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Requests for reprints should be addressed to D. M. K., 24a LyndaleAvenue, London N.W.2.

REFERENCES

Barker, M. H., Capps, R. B., Allen, F. W. (1945) J. Am. med. Ass. 128, 997.Katz, R., Velasco, M., Klinger, J., Alessandri, H. (1962) Gastroenterology,

42, 258.Krugman, S., Ward, R., Giles, J. P. (1962) Am. J. Med. 32, 717.Nefzger, M. D., Chalmers, T. C. (1963) ibid. 35, 299.Sherlock, S. (1963) Diseases of the Liver and Biliary System. Oxford.Swift, W. E., Jr., Gardner, H. T., Moore, D. J., Streitfeld, F. H., Havens,

W. P., Jr. (1950) Am. J. Med. 8, 614.

HYPERTENSIVE ANGIOPATHY IN

FAMILIAL CHLORIDE DIARRHŒA

A. PASTERNACKM.D. Helsinki

J. PERHEENTUPAM.D. Helsinki

From the Children’s Hospital and the Renal Ward, FourthMedical Department, University of Helsinki, Finland.

HYPERTENSIVE disorders of different aetiology are

associated with vascular changes of various degrees.Clinically, acceleration of the vascular changes denotesa poorer prognosis. Experiments and clinical studies

concerning the aetiology and pathogenesis of the vascular

Fig. I-Case 2: renal biopsy specimen.Medium-sized contracted and hypercellular arteries. (Hxma-

toxylin-van Gieson, x 200.)

changes are therefore of primary importance. In kidneybiopsy specimens of seven children with familial chloridediarrhoea (F.C.D.) we have found vascular changes resembl-ing those in hypertensive disease. In the four childrenwho underwent muscle biopsy, the same changes wereseen. The blood-pressure in all the patients was normal.

Fig. 2-Case 4: renal biopsy specimen.Two contracted and hypercellular arteries. The smaller vessel has

a very narrow lumen. (HaEmatoxylin-van Gieson, x 200.)

We believe that the findings contribute to our knowledgeof the genesis of vascular changes in arterial hypertension.

Patients

The series comprised seven children (see accompanyingtable). In all except two, F.c.D. was diagnosed during thefirst month of life. Persistent watery diarrhoea withmassive loss of chloride, sodium, and potassium in thestools is apparently the primary disturbance in this

syndrome. The resulting very low levels of these ions in

Fig. 3-Case 4: renal biopsy specimen.Medium-sized vessel with thick wall but well-preserved internal

elastic lamina. (Weigert’s elastic stain, x 200.)

the plasma (and body) and extracellular alkalosis can beeffectively combated with appropriate substitution therapy.The balance thus attained is associated with large urinarylosses of potassium in contrast to very small amounts ofsodium and chloride in the urine-a state consistent with

strong secondary hyperaldosteronism.Detailed clinical and physiological studies were made

on these children (Perheentupa et al. 1966). For a dis-cussion of the vascular changes only a few of the dataare important.

1048

Measurements of the bromide space and estimations ofthe volume of the gastrointestinal tract suggested thatthe effective extracellular volume was greatly reduced.Plasma-renin activity in the youngest (case 1) and theoldest (case 7) of our patients, measured by Dr. R. Veyrataccording to the method of Boucher et al. (1964), wasraised. Renin activity in case 1, expressed as angiotensinequivalents, was 29 m[.Lg. per litre per min.; urinary aldo-sterone excretion was 16-8 g. per 24 hours. In case 7these figures were 19 mg. per litre per min. and 19-2 g.per 24 hours. Taken together with high urinary aldo-sterone excretion in the same children this was strongevidence for secondary hyperaldosteronism. In all the

patients (see table) repeated measurements of the blood-pressure gave normal values.

BiopsyKidney biopsy specimens (figs. 1-3) were obtained

under halothane anaesthesia from all the patients per-cutaneously ; specimens of skeletal muscle were takenfrom four of them (see table).The kidney and muscle tissues were fixed in 10%

formaldehyde, embedded in paraffin, and sectioned at5-7 . The sections were stained with haematoxylin-vanGieson, the periodic-acid/Schiff (P.A.S.) procedure, vanKossa stain for calcium, and Weigert’s elastic stain.

