BRITISH MEDICAL JOURNAL

27

DECEMBER

1975

and impulsiveness, together with adverse school influences such as high teacher turnover, combine to exacerbate and perpetuate the problem. The educational and remedial implications of the two types of disorder are uncertain. They are likely to be important, for, though both groups have problems and need help, the backward reader is functioning at an appropriate level for himself whereas the child with specific reading difficulty is underachieving to an important extent. The secondary emotional problems must be different for the two groups, and probably the remedial therapy should be different also. What are the implications for the doctor or teacher ? Firstly, any child whose reading is two years or more behind his chronological age should be assessed by an educational psychologist, a doctor, and probably a social worker. This assessment should be made during the primary school years in the hope that early identification and classification of the problem will allow better understanding and help for the child both family and school. 1 Critchley, M, The Dyslexic Child. Springfield, Thomas, 1970. Rutter, M, and Yule, W, of Child Psychology and Psychiatry, 1975, 16, 181.

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Differential diagnosis of the hepatic porphyrias Hepatic porphyria is usually diagnosed on the basis of clinical findings and the measurement of porphyrins and their precursors in urine and faeces.' In practice, porphyria presents in two main ways: as an acute disease with abdominal pain, vomiting, and neuropsychiatric manifestations; and (the cutaneous type) as a photosensitising disease of the skin. In the acute presentation it is essential to examine the urine for 3-aminolaevulic acid, porphobilinogen, and excess porphyrins. The faeces must also be examined for excess coproporphyrin and protoporphyrin because in both variegate porphyria (mixed porphyria) and hereditary coproporphyria there are excessive amounts of porphyrins in the faeces. When the cutaneous manifestations of porphyria present for the first time the diagnosis should be confirmed by examination of the urine for uroporphyrin, coproporphyrin, 8-aminolaevulic acid, and porphobilinogen; of the faeces for coproporphyrin and protoporphyrin; and of the blood for protoporphyrin and coproporphyrin. In the type of cutaneous porphyria which is provoked by alcohol and other hepatotoxic substances the urine contains excessive quantities of porphyrins. In other types of cutaneous hepatic porphyria, such as variegate porphyria, the amounts of faecal porphyrins will always be raised. Examination of the blood porphyrins may be the only way of diagnosing erythropoietic protoporphyria.2 More difficult to establish is the diagnosis of latent cases of porphyria, though measurement of uroporphyrinogen cosynthetase in the red cell has been shown to be useful in the recognition of acute intermittent porphyria.3 Further methods of measuring enzyme levels in the blood will probably be developed soon to help in the diagnosis of latency. The basis of diagnosis, therefore, is the accurate measurement of porphyrin concentrations in urine, faeces, and blood, and the methods in use are many. The most commonly used-and indeed probably the most effective-are those

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described by Rimington,4 which depend on simple extraction techniques followed by spectrophotometric or spectrofluorimetric measurement of the porphyrin fractions thus obtained. Another proved technique for the separation of porphyrin fractions is by thin-layer chromatography.5 Other methods of porphyrin estimation have included separation on Sephadex dextran gels,6 ion exchange chromatography,7 electrophoresis,8 counter current analysis, 9 magnetic circular dichroism spectroscopy,' 0 and atomic absorption spectrophotometry.1' One recently described method which shows great promise is high pressure liquid chromatography.'2 In the measurement of porphyrin precursors the method of choice remains that of Mauzerall and Granick,"3 in some cases with modifications. In the main the chromatographic techniques are excellent as research tools, but in the normal day-to-day usage in clinical biochemistry laboratories they lack the ease of operation and the throughput achievable with extraction techniques. Since the differential diagnosis of the porphyrias depends on the varying patterns of porphyrin excretion and production, it rests ultimately on these methods for measuring porphyrins and their precursors. An addition to this diagnostic sequence was the description of the so-called X porphyrin by Rimington et al'4 in 1968. This is a porphyrin-peptide complex measurable by extraction techniques which may be used in the differential diagnosis of cutaneous and non-cutaneous porphyrias.'5 In normal circumstances only three of the different forms of hepatic porphyria are likely to present with skin lesions: cutaneous hepatic porphyria, variegate porphyria, and hereditary coproporphyria. Of these three, moreover, only two are likely to be confused-variegate porphyria and cutaneous hepatic porphyria. Normally these may be distinguished by the lack of familial history and absence of porphyrin precursor excretion in cutaneous hepatic porphyria, despite the similarity of skin lesions in both diseases. Diagnosis is important, because the current treatment of cutaneous hepatic porphyria is venesection (which produces a fall in porphyrin production and excretion and rapid remission of cutaneous signs and symptoms'6). Such treatment would have little effect in variegate porphyria. Elder'7 has described differentiating cutaneous hepatic porphyria or porphyria cutanea tarda from the other porphyrias by the measurement of the recently described isocoproporphyrin. This method is based on a two-dimensional chromatographic separation of faecal porphyrins. Those similar techniques already described depend on the patterns of excretion as measured by chromatographic methods rather than the presence or absence of these porphyrins.'8 Because oftheir complexity sach specialised techniques, including the measurement of plasma porphyrin concentrations in cutaneous hepatic porphyria,'9 should be applied only when the diagnosis is otherwise doubtful. 1

