1334

22. Bishop, C., Honey, M., Taylor, D. G. Brit. med. J. July 16, 1960, p. 191,23. Woodward, W. W. Lancet, Nov. 19, 1960, p. 1120.24. Granick, S. Bull. N.Y. Acad. Med. 1949, 25, 403.25. Gillman, J., Gillman, T. Perspectives in Human Nutrition. New York,

1951.26. Walker, A. R. P., Arvidsson, U. B. Trans. R. Soc. trop. Med. Hyg.

1953, 47, 536.27. Bothwell, T. H., Bradlow, B. A. Arch. Path. 1960, 70, 279.

ing success-rate. 6 When facilities for observation are

exceptionally good-for example, when the patient is

being observed electrocardiographically 22-the situationis somewhat different. Here defibrillation may beachieved by a catheter electrode,’ 15 or by direct cardiacpuncture of the ventricular cavity and the passage ofdefibrillating shocks through an insulated needle with abare tip. Provided such equipment is kept ready, atherapeutic test need take only a few seconds beforethoracotomy and intermittent manual compression areinitiated.

Asystolic arrest is thus the remaining hurdle. WooD-WARD 23 has found that sometimes the heart-beat isrestored by immediately elevating the limbs, which fillsthe arrested heart with blood; but the main method oftreatment is still direct manual compression coupledwith intracardiac injection of adrenaline or calciumchloride.

Iron-retention Diseases

H1MOCHROMATOSIS in the form of " bronzed dia-betes " is well known, though uncommon, in Europe andAmerica. It is thought to be caused by slightly increasedabsorption of dietary iron, amounting to about 3-5 mg.daily throughout life.24 In South Africa excessive iron inthe tissues of the Bantu population was first noted someyears ago; and examination of tissues from patientswho had died in hospital or accidentally suggestedthat the prevalence of such siderosis lies between

40% and 88%. The amounts of iron have varied from aslight excess to a deposition as severe as in idiopathichaemochromatosis. This state of affairs has been

explained in two different ways. J. and T. GILLMAN 25considered that the siderosis was caused by a widespreadmetabolic defect associated with chronic malnutrition;whereas WALKER and ARVIDSSON 26 believed that it wascaused by excessive iron intake, because the Bantu cooktheir food and prepare their beer in iron cooking-vessels.The two schools also differed about the pathologicalchanges in the liver. The GILLMANS thought that ironwas first deposited in the liver cells themselves, whereasWALKER’S group thought the reticuloendothelial cellswere first involved. BOTHWELL and BRADLOW 27 have

reinvestigated this problem by examining tissue fromBantus who had died accidentally; they studied thehistopathological changes in the liver and, in some cases,the spleen, and they estimated the amount of iron in thetissues.

BOTHWELL and BRADLOW studied the livers of 147

patients and the spleens of 50; most of the patients wereaged 20-50, and only 16 were females. The ironconcentration in the liver exceeded the normal maximumof 0-1% in all except 16; and the concentration tendedto rise with age, reaching a maximum at 40-50 when the.average iron concentration was as much as 1-10%.

28. Gillman, T., Hathorn, M., Canham, P. D. Amer. J. Path. 1959, 35, 349.29. Heilmeyer, L., Keiderling, W., Wohler, F. German med. Monthly,

1959, 4, 111.30. Golberg, L., Smith, J. P. Amer. J. Path. 1960, 36, 125.

Some degree of siderosis of the liver was found in 89%of the patients; in 59% it was mild (i.e., not more than1-0%, which is a concentration of the same order as thatin idiopathic hsemochromatosis). Histological studiesshowed quite clearly that the hxmosiderin granuleswere deposited first in the liver cells, and appeared inthe Kupffer reticuloendothelial cells only when thehigher concentrations of iron were present. Portalfibrosis developed only when the iron concentrationwas really high; of 40 subjects with iron concentrationsbetween 0-50 and 1-99% only 8 had mild portal fibrosis,and in 1 it was assessed as moderate. But the 11

patients with iron concentrations above 2% all had

portal fibrosis; in 2 this was mild, in 5 moderate, andin 2 severe; in 2 there was frank cirrhosis. Investigationof the spleens showed that the iron concentrations

