J. clin. Path., 1970, 23, 362-369

Parathyroid adenomas associated with themalabsorption syndrome and chronicrenal disease

J. F. SMITHFrom the Department of Morbid Anatomy, University College Hospital Medical School, London

SYNOPSIS The pathology of the parathyroid glands in two cases in which hyperparathyroid-ism was associated with chronic renal disease and 10 in which the association was with themalabsorption syndrome is described. It is concluded that whereas in chronic renal diseasethe development of an autonomous adenoma may be preceded by anatomical secondarydiffuse hyperplasia such a stage is not proven when the adenomas develop against a backgroundof the malabsorption syndrome. The importance of this latter association is stressed.

Primary hyperparathyroidism is a condition inwhich hyperplasia and benign or malignantneoplasia developing without known cause leadto hypercalcaemia and varied clinical mani-festations, the most common being renal calculiand osteitis fibrosa. Clinical cure with the de-velopment of normal blood chemistry followsremoval of the excess of parathyroid tissue unlessirreversible changes have developed in thekidneys or other tissues.

Secondary hyperparathyroidism is the termgenerally restricted to those cases in whichhyperplasia of all four parathyroid glands(albeit of uneven degree in the various glands)is associated with renal failure, osteomalacia,or rickets, and is thought to be a compensatoryhyperplasia induced by hypocalcaemia. Whetherother triggers can initiate this compensatoryhyperplasia is at present unknown.

Tertiary hyperparathyroidism is a term usedby Davies, Dent, and Watson (1968) to describecases in which a presumed secondary hyper-parathyroidism has evolved to the developmentof an autonomous adenoma in one gland withconsequent hypercalcaemia and associated clin-ical changes which are reversed by the removalof the tumour. In the 12 cases they describethere was clinical evidence of a condition thoughtto be associated with secondary hyperparathy-roidism, namely, renal disease in two, and themalabsorption syndrome, usually with osteomal-Received for publication 4 March 1970.

acia, in ten. In several of these blood calciumrose from normal levels while under observation,but the clinching evidence of a marked hypo-calcaemic period was seen in only one beforeoperation.

In this paper the pathology of the parathyroidsin these 12 cases is presented. The thesis isdeveloped that in 11 there is no anatomicalevidence for a secondary diffuse hyperplasiapreceding the adenomas. The importance ofthe association of parathyroid adenomas withthe malabsorption syndrome is stressed and thepossible mode of their evolution is brieflydiscussed.The main clinical details are presented in

Table I. The case numbers are those in theUniversity College Hospital series of operatedhyperparathyroid patients. The changes in theparathyroids from operative specimens aresummarized in Table II. It should be mentionedthat it is the practice of Mr D. R. Davies toconfirm the histological state of all four para-thyroids at operation if possible, and to removesuch tissue as is thought to be necessary tocure the patient; 10 of these cases had a singleadenoma resected, one had two adenomasremoved, and one had an adenoma and twohyperplastic glands removed. It is usuallypossible to decide from the tissue removedwhether the non-adenomatous parathyroids arenormal or hyperplastic, but if the amount oftissue provided is small it is only possible to

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Parathyroid adenomas associated with the malabsorption syndrome and chronic renal disease

Case Name Age Year Preoperative Chemical Findings Evidence of Bone Disease Operative Aetiological PreviouslyNo. & Sex of Op- Findings Factor Reported

eration Calcium P Phosphatase OM HPT(mgl1OO ml) (KA units)

S E.S. 64 F 1951 14 5 2-5 63 None Radiograph Adenoma Gluten-sensitive Dent and(9-5 g) enteropathy Garretts (1960)

11 L.D. 41 F 1955 11-4 2-0 69 Radiograph Radiograph 2 Adenomata Gluten-sensitive Davies et al(150 mg & I g) enteropathy (1956)

