forty-nine patients, arranged in ascending order of histamine values which

Transcription

1 286 J. Physiol. (I954) i26, HISTAMINE CONTENT OF HUMAN SKIN IN DIFFERENT CLINICAL DISORDERS BY W. FELDBERG AND A. A. LOESER* From the National Institute for Medical Research, Mill Hill, London, N. W. 7 (Received 1 May 1954) Little is known about the part histamine plays in different non-allergic disorders, although there are some observations on animals suggesting a correlation between tissue histamine and thyroid activity (Goltz & Dragstedt, 1940; Hoffmann & Hoffmann, 1944). Further, one of us observed that in hyperthyroid women there is a lower incidence of malignant growth of the breast than among the average female population, and discussed the possibility of a relationship between tendency to malignant growth and histamine content of the tissues (Loeser, 1953, 1954a, b). So far Harris (1927) seems to be the only author who has made a more detailed determination of the histamine equivalent of extracts prepared from human skin by assaying their depressor action on the cat's arterial blood pressure against histamine. The histamine equivalent of skin samples taken from nine breasts was found to be between 5-7 and 7-6, and from three thighs between 8 and 8'8 pug/g. The number of his cases was rather small and in our greater number of patients more individual variation in the histamine equivalent of skin was found than was to be expected from his results. METHODS The skin was removed during operations or excised under local anaesthesia and transported, straight after removal, from the operating theatre to the laboratory, where it was freed from loose subcutaneous tissue and fat, weighed, and minced in a mortar with a little sand and acidified (HCI) 0-9 % NaCl solution. The samples weighed between 30 and 300 mg. The minced extracts were boiled for a minute, filtered, neutralized with NaOH, and assayed against histamine on the atropinized guinea-pig's ileum preparation. All histamine values refer to the base. The time between removal of the skin and extraction was usually less than 1 hr. Sometimes the skin of the same patient was re-examined after special treatment. RESULTS Table 1 summarizes the results obtained, in the course of 40 months, from forty-nine patients, arranged in ascending order of histamine values which vary between 1V8 and 26-7,ug/g (mean 8-8,g/g). All skin samples except two were from women. * Consultant gynaecologist to St Saviours Hospital, London, N.W. 1.

2 HISTAMINE IN HUMAN SKIN 287 TABLE 1. Histamine equivalents of human skin in Ztg/g tissue from abdomen (A), breast (B) and neck (N). All values except those of Nos. 12 and 45 from women. No. Age 3ite Histamine (pg/g) Case history 1 42 A 1.8 Advanced mammary carcinoma; metastases in pelvis; deep X-ray treatment of pelvis 2 30 A 2-5 Acute hypothyroidism 3 32 A 3-6 Hypothyroidism; infantilism of genitals 4 29 A 3-6 Hypothyroidism; inflammatory ovarian cyst 5 40 A 4-0 Obesity; inflammatory ovarian cyst 6 41 A 4-0 Beginning menopause; obesity; hypothyroidism 7 38 A 4-2 End of pregnancy 8 21 A 4-3 Infantilism; appendicitis 9 34 A 4-7 Hypothyroidism; obesity; fibroids of uterus A 5-0 End of pregnancy B 5-2 Hypothyroidism; advanced mammary carcinoma with metastases A 5-3 Advanced pancreas carcinoma B 6-0 Early mammary carcinoma B 6-0 Advanced mammary carcinoma with skin metastases; thyrotoxicosis treated with sodium thiouracil A 6-1 Inflammatory ovarian cyst A 6-2 Fibroids of uterus A 6-3 Menopause A 6-5 Inoperable cancer of ovary A 6-6 Allergic rhinitis A 7-0 Shrinking fibroids of uterus A 7-3 End of twin pregnancy A 7-5 Advanced cancer of ovary; liver metastases A 7-7 Early mammary carcinoma; ovarian cyst; thyroidectomy 2 years previously A 7-7 Menopause A 8-0 End of pregnancy A 8-1 Obesity; fibroids of uterus A 8-4 Fibroids of uterus; hypothyroidism treated for 20 years, but not during the last 4 weeks, with dry thyroid B 8-5 Benign cysts of breast A 8-8 Ovarian cyst A 8-8 Fibroids of uterus A 9-2 Advanced cancer of uterus; obesity A 9-5 Fibroids of uterus A 10-0 Menopause A 10-5 End of pregnancy; hyperthyroidism A 10-6 Inoperable cancer of the ovary treated with dry thyroid A 10-8 Menopause; allergic patient B 11-0 Advanced mammary carcinomawith liver metastases; treated with dry thyroid A 11-3 Menopause N 11-5 Thyrotoxicosis B 11-0; 13-0 Advanced mammary carcinoma; treated with large doses of dry thyroid N 12-7 Thyrotoxicosis B 13-6 Hyperthyroidism; precancerous hyperkeratosis A 13-8 Menopause; treated with dry thyroid A 13-9 Fibroids of uterus; hyperthyroidism after partial thyroidectomy N 15-0 Thyrotoxicosis N 15-0 Thyrotoxicosis A 17-4 Hyperthyroidism; ovarian cyst N 17-6 Thyrotoxicosis A 26-7 Allergic eczema and migraine; treated with injections of own blood 19 PHYSIO. CXXVI

