J. clin. Path. (1956), 9, 316.

ADRENAL FAILURE DUE TO BILATERAL SUPRARENALINFARCTION ASSOCIATED WITH SYSTEMIC NODULAR

PANNICULITIS AND ENDARTERITISBY

M. S. R. HUTT AND J. L. PINNIGERFrom the Louis Jenner Laboratory, St. Thomas's Hospital, London

(RECEIVED FOR PUBLICATION JANUARY 20, 1956)

Although involvement of the periadrenal vesselsis frequent in cases of hypersensitivity angiitis orpolyarteritis nodosa, it rarely results in clinicaladrenal insufficiency. The present case is reported,first because infarction of the suprarenals led tothis clinical state, and secondly because of theunusual and complex nature of the underlyingpathological process.

Case ReportMr. C. B., aged 49, was admitted to hospital on

July 21, 1954, complaining of continuous abdominalpain and vomiting for two days. The patient hadbeen under treatment since 1951 for pulmonary tuber-culosis, and was receiving streptomycin and P.A.S.at the time of his admission; there had been norecent evidence of activity of the lung lesion. Hehad been admitted to hospital in January, 1954, com-plaining of abdominal pain for 11 days, and wasfound at operation to have a perforation of the smallbowel. This was sutured and an end-to-end anas-tomosis of the bowel was performed. The histologicalreport was as follows:

" Chronic inflammation of the wall of the smallintestine, with superadded acute inflammation andperitonitis. A regional lymph node shows chronicinflammation. No specific inflammatory features."Following this operation the patient made an un-

eventful recovery, but about three months beforethe present admission he began to complain of vagueabdominal pain in the right iliac fossa and right loinassociated with occasional vomiting. Two daysbefore admission this pain became continuous and hevomited after all food. On examination the patientshowed tenderness and guarding in the right iliac fossaand hypochondrium and a continued pyrexia.

Laboratory Findings (July 22, 1954).-Haemoglobin,100% (Haldane); W.B.C., 4,200/c.mm. (neutrophils55%, lymphocytes 28%, monocytes 3%, eosinophils11%, basophils 3%). A urine examination gaveprotein + +, mucus +, red blood cells + + +, moder-ate numbers of white blood cells and epithelial cells,but no casts. Plasma electrolytes (mEq./1.) Na 134,K 5.1, Cl 90.5, CO2 23.2, blood urea 38 mg.00.

Progress.-The patient's abdominal pain and fevercontinued over the next few days with occasionalvomiting. There was progressive depletion of sodiumand chloride ions despite the administration of largeamounts of sodium chloride and lactate, both intra-venously and by mouth. This loss was associatedwith a good urinary output (1,000 to 1,800 ml.) andhigh urinary chlorides (3-4 g./l.). Further investiga-tions included intravenous and retrograde pyelograms,both of which appeared normal, though during thelatter blood-stained urine was seen coming from bothureteric orifices. A barium meal was also normal.On July 29, 1954, the patient developed discrete in-durated macules on the trunk, and a biopsy of one ofthese showed infarction of the skin and focal in-flammatory cell infiltration of the subcutaneous fat.He continued to have severe abdominal pain andvomiting, and the blood urea level had now risen to64 mg. %. Treatment with antituberculosis drugs,streptomycin and I.N.H., and later with terramycin,had no effect on the fever. By August 3 the patient'sblood pressure had fallen to 80/60 mm. Hg, themacular rash was beginning to fade, and the patientshowed increasing weakness and apathy. As can beseen in the accompanying Table, intravenous therapy

TABLEPLASMA ELECTROLYTES (mEqllitre)

Date | Na+ K+ | CI- HCO3 Blood UreaDateNa~~~~~K~~~ (mg.%)

