CASE 33 231 omeprazole 80mg/day plus loperamide 8 \200\22312mg, 4 times per day plus codeine 60mg, 4 times per day consider octreotide 3 times per day. Stop octreotide after 72 hours if the impact on the ou tput is <300mL/d. If the output <1500mL/day at this stage, polymeric supplements can be introduced. If the ou tput >1500mL/day, a plan for long term intrave- nous fluids or parenteral nutrition will be necessary, arranged through a specialist center. This patient had a good recovery from this episode and went on to have a re-anastomosis 3 m onths later. He returned to Kazakhstan shortly after this and remains well. Further reading Nightingale J, Woodward JM (2006). Small Bowel and Nutrition Committee of the British Society of Gastroenterology. Guidelines for management of patients with a short bowel. Gut; 55(Suppl. 4): iv1 \200\22312. Lochs H, Dejong C, Hammarqvist F, Hebuterne X et al. (2006). ESPEN Guidelines on enteral nutrition. Gastroenterology Clin Nutr; 25: 260 \200\22374. Abu-Elmagd KM. Intestinal transplantation for short bowel syndrome and gastrointestinal failure: current consensus, rewarding outcomes, and practical guidelines. Gastroenterology 2006; 130(Suppl 1): S132 \200\2237. OXFORD CASE HISTORIES 232 Case 34 A 28-year-old Caucasian woman, who worked for the military, presented with a 12-month histo ry of passing blood per rectum. Bright red blood was mixed in with the stool at almost ever y bowel motion. There was no blood on the paper or otherwise in the pan. Over the same peri od, her bowel habit had started alternating between being loose and constipated. She also r eported occasional colicky abdominal pain, not related to opening her bowels. She had not l ost any weight. She had no relevant past medical history or family history. Examination of the abdomen was unremarkable. A digital rectal examina- tion and proctoscopy revealed no abnormalities and no source of bleeding. Investigations showed: 9/L, ESR 29mm/hr Hb 7.7g/dL, MCV 58fL, platelets 485 x 10 Colonoscopy: a concentric, stenosing tumor at the hepatic flexure Histopathology showed a moderately differentiated adenocarcinoma with a large mucinous comp onent and surrounding inflammatory infiltrate. She was referred to a colorectal surgeon and oncologist for further investigation and appro priate management. Questions 34a) Should rectal bleeding always be investigated? 34b) What is the best investigation for this patient? 34c) What should you tell the patient to expect regarding further investi- gation and management? 34d) What effects and side effects can the patient expect from adjuvant chemotherapy? 34e) Should family members be screened? This page intentionally left blank OXFORD CASE HISTORIES 234 Answers 34a) Should rectal bleeding always be investigated? Bright red blood per rectum is a common symptom. In a survey of the general population in t he UK, 20% of people between 20 and 80 years of age reported blood loss per rectum within t he preceding 6 months. The most common cause is hemorrhoids, although this does not, of cou rse, exclude more proximal pathology. Patients >50 years of age should best have full colon ic imaging, either by colonoscopy or CT scanning (below). The management of younger patient s is subject to some debate. The American Society for Gastrointestinal Endoscopy guidelines (2000) state that colonoscopy is \200\230generally indicated \200\231 for patients with v isible rectal bleeding. This is not universally accepted and practice varies, because the j udicious allocation of resources needs to be balanced against the possi- bility of missing serious pathology. A prospective cohort study of colonoscopy for investigating a history of visible rectal ble eding in 622 patients from Italy confirmed that colonic malignancy is very rare in patients <50 years of age. In the group of 312/622 patients <40 years of age, only 2/312 (0.6%) had a colonic malig- nancy (both were distal to the splenic flexure and in reach of a flexible sigmoidoscope). Diverticular disease was found in 11/312 (3.5%), and 10 (3.2%) had ulcerat ive colitis, both easily diagnosed by flexible sigmoi- doscopy. Malignancy of the colon doe s, however, sometimes occur in young people. Diagnosis may be delayed as a consequence of a low index of suspicion, and this may be associated with a worse outcome. Concomitant iron deficiency anemia in this young patient influences the choice of investigation (below). It is probable that tumor biology is different and more aggressive at a younger age. 34b) What is the best investigation for this patient? It is clear that the risk of colorectal cancer in a 28-year-old patient with- out a family history of the condition is extremely low. There are, how- ever, clinical points of note. T he rectal bleeding was constant, with almost every bowel motion, mixed in with stool