: 2.0 \200\2232.5mg/kg/day of azathioprine, Azathioprine or mercaptopurine or 1.0 \200\2231 .5mg/kg/day of mercaptopurine, appear to be effective in both closing and maintaining closu re of perianal fistulae. Evidence comes from a meta-analysis of five trials where perianal fistula closure was assessed as a secondary endpoint. Over 50% of patients treated dem- ons trated fistula healing versus 21% of controls. In this case azathio- prine was started as p rimary prophylaxis to reduce the risk of relapse, because of the poor prognostic features. Infliximab or adalimumab : infliximab was the first agent shown to be effective in a contro lled trial for inducing closure of perianal fistulae, and for maintaining this response. Fo r treatment of simple or com- plex perianal fistulae, 5mg/kg infusions at weeks 0, 2, and 6 induced complete cessation of all drainage in 69% at 14 weeks. After a year of maintenance infliximab 5mg/kg every 8 weeks, 36% had complete closure compared with 19% on placebo (p= 0.009), with a reduction in hospitalization and surgery. The combination of medical and sur gical management has not been subject to a randomized trial, but case series report around two-thirds achieving complete closure. This patient had adalimumab at an early stage after drainage of the abscess, because of the poor prognostic features. It was stopped because of practical constraints on availability and he had recurrent fistulae. He needed further examinations under anesthetic and seton pl acement, which remained in place over 6 months. He was restarted on adalimu- mab and is now well, with no evidence of fistulizing disease for over 2 years. Further reading Ardizzone S, Maconi G, Cassinotti A, Massari A, Bianchi Porro G (2007). Imaging of perinanal Crohn \200\231s disease. Dig Liv Dis; 39: 970 \200\22378. Behm BW, Bickston SJ (2008). Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn \200\231s disease. Cochrane Database Syst Rev; 1: CD006893. Hyder SA, Travis SPL, Jewell DP, George BD (2006). Fistulating anal Crohn \200\231s disease : results of combined surgical and infliximab treatment. Dis Colon Rectum; 49: 1837 \200\2234 1. OXFORD CASE HISTORIES 126 Kamm MA, Ng SC (2008). Perianal fistulizing Crohn \200\231s disease: a call to action. Clin Gastro Hepatol; 6: 7 \200\22310. Parks AG, Gordon PH, Hardcastle J (1976). A classification of fistula-in-ano. Br J Surg; 63 : 1 \200\22312. Pearson DC, May GR, Fick GH, Sutherland LR (1995). Azathioprine and 6-mercaptopurine in Crohn \200\231s disease. A meta-analysis. Ann Intern Med; 122: 132 \200\22342. Singh B, George BD, Mortensen NJ (2007). Surgical therapy of perianal Crohn \200\231s disea se. Dig Liv Dis; 39: 988 \200\22392. CASE 20 127 Case 20 A 36-year-old woman, who worked as a bank teller, was referred with an 18-month history of epigastric pain. The referring family practitioner had checked Helicobacter pylori serology , which was positive. Triple eradication therapy had been prescribed and her symptoms had s ettled for a while, but recurred. Serology for H. pylori was again positive. Triple therapy was again given, but symptoms persisted. She was referred for consideration of endoscopy. She reported epigastric pain made substantially worse by food. Symptoms improved with anti- acids and omeprazole, but not entirely. She complained of nausea, but no vomiting, and ther e had been no change in bowel habit. She had recently been treated for iron deficiency and had lost weight after dieting, although she remained overweight on examination, with no oth er abnormality. In view of weight loss and iron deficiency in the context of persistent dyspepsia, a gastro scopy was requested. This was reported as normal; duode- nal biopsies were normal, but gast ric biopsies revealed H. pylori-associated gastritis. She was prescribed third-line therapy for H. pylori (tetracycline 500mg and bismuth subsali cylate 525mg four times daily, metronidazole 400mg three times daily, and omeprazole 20mg t wice daily, all for 2 weeks). On completion of this complex course her symptoms had improve d, but not disappeared. A C14-urea breath test confirmed H. pylori eradication. Since her p ain was worse after meals, a prokinetic drug was added with some effect. Questions 20a) What is dyspepsia? 20b) How are symptoms of dyspepsia caused when there is no ulcer? 20c) What are the indications for H. pylori eradication? 20d) What are the appropriate tests for H. pylori? 