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thoughtfully, and always with a caveat about toxicity. For fartoo long physicians have had the conditioned reflex that ther-apy for congestive cardiac failure must include digoxin.Gateside Hospital,Greenock, Inverclyde ROBERT LAMB

PREOPERATIVE DISTINCTION OF ADENOMAFROM HYPERPLASIA IN PRIMARY

ALDOSTERONISM

SIR,-We read with great interest the paper by Mr Clarkeand his colleagues entitled Severe Hypertension in PrimaryAldosteronism and Good Response to Surgery (March 3, p.452). Our experience with 51 patients with primary aldoster-onism’ in many ways accords with that of Clarke et al. How-

ever, we would like to make some points about their paper.Although spontaneous hypokalaemia is the most practical

screening method for detecting patients with primary aldoster-onism, some patients will escape detection if this method aloneis relied on. By evaluating the renin-angiotensin-aldosteronesystem in a selected but large population of hypertensive pa-tients,2 we found that about 20% of patients with primaryaldosteronism had serum-potassium at or above the lower limitof normal. I

Our second point is related to the usefulness of the paradoxi-cal fall in plasma-aldosterone when concentrations at 8 A.M.after overnight recumbency are compared with those obtainedat noon after 4 h of ambulation. The anomalous response to

upright posture is thought to be due to the predominant modu-lating effect of A.C.T.H. on aldosterone production in patientswith aldosteronoma. 1.4 A.C.T.H. secretion is thought to reach apeak between 6 A.M. and 8 A.M. Thus, by sampling blood at 9A.M. and noon Clarke et al. may have missed the peak aldoster-one response and narrowed the difference between the plasma-aldosterone concentrations of the two samples during evaluationof postural response. Furthermore A.C.T.H. release is episodicand can be stimulated by venepuncture or other stresses.

Hence, a single observation of the postural response of plasma-aldosterone has to be interpreted cautiously and in the light ofthe corresponding plasma-cortisol concentrations.

Finally, at room temperature there is significant flux ofaldosterone from the plasma to the red blood-cells,5 so the con-sistency of the handling and processing of the paired blood-samples may be important. Only 1 of Clarke’s 4 adenoma pa-tients had a discernible increase in plasma-aldosterone withambulation. Thus, in all 3 of the patients demonstrating a fail-ure of increase in plasma-aldosterone on standing, an adenomawas found. This is comparable with our experience (adenomasin 24/26 patients with the anomalous response) and with pre-vious reports. 1,4,6.1 7

While we agree with Clarke et al. that no single diagnostictechnique can be relied upon exclusively to separate adenomafrom hyperplasia, our experience suggests that the anomalousplasma-aldosterone response, when observed, is a reliable indi-cator of the presence of adenoma. A.C.T.H.-stimulated adrenalvenous sampling, in contrast to isotopic adrenal scanning, hasbeen the more reliable localising technique in our hands.’ It is

1 Weinberger, M. H., Grim, C E., Hollifield, J. W , Kem, D. C., Ganguly, A.,Kramer, N J., Yune, H. Y., Wellman, H., Donohue, J. P. Ann. internMed 1979, 90, 386.

2. Grim, C. E., Weinberger, M. H., Higgins, J. T., Kramer, N J. J. Am. med.Ass 237,1331.

3 Ganguly, A., Melada, G. A., Luetscher, J. A , Dowdy, A. J. J clin. Endocr.Metab 1973, 37, 765

4 Schambelan, M., Brust, N L., Chang, B. C. F., Slater, K. L., Biglieri,E. G ibid 1976, 43, 155.

5 Chavarri, M., Luetscher, J. A , Dowdy, A J., Ganguly, A. ibid. 1977, 44,752.

6 Biglieri, E G , Schambelan, M., Brust, N., Chang, B., Hogan, M. Circula-tion Res. 1974, 34/35, suppl 1, p 183.

7 Mantero, F , Gion, M , Aramanini, D., Opocher, G. Clin Sci. mol. Med.

1976, 51, 329s

a difficult technique and demands considerable skill for suc-cess. The prediction of probability of adenoma or hyperplasiaby use of a multiple logistic function has also been highly suc-cessful.8,9

Clarke’s observation of severe hypertension in primaryaldosteronism accords with our experience’ in which 33/51such patients had diastolic blood-pressure >120 mm Hg. Theresponse to surgery in our patients was also similar to thatobserved by Clarke et al. and other groups.Our preliminary experience of localisation of adenomas in 4

of 6 patients by computerised tomography’O suggests that thisis a potentially useful, non-invasive technique.

Specialised Center ofResearch in Hypertension,

Indiana University Medical Center,Indianapolis, Indiana 46223, U.S.A.

ARUNABHA GANGULYMYRON H. WEINBERGER

IS "IDIOPATHIC ŒDEMA" IDIOPATHIC?

