795

genase. This latter possibility—i.e., abnormal dehalo-genation-must remain speculative, since we have noevidence of it from thyrotoxic patients.An alternative explanation is the one originally put

forward by Plummer-namely, that there are two types ofthyrotoxicosis. Such a concept would fit the present data.Plummer suggested that exophthalmic goitre and adeno-matous goitre with hyperthyroidism were distinct entities,but also stated that in about 20% of his patients withexophthalmic goitre the disease was superimposed on anexisting adenomatous goitre; in other words, there wasan overlap between the two types. Our data do not

support Plummer’s classification, in so far as this is basedon the recognition of adenomatous and diffuse goitre.However, it is often very difficult to decide on clinicalgrounds alone which type of goitre is present. As grosslyenlarged thyroids are almost always nodular, there mustbe some association between nodularity and gland size.The highly significant difference in mean gland size in ourtwo groups might therefore be taken as evidence infavour of Plummer’s basic hypothesis.

It is generally accepted that in patients who have largegoitres disproportionately large amounts of radioactiveiodine may be required to control thyrotoxicosis. In our

series, patients with large goitres have iodinated tyrosinesin the plasma more frequently than patients with smallgoitres. The cases also show an association between thepresence of iodinated tyrosines and the result of treatmentby radioactive iodine, as estimated by the " T " factor.The reason for the highly significant difference betweenthe mean values of " T " in the two series is that, of thosepatients (41 in all) without iodinated tyrosines in theplasma, 13 were finally classified clinically as myxcedema-tous with only 1 still thyrotoxic. Of those patients (43 inall) with iodinated tyrosines, only 4 were myxcedematous,but 16 were still thyrotoxic. These differences in theclinical results, as was to be expected from the " T "values, are statistically highly significant. All patientswho required more than one treatment with radioactiveiodine had iodinated tyrosines in their blood.We are at present unable to explain our results, but

from a practical clinical standpoint they seem of consider-able importance. Estimation of the presence or absenceof iodinated tyrosines makes it possible to select high orlow radiation doses respectively for those patients whosethyrotoxicosis is likely to prove " radioresistant " or

4’radiosensitive ", and who if given too little or too

much treatment would remain thyrotoxic or becomemyxoedematous.

SummaryA preliminary tracer dose of 131 was given to 92 cases

of thyrotoxicosis and a detailed study of the radioactiveconstituents of the plasma was made.In approximately half the cases (43) iodinated tyrosine

derivatives were found in the plasma.The patients who had iodinated tyrosines in the

plasma had also a greater mean gland weight and weremore

" radioresistant " than those without iodinatedtyrosines.By estimating the iodinated tyrosine derivatives in the

blood, patients who will need high doses or low doses ofradioactive iodine can be selected.

We are grateful to our clinical colleagues at New End Hospitalfor their cooperation. We should also like to thank Mrs. Valerie

Parker of the M.R.C. Department of Clinical Research, UniversityCollege Hospital Medical School for technical assistance.We are particularly indebted to Dr. Raymond Greene and Dr. E.

Pochin for valuable advice and criticism.

REFERENCES

Abbatt, J. D., Parran, H. E. A. (1956) in Advances in Radiobiology (editedby de Hevesy, Forssberg and Abbatt); p. 305. Edinburgh.

Blomfield, G. N., Jones, J. C., Macgregor, A. G., Miller, H., Wayne, E. J.,Weetch, R. S. (1955) Brit. med. J. ii, 1223.

Brown, F., Jackson, H. (1954) Biochem. J. 56, 399.Chapman, E. M., Maloof, F. (1955) Medicine, Baltimore, 34, 261.Farran, H. E. A., Parker, V., Abbatt, J. D. (1957) Brit. J. Radiol. 30, 445.Fraser R., Hobson, Q. J., Arnott, D. G., Emery, E. W. (1953) Quart. J. Med.