and no t otherwise noticed in the bowl or on the toilet paper. This is not typical of anal canal b leeding. The fact that the blood was described as \200\230bright red \200\231 is an unreli able indi- cator of the distance of pathology from the anus. Furthermore, the patient repor ted intermittent colicky abdominal pain. Of most note, however, our patient had a profound microcytic anemia. The elevated platelet count can be assumed to indicate either significan t chronic blood CASE 34 235 loss, or an acute phase response, both of which indicate serious pathology. The elevated ES R is more difficult to interpret, because red blood cells tend to sediment more quickly in the presence of anemia. Bright red rectal bleeding with normal proctoscopy, colicky abdomi- nal pain, and microcyti c anemia requires thorough examination of the colon to confirm or exclude significant organ ic pathology. It is debatable whether the patient should have an upper gastrointestinal end oscopy as well to exclude villous atrophy associated with coeliac disease: this should gene rally be routine in patients with iron deficiency anemia (see Case 38), but in the present case the rectal bleeding gives clear evidence of colonic pathology. Colonoscopy is the proc edure of choice in this patient, because she is young and should be spared unnecessary radi a- tion associated with CT colonography. Colonoscopy has the added ben- efit of enabling mu cosal biopsy for histopathological diagnosis. Colorectal imaging has, however, undergone a revolution in the past 5 years and colonoscopy should not be assumed always to be the default investigation. The optimal technique depends on: Purpose of the investigation Most likely pathology (carcinoma, polyps, IBD, or telangiectasia) Age of patient, comorbidity, and available resources (waiting times). Barium enema and flexible sigmoidoscopy Advantages colonoscopy; flexible sigmoidoscopy images the sigmoid colon. : reliably images caecum; may be more available than Limitations : colonoscopy still needed if a potential polyp is identified; adequate separat ion of sigmoid loops cannot always be achieved (hence need to be combined with flexible sig moidoscopy). Barium enema may still miss polyps >1cm, although reliably (96%) identifies co lorectal cancer. CT techniques and colonoscopy have made barium enema virtually obsolete in developed countries. Flexible sigmoidoscopy Advantages : simple, safe procedure; usually performed without seda- tion after a phosphate enema without full bowel preparation; allows biopsies to be taken. Initial procedure of ch oice for assessing in- patients with diarrhea (bloody or otherwise) and out-patients with d istal colonic bleeding. Limitations : does not image the proximal colon. OXFORD CASE HISTORIES 236 Colonoscopy Advantages the elderly or frail; allows therapeutic intervention. : gold-standard for colonic imaging at all ages except for : lack of capacity to meet demand in many hospitals; poten- Limitations tially incomplete e xamination (caecal intubation rate may be 85 \200\22390%); risk of perforation (about 0.1%) ; need for bowel preparation (risk of potentially serious metabolic disturbance in elderly) . CT colon (also called minimal or long preparation CT colonography) : minimal preparation. Bowel preparation only needs a few Advantages milliliters of gastrog raffin contrast over 3 days prior to procedure. Sensitivity is 85 \200\22390% for colorecta l cancer. Initial colonic imaging procedure of choice for elderly or frail patients. Limitations : less sensitive than CT colonography or barium enema. CT colonograpy (also called virtual colonoscopy/CT pneumocolon) Advantages : sensitivity as good as colonoscopy in trained hands. Initial colonic imaging p rocedure of choice in many centers for patients >45 years of age when the aim is to exclude cancer; provides some limited additional information from cross-sectional imaging of the w hole abdomen; reduces the need for colonoscopy by 10 \200\22320%. The major advantage over barium enema is that there is no need for flexible sigmoidoscopy. Limitations : radiologist time to scrutinize scans (20 \200\22330min/scan); extracolonic pa thology may not be detected, since intravenous contrast is not given routinely. 