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. Anorexia nervosa is a complex psychiatric illness with potentially severe medical consequen ces. Patients in the pre-terminal phase com- monly have bradycardia, hypotension, and dehyd ration; amenorrhoea and leucopenia occur at an earlier stage. Delayed gastric emptying, hai r loss, and the presence of lanugo (a fine hair pattern on the face, neck, and trunk) are a lso associated with severe anorexia nervosa. Anemia should not be attributed to anorexia ne rvosa without further investigation (below). Of particular concern for adolescents is the p otential for delayed onset of puberty and growth. Malnutrition and hormonal dysfunction may contribute to bone loss. Functional and structural brain abnormalities may also occur in indi- viduals with anorexia nervosa, including enlarged ventricles and decreased gray matter or cognitive deficits in problem solving, attention, memory, and verbal or visuospatial processing. This leads to di sorders of executive functioning, so that rational decision making is impaired. This needs to be understood by the general medical team, who are otherwise inclined to dismiss such pa tients as \200\230mad \200\231. The attitude that such patients have a self-inflicted inju ry and must accept the consequences, because they \200\230do not know what is good for the m \200\231 is a complete failure to under- stand the cognitive consequences of starvation. Electrolyte disturbances may be exacerbated by purging or induced vomiting. Elevated hepati c transaminases and renal insufficiency are warning signs of impending death. Cardiac arrhy thmias (including a prolonged QT interval) with sudden death are the consequence of hypokal aemia, hypomagnesaemia, or hypophosphataemia. 37b) What other diagnoses should be considered in a patient with anorexia nervosa? Other diagnoses that should be considered include: Coeliac disease part of this patient \200\231s workup : an anti-endomysial antibody should be checked as CASE 37 253 : a high CRP, anemia, or thrombocytosis should Crohn \200\231s disease always raise the pos sibility of Crohn \200\231s disease, which can present with anorexia, weight loss, and no p ain or diarrhea. Sadly there is a substantial literature on Crohn \200\231s disease misdiag nosed as anorexia nervosa (or pituitary failure) should be considered if Addison \200\231s disease there is a low Na with a normal or relatively high K. Very readily over- looked Paracetamol (or other drug) overdose may account for the abnormal liver function tests and needs to be considered in the context of acute deterioration in any patient with anorexia n ervosa Always beware a diagnosis of anorexia nervosa if the individual does not have the disturbed body image that characterizes the condition. 37c) How is the patient \200\231s condition best treated? The metabolic mayhem must be recognized as an emergency, but careful re-feeding will revers e the abnormalities. The major adverse consequence of medical treatment of patients with an orexia nervosa is the refeeding syndrome (see Case 49), which is potentially life threateni ng. The prin- cipal biochemical features of this syndrome are hypophosphataemia, hypomagnes aemia, hypokalaemia, fluid retention, and thiamine deficiency. This causes peripheral oedem a (a useful clinical sign of pre- terminal anorexia), congestive heart failure, cardiac dys rrhythmias, skel- etal muscle weakness, respiratory failure, metabolic acidosis, ataxia, se izures, or encephalopathy and death. When a patient with anorexia nervosa has hypokalaemia, hypophos- phataemia, elevated transa minases, bradycardia, or thrombocytopenia, urgent intravenous treatment is necessary. Initial management Intravenous fluids are required to correct dehydration. Electrolyte (K, Mg and P) replacement: the patient should be monitored twice daily until st able, which is usually within 72 \200\22376 hours (refeeding guidelines: see Case 49). Intravenous vitamins are required, including thiamine (e.g. Pabrinex 2 vials, for 3 days). Monitoring: pulse rate, blood pressure and temperature should be moni- tored every 6 hours. Patients with heart rates <50 beats/min or orthostatic hypotension should be on bed rest. OXFORD CASE HISTORIES 254 Psychiatric asessment (see below), almost invariably requiring detention under the Mental H ealth Act or equivalent, is required to ensure compli- ance with controlled refeeding. Controlled refeeding: oral refeeding is the best approach to weight resto- ration, but pati ents who are critically