Severe vascular and other morphological changes wereobserved (see table). In the kidneys the vascular changeswere limited to arteries of medium and small size and toarterioles. The most striking finding was thickening ofthe walls of the interlobar, arcuate, and small corticalarteries. This was mainly due to hypercellularity andswelling of the muscle cells of the medial layer. Theintimal endothelium bulged into the narrowed arteriallumen. The internal elastic lamina was normal. In thesmall arteries the wall was sometimes partly homogeneousand gave positive staining with P.A.S. The arterioles werethick-walled with a narrowed lumen. The arteriolarmuscle-cells lay in concentric layers. In the kidneys withjuxtaglomerular hypertrophy the afferent arteriole was

mostly surrounded by an increased number of cells. In afew instances the juxtaglomerular apparatus was evenmore hypertrophied, giving the appearance of a densemass. In the large vessels the amount of perivasculartissue was also increased.. No inflammatory reaction waspresent round the vessels. The internal elastic laminawas normal in most vessels. In some it was slightlyfragmented, but no duplication was observed.

Dilated tubules with vacuolar epithelium (i.e., signs ofhypokalasmic nephropathy) were seen in three of theyounger patients.

In the biopsy specimens from the older children (cases 4and 7) several hyalinised glomeruli were observed.

Characteristically, these destroyed glomeruli lay close toarteries which were almost completely obstructed.

In the muscle biopsy specimens the small arterioles werenarrowed, but there was no hyalinisation of the arteriolarwalls. The medium-sized arteries were narrow and themuscular layer hypertrophied.

Discussion

The main characteristics of the vascular changes werespasm of small arterioles, an increase in the number andswelling of medial muscle cells, partial hyalinisation of thevascular wall, and (in the large vessels) an increasedamount of adventitial tissue. These changes are bestclassed as belonging to the group of hypertensive vascular

disease (Sommers et al. 1958). The lesions were mostadvanced in the older children, in whom almost obliteratedvessels were seen. It must be pointed out, however, thatin no case could the lesions be classed as malignant,because necrosis of the vascular wall and a strong cellularreaction were absent.

Many reports have been published on the pathogenesisof the vascular changes in hypertension.

Clinical observations have shown that hypertensive vasculardisease is preceded by hypertension (Castleman and Smith-wick 1943, Sommers et al. 1958). Moderate hypertension withslow progress mainly presents hypertrophy of the vascular wall(Boyd 1961). This is the picture seen in benign essential

hypertension. Results from experimental hypertensive disease(Wilson and Byrom 1939) show that when progressive hyper-tension is produced in rats the vascular reaction consists mainlyin cellular hypertrophy, whereas an abrupt rise of intravascularpressure in the main produces necrosis of the vascular walls.McCormack et al. (1958) demonstrated that when experimentalhypertension (of a degree which usually produces necroticvascular lesions in the small vessels) was treated with hydral-azine changes of this type could be avoided, that the changeswere confined to the larger vessels and were of a more hyper-trophic type.Whatever the cause, increased pressure on the vascular

wall has appeared to be the essential factor leading tovascular changes in hypertension. Acceleration of the

changes (i.e., necrosis of the arterial wall) has been asso-ciated with an acute increase of or extremely high intra-vascular pressure.None of the seven children with familial chloride

diarrhoea had hypertension before or during renal or

muscular biopsy. That systemic hypertension was neverobserved in the present series warrants the inference thatthere had been no increased pressure in the blood-vesselsexamined. The finding of the vascular changes wastherefore unexpected. From the data obtained in ourclinical studies (Perheentupa et al. 1965a and b, 1966)and the kidney-biopsy findings previously reported(Pasternack et al. 1966), the following conclusions may bedrawn. F.C.D. is a state involving longstanding hypo-volsemia, which is responsible for the juxtaglomerularhyperplasia that is associated with increased secretion ofrenin (proved in two of the children), high angiotensinactivity, and secondary hyperaldosteronism. The highaldosterone secretion cannot maintain normovolsemiaowing to the constant loss of salt and water through theintestine.

