Perforation of a peptic ulcer is the most common complication after hemorrhage. Up to 7% of peptic ulcers perforate. Penetration refers to direct extension of an ulcer into an adjace nt organ, as opposed to free intraperitoneal perforation. A perforated peptic ulcer require s surgery. With the availability of acid suppression and eradication therapy, an omental pa tch (simple closure of the defect) is the procedure of choice. Eradication of H. pylori is highly effective at preventing recurrent duode- nal ulcer perforation, and makes long-term acid suppression unneces- sary. The most important prognostic factor determining outcome is time to diagnosis and appropriate surgery. Delayed diagnosis (>24 hours) is associated with significant reduction in survival and a hi gh index of suspicion needs to be maintained, espe- cially for patients on corticosteroids or of advanced age, when clinical features of peritonitis may be masked. Any acutely ill el derly patient without a clinically identifiable explanation for their condition needs thoro ugh evaluation of the abdomen, with appropriate radiological imaging. Conversely, it is wor th noting that cocaine may be associated with duodenal ulcer perforation, which should be c onsidered when per- foration presents in young patients. Gastric outlet obstruction occurs in up to 2% of patients with PUD. It may be inflammatory, presenting acutely with oedema in the duodenal bulb obstructing the gastric outlet, which may resolve with medical therapy. More commonly it is chronic, due to recurrent ulceration with fibrosis, causing a fixed stenosis of the gastric outlet. This is an indication for pn eumatic (balloon) dilatation in conjunction with appropriate medical therapy (acid suppress ion and eradication therapy). If unsuccessful, a definitive surgical procedure is warranted . OXFORD CASE HISTORIES 196 PUD is occasionally refractory to medical therapy. A refractory ulcer is defined as an ulce r of >5mm that does not heal after appropriate PPI therapy (above). Missed H. pylori infect ion, continued NSAID ingestion and Zollinger \200\223Ellison syndrome need to be considered . Our patient had a diagnosis of visceral perforation made within 4 hours of presentation, an d was appropriate for surgery, which was suc- cessful. Eradication therapy was prescribed, but since it was thought to be associated with prednisolone for her autoimmune liver diseas e, PPIs were continued long term. Confirmation of successful eradication of H. pylori would normally be achieved by a breath test 4 weeks after ces- sation of therapy, but because of the need to continue PPI therapy, a repeat endoscopy and mucosal biopsy for histopathology was arranged 8 weeks after surgery. Further reading Behrman SW (2005). Management of complicated peptic ulcer disease. Arch Surg; 140: 201 \200\2238. Kocer B, Surmeli S, Solak C, Unal B et al. (2007). Factors affecting mortality and morbidit y in people with peptic ulcer perforation. J Gastroenterol Hepatol; 22: 565 \200\22370. Medicines Advisory Committee. Oxford Radcliffe Hospitals (2009). Adult guidelines: 1) Prescribing proton pump inhibitors, 2) Helicobacter pylori eradication. Medicines inform ation leaflet. Oxford Radcliffe Hospitals NHS Trust; 2(6). Yuan Y, Padol IT, Hunt RH (2006). Peptic ulcer disease today. Nat Clin Pract Gastroenterol Hepatol; 3: 80 \200\2239. CASE 29 197 Case 29 A 50-year-old male university science lecturer presented for follow up with his gastroenter ologist. He had previously had recurrent acute pancreatitis with four episodes over a perio d of 3 years, each with a marked increase in serum amylase. The last attack was a year ago. He denied drinking any alcohol. A cholecystectomy had been carried out after his second at tack of pancreatitis. He reported some postprandial fullness and 4kg weight loss. He had no other medical history and was on no medication. Examination was normal. Investigations showed: 9/L, platelets 145 x 109/L Hb 14.0g/dL, WCC 5.6 x 10 mol/L mol/L, AST 40 IU/L, ALT 40 IU/L, ALP 60 IU/L, Na 135mmol/L, K 4.1mmol/L, urea 3.5mmol/L, creatinine 75 Bilirubin 15 GGT 35 IU/L, albumin 40g/L Amylase normal CA 19.9 normal A CT of the abdomen carried out 2 years previously had shown a pseudocyst in the head of th e pancreas. Follow-up CT of the abdomen is illustrated (Fig. 29.1 and 29.2). An endoscopic ultrasound (Fig. 29.3) was carried out to characterize the lesion. This showe d a very large cystic dilatation of the main pancreatic duct. There were multiple papillary projections. The main pancreatic duct was grossly dilated. A \200\230fish-mouth \200\231 papilla was also seen (Fig. 29.4 in the central colored section). Questions 29a) What are the causes of recurrent acute pancreatitis? 29b) What is the differential diagnosis of the above lesion? Describe how to differentiate between these diagnoses. 