Fig. 24.3 (see color plate 8) Photomicrograph showing sheets of uniform cells (lymphocytes) infiltrating and expanding small intestinal villi (arrow). Immuno- histochemistry showed m onoclonal cells of B cell origin. OXFORD CASE HISTORIES 160 Further reading Banks PM (2007). Gastrointestinal lymphoproliferative disorders. Histopathology; 50: 42 \200\22354. Koniaris LG, Drugas G, Katzman PJ, Salloum R (2003). Management of gastrointestinal lymphoma. J Am Coll Surg; 197(1): 127 \200\22341. Siddiqui MA, Scott LJ (2007). Imatinib: a review of its use in the management of gastrointestinal stromal tumors. Drugs; 67(5): 805 \200\22320. CASE 25 161 Case 25 A 62-year-old divorced defense lawyer presented with confusion and ascites. His daughters r eported that ascites had been present for about a year. Apparently he had stopped drinking alcohol 6 months previously, but he had drunk about 20 units of alcohol per day for 30 year s. Mild confusion had been present for 3 months, but it had become worse in the 2 weeks bef ore admis- sion. Medication at the time of presentation included lactulose, frusemide 80mg/ day, and spironolactone 100mg/day. Intravenous 5% dextrose was administered on presentation to the emergency department. On examination he was disorientated in time and place. Asterixis was present, but he was af ebrile with a pulse rate of 66bpm, and blood pressure 115/60mmHg. There were multiple spide r naevi and moderate muscle wasting. The liver was palpable 4cm below the costal margin and there was a moderate amount of ascites. Rectal examination revealed melaena. Investigations showed: 9/L, platelets 100 x 109/L Hb 12.8g/dL, WCC 5.8 x 10 mol/L, urea 6mmol/L Na 129mmol/L, K 3.6mmol/L, creatinine 86 mol/L, ALP 137 IU/L, ALT 33 IU/L, albumin 24g/L Bilirubin 59 Prothrombin time 19.8 sec CRP <8mg/L \200\230Liver disease screen \200\231 normal or negative (see Case 1) Cranial CT scan showed cerebral and cerebellar atrophy with a small chronic subdural hemorr hage. The CT appearance was similar to a CT carried out 6 months previously. Abdominal ultrasound showed a small shrunken liver, gross ascites, pat- ent portal and hepa tic veins; no focal liver lesions; normal sized spleen. Questions 25a) What is the cause and pathophysiology of the disorientation? 25b) What is the immediate management? Initially the patient improved, but he deteriorated with similar symptoms 3 weeks later. Th e patient was unable to return home, because he remained too confused. 25c) What further treatment would you suggest? OXFORD CASE HISTORIES 162 Answers 25a) What is the cause and pathophysiology of the disorientation? This patient almost certainly has cirrhosis (excessive alcohol in the past, spider naevi, h ypoalbuminaemia, increased prothrombin time, thrombocytopenia, ascites, shrunken liver) and the most likely cause of the disorientation and confusion is hepatic encephalopathy. Non-h epatic causes should always be considered, including intracranial hemorrhage and Wernicke \200\231s encephalopathy. Although there was sig- nificant brain atrophy seen on the CT, th is correlates poorly with mental state. Theories to explain hepatic encephalopathy in patients with cirrhosis include: Disorder of astrocyte function with Alzheimer type II astrocytosis Changes in gene expression in the brain that up-regulate or down- regulate transportation p roteins Ammonia hypothesis GABA hypothesis Neurosteroids. Astrocytes play a key role in the regulation of the blood \200\223brain barrier, and the de toxification of chemicals (including ammonia), and it is pos- sible that neurotoxic substan ces, including ammonia and manganese, gain entry to the brain in liver failure. These neuro toxic substances may then contribute to morphological changes in astrocytes. Astrocytes may undergo Alzheimer type II astrocytosis in cirrhosis, although this is not observed in fulm inant hepatic failure. Genes coding for transportation proteins, for example the peripheral-type benzodiazepine re ceptor, may be up-regulated and others down- regulated in cirrhosis and fulminant hepatic f ailure. This may impair neurotransmission. Hyperammonaemia may affect cognitive function. Ammonia is pro- duced in the gastrointestina l tract by bacterial degradation of amines, amino acids, purines, and urea. Ammonia is also produced by entero- cytes, which contain glutaminase to convert glutamine to glutamate and ammonia that is normally detoxified in the liver by conversion to urea. In cirrhosis, the decreased functioning hepatocyte mass reduces detoxi- fication of ammonia by these processe s. Portosystemic shunting also diverts ammonia-containing blood away from the liver, and bo th factors contribute to hyperammonaemia. CASE 25 163 Ammonia is also consumed by the conversion of glutamate to glu- tamine by glutamine synthet ase by normal skeletal muscle, even though cells do not possess the enzymatic machinery of the urea