Acute colitis due to methyldopa

A case of acute colitis due to amihypertensive therapy with methyldopa is reported . The colonic biopsies showed heavy infiltrates of eosinophils with crypt abscesses, cryptitis and vascular cuffing. Cessation of methyldopa therapy relieved the colitis with recurrence after restarting methyldopa on two separate occasions. Can J Gastroenterol 1989;3(5):182-184

a la methyldopa a soulage la colite, qui a recidive avec la reprise du traitement en d eux occasions.
M ETHYi ODOPA, AIONE OR IN CON- cert with a diu retic, is presen tly an infrequen tly p rescribed porent antihypertensive drug with severa l well known pharmacological side effects related to the nervous or cardiovascular system (I); uncommon allergic reactions.such as hepatitis and a Coombs' posi-tive hemolytic anemia, have also been reported (2)(3)(4)(5)(6).Even more rarely, an acute allergic colitis, wh ich is reversible with cessation of the meth yldopa therapy, has been reported wi th methyldopa use (2,3.6-9).Herein the clinical and pathological features of a case of methyldopa coli ti s are described.

CASE PRESENTATION
A 7 l-year-old afebrile woman was adm itted to hospital with a fo ur day history of crampy lower abdominal pain and watery green d ia rrhea.The stool did not con tain blood or mucus.The blood pressure was 110/45 mmHg with a heart rate of 86 beats/min .The physical exa mination was normal.On admission, med ications were isosorbid e dinitrate IO mg qid, digoxin 0.25 mg daily, triazolam 0.25 mg at bedtime and alphamethyldopa 250 mg b id .The alphamethyldopa had been started three months previously for the treatment of hypertension.
All medication was stopped and the patient rehydratcJ .In hospital.she had eigh t to IO watery green large volume bowel movements per day, wh ich were negative for occult blood .Investigation revealed a hemoglobin of 11. l g/dL and a white blood cell cou n t of 17,700/mml with 98.6% granulocytes.Stool cultures were negative for ca mpylobacter, salmone lla.shigclla and yersinia.
By the seventh hospital day the pa• tient had no rmal formed bowel movements.She remained normorcns1ve, so Figure 1) Colonic biopsy showing incense inflammatory in/iltrace including crypc abscess formacion (arrow head).Note that the inflammarion stops ac the lwel of rhe musculam m11wsa the alpha-methyldopa was not restarted .She was discharged with a provisional diagnosis of viral gastroenteritis, more by reason of exclusion than by any specific evidence of viral infection.
Two months later the patient presented to the eme'rgency department with a two week history of diarrhea identical to the previous episode.She had been restarted by her family physician on a combination medication con sisting of alphamethyldopa 250 mg and hydrochlorothiazide 25 mg twice daily, because she had been found to be hypertensive in follow-up .On this occasion, a sigmoidoscopy was performed which revealed a very watery, greenish-brown stool without blood or mucus.The rectal mucosa was diffusely erythematous with obliteration of the vascular pattern, but there was no ulceration or contact friability.A rectal biopsy was obtained.Hemoglobin was 12.0 g/dl, white blood count ll ,400/mm 3 with 94% granulocytes and no eosinophils.The zeta sedimentation rate was 0. 7 mm/h (normal 0.4 to 0.54 ).With the exception of an albumin of33 g/L the remainder of her biochemistry, including liver function tests, was normal.Stool cultures were again negative.
It was felt that the colitis might be related to alpha-methyldopa, and the drug was stopped.Immunological studies were performed.Antinuclear antibody was negative; Coombs' test was negative; IgA and lgM were all normal.lgE was 52 iu/ml (normal less than 25).Serum C , was [670 mg/L (normal 550 to 1200), C, was 598 mg/L (normal 200 to 500).Total complement CH, 00 was 130 units (normal 55 to 87).The diarrhea rapidly resolved, a nd one month later the patient underwent flexible sigmoidoscopy at which time the rectosigmoid mucosa was normal.There was marked diverticulosis.A barium enema revealed only uncomplicated diverticular disease.
Three weeks later the patient took a single tablet of the alpha-methyldopa/ hydrochlorothiazidc combinati on because her ankles had become edematous.Within 12 h diarrhea had returned associated with fecal incontinence.The stool was nonbloody, but there was considerable mucus and crampy lower abdominal pain .A sigmoidoscopy revealed marked erythema of the mucosa.Another rectal biopsy was obtained.The diarrhea resolved and peripheral edema has been controlled with hydrochlorothiazide 50 mg daily.lschemic heart disease has continued to be treated with isosorbide di nitrate 10 mg qid.