ill with electrolyte disturbance require controlled nasogastric fee ding. Such patients are archetypal manipulators, encouraging doctors and nurses to believe that such an invasive approach is unnecessary, that they have learned a lesson, and that or al refeeding is possible. When life is threatened by transaminitis, elec- trolyte disturban ce, or bradycardia, do not believe it. It is important to liaise with the consultant psychi atrist, but the cognitive impairment asso- ciated with starvation precludes rational behavi or. Such patients create havoc on a general ward, preventing controlled refeeding and calli ng on staff out of hours to change their treatment. Although nasogastric feeding can be vie wed as coercive by patients, in retrospect, most patients and families consider nasogastric feeding to have been helpful in recovery. It helps to have defined protocols for managemen t and (as importantly) to stick to agreed treatment plans. Dietitian: a weight gain of 0.2kg/day is a reasonable goal. The dietitian is best placed to be the single person who governs the refeeding regimen, and without whose sanction no trea tment is ever changed. This appears unduly dogmatic, but without a single person responsibl e for controlled refeeding, the regimen is always manipulated and changed, usually by appea l to doctors on call or nurses unfamiliar with the treatment plan. It should be emphasized that the dogmatic approach to controlled refeeding only applies to the stage of biochemical disturbance, since this is a life- threatening event. Once refeeding has been accomplished , a cooperative consensual approach is (inevitably) more productive. Continuous supervision: a framework for managing patients with life- threatening anorexia n ervosa is best established in advance. In practice, patients with biochemical disturbance r equiring nasogastric refeeding should have 1:1 care with a psychiatric nurse or assistant. This may seem an impossible goal, but without continuous attention, the patient will interr upt feeding (pull out the tube, tip the feed down the sink), march up and down the ward to burn energy, or binge on carbohydrates rather than follow a controlled eating schedule. Thi s then defeats the object. Since the mortality of severe anorexia nervosa is 30%, any other condition with this mortality would merit special nursing care. CASE 37 255 Consistent nursing instructions: so challenging to general medical and nursing staff are th ese patients that a protocol agreed in advance (between general physician, psychiatrist and appropriate specialist colleagues) is the only way to ensure consistent care. Distinguish between the medical emergency of the refeeding phase for biochemical disturbanc e, and the psychiatric phase for addressing the psychological disturbance that has lead to anorexia nervosa. Long-term management Medical hospitalization is often brief and does not allow adequate time for psychiatric int ervention. Liaison with a psychiatrist with a special interest in eating disorders is a cru cial part of continuing management and care. 37d) What is the legal context in which treatment is conducted? A key concept in the ethical and legal analysis relating to compulsory treatment is that of the capacity to consent to, or refuse, treatment. An adult patient with such capacity has the right to refuse any, even life-saving, treatment. On this account, compulsory treatment is only justified if the patient lacks capacity. Most mental health statutes inter- nation ally allow mental health professionals to detain and treat patients with a psychiatric diso rder who are at risk to themselves or others, with- out consideration of whether or not the patient lacks capacity. There are exceptions to this, since the question of capacity is th e key factor in the compulsory treatment of anorexia nervosa. Treatment without consent and the management of treatment refusal is particularly contentio us in the context of anorexia nervosa. The dilemma is that it is very difficult to engage p atients in psychological therapies if treatment is compulsory. Furthermore, refeeding unwil ling patients may lead to short-term weight gain, but be ineffective in the long run. Outcome studies suggest that the long-term prognosis following compulsory treatment is poor . Even if compulsory treatment were shown to be effective, there remains an ethical debate about the circumstances in which compulsory treatment is justifiable. Anorexia nervosa at a pre- terminal phase often involves implementing a refeeding program that