20e) What is the further management of this patient? OXFORD CASE HISTORIES 128 Answers 20a) What is dyspepsia? The term dyspepsia encompasses a heterogeneous group of disorders. It can be defined as the presence of epigastric pain after eating. It is generally applied to symptoms thought to b e of gastroduodenal origin and should exclude heartburn, or symptoms thought to be originat ing from the biliary tree or pancreas. For clinical convenience, it can be sub- classified into uninvestigated and investigated. In primary care dyspepsia is extremely common and may affect up to 30% of the population at one time or another. \200\230Test and treat \200\231 is a practical initial approach to management. Patients wi thout alarm signs of weight loss, vomiting, evidence of gastrointesti- nal bleeding or anem ia, and not on NSAIDs, can have a non-invasive test for H. pylori (see below). If positive, eradication therapy is given and the patient reassessed. Upper gastrointestinal endoscopy is appropriate for patients with dyspepsia and alarm symptoms, those with new-onset dyspeps ia >50 years of age, and where symptoms persist despite eradi- cation of H. pylori. This is indicated to identify peptic ulcer disease, coeliac disease, cancer, or gastro-oesophageal reflux, which are the com- mon causes of organic dyspepsia. In the absence of alarm signs, an endoscopy will usually be normal and is unlikely to make any difference to management. Dyspepsia in the absence of an organic cause is known as functional dyspepsia, or non-ulcer dyspepsia. The Rome III diagnostic criteria for functional dyspepsia stipulate that the di agnosis can be made where one or more symptoms including bothersome postprandial fullness, early satiation, epigastric pain or epigastric burning, have been present for at least 3 mo nths, with first onset 6 months before diagnosis, in a patient with no structural explanati on for their symptoms. Our patient had a normal endoscopy, with normal distal duodenal biopsies excluding coeliac disease. Her symptoms were predominantly postprandial and, given the time scale, she met th e Rome III criteria for a diagnosis of functional dyspepsia. The finding of H. pylori-assoc iated gastritis does not explain her symptoms, since functional dyspepsia persists after ef fective treatment of H. pylori in most patients. The inter- action between H. pylori and dy speptic symptoms is complex; a positive test does not exclude functional dyspepsia. Nausea may be of central or gastroduodenal origin and does not change the diagnosis of functional dyspepsia in our patient. CASE 20 129 20b) How are symptoms of dyspepsia caused when there is no ulcer? Three factors are thought to be involved in functional dyspepsia. These are delayed gastric emptying (in about 25%), impaired gastric fundal relaxation in response to a meal with res ulting impaired accommoda- tion (in about 40%), and visceral hypersensitivity, specifically in the duodenum in response to acid or lipids. Basal acid secretion is normal in patients with functional dyspepsia. Smoking, alcohol intake and NSAIDs are not risk factors for deve loping functional dyspepsia, although once functional dyspepsia has occurred, then patients are more likely to develop symptoms if they use NSAIDs. The role of H. pylori in functional dyspepsia remains unclear. It is pos- sible that H. pyl ori infection constitutes a spectrum of illness, from asymp- tomatic infection with an exag gerated (2-fold increase) gastric acid response to a stimulus, through symptoms of dyspepsi a without ulcera- tion (associated with a stimulated increase in gastric acid production of up to 4-fold), to peptic ulcer disease in patients with a marked (6-fold) increase in stim ulated gastric acid production. This is likely to be an over- simplification. It does not a ccount for the diversity of patients with asymp- tomatic, but severe fundal- or pan-gastrit is associated with reduced gastric acid production, in contrast to those with antral gastri tis who develop peptic ulcer disease. Furthermore, <10% of patients with dyspepsia who are positive for H. pylori and undergo eradication therapy have symptom resolution. Nor does it account for those with atrophic gastritis, intestinal metaplasia, and an increased risk of gastric cancer. Psychological factors, especially anxiety, are associated with functional dyspepsia. Whether this is causal or whether it influences health-seeking behavior, is uncl ear. 20c) What are the indications for H. pylori eradication? An initial \200\230test and treat \200\231 approach for our patient was appropriate. She w as young and at the time of presentation, had no alarm signs. This strategy is cost effecti ve as long as the population prevalence of H. pylori is >15%. Below this threshold, there i s an increase in false- positive tests, followed by unnecessary treatment with antibiotics. Nevertheless, the number-needed-to-treat is between 12 and 15 (NNT = the number of patient s with H. pylori and dyspepsia who need to receive eradication therapy in order to achieve symptom resolution in 1 patient). The general view is that H. pylori eradication for uninve stigated dyspepsia without alarm signs is recommended and reasonable. This approach in our patient was, however, unsuccessful. She had an upper gastrointestinal endoscopy, because an emia and some weight loss had OXFORD CASE HISTORIES 130 occurred, so coeliac disease