22, 99.Larsson, L. G. (1955) Acta Radiol. Stockh. 43, 126.Macgregor, A. G. (1957) Brit. med. J. i, 492.Plummer, H. S. (1928) Trans. Ass. Amer. Phycns. 43, 159.

DISSEMINATED LUPUS ERYTHEMATOSUS

OF THE ALIMENTARY TRACT

JOHN BRUCEC.B.E., T.D., P.R.C.S.E.

REGIUS PROFESSOR OF CLINICAL SURGERY, UNIVERSITY OF EDINBURGH;SURGEON-IN-CHARGE, EDINBURGH ROYAL INFIRMARY AND THE GASTRO-

INTESTINAL UNIT, WESTERN GENERAL HOSPITAL, EDINBURGH

WILFRED SIRCUSM.D. Lpool, Ph.D. Sheff., M.R.C.P.E., M.R.C.P.

LECTURER IN MEDICINE, UNIVERSITY OF EDINBURGH; PHYSICIAN,GASTRO-INTESTINAL UNIT, WESTERN GENERAL HOSPITAL, EDINBURGH

MORE than sixty years ago Osler (1895) reported elevencases of erythema exudativum multiforme, in all of whichgastrointestinal crises-abdominal colics, usually with

vomiting and diarrhoea-were part of the disease.Material for histological study did not become available

in these cases and though in the ensuing half centuryinvolvement of the digestive tract in disseminated lupuserythematosus, as the disease became known, was fre-quently noted, little was known about the pathologicalbasis of the alimentary symptoms. Of 105 cases carefullyanalysed by Harvey et al. (1954) ulceration of the smallintestine with underlying " acute arteritis and thrombosisof small vessels " was observed in 3 instances. In 1 case" the entire intestinal tract was cedematous, many of thesmall vessels were the site of an arteritis, the mucosa wasinfiltrated with plasma cells and there were areas ofulceration ". Ileus of the small intestine occurred in 5of 87 cases reported by Brown et al. (1956) who made aplea for careful necropsy studies in this disease in order toelucidate its mechanism.The case reported here is unique in the number of

intestinal crises and in the opportunity to study thehistological findings in the acute phase of an episode andalso after death. It emphasises in the natural history of theactive disease the long period that may elapse before adiagnosis is established with laboratory precision.

Case-record .

On May 21, 1955, a single woman of 27, a book-keepingclerk, was admitted to the Gastro-intestinal Unit as an

abdominal emergency. Three days before she had had epi-gastric discomfort merging slowly into central abdominal colic.Nausea, vomiting, and diarrhoea were associated from thebeginning. On the day of admission the pain localised in theright iliac fossa. The only previous history of note was threediscrete epileptiform seizures between 1949 and 1951, whichdid not recur after she started to take phenobarbitone daily.There was slight fever (100°F) and a raised pulse-rate (97).

The white-cell count was 1600 per c.mm. General abdominaltenderness was present, and was maximal in the right iliac fossa.Rebound tenderness was marked and rectal examinationshowed tenderness in the pouch of Douglas. Bowel soundswere infrequent and poor.

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Fig. 1-Follow-through of barium meal inFebruary, 1956, showing spasticity andirregularity of ileum.

A presumptivediagnosis of appen-dicitis was madeand laparotomy wasperformed. Theabdominal cavitycontained approxi-mately three pintsof clear yellow fluid.Throughout itslength the smallintestine was dif-

fusely congested,and a few of themesenteric glandswere enlarged andfleshy. The appen-dix and other viscera

appeared normal,but appendicectomywas carried out.

Nausea and vomit-

ing continued on

the day after opera-tion and gastric as-piration and intra-venous fluid and

electrolytes were needed. The temperature remained elevated(102°F) and an erythrocyte-sedimentation rate (E.S.R.) of65 mm. in one hour was noted. Streptomycin (2 g. daily) wasgiven by injection.By the fifth postoperative day the patient was free from

symptoms and seemed well, but an intermittent pyrexia con-tinued until she was discharged on the twenty-second day afteroperation, and the E.s.R. remained at 100. A Mantoux test wasnegative to 1/100 dilution, and a barium meal showed slightchanges of " instability and minor flocculation of barium in theloops of the small intestine consistent with a diagnosis ofnon-specific enteritis ". Balance studies showed normal fatexcretion.The day after discharge (June 14) she had to be readmitted.