29c) How would fine-needle aspiration assist in diagnosis of this lesion? 29d) How should this patient be managed? OXFORD CASE HISTORIES 198 Fig. 29.1 CT scan. Fig. 29.2 CT scan. Fig. 29.3 Endoscopic ultrasound. MPD: main pancreatic duct CASE 29 199 Fig. 29.4 (see color plate 13) Papilla at ERCP. Mucin extruding (small arrow) from the dist orted papilla (large arrow). OXFORD CASE HISTORIES 200 Answers 29a) What are the causes of recurrent acute pancreatitis? Any cause of acute pancreatitis may lead to further episodes if it is not corrected. The hi story and conventional diagnostic tests including blood tests for calcium and triglycerides , abdominal ultrasound to look for gallstones, MRCP, and CT scan of the abdomen, generally detect the cause of recurrent episodes of pancreatitis in 70% of cases. Endoscopic ultrasou nd may detect small stones in the common bile duct missed at ultrasound or MRCP. In view of the potential complications from ERCP (see Case 9), ERCP is now rarely an appropriate diag nostic investigation, although may be an appropriate therapeutic intervention. Causes of recurrent pancreatitis are shown in Table 29.1. 29b) What is the differential diagnosis of the above lesion? Describe how to differentiate between these diagnoses Based on the CT and endoscopic ultrasound findings, the main differen- tial diagnoses in th is case are: \200 Pancreatic cystic neoplasm: papillary mucinous neoplasm Mucin-producing tumors: intraductal (IPMN) and mucinous cystic neoplasm (MCN) Serous cystadenoma (SCA) Inflammatory pseudocyst, secondary to previous pancreatitis Cystic adenocarcinoma. Although inflammatory pseudocysts are more commonly associated with episodes of acute pancr eatitis, it is important to exclude non-inflammatory cystic lesions that can cause acute pa ncreatitis, because they can have a risk of malignant transformation. This lesion is most likely to be intraductal papillary mucinous neoplasm (IPMN). IPMN is a cystic neoplasm arising from the pancreatic duct, with mucin-producing epithelium. The CT s can and endoscopic ultra- sound (Figs 29.1 \200\22329.3) show that the main pancreatic duct is markedly dilated and has papillary-type projections. Solid nodules in the wall of the p ancreatic duct and the \200\230bright \200\231 sonographic features of mucin were seen. A \200\230fish-mouth \200\231 papilla, with mucin extruding from the ductal orifice, is char acteristic of intraductal papillary mucinous neoplasm (Fig. 29.4). These lesions have a hig h risk of malignant transformation and can present with acute pancreatitis that is often re current. They are commonly misdiagnosed as the far more common \200\230pseudocysts \200 \231. CASE 29 201 Table 29.1 Causes of recurrent pancreatitis Mechanical Congenital Pancreatic divisum, annular pancreas Acquired Gallstones (most frequent aetiological factor) Microlithiasis (<2mm in diameter and usually seen at endoscopic ultrasound and ERCP) Gallbl adder sludge (usually seen on ultrasound) Common bile duct macrolithiasis Sphincter of Oddi dysfunction (third most common cause of recurrent acute pancreatitis afte r gallstones and alcohol Benign and malignant tumors of the pancreatic ductal systems Stric tures of the pancreatic duct Choledochocele Toxic Alcohol (very common cause) Organophosphates Drug-induced (dose-dependent or idiosyncratic reactions) Examples \200\223 azathioprine, oestrogens, metronidazole, corticosteroids Metabolic Hypertryglyceridaemia Hypercalcaemia Familial and inherited Cystic fibrosis transmembrane regulator (CFTR) gene mutation Trypsinogen gene mutation Miscellaneous Vasculitis Viral (mumps coxsackie) or parasitic infection Tuberculosis Idiopathic (<10% of cases if investigated in detail) As for differentiating an intraductal papillary mucinous neoplasm from other pancreatic cys ts, Table 29.2 summarizes the characteristics of four common cystic lesions. A post-inflamm atory pseudocyst is by far the most common. OXFORD CASE HISTORIES 202 29c) How would fine-needle aspiration assist in the diagnosis of this lesion? Endoscopic ultrasound-guided, fine-needle aspiration yields fluid for cytology and chemical analysis. Cytology can be obtained in up to 80% of pancreatic cystic lesions (Table 29.2). Cyst fluid should be analyzed for amylase (indicating communication with the pancreatic du ct), and tumor markers such as CEA. Interpretation remains difficult and specialist advice is appropriate. A prospective study of 112 cysts reported a CEA <5ng/mL Table 29.2 Differentiating pancreatic cystic lesions Clinical Morphology Cystic fluid Cytology Malignant potential Intraductal papillary mucinous neoplasm Equal gender distribution Macrocyctic-and microcystic with dilatation of pancreatic duct Viscous, transparent, with mucin Mucinous columnar cells with