3 288 W. FELDBERG AND A. A. LOESER Skin region. Thirty-seven samples were obtained from the abdomen, seven from the breast and five from the neck. The histamine values of the abdominal skin varied from between 1-8 and 26-7 (mean 8-0 jug/g) or, if the abnormally high single value of sample no. 49 is not included, between 1j8 and 17-4 (mean 7-5,ug/g). This mean value is a little lower than the mean value for the histamine content of skin from the breasts. The values from the seven breast skin samples varied between 5-2 and 13-6, and the mean value was 9-0,g/g. From these figures we cannot conclude with certainty that the histamine content of the skin of the breasts is higher than that of the abdomen, because only seven estimations were made, and those were from persons with different diseases and treatment and the individual variations were great. It would be necessary, in order to obtain a decisive answ A' either greatly to increase the number of extractions or, even better, to determine the histamine content of skin from both regions in the same patient. The skin from the neck certainly yielded higher histamine values on the average than that from the abdomen or breasts. The skin samples from the neck were obtained in all cases from patients operated on for thyrotoxicosis. Since increased thyroid activity apparently increases the histamine content of skin, as will be shown later (see p. 289), it is not possible to be certain whether these high values are solely the result of the endocrine disturbance or reflect a normal, high histamine content of the skin of the neck as well. This possibility cannot be excluded, because regional variations in skin histamine have been found in various animal species (Feldberg & Miles, 1952; Smith, 1953). Age. It is difficult to draw conclusions from our results about the effect of age on the histamine content of skin, because some age groups are not represented and others by only a few samples. No children are included, the youngest patient being 21 years old. Taking into consideration the forty-fouar samples from the abdomen and the breasts and omitting those from the neck, only six were from patients between 20 and 30 and only two from patients over 60 years. The mean values for these two age groups were 5-2 and 7-9 ug/g respectively. The mean value of the thirty-six samples from patients between 31 and 60 years was 8-7 ug/g. Pregnancy. Table 1 includes the histamine content of abdominal skin obtained during Caesarian operations at the end of five pregnancies. One skin (no. 34) was from a hyperthyroid patient; the mean histamine value from the other four samples was 6-1,g/g, which is below the mean histamine content. However, one sample was from a patient aged 30 and the mean value of skin samples of this age group is lower. From the few results obtained, it is only possible to say that pregnancy certainly does not cause a profound change in the histamine content of skin; there is either no effect, or pregnancy is associated with a somewhat subnormal value.