and other disorders needed excluding. Had she had persistent s ymptoms after eradication therapy without alarm signs, a breath test would have confirmed w hether or not H. pylori infec- tion was still present. She was found to have persistent H. pylori infection and unexplained iron deficiency anemia. Severe H. pylori-associated gastritis has been associated with iron defi- ciency, but shoul d not be assumed to be the cause unless other causes, including coeliac disease, have been excluded. Possible mechanisms include occult blood loss from gastritis, reduced availabilit y of ferrous iron for absorption due to reduction in acid production, or bacterial utilizat ion of iron. It is conceivable that H. pylori infection may exacer- bate iron deficiency du e to other causes, or reduce response to replace- ment therapy, notably in pregnancy or men orrhagia. Consequently H. pylori eradication is recommended in patients with iron deficienc y, if infected. Investigation of the colon is still mandatory, and H. pylori can only be as sumed to be the cause of iron deficiency once other causes for blood loss have been exclude d. Another indication for eradication ther- apy is long-term proton pump inhibitor therapy. It is possible that proton pump inhibitors in the context of active H. pylori infection ma y accelerate the loss of specialized gastric glands with resulting atrophic gastritis and a n increased risk of gastric cancer. It is also established that H. pylori is a known gastri c carcinogen. Although population screening is not recommended, it is difficult to ignore a positive test. Testing and not treating does not make sense in practice. 20d) What are the appropriate tests for H. pylori? Our patient had a serological test for H. pylori and was then retested after treatment. Thi s is inappropriate, but all too common in practice, due to misunderstanding basic immunolog y. Serology is simple, widely available and inexpensive, unaffected by proton pump inhibito r (PPI) therapy, but is unable to distinguish between past and current infection. The princ ipal role for serology is at initial presentation: infection is assumed to be current if th e antibody is positive and no eradication therapy has been given. It is an IgG antibody tes t, so will remain positive after eradication. Confirmation of eradication is best performed by the urea breath test, at least 4 weeks aft er treatment, once the patient has been off PPI therapy for at least 2 weeks. The urea brea th test has a sensitivity of 94% and a specifi- city of 95%. Endoscopic confirmation of era dication is only appropriate in those patients who need an endoscopy for other reasons, suc h as a gastric CASE 20 131 ulcer that needs re-biopsy, or if antibiotic sensitivity of the Helicobacter spp. needs to be determined in refractory disease. At endoscopy, antral biopsies for H. pylori should be sent for histopathology or a rapid urease test may be performed. Rapid urease testing read within an hour has an accuracy of 90%. The sensitivity improves up to 24 hours at the cost of specificity. For urea breath test and rapid urease testing, PPI therapy can lead to fals e- negative results so is best stopped 2 weeks before endoscopy if this matters. Our patien t had positive H. pylori serology, followed by eradication therapy and then (inappropriatel y) repeat serology. Subsequent biopsies taken at endoscopy confirmed active H. pylori-assoc iated gastritis. As far as treatment is concerned, first-line eradication therapy would have been a PPI (e.g . lansoprazole 30mg or omeprazole 20mg), clarithro- mycin 500mg and amoxicillin 1g or metro nidazole 400mg, all twice daily for 1 week. These regimens achieve up to 90% eradication af ter 7 days, but higher rates of eradication are reported after 14 days \200\231 therapy. Ma crolide antibiotics in the general population are blamed for resistance to clarithromycin ( 4% in northern Europe, but up to 20% in southern Europe). Metronidazole resistance is 20 \200\22340% in Europe, but as high as 80% in developing nations, due to its extensive use a gainst parasites. For second-line therapy, a repeat course of antibiotics (emphasizing the need for adherence ), but exchanging metronidazole for amoxicillin or vise versa) is recommended. Local practi ce may differ. For third-line therapy, the addition of bismuth (as in our case) is recommen ded, but clarithromycin avoided, unless the strain of H. pylori is known to be sensitive. T etracycline was used as an alternative in our case. Failure of third-line therapy is an ind ication for antral mucosal biopsy for antibi- otic susceptibility testing at a specialist c enter. No recommendations for fourth-line therapy exist, but levofloxacin and rifabutin hav e emerged as possible candidates. Fluoroquinolones (such as levofloxacin) are increasingly associated with Clostridium difficile-associated diarrhea, while rifabutin may promote myco bacterial resistance. 