atypia Yes 6 \200\2237th decade Fluid stains positive for mucin Recurrent pancreatitis or abdominal pain occasionally found Mucinous adenocarcinoma Females in 5th decade, especially from Asia, Macrocystic or septated, may have thickened walls Viscous, transparent, with mucin Unique ovarian- like stroma Yes Often coincidentally detected, but can cause pain if large Peripheral calcification, with a solid component, No communication with pancreatic duct Serous cystadenoma Females in 7th decade Microcystic or honeycomb lesion Thin, non-mucinous, haemorrhagic Monomorphic cuboidal cells with clear, PAS-positive cytoplasm No 20% are macrocystic Post-inflammatory pseudocyst History of acute pancreatitis Unilocular, thick walled Glutinous, dark and opaque Inflammatory cells, without mucin or epithelial cells No Septations are unusual CASE 29 203 consistent with a serous cystadenoma, but when >192ng/mL indicated a mucinous adenocarcinom a (sensitivity 75%, specificity 85%). No other tumor markers (including CA 19.9) are accura te enough to provide a definitive diagnosis. When morphological criteria, cytology, and CEA >192ng/mL were combined, endoscopic ultrasound could differentiate mucinous from serous le sions with 91% sensitivity and 31% specificity. The aspirate of this lesion had a high amylase resulting from commu- nication with the panc reatic duct. Cytology showed columnar cells with atypia, and a CEA of 230ng/mL. This was co nsistent with an intraductal papillary mucinous neoplasm. 29d) How should this patient be managed? Main duct mucin-producing tumors should, in general, be considered for resection. Endoscopi c ultrasound helps predict potential malignancy on the basis of cyst wall thickness, intram ural nodules, cystic dilatation of the main pancreatic duct and intracystic compartments >1 0mm. Intraductal papillary mucinous neoplasms are often multifocal, with a recurrence rate of 10% after surgery. Surveillance by ultrasound or MRCP may be appropriate and should be d iscussed with the patient. This is in contrast to mucinous cystic neoplasms, which do not r ecur after resection. Before surgery, it is important to consider: symptoms age and life expectancy degree of surgical risk location and size of lesion. Current mortality for patients undergoing pancreaticoduodenectomy is <2% in established cen ters. Specialist advice is appropriate. This patient underwent a pancreaticoduodenectomy (Whipple \200\231s pro- cedure). Histopath ology confirmed an intraductal papillary mucinous carcinoma. The common bile duct and main pancreatic duct were free of tumor at the resection margin. Further reading AGSE guideline (2005). the role of endoscopy in the diagnosis and the management of cystic lesions and inflammatory fluid collections of the pancreas. Gastrointest Endosc; 61: 363 \200\22370. Brugge WR, Lauwers GY, Sahani D, Fernandez-del Castillo C, Warshaw AL (2004). Cystic neoplasms of the pancreas. N Engl J Med; 351: 1218 \200\22326. OXFORD CASE HISTORIES 204 Brugge WR, Lewandrowski, Lee-Lewandroxski E et al. (2004). The diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst (CPC) study. Gastr oenterology; 126: 1330 \200\2236. Tanaka M, Chari S, Adsay V et al. (2006). International consensus guidelines for management of intraductal paillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology; 6: 17 \200\22332. CASE 30 205 Case 30 A 70-year-old woman was referred for assessment of loss of appetite, nausea, and weight los s of 12kg over the preceding 12 months. She had an iron-deficient, microcytic anemia. Her past medical history included pernicious anemia, common variable immune deficiency, and bronchiectasis. On examination she had crackles generally heard across her lung fields, to gether with hepatomegaly. Questions 30a) What is pernicious anemia? 30b) What other diseases are associated with pernicious anemia? 30c) Discuss the differential diagnosis and appropriate investigations 30d) Discuss the causes and features of the diagnosis. 30e) How is pernicious anemia treated? OXFORD CASE HISTORIES 206 Answers 30a) What is pernicious anemia? Pernicious anemia is the consequence of vitamin B12 deficiency resulting from autoimmune de struction of the gastric parietal cell mass and con- sequent absence of intrinsic factor. T he type of gastritis is termed chronic atrophic gastritis Type A (as opposed to type B, due to Helicobacter pylori). Type A gastritis predominantly affects the gastric corpus, causin g mucosal atrophy, achlorhydria, and secondary hypergastrinaemia. Gastrin concentrations ma y approach those seen in Zollinger \200\223Ellison syndrome (ZES) from gastrin-secreting tu mors. In contrast to ZES, hypergastrinaemia is secondary to achlorhydria, with a high antra l pH; it is therefore not associated with excessive gastric acid production or