cycle. Muscular glutamine synthetase activity increases in cirrhosis and portosyst emic shunting, but when muscle wasting occurs in advanced cirrhosis, this potentiates hyper ammonaemia. Glutamine synthetase is also expressed in the kidneys and cerebral astrocytes. The kidney plays a key role in ammonia excretion, but astrocytes are unable to up-regulate glutamine synthetase activity, so the brain is vulnerable to hyperammonaemia. Ammonia has m ultiple neurotoxic effects. It alters the transit of amino acids, water, and electrolytes b y astrocytes and neurons, impairs amino acid metabolism, energy utilization, and inhibits b oth excitatory and inhibitory postsynaptic potentials. Treatments that decrease blood ammon ia are associated with improvement in hepatic encephalopathy, but serum ammonia is normal i n 10% of patients with encephalopathy. Furthermore, many patients with cirrhosis have eleva ted ammonia levels without evidence for encephalopathy, and infusion of ammonia does not in duce the electroencephalographic changes associated with hepatic encephalopathy when it is administered to patients with cirrhosis. There is little role, therefore, for measuring amm onia concentrations in hepatic encephalopathy. GABA (gamma-aminobutyric acid) is a neuroinhibitory substance produced in the gastrointesti nal tract. Of all brain nerve endings, 24 \200\22345% may be GABAergic, which generate inhi bitory postsynaptic potentials. It was previously thought that encephalopathy was related t o excess GABA and stimulation of endogenous benzodiazepine receptors, since fluma- zenil im proved cerebral function in some patients. However, further work has demonstrated no change in brain GABA and it now appears that flumazenil improves mental function in only a small percentage of patients with cirrhosis. The neuronal GABA receptor complex also contains a binding site for neurosteroids, which ha ve been implicated in encephalopathy since elevated levels of allopregnanolone, the neuroac tive metabolite of preg- nanolone, has been found in the brains of cirrhotic patients dying of hepatic encephalopathy. 25b) What is the immediate management? : tracheal intubation for patients with severe encepha- Airway support lopathy may be necessary. Discontinue 5% dextrose infusion, since this is likely to exacerbate hyponatraemia (Na 129m mol/L). If the patient needs intravenous OXFORD CASE HISTORIES 164 volume expansion, 20% albumin should be considered, especially if there is renal impairment (see Case 11). , since there is both hyponatraemia and gastrointestinal Stop diuretics bleeding. The gastr ointestinal bleeding may provoke pre-renal failure, so renal function needs to be optimized by appropriate volume expansion. Oral and rectal lactulose at a dose that produces 2 \200\2233 loose bowel motions per day i s required. If the patient is deteriorating, 30mL orally, rectally or by nasogastric tube, may be required every 1 \200\2232 hours to induce a rapid laxative effect. Lactulose inhibi ts intestinal ammonia production by a number of mechanisms. Lactulose is converted to lacti c acid, which acidifies the gut lumen, inhibits ammoniagenic col- iform bacteria, and promo tes non-ammoniagenic lactobacilli. Lactic acid also favors the conversion of NH4+ to NH3 an d promotes the passage of NH3 from tissues into the lumen. Lactulose conceivably works as a laxative, reducing colonic bacterial load, but this is debat- able. Care should be taken, because lactulose overdose may cause ileus, severe diarrhea, electrolyte disturbance, and h ypovolaemia. Do not restrict dietary protein , especially in advanced disease, since these patients are usually markedly malnourished. A protein intake of 1 \200\2231.5g protein/kg/day is recomme nded. Active management of the precipitating event the focus of treatment. (Table 25.1) should be Blood in the upper gastrointestinal tract increases ammonia production and nitrogen absorpt ion from the gut. A gastroscopy should be per- formed as soon as it is felt safe to do so, in case variceal banding is neces- sary (see Case 5). Sepsis, including spontaneous bacteri al peritonitis, should be excluded, since infection may predispose to impaired renal functi on and to increased tissue catabolism, both of which increase blood ammonia levels. It is c rucial that multiple blood cultures, a urine sample, and a diagnostic ascitic tap are carri ed out. Renal impairment leads to decreased clearance of urea, ammonia, and other nitrogeno us com- pounds. Drugs that act on the central nervous system are best avoided, including op iates, benzodiazepines, antidepressants, and antipsychotic agents, since these may worsen e ncephalopathy. Constipation increases intestinal production and absorption of ammonia. Hepa tocellular carcinoma needs to be considered and excluded (see Case 14). Diuretic therapy ca n lead to decreased serum potassium levels and alkalosis, which may facilitate the conversi on of NH4+ to NH3. CASE 25 165 Table 25.1 Precipitants of hepatic encephalopathy Gastrointestinal bleeding Sepsis Electrolyte disturbance Renal impairment Dehydration Drugs Constipation Progression of underlying liver disease Hepatocellular carcinoma Diuretic the rapy Dietary protein overload (rare) In the absence of a readily identifiable precipitant, infection should be assumed, so our p atient was started on broad-spectrum intrave- nous antibiotics (a third-generation cephalos porin). Initially the patient improved, but he deteriorated with similar symptoms 3 weeks l ater. The patient was unable to return home, because he remained too confused. 