20e) What is the further management of this patient? Functional dyspepsia may be divided into a postprandial distress syndrome (meal-related fun ctional dyspepsia), characterized by early satiation and/or postprandial fullness and an ep igastric pain syndrome (meal-unrelated functional dyspepsia). Meal-related symptoms are att ributable to dysmotility, whereas meal-unrelated symptoms appear to respond better to acid suppression. There is substantial overlap between the two groups. It follows that once H. p ylori has been eradicated, OXFORD CASE HISTORIES 132 persistent meal-related symptoms are appropriately treated with a prok- inetic such as domp eridone 10mg before a meal. Metoclopramide is an alternative, but crosses the blood \200 \223brain barrier and may cause dystonia in a minority. A PPI may be added if postprandial symptoms persist. For meal-unrelated symptoms, PPI therapy is first line, with the later ad dition of a prokinetic if necessary. To either pattern of symptoms, a tricyclic is the next step. A tiny dose of amitriptyline (10 \200\22325mg at night) is often used, but evidence of efficacy is limited. Further reading DuBois S, Kearney DJ (2005). Iron-deficiency anemia and Helicobacter pylori infection: A review of the evidence. Am J Gastroenterol; 100: 453 \200\2239. Geeraerts B, Tack J (2008). Functional dyspepsia: past, present and future. J Gastroenterol ; 43: 251 \200\2235. Malfertheiner P, Megraud F, O Morain C, Bazzoli F et al. (2007). Current concepts in the ma nagement of Helicobacter pylori infection: the Maastricht III consensus report. Gut; 56: 77 2 \200\22381. Megraud F (2007). Helicobacter pylori and antibiotic resistance. Gut; 56: 1502. O \200\231M orain C (2006). Role of Helicobacter pylori in functional dyspepsia. World J Gastroenterol; 12: 2677 \200\22380. Tack J, Talley NJ, Camilleri M, Holtman G et al. (2006). Rome III Gastroenterol; 130: 1466 \200\22379. CASE 21 133 Case 21 The gastroenterology registrar was called to see a 38-year-old woman with multiple sclerosi s, right upper quadrant pain, and fever. She had had chole- cystitis a week earlier and a l aparoscopic cholecystectomy 5 days ago. Histopathology had shown a gangrenous gallbladder w ith several areas of microperforation. Initially her recovery had been good, but on postope rative day 5 she developed severe right upper quadrant pain, back pain, and fevers. Her onl y medications were the oral contraceptive pill and interferon treatment for her multiple sc lerosis. There was a family history of thrombosis, and pro- phylactic low molecular weight heparin had been given perioperatively. On examination her pulse was 100bpm and blood pressure 130/70mmHg, with a temperature of 37 .9 C. There was no rebound tenderness in the abdo- men, but there was mild tenderness in t he right upper quadrant. There was no hepatomegaly, splenomegaly or ascites. Wounds from th e laparoscopic surgery did not appear to be inflamed. Rectal examination was normal. Investigations showed: 9/L, platelets 360 x 109/L Hb 14.5g/dL, WCC 12.5 x 10 mol/L Na 135mmol/L, K 4.0mmol/L, urea 6.0mmol/L, creatinine 100 mol/L, ALT 60 IU/L, ALP 100 IU/ L, GGT 66 IU/L Bilirubin 10 Prothrombin time 11.0 sec Questions 21a) What is the most likely cause of the abdominal pain? 21b) What investigations should be done to confirm the diagnosis? 21c) Why does this problem occur? 21d) What are the possible consequences of the above condition? 21e) How should this patient be managed? OXFORD CASE HISTORIES 134 Answers 21a) What is the most likely cause of the abdominal pain? The most likely diagnosis is acute portal vein thrombosis. The clinical features of portal vein thrombosis differ according to the stage at which the portal vein thrombosis is discov ered. Acute portal vein thrombosis (as in our patient), generally presents with abdominal p ain, radiating to, or predominantly in the back. Occasionally there are no symptoms; it dep ends on the degree of occlusion. High fever may be present in the absence of any infection. Crampy abdominal pain, ileus, rectal bleeding, rebound tenderness, metabolic acidosis, and renal or respiratory failure can occur if there is complete occlusion or any complications . The pro- portion that progress to chronic portal vein thrombosis and the influ- ence of t reatment are unknown. In some patients, portal vein thrombosis can occur silently with non- specific symptoms, and the cause of portal vein thrombosis is often discovered in retrospec t, after gastrointestinal hemorrhage occurs. The differential diagnosis includes a subphrenic collection and bile duct injury from surge ry resulting in a biliary leak with secondary biliary peritonitis. Both are less likely on clinical grounds: a tender liver with a sympathetic pleural effusion would be expected in t he former and rebound tenderness in the latter. 