requires the use of strict supervision, enforcement of specific dietary plans, prevention of exercising or p urging, and nasogastric feeding. Recommendations will vary according to the jurisdiction, b ut it behooves any doctor or carer to make themselves aware of the legal constraints that g overn practice. OXFORD CASE HISTORIES 256 37e) What is the short-term and long-term prognosis? Although weight-restoration therapy is reliably helpful in the short-term management of ano rexia nervosa, the long-term benefit remains unclear. Even after successful completion of s tructured behavioral programs, attitudes about weight and eating behavior remain abnormal. As a result, relapse rates are high. For inpatient treatment programs, nearly 50% with anor exia nervosa who undergo weight-restoration therapy have a relapse during the first year af ter hospitalization. After weight restoration, outpatient treatment specifically aims to pre- vent relapse. Pati ents and families are informed about the need for vigi- lance regarding eating behavior and weight. The specific type of relapse prevention is selected on the basis of the patient \200\231s previous therapy and success with initial attempts at weight maintenance. Estimates of long-term full recovery for adolescents with anorexia nervosa range from 33% t o 57%, so relapse is common. There are few controlled studies on the efficacy of relapse-pr evention strategies. Antidepressant medication appears to be of limited value, although cog - nitive behavioral therapy may help some patients. Additional studies are needed to identi fy the essential components of care for patients with anorexia nervosa, as well as relapse- prevention strategies. People with anorexia nervosa have a 6 \200\2237-fold increase in mortality (including natur al and unnatural causes of death). Anorexia nervosa itself has a standardized mortality rat io of 650. Suicide accounts for 20 \200\22330% of deaths in anorexia nervosa. Factors assoc iated with an increase in fatal outcome include: Older age at first admission (>20 years of age) Repeated admissions Hospitalization for other psychiatric and somatic disorders. Further reading Attia E, Walsh BT (2008). Behavioral management for anorexia nervosa. New Engl J Med; 360: 500 \200\2236. Papadopoulos FC, Ekbom A, Brandt L, Ekelius L (2009). Excess mortality, cause of death and prognostic factors in anorexia nervosa. Br J Psychiatry; 194: 10 \200\22317. Sylvester C, Forman S (2008). Clinical practice guidelines for treating restrictive eating disorder patients during medical hospitalization. Curr Opin Paed; 20: 390 \200\22397. Tan J OA, Hope T, Stewart A, Fitzpatrick R (2006). Competence to make treatment decisions in anor exia nervosa: thinking processes and values. Philos Psychiatry Psychol; 13: 267 \200\22382. This page intentionally left blank OXFORD CASE HISTORIES 258 Case 38 A 38-year-old Asian pharmacist was referred from the endocrinology clinic for a gastroenter ology opinion. She had been treated for hypothyroidism for 12 years, but she remained persi stently tired, despite adequate thyroid replace- ment therapy. She reported a long history of tiredness, accompanied by headaches, joint pains, blisters o n her face, and occasional mouth ulcers. Gastrointestinal symp- toms included abdominal blo ating and occasional vomiting. She was taking thyroxine, alfacalcidol, potassium, zinc, mag nesium, selenium, and vitamin C supplements. She had had a thyroidectomy and parathyroidect omy 3 years before. She was a non-smoker and drank alcohol infrequently. Her mother had dia betes mellitus, and her father and grandfather both had bowel cancer in their sixties. Phys ical examination was unremarkable. Investigations showed: 9/L, platelets 279 x 109/L, MCV 86fL Hb 12.4g/dL, WCC 6.1 x 10 g/L, folate 2.9 g/L, vitamin B12 1815ng/L 4 13.0pmol/L Ferritin 6 TSH 0.28mU/L, free-T Albumin 47g/L, Ca 2.31mmol/L, glucose 6.4mmol/L LFTs normal Endomysial antibody: negative IgA <0.05g/L HLA DQB1 0201 (DQ2), HLA DQB1 0302/11 (DQ8). Questions 38a) What is the likely diagnosis and most appropriate investigation? 38b) What is the significance of the IgA concentration? 38c) What is the significance of the HLA typing? 38d) Name other disease associations. 38e) How should this patient be managed? 