57 M.B. 60 F 1960 10 0 3-9 9 None Radiograph Adenoma Renal glomerular Dent (1962)(1024) (1 8 g) failure

59 A.R. 48 M 1960 12 7 2-0 31 Radiograph Radiograph Adenoma Polycystic kidneys(4-5 g)

91 H.M. 59 F 1963 109 12-6 2-2 15 None None Adenoma Gluten-sensitive(1028) (1-5 g) enteropathy

107 A.G. 46 M 1964 9-6 10-8 1-8 28 Radiograph None Adenoma Vitamin D-resistant Glanville and(1028) (not weighed) osteomalacia Bloom (1965)

138 H.C. 67 F 1965 10-4 2-8 17 Radiograph Radiograph Adenoma Postgastrectomy(1025-6) (800 mg)

144 A.T. 46 F 1965 11-6 1 9 13 Biopsy Radiograph Adenoma Gluten-sensitive Smith and(1025-6) (2-4 g) enteropathy Stern (1967)

146 M.N. 65 F 1965 9-3 10-7 2-0 33 Radiograph None Adenoma Postgastrectomy(1021) (1024) (500 mg)

147 G.J. 47 F 1966 9-6 11-7 1-4 37 Radiograph Radiograph Adenoma Gluten-sensitive(1025-6) (1026-7) & biopsy & biopsy (3-1 g) enteropathy

158 D.S. 28 F 1966 9-7 10-3 2-5 131 Biopsy Radiograph Adenoma Gluten-sensitive(1024) (1024) & biopsy (2 g) enteropathy

185 V.G. 72 F 1967 11-3 2-2 9 Radiograph None Adenoma Postgastrcctomy(1024) & biopsy (1 g)

Table I Details ofpatients with tertiary hyperparathyroidism''Reproduced by kind permission of the authors (Davies et al, 1968).

Case No. State of Parathyroids at Operation

5 9 5 g adenoma1 1 150 mg and I g adenomas, 2 normal57 1-8 g adenoma, 1 normal, 2 doubtful59 4-5 g adenoma, 3 normal91 1-5 g adenoma, 3 normal107 1-2 g adenoma, 2 hyperplastic138 800 mg adenoma, 2 normal144 2-4 g adenoma, 2 normal146 500 mg adenoma, 3 normal147 3-1 g adenoma, 2 normal158 2 g adenoma, 2 normal185 1 g adenoma, 2 normal

Table II State ofparathyroids at operation inpresent series

determine whether it is indeed of parathyroidorigin. In such instances the biopsy is removedfrom a small parathyroid gland and the pre-sumption is that it is normal rather than hyper-plastic.More detailed pathology is given for patients

11, 57, and 59 who died four, five, and sevenyears respectively after removal of the tumour,and for cases 91 and 107.

Case 11

This woman had two operations for hyper-parathyroidism in 1955. At the first, an adenoma(150 mg) was removed and two normal para-thyroids were biopsied. At the second, anadenoma (1 g) with a rim of narrow normalparathyroid tissue was removed. There wasno evidence of recurrence of hyperparathyroid-ism after the second operation, but the patient

died in 1960 with fairly widespread reticulum-celled sarcoma which involved the mesentericglands conspicuously. Steatorrhoea had per-sisted during her period under observation andit is possible that there is a relationship betweenthis condition and the development of reticulum-celled sarcoma involving the bowel. No para-thyroid tissue was identified in the neck orelsewhere. (Details of the early history arerecorded by Davies, Dent, and Willcox, 1956.)

SALIENT POINTThe stimulus led to the formation of two aden-omas without diffuse hyperplasia of the parathy-roid tissue.

Case 57

This woman had been a patient at anotherhospital from 1936 onwards. Her many com-plaints included sinusitis on several occasionsand an important episode in 1954 when shehad an attack of renal disease diagnosed asB. coli pyelonephritis in which the blood urealevel rose to 320 mg% but fell to 62 mg on herdischarge a month later. It was 88 mg% a yearlater during an admission in which the diagnosiswas acute potassium depletion as a consequenceof purgation. At this time electrolyte disturb-ance was profound and included temporaryhypocalcaemia (Houghton and Pears, 1958). In1956 she had bone pain, x-ray evidence of osteitisfibrosa, a serum calcium level of 10-2 mg 100 ml

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364 J. F. Smith

Fig. 1 Case 57: biopsy of normal pqrathyroid.Haematoxy.'in and eosin X 92.

