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Lead Poisoningand Acute Intermittent Porphyria

LEAD poisoning and acute intermittent porphyriawould seem to be very far apart in xtiology. Thesevere abdominal pain of lead poisoning was firstnoted by HIPPOCRATES; and HUXHAM gave a classicaldescription of the " Devonshire colick " in 1759. Thatlead poisoning is entirely an acquired condition wasshown as long ago as 1772 by BAKER,2 who demonstratedthat the symptoms of the famous colick were due tolead contamination from the Devonshire cider presses.Acute intermittent porphyria, on the other hand, is amuch more recently recognised disorder. Its clinical

presentation was first recorded only at the endof the 19th century; and it is a genetically determinedstate, although it may be aggravated by chemical com-pounds. One point common to lead poisoning andacute porphyria is the doubt which surrounds themechanism underlying their symptoms. DAGG, GOLD-BERG, LOCHHEAD, and SMITH 3 have now made a

clinical, biochemical, and pathological comparison ofthe two diseases which may help to clarify these

problems. They compared the clinical features in 50patients with lead poisoning and in 50 patients withacute intermittent porphyria. There was a remarkable

similarity in the incidence of pain, both abdominal andnon-abdominal, constipation, vomiting, and neuro-

psychiatric manifestations (although changes involvingthe nervous system were commoner and more severe in

porphyria). The paresis of lead poisoning was entirelyof lower-motor-neurone type, whereas 10% of thecases of acute intermittent porphyria had evidence ofupper-motor-neurone involvement. Tachycardia andhypertension were present in both groups, althoughthese signs were more striking in acute intermittentporphyria. The prominent clinical difference betweenthe two diseases was the anaemia in 94% of cases of leadpoisoning and in only 1 patient with porphyria.The clinical similarity is matched by the biochemical

and pathological features. In both conditions there is a

pronounced urinary excretion of 8-aminolacvulic

acid, a porphyrin precursor. In most cases of acuteintermittent porphyria urinary excretion of porphobi-linogen, a later precursor of porphyrins, is greatly in-creased, but in lead poisoning there is only a slight rise.The urinary coproporphyrin is usually much increasedin lead poisoning, but less so in most cases of acuteintermittent porphyria. It seems that the stage beforethe formation of 8-aminolxvulic acid is disturbednot only in lead poisoning but also in acute intermittentporphyria, though in lead poisoning there are alsoseveral other abnormal stages of hacmbiosynthesis. A not-able resemblance is also to be found in the pathologicalchanges in the nervous system. In the two conditionsthere is a similar type of segmental demyelination,axonal degeneration, and nerve-cell degeneration affect-ing the peripheral nerves and the central nervous

1 Huxham, J., 1759. See in Classic Descriptions of Disease. Springfield,Ill., 1955.

2. Baker, G. Med. Trans. Coll. Phycns. Lond. 1772, 2, 235.3. Dagg, J., Goldberg, A., Lochhead, A., Smith J. Q. Jl Med. 1965, 34, 163.

system. In acute porphyria in man the liver is the mainsite for the porphyrins and their precursors, whereas thecentral nervous system does not contain abnormallylarge quantities of these substances. It has been sug-gested that the neurological manifestations of acuteintermittent porphyria are only indirectly related to thehepatic defect, the liver failing to synthesise a factoressential for the nutrition of nervous tissue.4 There isevidence that the bone-marrow is the predominant siteaffected in lead poisoning. DAGG and his colleaguesalso compared experimental lead poisoning and experi-mental porphyria in rabbits. In experimental porphyriacaused by the administration of allyl isopropylacetamide,the liver was the main site for excess porphyrins andporphyrin precursors; and in experimental lead poison-ing the bone-marrow was the chief situation. There arethus fundamental differences in the tissue sites of bio-chemical abnormality in the experimental and probablyin the related human diseases. Lead may effect changesin nervous tissue by a direct action, in contrast to theindirect hepatic mechanism of acute intermittent por-phyria. This possibility may be relevant to the findingsof MoNCRiEFF and his colleagues that there was a

higher blood-lead level in a group of children withmental deficiency, and that treatment of some of thesechildren with lead-chelating compounds improvedtheir mental state. The direct action of lead on thebone-marrow red-cell precursors is responsible for theanaemia in lead poisoning, and DAGG and his colleaguesshowed that the anasmia was caused by a hamolyticprocess as well as by direct inhibition of haemoglobinformation.