38f) What if the patient does not respond to standard management? This page intentionally left blank OXFORD CASE HISTORIES 260 Answers 38a) What is the likely diagnosis and most appropriate investigation? The likely diagnosis is coeliac disease. An upper gastrointestinal endoscopy and distal duodenal biopsy should be carried out. The definitive investigation for coeliac disease is an upper gastrointesti- nal endoscopy a nd distal duodenal biopsy. The likely diagnosis of coeliac disease is suggested by the low iron and folate, both of which are absorbed in the proximal small bowel, which is primarily involved in coeliac dis- ease. A biopsy should always be recommended, even if endomysial a nti- body positive, because of the implications of a life-long gluten-free diet (below). Endoscopy: scalloped and fissured duodenal mucosa (Fig. 38.1 in cen- tral colored section) Histology: subtotal villous atrophy, crypt hyperplasia and a significant increase in intrae pithelial lymphocytes (Fig. 38.2 in central color section). The diagnosis of coeliac disease in this patient was based on the clinical symptoms (fatigu e, mouth ulcers), iron and folate deficiency, and his- topathology. The endomysial antibodi es were negative, because the patient has IgA deficiency (below). The HLA typing is charact eristic of coeliac disease, although this is generally only performed when there is diagnos tic doubt (below). Villous atrophy on its own is not specific for coeliac disease. Improvem ent of histological grade on a gluten-free diet confirms the diagnosis although, if there i s a clinical response, endos- copy is not routinely repeated. Other conditions associated w ith villous atrophy in the small bowel include giardiasis, NSAID ingestion, Crohn \200\231s disease, Whipple s disease, common variable immune deficiency, radia- tion enteropathy, HI V infection, tuberculosis, and tropical sprue (which has almost disappeared from clinical p ractice). Coeliac disease in adults now most commonly presents with iron defi- ciency anemia, but may present with non-specific gastrointestinal symp- toms such as anorexia, abdominal pain, vo miting and diarrhea, or less commonly constipation. The patient may report weight loss or f ailure to gain weight. It may also cause arthralgia, alopecia, dermatitis herpeti- formis, oral ulcers, abnormal liver functions (transaminitis), or neurologi- cal manifestations (mi graine, cerebellar ataxia, or peripheral neuropathy). CASE 38 261 Fig. 38.1 (see color plate 18) An endoscopic photograph of this patient \200\231s duodenum, showing a paucity of folds (large arrow) with fissuring (small arrow), although endoscopy in coeliac disease is commonly normal. Coeliac disease has a worldwide distribution and all races are affected. Prevalence data fr om southern Asia and Africa are scant. The true inci- dence in countries where rice, rather than wheat is the staple may be underestimated. The prevalence in Western Europe and North America is 1:100 to 1:300 people. Fig. 38.2 (see color plate 19) A photomicrograph showing subtotal villous atrophy, with blu nting of the villi (large arrow), crypt hyperplasia (small arrow), and increased intraepith elial lymphocytes (tiny arrows). OXFORD CASE HISTORIES 262 38b) What is the significance of the IgA concentration? This patient has isolated IgA deficiency. Isolated IgA deficiency is the most common primar y deficiency of humoral immunity. Low serum IgA renders the endomysial antibody test unreli able for the exclusion of coeliac disease. If the diagnosis is strongly suspected (such as in someone with unexplained iron deficiency, or a family history of coeliac disease), then small bowel (distal duodenal) biopsies need to be obtained. Antibodies to tissue transgluta minase are of the IgG subclass and are both sensitive for the diagnosis of coeliac disease in patients with IgA deficiency, but may be positive in patients with other autoimmune dis- orders. People with IgA deficiency may have antibodies to IgA, which may predispose to tra nsfusion reactions. Selective IgA deficiency is more common in patients with coeliac diseas e than in the general population, with 1 case in 40, compared with 1 in 400. There is no sp ecific therapy. IgA deficiency is thought to be associated with a higher incidence of autoi mmune disease, atopy, and infections. 38c) What is the significance of the HLA typing? The HLA typing is consistent with coeliac disease. The main value of HLA typing is to exclu de, rather than confirm the diagnosis. Not all peo- ple with either HLA DQ2 or HLA DQ8 have coeliac disease, but the dis- ease does not occur in patients without either of these alle les. Therefore, the absence of both of these alleles has a high negative predictive value. This is useful in cases where endomysial antibodies are negative and dis- tal duodenal biop sies are inconclusive. Subtle histopathological signs may be difficult to interpret, and im provement on a gluten-free diet difficult to determine if the index biopsy showed minor cha nges, such as an increase in intraepithelial lymphocytes without villous atrophy. Our patie nt had both susceptibility alleles. 