gas- troduod enal ulceration. Destruction of chief cells leads to low serum levels of pepsinogen I. Pernicious anemia is more common in people of northern European decent, and the prevalence in the UK is estimated at 120 per 100,000. It is slightly more prevalent in women, with a r atio of 1.6:1. Ninety percent of cases develop >40 years of age, with a peak at 60 years of age. Patients are generally asymptomatic before severe corpus atrophy has occurred. Once the dis ease is advanced and vitamin B12 (cobalamin) concentrations are reduced, patients often dev elop non-specific symptoms of fatigue, nausea, or weight loss. Mucosal consequences of B12 defi- ciency manifest with a sore tongue which is beefy red. A megaloblastic anemia with ma rked macrocytosis is characteristic, but neurological symptoms are the most worrying. A mye lopathy affecting the posterior columns of the spinal cord manifests as loss of propriocept ion, and a peripheral neuropathy develops. A useful clinical clue is an extensor plantar re sponse in the absence of ankle tendon reflexes. Psychiatric dis- turbances with paranoia ( \200\230megaloblastic madness \200\231) may occur, but advanced cases are now uncommon. Wit hout cobalamin replacement the course is fatal. Advanced gastric atrophy is visible at endoscopy, with loss of rugal folds and visible subm ucosal vessels. Biopsies should be taken to confirm severe atrophy of the corpus, with spar ing of the antral mucosa. Intestinal metaplasia may be present. An earlier stage of type A gastritis has been described (a so-called \200\230proliferative stage \200\231), with hype rplasic polyps sec- ondary to the hypergastrinaemia. Type A autoimmune gastritis should be suspected in people who have multiple gastric polyps in the absence of long-term therapy wi th a proton pump inhibitor. CASE 30 207 30b) What other diseases are associated with pernicious anemia? Pernicious anemia is associated with other autoimmune diseases, including adrenal insuffici ency, hypothyroidism, Grave \200\231s disease, type 1 diabetes, myasthenia gravis, vitiligo , alopaecia, and coeliac disease. This association is sometimes referred to as polyglandula r autoimmune syndrome type II. Polyglandular autoimmune syndrome type II is inher- ited in a polygenic fashion, with an onset in adulthood, and is more common in females. The autosom al recessive polyglandular autoim- mune syndrome type I has its onset in childhood and may also include pernicious anemia. Pernicious anemia is also associated with prema- ture grayi ng of hair, blue eyes, blood group A, HLA B8 and DR3, and common variable immunodeficiency (as in our patient). Pernicious anemia is a well documented risk factor for gastric adeno- carcinoma. It is poss ible that common variable immunodeficiency increases this risk. Nevertheless, there is no r ecommended protocol for endoscopic screening of these patients. It is unclear whether the r isk is related to a combination of autoimmune (type A) gastritis and Helicobacter pylori-as sociated (type B) gastritis. An increased incidence of gastric mucosal carcinoid tumors has been reported, due to hyper- gastrinaemia. Carcinoid syndrome is not associated more often than by chance. Pancreatic and oesophageal malignancies may occur more frequently. 30c) Discuss the differential diagnosis and appropriate investigations. Before considering the specific clinical circumstances in the current patient, a brief comm ent about uncomplicated pernicious anemia is appropriate. The condition is so common in old er people that treatment of B12 deficiency is generally started without further investigati on. Investigation of a low serum vitamin B12 in younger patients includes measurement of ga stric parietal cell and intrinsic factor antibodies. False-negative results are common in o lder people. Thyroid function should be checked, because of the association with autoimmune thyroid disease. Addison \200\231s disease should be considered as a potential cause of pe rsistent fatigue in a patient with pernicious anemia. Folate concentra- tions should be mea sured to exclude concomitant folate deficiency as a cause of a macrocytic anemia. Terminal ileal disease (such as Crohn \200\231s) should be considered, but rarely causes B12 deficie ncy unless a long segment (>100cm) is affected or resected. Upper gastrointestinal endos- c opy is appropriate if there is doubt about the diagnosis, to obtain biop- sies from the bod y and antrum of the stomach; it is wise to take distal OXFORD CASE HISTORIES 208 duodenal biopsies to exclude small intestinal villous atrophy at the same time. The Schilli ng test uses isotopes of cobalamin to test absorption of an oral dose with and without intr insic factor; it is now obsolete. Measurement of serum gastrin or serum pepsinogen is unnec essary. For this particular