'~~~~~~~~.' 7nU 'Fig. 2 Case 57: mitosis in anaphase in chief-celledparathyroid adenoma. Haematoxylin and eosinx 560.

and a blood urea level of 53 mg%. She wasreferred to Professor Dent and admitted toUniversity College Hospital in March 1957when she was 57 years old. Dent (1962) hasdocumented the difficulty of deciding whetherthis patient's severe bone disease was a mani-festation of secondary or primary hyperpara-thyroidism at that time because of the normalserum calcium level and the dramatic responseof her symptoms to dihydrotachysterol withoutmarked elevation of the serum calcium. How-ever, symptoms eventually recurred and in1960 the ionized calcium level was consistentlyraised even when she was off dihydrotachysterol.

In April 1960 a parathyroid adenoma (1 -8 g)was removed which had a rim of normal glandat one edge. The other three parathyroids wereidentified, confirmed histologically, and beingof normal size, were left in situ. One of the biop-sies from these showed normal tissue, the acinibeing well separated by fat (Fig. 1); the othertwo showed compact glandular tissue with somefat between acini. It is with such biopsies thatone is uncertain whether the tissue is normal orslightly hyperplastic. The adenoma was chief-celled, some areas had larger nuclei than others,and in a single section through the whole adenomafour mitoses were identified (Fig. 2).

In the first few years after operation thepatient's condition was improved, but shegradually developed progressive renal failureand died in 1965, the blood urea level rising to255 mg% in 1964 and 350 mg% in 1965. Theblood pressure rose to 220/120 mm Hg in 1965,but dropped to normal levels a few months laterbefore she died.At necropsy the three residual parathyroid

glands were conspicuously hyperplastic, thekidneys contracted (the left 90 g, the right 80 g)with fine surface granularity and a few largerscars, but no calyceal deformity. Microscopicalexamination of the kidneys showed extensivetubular damage, dilated and hypertrophiedtubules, some glomeruli altered and atrophiedby ischaemia, and others showing changes con-sistent with chronic glomerulo-nephritis. Therewas conspicuous hypertrophy of the intima ofmedium-sized arteries. On the whole, it wasthought that the changes were more suggestiveof chronic glomerulonephritis than of chronicpyelonephritis.

SALIENT POINTSThe renal pathology in this case is difficultto unravel, but the salient points as regardsfunction were the transient episode of uraemiain 1954 and the gradual development of uraemiabetween 1960 and 1965. The parathyroid adenomaremoved in 1960 was unusual in that mitoticactivity was present. The bulk of the evidenceindicates that the remaining parathyroids werenot hyperplastic at this time (one normal, two

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Parathyroid adenomas associated with the malabsorption syndrome and chronic renal disease

Fig. 3 Case 91: biopsies of three normal parathy-roids. Haematoxylin and eosin x 25.

with fat in compact tissue from glands of normalsize, and normal gland at the periphery ofthe adenoma) but became hyperplastic during thedevelopment of uraemia between 1960 and 1965.

Case 59

This man was first admitted to UniversityCollege Hospital in 1953 at the age of 41 withanaemia. This was thought to be partly due todeficiency of ascorbic acid in his diet and heresponded to therapy. A few years later hebegan to sluffer from bone pain and to loseheight. This was followed by muscular weaknessand more severe bone pain which led to extensiveinvestigation when raised plasma calcium,lowered plasma phosphorus, and raised plasmaalkaline phosphatase levels, and a skeletalradiograph showing typical changes of hyper-parathyroidism led to an exploration of theneck. A parathyroid adenoma weighing 4-5 gwas removed and three normal parathyroidswere identified and confirmed by biopsy. Atthis time there was a question of changes ofosteomalacia being present in the bones as well