On leaving hospital she took Epsom salts because of backache,and within a few hours had profuse diarrhoea, central abdominalcolic, and then repeated vomiting.The temperature was raised to 99-4°F and the pulse-rate to

110. The abdomen was distended and tender especially in theright iliac fossa, and bowel sounds were absent. Vomitingcontinued, and hiccups and dehydration necessitated gastricsuction and intravenous therapy. The E.S.R. was 63 and thewhite count 7200. The attack subsided gradually over six days,but even when she was apparently well again the E.s.R. wasstill 100.

She was kept under observation for a further three weeks.During this period a repeat barium meal showed coarse jejunalmucosa with irregular dilatation of the intestinal loops. Thewhite count fell to 3400, the serum-albumin was low, and therewas hyperglobulinxmia, mainly due to elevation of the &bgr;-frac-tion. Repeated blood-cultures and repeated fsecal cultures werenegative and all serum-agglutination reactions, includingbrucella and the Paul-Bunnell tests, were likewise negative.Guineapigs inoculated with the peritoneal fluid removed atlaparotomy remained healthy. She was discharged on July 13.The same evening, two hours after a meal of fried chipped

potatoes and pickles, abdominal colic, vomiting, and diarrhoearecurred and she had to be readmitted. The signs were exactly’as in previous attacks, but the white count was now 2400.Symptoms subsided in three days on a regime of drip andsuction, and eleven days later she was discharged on a mainten-ance dose of prednisone (75 mg. per day) begun one week before.

She remained symptomless until Jan. 14, 1956, and gaineda stone in weight. Then, after a party at which she had con-sumed much food and alcohol, she was again seized withabdominal colic, vomiting, and diarrhoea, and as these con-tinued for four days she was readmitted. The signs were

exactly as before and again she required drip and suction.Anti-histamine (promethazine) was added to the treatment.The white count was 1900, the E.S.R. remained between 50 and100, and an intermittent pyrexia up to 100°F continued for thenext month. An enlarged gland in the right axilla was excisedand was reported to show only non-specific hyperplasia of thecells lining the sinuses. Barium meal again showed irregularityand coarsening of the mucosa of the jejunum and ileum, andthe terminal ileum had the appearance of Crohn’s disease

(fig. 1). An aspiration sample of bone-marrow was normal andno lupus-erythematosus (L.E.)-cell phenomena were observedeither in the marrow or in the peripheral blood. Wassermannand Kahn reactions were negative. Leucopenia varied in tensuccessive blood-counts from 1600 to 2600. During this attackthe dose of cortisone was increased and a total of 1-5 g. was

given over sixteen days. It was by now obvious that thewoman was experiencing recurring bouts of fairly acute small-intestine obstruction; and though the pathological cause of theattacks could not be dogmatically stated, the likeliest explana-tion was some form of regional enteritis.The uncertainty of the diagnosis and the severity of the

attacks were considered to justify operative exploration of theabdomen, and laparotomy was carried out on Feb. 24, 1956.

. Free fluid was again present in quantity in the abdominalcavity. The jejenum was grossly abnormal from a point40 cm. below the duodenojejunal flexure for a distanceof 130 cm. The loops were strikingly heavy, intenselycongested and of a deep plum colour. The mesenterywas congested, and frankly oedematous, and the mesen-

teric glandswere enlarged.Subserous ec-

chymoses ap-peared wher-ever the bowelwas handled.Because of theunusual ap-pearance, thebowel wall wasincised. It was1 cm. thick,apparently as aresult of grossoedema of the

submucosa,and the cut

surface exuded

watery fluid.The mucousmembranelooked normalto the nakedeye. At eachend of the af-fected segmentthere wereshort transi-tional zones