patient, nausea and loss of appetite are non-specific, but our patient had hepatomegaly, which makes malignancy more likely. Metabolic disturbance (hyponatraemia, hypercalcaemia), drugs and intracranial pathology should also be considered. The weight lo ss and iron deficiency call for urgent assessment, although achlorhydria can decrease iron absorption. Weight loss should not simply be ascribed to a loss of appetite and reduced food intake. Un derlying malignancy and gastric carcinoma in association with pernicious anemia tops the li st, with hepatomegaly from metastases. Malabsorption, from coeliac disease associated with pernicious anemia, or villous atrophy associated with common variable immunodeficiency is p ossible, but would not explain the hepatomegaly. Endomysial or tissue transglutaminase anti bodies are of no diagnostic value in immunodeficiency, owing to low IgA and IgG concentrati ons. Non-Hodgkin lymphoma associated with common variable immuno- deficiency could account for the systemic symptoms and hepatomegaly. Finally, bronchiectasis with chronic airways in fection may cause weight loss. Hepatomegaly might conceivably be due to amyloidosis of the AA type, although this usually presents with renal disease before organo- megaly is evident . An upper gastrointestinal endoscopy is the investigation of choice to identify a gastric ca rcinoma, or obtain small intestinal biopsies. This patient had a gastroscopy which revealed a large gastric tumor involv- ing the posterior wall of the stomach, extending from the up per body to the pre-pyloric antrum. Histopathology revealed a gastric adenocarci- noma. A s taging CT scan of the abdomen and pelvis was requested (Fig. 30.1) and this revealed a larg e gastric tumor with locally advanced disease extending through the wall of the stomach int o the lesser omen- tum, lymph node enlargement at the porta hepatis and coeliac axis, and m ultiple focal liver lesions suggestive of metastases. Stage T3N2M1. 30d) Discuss the causes and features of the diagnosis. Gastric adenocarcinoma has declined worldwide since the 1930s. Even so, gastric cancer rema ined the second most common cause of cancer- related death worldwide in 2002. The decline o nly applies to antral (non- cardia) gastric tumors, probably from better food preservation following CASE 30 209 Fig. 30.1 CT scan showing a large gastric tumor (large arrow) extending through the wall of the stomach into the lesser omentum, with lymph node enlargement at the porta hepatis and coeliac axis, and multiple focal liver lesions (small arrow) consistent with metastases. the advent of refrigeration, and a reduction in H. Pylori infection. H. pylori is classifie d as a class I carcinogen by the WHO. The incidence of gastric cancer remains high in the F ar East (Japan and China), thought to be due to the consumption of high volumes of raw and preserved fish with a high nitrate content. Bacteria convert nitrates to carcinogenic nitri tes. H. pylori-associated (type B) chronic gastritis may lead to gastric atrophy, intestina l metaplasia, dysplasia, and cancer. Chronic autoimmune gas- tritis (type A) may cause gast ric cancer via the same sequence of events, and the common factor appears to be the chronic inflammation. Both type A and B gastritis are associated with intestinal type tumors, as o pposed to the diffuse type responsible for linitis plastica. Gastric cancers typically present late. Tumors localized to the mucosa, which have the best chance of cure when completely resected, are usually asymptomatic, and found incidentally or in association with a screening program. These \200\230early gastric cancers \200\231 a re more commonly encoun- tered in Japan than in the UK, although it is difficult to demonst rate that this is because of ready access to endoscopy. Symptoms usually herald spread of t he tumor. Direct transmural extension involves adjacent organs. Lymphatic spread occurs rel atively early. Distant metastases most commonly involve the liver. Metastatic involvement o f the supra- clavicular nodes on the left (Virchow \200\223Trossier), a periumbilical nodul e (Sister Mary Joseph nodule), or transperitoneal spread with malignant ascites, all imply advanced disease. OXFORD CASE HISTORIES 210 As for all cancers, a histopathological diagnosis is essential and tissue is readily obtain ed through endoscopic biopsies. Gastric cancer is generally staged according to the TNM cla ssification, and may also be categorized into stages I \200\223IV. Our patient already had distant metastases (M1), which made her disease stage IV, regardless of the depth of tumor invasion into the gastric wall (T3) or lymph node involvement (N2). 