22.7.55 134 5 1 90s5 23 2 3823.7.55 130 4-6 84.53.8.55 103 5 8 72 19 645.8.55 125 4 6 100 137.8.55 118 49 87 175

had little effect in raising the serum electrolytesthroughout his illness. The patient's conditiondeteriorated steadily, and on August 6 he showedsigns of over-hydration with ankle oedema and basalcrepitations. He died on the following day, 18 daysafter admission to hospital.The association of fever and haematuria, to-

gether with evidence of renal impairment and theabnormal electrolyte findings, suggested clinically

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ADRENAL FAILURE DUE TO SUPRARENAL INFARCTION

that this patient had a renal lesion with a tubulardefect resulting in salt loss. Adrenal failure dueto Addison's disease was considered, but wasthought unlikely in view of the short history,absence of pigmentation, and associated findingssuch as haematuria and the rash. Cortisone wasstarted 24 hours before death, but no further inves-tigations were carried out after its administration.

NecropsyNecropsy was performed on August 9, 1954.The body was that of a middle-aged man show-

ing marked oedema of the legs and back, and anoccasional small area of pigmentation on the trunk.

Cardiovascular System.-The pericardial sac,heart muscle, and valves appeared normal. Thecoronary arteries and large vessels were mildlyatheromatous.Respiratory System.-Approximately 200 ml. of

straw-coloured fluid was present in each pleuralsac. The trachea and main bronchi contained alittle mucopus, and both lungs were markedlyoedematous, particularly at the bases. There wasa cavity, 1 cm. in diameter, in the apex of the leftlower lobe, having a firm, well-defined fibrous walland containing caseous material.Alimentary System and Other Intra-abdominal

Organs.-The oesophagus and stomach werenormal. There was a nodule of white tissue,approximately 2.5 cm. in diameter, on the anteriorsurface of the first part of the duodenum, whichwas slightly raised above the peritoneal surface,but which did not involve the mucous membrane.Some small superficial ulcers were present in themucous membrane of this part of the duodenum.The rest of the small bowel was normal apart fromthe scar of an anastomosis 15 cm. from thebeginning of the jejunum. The large bowel wasnormal. Enlarged soft lymph nodes of up to 2 cm.in diameter were present around the aorta, thecoeliac axis, and the splenic hilum. The liver wasof normal size, but was pale and appeared to beslightly firmer than normal. The gall bladder andpancreas were normal.The spleen was enlarged approximately to twice

its normal size and the splenic pulp was very soft.The adrenal glands were fixed to the surroundingtissues by young vascular connective tissue whichextended on to the surface of both kidneys. Onsection the normal anatomical outlines were seento be present, but the cortices were very pale andfirm apart from a small haemorrhagic area in theright adrenal.The kidneys were congested but were otherwise

normal. The pelvis of the right kidney showed

several small submucous haemorrhages. The renalvessels appeared normal. The urinary bladdershowed evidence of a recent cystitis.Bone Marrow.-This was not examined.

HistologySmall BoweL-.The biopsy section taken at the

site of perforation shows a severe chronic inflam-mation throughout, part of the perforation wallbeing lined by granulation tissue. The inflam-matory reaction is not specific, but in the fattytissue foci are present where there is degenerationof the fat cells, associated with a histiocytic andgiant cell reaction. Many of the histiocytes appearto be stretched over the surface of intact fat cells(Fig. 1). Some of the larger arteries and veinsshow narrowing of their lumina by a loose con-nective tissue in the intima, and the arteries arepermeated with fibrin in the region of the internalelastic lamina (Fig. 2).

4%r X;.; X. ->KJ;FIG. I.-Mesenteric fatty tissue, adjacent to site of perforation of

small bowel, showing the pleomorphic cell reaction described inthe text. Stained by haematoxylin and eosin (x 240).