21b) What investigations should be done to confirm the diagnosis? Doppler ultrasonography is a first-line investi- Duplex (or color-flow) gation, because of accuracy, cost, and lack of intervention. It is limited by obesity and overlying bowel gas that prevents imaging of the portal vein. It helps exclude an abdominal (subphrenic) collec tion (as in our case). Contrast -enhanced CT abdomen: the portal vein supplies 75% of the blood flow to the liver. Therefore, peak liver contrast enhancement occurs during the portal venous phase, and a de crease in portal flow can be detected. Magnetic resonance angiography needs to be precisely defined. is required only if the anatomy 21c) Why does this problem occur? General thrombogenic factors are present in approximately 60% Local factors are present in approximately 40%. This explains why in the course of chronic (although latent) state of thrombophilia, throm- bosis develops suddenly in the portal veno us system CASE 21 135 : acute pancreatitis, diverticulitis, Focal inflammatory lesions appendicitis (Bacteroides spp. bacteraemia), cholecystitis, inflam- matory bowel disease : splenectomy, colectomy, gast- Injury to the portal venous system rectomy. As a rule, thes e operations do not precipitate portal venous thrombosis unless there is an associated thro mbogenic state or portal hypertension Malignancy : especially lymphoproliferative or hematological disease or (e.g. polycythaemia rubra vera), causing prothrombotic changes or compression Cirrhosis : advanced disease Multiple factors are present in 15% of patients No identifiable cause : in 20% of patients. 21d) What are the possible consequences of the above condition? Portal vein thrombosis is an important condition because of serious long-term complications . The possible consequences of portal vein thrombosis are as follows. Extension of the thrombus upstream Ischaemia results from the extension of the thrombus into the mesenteric veins and venous a rches. When ischaemia continues for several days, intestinal infarction may follow. Intesti nal infarction is responsible for death resulting from peritonitis and multiple organ failu re in up to half of those who die from portal vein thrombosis, even when resection of the i nfarcted gut is carried out. Extensive intestinal resection due to venous thrombosis is a m ain cause of short bowel syndrome leading to long-term parenteral nutrition (see Cases 33, 49). Small bowel stenosis rarely com- plicates mesenteric venous ischaemia. Extension of the thrombus downstream Unless thrombosis occurs in a patient with underlying cirrhosis, the con- sequences for the liver are barely discernible. The serum albumin and prothrombin time usually remain at low normal values, while bilirubin is normal. There is also rapid development of collateral ve ins, often leading to cavernous transformation of the portal vein. Portal hypertension Portal pressure is increased to allow portal perfusion through collateral veins. Gastrointe stinal bleeding from oesophageal and gastric varices OXFORD CASE HISTORIES 136 may occur after an unpredictable period. Ascites does not occur in isolated portal vein thr ombosis, and the presence of ascites or abnor- mal liver function tests raises the possibil ity of coexistent hepatic vein occlusion. 21e) How should this patient be managed? This patient needs to be anticoagulated to reduce the risk of complica- tions or more exten sive thrombosis, initially with therapeutic doses of subcutaneous low molecular weight hepa rin. A thrombophilia screen (below) is appropriate, then warfarin commenced. The duration o f war- farin therapy depends on whether thrombogenic factors are found: life long if presen t, for 6 months if not. The oral contraceptive pill should be stopped. Thrombophilia should be excluded, even when there is a local cause for portal vein thrombos is. The converse also applies. Comprehensive investigation is recommended (Tables 21.1, 21. 2, 21.3) because several thrombogenic factors may occur in the same person. Specialist haem ato- logical advice is generally appropriate. Our patient was found to have protein C deficiency, and life-long anticoagulation was recommended. Table 21.1 Acquired thrombophilic conditions Condition Investigations Primary myeloproliferative disorders JAK-2 mutation Refer to hematologist for bone marrow biopsy Paroxysmal nocturnal haemoglobinuria Blood flow cytometry for CD55 and CD59 deficient cells Antiphospholipid syndrome Anticardiolipin ELISA, lupus anticoagulant Hyper-homocysteinaemia Serum homocystein concentration after methionine load Systemic illness, such as ulcerative colitis, Crohn \200\231s disease, Beh et \200\231s di sease As indicated by symptoms CASE 21 137 Table 21.2 Inherited thrombophilic conditions Condition Investigations Antithrombin Antithrombin concentration Protein C deficiency Protein C concentration Protein S deficiency Protein S concentration Factor V Leiden deficiency Activated protein C resistance/G1691A polymorphism