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). In our patient, persistent symptoms had been preceded by infectious diarrhea and had not ab ated following antibiotic therapy, with subse- quent negative stool samples. A diagnosis of post-infective irritable bowel syndrome was therefore made. A diagnosis of post-infective IBS must be preceded by an episode of infective gastroenteritis with two or more of the fol lowing criteria: fever, vomiting, diarrhea, and a positive stool culture. In 1962 Chaudry a nd Truelove described a cohort of 130 cases of \200\230irritable colon syndrome \200\231. They reported that 26% of patients in their cohort associated the onset of their symptoms w ith an episode of acute dysentery. This was the first clear description of post- infective IBS. The largest study has involved 840 patients with Campylobacter jejuni infection. Of th ese, 794 were studied, and 103 or 14% met criteria for post-infectious IBS. The predominant symptom was loose stools. A third study reported 169 students with travelers \200\231 diar rhea, of whom 10% developed post-infective IBS with predomi- nantly diarrhoeal symptoms. 32b) What are the risk factors for development of the syndrome? The risk factors are similar to IBS of any etiology, not preceded by infec- tion. Pre-exist ing psychological disorders of anxiety and depression are more frequent in patients with po st-infective IBS, but such a history is less common in post-infective IBS than other forms of IBS. Female gender and an age <30 years have been shown to confer a greater risk of deve loping post-infective IBS. Nevertheless, the duration of the precipi- tating infection is o ne of the strongest risk factors. When the initial ill- ness lasts >3 weeks, the risk of de veloping post-infective IBS increases 11-fold compared with a duration <1 week. Specific ba cteria may also increase the risk, possibly due to an increased severity of mucosal dam- ag e and longer duration of infection. Infection with Campylobacter or Shigella species carrie s an increased risk of developing post-infective IBS compared with Salmonella sp. Vomiting in the course of the illness has been shown to reduce the risk of post-infective IBS. CASE 32 223 Table 32.1 International criteria (Rome III: 2006) for the diagnosis of IBS ROME III diagnostic criteria ROME II diagnostic criteria Irritable Bowel Syndrome Irritable Bowel Syndrome At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal d iscomfort or pain that has two out of three features: Diagnostic criterion* Recurrent abdominal pain or discomfort** at least 3 days/month in last 3 months associated with two or more of the following: Relieved with defaecation Onset associated with a change in frequency of stool Onset associ ated with a change in form (appearance) of stool. Improvement with defaecation Onset associated with a change in frequency of stool Onset ass ociated with a change in form (appearance) of stool Symptoms that cumulatively support the diagnosis of Irritable Bowel Syndrome: Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to dia gnosis. Abnormal stool frequency (for research purposes \200\230abnormal \200\231 may be defined a s >3 bowel movements/day and <3 bowel movements/week) Abnormal stool form (lumpy/hard or lo ose/watery stool) Abnormal stool passage (straining, urgency, or feeling of incomplete evac uation) Passage of mucus Bloating or feeling of abdominal distension \200\230Discomfort \200\231 means an uncomfortable sensation not described as pain. In pathophysiology research and clinical trials, a pain/discomfort frequency of at least 2 days a week during the screening evaluation is recommended for subject eligibility. 32c) How does it develop? Serotonin (5-hydroxytryptamine or 5HT) is found in enterochromafin cells in the gut. These enterochromafin cells have been shown to be increased in the rectal mucosa of patients with post-infective IBS when compared with patients with other types of IBS. Consistent with th is observation, postprandial levels of plasma serotonin are increased in patients with post -infective IBS. Serotonin affects gastrointestinal motil- ity and secretions from enterocyt es, as well as visceral sensation. Inflammation may play a part in post-infective IBS, illu strated by increased numbers of intraepithelial lymphocytes and lamina propria lymphocytes, which persist for at least a year after the acute infection. This has been associated with altered intestinal permeability. Furthermore, an increased level of IL-1 in the rectal m ucosa of patients with enteric infection who go on to develop post-infective IBS has been r eported OXFORD CASE HISTORIES 224 when compared with those who make a full recovery. Even so a double- blind placebo-controll ed trial of prednisolone in post-infective IBS showed no improvement in symptoms, even