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M. S. R. HUTT and J. L. PINNIGER

Skin.-The biopsy shows that there is infarctionof skin leading to necrosis of epidermis and acces-sory skin structures in the dermis, and secondaryinfection of the ulcerated surface (Fig. 3). Fociare present in the underlying subcutaneous fattytissue showing similar changes to those describedfor the small bowel. No vascular changes can beidentified.Adrenals.-There is widespread necrosis in both

adrenals, taking the form of coalescing infarcts,with intervening small islands of surviving, thoughdegenerate, cortical tissue. The necrotic tissue isheavily infiltrated with fibrin and red blood cellsand includes a number of thrombosed bloodvessels. The periadrenal connective tissue con-tains an abundant cellular exudate (Fig. 4).These cells are predominantly histiocytes, lympho-cytes, and granulocytes ; a smaller number of

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FRo. 2.-Mesenteric fatty tissue, and serosa adjacent to the site ofperforation of the small bowel. The large artery shows intimalproliferation of loose connective tissue and fibrin deposition inthe region of the internal elastic lamina. Fig. 1 is a high-powerview of one of the areas of fat shown here. Stained by haema-toxylin and eosin (x 40).

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by haematoxylin and eosin (x 40).

multinucleate giant cells are also present. Hereand there degenerative changes are present in thefatty tissue which are associated with a histiocyticreaction, including "foam" cells. There isdeposition of fibrin on the intimal surfaces of manyof the arteries and veins in the periadrenal fattytissue, and in the case of some of the arteries ithas permeated into the wall. In the latterinstances the intima is thickened through the for-mation of a loose connective tissue (Fig. 5), butthis proliferation is frequently present in theabsence of fibrin deposition. Some of the largerarteries show necrosis of their walls associatedwith an inflammatory cell infiltration, the support-ing connective tissue being still apparently healthy,apart from the presence of inflammatory cells. Nothromboses could be seen in any of the vessels,except those within the infarcted adrenals.Lymph Nodes.-Three nodes were examined.

The general architecture has been partially obli-terated in two of them. All show sinusoidal

318

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ADRENAL FAILURE DUE TO SUPRARENAL INFARCTION 319

:~~~~~~~~~~~~~~~~~~~~~~~~~~~~~T'A- 5 <

FIo. 4.-Section showing necrotic adrenal with chronic inflammation and endarteritic thickening inperiadrenal fatty tissue. Stained by haematoxylin and eosin (x 30).

FsG. 5.-Artery in periadrenal tissue showing narrowing of lumen by loose connective tissue and depositionof fibrin in the region of the internal elastic lamina. Stained by haematoxylin and cosin (x 140).

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M. S. R. HUTT and L. L. PINNIGER

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FIG. 6.-Epicardial fatty tissue showing pleoinorph^ccellular reaction with giant_cells,and containing a

smalareryi on te ntim' s . S e by h n a240).; # # t w"'to,' xH>:92;.

tk twe fwi * t|ooet S 8 8 & i ^ W t t;~~~~~~~i,$F**^ ** \ . % t .... ;'.,-;.2.E...................^E.-.!..;.9.~s

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FIG. 6.-Epicardial fatty tissue showing pleomorphic cellular reaction with giant cells, and containing asmall artery with a deposit of fibrin on the intimal surface. Stained by haematoxylin andeosin(x 240).

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FIG. 7.-Myocardium showing cellular infiltration together with degeneration of myocardial fibres.

Stained by haematoxylin and eosin (x 240).

dilatation, and the sinusoids contain a large num-

ber of multinucleate giant cells, together with

histiocytes and lymphocytes. The cytoplasm ofsome of the giant cells appears foamy.

Spleen.-The Malpighian corpuscles are fre-

quently atrophic, contrasting with the cellular

pulp in which granulocytes and reticulum cells are

plentiful.

320

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ADRENAL FAILURE DUE TO SUPRARENAL INFARCTION

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FIG. 8.-Kidney showing cellular infiltration ofparenchyma and arterialintimal thickening. Stained by haematoxylin and eosin (x 140).