34c) What should you tell the patient to expect regarding further investiga- tion and management? Surgical resection is appropriate. She will need a thoracoabdominal and pelvic CT scan to s tage the tumor and exclude metastases. MR scan of the abdomen is generally only needed as w ell for patients with rectal cancer, because it better defines pelvic anatomy than a CT sca n. If imag- ing excludes metastases, resection of the primary tumor performed by a speciali st colorectal surgeon using a laparoscopic-assisted approach, is the next step. Discussion about the surgical technique is done with the specialist colorectal surgeon, if laparoscopi c expertise or equipment is not locally available, then a patient this young is usually bes t referred to CASE 34 237 a specialist center. The chance of needing a stoma with a tumor at the hepatic flexure is l ow. The resected tumor is then further staged by histopathology. This is the most reliable pred ictor of long-term outcome. It forms the basis of decisions regarding adjuvant chemotherapy . Staging may be based on the TNM (tumor-node-metastasis) staging system or on the older Du kes \200\231 system (Tables 34.1 \200\22334.3). Adjuvant chemotherapy is generally offered to all patients following resection who are found to have stage III (node positive) disease (Dukes \200\231 stage C), if they are fit enough for a 6-month course of chemotherapy. Age has to be considered, because survival benefit from chemotherapy must be seen in the conte xt of the patient \200\231s population-based life expectancy. 34d) What effects and side effects can the patient expect with adjuvant chemotherapy? There is a modest, but clear survival benefit for patients with Dukes \200\231 C carcinoma of the colon who receive adjuvant chemotherapy. The abso- lute benefit for stage III (node- positive) disease is about 10% over 5 years for 5-fluorouracil (5-FU)-based chemotherapy. T he addition of oxalip- latin may add a further 5% absolute survival benefit in this group. Higher risk patients with node-negative disease and transmural (T4, Table 34.1) tumors, or presentation with bowel perforation or obstruction, may benefit more. Chemotherapy for stag e II colorectal cancer is less well defined. Patients may have an absolute survival benefit of just 4% from 5-FU-based chemotherapy. Oxaliplatin has not been shown to add any benefit in these patients. Therapy needs to be tailored to the individual and account taken of their views. 5-FU is us ually administered for 5 days out of every 28 for a total of 6 cycles. The drug is given ei ther as a daily bolus or a continuous infusion, and is administered with folinic acid (leuc ovorin). Side effects from bolus regimens include neutropenia, stomatitis, and diarrhea, wh ich are less common with continuous infusions. On the other hand, continuous infusions have a higher rate of hand and foot syndrome Table 34.1 Dukes \200\231 classification of colorectal cancer A Tumor confined to the mucosa and submucosa B Tumor invading the muscularis propria (B1=T2 N0M0; B2=T3N0M0) C With lymph node(s) involvement D With distant metastasis OXFORD CASE HISTORIES 238 Table 34.2 TNM staging for colorectal cancer Primary tumor (T) Tx Primary tumor cannot be assessed Tis Carcinoma in situ T1 Tumor invades submucosa T2 Tumor invades muscularis propria T3 Tumor invades through the muscularis propria into the subserosa T4 Tumor directly invades other organs or structures, or perforates visceral peritoneum Regional lymph nodes (N) Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastases in 1 \200\2233 regional lymph nodes N2 Metastases in 4 regional lymph nodes Distant metastases (M) Mx Presence or absence of distant metastases cannot be determined M0 No distant metastases detected M1 Distant metastases detected (painful erythematous rash of the hands and feet), which is also the major side effect of c apecitabine (an orally administered prodrug of 5-FU). Capecitabine has also been associated with severe secretory diar- rhoea causing hypomagnesaemia and hypokalaemia. Oxaliplatin ma y cause paraesthesiae and a cumulative, dose-related peripheral neuropathy, which may be ir reversible. Table 34.3 Stage grouping and 5-year survival Stage TNM classification Approximate 5-year survival (%) I T1 \200\2232, N0, M0 90 IIA T3, N0, M0 80 \200\22385 IIB T4, N0, M0 70 \200\22380 IIIA T1 \200\2232, N1, M0 65 \200\22380 IIIB T3 \200\2234, N1, M0 50 \200\22365 IIIC T1 \200\2234, N2, M0 25 \200\22350 IV T1 \200\2234, N0 \200\2232, M1 5 \200\2238 CASE 34 239 Our patient underwent a laparoscopic-assisted, extended right hemicolectomy. Histopathologi cal staging showed a completely resected tumor with no affected lymph nodes, T3N0M0 (stage IIA, Dukes B2). She received 6 cycles of capecitabine, which was well tolerated. Stage IIA colon cancer (T3N0M0) has a 5-year survival rate of around 80%, after resection with curati ve intent (Table 34.3). 