Factor II gene mutation G20210A polymorphism Methyl-tetrahydrofolate reductase mutation C677T polymorphism Table 21.3 Risk factors for portal vein thrombosis Oral contraceptives Mild increased risk of portal vein thrombosis. Associated cause of thrombophilia common. Pregnancy Uncommonly reported in association with portal vein thrombosis Further reading Harmanci O, Bayraktar Y (2007). Portal hypertension due to portal venous thrombosis: etiology, clinical outcomes. World J Gastroenterol; 13: 2535 \200\22340. James AW, Rabl C, Westphalen AC, Fogarty PF, Posselt AM, Campos GM (2009). Portomesenteric venous thrombosis after laparoscopic surgery: a systematic literature revie w. Arch Surg; 144: 520 \200\2236. Primignani M, Mannucci PM (2008). The role of thrombophilia in splanchnic vein thrombosis. Semin Liver Dis; 28: 293 \200\223301. Spaander VM, van Buuren HR, Janssen HL (2007). Review article: The management of non-cirrhotic non-malignant portal vein thrombosis and concurrent portal hypertension in ad ults. Aliment Pharmacol Ther; 26(Suppl. 2): 203 \200\2239. Thomas RM, Ahmad SA (2009). Management of acute post-operative portal venous thrombosis. J Gastrointest Surg Jul 7 [epub ahead of print]. OXFORD CASE HISTORIES 138 Case 22 A 67-year-old Caribbean woman with chronic renal disease needing dialysis was admitted with diarrhea. Three months before she had had an episode of antibiotic-associated diarrhea, re sulting from Clostridium difficile. She had been treated, the diarrhea had resolved, and sh e had no further courses of antibiotics in the interim. She also had psoriasis, had been on prednisolone for many years, and had diverticulosis. At presentation, she described diarrhea for 5 days, with loss of continence, preceded by so me rectal bleeding 2 days before that. No family members had diarrhea. The day before prese ntation, she had developed abdominal pain, which was getting worse. She had collapsed at ho me, feverish, confused and shaking (possibly a rigor). Her temperature was measured at 38 C. On examination, she had a pulse rate of 100bpm, respiratory rate of 14/min and a blood pres sure of 140/65. Abdominal examination revealed a tender lower abdomen, with guarding and pe ritonism. Diverticulitis was diagnosed, and she was treated with intravenous coamoxiclav an d metronidazole. Investigations on admission showed: 9/L, platelets 172 x 109/L Hb 13g/dL, WCC 12.6 x 10 CRP 159mg/L mol/L Na 135mmol/L, K 5.0mmol/L, urea 25.4mmol/L, creatinine 526 LFTs normal, albumin 36g/L Abdominal radiograph: non-specific bowel gas pattern Chest radiograph: no free intraperitoneal air, lungs clear CT of the abdomen: enhanced fluid-filled sigmoid and ascending colon, in keeping with colit is. No signs of perforation. No collection (Fig. 22.1). The following day she had had six diarrhoeal stools over 12 hours, and was pyrexial with a heart rate of 136bpm. Abdominal examination was unchanged apart from distension. Stool exam ination had detected Clostridium difficile toxin (CDT). Coamoxiclav was stopped, oral vanco mycin started (125mg four times daily), with intravenous hydrocortisone 100mg four times, a nd metro- nidazole 500mg three times daily. Her clinical condition did not improve. She was transferred to gastroenterology and an urgent surgical opinion was requested. CASE 22 139 Fig. 22.1 Contrast-enhanced CT scan of the abdomen, showing a fluid-filled colon (arrow), w ith enhancement of the colonic wall, in keeping with colitis. Investigations on transfer showed: 9/L, platelets 203 x 109/L Hb 12.0g/dL, WCC 18.21 x 10 CRP >160mg/L mol/L Na 138mmol/L, K 4.5mmol/L, urea 24.5mmol/L, creatinine 418 LFTs remained normal, albumin 23g/L Abdominal radiography: dilated colon with a maximum diameter of 11.5cm (caecum). No evidenc e of free gas (Fig. 22.2). Questions 22a) Why is C. difficile infection becoming more severe? 22b) What is the diagnosis in this patient and how is it best made? 22c) How is severe C. difficile-associated diarrhea best treated? 22d) Discuss the complication that has occurred and its management. 22e) What strategies may prevent outbreaks in hospitals? OXFORD CASE HISTORIES 140 Fig. 22.2 Plain abdominal radiograph showing dilatation of the transverse and descending co lon, with marked caecal dilatation, measuring 11.5cm (arrow). This page intentionally left blank OXFORD CASE HISTORIES 142 Answers 22a) Why is C. difficile infection becoming more severe? Virulence is attributed to an increase in the production of toxins A and B. This appears to be due to mutations in the tcdC regulatory genes, the product of which normally regulates and inhibits production of toxins A and B by tcdA and tcdB genes, respectively. The consequ ence is a 10-fold increase in production of toxins A and B by the NAP1/027 strain, relative to the many toxigenic strains that cause milder disease. Non-toxigenic strains do not caus e disease. In addition to toxins A and B, NAP1/027 strains