Heart.-The pericardial fat shows an occasionalfocus of chronic inflammatory cells, includinggiant cells, similar to that seen in the periadrenaltissue. The inflammatory reaction is in placesassociated with degeneration of fatty tissue lead-ing to the formation of " foam " cells. A smallartery in the fat adjacent to the myocardium iscuffed by this inflammatory exudate, and showsslight fibrin deposition on the intimal surface(Fig. 6). The visceral pericardial lining appearsnormal. There is a patchy cellular infiltration ofthe myocardium. The inflammatory cells lie some-times between the muscle fibres, which are here invarying stages of degeneration (Fig. 7). The cellsare occasionally collected in the paravascular con-nective tissue in a manner reminiscent of Aschoffnodes. No intravascular thrombi have beenobserved.Kidneys.-Focal collections of inflammatory

cells similar to those already described are presentin the cortex, medulla, and peripelvic tissue of thekidney. Some of these cells are in relation toarteries which show intimal thickening (Fig. 8).

No intravascular thrombus, arteriolar necrosis, orthickening has been identified. The majority ofglomeruli appear normal, though one shows cap-sular crescent formation.Liver.-There is a slight increase of fibrous

tissue in the portal tracts which are infiltrated byhistiocytes and other chronic inflammatory cells insmall numbers.Duodenum. - Ectopic pancreatic tissue is

present in the duodenal wall (the grey plaque notedmacroscopically). There is a shallow inflammatoryulcer of the mucous membrane, and the pleo-morphic inflammatory cellular reaction describedfor the periadrenal tissue extends here into thesubmucosa. A vein in this situation shows a fibrinlining to its intima, and an adjacent artery has itslumen nearly obliterated by intimal fibrous pro-liferation.Pancreas.-There is advanced autolysis. An

occasional collection of chronic inflammatory cellsis present in the adjacent fat.Lungs.-The lungs are congested, and tubercles

are present in the sections taken from the left lowerlobe. Some appear inactive, but one has cavitatedand shows slight endothelioid palisading of its wall,and another solid tubercle shows similar slight pali-sading.

DiscussionAcute adrenal failure in the adult may be the

manifestation of an Addisonian crisis or, less com-monly, be due to bilateral adrenal haemorrhage.The latter change is usually associated with localinfection, septicaemia, neoplasm, or trauma; onlya few cases have been reported as having noobvious precipitating factor. Berte (1953) re-viewed the literature and could find only 17such cases where haemorrhages occurred into bothadrenals. On each occasion the haemorrhage intothe glands was gross, causing disorganization oftheir structure: thrombosis of the adrenal veinswas present in seven of the cases. Recently Plaut(1955) looked for adrenal cortical necrosis in 129unselected necropsies of adult males, and foundthe change present focally in 11. In seven of thesethe adrenal veins contained thrombi, but there wasnever any abnormality in the periadrenal arteriesor arterioles. Plaut found no significant correla-tion of the necroses with the ages of the patientsor their clinical features. It appears that thepicture of bilateral and extensive anaemic infarc-tion of the adrenals is distinctly rare.The case under review differs from those studied

by Berte in that the picture was one of infarc-tion rather than haemorrhage and the necrosis was

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far more complete than in any of the adrenalsexamined by Plaut. The absence of major adrenalhaemorrhage, together with the maintenance of amacroscopically normal glandular outline, the in-volvement of medulla as well as cortex and thepresence of a widespread abnormality of peri-adrenal arteries, make it seem certain that theadrenal necrosis was in fact the result of a shut-ting down of arterial supply. However, the com-plex arterial system of the gland with the numeroussmall vessels of supply arising from more than onemajor artery (Anson, Cauldwell, Pick, and Beaton,1947) makes it unlikely that the infarction couldhave been due to embolism or thrombosis, andindeed such features were not seen in the manysections examined. Vascular spasm remains theonly reasonable alternative explanation for thephenomena observed.The adrenal necrosis formed part of a wide-