30e) How is this condition treated? Once distant metastases are present, gastric cancer is unresectable, and median survival is <1 year. Large tumors that adhere to adjacent organs and involve regional lymph nodes with out distant metastases, although potentially resectable, carry a 5-year survival of <10%. N on-adherent invasive gastric cancer, with or without lymph node involvement, carries a 5-ye ar survival of <30% after resection. Tumors that invade the sub-mucosa and do not affect no des have a 60% 5-year survival after resection. Resection of distal gastric cancer involves a subtotal gastrectomy. Diffuse or proximal tum ors require total gastrectomy. There has been much debate between Japan and the West about the extent of lymph node clearance. Lymph node resection involves removal of nodes along th e lesser curve, the greater curve (N1/D1), the left gastric artery, the hepatic artery, the coeliac artery, and the splenic artery (N2/D2). D1 resection involves removal of the affec ted part of the stomach or the whole stomach along with the lesser and greater omentum. D2 resection includes the omental sac, part of the transverse mesocolon, clearance of nodes su rrounding the above mentioned arteries, and partial resection of adjacent organs (spleen an d pancreatic tail). Extended (D2) lymph- adenectomy adds to the surgical complications with out a significant survival benefit, so D1 resection is usually recommended. Adjuvant chemotherapy adds no clinically significant survival benefit, but perioperative ch emotherapy with platinum-based regimens, seems to improve survival. One trial has shown tha t 3 cycles of preoperative and 3 cycles of postoperative combination therapy with epirubici n, cis- platin and 5-fluorouracil (ECF regimen) was associated with a 5-year survival of 36 %, compared with 23% for those having surgery alone; this was confirmed in a subsequent stu dy. Two-thirds of gastric cancers diagnosed in the West are unresectable or have metastasized a t the time of diagnosis. Depending on the patient \200\231s health, palliative chemotherapy may be given. The choice of chemo- therapy is large, which suggests that none show particu lar advantage, so CASE 30 211 specialist advice is appropriate. Post-operative chemoradiation is prac- tised in the USA. The standard of care in the UK is ECF, which offers a small survival benefit. Oxaliplatin a nd capcytabine may be substituted for cisplatin and 5-fluorouracil (EOX regimen). Docetaxel may be sub- stituted for epirubicin, and may have some benefit over ECF at the cost of mor e frequent neutropenia. Irinotecan with 5-fluorouracil (IFL regimen) has also been tested a nd may be better than cisplatin and 5-fluorouracil, the latter being a commonly used regime n in the USA. Targeted therapies with monoclonal antibodies to the epidermal growth factor receptor (cetuximab), and vascular endothelial growth factor (bevacizumab) and tyrosine kin ase inhibitors (erlotinib and gefitinib) are under investigation. The matrix metalloprotein ase inhibitor mari- mastat did not fulfill early promise. It needs to be remembered that the current chemotherapeutic regi- mens are toxic and offer a small survival benefit. Our patient opted for palliative radiotherapy for symptom control . Further reading Bonenkamp JJ, Hermans J, Sasako M et al. (1999). Extended lymph-node dissection for gastric cancer. N Engl J Med; 340: 908 \200\22314. Foukakis T, Lundell L, Gubanski M, Lind PA (2007). Advances in treatment of patients with gastric adenocarcinoma. Acta Oncologica; 46: 277 \200\22385. Karlson B-M, Ekbom A, Wacholder S et al. (2000). Cancer of the upper gastrointestinal tract among patients with pernicious anemia: A case-cohort study. Scand J Gastroenterol; 35 : 847 \200\22351. Orlando LA, Lenard L, Orland RC (2007). Chronic hypergastrinaemia: causes and consequences. Dig Dis Sci; 52: 2482 \200\2239. Peter S, Beglinger C (2007). Helicobacter pylori and gastric cancer: The causal relationshi p. Digestion; 75: 25 \200\22335. OXFORD CASE HISTORIES 212 Case 31 A 60-year-old retired female secretary who had had two renal transplants for adult polycyst ic kidney disease, presented unwell with 5 weeks of profuse, watery (non-bloody) diarrhea a nd 9kg weight loss. She had had her first transplant in 1992, which failed in 1997 because of rejection. The second trans- plant was in 2000 and this was functioning well. She also h ad Type 2 diabetes mellitus, gout, and epilepsy (no seizures for 3 years). Daily medication s were sodium valproate 400mg, frusemide 250mg, allopurinol 100mg, doxazosin 8mg twice dail y, loratidine 10mg, mycophenolate 2g, prednisolone 5mg, ator- vastatin 10mg, aspirin 75mg, and colchicine or codydramol, as needed. She looked unwell, with a pulse rate of 90 beats per minute, a temperature of 37.8 C, and blood pressure 140/75mmHg, with a 15mmHg postural drop. There was no local tenderness in th e abdomen, and the transplanted kidney was palpable in the left iliac fossa. Investigations showed: 9/L, platelets 355 x 109/L Hb 13.4g/dL, WCC 10.7 x 10 Na 138mmol/L, K 3.7mmol/L, urea 21.5mmol/L, creatinine 182 mol/L (stable for this patient ) Bilirubin 3 min 41g/L mol/L, ALT 40 IU/L, ALP 191 IU/L, GGT 50 IU/L, albu- Abdominal radiograph: normal, with no colonic dilatation. Questions 31a) What are the possible causes of the diarrhea? 