We suggest that the high angiotensin activity causeschronic vasoconstriction, as shown by the contractedblood-vessels observed by us. But, owing to the persistenthypovolaemia, this does not cause hypertension. Despitethe absence of hypertension, changes follow in the vesselsbecause of the chronic vasoconstriction. These changesresemble those in benign essential hypertension, in whichone of the active pathogenetic factors is arteriolar con-striction (Pickering et al. 1961). In other words, arterialand arteriolar changes consisting mainly in medialhypertrophy seem to appear in disorders associated withchronic vasoconstriction even in the absence of hyper-tension. The absence of necrotic changes of the arteriesin our series, on the other hand, constitutes furtherevidence in favour of the views already cited which stressthe importance of increased intravascular pressure for theacceleration of hypertensive vascular disease.On the basis of our findings one practical conclusion

can be drawn. Treatment of mild cases of hypertension

1049

by means of agents that prevent vasoconstriction seemsworth while. In the treatment of advanced hypertensionsuch agents may still be beneficial. Another implication isthat the constrictive narrowing of the arteries producesprogressive destruction of nephrons, with consequentimpairment of kidney function.

SummaryVascular changes resembling those of hypertensive

angiopathy were found in seven children with familialchloride diarrhoea and normal blood-pressure.Requests for reprints should be addressed to A. P., Hakolahdentie 6,

Helsinki 20, Finland.

REFERENCES

Boucher, R., Veyrat, R., de Champlain, J., Genest, J. (1964) Can. med. Ass.J. 90, 194.

Boyd, W. (1961) A Textbook of Pathology. London.Castleman, B., Smithwick, R. H. (1943) J. Am. med. Ass. 121, 1256.McCormack, L. J., Béland, J. E., Schneckloth, R. E., Corcoran, A. C. (1958)

Am. J. Path. 34, 1011.Pastemack, A., Perheentupa, J., Launiala, K., Hallman, N. (1966) Acta

Endocr., Copenh. (in the press).Perheentupa, J., Eklund, J., Hallman, N. (1965a) Pediatrics, 35, 506.

— — Kojo, N. (1965b) Acta pœdiat., Stockh. 54, 119.— Launiala, K., Pasternack, A., Hallman, N., Veyrat, R. (1966)Unpublished.

Pickering, G. W., Cranston, W. I., Pears, M. A. (1961) The Treatment ofHypertension. Springfield, Ill.

Sommers, S. C., Relman, A. S., Smithwick, R. H. (1958) Am. J. Path. 34, 685.Wilson, C., Byrom, E. B. (1939) Lancet, i, 136.

5-HYDROXYINDOLE COMPOUNDS IN

THE CEREBROSPINAL FLUID OF PATIENTS

WITH PSYCHIATRIC OR NEUROLOGICAL

DISEASES

G. W. ASHCROFTM.B. Manc., D.P.M., M.R.C.P.E.

T. B. B. CRAWFORDPh.D. Edin.

D. ECCLESTONM.B. Aberd., Ph.D. Edin., D.P.M.

D. F. SHARMANPh.D. Edin.*

OF THE MEDICAL RESEARCH COUNCIL UNIT FOR RESEARCH IN BRAIN

METABOLISM, PHARMACOLOGY DEPARTMENT, EDINBURGH UNIVERSITY

ELIZABETH J. MACDOUGALLM.B. Edin., D.P.M.