PATHOLOGY
The rectal biopsies showed inflammation confined to the mucosa (Figure l).The surface epithelial layer was thinned and infiltrated by eosinophils.Minute superficial aphthous ulcers were also Methytdopa-lnduced colitis present.Large eosi nophilic crypt abscesses were prominent a nd associated with cryptitis.The epithelial cells lining the crypts were attenuated near the surface of the biopsy, but deeper, toward the muscularis mucosa, the crypt epithelial cells were swollen with pyknotic nuclei.The goblet cell population was markedly decreased.The lam ina propria between the crypts showed a mixed infiltrate of plasma cells and lymphocytes.Margination of the blood vessels by eosinophils was prominent (Figure 2).

DISCUSSION
Since the introduction of methyldopa in 1961, numerous side effects have been reported including fever, hepatitis, pancreatitis, myocarditis and a Coombs' positive hemolytic anemia ( L.5).The first reported case of methyldopa-induced colitis by Bonkowsky and Brisbane in 1976 was published about 15 years after the introduction of the drug (2).Since that initial report, 17 cases have been reported in the European and North American literature (3,8.9).
The pathogenesis of the colitis, as well as the hemolytic anemia a nd hepatitis is not completely explained.The stud ies of Kirtland and colleagues ( 10) showed that methyldopa causes increased lymphocytic cyclic AMP resulting in inhibi- tion of suppressor T-cell function, which in turn leads to unregulated au toancibody production by B cells.This then results in hemolytic anemia.This mechan ism does not, however, explain the colitis.An autoimmune or type [II immune reaction wou ld cause decreased complement levels (it was increased in the present case) due to binding by antigenan ti body comp lexes.As well, lgE which was raised in this patient is not a complement-fixing a ntibody, whereas lgG and lgM a re.The histological picture in methyldopa colitis is more in keeping with a type I immediate hypersensitivity anaphylactic reaction.The patient beco mes se nsitized to methyldopa, and re-exposure to the drug causes degra nulation of mast cells and basophils mediated by lgE antibody.The histamine and other factors released from the granules result in smooth muscle contraction and in creased vascu lar permeability which in turn result in diarrhea.The chemotactic facto rs released account for the large eosinophilic infiltrate seen in the biopsy ( 11 ).
A type I hypersensitivity reactio n is supported by the clinical history in the present case.The colitis followed a three month course of methyldopa, enough time for immune reactions to develop.Onset o f colitis a fter taking methyldopa, both on prescription of the patient's physician and on the patient's own initiative would seem to confirm the methyldopa-colitis re lationship.
lt would be presumptuous to attempt to delineate specific pathologic features of this condition on the basis of one case.Other than a brief mention of the pathology in the first reported case (2), no other case description mentions pathological findings.Many of the features described such as the eosinophilic crypt abscesses, ulcerated su rface epithelium and vascular eosinophilic cuffing suggest inflammatory bowel disease, infective coli tis or, although rare in the colon, eosinophilic gastroenteritis in the differen tial diagnosis, and may be difficult, if not impossible, to distinguish from these other conditions.lt would be unusual to see such a great eosinophilic infiltrate in infective colitis or inflammatory bowel disease, but it could be seen in eosinophilic gastroenteritis.The symptoms of eosinophilic gastroenteri tis are usually obstructive, due to diffuse thickening of the intestinal wall, in contrast to the diarrhea seen in methyldopa colitis ( 12).
The patient's age (71 years) and endoscopic findin gs of an erythematous mucosa with loss of vascular pattern sug-gestS an ischemic colitis.The histological findings, however, did not show pseudomembrane formation, hemosiderin deposits or fibrosis, as one would expect to see in acu te o r ch ronic ische mic colitis.Parasites can cause an intense eosinophilic infiltrate, but the pattern of inflammation such as gran uloma formation in schistosomias is and/or identification of the parasite in the biopsy o r stool should help make the diagnosis apparent in most cases.
In summary, a case of colitis due to methyldopa therapy, that recurred following two re-introductions of the drug, has been described.Any hypertensive patient with onset of persistent crampy diarrhea should be questioned as to antihypertensive drug therapy.A history of methyldopa ingestio n , together with a heavy eosinophili c infiltration in a co lon ic b iopsy, should co nfirm the diagnosis of methyldopa colitis.