38d) Name other disease associations Conditions associated with coeliac disease include: Autoimmune disorders Malignancy Chromosomal disorders. Coeliac disease is associated with autoimmune disorders (autoimmune thyroid disease, Addiso n \200\231s disease, hypoparathyroidism, pernicious anemia, and Type 1 diabetes mellitus). Patients have an increased risk of developing malignancy, including intestinal (enteropathy -associated CASE 38 263 T-cell) lymphoma and extraintestinal lymphoma, oropharyngeal and oesophageal adenocarcinoma , cancers of the small and large bowel, hepatobiliary system, and pancreas. The risk of bre ast cancer appears to be reduced. An increased frequency of coeliac disease has been report ed in patients with chromosomal disorders such as Turner \200\231s syndrome, Down \200\231s syndrome and William syndrome, but it is difficult to determine whether this reflects repo rting bias. 38e) How should this patient be managed? Management of coeliac disease includes: Lifelong gluten-free diet Screening for vitamin and mineral deficiencies Screening for osteoporosis. The only accepted therapy for coeliac disease is the life-long exclusion of gluten from the diet. This implies elimination of wheat, barley and rye. Rice, corn and oats are gluten fr ee, but oats may be contaminated with gluten during growing or processing. An experienced d ietitian should be asked to give detailed advice about gluten-free sources of starch that c an be used as flour alternatives for baking. Gluten-free prod- ucts, including bread, can b e obtained on prescription in the UK, for patients with a diagnosis confirmed by biopsy. Patient support organizations are available and patients are advised to join a local organi zation such as Coeliac UK in the UK (www.coeliac. org.uk). Newly diagnosed patients with co eliac disease should be screened for deficiencies of vitamins and minerals, including iron, calcium, vita- min B12 and folate. Any deficiencies should be treated. All patients should also be screened for osteoporosis, which is prevalent; adherence to a gluten-free diet is associated with improvement in bone mineral density, although calcium supplements are commo nly needed. The dietitian should estimate dietary calcium intake. Endomysial antibodies may be repeated after several months on a gluten-free diet; a persist ently positive test suggests poor compliance with a gluten-free diet, and is an indication for repeat endoscopy and biopsy to assess the histological response. A negative test does n ot neces- sarily imply dietary compliance, which is best assessed by a specialist dietitian . Antibodies of the IgG subclass are not reliable for follow up of dietary compliance, sinc e these remain positive. A poor clinical response is also an indication for repeat endoscop y and biopsy, although other diagnoses should be considered. OXFORD CASE HISTORIES 264 38f) What if the patient does not respond to standard management? Causes of management failure in coeliac disease include: Dietary non-compliance Wrong diagnosis Associated condition Progression to a complication. The intentional or unintentional ingestion of gluten is the usual cause of a poor therapeut ic response or recurrent symptoms. Much depends on the symptoms. The first thing to do is t o ask a dietitian to make a formal reassessment of dietary compliance. The next step is to consider the symptoms: persistent diarrhea may result from associated microscopic colitis ( remember that coeliac disease rarely causes diarrhea without weight loss), hypolactasia, ba cterial overgrowth, thyrotoxicosis, inflam- matory bowel disease, or pancreatic insufficien cy. Persistent fatigue may be due to Addison \200\231s disease, hypothyroidism, or nutritio nal deficiency (iron, magnesium, zinc). When there is loss of an initially good response, p rogression to a complication should be considered. Serious complications of coeliac disease are rare, but include refrac- tory sprue, ulcerati ve jejunitis, enteropathy-associated T-cell lymphoma, or intestinal adenocarcinoma. Repeat endoscopy with a request to the histopathologist for immunohistochemistry to exclude clonal expansion of T-cells is important, as well as cross-sectional (CT) imaging to look for lym phadenopathy. Double-balloon enteroscopy to obtain tissue is appro- priate if a lesion is i dentified; the alternative is a laparoscopic full thick- ness intestinal biopsy. Strict com pliance with a gluten-free diet reduces the risk of these complications if maintained over the long term. Further reading Cataldo F, Lio D, Marino V, Picarelli A et al. (2000). IgG1 antiendomysium and IgG antitissue transglutaminase (anti-tTG) antibodies in coeliac patients with selective IgA de ficiency. Gut; 47: 366 \200\2239. Catassi C, Fasano A (2008). Celiac disease. Curr Opin Gastroenterol; 24: 687 \200\22391. Ha ines ML, Anderson RP, Gibson PR (2008). Systematic review: The evidence base for long-term management of coeliac disease. Aliment Pharmacol Ther; 28: 1042 \200\22366. Heap GA, van He el DA (2009). Genetics and pathogenesis of coeliac disease. Semin Immunol May 13. [Epub ahead of print]. CASE 39 265 Case 39 A 76-year-old non-English speaking woman presented to the gastroenterology outpatient depar tment with a 4-month history (through an interpreter) of nausea, decreased appetite, early satiety, and 3kg weight loss. She had mild abdominal discomfort and pancreatic surgery 25 y ears previously for a pancre- atic abscess, but no history of diabetes or steatorrhoea. She had atrial fibrilla- tion, for which she was on warfarin. On examination, her pulse rate was 76 and irregular, consistent with atrial fibrillation, b lood pressure 125/86mmHg, and she was afebrile. No abdominal masses were palpable. Investigations showed: 9/L, platelets 165 x 109/L mol/L Hb 11.5g/dL, WCC 5.6 x 10 Na 130mmol/L, K 4.1mmol/L, creatinine 85 mol/L, AST 25 IU/L, ALT 35 IU/L, ALP 60 IU/L, GGT Bilirubin 20 70 IU/L. In view of the anemia and symptoms, she had a gastroscopy. This did not reveal any mucosal lesions, and the stomach inflated well, but there was an impression of extrinsic compressio n of the stomach. A CT of the abdomen was carried out (Figs 39.1 and 39.2). Questions 39a) Explain the CT appearance and the differential diagnosis. 39b) Explain the management options for this patient and the pros and cons of each option. 39c) What are the complications of the above management strategies? OXFORD CASE HISTORIES 266 Fig. 39.1 CT scan. Fig. 39.2 CT scan. This page intentionally left blank OXFORD CASE HISTORIES 268 Answers 39a) Explain the CT appearance and the differential diagnosis The CT shows a pancreatic pseudocyst. There is a low attenuation, unilocular cyst, with acc ompanying signs of an atrophic pancreas. If this were a complex pseudocyst, the density of the fluid would be higher than in an uncomplicated pseudocyst, owing to the presence of hem orrhage or gas that develops because of bacterial infection. The precise relation- ship to the stomach can be seen. There is no associated calcification or pancreatic duct dilatation . Pancreatic pseudocysts need to be distinguished from pancreatic cystic neoplasms (see Case 29), acute fluid collections, organized pancreatic necrosis, pancreatic abscess, pseudoaneu ryms, and duplication cysts. Pseudocysts result from pancreatic inflammation or trauma leading to pancreatic duct disrup tion and the accumulation of fluid in the lesser sac. They are usually anechoic on ultrasou nd and unilocular. They generally contain thin brown fluid, rich in amylase and inflam- mat ory cells, but no mucin (see Table 29.1). They are not lined by a true epithelium (hence th e term pseudo-) and therefore have no malig- nant potential. Instead, they have a thick wal l of granulation tissue that takes approximately 4 \200\2236 weeks to develop after an epis ode of acute pancreatitis. The incidence is 10 \200\22320% after acute pancreatitis and 20 \200\22340% in chronic pancreatitis. Most pseudocysts regress within 6 weeks Fig. 39.1 CT scan showing a low attenuation, unilocular cyst (long arrow), with accompanyin g signs of an atrophic pancreas (short arrow), in the lesser sac (stomach shown by medium a rrow). CASE 39 269 of diagnosis, and an expectant management is appropriate in the first instance. Chronic pse udocysts are more commonly associated with chronic pancreatitis. 