34e) Should family members be screened? Our patient had colon cancer diagnosed at 28 years of age. This implies an increased risk o f colon cancer in first-degree relatives. Screening for family members should be instituted . British Society of Gastroenterology (BSG) guidelines recommend that patients who have one f irst-degree relative diagnosed with colon cancer <45 years of age should have a full colono scopy at the time of consultation for an indicative family history, or at 35 \200\22340 yea rs of age, whichever is later. Further surveillance is guided by findings at the initial co lonoscopy. If the first colonoscopy is normal, a second colonoscopy is recommended at 55 ye ars of age. American Gastroenterology Association (AGA) guidelines recom- mend that first-degree relati ves of patients diagnosed with colorectal cancer at <60 years of age should have colonoscop y performed every 5 years, starting at 40 years of age or at an age 10 years younger than t he index case. Our patient was 28 years old at the time of diagnosis. AGA guidelines imply initiation of screening colonoscopy in first-degree rela- tives at 18 years of age, and eve ry 5 years thereafter, which many health- care systems would feel too burdensome for the di agnostic return. Testing of the tumor for microsatellite instability with MSI analysis or l oss of a mismatch repair gene is appropriate when colorectal cancer is diagnosed in young p atients (see Case 17). Further reading Crosland A, Jones R (1995). Rectal bleeding: prevalence and consultation behavior. BMJ; 311: 486 \200\2238. Dunlop MG (2002). Guidelines on large bowel surveillance for people with two first degree r elatives with colorectal cancer or one first degree relative diagnosed with colorectal canc er at <45 years. Gut; 51(Suppl. V): v17 \200\223v20. Levin B, Lieberman DA, McFarland B et al. (2008). American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society Task Force; American College of Radiology Colon Can cer Committee. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American OXFORD CASE HISTORIES 240 Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American Coll ege of Radiology. Gastroenterology; 134: 1570 \200\22395. Spinzi G, Dal Fante M, Masci E et al. (2007). Lack of colonic neoplastic lesions in patient s under 50yr of age with hematochezia: a multicentre prospective study. Am J Gastroenterol; 1 02: 2011 \200\22315. Wolpin BM, Mayer RJ (2008). Systemic treatment of colorectal cancer. Gastroenterology: 134; 1296 \200\2231310. CASE 35 241 Case 35 A 19-year-old drugstore student presented with perianal pain, diarrhea, 7kg weight loss, na usea, and vomiting over a 4-month period. He had traveled to Pakistan to see relatives 5 ye ars previously, but had otherwise been born and brought up in the UK. He had a perianal abscess, which was drained under anesthetic and a flexible sigmoidoscopy was carried out. This showed rectal ulceration. Biopsies were consistent with Crohn \200 \231s disease; Ziehl \200\223Nielsen stain and a gamma-interferon release assay QuantiFERON -TB Gold were negative. He was treated with cor- ticosteroids and antibiotics after drain age of the abscess, with a good response. Azathioprine was started as primary prophylaxis a gainst relapse. Two weeks after discharge from hospital he was re-admitted with diarrhea for 48 hours, fever (39.4oC), chills, rigors, and arthralgia. Investigations showed: 9/L, platelets 544 x 109/L Hb 12.3g/L, WCC 20.6 x 10 CRP >160mg/dL mol/L, ALT 38 IU/L, ALP 257 IU, albumin 42g/dL Bilirubin 16 Chest radiograph: normal MRI abdomen and pelvis: normal. Questions 35a) What is the most likely diagnosis? 35b) What is the best management on admission? 35c) What are the treatment options on recovery? 35d) What are the treatment-related risks of lymphoma? OXFORD CASE HISTORIES 242 Answers 35a) What is the most likely diagnosis? The most likely diagnosis is azathioprine toxicity. The most common symptoms of intolerance , which affect up to 20% of patients, are flu-like symptoms (myalgia, headache, diarrhea) t hat characteristically occur after 2 \200\2233 weeks and cease rapidly once the drug is wit hdrawn. Profound leu- copenia can develop suddenly and unpredictably, in between blood test s, although it is very rare within a month of starting therapy (<0.3%) and also rare at any stage during therapy (approximately 3%). Hepatotoxicity and pancreatitis are uncommon (<5% ). A recurrent abscess complicating Crohn \200\231s disease is unlikely in view of the normal MRI. A new infection needs to be considered, for example CMV or EBV, but it is too early fo r azathioprine to have caused appre- ciable immunosuppression. It is possible that this cou ld still have been a missed diagnosis of tuberculosis (see Case 26). This had been consider ed and a QuantiFERON -TB had been performed and was negative. There are two new techniques of interferon- release assays that target two specific prote ins of Mycobacterium tuberculosis (ESAT-6 and CFP- 10). These are not affected by BCG-vacci nation or environmental myco- bacterial exposure, and are commercially available (ELISPOT o r QuantiFERON -TB). Multiple studies, including immunocompromised patients, have demonstra ted that interferon- release assays are more sensitive and specific than a standard tuber culin skin test, although they have not been validated in patients with inflammatory bowel disease. The problem is that sensitivity may still be appreciably less than 100%, so gastro enterologists (and others) should beware the false sense of security of a negative ELISPOT or QuantiFERON -TB result. 