thou gh mucosal lymphocytes were reduced. The IL-10/IL-12 ratio is depressed in patients with IB S. IL-10 is an anti-inflammatory cytokine, and IL-12 is pro- inflammatory. A trial showing improvement in symptoms on the administration of probiotics has shown norma lization of the IL-10/IL-12 ratio. This has yet to be replicated, but is suggestive of an i nflammatory component in the etiology of the disorder. A genetic component related to incre ased production of IL-10 has been shown to be less common in patients with IBS. IBS-type sy mptoms are increasingly recognized in patients with otherwise quiescent inflammatory bowel disease, suggesting an overlap between inflammation and dysmotility, which is not surprisin g when considered. Another factor that may play a role is bile salt malab- sorption after e nteric infections. Lactose intolerance, however, is less common in adults than in the pedia tric population following enteric infection. 32d) How can it be managed? As for IBS in general, the treatment of post-infective IBS is directed at symptom relief. I t follows that IBS is subcategorized, based on the predominant symptom into constipation-pr edominant IBS (C-IBS), diarrhea-predominant IBS (D-IBS) and alternating or mixed symp- toms (M-IBS). Our patient complained of abdominal pain along with an increased stool frequency. Lifestyle factors need to be reviewed. Excessive caffeine intake (xan- thines stimulate cAM P) and even small amounts of alcohol can cause diarrhea. Constipation on the other hand is sometimes exacerbated by inactivity, inadequate fluid intake, and a diet low in soluble fib er. Soluble fiber supplementation (for instance, with a tablespoon of Golden Linseed daily, mixed with a live yogurt or a fruit comp te) can improve con- stipation, but has little e ffect on pain. Fermentation of fiber may increase symptoms of bloating and flatulence. Spec ialist dietary advice to reduce resistant starch intake is often helpful when symptoms of b loating and or diarrhea predominate. Resistant starch is that component of complex carbohyd rate (starch) that remains undigested in the small intestine. This then gets fermented by c olonic bacteria to cause bloating. Foods high in resistant starches include bread, potatoes and pasta that are pro- cessed to prolong their shelf-life. Fiber intake needs to be titra ted to the individual if it is to make any difference at all. CASE 32 225 Loperamide or codeine slow bowel transit and may be beneficial in patients with increased s tool frequency. Loperamide has little effect on pain, while codeine may become habit formin g. Colicky pain may be treated with antispasmodics such as hyoscine butylbromide or mebev- erine. Pediatric doses of antidepressant medication may have a particu- larly useful role i n D-IBS and pain. Tricyclic antidepressant compounds like amitriptyline are effective for p ain at low doses (10 \200\22330mg at night), which would be subtherapeutic for depression. Their anticholinergic effects, which delay bowel transit, may help symptoms of D-IBS. Selec tive serotonin reuptake inhibitors (SSRIs) may similarly improve pain per- ception, but may cause diarrhea. Serotonin receptor modulators have been shown to have good therapeutic eff ect, but are not commonly used be-cause of their side effects. Other pharmacological and non-pharmacological approaches may be necessary for refractory sy mptoms. Tegaserod, a partial 5-HT4 agonist, was shown in an initial trial to benefit women with C-IBS. It accelerates bowel transit, increases bowel frequency, and improves abdominal pain. Unfortunately, because of increased cardiovascular events, this drug is not availabl e. Alosetron, a 5-HT3 antagonist, was found to be beneficial in D-IBS in women, by increasi ng small intestinal absorption, slowing colonic transit and improving visceral pain. Compli cations of severe con- stipation, ischaemic colitis, and bowel perforation lead to withdraw al or restricted use of this drug. A trial of colestyramine or colesevalam, for possible bi le-salt malabsorption, is sometimes worth exploring when diarrhea is troublesome. There is no evidence to support the use of anti- biotics for bacterial overgrowth. Acupuncture and h ypnotherapy are complementary approaches that have been subject to randomized con- trolled trials and may be suggested to patients who do not have adequate symptom relief. Some patie nts opt for alternative or complementary therapies, for which evidence is lacking, but indi vidual cases may benefit. 