39b) Explain the main management decisions for this patient and the pros and cons of each option. The main management decision is whether to be conservative (no drain- age) or interventiona l (drainage). The size of pseudocyst is not itself an indication for drainage. Patients wit h a stable pseudocyst do not require therapy unless they have symptoms. Pseudocyst drainage should be con- sidered in the following circumstances: Abdominal pain Gastric outlet obstruction Early satiety Weight loss Jaundice Suspected infection of the cyst Increasing size of the cyst. The patient had abdominal discomfort, early satiety, and weight loss. There was no evidence of gastric outlet obstruction or jaundice. In view of the history of pancreatic surgery an d the atrophic pancreas, it was assumed to be a chronic pseudocyst. Comorbidity had to be c onsidered in the management. The patient was on warfarin for atrial fibrillation, which wou ld need to be stopped before drainage. Drainage can be achieved by: Surgery (cystogastrostomy) Percutaneous insertion of catheter under radiological guidance Endoscopic drainage guided by endoscopic ultrasound. This is possi- ble in 90% of cases, ei ther through the wall of the stomach or duode- num, with the insertion of a flanged stent. There are no prospective studies that compare endoscopic drainage to conservative managemen t, percutaneous or surgical drainage. Nevertheless, endoscopic drainage is probably the tre atment of choice since it is less interventional than surgery and does not involve an exter - nal drain that is prone to infection. It may not be possible if the cyst contents are thi ck, or the cyst is multilocular. OXFORD CASE HISTORIES 270 39c) What are the complications of the above management strategies? The complications of conservative management are that the patient \200\231s symptoms are un likely to resolve and may deteriorate. Surgical management carries appreciable morbidity (6 \200\22337%) and mor- tality (1 \200 \22316%), with a cyst recurrence rate of up to 20%. Percutaneous drainage has a high recurr ence rate (up to 70%). Although continuous percutaneous drainage with an indwelling cathete r decreases recurrence, the complication rate is 5 \200\22360%, including infection, bleedi ng, and fistula formation. Endoscopic drainage has a morbidity of 9 \200\22325%, resulting from complications such as bleeding from penetration of adjacent vessels or varices, perfor ation, infection, pancreatitis, stent migration or occlusion, and pancreatic duct damage. I nfection of a pseudocyst usually indicates inadequate drainage of fluid. The mortality is 0 \200\2231%. Definitive treatment is possible in up to 75%, and recurrence rates as low as 5% have been reported. However, endoscopic drainage of pseudocysts should be carried out on ly with interventional radiology support and surgical back up. Our patient underwent endoscopic drainage under endoscopic ultra- sound guidance and had tw o transmural stents inserted. Her symptoms resolved. After stenting, it was decided to disc ontinue her warfarin, since it had only been given for atrial fibrillation and there was no evidence of mural thrombus or history of a cerebrovascular event. Further reading AGSE guideline (2005). The role of endoscopy in the diagnosis and the management of cystic lesions and inflammatory fluid collections of the pancreas. Gastrointest Endosc; 61: 363 \200\22370. Brugge WR, Lauwers GY, Sahani D, Fernandez-del Castillo C, Warshaw AL (2004). Cystic neoplasms of the pancreas. N Engl J Med; 351: 1218 \200\22326. Vignesh S, Brugge WR (2008). Endoscopic diagnosis and treatment of pancreatic cysts. J Clin Gastroenterology; 42: 493 \200\223506. CASE 40 271 Case 40 A 42-year-old shop assistant with hypertension and obesity had a routine blood test, which showed a raised ALP. She was asymptomatic. She was on ramipril 5mg/day and a combined oral contraceptive pill. She had lost 10kg in 5 months, but attributed this to a diet. She did n ot smoke or drink. Examination, including breast and rectal examinations, was normal. Investigations showed: 9/L, platelets 405 x 109/L, MCV 86fL Hb 12.3g/dL, WCC 10.19 x10 Electrolytes and renal function normal mol/L, ALT 16 IU/L, ALP 527 IU/L, albumin 48g/L g/L, CA125 7 IU/L, CA 19-9 <1 IU/L Bilirubin 5 AFP 3.0 IU/mL, CEA 0.5 Ultrasound scan: multiple liver lesions, consistent with metastases MRI: multiple large, irregular, enhancing lesions occupying about a third of the liver. Nor mal spleen, kidneys, adrenals, pancreas (Fig. 40.1) Questions 40a) Discuss the clinical dilemma and differential diagnosis in this patient. 40b) How would you investigate the problem? 40c) Discuss the diagnosis. 40d) How should the condition be managed? 40e) What other advice might you offer? Fig. 40.1 Multiple focal liver lesions with irregular enhancement. OXFORD CASE HISTORIES 272 Answers 40a) Discuss the clinical dilemma and differential diagnosis in this patient.