SIR,-Dr MacGregor and his colleagues (Feb. 24, p. 397)have studied ten women with the so-called "idiopathic oedema"at a time when diuretics had been suddenly stopped. Nine pa-tients gained several kilograms and oedema reappeared. Mac-Gregor et al. stress the point that, on a normal sodium diet andwithout diuretics, seven patients progressively lost theiroedema over a 20-day period. They concluded that thesewomen had had diuretic-induced oedema and had become

dependent on the drug. The reasons why these patients hadstarted taking diuretics are unclear.The Charing Cross Hospital workers are right when they

emphasise that, in the face of oedema of unknown origin, clin-icians should look for diuretic abuse. However, in our opinion,iatrogenic oedema apart, multifactorial oedema does exist, andour reasons for thinking this are:

(1) Our first published case (1955) was in a patient withoedema and weight gain which developed every time she ate ahigh-salt meal. At that time diuretics were not on the market. 1.2

(2) Patients with oedema not related to the consumption ofdiuretics, such as those described by J. A. Luetscher, D. H. P.Streeten, and their colleagues, do not tolerate an overload ofsalt without discomfort (severe headache, nausea, troubles ofthe vision, and sometimes papillary oedema). In these patients,urinary sodium excretion stays at a very low level and urinaryaldosterone values do not return to normal.

(3) Some cases seem to be due to psychological stresses. Oneof G. W. Thorn’s patients first had oedema a week after herhusband’s death. Thorn called such cases "psychic" oedema.

(4) Fig. 1 in the paper by MacGregor et al. shows that threeof their ten patients maintained their weight gain after di-uretics were withdrawn despite the fact that their aldosteronelevels returned to normal.

(5) Of six patients with idiopathic oedema now under investi-gation by us and on a low-salt diet (3-5 g a day) three havenatriuretic-factor levels which accord with their salt intake,but the remaining three have high values of natriuretic factorin their urines equal to those observed in normal subjects on9x-fludrocortisone the day before they escaped from the salt-retaining effect of steroids. However, in contrast to these sub-jects who do escape from the salt-retaining effect of the steroid,natriuresis did not increase in the patients with oedema. Thus

8 Ferris, J B., Brown, J. J., Fraser, R., Kay, A. W., Neville, A. M., O’Muir-cheartaigh, I. G., Robertson, J. I. S., Symington, T., Lever, A F Lancet,

1970, ii, 9959. Luetscher, J. A., Ganguly, A., Melada, G. A., Dowdy, A. J. Circulation Res

1974, 34/35, suppl 1, p. 3410. Ganguly, A., Pratt, J H., Yune, H. Y., Grim, C. E., Wemberger. M H

Archs intern Med (in the press).1. Mach, R. S , Fabre, J., Muller, A. F , Neher, R. Schweiz. med. Wschr 1955,

85, 1229.2 Mach, R. S. Schweiz. med Wschr. 1976, 106, 161.3. Bourgoignie, J. J , Klahr, S., Bricker, N. S. J. clin. Invest, 1971, 50, 303

827

failure of the kidney to respond to natriuretic factor bynatriuresis may explain some cases of idiopathic oedema.The paper by MacGregor et al. is very important because of

its therapeutic implications, but there is still research to bedone on the origin of oedema which cannot be explained evenwhen diuretic therapy is taken into account.

Department of Medicine,Cantonal Hospital,1211 Geneva 4, Switzerland

R. S. MACHH. FAVRE

ARE STEROID INHALERS SAFER THAN TABLETS?

SIR,-This rhetorical question posed by your editorial ofMarch 17 (p. 589) seems provocative in the U.K., where beclo-methasone dipropionate aerosols and, recently, powder in-

halers, have become standard treatment for asthma at all ages,as the editorial states. Eight and a half years of experience oftherapy without side-effects other than occasional thrush orhoarseness is the background to our comments on an editorialbased on research which can be criticised on many counts.The efficacy of beclomethasone dipropionate (B.D.P.),

together with lack of significant adrenal suppression or otherserious side-effects, was first reported from this centre in1972.’ Many studies have confirmed our findings, and theliterature on B.D.P. is now so voluminous that the collected

reprints weigh around 4 kg. You do not cite our periodicalreports on the long-term progress of our patients.2-4 The mostrecent5 describes the course of 600 asthmatics treated con-

tinuously with B.D.P. for over five years; 1350 patient-years oftreatment had been given up to the end of 1975, 155 werechildren, and three more trouble-free years can now be addedto the total.