as osteitis fibrosa. Furthermore, the bloodurea level was slightly raised. During thefollowing years the bone symptoms improvedconsiderably, but the patient continued to havesome degree of steatorrhoea although a fatbalance study gave an equivocal result and anintestinal biopsy in 1966 was normal. He grad-ually became increasingly uraemic and diedwith a blood urea level of 350 mg% in 1967at the age of 55. Postmortem examination waslimited and it was not possible to dissect theneck properly, but no residual parathyroidtissue was identified. Both kidneys showedextensive polycystic disease as well as the effectsof calcium deposition in the remaining paren-chyma. The lumbar vertebrae showed areas ofcystic change in the centres and more dense boneadjacent to the intervertebral discs. Microscopicexamination showed extensive nephrocalcinosiswith gross tubular atrophy in the residualrenal parenchyma as well as some glomerularlesions. Some degree of osteomalacia was presentin the lumbar vertebrae, but no residual osteitisfibrosa.

SALIENT POINTSAt the time of removal of the adenoma theimpairment of renal function was slight andthere was no evidence of hyperplasia of the otherparathyroids. It is probable that some degreeof malabsorption of an uncertain nature waspresent in this patient and that the osteomalaciawas a consequence.

Case 91

This woman was treated for the Plummer-Vinson syndrome and associated anaemia atUniversity College Hospital from 1952 onwards.At that time there was evidence of steatorrhoeawhich became more convincing, although inter-mittent, in subsequent years. In 1961 she wasfound to have a daily fat excretion of 14-4 g; duo-denal mucosa showed severe villous atrophy, andthe plasma calcium level was 10-9 mg/100 ml.She improved on a gluten-free diet, but theplasma calcium level slowly rose to 12-6 mg/100 ml in June 1963. The bones were thoughtto show changes of osteoporosis with collapseof L3. In August 1963 she was diagnosed ashaving hyperparathyroidism with calculi inthe right kidney, and at operation a chief-celledparathyroid adenoma weighing 1-5 g was re-moved and biopsies of three normal parathyroidswere taken (Fig. 3). A mitosis was identifiedin the section of the adenoma which showed adistinct margin of normal parathyroid at theborder (Figs. 4 and 5). After the operationshe had a transient period of hypocalcaemiafrom which she recovered and has since beenreasonably well on a gluten-free diet. There has

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Fig. 4 Case 91: chief-celled adenoma with mitosisin metaphase. Haematoxylin and eosin x 560.

Fig. 5 Case 91: normal parathyroid at edge ofadenoma. Haematoxylin and eosin x 140.

been no evidence of recurrence of hyperpara-thyroidism.

SALIENT POINTSThis is a case with very good biopsies of threenormal parathyroid glands, a rim of normalparathyroid around an active adenoma, and ashort period ofhypercalcaemia.

Case 107

This patient has been reported in detail byGlanville and Bloom (1965).At the age of 31 this man developed osteo-

malacia which was shown to be a case of type IIrenal tubular osteomalacia, in which renalglycosuria is associated with phosphaturia.He became symptom-free after treatment withdihydrotachysterol for about five years whenhe developed pains in the lower limbs whichfollowed a reduction in the dose of dihydro-tachysterol because of hypercalcaemia. In-vestigation showed a recurrence of osteo-malacia with a persistently raised alkalinephosphatase level and Looser zones on theradiographs. All the evidence indicated that thehypercalcaemia which persisted after stoppingdihydrotachysterol was a manifestation ofhyperparathyroidism. On exploration of theneck a chief-celled adenoma weighing 1-2 g(Figs. 6 and 7) and two hyperplastic glandswere identified (Fig. 8); the adenoma wasremoved together with one gland and two-

Kb thirds of the other. No normal parathyroid wast identified around the adenoma but some was

present at the edge of one of the hyperplasticglands. The fourth parathyroid was not identified.There was symptomatic improvement, withreduction of the blood calcium levels which haspersisted.