32e) What is the long-term outlook for this patient? Patients with IBS, whether post-infective or not, generally have a chronic relapsing and re mitting symptom pattern. The likelihood of resolution in the long term is better in patient s without significant psychological comorbidity. Similarly, patients with an acute onset of symptoms, achieve resolution more often compared with those with a gradual onset of sympto ms. One study showed resolution of symptoms at 6 years of follow-up in 43% of patients with post-infective IBS, compared with 31% in patients with IBS not following an infection. In another study, OXFORD CASE HISTORIES 226 80% of patients with post-infective IBS still had some symptoms of IBS after 5 years. This group had had documented Salmonella sp infection prior to the onset of symptoms. Our patient was reviewed 11 months after initial symptom onset. Symptoms were much improved, but still present at this stage. Further reading Drossman DA (2006). The functional gastrointestinal disorders and the Rome III process. Gastroenterology; 130: 1377 \200\22390. Du Pont AW (2008). Postinfectious irritable bowel syndrome. Clin Infect Dis 2008; 46: 594 \200\2239. Spiller R, Campbell E (2006). Post-infectious irritable bowel syndrome. Curr Opin Gastroenterol; 22: 13 \200\2237. Spiller RC (2007). Role of infection in irritable bowel syndrome. J Gastroenterol; 42(Suppl . XVII): 41 \200\2237. Spiller R, Aziz Q, Creed F, Emmanuel A et al. (2007). Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut; 56: 1770 \200\22398. CASE 33 227 Case 33 A 61-year-old British man living in Kazakhstan was well until he developed severe abdominal pain with a fever. A diagnosis of acute diverticulitis, perfora- tion, and peritonitis was made. He underwent an emergency laparotomy, which confirmed a perforated sigmoid diverticu lum. The sigmoid colon was resected and a loop ileostomy was formed. His postoperative reco very was good, but 3 weeks after discharge he presented with nausea, decreased appe- tite, and lethargy. He described emptying his ileostomy bag about 4 times/day, but was unsure of the volume. On examination the patient looked dehydrated. The wound was clean. The stoma looked healthy and easily admitted a little finger. On rectal examination there was no pus. On sigmoidosc opy there was a healthy rectum. Investigations showed: 9/L, platelets 824 x 109/L Hb 15.3g/dL, WCC 10.7 x 10 Na 119mmol/L, K 6.1mmol/L, urea 41.2mmol/L, creatinine 402 mol/L Mg 0.49mmol/L mol/L, AST 34 IU/L, ALP 204 IU/L, albumin 49g/L Bilirubin 18 ESR 16mm/hour, CRP 4.3mg/L CT scan: normal postoperative appearances, with no abscess formation. Questions 33a) What problem has this man developed? Which non-gastroentero- logical condition has similar clinical features? 33b) What are the possible causes of 33a? What is the most likely cause in this case and why? 33c) What is the initial management? 33d) If the patient does not respond to the initial management, what is the next step? 33e) If the patient has been nil by mouth, what is the best way of reintro- ducing oral intake? OXFORD CASE HISTORIES 228 Answers 33a) What problem has this man developed? Which non-gastroenterologi- cal condition has similar clinical features? This man has ileostomy dysfunction (a high output stoma syndrome), which has clinical and b iochemical features similar to Addison \200\231s disease. The dehydration and electrolyte d isturbance associated with ileostomy dysfunction presents with the clinical and biochemical appearance of Addison \200\231s disease (hyponatraemia, hyperkalaemia, lethargy), but the adre- nal function is normal. This man also had abdominal pain prior to surgery, and Addiso n \200\231s disease is associated with abdominal pain. However, in this patient, the abdomi nal pain was explained by the perforated diverticulum. 33b) What are the possible causes of 33a? What is the most likely cause in this case, and why? The possible causes of ileostomy dysfunction are: Inappropriate diet (either solid or liquid components) Bacterial overgrowth Partial obstruction (strictures, or a parastomal hernia) Prestomal ileitis Infection Short bowel syndrome Gastric acid hypersecretion Coincidental undiagnosed disease. Hyperosmolar or hypo-osmolar fluids from an inappropriate diet will promote fluid flux into the intestinal lumen, and if the sodium content of the jejunal fluid is <90mmol/L, then th ere is no net water absorption. This is not important where there is functioning distal ile um or colon, but in the absence of either, dehydration and sodium depletion occur rapidly. Bacterial overgrowth may cause ileostomy dysfunction, but is unlikely in this case because there was no small intestinal resection: it is the loss of the ileocaecal valve when re-ana stomosed to the colon that increases the risk of bacterial overgrowth of the small intestin e. Partial obstruction caused by strictures or parastomal hernia may cause ileostomy dysfun ction, but in this case there was no obvious hernia on examination and the stoma readily ad mitted a little finger. Prestomal ileitis is more likely to occur if the original resection was for inflammatory bowel disease. CASE 