a few centi-metres longbefore a normal appearance and feel were resumed. A segment10 cm. long just proximal to the ileocascal junction showedsimilar changes. In the abnormal areas the lumen of theintestine was so reduced by the oedematous thickening of thewall that it was virtually non-existent. The rest of the aliment-ary tract was normal, but it was observed that towards the endof the exploration the subserous vessels throughout the lengthof the small intestine became markedly dilated and even thepreviously normal gut wall seemed to swell. A portion of tissueat the site of the jejunal incision and a mesenteric gland weretaken for histological study; no other procedure was attempted.

Microscopic examination of the intestinal wall was reportedto show " marked oedema of the submucous layer and infiltra-

Fig. 2-Biopsy of jejunum taken at laparo-tomy (Feb. 24, 1956), showing oedema of thesubmucosa and perivascular cellularity (x 45).

797

tion by plasma cells, macrophages, and eosinophils (fig. 2). Amore acute inflammation was present in the region of the innercircular muscle layer, with infiltration by polymorphs and afew eosinophils. The lymph node shows non-specific sinuscatarrh ".

Three weeks after operation the patient was free from symp-toms and was discharged. During her stay in hospital dailyblood-counts showed continuing leucopenia; there was noevidence of L.E.-cell phenomena. Snapper’s test on a 2-hourclot was likewise negative. The E.s.R. had remained around100.

She remained well for only twelve days; then she had atypical attack and she was readmitted on April 3. The whitecount had fallen to 700, with 61% lymphocytes. On thisoccasion the attack subsided without drip and suction on25 mg. promethazine q.i.d. and her stay in hospital was onlyeight days.The fifth attack of intestinal obstruction came sixteen days

later and was again severe enough to warrant admission. Dripand suction therapy was not required, and the episode subsidedin three days on cortisone (200 mg. daily). She was dischargedafter twelve days.A sixth attack a month later subsided at home on four days

of intensive cortisone therapy (250 mg. daily); and yet another,a month after, on the same regime. Maintenance therapy withpromethazine 25 mg. t.d.s. was now instituted. Leucopeniaand a high sedimentation-rate continued unchanged. She hadan eighth attack in September, 1956, while she was still takingthe anti-histamine, and it also responded to cortisone. Theanti-histamine was accordingly stopped and daily cortisone(50 mg.) and oral potassium supplements substituted.On Oct. 15, 1956, she was readmitted. Three days before

she had developed swelling of the joints of the fingers, wrists,and ankles and had become strange in her behaviour. She wasfound to be confused, irrational, and extremely restless to thepoint of manic excitement. The temperature was 100°F,pulse-rate 106. The liver was enlarged to a fingerbreadthbelow the costal margin, and there was spindle-shaped swellingof the interphalangeal joints of both hands. There were no

organic neurological signs.The maniacal state deteriorated and she was transferred to

the Royal Edinburgh Hospital for Mental Disorders where sheremained from October, 1956, to June, 1957. During this timeshe was kept under observation by one of us (W. S.) and nofurther gastro-intestinal episodes occurred. Abnormal loopsof small intestine were still obvious in barium-meal studies,however, and leucopenia and high E.S.R. persisted. There wereseveral episodes of swelling and pain in the joints of hands,arms, and legs. Rubbery, enlarged glands became palpable inthe axillae and groins. Peripheral blood and marrow remainedfree of L.E. cells and Snapper’s test was still negative.

In June, 1957, the fingernails gradually became a densewhite colour. Her mental state, which had fluctuated frommaniacal excitement to mute withdrawal requiring forced feed-ing, had improved considerably, and on June 6 she was wellenough to be transferred to the Gastro-intestinal Unit. Psycho-metric studies before transfer had demonstrated impairment ofconceptual function, learning efficiency, comprehension, andboth expressive behaviour and motor coordination. A lumbarpuncture showed 35 cells per c.mm. and 61 mg. per 100 ml. ofprotein in the cerebrospinal fluid. In view of this it wasbelieved that she now suffered from an organic disorder of thebrain and the original concept of a steroid-induced disease wasabandoned.