spread systemic disorder which included vasculardisease, inflammatory cell infiltration of fattytissue, and focal parenchymatous inflammatorycell infiltration as the main features. It becameevident from a review of the surgical intestinaland skin biopsy specimens that the lesions herearose as a result of the same pathological change.The vascular lesions were observed in the peri-

adrenal and perirenal tissues, the epicardial fat,and in the wall of the intestine. The most fre-quent changes were endovascular intimal thicken-ing by a loose connective tissue, seen more fre-quently in arteries than veins, and the depositionof fibrin. The latter usually formed a lining tothe intima, but in one or two arteries it was pre-sent in the wall, the arteries then showing intimalproliferation as well. A third change most evidentin the periadrenal fatty tissue was one of necrosisof the wall, associated with inflammatory cellinfiltration.

All these changes are those which are shared bypolyarteritis nodosa and forms of disseminatearteritis, as Pagel (1951) and McLetchie and Gillis(1955) have shown, and it is clear that the promi-nent clinical features of intestinal perforation,multiple skin infarction, and finally adrenal in-sufficiency were all due to this vascular disorder.The other major pathological change in this case

was the widespread involvement of fatty connec-tive tissue by a form of inflammatory reaction.Part of the inflammation could be ascribed tosecondary infection in the bowel and a reactionto necrotic tissue in the region of the suprarenals.That this was not the whole story is indicated bythe pleomorphic nature of the cellular exudate,consisting of lymphocytes, polymorphs, histio-

cytes, and multinucleate giant cells, and by thefact that the focal changes seen in the fatty tissuewere strikingly uniform, indicating that there wasa basic change occurring in fat cells; also similarcollections of cells were seen within the viscera,such as the kidney and heart. The pleomorphicnature of the cells calls for a consideration that aform of Hodgkin's disease was the basic pathologi-cal process, especially as some of the abdominallymph nodes were involved. This seemed to beruled out, because nowhere could the cellularchange be ascribed to an autochthonous hyper-plasia of reticulo-endothelial cells, the giant cellswere not of Hodgkin type, and the changes in thelymph nodes seemed to be largely those of drain-age and histiocytic activity.The association of inflammation of fatty tissue

with vascular change is well recognized in systemicnodular panniculitis (Weber Christian disease).Steinberg (1953) reviewed the literature on thissubject and stressed that perivisceral adipose tis-sue is frequently involved and that periarteritis andintimal proliferation form a part of the essentialpathological features. The present case is remark-able in that the vascular lesions were so marked,and that they led to the unusual clinical featuresof infarction of gut, skin, and adrenals. The patho-logical findings here appear to represent a morpho-logical linkage between disseminate endarteritis,polyarteritis, and systemic nodular panniculitis,and suggest that they are merely different expres-sions of one fundamental process.No further light is thrown on the aetiology of

these conditions, though sensitivity to antitubercu-lous drugs could have been an initiating factor.

SummaryA case of adrenal insufficiency due to bilateral

infarction of suprarenals is reported. Symptomswere also present due to infarction of small boweland skin. These lesions were associated histo-logically with systemic panniculitis and end-arteritis. The suggestion is made that the under-lying pathological process was an unusual mani-festation of the so-called collagen disorders.

We are indebted to Mr. A. E. Clark for the photo-micrographs.

REFERENCES

Anson, B. J., Cauldwell, E. W., Pick, J. W., and Beaton, L. E. (1947).Surg. Gynec. Obstet., 84, 313.

Berte, S. J. (1953). Ann. intern. Med., 38, 28.McLetchie, N. G. B., and Gillis, D. A. (1955). Amer. J. clin. Path.,

25, 502.Pagel, W. (1951). Journal of Clinical Pathology, 4, 137.Plaut, A. (1955). Amer. J. Path., 31, 93.Steinberg, B. (1953). Ibid., 29, 1059.

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