25c) What further treatment would you suggest? For chronic encephalopathy (unresponsive to therapy), consider the following treatments. Imaging of splanchnic vessels systemic shunts potentially amenable to radiological occlusio n. to identify large spontaneous portal- Neomycin or other non-absorbable antibiotics such as rifaxamin, in an effort to decrease th e colonic concentration of ammoniagenic bac- teria. Neomycin is reserved as a second-line a gent, after initiation of treatment with lactulose, because it risks ototoxicity and nephro toxicity from some systemic absorption. Rifaxamin, unavailable in the UK but widely used in Europe, is better tolerated and may be as effective as lactulose at improving hepatic ence phalopathy. Treatment to increase ammonia clearance : l-ornithine l-aspartate (LOLA) is a stable salt o f the constituent amino acids. l-ornithine stim- ulates the urea cycle, with resulting loss of ammonia. Both l-ornithine and l-aspartate are substrates for glutamate transaminase, wh ich increases glutamate and then consumes ammonia in the conversion of glutamate to glutami ne by glutamine synthetase. LOLA was found to be effective in treating hepatic encephalopat hy in a number of European trials. Oral zinc administration has the potential to improve OXFORD CASE HISTORIES 166 hyperammonaemia by increasing the activity of ornithine transcar- bamylase, an enzyme in th e urea cycle. Occlusion of TIPSS or surgical shunts if a patient has had a procedure to reduce portal hyp ertension. Experimental therapy with AST-120 carbon microspheres, which has been shown to reduce encep halopathy in preliminary trials. liver transplantation. Referral for This patient was referred and listed for liver transplantation for chronic hepatic encephal opathy. He made a slow recovery post-transplant, but is now well, with no confusion 7 years post-transplant. The explant liver showed no evidence of recent alcohol use. Further reading H ussinger D, Schliess F (2008). Pathogenetic mechanisms of hepatic encephalopathy. Gut; 57: 1156 \200\22365. Morgan MY, Blei A, Gr ngreiff K et al. (2007). The treatment of hepatic encephalopathy. Metab Brain Dis; 22: 389 \200\223405. Wright G, Jalan R (2007). Management of hepatic encephalopathy in patients with cirrhosis. Best Pract Res Clin Gastroenterol; 21: 95 \200\223110. CASE 26 167 Case 26 A 47-year-old South African man was admitted with right flank and right iliac fossa pain, o f 1 month \200\231s duration. The pain was constant, but exacerbated by eating. He describe d weight loss, night sweats, and an intermittent non-productive cough on direct questioning . On examination his pulse rate was 96bpm, and blood pressure 121/90mmHg. He was apyrexial. H is weight was 62kg, 8kg less than he last recalled. The abdo- men was tender in the right i liac fossa, with no abdominal masses and no peritonism. He was still well nourished and did not have lymphadenopathy, but was pale and had finger clubbing. After 48 hours in hospital he developed diarrhea and fever up to 39 C. Investigations showed: 9/L Hb 10.8g/dL, MCV 82 fL, WCC 7.9 x 10 CRP 110mg/L Albumin 18g/L Chest radiograph showed right upper lobe and left mid-zone infiltra- tion. The left cardiac border was indistinct. Small cavities were visible in both infiltrates (Fig. 26.1) Colonoscopy showed several small ulcers, scattered around the caecum; stenosed terminal ile um with several large ulcers (Fig. 26.2 in the central color section), and intensely hypera emic, nodular and friable mucosa in between. Proximal to these lesions the mucosa was norma l. Multiple biopsies were taken for histopathology and microbiology. Questions 26a) Name and discuss this disease. 26b) How is the diagnosis made? 26c) Discuss the clinically relevant issues. 26d) Describe the management. 26e) What messages does this case carry for doctors practicing in developed countries? OXFORD CASE HISTORIES 168 Fig. 26.1 A chest radiograph showing right upper lobe and left mid-zone (lingula) infiltrat es. There is cavitation in both areas. Fig. 26.2 (see color plate 9) An endoscopic view of the terminal ileum, showing a large ulc er, surrounded by inflamed mucosa. This page intentionally left blank OXFORD CASE HISTORIES 170 Answers 26a) Name and discuss this disease. The diagnosis is intestinal tuberculosis. Tuberculosis (TB) is on the increase, with statis tics from 2004 indicating an incidence of 8.9 million cases per year. The disease accounts for 1.7 million deaths per year. Mycobacterium tuberculosis, the responsible agent, is the most common mycobacterium in the M. tuberculosis complex. Another member of this complex, M . bovis, is traditionally responsible for some cases of intestinal tuberculosis, but has be come much less common since milk pasteuriza- tion. M. bovis typically causes intestinal dis ease through the ingestion of milk and is not associated with pulmonary disease. In contras t, respira- tory infection is by far the most important portal of entry for disease caused by M. tuberculosis. Infection occurs through inhalation of infectious droplets from a per- son with active pulm onary TB. Tiny droplets (<10 m) from coughing or sneezing remain suspended in the air, and when inhaled find their way to the most distal airways. Bacilli are then phagocytosed by a lveolar macro- phages, but the bacillus can evade lysosomal degradation and multiply, event ually rupturing the macrophage. The risk of infection depends on exposure, but the risk of developing active disease depends on the host \200\231s immune response. Only 10% of people infected will develop active TB. Primary infection in childhood in developing countries is associated with haematogenous spread of TB bacilli throughout the body, whether active dis ease develops at that stage or not. These bacilli remain dormant and most never reactivate. Secondary, or reactivated infection, may occur years later and presents differently. Althou gh secondary TB in an immunocompetent host is usually confined to the lungs, about 15% of c ases are extrapulmonary. In order of frequency, extrapulmonary TB involves lymph nodes, the genitourinary system, bones and joints, meninges, gastrointestinal tract, and pericardium. This list excludes miliary TB, which may be present in multiple organs simultaneously, thr ough haematogenous spread. It is worth noting that tuberculosis can affect any organ in the body. Abdominal TB (11 \200\22316% of cases of extrapulmonary TB) may involve the intestine (from the mouth to the anus), abdominal lymph nodes, peritoneum, or solid organs. Intestinal TB is most commonly (50 \200\22355%) ileocaecal in immunocompetent patients. This may be due t o relative stasis, lack of digestive activity, or phagocytosis of M. tuberculosis by the M- cells on Peyer \200\231s patches. Similar conundra apply to the common CASE 26 171 ileocaecal location of Crohn \200\231s disease. A useful practice point is that if intestin al TB affects a region distant from the ileocaecal valve, then immunocompromise (such as HI V infection) should be suspected. Intestinal infection is usually caused by swallowing infected sputum in people with pulmona ry TB, but may occur from reactivation of primary TB. In one series, almost half of patient s with pulmonary TB had intesti- nal involvement, often without abdominal symptoms. However , only 50 \200\22360% of people with intestinal TB have overt pulmonary TB. The fre- quency of lesions is broadly inversely proportional to the distance from the ileocaecal valve. Oe sophageal TB is rare and accounts for 0.2% of cases, while gastric tuberculosis occurs in 1 % of abdominal TB. Duodenal TB is often isolated, without evidence of pulmonary TB in 80%. Tuberculosis of the colon may be segmental, rectal, or less frequently diffuse. Tuberculosi s of the anus may present as fistulating disease. The clinical mimicry of Crohn \200\231s d isease is striking and potentially a major diagnostic pitfall in the developed world. 26b) How is the diagnosis made? The clinical presentation of abdominal TB is non-specific. Abdominal pain is the most commo n symptom, present in >90%. Fever may occur in two-thirds. Half have night sweats and weigh t loss, with diarrhea in only 10 \200\22315%. Radiographic imaging by ultrasound, barium st udies, CT or MRI does not make a definitive diagnosis. This also applies to endo- scopic ap pearances, but endoscopic biopsies are the mainstay of (eventual) diagnosis. The diagnosis of TB depends on the demonstration of TB bacilli in samples of body fluid (mo st commonly sputum) or tissue. Microscopy of sputum, although able to deliver a rapid diagn osis, is insensitive, since it is positive in only 40 \200\22360% of cases of pulmonary TB. It is even less sen- sitive in abdominal TB since 40% will not have pulmonary involvement. Definitive diagnosis relies on culturing M. tuberculosis or by amplifying DNA through the polymerase chain reaction (PCR) in body fluid or tis- sue. The drawback of culture is the 4 \200\2238 weeks required for growth. Culture in liquid media is faster and may deliver res ults within 2 \200\2233 weeks. PCR is more rapid, and stool specimens may be positive in up to 90% of cases of intestinal TB. Positive PCR on formalin-fixed, paraffin-embed- ded inte stinal mucosal biopsies has been reported in up to 75% of cases of intestinal TB. In the Western world, failure to suspect the diagnosis is a cause of diagnostic delay. When tissue has been obtained from a lesion, biopsies should be formalin-fixed for histopatholo gy and also sent in saline to OXFORD CASE HISTORIES 172 microbiology for culture. Caseating granulomas and acid-fast bacilli are seen only in a min ority of endoscopic mucosal biopsies from patients with intestinal TB. While granulomas may be seen in 40%, only a fourth of these (i.e. 10% of all cases) have caseation. The yield o f biopsy culture is also low <20%, but has the useful potential for determining antibiotic sensitivity. Tuberculin skin testing and interferon-g-release assays (e.g. ELISPOT , QuantiFERON -TB) both measure an immune response to mycobacte- rial antigens (see Case 35 for more detail). They are both useful for screening for latent tuberculosis in areas of low incidence and pr eva- lence. They are unable, however, to distinguish between latent and active tuberculosis . A positive tuberculin skin test may be caused by vaccina- tion with Bacille Calmette-Gu rin (BCG), which also limits its useful- ness. Neither test is useful in areas of high inci dence, where exposure of the population to TB is extensive. Histopathology is usually (but by no means always) diagnostic. Epithelioid cell granulomas, with central caseous necrosis are typical of TB. This reflects the dominant cell-mediated immune response, with macrophages and T-lymphocytes (CD4 cells of the TH1 phenotype) being most important. T-lymphocytes play a central role in activating macrophages through product ion of cytokines (especially IFN and TNF ). Macrophages aggregate around the site of pri mary infec- tion, forming granulomas, which contain the infection. Delayed-type hypersensit ivity (type IV immune response) plays a lesser role. It repre- sents a reaction to mycobact erial antigens and leads to destruction of macrophages and caseation. Delayed hypersensitiv ity also inhibits mycobacterial growth and is responsible for the tissue damage seen in tub erculosis. In our patient, demonstration of acid-fast bacilli in the terminal ileal biopsies was suffi cient to diagnose intestinal TB. Biopsies from the caecum and terminal ileum showed multipl e epithelioid cell granulomas in the lamina propria. Granulomas in the ileal biopsies showe d caseation. Ziehl \200\223Nielsen stain showed acid-fast and alcohol-fast bacilli at both sites. (Figs 26.3 and 26.4 in the central color section). Although the chest radiograph was consistent with TB, the patient had no sputum, so the diagnosis was made on microscopy of intestinal mucosal biopsies obtained at colonoscopy. Stool samples were sent only after the diagnosis of TB, to exclude acute bacterial infection as a cause for diarrhea. Therapy was started. Tissue culture subsequently showed M. tuberculosis sensitive to all four first-li ne antituberculous drugs. CASE 26 173 Fig. 26.3 (see color plate 10) Mucosal biopsy from the terminal ileum, showing a large epit helioid cell granuloma with central caseation (arrow). 26c) Discuss the clinically relevant issues. The clinical, radiological and histological picture is characteristic of secondary (reactiv ation) of pulmonary TB with concomitant ileocaecal TB in an immunocompetent host. This impl ies a degree of containment of the infection. Our patient tested negative for HIV. Tubercul osis in the HIV-positive host, especially when advanced, presents differently. Lung lesions more closely resemble those of primary TB, and microscopy of mucosal biopsies do not revea l granulomas (consider the pathogenesis, above). There may be numerous neutrophilic micro-a bscesses and numerous acid-fast bacilli, in contrast to few acid-fast bacilli in those with Fig. 26.4 (see color plate 11) Acid-fast and alcohol-fast bacilli (arrows) in a mucosal bio psy. OXFORD CASE HISTORIES 174 well formed granulomas in immunocompetent hosts. Extrapulmonary TB occurs more frequently i n HIV-positive patients (in half or more cases). Intestinal TB may be complicated by stricturing, which may resolve rapidly on treatment, al though an appreciable minority may require stric- tureplasty or resection to relieve obstru ctive symptoms. Malabsorption may be due to stasis proximal to strictured bowel, with subse quent bacterial overgrowth (see Case 10). A more serious complication is that of spontaneou s perforation of the terminal ileum. In India, TB of the terminal ileum is second only to t yphoid as a cause of terminal ileum perforation. Finally, digital clubbing in our patient implies a suppurative lung complication. This incl udes lung abscesses in a pre-existing cavity, although our patient had no evidence of an ab scess on chest radiography. Secondary bronchiectasis may also lead to clubbing, from chroni c sup- puration. Our patient had no evidence of a lung tumor or cardiac cause for clubbing. Uncomplicated TB does not cause clubbing. 26d) Describe the management Standard therapy means treatment for 6 months, using four drugs for 2 months and two drugs for 4 months. This is curative in most patients, provided the organism is sensitive. Rifamp icin 5mg/kg, isoniazid (INH) 10mg/kg, ethambutol 15mg/kg and pyrazinamide 20mg/kg are given for the first 2 months. This is the bactericidal stage and is followed by a 4-month contin uation (sterilization) stage, in which rifampicin and iso- niazid are given. At least one r andomized trial has shown that a 6-month course of therapy with this regimen had a cure rat e of 99%, compared with 12 months of isoniazid and ethambutol alone, which had a cure rate of 94%. Rifampicin and isoniazid may both cause a hepatitis, which may lead to fulminant he patic failure (see Case 1). Should hepatitis (ALT >3-fold elevated) develop, both need to b e stopped and reintroduced one-by-one, to identify the culprit. Pyridoxine (vitamin B6) is advocated if isoniazid is administered, to prevent the developme nt of peripheral neuropathy. It should be remem- bered that pyridoxine can itself cause per ipheral neuropathy if adminis- tered in excess of the recommended daily requirement. Ethamb utol may cause optic neuritis and pyrazinamide can precipitate gout. Specialist advice is b est sought when managing intestinal TB, because management includes contact tracing and mon itoring compliance with therapy, which are facilitated by a multidisciplinary team. CASE 26 175 Drug resistant TB is becoming a global problem as the result of monotherapy and/or non-comp liance to drug regimens. Multi-drug resistant (MDR) tuberculosis, prominent since the 1990s , is defined as M. tuberculosis resistant to at least rifampicin and isoniazid. Extensively drug resistant (XDR) tuberculosis implies resistance to rifampicin, isoniazid, any fluoroq uinolone and at least one of the injectable second line drugs (amikacin, capreomycin, or ka namycin). The spread of MDR and XDR tuberculosis can only be stemmed by appropriate infecti on control measures and ensuring patient compliance with ther- apy, such as through directl y observed treatment. Compliance with therapy is a more appropriate term than adherence in these circum- stances, because of the implications for public health that may merit enforce ment. 26e) What messages does this case carry for doctors practicing in developed countries? Although 80% of new cases of TB occur in developing regions of the world, it also occurs in industrialized countries among migrants, mar- ginalized communities, and immunocompromised patients, including chronically debilitated or elderly patients. Because the incidence of intestinal TB is very low in developed countries, the index of suspicion is also low and th e diagnosis delayed. In contrast, Crohn \200\231s disease is common in developed countries. For the gastroenterologist this is par- ticularly important, since both are chronic granul omatous diseases with a similar distribution. The clinical presentation with abdominal pain , weight loss and diarrhea is also similar, as is the endoscopic appear- ance. If the chest radiograph is normal, other imaging may not adequately distinguish between the two. Micros copy of tissue samples may not reveal acid-fast bacilli, and granulomas may be of very simi lar appearance. The diagnostic differentiation is extremely important. If Crohn \200\231s disease is mistak en for TB, therapy may be delayed and potentially harm- ful antituberculous drugs may be pr escribed inappropriately. On the other hand, TB is usually curable with a 6-month course of chemother- apy, and diagnostic delay may lead to institution of therapy when it is too lat e. Furthermore, misdiagnosis of TB as Crohn \200\231s disease may lead to the administratio n of corticosteroids or anti-TNF therapy, with dire consequences. The clinician needs to focus on factors that put the likely diagnosis in context. The pros and cons of each possibility are best listed, so that the OXFORD CASE HISTORIES 176 less likely diagnosis is rejected. Such factors include a family history of inflammatory bo wel disease, or a history of TB contacts, and these should be obtained. Diarrhea is more co mmon in Crohn \200\231s disease. Fever is more common in TB. Radiologically, ileocaecal TB destroys the ileocae- cal valve and caecum, which is not typical of Crohn \200\231s. Althou gh ulcer- ation of the terminal ileum is seen in both conditions, radial, circumferential u lcers, with intensely inflamed surrounding mucosa are more typical of TB. Ulceration in Cro hn \200\231s disease is more often longitu- dinal, with normal mucosa in between. Aphthoid ulcers are uncommon in TB, but the findings remain subjective and there is considerable ove rlap. The typical granulomas of TB are often multiple, large, and confluent, with caseous n ecrosis. Crohn \200\231s granulomas are usually single and do not show caseation. If uncertain, initial therapy will be guided by the prevalence in the particular area. If i n doubt, the possibility of TB should be treated first, because of the dire consequences of treating TB with immunomodula- tors for Crohn \200\231s disease. Surgical resection of the area, if localized, should be considered, since this may be diagnostic as well as therapeu tic. Further reading Epstein D, Watermeyer G, Kirsch R (2007). Review article: the diagnosis and management of Crohn s disease in populations with high-risk rates for tuberculosis. Aliment Pharmacol Ther; 25: 1373 \200\22388. Gan HT, Chen YQ, Ouyang Q et al. (2002). Differentiation between intestinal tuberculosis an d Crohn s disease in endoscopic biopsy specimens by polymerase chain reaction. Am J Gastroe nterol; 97(6): 1446 \200\22351. Khan R, Abid S, Jafri W, Abbas Z et al. (2006). Diagnostic dilemma of abdominal tuberculosis in non-HIV patients: An ongoing challenge for physicians. World J Gastroentero l; 12: 6371 \200\2235. Jassal M, Bishai WR (2009). Extensively drug-resistant tuberculosis. Lancet Infect Dis; 9: 19 \200\22330. Pettengell KE, Larsen C, Garb M, Mayet FG et al. (1990). Gastrointestinal tuberculosis in patients with pulmonary tuberculosis. Q J Med; 74: 303 \200\2238. Sharma MP, Bhatia V (2004). Abdominal tuberculosis. Indian J Med Res; 120: 305 \200\22315. This page intentionally left blank OXFORD CASE HISTORIES 178 Case 27 A 27-year-old male teacher presented with a 2-year history of intermittent dysphagia for so lids, which occurred about once every three meals. There was no regurgitation, bolus obstru ction, odynophagia, or chest pain. His weight was stable and there was no history of melaen a or haematemesis. He had reflux, which caused intermittent heartburn, but symptoms were co ntrolled with omeprazole. This had not made any difference to the dysphagia. The only other medical history was childhood asthma. There was a family history of Crohn \200\231s disease, but no other family history of gastrointestinal disease. On examination, he was fit and well, with a body mass index of 25kg/m2. His hands, skin, an d abdomen were normal, with no tremor, normal speech, no goiter, and no abdominal findings. Investigations showed: Barium swallow: there was no structural abnormality in the hypophar- ynx or esophagus and n o stricture. There was transient hold up of a swallowed marshmallow. The gastro-oesophageal junction opened normally. Gastroscopy: esophagus, stomach and duodenum looked normal. Oesophageal, gastric and duoden al biopsies were taken. Questions 27a) What is the differential diagnosis? 27b) By examining the oesophageal biopsy (Fig. 27.1 in the central colored section), what is the diagnosis? 27c) What changes could be present on endoscopy in this condition? 27d) What is the treatment of this condition? 27e) What is the prognosis? This page intentionally left blank OXFORD CASE HISTORIES 180 Answers 27a) What is the differential diagnosis? The differential diagnosis is: Eosinophilic oesophagitis Peptic stricture from gastro-oesophageal reflux Achalasia Muscle disorders Muscular dystrophies Hyper or hypothyroidism Myasthenia gravis Oesophageal involvement in systemic conditions (e.g. scleroderma) Oesophageal spasm. Intermittent dysphagia in a young adult over many years (particularly with an episode of fo od impaction), should raise the possibility of eosinophilic oesophagitis. This becomes more likely with a personal or family history of allergic disorders. It should always be consid ered in the differential diagnosis of chronic unexplained dysphagia, but has been recognize d only relatively recently. The barium swallow is usually normal, but strictures of varying length and diameter can occur. Distinguishing eosinophilic oesophagitis from gastro-oesophageal reflux disease can be diff icult, but the latter only causes food impaction if a mechanical stricture (which should be visible on barium swallow) is present. It is notable that a proton pump inhibitor relieved reflux symp- toms in this patient, but did not relieve dysphagia. Dysphagia due to severe oesophagitis without a stricture is not that uncommon, but the sensation is relieved by aci d suppression. Achalasia should be considered, but several features make the diagno- sis unlikely. Patient s with achalasia tend to have dysphagia for both sol- ids and liquids. Furthermore, chest p ain occurs in up to half of patients, and 60 \200\22390% describe regurgitating undigested foods during or shortly after a meal. The barium swallow might also be expected to show fea tures of achalasia given the 2-year history. The typical feature of achalasia on barium swa llow is the \200\230bird \200\231s beak \200\231 appearance of the gastro-oesophageal junc tion, due to the non-relaxing sphincter, and sometimes associated with a dilated esophagus. Fluoroscopy during the swallow may reveal decreased peristalsis. At endoscopy, there may b e a transient resistance to the passage of the endoscope through the gastro-oesophageal jun ction CASE 27 181 that is recognized by an experienced endoscopist alert to the potential diagnosis. Muscular disorders must not be overlooked, but often are at first presentation. There are t hree categories to consider. The first is mus- cular dystrophy: two uncommon forms of muscu lar dystrophy involve the striated muscles of the pharyngo-oesophageal region. Dystrophia m yotonica is a familial disease characterized by myopathic facies, myotonia, swan neck, musc le wasting, frontal baldness, testicular atro- phy, and cataracts. Oculopharyngeal dystroph y is a syndrome that presents later in life with ptosis and dysphagia, with a dominant pat- tern of inheritance. The second category is hyperthyroidism or hypo- thyroidism, which can also affect striated musculature. The third muscle disorder is myasthenia gravis, which is a disorder of the motor end plate, affecting the striated oesophageal musculature with cli nical manifestations that resemble the myopathies. The characteristic fea- ture is fatigue during repeated effort, with successive attempts to swal- low (pharyngo-oesophageal transfe r) causing more symptoms as the meal progresses. Systemic conditions such as scleroderma, polymyositis, or mixed con- nective tissue disease can involve the esophagus. Other findings such as sclerodactyly, telangiectases or weaknes s, are generally detected in conjunction with symptoms of dysphagia. Oesophageal spasm generally presents with retrosternal chest pain, with episodes lasting fo r minutes or hours. Intermittent dysphagia occurs in 30 \200\22360% of patients. A barium s wallow can reveal a \200\230corkscrew Fig. 27.1 (see color plate 12) Mid-oesophageal biopsy from a patient with dysphagia and a n ormal esophagus at endoscopy. OXFORD CASE HISTORIES 182 esophagus \200\231, due to dysfunctional circular muscle contractions that in extreme situa tions trap barium between powerfully contracted segments. The endoscopic appearance is norm al. 27b) By examining the oesophageal biopsy (Fig. 27.1 in the central color section) what is the diagnosis? The diagnosis is eosinophilic oesophagitis. The diagnosis hinges on histopathological evide nce of eosinophils infiltrating the oesophageal mucosa. It is well recognized that other di seases are associated with eosinophilic infiltration of the esophagus, including gastro-oes ophageal reflux, but with a lesser degree of eosinophilic infiltrate. For diagnosis of eosi nophilic oesophagitis, the eosinophilic infiltration in the squamous epithelium should exce ed 20 eosinophils/high power field at x400 mag- nification. Mid-oesophageal biopsies should be the standard of care for patients with dysphagia and a normal endoscopy. 27c) What changes could be present on endoscopy in this condition? Typical endoscopic findings of eosinophilic oesophagitis include mucosal longitudinal linea r furrows, a corrugated appearance or plaque-like exu- dates, friability of the oesophageal mucosa ( \200\230cr pe-paper \200\231 mucosa), and strictures of variable length. Most pa tients appear to have a normal esophagus at endoscopy, so the endoscopist should be encoura ged to take biopsies. 27d) What is the treatment? Corticosteroids, either topical or systemic, are generally effective. Initial treatment sho uld be swallowed fluticasone (220 g dose x four puffs, swallowed with a minimal amount of water twice daily, instructing patients not to eat or drink for 2 hours after each dose). C ontinue ther- apy for 6 weeks, if there is a response. Recurrent symptoms are best treated with the same dose, but for a longer period. If there is no initial response, systemic cort icosteroids (prednisolone 40mg/day, tapered over 6 weeks) should be considered. Elimination diets: although eosinophilic oesophagitis appears likely to be an allergic diso rder, identifying the triggering allergens (food or environmental) is labor intensive and u nproductive. Patients may have multiple allergies, making it difficult to comply with aller gen-avoidance or food restriction. Pediatric patients are often treated with an elimina- ti on or liquid diet and improve, but they comply with food restriction better than adults. CASE 27 183 Oesophageal dilatation: patients with eosinophilic oesophagitis are at increased risk for m ucosal tears and perforation after oesophageal dilata- tion. Medical treatment of eosinophi lic oesophagitis decreases the risk of strictures. Dilatation should be carried out only in patients who fail medical therapy and have severe dysphagia. New therapies such as anti-IL5 monoclonal antibody therapy are evolving. 27e) What is the prognosis of this condition?