Liver-function tests were now abnormal: thymol turbidity9 units, zinc turbidity 23 units, and cephalin-cholesterolflocculation 4+. Needle biopsy of the liver showed slightthickening of the portal tracts but no other more specificchange. The bromsulphthalein retention test was normal.Biopsies of the enlarged glands in the groin showed only anincrease in the lymphoid content and the fibrous stroma. Aportion of muscle showed no evidence of arteritis in 140 sections.

Fig. 3-Necropsy specimen. Vessel in seross of stomach showingacute arteritis ( x 150).

She improved still further, gained weight, and was dischargedon June 20, 1957. For four months she remained well and thena ninth attack of intestinal obstruction necessitated readmission,and drip and suction therapy. On Oct. 11 L.E. cells were presentin large numbers in the peripheral blood. Snapper’s test wasnow positive. Steroids (prednisolone 10 mg. per day mainten-ance) were resumed and she was allowed home. She returnedto work in November, 1957, complaining only of moderatefatigue and amenorrhcea.On Dec. 1957 there was a tenth attack of intestinal obstruc-

tion, which required admission and drip and suction therapy.Her knee-joints were inflamed. As the abdominal attacksettled, there was gross deterioration in her cerebral state.

L.E. cells were continually and abundantly present, and redcells as well as a large amount of albumin in the urine.Creatinine clearance was only 88 litres in twenty-four hours.Prednisolone dosage was increased but since catatonia andincontinence supervened she had to be transferred to the mentalhospital. From January to March, 1958, there was rapid im-provement, but on March 27 a severe recurrence (eleventh) ofthe acute abdominal disorder necessitated readmission to theGastro-intestinal Unit.

Ptosis of the left eyelid and athetoid movement of the armswere noted. The intestinal obstruction was quickly relievedbut over the next two weeks her general state deteriorated andshe lapsed into coma. There was bleeding from the gums, andbilateral extensor plantar reflexes. She died in coma on

April 30, 1958.

Postmortem FindingsNecropsy was performed four and three-quarter hours

after death. The following is a summary of the pathologicalfindings in the alimentary tract. A fuller account will be givenelsewhere (Gordon 1959).The oesophagus showed oedema involving the full thickness

of the wall. The stomach was dilated and contained 2 litresof fluid. The small intestine from the duodenojejunal flexureonwards was dilated, the wall thick and oedematous, the mucosaslightly hyperxmic, and showing a few small ulcers. The largeintestine was also oedematous with thickening of the wall mostmarked in the cxcum and lower part of the sigmoid colon.Moderately enlarged lymph-nodes were present in the neck,axillae, groins, mediastinum, and along the abdominal aorta.All other viscera and tissues including the bone-marrow, thejoints, and the brain appeared macroscopically normal.

Histological study revealed acute and chronic vascularlesions of disseminated lupus erythematosus throughout thelength of the alimentary tract. Arterial lesions were present inan acute form in the oesophagus, stomach, and colon, and in achronic form in the small intestine. They consisted of peri-adventitial cuffs of plump dark cells (presumably histiocytes orfibroblasts) arranged more or less radially in the early lesions

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Fig. 4-Necropsy specimen. Vessels in serosa of jejunum showingconcentric adventitial fibrosis of chronic type ( 150).