produce a third toxin, called bi nary toxin, unrelated to the gene loci for toxin A or B. Binary toxin is enterotoxic, but i ts role is currently unclear. NAP1/027 strains have a high level of resistance to fluoroqui - nolone antibiotics, which has not previously been seen. The emergence of resistant strains is favored in hospital environ- ments, where fluoroquino lones are commonly prescribed. Some of the increased mortality is related to sicker, more e lderly patients in the cur- rent hospital environment. It has been recognized, however, tha t Clostridium difficile-associated diarrhea can affect young people in the community throug h direct person-to-person contact, peripartum women, and patients with inflammatory bowel d isease. 22b) What is the diagnosis in this patient and how is it best made? This patient has pseudomembranous colitis and toxic megacolon. C. difficile infection can b roadly be considered as a spectrum from asymptomatic carriage, to C. difficile-associated d iarrhea, to pseu- domembranous colitis (loosely defined as Clostridium difficile-associated diarrhea with a systemic inflammatory response, sometimes referred to as severe CDAD). Any hospitalized patient with diarrhea, especially those who have had an antimicrobial within the preceding 8 weeks, should be tested for C. difficile toxin. Common culprit antibiotics are cephalosporins and fluoroquinolones. Clindamycin was a particular cause in the past, bu t is now used much less frequently. Additional risk factors include immunosuppression, uraemia, age >65 years, burns, chronic p ulmonary disease, cancer, proton-pump inhibitor therapy, chemotherapy, post-pyloric tube fe eding, and admis- sion to an intensive care unit. Diarrhea is the hallmark and the most com mon presentation, but unexplained leucocytosis in a hospitalized patient should prompt a se arch for C. difficile toxin. Diagnosis of CDAD requires demonstration of bacterial toxin in the feces. The \200\230gold stand- ard \200\231 is the stool cytotoxin assay with a sensi tivity of 67 \200\223100% and CASE 22 143 specificity of 85 \200\223100%. It takes up to 3 days, and ELISA is faster and cheaper. ELI SA is less sensitive if an assay is used that tests only for toxin A. Tests for both toxins (TOX A/B TEST) have a sensitivity of 92 \200\22394% and a specificity of 100%. The chance of a false-negative result reduces if the test is repeated three times. Culture alone may i solate C. difficile, but does not distinguish between toxigenic and non-toxigenic strains. Flexible sigmoidoscopy with visualization of the mucosa may demon- strate non-specific coli tis, but the presence of pseudomembranes is pathognomonic (Fig. 22.3 in the central color s ection) and indicates severe disease. Plain abdominal radiography is useful to exclude toxi c dilatation (maximum colonic diameter >5.5cm). A CT scan is appropri- ate for patients wit h toxic dilatation in preference to endoscopy, to look for early signs of perforation (intr amural gas). 22c) How is severe C. difficile-associated diarrhea best treated? Treatment starts with general fluid resuscitation and withdrawal (if possible) of any offen ding antibiotic. Supportive care depends on the severity of disease at presentation, with p seudomembranous colitis being associated with hypotension, acute renal failure, abdominal p ain, disten- sion with ileus, marked peripheral leucocytosis, pseudomembranous colitis, or toxic megacolon. Before 2006, two antibiotics were commonly used. Metronidazole used to be as effective as vancomycin (response rate Fig. 22.3 (see color plate 7) Endoscopic image of the sigmoid colon, in a patient with pseu domembranous colitis. The mucosa exhibits circumferential hyperaemia and oedema. There are discrete pseudomembranes (arrow). Pseudomembranes are characteristic of pseudomembranous co litis, and indicate severe colonic involvement. OXFORD CASE HISTORIES 144 90 \200\22398%). Since then, the severity of hospital-acquired C difficile has increased an d responsiveness to metronidazole has declined. In our insti- tution, vancomycin is now fir st-line therapy in all cases. Resistance to vancomycin has not yet been described. Vancomyc in is significantly more effective than metronidazole in severe disease (98% vs 76%, p=0.02 ). On the other hand, oral vancomycin cannot be expected to have an equivalent effect in th e presence of ileus or toxic megacolon, while intravenous vancomycin is ineffective because it does not reach the intes- tinal lumen. Consequently (and without much evidence), oral v ancomy- cin and intravenous metronidazole 500mg are often used in severe cases. Teicoplanin is an alternative. To this may be added corticosteroids, on the basis that the colonic inf lammation is toxin driven, rather than infec- tive. Once again, this is empirical therapy, with only anecdotal evidence. The opinion of an experienced colorectal surgeon should be so ught in severe