31b) What investigations should be done and what treatment adminis- tered while waiting for these investigations? 31c) Describe the findings on the sigmoidoscopy photograph and the histology (Figs 31.1 \200\22331.3 in the color section). 31d) What is the diagnosis and describe different methods for diagnosis? 31e) What is the treatment for the above condition? This page intentionally left blank OXFORD CASE HISTORIES 214 Answers 31a) What are the possible causes of the diarrhea? The possible causes of the diarrhea are best categorized as infective, medication related, and \200\230other \200\231. Infective Bacterial: spp (Campylobacter sp or Shigella spp usually cause bloody Salmonella diarrhea). Clostridium difficile (pseudomembranous colitis) commonly presents as watery diarrhea, low grade fever, and crampy abdominal pain, although it is often bloody. Symptoms usually begin during, or up to 6 weeks after, antibiotic therapy. C. difficile colitis is more likely to occur in the absence of antibiotics in transplant recipients. Severe pseudomembranous coli tis can cause toxic megacolon, which is fatal in up to 60% of patients, largely because of comorbidity (see Case 22). Viral and parasitic: CMV, rotavirus: the anti-CMV response is predominantly cell medi- ated. Calcineurin inhibit ors (tacrolimus or cyclosporin) suppress T-cell proliferation, thereby predisposing transpl ant recipients to CMV colitis. Risk factors for CMV infection include: CMV-negative recipie nt receiving organ from CMV-positive donor, use of mono- clonal antibody to treat rejection (OKT3), and older recipients (>55 years). CMV disease most frequently manifests as a non-s pecific syndrome of fever, myalgia, malaise, leucopenia, and/or thrombocy- topenia. CMV in the gut generally presents as fever, diarrhea, and abdominal pain. Gastrointestinal bleedin g may also complicate severe CMV enteritis or colitis. There are rare instances of perforat ion resulting from CMV colitis and megacolon. Microsporidia, cryptosporidia, and parasites: Should be considered in immunocompromised individuals. Medication-related Immunosuppressive agents (especially mycophenolate, ciclosporin, tacrolimus, and sirolimus) . Questions regarding recent changes of medication are important CASE 31 215 Non-immunosuppressive agents (e.g. antiarrhythmics, antibiotics, antihypertensives, diureti cs, diabetic medication, laxatives, proton pump inhibitors, protease inhibitors). Other Post-transplant lymphoproliferative disorder : this can vary from a low grade, indolent pro cess to an aggressive neoplasm. Clinical fea- tures suggesting this diagnosis include lymph adenopathy, unexplained fever, and systemic features, such as weight loss Colon cancer : unlikely, because of acute onset Bacterial overgrowth : commonly presents with abdominal pain, diar- rhoea, bloating, weight loss, or weakness. There is usually a history of small bowel diverticula, dysmotility, str ictures, or surgically formed blind loops Lactose intolerance abdominal cramps and diarrhea. It is unlikely to cause weight loss. : the main symptoms are bloating, flatulence, Colonic ischaemia : possible, given the age and comorbidity, but this usually presents with sudden-onset, crampy, abdominal pain, an urgent desire to defecate, and passage of bright red or maroon blood mixed with the stool, within 24 hours. Mild to moderate abdominal tende rness is often present over the involved segment of bowel. New presentation of inflammatory bowel disease or flare of pre-existing inflammatory bowel disease: this is unlikely given the sudden onset. 31b) What investigations should be done and what treatment administered while waiting for these investigations? Investigations that should be requested are: Stool microscopy/cytology/sensitivity, ova/cysts/parasites, and toxin assay C. difficile Flexible sigmoidoscopy to obtain biopsies Check CMV status of patient and donor Colonoscopy is best avoided in the acute stage as bowel preparation exacerbates the physiol ogical disturbance caused by severe diarrhea. Treatment should be oral and intravenous fluids to support renal graft function. Oral intak e can be continued. Intravenous hydrocortisone is best started on admission, while waiting for stool cultures and mucosal biopsy results to return, because acute ulcerative colitis i s a diagnostic possibility. It is better to treat both the possibility of acute ulcerative OXFORD CASE HISTORIES 216 colitis and infective colitis, rather than either alone. Vancomycin (to cover C. difficile) and ciprofloxacin or azithromycin (to cover Gram- negative pathogens) are appropriate anti biotics. 