628 BRITISH MEDICAL JOURNAL 17 MARCH 1973 may wronglly lead to the diagnosis of primary hyperaldo- 13 Mitchell, J. D., Baxter, T. J., Blair-West, J. R., and McCredie, D. A., Archives of Disease in Childhood, 1970, 45, 376. steronism and even to the excision of the wrong endocrine 14 Voute, P. A., Meer, J. van der, and Staugaard-Kloosterziel, W., Acta Endocrinologica, 1971, 67, 197. Br Med J: first published as 10.1136/bmj.1.5854.628 on 17 March 1973. Downloaded from gland. 15 Hudson, J. B., Chobanian, A. V., and Relman, A. S., New England The opposite clinical syndrome-primary lack of renin or J'ournal of Medicine, 1957, 257, 529. 16 Jacobs, D. R., and Posner, J. B., Metabolism, 1964, 13, 522. hyporeninism-has also been recognized recently. In this 17 Vagnucci, A. H., Journal of Clinical Endocrinology and Metabolism, 1969, disease primary lack of renin (and hence of its active pro- 29, 279. 18 Perez, G., Siegel, L., and Schreiner, G. E., Annals of Internal Medicine, duct angiotension II) apparently leads to selective deficiency 1972, 76, 757. of aldosterone associated with normal cortisol production. 19 Ferrara, E., Werk, E., Hanenson, I., Privirera, P., and Kenyon, C., Clinical Research, 1970, 18, 602. The literature contains reference to some 20 cases of isolated 20 Schambelan, M., Stockigt, J. R., and Biglieri, E. G., New England J ournal of Medicine, 1972, 287, 573. analdosteronism, the first a report by J. B. Hudson and his 21 Weidman, P., et Clinical Research, 1972, 20, 249. colleagues15 in 1957. Only recently however has the primary al., deficiency been recognized as renin lack in at least some of these patients. At page 650 of this issue of the B.M.7. we publ.sh what appears to be the first report of a case in Britain. Isolated hypoaldosteronism usually occurs in elderly Pruritus Vulvae patients and is characterized by attacks of loss of con- sciousness, cardiac arrhythmias, muscle weakness, and Vulval irritation, or pruritus vulvae, is a distressing and weight loss. It should be considered when severe hyper- sometimes baffling and intractable symptom. It can have a kalaemia occurs with only a moderate rise of blood urea variety of local or general causes. A careful search for them and where cortisol production is normal. The symptoms are is an essential prelude to treatment, since elimination of the due to the electrolyte derangements, since treatment with cause usually brings relief. ion exchange resins leads to a prompt clinical remission, Among the common causes are irritating discharges, which is maintained when plasma electrolytes are kept which may come from the cervix, vagina, or urethra. Particu- normal with mineralocorticoid replacement therapy. While larly common and readily recognized by bacteriological ex- the selective deficiency of aldosterone in a few of these amination are those due to infection by Trichomonas patients may have been due to a block in the biosynthetic vaginalis or Candida albicans. Vulval irritation may some- pathway leading to aldosterone,16-18 primary lack of renin times be the result of urinary incontinence. Special mention now seems a likely explanation in the remainder. This idea must be made of diabetic vulvitis, when to some extent the was put forward originally by D. R. Jacobs and J. B. vulvitis may be due to irritation by the heavily sugar-laden Posner16 in 1964, but remained unsupported until recent urine, but Candida albicans infection is a frequent accom- reports in the syndrome of low plasma levels of renin18-21 paniment of it. and angiotensin II,18 persisting even during the stimulus of Local disease of the skin may be part of a general skin sodium deprivation. Evidence that the lack of aldosterone in disease such as psoriasis, eczema, or herpes. Lichen sclerosis these patients is secondary to the low circulating levels of may be present, a condition which may affect other parts of http://www.bmj.com/ angiotensin II is provided by the Glasgow group (this week), the body but very frequently affects the vulva. Here the who report a distinct increase of plasma aldosterone when vulva and perianal regions show patchy, white, atrophic plasma angiotensin II was raised in their patient by infusion changes. Histologically there is hyperkeratosis, atrophy of of synthetic angiotensin. epithelium, and flattening of rete pegs and Malpighian layer. These reports of primary hyper- and hyporeninism are of Usually it does not progress, but occasionally leukoplakia can interest in several ways. For the clinician primary hyper- supervene. reninism becomes another potentially remediable cause of Leukoplakia and kraurosis vulvae are specific lesions hypertension, while hyporeninism should be considered in which may be associated with pruritus vulvae. The on 28 September 2021 by guest. Protected copyright. al cases of unexplained hyperkalaemia, particularly since characteristic white patches of leukoplakia are associated treatment is so simple and effective. In pathophysiological