paralleled those in the liver.These results support the opinion of the GILLMANS,

which is linked with the observation that a similardistribution of iron in the liver is found in animals fedon deficient diets with considerable added iron.2$The

appearances are quite different from those caused byiron accumulations following haemolysis or infection; inthese circumstances it is the reticuloendothelial cellsthat take up most of the iron. 29 But BOTHWELL andBRADLOW cite an investigation which suggests that thediet of the Bantu in Johannesburg, though not optimal,is not in fact gravely deficient in any of the mainconstituents and is certainly not comparable to the

laboratory animals’ diet of uncooked corn meal. Amongthe Bantu iron intake is undoubtedly excessive, oftenexceeding 100 mg. a day, and the average serum-ironlevel in Bantu males is about twice that in white males.On the other hand, it has proved very difficult to producecirrhosis of the liver in animals by overloading thetissues with iron; and since recent investigations andthe features of idiopathic hxmochromatosis suggestthat portal fibrosis depends on the iron exceeding aminimum concentration, some additional factor mustbe needed. Chronic malnutrition does not seem to be asufficient explanation, nor does variation in the ratio ofiron and phosphorus in the diet. A different explanationhas been proposed by GOLBERG and SMITH. 30When rats are given excessive amounts of iron by

parenteral injection, iron accumulates in the liver andother tissues, but no hepatic cirrhosis is found evenafter so large a stretch of a rat’s life as two years.GOLBERG and SMITH found that when such iron over-

loading was combined with oral administration of theantimetabolite DL-ethionine, or with a diet poor in

protein and vitamin E, hepatic cirrhosis appearedwithin a few weeks. They think that the mechanism ofthe siderosis is " primarily one of excessive iron-

binding in the liver, from which the increased intestinalabsorption follows secondarily ". And they point outthat in these conditions, unassociated with haemolysisor marrow aplasia, the common factor is " actual orpotential liver damage, the latter taking the form of

1335

1. Schwartz, W. B. New Engl. J. Med. 1949, 240, 173.2. Rentchnick, P. Chemotherapia, 1960, 1, 225.3. Gaunt, R., Renzi, A. A., Chart, J. J. ibid. p. 238.4. Hadgraft, J. W. Pharm. J. 1960, 184, 277.5. Sherlock, S. Practitioner, 1960, 185, 492.

disordered metabolism of the hepatic cell". Theysuggest that such liver damage involves the excessiveproduction of an iron-binding material which they call" haptosiderin ", and which may be similar to the

copper-binding polypeptide isolated from the liver inWilson’s disease. This explanation would reconcilethe hypotheses of GILLMAN and of WALKER and theirco-workers since the disordered hepatic metabolismpostulated by GILLMAN would be responsible for theexcessive iron uptake from the undue amount of ironin the diet noted by WALKER. GOLBERG and SMITHbelieve that the low protein content of the Bantu dietmay be the responsible factor; the survey in Johannes-burg indicated that the average daily intake of animalprotein was 25 g. and of vegetable protein 39 g., whichis certainly less than the usually recommended dailyminimum of 80-100 g. protein. Other deficiencies

may be revealed by further work on this syndrome.

Annotations

DIURETICS

THE observations that the sulphonamides were poten-tially diuretic eventually led to the production of potentdiuretics such as the chlorothiazides. Their widespreaduse in the past two years or so has underlined theirvalue in the management of oedema and has alsoenhanced our understanding of kidney function. Theseadvances in knowledge have been assembled in a specialissue of Chemotherapia 2 in honour of the recent BasleInternational Congress of Internal Medicine at whichoedema was discussed.The benzothiadiazine group of diuretics probably affect

sodium excretion in the proximal tubule and potassiumexcretion in the distal tubule, and some support for this isafforded by the studies of Darmady and of Gaunt et al. 3on the selective localisation of radioactive hydrochloro-thiazide in these areas. The mechanism of tubularinterference is ill-understood, but the effect on sodium andpotassium excretion determines their main advantage anddisadvantage. To displace the prototype, new diureticsacting in this manner should be expected to cause increasedsodium excretion with diminished potassium excretion.Thus far, none of the growing family of chlorothiazideanalogues has a significant advantage; instead, commercialcompetition has led to such small refinements as the incor-poration of potassium; but the dose of potassium chosen bythe pharmaceutical company may be too small. When long-term diuretic therapy is necessary, and particularly whenthe underlying cause of oedema is hepatic cirrhosis,adequate oral potassium supplements are essential. Thisis effectively and palatably administered in an effervescenttablet containing potassium bicarbonate, potassium acidtartrate, and anhydrous citric acid, as devised by Had-graft at the Royal Free Hospital. Each tablet containsabout 6-5 mEq. of potassium and is equivalent to 0-5 g.of potassium chloride; a dose of 8 tablets daily is recom-mended for cirrhotic patients on a low-sodium diet. Õ