35b) What is the best management on admission? The best management is to stop azathioprine immediately. Although it is likely that this is azathioprine toxicity, investigation and treatment of other possibilities should be undert aken until a diagnosis is established. These include blood cultures, intravenous corticoste roids and empirical antibiotics. In this case, the patient made a rapid and full recovery c on- sistent with azathioprine toxicity. 35c) What are the treatment options on recovery? This patient has multiple poor prognostic factors including young age, perianal disease and corticosteroid treatment at diagnosis. The best treat- ment for this patient includes immu nomodulator therapy, because it has CASE 35 243 potential for modifying the future course of the disease. Mercaptopurine is inappropriate s ince there was hyper-acute intolerance of azathioprine. Mercaptopurine has a role in subacu te intolerance, characterized by nausea and flu-like symptoms, but without hepatitis, pancr eatitis, or fever. Up to 70% of patients with this pattern of intolerance to azathio- prine can tolerate mercaptopurine, but patients should be warned that a third cannot tolerate me rcaptopurine: this is evident after a dose or two of mercaptopurine. Mercaptopurine should then be stopped and further advice sought. Methotrexate should be considered. Intramuscular methotrexate 25mg/ week has been compared with azathioprine 2mg/kg/day in 54 patients with corticosteroid-dependent active Crohn \200\231s disease, and no difference in this under-p owered study was found between the two medications, either for effect or speed of response. Unlike azathioprine, methotrexate has been subject to properly powered randomized controll ed trials for induction and maintenance of remission in corticosteroid-dependent Crohn \200 \231s disease. Variable absorption of oral methotrexate has been dem- onstrated compared wi th subcutaneous administration, but for practical reasons oral dosing is more convenient an d preferred by patients. If methotrexate is used, concurrent administration of folic acid o nce a week is advisable (the alliteration Methotrexate on Monday, Folic acid on Friday is o ften helpful). Biological therapy should also be consid- ered. Specialist advice from a gas troenterologist specializing in inflam- matory bowel disease is generally appropriate for m anaging Crohn \200\231s disease refractory to one immunomodulator, so that the strategy and timing of biological therapy can be planned. 35d) What are the treatment-related risks of lymphoma? There is about a four-fold increased risk of lymphoma in patients treated with azathioprine or mercaptopurine relative to the lymphoma rate expected in the general population. As aza thioprine and mercaptopurine tend to be used in more severe cases of inflammatory bowel dis ease, the increased risk of lymphoma could be a consequence of the medication, the severity of the underlying disease, or a combination of the two. It is unclear how the risk of lymp homa changes when therapy is discontinued and whether the risk is dose related. Even if the increased risk is attribut- able to the medication, it is unlikely to outweigh the potenti al benefits of these medications for most patients. Prospective evidence from a large Frenc h (CESAME) study suggests a two-fold increase; this means that OXFORD CASE HISTORIES 244 the number-needed-to-harm by lymphoma from azathioprine/mercap- topurine is between 4500 an d 11500 at 20 \200\22330 years of age. This puts the absolute risk in perspective. It is also important to consider that inflammation is an independent risk factor for colore ctal neoplasia in inflammatory bowel disease. Further data from the CESAME study, a cross-s ectional IBD French cohort designed to determine prospectively the risk of cancers associat ed with the use of immunosuppressive therapy, has shown a 3-fold decreased risk of advanced colorectal neoplasia in patients with Crohn \200\231s disease or ulcerative colitis on thi opurine therapy. This raises the possibility that the anti-inflammatory effect of thiopurin es on the colonic mucosa carries a greater benefit on the risk of colorectal neoplasia than a deleterious effect through drug-induced immunosuppression. Further reading Beaugerie L, Seksik P, Carrat F, for the CESAME Study Group (2009). Thiopurine therapy is a ssociated with a three-fold decrease in the incidence of advanced colorectal neoplasia in I BD patients with long-standing extensive colitis: the CESAME prospective data. J Crohn \200 \231s & Colitis; 3: S5. Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD (2005). Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercapto purine. Gut; 54: 1121 \200\2235. McGovern DPB, Travis SPL (2006). 6-mercaptopurine or azathioprine? In: Irving P, Rampton DS , Shanahan F (Eds). Clinical Dilemmas in IBD. Blackwell Publishing: Oxford, Chapter 13: 45 \200\2237. CASE 36 245 Case 36 A 55-year-old woman who worked as a publisher presented with an 8-week history of diarrhea. She reported up to 12 bowel movements in 24 hours with nocturnal waking to open her bowels . Stools were loose, but contained no macroscopic blood. She experienced lower abdominal cr amps and urgency before having to pass stool, and this was especially prominent after a mea l. She had no fever or chills but had lost weight. Symptoms started after a course of Co-am oxiclav, which was prescribed for a chest infection. The diarrhea was having an appreciable impact on her quality of life, interfering with normal daily excursions for fear of not be ing near a toilet. She had chronic backache, suffered from depression, and was hypothyroid. She was receiving fluoxetine, thyroxine, and had been taking diclofenac for years. Investigations showed: 9/L, platelets 320 x 109/L Hb 14.1g/dL, WCC 8.13 x 10 ESR 8mm/hour CRP 45mg/L EMA negative TSH 2.63mU/L g/g, no excess fecal fat Fecal elastase >500 Stool culture negative, stool C. difficile toxin negative. Questions 36a) Discuss the differential diagnosis. 36b) What further investigations are appropriate? 36c) What are the characteristics of this condition? 36d) What are the etiology and the mechanisms of diarrhea? 36e) How would you manage this patient and what is the long-term outlook? OXFORD CASE HISTORIES 246 Answers 36a) Discuss the differential diagnosis. The clinical problem is chronic diarrhea (diarrhea persisting for >3 weeks). It is importan t to distinguish functional diarrhea (IBS, see Case 32) from that resulting from an organic cause. Clear indicators of an organic cause are a history of nocturnal diarrhea and weight loss, as in this patient. Colorectal cancer is possible, but unlikely, since it gener- all y causes a gradual change in bowel pattern with an increase in stool frequency to a few tim es a day, rather than diarrhea a dozen times a day. An elevated CRP suggests underlying inf lammation. Although the diar- rhoea was of sudden onset, there were no other symptoms of in fection (no fever or chills), no risk factors for infection (travel history), and stool cul ture was negative. The onset of diarrhea after a course of Co-amoxiclav, raises the possibi lity of antibiotic-associated diarrhea (see Case 22). A test for Clostridium difficile toxi n in a stool sample was negative. The clavulanic acid in Co-amoxiclav can act to stimulate bowel motility, and penicillin has rarely been described to cause colitis. Antibiotic-assoc iated diarrhea in the absence of C. difficile generally remits after withdrawing the offend ing drug. Other common conditions need to be excluded. Our patient was hypothyroid and was taking thy roxine. Overtreatment was excluded by a normal TSH. Coeliac disease was effectively exclude d with a negative endomysial antibody test (see Case 38) in the presence of a normal IgA co ncentration. New onset ulcerative colitis is highly unlikely in the absence of visible bloo d in the stool. Crohn \200\231s disease is possible, because of an elevated CRP, and most p atients with Crohn \200\231s colitis have non- bloody diarrhea. There was no history of ste atorrhoea and no risk fac- tors for chronic pancreatitis, but in view of the weight loss, p ancreatic function tests were requested. The fecal elastase was normal, reliably excluding exocrine pancreatic insufficiency. Bacterial overgrowth is unlikely in an otherwise healthy person at this age, since it is usually associated with anatomic alteration in the small b owel, by jejunal diver- ticulosis (see Case 10), or surgery. Clues to the etiology were the patient \200\231s age, female gender, and the fact that she was taking diclofenac. Diclofe nac may cause NSAID-induced enteropathy or microscopic colitis. 36b) What further investigations are appropriate? Colonoscopy is the investigation of choice to obtain mucosal biopsies throughout the colon (see discussion on colonic imaging, Case 34). CASE 36 247 Mucosal biopsies are essential in a patient with diarrhea even if the colonic mucosa looks normal, as in this case. There is rectal sparing in 10 \200\22340% of patients with microsc opic colitis, which is confined to the right side of the colon in 10%. Consequently full co lonoscopy is optimal, but a flexible sigmoidoscopy and biopsies from the left colon will se cure the diagnosis in 90%. The choice of investigation depends on availability, but full co lonic imaging is mandatory, so colonoscopy was requested. In this patient, the histopathology of the terminal ileum, rectum and sigmoid mucosal biops ies was normal. Biopsies of the ascending colon, transverse colon, and descending colon sho wed an increase in chronic inflammatory cells in the lamina propria and intraepithelial lym phocy- tosis, consistent with lymphocytic colitis, one of the types of micro- scopic coliti s (Fig. 36.1 in central color section). 