Space permits critical review of only a few aspects of the in-vestigation by Wyatt and colleagues.6 The recommended dose,on both sides of the Atlantic, is 400 fLg per day, although largerdoses may be used initially and are recommended by Toogoodet al.7 Of our 600 cases, only 10% required a maximum of 600fig; 48% needed 450 ug, and the remainder needed less. Wyattet al. do not explain why they used doses up to 800 p.g.The design of the study is difficult to unravel, and the

number ef cases seems too small to permit reliable statisticalanalysis. We are advised that both the design of the study andthe analysis of the data are inadequate. The presentation ofresults is misleading, and patients were not allocated to groupsat random. The study was completely open, admitting possiblebias in comparisons of regimens. Steroid dosages and assess-ment times within groups varied widelyThe depression below control values of the morning serum-

cortisol observed after B.D.P. alone of from 18 to 15 ug/dlseems unlikely to be of clinical importance; and it is difficultto see what a value of 11 ug/dl after B.D.P., when prior alter-nate-day steroids had been given for varying periods, means.The effects of steroids on the skin have always suggested

that similar changes could occur in the bronchi from long-termB.D.P., but no such changes have been found. Adverse effectswould appear soonest in the nasal mucosa when practically thewhole dose is applied to the same small area several times a dayfor years on end, but nasal biopsy8,9 has revealed no adversechanges. The nasal epithelium behaves in a different mannerto the skin; probably its cells regenerate more rapidly. Onlyabout 10% of the dose is actually inhaled into the bronchi and

1 Brown, H. M., Storey, G., George, W. H. S. Br. med. J. 1972, i, 5852 Brown, H M., Storey, G. ibid 1974, iii, 161.3 Brown, H M., Storey, G. Clin. Allergy, 1974, 4, 331.4 Brown, H. M., Storey, G. Postgrad. med. J. 1975, 51, suppl. 4, 59.5 Brown, H. M, Storey, G., Jackson, F. A. Br. J. clin. Pharmac 1977, 4,

259s6 Wyatt, R , Wascher, J., Weinherger, M., Sherman, B. New Engl J. Med

1978, 299, 1387.7 Toogood, J. H., and others J. Allergy clin. Immunol. 1977, 59, 298.8 Brown, H M Br med J. 1977, i, 376.9 Chatterjee, S S., Nassar, W Y., Butler, A. G., Poynter, D. ibid. 1977, i, 377.

distributed over a wide area, so fears of late atrophic changeseem groundless. Complete lungs from three patients who diedfrom causes other than asthma and who had used B.D.P. dailyfor three to six years, have also shown no changes. These find-ings will be published elsewhere.We are trying to publish a survey of 155 children treated

with B.D.P. for from two to eight years. The fact that there areno new and alarming findings may be the reason why TheLancet, amongst several other journals, does not feel that evena short account would interest readers. Presumably good newsis no news and not worthy of publication. Editorials such asyours of March 17 may cause unnecessary alarm over B.D.P.treatment. The evidence that B.D.P. is far safer than oral ster-oids is now incontrovertible.

Midlands Asthmaand Allergy Research Association,

Chest Clinic,Derby DE1 1RX

H. MORROW BROWN

F. A. JACKSON

SIR,-You cautiously approve (March 17, p. 589) of the useof steroid aerosols in bronchial asthma. I agree with you, as faras the ordinary patient with mild asthma is concerned, whootherwise may need a daily oral maintenance dose of less than10 mg prednisolone. With the severe asthmatic however-who, during weeks and months of observation has been relia-bly proved to require a maintenance dose of 10 mg or muchmore-the outcome may not be the same. In the few previouspapers from the U.K. the more severe cases have usually notbeen reported individually but mixed with a large majority ofmild ones. When patients are reported individually (as hasbeen done in two very detailed papersl,2 from North America)the addition of steroid aerosol to the oral maintenance dose isshown not to reduce dramatically the oral prednisolone doseneeded. The reduction was usually a little over 6 mg/day,whether the previous oral dose had been 12, 20, or 30 mg/day.A U.K. paper3 which you cite provided a similar result, butthis is not clear cut, because data are not provided for patientsindividually.

In these more severe cases, therefore, an oral corticosteroiddose would have to be given in addition to the aerosol. But theaerosol depends on absorption from a bronchial membranewhich is changing constantly under varying infections and var-ious nervous stimuli. Further research is needed to determineif this is preferable to a slightly higher, but dependable, singleoral prednisolone dose. If oral maintenance plus aerosol is

chosen, close medical supervision is mandatory, so that in casesof sudden deterioration the maintenance dose can be in-creased without delay.9 Park Crescent,London N3 H. HERXHEIMER

MANIA SECONDARY TO THYROID DISEASE

SIR,-Your editorial (Feb. 10, p. 307) on secondary mania,besides being most generous to our paper on the subjects wasboth important and timely. It highlights a previously undes-cribed affective syndrome of growing clinical and theoreticalimportance.You correctly point out that thyrotoxicosis is "surprisingly

and conspicuously absent" from our list of possible causes.This omission stemmed, not from any rejection of the possibi-lity of such an association, but from our inability to find inprint a well-described case that lacked confusional symptoms.

1. Toogood, J. H., Lefcoe, N. M., Haines, D. S M., Chuang, L., Jennings, B.,Errington, N., Baksh, L., Cauchi, M. J. Allergy clin. Immun. 1978, 61,355.

2. Bacal, E , Patterson, R ibid. 1978, 62, 72.3. Cooper, E J., Grant, I. W. B. Q. Jl Med. 1977, 46, 295.4. Mellis, C. M., Phelan, P. D. Thorax, 1977, 32, 29.5. Krauthammer, C., Klerman, G. Archs gen Psychiat. 1978, 35, 1333.