< SALIENT POINTSThis is the only case in the series in which

H there is pathological evidence compatible withan adenoma arising against a background ofhyperplastic parathyroid glands. Probably thestimulus to parathyroid hyperplasia had been

t persistent and reltttively steady for many years.The nature of the stimulus in this case has not

* been defined clearly. It was not due to hypo-calcaemia during the time of observation.

J Discussion

The most important fact about these patientsis that they develop parathyroid adenomas.The mechanism of this process is interestingboth from the clinical and the general angle.

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Parathyroid adenomas associated with the malabsorption syndrome and chronic renal disease

Fig. 6 Case 107: chief-celled adenoma. Haematoxylinand eosin x 140.

The possible mechanisms appear to be several.

The metabolic situation in each case was such

as to cause secondary parathyroid hyperplasia,and one of the hyperplastic glands became

autonomous forming an adenoma. This reversed

the biochemical trend with cessation of the

stimulus to secondary hyperplasia and involution

of the remaining parathyroid tissue. (This was

the hypothesis of Davies et al, 1968.)The metabolic situation in each case triggered

a group of more sensitive cells in one glandcausing a neoplasm which was at first conditionedbut later became autonomous, without anyintervening stage of diffuse secondary hyper-plasia.

Sometimes the first mechanism operates and

in other cases the second. In deciding between

them, it is necessary to consider (a) the responseof the parathyroid tissue where it was possibleto follow this for some time; (b) the incidence

of parathyroid hyperplasia in this series at the

time of operation; and (c) the response of other

endocrine tissues after reversal of a metabolic

situation, eg, the effect of the iodine level of the

blood on the thyroid.Case 57 is the only one which enables us to

answer question (a). The evidence as summarizedat the end of the case history indicates thatsecondary hyperplasia was not present at thetime of the operation but developed during theperiod of uraemia between 1960 and 1965.Before 1960 there was no prolonged period ofuraemia, but the transient episode in 1954 mayhave been the initiating factor in the developmentof the adenoma removed in 1960. The onsetof steadily progressive uraemia then led tosecondary hyperplasia of the remaining threeparathyroids. This suggests that a more sensitivegroup of parathyroid cells responded to aninitial stimulus and the whole mass of parathyroidtissue to a later prolonged stimulus.

In answering question (b) it is convenient torefer to Table II which indicates that hyperplasiawas not associated with any of these adenomasat operation except in case 107, in which thebackground of type II renal osteomalacia isassociated with phosphaturia and not at anytime with a low blood calcium level. The ab-normal metabolism here in some way provideda steady stimulation to the parathyroid tissueover many years. This resulted in hyperplasiaof most of the parathyroid tissue. (I may mentionhere that in diffuse hyperplasia the processsometimes leaves a little parathyroid tissueunaffected, as in this case.) With time the hyper-plastic tissue in one parathyroid formed anadenoma. This did not lead to involution ofthe other parathyroids. Thus in this case theevidence is in favour of the first mechanismpostulated but without subsequent involutionof non-adenomatous parathyroid tissue. Thefew other cases recorded in the literature inwhich autonomous adenomas develop from abackground of longstanding chronic uraemiahave shown diffuse hyperplasia in the rest ofthe parathyroid tissue (Massachusetts GeneralHospital Case Records, 1963; Golden, Canary,and Kerwin, 1965).

In the remaining cases in Table II there isno evidence that anatomical hyperplasia wasassociated with an adenoma at the time ofoperation. Of these case 57 had a renal back-ground as discussed above, but no period ofprolonged chronic uraemia before the operationin 1960. In case 59 the evidence suggests that thebackground was malabsorption before the oper-ation.

In the remaining nine cases the background wasundoubtedly malabsorption of some form withosteomalacia present in eight. It seems veryunlikely to me that involution to normal wouldhave occurred in all the non-adenomatous para-thyroids in these cases if anatomical hyperplasiahad indeed been present. It seems equally un-likely that a rim of normal parathyroid wouldbe formed by involution around an adenoma asis clearly illustrated in Figure 5. It is also perti-nent that although many argue that secondaryhyperparathyroidism develops in osteomalacia

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Fig. 7 Case 107: chief-celled adenoma. Haematoxylinard eosin x 560.