with hyperkeratosis and thickening of the epidermis, with terms hyper- and hyporeninism shed considerable light on overactivity of the Malpighian layer and degeneration of the the role of the renin-angiotensin system in the regulation of corium. The hypertrophic form of leukoplakia is of partic- aldosterone secretion and blood pressure. Primary hyper- ular importance because of its pronounced premalignant reninism is a condition in which an excess of circulating tendencies. Traditionally, a late atrophic stage of leuko- renin apparently leads to a reversible increase of aldo- plakia has been described too, the histological features of sterone secretion and blood pressure, while primary which are identical with those of lichen sclerosis. hyporeninism leads to a reversible deficiency of aldosterone The term kraurosis is reserved for a condition whose main persisting in the presence of hyperkalaemia, otherwise a features are atrophy and shrinkage of tissues, with flattening potent stimulus to aldosterone production. of epithelium, affecting the labia and particularly the vaginal introitus. But it should be noted that the clinically helpful 1 Tigerstedt, R., and Bergman, P. G., Skandinavisches Archivfur Physiologie, 1898, 8, 223. distinctions drawn here between lichen sclerosis, leuko- 2 Starling, E. H., Lancet, 1905, 2, 339. plakia, and kraurosis are not universally accepted. T. N. A. 3Starling, E. H., Proceedings of the Royal Society of Medicine, 1914, 7, part 3, Therapeutic Section, p. 29. Jeffcoate and A. S. Woodcock,' for example, consider there Robertson, P. W., et al., American Journal of Medicine, 1967, 43, 963. is no good evidence that lichen sclerosis and are 5 Kihara, I., Kitamura, S., Hoshino, T., Seida, H., and Watanabe, T., Acta leukoplakia PathologicaJaponica, 1968, 18, 197. separate entities. There are in addition other cases, variously 6Eddy, R. L., and Sanchez, S. A., Annals ofInternal Medicine, 1971,75,725. 7 Bonnin, J. M., Hodge, R. L., and Lumbers, E. R., Australian and New named Bowen's disease, Paget's disease, and carcinoma in Zealand J'ournal of Medicine, 1972, 2, 178. situ, in which the features of intraepithelial carcinoma exist. 8 Conn, J. W., et al., Archives of Internal Medicine, 1972, 130, 682. 9 Schambelan, M., and Biglieri, E. G., Clinical Research, 1972, 20, 439. Ulcerative vulval lesions include some venereal conditions 10 Laragh, J. H., et al., American Journal of Medicine, 1972, 52, 633. not often seen in Great Britain-namely, granuloma ven- "I Barraclough, M. A., et al., Lancet, 1965, 2, 1310. 12 British Medical Journal, 1968, 3, 327. ereum and lymphogranuloma inguinale. Behcet's syndrome BRITISH MEDICAL JOURNAL 17 MARCH 1973 629 is the name attached to an uncommon association of vulval and oral ulceration with acute inflammatory lesions in the New Ideas on Vitamin D eye. An ill-defined group, it seems probable that more than Br Med J: first published as 10.1136/bmj.1.5854.628 on 17 March 1973. Downloaded from one disease has in fact been described under this head. Few efforts in clinical and biochemical research have been so Though uncommon in Britain nowadays, tuberculous and well rewarded in recent years as those devoted to the action syphilitic ulcerations must be borne in mind, while occasion- of vitamin D. Firstly, several metabolites of vitamin D with ally carcinomatous ulcers may present with pruritus, especially greater biological activity than the parent compound have if superimposed on leukoplakia. While they are not usually been identified, and some have been adnministered to patients ulcerated, mention may be made here of condylomata acumi- with bone disease. Secondly, long-term administration of nata. These are viral papillomata or warts, often profuse, and enzyme-inducing agents has been shown to alter the rate of associated with intense irritation. It is wrong to think that metabolism of vitamin D, and perhaps to cause osteomalacia. they are always or even usually of venereal origin. Thirdly, a new and plausible hypothesis of the interrelation- Various antiseptics, detergents, and other chemicals can ship between vitamin D and parathyroid hormone has been cause vulval irritation. Some patients are susceptible to proposed and in part substantiated. symptoms from comparatively mild insults-for example, Vitamin D was the name given by E. V. McCollum and underclothing insufficiently rinsed free of soapflakes. The his colleagues in 1922 to the antirachitic factor isolated from nature of the irritant may be disclosed only by a very care- cod liver oil.1 The active vitamin is found in few natural sub- fully taken history. stances, but precursors (or provitamins) are found in both Sometimes the most thorough examination fails to show plants and animals. The precursors are sterols. Plant pro- any local cause or systemic disease, and then it is important vitamin D (or ergosterol) acquires vitamin D activity when to remember that vulval irritation may be a