Any well-directed attempt to correlate the clinicalmanifestations of a disease with its pathology and bio-chemistry has, in the past, been rewarding; and thisstudy of lead poisoning and acute porphyria shouldprove no exception. The essential problem is nowclear-to unravel the biochemical abnormality in thenervous systeih which is present in both conditions.

The Nottingham Medical SchoolTHE Minister of Health announced in Parliament a

year ago that a new medical school was to be establishedin the University of Nottingham, with an intake of 100students a year, in conjunction with a new teachinghospital of 1200 beds. This action brought to a

decisive stage long-cherished plans at Nottingham. In

October, 1964, with the approval of the UniversityGrants Committee, the university decided to set up amedical-school advisory committee " to offer to the

University advice and recommendations about medicaleducation, teaching and research, about the best

arrangements for the nature and layout of the buildingsrequired, and about the University’s administrative

relationships with the other bodies concerned ". Under4. Goldberg, A., Rimington, C. Diseases of Porphyrin Metabolism.

Springfield, Ill., 1962.5. Moncrieff, A. A., Koumides, O. P., Clayton, B. E., Patrick, A. D.,

Renwick, A. G. C., Roberts, G. E. Archs Dis. Childh. 1964, 39, 1.See Lancet, 1964, i, 867.

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the chairmanship of Sir GEORGE PICKERING, the com-mittee got to work in December and, with great expedi-tion, after hearing much evidence from experts both inBritain and in the United States, has now produced itsreport.’ This formidable task was also a great oppor-tunity, which, in large measure, the committee hasseized. " To make proposals which are at once imagina-tive and practical "’was the committee’s aim, and in sodoing to take what is best of the new and to get rid of theworst of the old. The report defines the objectives whichshould determine not only the nature of the medicalcurriculum but also the buildings of the medical schooland hospital. They are to develop and strengthen thelinks between medical school and the rest of the uni-

versity, between the preclinical and clinical parts of theschool, and between the hospital and the community itwill serve. Thus, while the medical school and hospitalshould be built as a unit (and the name of Universityof Nottingham Medical Centre is proposed to give forceto the idea), the hospital must be in every sense acommunity hospital, serving all the medical needs of adefined population. Carrying the principle of integra-tion and unity to all levels, the report suggests that thegoverning body of the teaching hospital should beconstituted jointly by the regional board and the

university, acting as equal partners. Thus, professorsand senior lecturers, consultants, registrars, and house-men would all be appointed by a single body who wouldbe responsible for obtaining the necessary money fromthe Ministry of Health and the University GrantsCommittee. Such a scheme will involve an amendmentto the National Health Service Act.The formal enunciation of guiding principles does not

give an adequate idea of the comprehensive plan whichhas been provided. It has been called a " revolution inmedical studies ", but this is not really so, for theradical changes which are suggested have all had theirorigin in the ferment of ideas about medical educationwhich has gone on throughout this country and NorthAmerica in the past ten years. The Nottingham com-mittee has steered a course that is more likely to giverise to evolution than to the instabilities of revolution.The plan should find favour not only with those whodeplore the isolation of the medical student from

university life, but also with those who believe that theteaching hospital of the future must operate as the maincentre of its area for community health and postgraduateeducation. The medical student at Nottingham willenter a three-year preclinical course leading to a B.sc.,of which the final year will generally be taken as anhonours course. This will train him " as a biologicalscientist whose interest is centred on man ". The rangeof subjects is broad and includes biometry, genetics, andbehavioural sciences. To make this possible, to enablemost students to take an honours course in science, theplanning and conduct of the course must be

" taken outof the hands of departments and entrusted to the

statutory curriculum committee ". The unwritten codeof practice by which in the past each professor has1. Report of the Medical School Advisory Committee, University of

Nottingham, June, 1965.2. Times, June 25, 1965.