cases, because subtotal colectomy may be lifesaving, although the timing is always difficult to judge. Most patients have resolution of symptoms after 3 \200\2235 days . Vancomycin is generally continued for 2 weeks. Shorter courses, especially in the case of recurrent CDAD, may be associated with relapse. Following resolution of the first episode, recurrent CDAD develops in about 20%, irrespecti ve of antibiotic therapy. Recurrence probably results from impaired re-colonization with no rmal bowel flora, possibly as a consequence of the antibiotic therapy, and not from antibio tic resistance. It typically occurs 4 weeks later. Recurrence of CDAD is generally more sev ere than the initial infection, possibly because of the weakened state of a patient who oft en has multiple comorbidities. Passive immunotherapy with intravenous immunoglobulin (which contains antibodies to toxins A and B) reduces recurrence, or is effective in severe cases . Probiotics (treatment with Saccharomyces boulardii, or Lactobacillus plantarum GG) may re duce recurrence, but are ineffective as therapy. Therapies aimed at restoring bowel flora h ave been reported. Administration of donor feces (from a family member, after filtering), e ither through a nasogastric tube or at colonoscopy, have been reported to prevent recurrenc e in case series, but (perhaps not surprisingly!) such therapy remains unpopular. Other non -absorbable antibiotics such as nitazoxinide or rifaximin con- tinue to treat antibiotic-as sociated diarrhea with more antibiotics. Tolevamer, an inert polymer that binds toxins A an d B, but has no anti- microbial activity, is promising. Although inferior to current antibi otic regimens, those subjects who responded to tolevamer had fewer recur- rences (3% vs 23% after vancomycin and 27% after metronidazole). CASE 22 145 22d) Discuss the complication that has occurred and its management. Our patient with recurrent CDAD had a systemic inflammatory response syndrome (SIRS) and co lonic dilatation >5.5cm. This represents toxic megacolon and is a medical emergency whateve r the cause. Paradoxically, diarrhea may subside because of colonic dilatation and ileus, b ut tachycardia, abdominal pain, tenderness or hypotension and leucocytosis should alert the clinician to the need for (or to repeat) plain abdominal radiography. Toxic megacolon is d efined as a colonic diameter >5.5cm in a patient with SIRS, or any three of the following s igns: fever (>38 C), tachycardia (>120bpm), peripheral leucocytosis (>10.5 x 109/L), anemi a plus dehydration, altered mental status, or electrolyte disturbance. Risk factors for sev ere CDAD in our patient include recurrent CDAD and comorbidity (chronic renal disease need- ing dialysis). The lack of clinical response to treatment prompted surgi- cal consultation . Observation for a further 2 days saw no improvement, so a subtotal colectomy was carried out. It is important to recognize the limited physiological reserve of sick, elderly patien ts, so a decision to (or not to) operate should be made at an early stage by an experienced colorectal surgeon. Even timely surgery in these severely ill patients is associated with a mortality of 30%. The procedure of choice is a subtotal colectomy. Less extensive colecto my has been associated with a high mortality. Our patient made a full recovery following he r surgery. Pathology of the resected colon confirmed pseudomembranous colitis. 22e) What strategies may prevent outbreaks in hospitals? Rationalization of antibiotic use, with restrictions on cephalosporins and fluoroquinolones , reduces the incidence of CDAD. Antibiotics (even prophylactic doses, prior to certain pro cedures) should be used only when indicated. Clostridium difficile is a spore-forming bacil lus. Spores may persist for long periods in the environment and are not killed by standard alcohol-containing hand rubs available in NHS hospitals. Thorough hand washing is the only effective way of removing C. difficile spores from hands, following contact with a patient. Isolation of patients with proven CDAD may restrict spread in a ward. Of particular impor- tance is access to dedicated toilet facilities for patients with CDAD. Establishment of sp ecific wards to manage patients with CDAD, while in principle attractive, may be logistical ly impossible. Resources are often unavailable and patients still need to be managed for th eir primary illnesses. OXFORD CASE HISTORIES 146 Further reading Kelly CP, LaMont JT (2008). Clostridium difficile \200\223 more difficult than ever. N Eng l J Med; 359: 1932 \200\22340. Kuipers EJ, Surawicsz CM (2008). Clostridium difficile infection. Lancet; 371: 1486 \200 \2238. Jaber MR, Olafsson S, Fung WL, Reeves ME (2008). Clinical review of the management o f fulminant Clostridium difficile infection. Am J Gastroenterol; 103: 1 \200\2239. Gan SI, Beck PL (2003). A new look at toxic megacolon: An update and review of