Moore, M R, and Goldberg, A, in Iron in Biochemistry and Medicine, eds A Jacobs and M Worwood. London, Academic Press, 1974. 2 Beattie, A D, and Goldberg, A, in Blood and Its Disorders, eds R M Hardisty and D J Weatherall. Oxford, Blackwell, 1974. 3 Meyer, U A, et al, New England Journal of Medicine, 1972, 286, 1277. 4Rimington, C, Association of Clinical Pathologists Broadsheet No 70, 1971. 5 Doss, M, South African J3ournal of Laboratory and Clinical Medicine, 1971,17, 221. 6 Rimington, C, and Belcher, R V, J3ournal of Chromatography, 1967, 28, 112. 7 Doss, M, and Schmidt, A, Zeitschrift fur klinische Chemie und klinische Biochemie, 1971, 9, 99. 8 Fischl, J, et al, Clinical Chemistry, 1970, 16,331. 9 Barnes, H D, South African Journal of Laboratory and Clinical Medicine, 1963,9, 177. 10 Kalman, S M, et al, Analytical Biochemistry, 1973, 52, 83. 1

Bourdon, R, Yonger, J, and Ataie, M, Annales de Biologie Clinique, 1972, 30,427.

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Lim, C K, Gray, C H, and Stoll, M S, in Porphyrins in Human Disease, ed M Doss, Basle, Karger, 1975. 13 Mauzerall, D, and Granick, S, Journal of Biological Chemistry, 1956, 219, 435. 14 Rimington, C, Lockwood, W H, and Belcher, R V, Clinical Science, 1968, 35,211. 16 Moore, M R, Thompson, G G, and Goldberg, A, Clinical Science, 1972, 43, 299. 16 Allen, B R, et al, British Journal of Dermatology, 1975, 93, 37. 17 Elder, G H, Journal of Clinical Pathology, 1975, 28, 601. 18 Doss, M, in Clinical Biochemistry, Principles and Methods, eds H C Curtius and M Roth. Berlin, De Gruyter, 1974. 19 Moore, M R, et al, Clinical Science and Molecular Medicine, 1973, 45,711. 12

Vesicoureteral reflux and its familial distribution The genitourinary tract is one of the commonest sites of congenital malformation, and several anomalies may coexist in one individual: for instance, primary vesicoureteral reflux due to a short intramural ureter may be associated with dysplasticl 2 or with duplex kidneys.3 4 Since Stephens et a15 observed reflux and megaureter in identical twins there have been many reports of familial reflux, and over 80 families have now been described. Vesicoureteral reflux has been found in up to five members of a family6 and spanning one to four generations.7 In one family reflux or other renal tract anomalies were found in eight first- or second-degree relatives.8 Though this familial aggregation suggests a hereditary basis for at least some types of primary vesicoureteral reflux, there is no uniform pattern of inheritance. In one group of families it seems that the patients are almost exclusively male.7 9 Those described in detail have had severe reflux and extensive renal damage of the obstructive atrophy type; there has been little evidence of urinary tract infection. In one of this group of families the pedigree strongly suggests an X-linked mode of genetic transmission9 and in another autosomal dominant inheritance of the trait with incomplete penetrance. 7 In the other, more heterogeneous group both sexes are affected, but females more than males,6 8-13 and reflux may often be shown without any coexisting renal damage-for example, in a grandmother of 72 with presumed lifelong reflux6 and in a 23-year-old mother of three girls, all four with reflux.°0 Repeated urinary tract infection is common in affected members of these families, and has occurred in all the patients with renal scarring, which is generally of the classical, coarse pyelonephritic type.6 811 The inheritance of reflux in these families is less clear, but Burger6 14 suggests a multifactorial genetic basis acting at the vesicoureteral junction and subject to environmental factors such as age, infection, and pressure. These observations are important in piecing together the modes of inheritance of vesicoureteral reflux, but widespread radiological investigation for this purpose alone is scarcely

BRITISH MEDICAL JOURNAL

27 DECEMBER 1975

justified, and the pattern will be clarified as more family studies emerge in the course ofroutine care. A more practical application of the findings might be in the early identification of infants or children with vesicoureteral reflux, since reflux is of considerable importance in the pathogenesis of kidney damage associated with infection, which is likely to start at an early age.'5 Reports of individual families with reflux give no indication of the risk of finding it in the relatives of an isolated affected patient, but Burger calculated14 that in a family with at least two affected members the risk of finding reflux in further members was 13.6%. The incidence of reflux in the population is not known, but it probably occurs at some time in at least 0O5-1-0% of girls. The implications of these studies are that the clinician should be aware that vesicoureteral reflux may be familial and that in siblings, parents, or offspring of patients with reflux (and particularly those with renal scarring) he should maintain a high index of suspicion and test the urine for infection in those who are unwell. When should radiological investigation of the rest of the family be undertaken? Two groups in whom it has been advocated are first-degree relatives-with urinary infection or symptoms-of patients with vesicoureteral reflux, particularly with scarring,'6 and families with two or more affected members, perhaps even if asymptomatic.'3 Limited two-film intravenous urography would be appropriate in the first instance, with micturating cystography if the kidneys were abnormal or in children under the age of 3. How many of the children ascertained by such study would merit anything more than observation remains to be seen. The children with reflux identified by one prospective family study12 were asymptomatic, uninfected, and had normal kidneys. If further families are recognised in which severe reflux and renal damage affect males predominantly then cystourethrography at an early age might be justifiable in boys. In the absence of any simple and acceptable method of screening for reflux, however, firm recommendations about the radiological investigation for familial reflux cannot be made at present.

Journal of Surgery, 1963, 33, 114. 2 Stecker, J F, Rose, J G, and Gillenwater, J Y, Journal of Urology, 1973, 110,341. 3 Amar, A D, British-Journal of Urology, 1968,40,385. 4 Atwell, J D, et al, Archives of Disease in Childhood, 1974, 49, 390. Stephens, F D, Joske, R A, and Simmons, R T, Australian and New Zealand3Journal of Surgery, 1955, 24, 192. 6 Burger, R H,J'ournal of Urology, 1972, 108,249. 7 Lewy, P R, and Belman, A B, Journal of Pediatrics, 1975, 86, 851. 8 Frye, R N, Patel, H R, and Parsons, V, Nephron, 1974, 12, 188. 9 Middleton, G W, Howards, S S, and Gillenwater, J Y,Journal of Urology, 1975,114,36. 10 Tobenkin, M I, Southern MedicalJ7ournal, 1964, 57, 139. 1 Mulcahy, J J, et al,Journal of Urology, 1970, 104,762. 12 Bredin, H C, et al,Journal of Urology, 1975, 113, 623. 13 Zel, G, and Retik, A B, Urology, 1973,2,249. 14 Burger, R H, and Burger, S E, Urologic Clinics of North America, 1974, 1,419. 15 Asscher, A W, and Brumfitt, W, eds, Kidney International, 1975, suppl No 4. 16 Girdany, B R, and Price, S E, Journal of Pediatrics, 1975, 86, 998. 1 Bialestock, D, Australian and New Zealand

Editorial: Differential diagnosis of the hepatic porphyrias.

BRITISH MEDICAL JOURNAL 27 DECEMBER 1975 and impulsiveness, together with adverse school influences such as high teacher turnover, combine to exac...
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