33 229 Infection (including small intestinal Clostridium difficile) should be excluded and stool s hould be routinely sent for toxin assay, microscopy, culture, and sensitivity. Short bowel is commonly considered in ileostomy dysfunction, but is less commonly the cause. In this ca se no small bowel was resected. The surgical notes should always be scrutinized, and if the remaining small bowel looks <2m in length, it is good practice for the surgeon to measure the length of the remaining gut from the duodenojejunal flexure. In some instances, there i s inaccurate estimation of the proportion of small bowel resected, resulting in unexpected short bowel syndrome. In gen- eral, the length of the remaining jejunum is of critical impo rtance: patients with a jejunal length of less than 100cm cannot maintain ade- quate nutrie nt absorption on oral feeding and will require long-term parenteral nutrition. Patients wit h a jejunal segment >100cm can usually maintain nutritional balances, but may have stomal l osses of fluid, mag- nesium, and electrolytes that may need regular parenteral crystalloid. The loss of the ileum results in obligatory bile acid and cobalamin (B12) malabsorption. T he colon is of paramount importance in maintaining fluid and electrolyte balance. Defining the anatomy of the remaining bowel (both small and large) is of fundamental importance to m aking strategic management decisions. The exact mechanism of gastric acid hypersecretion is unknown. It may be related to the removal of intestinal peptides that normally inhibit gas tric acid secretion and/or gastrin release. Finally, coincidental undiagnosed disease causi ng malabsorption (e.g. villous atrophy, hyperthyroidism, hypolactasia, pancreatic insuffici ency, dysmotility) should not be overlooked. 33c) What is the initial management? The management of high output stoma involves: with intravenous fluids and electrolyte replacement Rehydration (including magnesium in particular) as necessary Measuring stoma output by asking nursing staff to measure the volume. The output should be <1200ml/day. A patient with an output >1500ml/day will not manage at home without parentera l fluids Dietician of drinks and food review of oral intake, especially the type of fluid, and quantity Medication review in particular looking for lactose-containing medi- cation, antidiarrhoeal agents, proton pump inhibitors, and prokinetic agents that may exacerbate high output stom a syndrome OXFORD CASE HISTORIES 230 Review surgical notes to determine amount of small bowel remaining Trial of empirical therapy: Dietary adjustments and isotonic fluids (see below) (to inhibit gastric acid hypersecretion, Omeprazole 80mg/day common in short bowel syndrome) 400mg three times daily for 1 week (in case of Metronidazole bacterial overgrowth) Loperamide (use tablets or capsules, because the elixir contains lactose). in very large doses, starting at 4 \200\22310mg four times daily 33d) If the patient does not respond to the initial management, what is the next step? If the patient does not respond to empirical therapy, that is if the output remains above 1 500ml/day, then establish basal output by making the patient nil by mouth and administering intravenous fluids for 48 \200\22372 hours. Electrolytes (Na, K, Mg) need to be monitored daily. If the basal output is >1200ml/day, then it is very unlikely that the patient will e ver manage without intravenous fluids at home. Advice from a specialist center with experti se in high output stomas is usually appropriate. 33e) If the patient has been nil by mouth, what is the best way of reintro- ducing oral intake? The best approach to reintroducing oral fluids is to establish the effect of isotonics alon e by mouth for 24 \200\22348 hours. This is the simplest \200\230chal- lenge \200\231 to s mall intestinal function, since net water absorption by the jejunum only occurs at a lumina l [Na]>90mmol/L. It is important to involve the dietician to educate the patient and nursin g staff how isotonic fluids are constituted (the WHO oral rehydration solution is made by a dding 3.5g NaCl, 2.9g trisodium citrate (or 2.5g NaHCO3), 1.5g KCL and 20 g glucose to 1L o f water), or 500mL Lucozade Sport plus 1 teaspoon salt. Commercial \200\230isotonic \200 \231 drinks do not contain enough sodium and should be avoided. The ileostomy output should be mea- sured whilst on isotonic fluids. If the output is <1200ml/day, the patient can est ablish the effect of solid food, under supervision by an experi- enced dietician. It should be recognized that general dieticians (let alone general surgeons!) often do not have suff icient experience to advise in this area and specialist advice from an intestinal failure u nit is often helpful. If the output is >1200ml/day, the following medications should be instituted, in succession: