OXFORD CASE HISTORIES 108 Table 17.2 Amsterdam II Criteria There should be at least three relatives with colorectal cancer or Lynch syndrome-associate d cancer: one relative should be a first-degree relative of the other two At least two successive generations should be affected At least one tumor should be diagnosed <50 years of age Familial adenomatous polyposis should be excluded All tumors should be verified by histopathological examination and not by history alone syndrome patients with a primary colorectal cancer, especially for patients <60 years of ag e. Endometrial cancer is the second most common malignancy in Lynch syndrome and female carrie rs of mutations are best offered endometrial cancer surveillance. This may include biennial gynecological examina- tion and transvaginal ultrasound starting at 30 \200\22335 years of age. Nevertheless, the impact of endometrial cancer surveillance on mortality remains uncl ear. There is a higher risk of endometrial cancer in MSH6- mutation carriers, so hysterecto my might be considered for these women after the menopause. Ovarian cancer is more likely if there are MSH2, MLH1, or MSH6 mutations. There is no estab lished surveillance regimen for ovarian cancer. Bilateral salpingo-o phorectomy should be considered after the comple- tion of child bearing, especially if there is ovarian cancer i n the family. The risk of gastric cancer in Lynch syndrome in the West is low. The yield fr om gastric cancer surveillance by endoscopy is very low, and surveillance is recommended on ly if there is a strong family history of gastric cancer. Urothelial tract screening is als o debatable and only rec- ommended if there is a family history of urothelial cancer. There are no formal surveillance programs for brain, small bowel, pancreas, biliary tract, or sk in cancers. 17e) Who in this patient \200\231s family should be screened and by what method? After identification of a mutation in an affected individual, genetic counseling and presym ptomatic mutation analysis should be offered to first-degree relatives. Detailed informatio n from an experienced clinical geneticist and good psychological guidance are prerequisites for sensitive presymptomatic diagnosis based on DNA testing. Identification of sub- jects carrying a MMR mutation is important, because surveillance can be restricted to these indiv iduals, while those without a gene defect can be reassured and spared from surveillance. Kn owledge of a mutation may CASE 17 109 influence decisions about conception, but may also affect life assurance or other aspects o f an individual \200\231s life. Once a mutation is identified, surveillance is continued for life. Screening colonoscopy is probably best performed every 1 \200\2232 years, start- ing at 25 years of age. Endometria l, ovarian, gastric, and urothelial tract screening should be discussed with the individual , as above. This family was diagnosed with an MSH6 mutation. This was initially identified in the color ectal cancer by MSI analysis. Her mother and her 35-year-old brother were found to carry th e mutation, although her younger sister and her father did not. Further reading Vasen HFA (2007). Review article: the Lynch syndrome (hereditary non-polyposis colorectal cancer). Aliment Pharmacol Ther; 26 (Suppl. 2): 113 \200\22326. Ramsoekh D, Van Leerdam ME, Wagner A, Kuipers EJ (2007). Review article: detection and mana gement of hereditary non-polyposis colorectal cancer (Lynch syndrome). Aliment Pharmacol Th er; 26(Suppl. 2): 101 \200\22311. OXFORD CASE HISTORIES 110 Case 18 A 22-year-old woman from Northampton, UK was seen in the gastroenterology clinic with a 2-y ear history of diarrhea, iron deficiency anemia, and a raised C-reactive protein (RP). She constantly felt below par. She passed liquid stool without visible blood up to 8 times a da y and more recently up to 3 times at night. She had intermittent abdominal pain and had los t weight, but ascribed this to being on a diet, since she otherwise felt well. She had no o ther medical history and was taking the oral contraceptive pill. She smoked 10 cigarettes p er day, but drank no alcohol. Travel history included a trip to Ireland a month previously, without any history of travel to developing countries. Physical examination was unremarkable, apart from a slight tachycardia of 92 bpm. She was n ot particularly pale. A rectal examination and rigid sigmoidoscopy were not carried out. Investigations showed: 9/L, platelets 632 x 109/L, MCV 74 fL Hb 10.3g/dL, WCC 8.1 x 10 g/L Ferritin 10 CRP 20mg/L mol/L Na 139mmol/L, K 3.9mmol/L, creatinine 78 mol/L Albumin 46g/L, ALT 13 IU/L, ALP 253 IU/L, bilirubin 4 Thyroid-stimulating hormone 0.38 mU/L Endomysial antibody negative, IgA normal Gastroscopy: multiple small ulcers starting in the second part of the duodenum, extending b eyond the limit of insertion of the endoscope. Biopsies from the second part of the duodenu m reported chronic ulceration. Colonoscopy and ileoscopy: severe ulceration and stricturing in the terminal ileum (Fig. 18 .1 in central color section). Multiple small ulcers were present in the caecum, distal asce nding colon, proximal transverse colon, and splenic flexure, with normal mucosa in interced ing areas and between ulcers. Histopathology: biopsies from the terminal ileum showed severe acute or chronic inflammatio n with ulceration and granulomas (Fig. 18.2 in central color section). CASE 18 111 Questions 18a) What is the diagnosis and how is it best classified? 18b) What extraintestinal manifestations may occur? 18c) Describe the management. 18d) How does smoking and potential pregnancy affect the condition? 18e) What is the prognosis? Fig. 18.1 (see color plate 5) An endoscopic view of the terminal ileum showing inflam- mati on and ulceration. Fig. 18.2 (see color plate 6) A photomicrograph showing non-caseating granulomas (arrows) i n a biopsy from the terminal ileum. OXFORD CASE HISTORIES 112 Answers 18a) What is the diagnosis and how is it best classified? The diagnosis is Crohn \200\231s disease. The diagnosis of Crohn \200\231s disease depends on four factors \200\223 the history, endoscopy, histopathology, and radiology. The histor y, endoscopic findings and histopathology are all consistent with Crohn \200\231s disease, although only a minority of biopsy specimens show submucosal granulomas. Crohn \200\231s disease most commonly involves the terminal ileum and/or colon. Isolated te rminal ileal disease occurs in about 30% at presentation and a further 30% have ileocolitis , with 30% having isolated colitis. Even though it can involve any part of the gut, it comm only stops where it starts: the pattern of involvement is usually stable over time in a sin gle patient, particularly in adults. This is a common cause of misconception, because infor mation about Crohn \200\231s disease usually starts by stating that it can affect any part of the gut. This gives the erroneous impression of creeping inflammation. Disease behavior can change, however, and Crohn \200\231s disease may be progressive, with the development o f com- plications. This includes stricturing and fistulization, requiring surgical interven tion. The Montr al classification classifies the disease according to: Age at presentation and >40 years [A3]) (i.e. 16 years or younger [A1], 17 \200\22340 years [A2], Maximal location of disease prior to first surgery [L1], colonic [L2], ileocolonic [L3], up per GI only [L4]) (i.e. terminal ileal Disease behavior (i.e. inflammatory, non-stricturing, non-penetrating [B1], stricturing [B2 ], or penetrating [B3], and perianal disease modifier [p]) With disease modifiers: Concomitant upper GI modifier to L1 \200\2233 involvement is indicated by adding L4 as a Perianal disease (see Case 19). is designated p and added to B1 \200\2233 where appropriate The Montr al classification recommends that disease behavior is assessed >5 years after di agnosis, acknowledging that the pattern of dis- ease can change. The cause of Crohn \200 \231s disease is unknown, but it prob- ably involves an abnormal immune response to luminal bacteria, in a CASE 18 113 genetically susceptible host. Multiple genes (32 in 2009, but rising) have been associated with Crohn \200\231s disease. These include genes involved in regulating the innate immune system (such as NOD 2), genes related to autophagy (such as ATG16L1), and genes involved in the adaptive immune system (such as IL23R). First-degree relatives of people with Crohn \200\231s disease have a slightly increased risk of developing the disease. There may be a primary defect in mucosal defense, as well as a dysregu- lated immune response. 18b) What extraintestinal manifestations may occur? Extraintestinal manifestations affect about 15 \200\22320% of patients, most commonly women with colonic disease. Extraintestinal manifestations may involve the eyes, skin, musculosk eletal system, or hepatobiliary system. Involvement of the lungs, kidneys, pancreas, heart, or central nervous system has also been reported, suggesting systemic inflammation in some individuals. Arthropathies may be divided into peripheral and axial arthropathies. Periphe ral arthritis may be pauciarticular (type 1), involv- ing the large joints of the lower lim bs and related to the activity of the underlying bowel disease. In contrast, a symmetrical polyarthropathy of the small joints (type 2), may run a more chronic course, unrelated to t he activity of the bowel disease. Peripheral arthritis occurs in about 10% of patients with Crohn \200\231s disease, and is more prevalent in patients with colonic involvement, compa red with isolated small bowel disease. Axial arthropathies, which include ankylosing spondy litis and sacroiliitis, are not associated with disease activity. Ankylosing spondylitis in patients with IBD is associated with HLA B27 in 50 \200\22380% of cases, which is a weaker association than ankylosing spondylitis without inflammatory bowel disease (94%). Cutaneous manifestations include erythema nodosum, occurring in up to 10% of patients. It i s a panniculitis, causing erythematous, tender nodules typically over the shins. It is usua lly associated with disease activity and commonly occurs with other extraintestinal manifes tations, such as uveitis or arthritis. Pyoderma gangrenosum is a severe skin manifestation, often independent of disease activity. It is painful and may persist for years. Pyoderma g angrenosum occurs in <2% of patients with Crohn s disease and characteristically affects ar eas exposed to minor trauma. It appears particularly susceptible to treatment with anti-TNF therapy. Sweet \200\231s syndrome is another neutrophilic dermatosis causing a florid eryt hematous papular rash, associated with fever and arthropathy, OXFORD CASE HISTORIES 114 on the face or trunk that is rarely associated with colonic Crohn \200\231s disease. Ocular manifestations include conjunctivitis, iritis, episcleritis, anterior uveitis, and very ra rely ocular myositis. Precise, ophthalmological diag- nosis should be considered essential. \200\230Eye Casualty \200\231 exists for this, because inaccurate diagnosis impairs visio n. Episcleritis may reflect the activity of bowel disease, but uveitis can progress indepen dently. Primary sclerosing cholangitis is the most common hepatobiliary manifestation of inflammato ry bowel disease. While more common in ulcerative colitis, it is prevalent in patients with colonic Crohn \200\231s disease and may be under diagnosed. 18c) Describe the management. Induction of remission is the first objective. This is most commonly achieved with oral cor ticosteroids. It is wise to have a standard reducing course, to avoid excessive cumulative dosing through ad hoc fluctuations in therapy. The Oxford regimen for the past 30 years has been to use prednisolone 40mg/day for 1 week, then 30mg/day for 1 week, then 20mg/day for a month, before decreasing by 5mg/day each week. Others start at 40mg/day and reduce by 5mg /day each week. There is no case for maintenance corticosteroids in Crohn \200\231s disease . If disease relapses just once as corticosteroids are tapered, then immunomodulators (such as azathioprine 2 \200\2232.5mg/kg/day) should be added. If corticosteroids can- not be wi thdrawn within 3 months, there is a case for referral to a spe- cialist center to consider biological or other therapy. Corticosteroid side effects may be early and dose related. These include mood disturbance, insomnia, dyspepsia, glucose intolerance, cosmetic, weight gain, and acne. Extended use may cause osteoporosis, avascular bone necrosis, hypertension, cataracts, dyslipidaemia, or my opathy, or increase the risk of infection. Rapid withdrawal may lead to acute adre- nal ins ufficiency. Even with gradual tapering, corticosteroid-induced pseudorheumatism may occur. Corticosteroid-related side effects are less common when corticosteroids with low systemic bioavailability are used. Budesonide is recommended for Crohn \200\231s disease of the term i- nal ileum and ascending colon, but is slightly less effective than predniso- lone. It is also ineffective at maintaining remission. Biological therapies (principally anti-TNF antibodies such as adali- mumab, infliximab, o r certolizumab pegol in some countries, includ- ing the USA) are a major advance in the tre atment of active Crohn \200\231s resistant to or relapsing after corticosteroids. Anti-TNF therapy can help avoid corticosteroids altogether, although it is always a balance between risks and benefit. CASE 18 115 Maintenance of remission and prevention of long-term complica- tions are secondary goals of therapy. Patients with mild Crohn \200\231s disease, not thought to be at risk of long-ter m complications, may be observed to see if they relapse after initial corticosteroid therap y. Mesalazine was commonly used in the past, but this had little benefit in Crohn \200\231s disease, either as induction or maintenance therapy. It is not recommended in current Euro pean guidelines. The main role for azathioprine is corticos- teroid sparing, to maintain re mission. Azathioprine should be started if a patient has a relapse within 12 months of trea tment with corticoster- oids. Azathioprine (or its metabolite mercaptopurine) may also be u sed for primary prophylaxis, since it is associated with a 50% reduction in the need for co rticosteroids over 18 months. Thiopurines (azathioprine/ mercaptopurine) have in the past b een introduced late in the course of Crohn \200\231s disease. Methotrexate is an alternativ e to azathioprine and probably no less effective, but is generally used only when thiopurin es cannot be tolerated. Methotrexate is teratogenic and contraindicated in pregnancy. Identifying patients at high risk of developing complications is poten- tially possible at diagnosis. Young age at diagnosis, perianal disease, stricturing disease, or the severity o f disease at diagnosis (measured by the amount of weight loss, or the need for corticostero ids at diagnosis) are factors to be taken into account. When three of these factors are pre sent, then up to 90% will have a poor outcome within 5 years, necessitating two or more res ections, a definitive stoma, or developing complex peria- nal disease. It is particularly i mportant to consider this in young people, because debilitating disease strikes at the most important years of their lives with respect to education, development of relationships, pr ocre- ation, career development and economic activity. Early use of biological therapy help s reduce hospitalization and surgery: since the future pat- tern of disease may conceivably be identified at presentation, this should be an impetus for early referral to a specialis t center. Such decisions are complex and merit discussion with the patient. Anti-TNF -therapy with adalimumab, certolizumab pegol (not available in Europe), or inflix imab (the first such therapy) are effective for induc- tion and maintenance. Anti-TNF the rapy is not without drawbacks. It is expensive and carries risks including infection (inclu ding tuberculo- sis), infusion reactions, or possibly lymphoma when used in combina- tion w ith azathioprine. The absolute risk of all these events is low, with <0.1 malignancies per 100 patient-years of treatment. Nevertheless, anti- TNF therapy has been the most substanti ve advance in the treatment of OXFORD CASE HISTORIES 116 Crohn \200\231s disease in the past decade, and is often introduced at too late a stage whe n irreversible bowel damage has occurred. Discussion at an early stage with an IBD speciali st is appropriate. Our patient was started on oral prednisolone at the time of diagnosis. Since she had extens ive disease with involvement of the proximal and distal small bowel, ileal, and colonic dis ease, primary prophylaxis with azathioprine was started. Smoking cessation was strongly adv ised (see below). She responded rapidly and has not needed corticosteroids since. The optim al duration of azathioprine therapy is unresolved. Evidence supports the continuation of th erapy for at least 3.5 years. Even after this period, relapse occurs after withdrawal of az athioprine in 14% after 1 year, 36% after 2 years, and 53% after 3 years. Remission is usua lly achieved on resumption of therapy. The risk of lymphoma during aza- thioprine therapy i s a theoretical concern, but even if the risk is increased 2 \200\2234 fold, the number-nee ded-to-harm (i.e. patients treated before one lymphoma occurs) exceeds 4000 <30 years of ag e. The general approach is to withdraw azathioprine after 5 years of therapy, based on the indi- vidual course of disease, and to reintroduce it if relapse occurs. 18d) How does smoking and potential pregnancy affect the condition? The risk of developing Crohn \200\231s disease is higher in active smokers. Smoking is also associated with the location of the Crohn \200\231s disease, since smokers with Crohn \200 \231s disease appear more likely to have disease in the ileum. Smokers have a higher incide nce and prevalence of complicated disease, with more strictures and fistulas, more often re quiring treat- ment with corticosteroids and immunosuppressants, and more often needing sur gery. Smoking cessation may bring rapid improvement in the course of the disease. Interesti ngly, patients with colonic disease appear to be less prone to the harmful effects of smoki ng. Female patients with Crohn \200\231s disease are more severely affected by smoking than their male counterparts. Perineal complications of Crohn \200\231s disease do not seem to be affected by smoking. It is important to consider that our patient is a young woman in her reproductive years (se e Case 23). Patients with Crohn \200\231s disease have an increased rate of voluntary child lessness (18%), compared with the general population (9%). They also tend to have fewer chi ldren. Involuntary childlessness, however, is no higher in patients with Crohn \200\231s di sease. Quiescent disease is associated with normal fertility, but active disease, previous surgery, involvement of fallopian tubes or ovaries, and perianal disease with resulting dys pareunia are associated with decreased fertility. Oral contraceptive medication has no effe ct on CASE 18 117 disease course, but the evolution of Crohn \200\231s disease during pregnancy is related to the level of activity at the time of conception. Quiescent disease at conception remains s o in two out of three patients during pregnancy, while active disease at conception remains active in the same proportion. Conception is therefore best planned at a time of disease r emission. As far as the effect of Crohn \200\231s disease on the pregnancy outcome is concerned, data are conflicting. Increased rates of prematurity, low birth weight, spontaneous abortion, a nd still birth are associated with poor disease control. This underlines the need for good disease control during pregnancy. Congenital abnormalities do not appear to be increased. The safety of medication during pregnancy is always a concern. Corticosteroids and azathiop rine are considered safe, despite poorly conceived and inadequately powered studies that ha ve failed to sepa- rate disease activity from drug administration. The advantage of well- c ontrolled disease probably outweighs the risk of any unconfirmed increased risk of adverse outcome. Recent data show that azathioprine cannot be detected in breast milk, so breast-fe eding is usually possible while continuing azathioprine. Anti-TNF therapy with adalimumab or infliximab is probably safe in pregnancy, but data are limited. Once again risk and ben efit should be assessed, and a drug should be admin- istered only if indicated (i.e. active disease not responding to conven- tional immunomodulators). Regarding the mode of delivery, patients with perianal Crohn \200\231s dis- ease should gen erally be advised to have a caesarian section, to protect the anal sphincter. Patients with quiescent disease and without perianal involvement may have normal vaginal delivery, but e pisiotomy should be avoided due to the risk of developing later perianal disease. All deci- sions related to pregnancy, delivery, and breast-feeding have high emo- tive components an d concerns, as well as being complex, so are best discussed between IBD and obstetric speci alists. 18e) What is the prognosis? At any one time, 55% of Crohn s disease patients are in remission, 15% have mildly active d isease, and 30% have significant disease activity. Mortality in patients with Crohn \200 \231s disease is slightly higher than the general population. Increased mortality is relate d to disease extent, duration, and female gender. Excess mortality is explained by disease- related deaths, but also by associated hepatobiliary disease, and by lung cancer, attributa ble to the preponderance of smokers in Crohn \200\231s disease patients. OXFORD CASE HISTORIES 118 Further reading Cho JH (2008). The genetics and immunopathogenesis of inflammatory bowel disease. Nature Rev Immunol; 8: 458 \200\22366. Korelitz B (2008). What are the rules when treatment with 6-MP/ASA is started? Inflamm Bowel Dis; 14(Suppl. 2): 262 \200\2233. Katz JA (2008). How long is it advisable to continue maintenance treatment of Crohn s disease? Inflamm Bowel Dis; 14(Suppl. 2): 264 \200\2235. Etchevers MJ, Aceituno M, Sans M (2008). Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease. World J Gastroenterol; 14(36): 5512 \200\22318. Mottet C, Juillerat P, Pittet V, Gonvers J-J et al. (2007). Pregnancy and breastfeeding in patients with Crohn s disease. Digestion; 76: 149 \200\22360. Lakatos PL, Szamosi T, Lakatos L (2007). Smoking in inflammatory bowel disease: Good, bad or ugly? World J Gastroenterol; 13: 6134 \200\2239. Rothfuss KS, Stange EF, Herrlinger KR (2006). Extraintestinal manifestations and compli- cations in inflammatory bowel disease. World J Gastroenterol; 12: 4819 \200\22331. Stange EF, Travis SPL, Vermeire S et al. for the European Crohn \200\231s and Colitis Organ ization (ECCO) (2006). European Consensus on the diagnosis and management of Crohn \200\231 s disease: definitions and diagnosis. Gut; 55(Suppl. 1): i1 \200\223i15. Travis SPL, Stange EF, L mann M et al. for the European Crohn \200\231s and Colitis Organi zation (ECCO) (2006). European Consensus on the diagnosis and management of Crohn \200\231s disease: current management. Gut; 55(Suppl. 1): i16 \200\223i35. Walker D, Orchard T (2008). Do extraintestinal manifestations predict disease course, sever ity and/or activity in IBD? Inflamm Bowel Dis 2008; 14(Suppl. 2): 200 \200\2231. CASE 19 119 Case 19 A 35-year-old male financial consultant presented to the emergency department with an extre mely painful perianal swelling, fevers, and difficulty walking owing to the perianal pain. He had had two previous perianal abscesses over the past decade, but both had settled with antibiotics. He had had an appendi- cectomy as a child and a right hemicolectomy 8 years pr eviously for a chronic caecal volvulus. On examination he had a pulse rate of 90bpm, blood pressure 135/80mmHg, and a temperature o f 37.8 C. Examination of the perianal area revealed two discharging sinuses, and celluliti s extending into the buttock. Investigations showed: 9/L, platelets 567 x 109/L Hb 14.5g/dL,WCC 15.3 x 10 mol/L, urea 6.0mmol/L Na 141mmol/L, K 4.0mmol/L, creatinine 80 CRP 160mg/L ESR 78mm/hour The emergency department registrar suspected underlying Crohn \200\231s disease and was unc ertain whether to arrange investigation through the gastroenter- ologists, or to call the s urgeons. In the event, both teams came and an MRI of the pelvis was subsequently carried ou t after the initial management (Fig. 19.1). Questions 19a) What initial management would you advise? 19b) What is the differential diagnosis and what further investigations are appropriate? 19c) What does the MRI show and how does this help to classify the disease? 19d) What other imaging modalities could be used? 19e) What treatment should be considered? OXFORD CASE HISTORIES 120 Fig. 19.1 MRI of the pelvis, performed later in the evaluation of the patient, after initia l management. This page intentionally left blank OXFORD CASE HISTORIES 122 Answers 19a) What initial management would you advise? The priority is to drain the perianal sepsis. This is done by an urgent examination under a nesthetic, so the surgeons should be called imme- diately. Perianal pain of this nature means that there must be an abscess, which is destructive and will damage the anal sphincter unless drained. Perioperative antibiotics (initially intrave nous, then oral metronidazole 400 \200\223500mg 3 times daily, and a quinolone or cephalosp orin for 7 \200\22310 days) are advisable in view of the extensive cellulitis. The surgeon should not only drain the abscess, but seek a fistula: a seton drain should be inserted at this initial presentation if the fistula tract can be identified. A seton (from the medieva l French for a \200\230bristle \200\231) is simply a loop of soft nylon that passes throug h the skin, fistula track, and anal canal to be tied off outside the body. Its purpose is t o prevent further abscess formation by keeping the fistula open until it heals spontaneousl y or with medical therapy. Acute perianal pain should be relieved by the examination under anesthetic, and if pain per sists or recurs in the following days, then it must be assumed that there is still undraine d sepsis. This is an indication for a repeat examination under anesthetic by an experienced colorec- tal surgeon. Intraoperative endoanal ultrasound may be helpful in iden- tifying a collection. In our case, two fistulas were identified, setons were inserted and a sigmoido scopy at the time of the examination under anesthetic showed evidence of active rectal Croh n \200\231s disease. An MRI was subsequently carried out to confirm the internal anatomy of the fistulous tracks. 