SENIOR REGISTRAR, CRAIG HOUSE, ROYAL EDINBURGH HOSPITAL

J. B. STANTONM.A., M.B. Cantab., D.P.M., F.R.C.P., F.R.C.P.E.CONSULTANT PHYSICIAN, NORTHERN GENERAL HOSPITAL

J. K. BINNSM.B. Edin., D.P.M., M.R.C.P.E.

CONSULTANT PSYCHIATRIST, LEVERNDALE HOSPITAL, GLASGOW

AN association between certain psychotic illnesses andmetabolic disturbances has long been considered. Thereis, for example, the possibility of an abnormality in themethylation of biogenic amines in schizophrenia (Friedhoffand Van Winkle 1962) although conclusive evidence forthis has not so far appeared (Lancet 1966); and a dis-turbance in amine metabolism in the brain has also beensuggested in depressive illness.The major obstacles to the examination of these ideas

are the technical problems associated with the study ofcerebral metabolism in man. The evidence so far presentedin favour of a disturbance of amine metabolism in

depression has been obtained either by inference from astudy of the biochemical effects of drugs, which eitherprecipitate or ameliorate depressive symptoms (Ashcroft,Eccleston, Knight, MacDougall et al. 1965) or from a* Present address: Agricultural Research Council, Institute of Animal

Physiology, Babraham.

study of the metabolites of the amines in the blood orurine (Rodnight 1961, Coppen, Shaw, Malleson, Ecclestonet al. 1965). Such studies often mean that changes inperipheral metabolism must be assumed to be paralleledby changes in cerebral metabolism.We have attempted to use the measurement of a meta-

bolite (5-hydroxyindolylacetic acid, 5-H.I.A.A.) in the

cerebrospinal fluid (c.s.F.), to reflect quantitative changesin the cerebral metabolism of the parent amine, 5-hydroxy-tryptamine (5-H.T.). Ashcroft and Sharman (1960)reported that 5-hydroxyindole compounds were presentin the lumbar C.S.F. of two groups of patients, one groupof depressed patients, the other of non-depressed patientswith neurological disease who were undergoing lumbarair-encephalography. Significantly lower concentrationsof 5-hydroxyindole compounds were found in the

depressed patients, a finding which has been confirmed byDencker et al. (1966). However, as a result of furtherstudies, it is now appreciated that the injection of the air(10-12 c.cm.) before withdrawal of c.s.F., which is a

routine procedure in air-encephalography, might itselfaffect the validity of the results. A further variable whichmight affect the concentrations could be the degree ofactivity of the patients just before lumbar puncture(Fotherby et al. 1963).We present here the results of an investigation of the

concentration of 5-hydroxyindolic compounds in thelumbar c.s.F. of patients with neurological disease and ofpatients with various psychiatric illnesses, the c.s.F. beingsampled under standardised conditions. We have also

attempted to investigate the effect of such variables as airinjection on the levels of 5-hydroxyindolyl compounds inlumbar fluid.

Materials and Methods

Selection of Patients with Depressive IllnessThe depressed patients were selected from those admitted to

Craig House, Royal Edinburgh Hospital over a period of ninemonths in 1959. The criterion for selection was simple; weincluded all patients in whom the main presenting symptomwas depression and in whom there was no evidence of schizo-phrenia or of the presence of directly contributing organicdisease. Twenty-four patients in this group had received nospecific antidepressant therapy in the 3-week period beforelumbar puncture, whilst eight were under treatment withimipramine. Routinely, night sedation was induced in all

patients with quinalbarbitone (’ Seconal’) 200 mg. Wherelumbar puncture was not essential for diagnostic purposes, thesituation was explained to the patients and their relatives andtheir permission was sought. Very few patients declined tocooperate. The mental state of the patient was re-evaluated onthe day of lumbar puncture and all patients classified in thisstudy as " depressed" had exhibited a sustained depression ofmood from the time of admission to the time of lumbar

puncture, in most cases a period of 3 to 4 days.The biochemist was unaware of the clinical diagnosis and

the results of clinical and biochemical evaluations were not

compared until the end of the study. In an attempt to correlateseverity of depression with biochemical findings, a simpleranking procedure was used, one of the clinicians (E. M.) beingasked to place the patients in rank order of severity of illness.

In ten patients, the lumbar punctures and estimates wererepeated after remission of the depressive symptoms.

Patients who had been receiving monoamine-oxidase in-hibitors within 3 weeks of hospital admission were excludedfrom the main study, but a small group of such patients wasstudied separately.Patients with Neurological Disease

Patients with organic disease of the central nervous systemwere selected from those undergoing diagnostic lumbar