claimed a permanent quota of the students’ timemust not recur. Integrated teaching, rather than con-secutive teaching, will be essential, and the time devotedto formal instruction and lectures will be reduced infavour of guidance towards private reading and practicaland written work. Anatomy should be taught by usingdemonstration specimens and models; teaching " oneday a week for three terms should be enough ". Detailedtopographical anatomy, like surgery, has become a

postgraduate subject for surgeons and other specialists.The whole preclinical science course should be suitablefor others besides medical students, such as school-

masters, Civil Servants, administrators, and non-

medical scientists, and 50 extra places, the committeesuggests, should be set aside for them.The General Medical Council in its evidence to the

Robbins committee in 1961 drew attention to the

increasing move towards premature specialisation at

school before the children reached a satisfactory standardof general education; and the council pointed out thatthe school education of future medical students " shouldnot be vocational in trend ". The suggestion for

Nottingham is that the doors to the preclinical courseshould be more widely opened to enable students witharts and science subjects at A level or arts subjects aloneto enter, provided they have an 0 level pass in mathe-matics, which is held to be essential. To fit thesestudents into the preclinical course in medical biologicalsciences will no doubt present difficulties, but theyshould not prove insuperable. Indeed, the exerciseshould be very rewarding. The purpose of the under-graduate course, both its preclinical and clinical parts,is to provide education for medicine, not to give voca-tional training. The development of postgraduateeducation has made the reform of undergraduateeducation possible. Vocational needs, vital though theyare, must follow education, but they must not be toolong delayed. The committee therefore proposes thatthe clinical period of the course should be reduced fromthree to two years, but only if a second or additionalpreregistration year is added. There are many who havefavoured this: it would give the student at an earlierstage direct responsibility for patients, give him anactive part in the work of the hospital, and reduce theperiod during which he has to suffer from being a passiveobserver. It has long been apparent that the newlyregistered doctor is not equipped to practise any branchof medicine, but the committee holds that this plan willput him in a better position to learn how to do so.The Nottingham plan will ensure that the teachers of

its medical school, no less than its students, will standto gain from being part of the corporate life of its

university. Moreover, it seeks to determine that themedicine taught and practised there will be based upona complete commitment to the idea that the medicalcentre serves all the medical needs of the community.This it could do only if it had close working relationsand some division of labour with the other hospitals ofthe Nottingham area, the general practitioners, and thelocal health authorities. There is emphasis on geriatrics,psychiatry, and a department of community health,

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which will have subdepartments of general practice,epidemiology, biometry and statistics, industrial medi-cine, and rehabilitation. Both medical centre and com-

munity should benefit, for the needs of each are not seenas separate or conflcting, but as interdependent.The report which Sir GEORGE PICKERING and his

committee have provided for Nottingham sets out in acoherent and practical way many ideas that have beenunder discussion for some time. If in eight years’ timethese plans are realised, and the first students enter theirclinical studies, the new school will be an exciting placefor students and teachers alike. It could not happen,of course, where traditions are already established. But

Nottingham-without faculty, teachers, or buildings-need look only to the future.

Annotations

POTASSIUM CHLORIDEAND INTESTINAL ULCERATION

LAST year Baker et al.1 drew attention to the associationof ulcers of the small intestine with the ingestion ofthiazide diuretics and potassium supplements in the formof enteric-coated potassium chloride. Several similar

reports have since appeared,2-5 and a typical syndromehas emerged of postprandial, colicky abdominal pain,often with nausea and vomiting, for days, weeks, or months,in patients who are taking such preparations. The physicalfindings are often unimpressive, but mild distension andabdominal tenderness have been consistently present.Barium studies have revealed distended loops of smallbowel, and in some instances a zone of obstruction withcircumferential narrowing. There have been several casesof perforation. Surgical exploration has shown dilatedbowel distal to a sharply delineated zone of cicatricialnarrowing with partial, or almost complete, obstruction.The bowel immediately proximal to this region wasoedematous and haemorrhagic. Although most cases havebeen explored surgically, Abbruzzese and Gooding 6 havenow described a patient with the same symptoms, signs,and radiological appearances, who spontaneously improvedon discontinuing treatment with thiazide and potassiumchloride.

Potassium chloride is poorly tolerated by the gastro-intestinal tract, and for this reason both the British

Pharlnacopceia and the National Formulary insist thattablets should be dissolved in water before administration.The enteric-coated preparations, however, are not releaseduntil they reach the small intestine, and Boley et al. havenow demonstrated in animals a possible mechanism oftheir toxic effects. In elegant experiments they fixedtablets of enteric-coated placebos, potassium chloride,thiazide/potassium preparations, and thiazides alonewithin the ileum or distal jejunum of mongrel dogs. Thelesions were examined post mortem one or two weeks later.No remarkable changes were seen at any of the sites where

1. Baker, D. R., Schrader, W. H., Hitchcock, C. R. J. Am. med. Ass.1964, 190, 586.

2. Lindholmer, B., Nyman, E., Raf, L. Acta chir. scand. 1964, 128, 310.3. Buchan, D. J., Houston, C. S. Can. med. Ass. J. 1965, 92, 176.4. Morgenstern, L., Freilich, M., Panish, J. F. J. Am. med. Ass. 1965,

191, 637.5. Lawrason, F. D., Alpert, E., Mohr., F. L., McMahon, F. G. ibid.

p. 641.6. Abbruzzese, A. A., Gooding, C. A. ibid. 1965, 192, 781.7. Boley, S. J., Schultz, L., Krieger, H., Schwartz, S., Elguezabal, A.,

Allen, A. C. ibid. p. 763.

placebos or thiazides alone were implanted. Intestine

exposed to potassium chloride, however, showed lesions ofseverity varying from sharply limited annular bluishridges with intact mucosa, through ulceration with earlystenosis, to gross infarction. The disparity betweenconspicuous submucosal oedema, hxmorrhage, andfibrosis, on the one hand, and relatively slight mucosalerosion or ulceration, on the other, suggested a primarilyvascular cause rather than direct erosion from the surface.The severity of reaction varied widely from animal toanimal, which accords with clinical experience; probablyseveral different factors contribute to this condition, ofwhich enteric-coating of potassium chloride, permittingrapid dissolution of the tablet and absorption over a shortsegment of small intestine, is one of the most important.If, as Boley et al. suggest, the primary mechanism is

vascular, then the presence of underlying vascular diseasewould render an individual more prone to ulceration.

Combined preparations of thiazides and potassiumchloride may be convenient, but they are open to severalobjections. The most obvious is that not all patients needthe same amount of potassium, but the most serious maybe its toxicity in the small bowel. A better-toleratedeffervescent potassium preparation 8 surely makes com-pressed forms of potassium chloride unnecessary, and thereis a strong case for their omission from future editions ofthe British Pharmacopaeia and National Formulary.

HEART-DISEASE, CANCER, AND STROKE

IN March, 1964, President Johnson appointed a

commission to form a " realistic battle plan leading to theultimate conquest of three diseases, heart disease, cancerand stroke which account for more than 70 % of the deathsin this country ". The commission, which included bothmedical and lay members, under the chairmanship ofDr. Michael De Bakey, has recorded its findings in afinal report of more than 600 pages.9 The main recom-mendations are: (1) creation of regional complexes forcare and clinical investigation of patients with heart-disease, cancer, and stroke; (2) categorical and non-categorical research institutes within existing institutions;and (3) establishment of diagnostic and treatment stationsfor these diseases.

From this country it is always hard to judge the purposeof such mammoth inquiries. The American MedicalAssociation 10 has attacked the report-in particular theproposals to establish regional centres for the care of

patients. In considering the implications of the recom-mendations, account must be taken of the Americanattitude to public expenditure on health. The House ofRepresentatives has recently passed a Medicare Bill,"which will provide health insurance for people over 65.Nevertheless there is growing concern about the increasein Government expenditure on medical research 12 ; and theprogramme for heart-disease, cancer, and stroke, whichproposes massive increases in expenditure both on researchand on medical care for these diseases, is likely to meetconsiderable opposition.The recommendations for additional expenditure are

based on exhaustive reviews of the three diseases, and8. Hadgraft, J. W. Pharm. J. 1960, 184, 277.9. President’s Commission on Heart Disease, Cancer and Stroke. U.S.

Printing Office, Washington, D.C. 1965. Pp. 644. $3.10. J. Am. med. Ass. 1965, 192, 299.11. See Lancet, 1965, i, 906.12. Science, 1965, 148, 608.