-long history of painless jaundice, pruritis, dark urine, and malaise. Examination revealed icterus, 1-cm hepatomegaly, gynecomastia, and shifting dullness. His blood tests were significant for markedly elevated liver function tests, low albumin, and prolonged prothrombin time. Abdominal computed tomography reported mild portal hypertension and ascites. The patient admitted to an approximately 2-year history of alcohol abuse. A diagnosis of acute-on-chronic liver disease secondary to alcohol dependence syndrome was made. He also reported a recent 2-month history of night blindness with difficulty reading in low light and adjusting to the dark in the evening time. Visual acuity and visual field examinations were normal bilaterally. Examination of the sclera revealed the following picture (Figure A). What is the next most appropriate blood test to explain these symptoms and signs? Look on page 2277 for the answer and see the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges nd Images in GI. Conflicts of interest: The authors disclose no conflicts.