36c) What are the characteristics of this condition? Microscopic colitis is a condition causing watery diarrhea in which the colonic mucosa look s normal (or near normal) at colonoscopy, but biopsies show a chronic inflammatory infiltra te in the lamina propria. There are two commonly recognized variants: lymphocytic colitis a nd collagenous colitis, but some authorities further subclassify to include \200\230micros copic colitis not-otherwise-classified \200\231, or \200\230microscopic colitis with giant cells \200\231. Microscopic colitis of any type may be accompanied by weight loss or abdom inal discomfort, and patients may have nausea, or suffer fecal incontinence. There is a fem ale predominance, which is more pronounced in people with collagenous colitis, which has a female to male ratio of 7:1. The female to male ratio in lymphocytic colitis is 2.4:1. The peak incidence is at the age of 65 years, but the disease can occur at all ages. Associated autoimmune conditions include thyroid disease (as in our patient), coeliac disea se, diabetes mellitus, rheumatoid arthritis, and asthma. Certain drugs are implicated in th e development of microscopic colitis, including NSAIDs, proton pump inhibitors, statins, se rotonin- reuptake inhibitors, ranitidine, aspirin, acarbose, lisinopril, ticlopidine, carba mazepine and flutamide. The rectal mucosa is more commonly spared in collagenous colitis (4 0%) than lymphocytic colitis (10%). Lymphocytic colitis is characterized by >20 intraepithe lial lymphocytes per 100 surface cells, and a normal basement membrane. Collagenous colitis is diagnosed on finding a subepithelial collagen band thickened to 10 m (the normal basem ent membrane is 3 m). The crypt architecture is normal in microscopic colitis. The variant s of microscopic colitis are OXFORD CASE HISTORIES 248 Fig. 36.1 (see color plate 17) Photomicrograph showing chronic inflammatory cells in the la mina propria, and intraepithelial lymphocytosis (arrow), consistent with lymphocytic coliti s. not exclusive: patients have been reported who have, at different times, three of the subty pes (lymphocytic colitis, collagenous colitis, and not- otherwise-classified). 36d) What are the etiology and mechanism of the diarrhea? The cause of microscopic colitis is not known. The hypothesis that an unidentified luminal antigen elicits an unregulated epithelial immune response in a genetically susceptible indi vidual is supported by the observation that diversion of the fecal stream leads to regressi on of inflammation, which returns once bowel continuity is re-established. This hypothesis is further strengthened by the response of microscopic colitis to an elemental diet. Famili al occurrence of microscopic colitis and lymphocytic colitis has been reported. Patients wi th lymphocytic colitis seem to be more likely to have a family history of coeliac disease, inflammatory bowel disease, and collagenous colitis. Familial cases may also result from sh ared environmental exposure. Infectious agents including Yersinia enterocolitica, Campyloba cter jejuni, and C. difficile have been reported in association with microscopic colitis, a nd a sea- sonal pattern of lymphocytic colitis has been suggested, but studies are inconclu sive. Stool culture is (by definition) negative at diagnosis. CASE 36 249 Many drugs have been associated with microscopic colitis, but causal- ity is not necessaril y proven. The association with autoimmune diseases raises the possibility of autoimmune eti ology, but no known antibody or serum marker exists. The mechanism of the diarrhea is not k nown precisely, but there is a secretory component with reduced net absorp- tion of Na+ and Cl \200\223. Nitric oxide is greatly increased in the colon, in proportion to the inflamma tion. Nitric oxide synthesis is induced by NFKB, which is activated in the epithelium of pa tients with collagenous colitis. Epithelial damage and possibly a barrier to diffusion crea ted by the collagen layer in collagenous colitis may contribute. On the other hand, fasting reduces diarrhea and indicates an osmotic component. Bile acid malabsorption may coexist a nd worsen diarrhea. 