5a

*~~~~,>*v s e~~~~~~~~~~~~~~~~~Sk

t.96v-*ik

Fig. 8 Case 107: hyperplastic parathyroid.Haematoxylin and eosin x 140.

asscciated with the malabsorption syndrome theanatomical evidence for secondary parathyroidhyperplasia is scanty. As Dent (1956) pointedout, the papers which describe secondary parathy-roid hyperplasia in rickets and osteomalacia dateback to the early years of this century before theclassical descriptions of metabolic bone disease.I have never encountered secondary hyperplasiain necropsies on cases of the malabsorptionsyndrome and am unaware of any series describ-ing it.

In considering (c),-other endocrine hyper-plasias-the best documented is that of the thy-roid. Here reversal of a metabolic situation maylead to involution of a hyperplastic tissue butthe result is often a gland with areas of fibrosis,cholesterolosis, and residual nodules of hyper-plastic tissue rather than a normal anatomicalstructure. In the adrenal cortex hypersecretionof hormones may be associated with diffusehyperplasia, nodular hyperplasia, adenoma, andcarcinoma. Thus, in an analysis of the adrenalcortex in 81 patients with Cushing's syndrome,Neville and Symington (1967) found bilateralhyperplasia in 69, adenomas in five, and carci-nomas in seven cases. In association with the 12tumours there was cortical atrophy of thenon-neoplastic adrenal tissue. It is often assumedthat this atrophy develops as a result of the tumoursecretion but this is not proved. In any event thereis no evidence that such adrenal neoplasmsdevelop from hyperplastic glands. I cannottherefore support the first mechanism postulatedby analogy from other endocrine tissues.

It is therefore suggested that in the abnormalmetabolic situation of the malabsorption syn-drome the second mechanism operates so thatparathyroid adenomas arise from groups ofcells more sensitive to stimulation, which becomesmall areas of hyperplasia within an otherwisenormal gland, then nodules, which could beregarded as conditioned neoplasms in thata feedback mechanism may still be operative,and then autonomous neoplasms. At this pointthe cells are altered so that they divide withouta persistent stimulus and hypercalcaemiaresults. It is interesting that in the adenomaremoved in case 91 a few mitoses were present.This is indicative of active, and probably re-latively rapid growth (we have seen mitoses inonly four of about 250 parathyroid adenomas),and suggests an unusually effective stimulus,or an unusual group of responsive cells (case 57also had mitoses). Whether the initial stimulusis a temporary hypocalcaemia or somethingunknown cannot be decided at present. Thesuggestions of Lloyd (1968) on parathyroidadenomas in relation to intermittent and con-stant stimuli are of interest.The possibility that different mechanisms

operate in the pathogenesis of parathyroidadenomas associated with the malabsorption syn-drome and those initiated by prolonged chronic

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Parathyroid adenomas associated with the malabsorption syndrome and chronic renal disease

renal disease should open up the search for otherfactors in parathyroid metabolism. Keynes andCaird (1970) have suggested that in cases asso-ciated with steatorrhoea and osteomalacia thehyperparathyroidism is primary but maskedinitially by vitamin D deficiency. This view canbe criticized because it gives no explanation forthe association of hyperparathyroidism with themalabsorption syndrome. The use of the word'primary' tends to dismiss the association; thewords 'secondary' and 'tertiary' endeavour tofit the association into known concepts. Itwould appear wise to keep an open mind atpresent, and even to look for other factors thanvariation in the plasma calcium and phosphoruslevels in parathyroid metabolism.

References

Davies, D. R., D2nt, C. E., and Watson, L. (1968). Tertiaryhyperparathyroidism. Brit. med. J., 3, 395-399.

Davies, D. R., Dent, C. E., and Willcox, A. (1956). Hyper-parathyroidism and steatorrhoea. Brit. med. J., 2, 1133-1137.