31c) Describe the findings on the sigmoidoscopy photograph and the histo- pathology The sigmoidoscopy picture reveals patchy mucosal erythema, with some ulceration and haemorr hagic patches. Standard haematoxylin and eosin staining revealed classic \200\230owl \200 \231s eye \200\231 inclusion bodies (Fig. 31.2); CMV immunohistochemistry was positive (Fig s 31.1, 31.2, 31.3). 31d) What is the diagnosis and describe different methods for diagnosis? The diagnosis is CMV colitis. Positive immunofluorescence on tissue biopsy has a 100% posit ive predictive value, but sensitivity is variable. Clinically significant CMV colitis can u sually be identified, however, on haematoxylin and eosin staining. Quantification of IgM an d IgG antibodies to CMV are unreliable and conventional CMV cultures have a sensitivity of about 50%. The CMV rapid antigen test has a high positive predictive value (100%), but can only be carried out on cellular specimens. Amplification by PCR has the highest negative pr edictive value (100%), but the positive Fig. 31.1 (see color plate 14) Photograph of mucosal appearance in the sigmoid colon: patch y erythema (large arrow), with some ulceration (small arrow) and haemorrhagic patches. CASE 31 217 Fig. 31.2 (see color plate 15) Haematoxylin and eosin staining of mucosal biopsy showing cl assic \200\230owl \200\231s eye \200\231 inclusion bodies (arrow). predictive value is only 60%. Reactivation of CMV in a previously infected recipient tends to be less clinically severe than de novo infection. 31e) What is the treatment for the above condition? CMV colitis is treated if the colitis is causing serious symptoms with high-dose intravenou s ganciclovir, but not for positive PCR alone. Viral resistance has been described. Other t herapies include a CMV hyper- immune globulin and foscarnet. Specialist advice is appropria te. Fig. 31.3 (see color plate 16) Positive immunohistochemistry for CMV. OXFORD CASE HISTORIES 218 Further reading Altiparmak MR, Trablus S, Pamuk ON et al. (2002). Diarrhea following renal transplantation. Clin Transplant; 16: 212 \200\22316. Ayre K, Warren BF, Jeffrey K, Travis SPL (2009). The role of CMV in steroid-resistant ulcerative colitis: a systematic review. J Crohn \200\231s & Colitis; 3: 141 \200\223148. Kaufman H S, Kahn A C, Iacobuzio-Donahue C et al. (1999). Cytomegaloviral enterocolitis: clinical associations and outcome. Dis Colon Rectum; 42: 24 \200\22330. Rubin RH (2001). Gastrointestinal infectious disease complications following transplantation and their differentiation from immunosuppressant-induced gastrointestinal t oxicities. Clin Transplantation; 15(Suppl. 4): 11 \200\22322. This page intentionally left blank OXFORD CASE HISTORIES 220 Case 32 A 42-year-old mother of three presented to her family practitioner with increased bowel fre quency, loose stools, and urgency, but without rectal bleeding. She had recently returned f rom a trip to Malaysia. A stool sample was sent, and culture revealed Campylobacter sp. She was treated with a course of antibiotics. Two months later she was reviewed by her family practitioner. She still passed frequent, po orly formed stools and had intermittent abdominal pain, although sometimes had constipation . She complained of abdominal bloating and was tired all the time. Avoidance of dairy produ cts had made no differ- ence. A repeat stool sample was negative. At this point, she was re ferred to a gastroenterology clinic. She was seen 3 months later. She reported frequent passage of semi-formed/ loose stools, wi thout blood or mucus. She had some urgency, especially on waking in the morning, but had no nocturnal diarrhea. Her stools flushed away easily and were not greasy. Defaecation was pr eceded by lower abdomi- nal pain, which settled temporarily on opening her bowels. Investigations: 9/L, platelets 267 x 109/L, MCV 89fL Hb 12.7g/dL, WCC 6.23 x 10 CRP <6mg/L U&E and LFT normal EMA negative, IgA normal TSH normal Colonoscopy normal Histology of colonic mucosa normal. Questions 32a) What is the likely diagnosis? 32b) What are the risk factors for development of this syndrome? 32c) How does it develop? 32d) How should it be managed? 32e) What is the long-term outlook for this patient? This page intentionally left blank OXFORD CASE HISTORIES 222 Answers 32a) What is the likely diagnosis? A history of abdominal pain for >3 months that improves on defaecation and is associated wi th a change in bowel frequency or stool consistency is highly suggestive of irritable bowel syndrome (IBS). The most com- monly used criteria are the Rome criteria, most recently upd ated in 2006 (Table 32.1).