symptom of exposed to ultraviolet light. It is then known as vitamin D2 or sexual frustrations or deep psychological conflicts, which calciferol. Animal provitamin -D (7-dehydrocholesterol) is need to be inquired into. Endocrine factors too may be found in the skin. It too is converted to an active compound aetiologically significant, the most conspicuous example (vitamin D, or cholecalciferol) by ultraviolet radiation. In being the frequent association of pruritus vulvae with the recent years the metabolic fate of vitamin D, in man and menopause. animals has ibeen studied (by using synthetic radioactive- The investigation of pruritus vulvae clearly entails more labelled cholecalciferol. Dietary vitamin D (mostly as DO) iS than a cursory history and examination. Special inquiry absorbed from the small intestine, and is supplemented by should be made of the possibility of irritant substances vitamin D, produced in the skin. It is now thought that applied to the vulva, and when the history is taken it is neither of these vitamins is biologically active but that both essential to explore the likelihood of psychological conflict are hydroxylated in the liver to form 25-hydroxycholecalci- playing some part in it. The examination should include a ferol (25-HCC for short) and 25-hydroxyergocalciferol, general inspection for skin lesions elsewhere on the body. which are active. More is known about 25-HCC than the The local examination must include urine and bacterio- other metabolite. It is produced in the liver, but in response logical testing and may need to be supplemented by viral or to what stimulus is uncertain. other special tests. Biopsy will be needed in cases of the It has been suggested that barbiturates induce the hepatic http://www.bmj.com/ chronic vulval dystrophies-lichen sclerosis, leukoplakia, enzymes responsible for the production of 25-HCC.2 3 Since kraurosis. and carcinoma in situ. 25-HCC is more active than vitamin D, this hypothesis is Needless to say, the most effective treatment is eradica- difficult to reconcile with the observation that epileptic tion of the cause, but hypertrophic leukoplakia vulvae, if patients on long-term barbiturate therapy may develop vita- confirmed, may warrant vulvectomy. When symptomatic min D deficiency as shown by hypocalcaemia and even treatment is required, the application of a bland ointment osteomalacia.4 However, inducing agents may perhaps also such as zinc and castor oil will often give temporary relief, transform 25-HCC into further (inactive) metabolites. Sup- on 28 September 2021 by guest. Protected copyright. while many cases benefit from local cordicosteroid therapy. port for this view comes from the recent observation that Ointments containing local anaesthetic preparations should the serum concentration of 25-HCC is lower in drug-treated not generally be used for long. epileptic patients than in controls and, further, serum con- For the permanent relief of the more chronic and intract- centrations of 25-HCC correlate well with those of serum alble cases two other types of procedure, aimed at denerva- calcium.5 While these findings suggest that hypocalcaemia tion of the affected area, have been proposed and occasion- results from a drug-induced inactivation of 25-HCC, the ally practised. In one, not likely to be resorted to until simp- effect of anticonvulsant drugs on other aspects of the kin- ler measures have failed, operative skin incisions are planned etics of vitamin D, such as its absorption, protein binding, to undercut and divide sensory nerves. J. H. Mering2 has and elimination, must not be discounted. used such a procedure to good purpose in selected cases. The fate of 25-HCC lies not only in the liver; it has Alternatively a similar effect may be obtained more simply now been clearly shown that it is further hydroxylated in by multiple local injections of absolute alcohol. Unfortunately the kidney to form 1, 25-dihydroxycholecalciferol (1, such injections can result all too readily in focal areas of 25-DHCC).6 There is now considerable evidence that 1, slough, but J. D. Woodruff and B. Thompson3 have shown 25-DHCC is the physiological mediator of active calcium that, with proper attention to technique and selection of cases, transport from the gut and also of mobilization of calcium worthwhile results can be obtained. from bone. The formation of 1, 25-DHCC may be under the control of the parathyroid gland. Its production is regulated either by the levels of calcium in the serum or by 1 Jeffcoate, T. N. A., and Woodcock, A. S., British Medical_Journal, 1961, some factor responsive to them. As the level of calcium in 2, 127. is This in 'Menng, J. H., American Journal of Obstetrics and Gynecology, 1952, the serum falls, more 1, 25-DHCC produced. 64, 619. turn makes more calcium available from intestine and bone. ' Woodruff, J. D., and Thompson, B., Obstetrics and Gynecology, 1972, 40, 18. Since parathyroid hormone also responds to the concen-