6. Veygrat, R. Chemotherapia, 1960, 1, 327.7. Goldner, M. G., Zorowitz, H., Akgun, S. New Engl. J. Med. 1960, 262,

403.8. Shaldon, S., McLaren, J. R., Sherlock, S. Lancet, 1960, i, 609.9. Shaldon, S. Proc. R. Soc. Med. (in the press).

10. Lancet, 1959, ii, 279.11. Laragh, J. H. in The Clinical Use of Aldosterone Antagonists (edited

by F. C. Bartter); p. 49. Oxford, 1960.12. Wolff, H. P., Koczorek, K. R., Buchborn, E. Lancet, 1957, ii, 63.

Hypokalxmia is but one of the undesirable consequencesof effective diuretic therapy; others include hypochlor-aemic alkalosis, low serum-electrolytes, hyperuricxmia,hyperglycasmia, and rashes and thrombocytopenia. 6The development of hyperglycasmia and glycosuria dueto these sulphonamide-type diuretics is somewhat

unexpected since another family of sulphonamides hasprecisely the opposite effect. Goldner et al. have shownthat this complication is restricted to diabetics and

prediabetics.When oedema is associated with hyperaldosteronism,

administration of the aldosterone-antagonising steroid,spironolactone, has a potent diuretic effect by acting on thedistal tubule. The use of spironolactone together withchlorothiazide has proved a synergistic combination incirrhotic patients with ascites resistant to either diureticalone. 8 Shaldon has reviewed his experience of themanagement of fluid retention in 51 cirrhotic patients inthe past eighteen months, in which spironolactone has beenavailable for clinical trial. 33 (65%) patients responded toa low-sodium diet and either a mercurial or chlorothiazide-

type diuretic, and 18 (35%) also needed spironolactone.Only 4 (8%) patients had no satisfactory diuresis, andthese subsequently died of liver failure. His recommendeddiuretic regimen for patients with hepatic cirrhosis is

initially rigid dietary salt restriction and bed rest; if thisis insufficient one of the chlorothiazides and potassiumare given. If thiazide therapy has not produced satisfactorydiuresis in a week, spironolactone is added and potassiumsupplements are reduced. Satisfactory diuresis usuallystarts within three days and continues at a slow steadyrate. Uninterrupted combined diuretic therapy may benecessary for some months to eliminate ascites, andthereafter it is continued indefinitely. Finally, if the patientfails to respond to this combination, it may be worth

administering an osmotic diuretic-intravenous mannitol-in an effort to initiate diuresis. This carefully plannedregimen has virtually eliminated resistant ascites, repeatedabdominal paracenteses, and the use of Southey’s tubes;but close supervision is imperative if electrolyte disturb-ances and hepatic coma are to be avoided.

Since the choice of diuretic was last discussed in thesecolumns,10 spironolactone, which then appeared promising,has become freely available and its value has been firmlyestablished. Its widespread and indiscriminate use may,however, lead to some disappointing results and to

criticism of its lack of efficacy in certain cedematous states.This can be expected if aldosterone antagonists are

administered where oedema is principally due to factorsother than hyperaldosteronism. Some patients with

congestive cardiac failure, for instance, do not secrete

aldosterone in excess 11; and it has been suggested thaturinary aldosterone levels are normal in " left-sided "heart-failure whereas they are elevated in " right-sided "heart-failure. 12 Spironolactone will be used more

rationally when a technique has been devised for detectingmore readily cases with hyperaldosteronism.To this means of peripheral blockade of aldosterone are

now being added central inhibitors of aldosterone secretion.One such substance-methbipyrapone or SU4885-

selectively inhibits the 11&bgr;-hydroxylation of steroids in