19b) What is the differential diagnosis and what further investigations are appropriate? Diagnosis of perianal Crohn \200\231s disease is not usually difficult (table 19.1), but th ere is no single method. The current view is that the diagnosis is established by a combina tion of clinical presentation, endoscopic appear- ance, radiology, and histopathology. Perianal abscesses or fistulae may precede the diagnosis by some years, as in this case. Al though the diagnosis of Crohn \200\231s disease was confirmed by flexible sigmoidoscopy at the initial examination under anesthetic and subsequent histopathology, full evaluation is needed after recovery, CASE 19 123 Table 19.1 Differential diagnosis of perianal Crohn \200\231s disease Cause Comment Tuberculosis usually includes peritoneal involvement and may be indistinguishable from Croh n \200\231s disease Infection Tuberculosis HIV may cause perianal ulceration indistinguishable from Crohn \200\231s disease HIV Syphilis Vasculitis Any vasculitis may cause focal colonic ulceration Beh et \200\231s Beh et \200\231s may cause perianal ulceration Lymphoma Mantle cell lymphoma in elderly males may be indistinguishable from Crohn \200\231s colitis at colonoscopy: histopathology should be diagnostic Mantle cell lymphoma Other Hidradenitis may present with florid buttock and perianal fistuas and be difficult to discr iminate from Crohn \200\231s disease Hidradenitis suppurativa Rectal mucosal prolapse Prolapse may cause rectal ulceration that looks (and feels) like Crohn \200\231s; disease h istology should discriminate so that a management strategy to induce remission and reduce the risk of relapse can be pla nned. This includes pelvic imaging by MRI, colonos- copy (with ileoscopy and serial biopsie s), and small bowel imaging (by MR-, CT-, or barium enteroclysis). It turned out that this patient had Crohn \200\231s disease limited to the distal colon, bu t the presentation with perianal disease at a young age (<40 years) puts him in a category with a poor prognosis (see Case 18) and high likelihood of needing further surgery or a sto ma in the next 5 years. This justifies a proactive approach to medical management. 19c) What does the MRI show and how does this help to classify the disease? The MRI (Fig.19.1) shows complex perianal disease. There is a left transphincteric fistula on a coronal, fat-suppressed (T2) image. Clinically, the most useful classification distinguishes simple from complex fistulae. (Table 19.2). There are other classifications, including that of Parks, which is more descriptive and can influence surgical decisions, although complicated to use in routine practice. This descri bes fistulas in precise anatomical terms, using the external sphincter as the reference poi nt. In this case the fistulas were transphincteric and suprasphincteric, so were categorize d as \200\230complex \200\231. OXFORD CASE HISTORIES 124 Transphincteric fistula Fig. 19.1 MRI of the pelvis, performed later in the evaluation of the patient, after initia l management. 19d) What other imaging modalities could be used? MRI of the pelvis is the gold standard for imaging perianal fistulae, but is rarely availab le immediately. It is appropriate for imaging fistulas when no abscess is suspected. It has an accuracy of 76 \200\223100% compared with examination under anesthetic, and may provide additional informa- tion. Endoscopic ultrasound is an alternative and has an accuracy of 5 6 \200\223100%, especially when performed by experts in conjunction with hydrogen peroxide enhancement. The choice of technique should depend on the expertise and availability of ima ging techniques in each center. The diagnostic accuracy of fistulography and pelvic CT scan ning are too low to be clinically useful. 19e) What treatment should be considered? Management of perianal Crohn \200\231s disease should involve gastroenterolo- gists and col orectal surgeons. The goal is complete healing, although cessation of drainage without heal ing of the fistulous track is generally the best that medical therapy alone can achieve. Table 19.2 Classification of fistulae Simple Complex Superficial Transphincteric Intersphincteric Suprasphincteric Extrasphincteric CASE 19 125 : this patient needed antibiotics because there were signs of Antibiotics systemic sepsis. In the absence of sepsis, antibiotics (metronidazole and ciprofloxacin) are often prescribe d for patients with draining fis- tulas, although there are no controlled trials. Case seri es report cessa- tion of drainage in about half of patients after 8 weeks, but recurrence i s common and antibiotics are best reserved for active sepsis. : 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.