36e) How would you manage this patient and what is the long-term outlook? Specific therapy includes withdrawing offending drugs and prescribing a corticosteroid with low systemic bioavailability, assuming that the diarrhea is interfering with lifestyle, as it was in our patient. Diclofenac was the likely cause in our patient and she was advised to stop this and substitute paracetamol, augmented by a trial of acupuncture and physio- th erapy for her back pain. Budesonide is the drug of choice. Budesonide 9mg/day for 6 \200\2238 weeks has been shown t o be effective in collagenous colitis for symptom resolu- tion and improvement of histology . It is then tapered to 6mg and then 3mg for respective 4 week periods, but lower doses may be effective. This is also effective in >90% of patients with lymphocytic colitis. Cortico steroids are not popular with patients, so care should be taken to discuss the reasons for using a corticosteroid that has a topical action on the colon and a low incidence of system ic side effects. The rapid resolution of diarrhea within days is usually greatly appreciate d. Dietary factors which may exacerbate diarrhea need to be excluded, including excessive alco hol intake and caffeine consumption. A dairy- free diet is rarely worthwhile. Concomitant d iseases including hyperthy- roidism and coeliac disease should be excluded. Drugs other tha n corticosteroids are not often effective. Mild diarrhea may be treated with colestyramine, a resin that binds bile acids, at 4g 1 \200\2233 times/day. Colesevelam is an alternative that is often more palatable. Loperamide has often already been tried by the patient to lit tle effect. Mesalazine can be tried and benefits about half, but less frequently induces re mission. There have been no adequate controlled trials. OXFORD CASE HISTORIES 250 Relapse occurs in two thirds if an offending agent cannot be identified or stopped. Intermi ttent or even long-term treatment with budesonide at the lowest effective dose may be requi red, although there is no trial to support this. In these circumstances calcium and vitamin D supplemen- tation should be considered (although treatment with budesonide for 2 years h as not been associated with significant loss of bone density). Azathioprine has been tried in corticosteroid-dependent microscopic colitis, although no controlled data have been publ ished. The long-term outlook is good, with 60 \200\22380% in long-term remission without me dica- tion, and normalization of histology after 3 years. A very small number of patients m ay have such refractory disease that requires surgical inter- vention, including split ileo stomy or colectomy. There is no increased risk of colorectal cancer with respect to the gen eral population. Further reading Bartlett JG (2002). Antibiotic-associated diarrhea. N Engl J Med; 346: 334 \200\2239. Chand e N, MacDonald JK, McDonald JW (2009). Interventions for treating microscopic colitis: a Co chrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group systematic re view of randomized trials. Am J Gastroenterol; 104: 235 \200\22341. Tysk C, Bohr J, Nyhlin N, Wickbom A, Eriksson S (2008). Diagnosis and management of microscopic colitis. World J Gastroenterol; 14: 7280 \200\2238. CASE 37 251 Case 37 A 19-year-old first-year university student was transferred to the emergency department sho rtly after the start of her second term, bedridden for a week, and with a history of anorex ia nervosa. On examination, she weighed 28.8kg (BMI 10.9kg/m2), had a bradycardia (pulse 46bpm), a temperature of 35.6oC, and blood pressure 94/57mmHg. Investigations showed: 9/L, platelets 79 x 109/L Hb 17.5g/L, WCC 9.0 x 10 mol/L Na 140mmol/L, K 3.6mmol/L, creatinine 84 Phosphate 0.33mmol/L, magnesium 0.92mmol/L Bilirubin 58 mol/L, ALT 540 IU, ALP 570 IU, albumin 39g/dL CRP normal Over the next 2 days, her blood results changed (Table 37.1). Table 37.1 Change in blood results Day Na K Cr Ca P Mg Bil ALT ALP Alb Hb Pl 1 140 2.8 73 2.35 0.72 0.83 67 586 628 35 14.3 45 2 139 3.6 70 2.25 0.65 0.84 68 601 681 36 15.2 33 Questions 37a) What is the most likely cause of hypothermia, bradycardia, and thrombocytopenia with a bnormal liver function tests in this patient? 37b) What other diagnoses should be considered in a patient with anorexia nervosa? 37c) How is the patient \200\231s condition best treated? 37d) What is the legal context in which treatment is conducted? 37e) What is the short-term and long-term prognosis? OXFORD CASE HISTORIES 252 Answers 37a) What is the most likely cause of hypothermia, bradycardia, and throm- bocytopenia with abnormal liver function tests in this patient? Anorexia nervosa is the likely cause of all of this patient \200\231s medical prob- lems. V irtually all organ systems are disrupted through starvation, char- acterized by anorexia ne rvosa. This patient is critically ill and needs admission for emergency medical care. The m ost striking feature is the BMI of 10.9kg/m2. Thrombocytopenia and abnormal liver function tests occur at a very late, pre-terminal stage of starvation.