(fig. 3), and with a progressively more circumferential dis-tribution until some late lesions showed the " onion-skin "

fibres resembling those typically encountered in the spleen(fig. 4). In the acute lesions the smooth muscle of the media ofthe vessels occasionally showed degenerative changes, andsometimes this amounted to necrosis. More rarely thrombosiswas present. Outwards from the adventitia the perivascularconnective tissue was oedematous and sparsely infiltrated withmononuclear cells, together with an occasional eosinophil. Theoverlying epithelium of the alimentary tract was largely intact,but in the jejunum there were old superficial ulcers denselyinfiltrated with plasma cells. In the colon there was somenecrosis of the smooth muscle, with neutrophil infiltration andarterial lesions of intermediate age (fig. 5). The immediatecause of death was acute infective peritonitis and a heavygrowth of Escherichia coli was obtained from the peritonealfluid.A reappraisal of the original lymph-node and jejunal biopsy

material was then made and previously undetected lesionssimilar to those revealed at necropsy could now be recognised.The lymph-node vessels showed adventitial fibrosis of the

Fig. 5-Necropsy specimen. Section of wall of colon showingaedema, neutrophil infiltration, and necrosis of muscle (x45).

" onion-skin " type and in the jejunum the acute type ofvascular lesion was present in association with the massivesubmucosal cedema. In fact, periadventitial cellularity wassufficiently marked in the acutely inflamed circular muscle coatto have suggested the correct diagnosis.

Discussion

Disseminated lupus erythematosus in which abdominalpain, vomiting, and diarrhoea were features was recordedby Dubois (1953) and he drew attention to the harmor-rhages into, or infarction of, the bowel wall.

In the group of 105 cases of Harvey et al. (1954) 1

patient had bloody diarrhoea and abdominal pain, andnecropsy showed extensive arteritis with thrombosis ofthe vessels and superficial ulceration of the mucosa in thesmall intestine. 4 other patients had abdominal pain anddiarrhoea, but the arteritis and mucosal ulceration werelocalised to the large bowel.

In 5 of the 7 cases with gastrointestinal symptoms inthe group of 87 cases reported by Brown et al. (1956)intestinal peristalsis was poor and tone in the bowel wasreduced, with symptoms and signs of intestinal obstruc-tion ; but structural lesions were not noted. In 1 patient,dilatation of the second and third parts of the duodenummimicked the superior mesenteric syndrome and a similarsegmental ileus was present respectively in the stomachand in the ileum in another 2 patients. Abnormal necropsyfindings in the alimentary tract were found in only 2 cases,1 showing intestinal oedema and submucosal haemorrhagesin the small intestine, and the other depots of collagenin the submucosa of the stomach. 1 of their cases

closely resembled ours, with episodes of acute small-bowel obstruction. At laparotomy the jejunum wasdistended, oedematous, and congested over a lengthof 30 cm. Unfortunately, histological studies were notmade.

We suggest that lupus erythematosus of the bowel canbe recognised both clinically and at operation in cases ofintestinal obstruction. Recurrent attacks of transientacute intestinal obstruction with segmental ileus on

radiological examination in young subjects, especiallywomen, with diarrhoea accompanied by pyrexia and

leucopenia, should suggest the diagnosis even in theabsence of other recognisable phenomena of the systemicdisease. At laparotomy swollen, soggy, deeply injectedlengths of small intestine are characteristic. The onlydifficulty in diagnosis-the differentiation between recur-rent Crohn’s disease and jejunitis acuta-may be resolvedby observing the transient nature of the attacks,with either spontaneous resolution or rapid improve-ment on steroids or anti-histamines within seventy-twohours.

The intestinal ileus probably reflects an acute inflamma-tory reaction in the bowel wall, with a direct effect uponboth the muscle and myenteric nerve plexus. Obstructionis due to obliteration of the lumen by massive oedema ofthe intestinal wall.

We are indebted to Dr. A. Gordon, of the pathology department ofthe Western General Hospital, for the detailed study of the patho-logical changes.

REFERENCES

Brown, C. H., Shirey, E. K., Haserick, J. R. (1956) Gastroenterology, 31, 649.Dubois, E. L. (1953) Ann. intern. Med. 38, 1265.Gordon, A. (1959) In preparation.Harvey, A. M., Shulman, L. E., Tumulty, P. A., Conley, C. L., Schoenrich,

E. H. (1954) Medicine, Baltimore, 33, 291.Osler, H. (1895) Amer. J. med. Sci. 110, 629.