Dent, C. E. (1956). Letter to Editor. Hyperparathyroidism andsteatorrhoea. Brit. med. J., 2,1546-1547.

Dent, C. E. (1962). Some problems of hyperparathyroidism.Brit. med. J., 2, 1419-1425. and 1495-15(0

Dent, C. E., and Garretts, M. (196G). Skin changes in hypo-calca-mia. Lancet, 1, 142-146.

Glanville, H. J., and Bloom, R. (1965). Case of renal tubularosteomalacia (Dent type 2) with later development ofautonomous parathyroid tumours. Brit. med. J., 2, 26-29.

Golden, A., Canary, J. J., and Kerwin, D. M. (1965). Concurrenceof hypzrplasia and neoplasia of the parathyroid glands.Amer. J. Med., 38, 562-578.

Houghton, B. J., and Pears, M. A. (1958). Chronic potassiumdepletion due to purgation with cascara. Brit. med. J., I,1328-1330.

Keynes, W. M., and Caird, F. I. (1970). Hypocalcaemic primaryhyperparathyroidism. Brit. med. J., 1, 208-21 1.

Lloyd, H. M. (1968). Primary hyperparathyroidism: An analysisof the role of the parathyroid tumor. Medicine (Balti-more), 47, 53-71.

Massachusetts General Hospital Case Records no. 29-(1963).New Engi. J. Med., 268,943-953.

Neville, A. M., and Symington, T. (1967). The pathology of theairenal gland in Cushing's syndrome. J. Path. Bact., 93,19-35.

Smith, R., and Stern, G. (1967). Myopathy, osteomalacia andhyperparathyroidism. Brain, 90, 593-602.

The April 1970 IssueTHE APRIL 1970 ISSUE CONTAINS THE FOLLOWING PAPERS

Histopathological findings in the combined immunity-deficiency syndrome COLIN L. BERRY

Postmortem detection of inapparent myocardialinfarction J. G. MCVIE

Mesonephroid tumours of the ovary M. C.ANDERSON AND F. A. LANGLEY

Vitamin B12 levels in erythrocytes in normal subjectsand in pernicious anaemia R. J. HARRISON

The effect of heat on the A, B, and H antigenicstrength of human red cells J. R. BOOTH,W. WAGSTAFF, AND D. VOAK

Von Willebrand factor and platelet adhesivenessDOMINIQUE MEYER AND MARIE-JOSE LARRIEU

The measurement of serum pyridoxal by a micro-biological assay using Lactobacillus caseiBARBARA B. ANDERSON, M. BARBARA PEART, ANDCATHERINE E. FULFORD-JONES

An evaluation of cholesterol determinations inserum and serum lipoprotein fractions by a semi-automated fluorimetric method GILL ROBERTSON ANDD. G. CRAMP

Mucopolysaccharide in the blood of a patient withneuroblastoma P. M. G. BROUGHTON, J. R. W.DYKES, SHIRLEY HOLT, J. W. RIDLEY, AND A. E. STEEL

Hepatic and renal complications arising fromaccidental carbon tetrachloride poisoning in thehuman subject W. C. ALSTON

The effect of carbon dioxide on the sensitivity ofBacteroidesfragilis to certain antibiotics in vitroH. R. INGHAM, J. B. SELKON, A. A. CODD, AND J. H.HALE

Recurrent urinary infections in general practiceR. N. GRUNEBERG

Affinity for glycoproteins of bacteria found in therespiratory tract in cystic fibrosis B. A. SAGGERSAND DAVID LAWSON

The differential attachment of antibiotics toglycoprotein and blood lymphocytes B. A. SAGGERSAND DAVID LAWSON

Computer analysis of routine pathology workschedules using a simulation programme M. E.CARRUTHERS

Technical methodsHistological fixation by microwave heating c. P.MAYERS

Book reviews/Notices

Letter to the Editor

Copies are still available and may be obtained from the PUBLISHING MANAGER,BRTISH MEDICAL ASSOCIATION, TAVISTOCK SQUARE, WC1H 9JR price 21s.

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