4 HISTAMINE IN HUMAN SKIN 289 Disorders of the thyroid. Our results suggest a correlation between thyroid function and histamine content of the skin. Of the nine cases in Table 1 with a histamine content under 5,tg/g, five were from patients with hypothyroidism. On the other hand, of the sixteen cases with values over 100,ug/g, nine were from patients with hyperthyroidism or thyrotoxicosis, and another four from patients treated either with large doses of thyroid hormone for a few weeks or TABLE 2. Histamine content of skin from twenty-two p. 'ients with disorders of the thyroid or thyroid treatment No. of Histamine case Age Site (,ug/g) Thyroid disorder or thyroid treatment 2 30 A 2-5 Acute hypothyroidism 3 32 A 3-6 Hypothyroidism 4 29 A 3-6 Hypothyroidism 6 41 A 4-0 Hypothyroidism 9 34 A 4-7 Hypothyroidism B 5-2 Hypothyroidism B 6-0 Thyrotoxicosis treated with thiouracil A 7*7 Thyroidectomy 2 years previously A 8-4 Hypothyroidism treated for 20 years with dry thyroid but not for last 4 weeks A 10.5 Hyperthyroidism A 10-6 Treated with dry thyroid B 11-0 Treated with dry thyroid for mammary cancer N 11-5 Thyrotoxicosis B Treated with massive doses of dry thyroid for mammary 13-0 cancer N 12-7 Thyrotoxicosis B 13-6 Hyperthyroidism A 13-8 Treated with dry thyroid A 13-9 Hyperthyroidism after partial thyroidectomy N 15-0 Thyrotoxicosis N 15-0 Thyrotoxicosis A 17-4 Hyperthyroidism N 17.6 Thyrotoxicosis with small doses over years. It is true that five of the high histamine values were obtained in skin samples from the necks of thyrotoxic patients, but even if these are excluded there remains a striking incidence of high histamine values with hyperthyroidism and thyroid treatment, namely eight out of eleven cases. In Table 2 are listed all skin samples (22) from the patients of Table 1 who had thyroid disturbances or treatment with thyroid in their case histories. Further evidence that thyroid activity increases the histamine content of skin was obtained in those few cases in whom it was possible to examine a second skin sample 3-5 weeks after oral administration of a total of between 3 and 14 g of dried thyroid gland. The results of six such cases are given in Table 3. In two there was no change, or practically none, in the histamine content of the skin, but in four the histamine content was increased between 38 and 133 %. The mean increase of all six cases was 60 %. No. 27 was a hypothyroid patient treated for 20 years with thyroid but not during the month 19-2

5 290 W. FELDBERG AND A. A. LOESER preceding the first removal of the skin. The second sample was obtained after thyroid treatment had again been going on for over 4 weeks. Tumours. There is no indication that benign tumours such as uterine fibroids are associated with changes in skin histamine. Table 1 contains eight cases with fibroids of the uterus. One (no. 44) was a hyperthyroid patient with a histamine equivalent of 13*9,ug/g skin; in the other seven cases (nos. 9, 16, 20, 26, 27, 30 and 32) the histamine values of skin varied between 4-7 and 9-5,ug/g (mean 7-5,ug/g). TABLE 3. Effect of oral administration of large doses of dried thyroid on histamine content of skin Histamine in,tg/g No. of Before thyroid After thyroid Increase case administration administration (%) * There is some suggestion that malignant growth is associated with a subnormal histamine content of skin. Table 1 contains thirteen cases of malignant tumours, three of which were from patients treated with large doses of thyroid gland; one was a hyperthyroid woman. In these the histamine content of the skin was over 10,ug/g (nos. 35, 37, 40 and 42). In the nine other cases (nos. 1, 11, 12, 13, 14, 18, 22, 23 and 31) the histamine content of the skin varied between 1-8 and 9-2 jug/g (mean 6-1,ug/g). Deep X-ray treatment seems greatly and permanently to reduce the histamine content of the exposed skin. The lowest histamine value (case no. 1) was from a skin region previously exposed to deep X-ray treatment. Further, from the hyperthyroid patient no. 42 with a histamine value of 13-6,g/g, a second sample of skin was excised at the time from a region exposed several years ago to radium treatment. This sample yielded a histamine equivalent of 2-5,ug/g. DISCUSSION Our results show that the histamine content of human skin shows wide individual variations which make it difficult to detect small changes if, as in the present experiments, the number of skin samples available for comparison is not great. Nevertheless, certain conclusions can be drawn. The histamine content of the skin at the end of pregnancy is either normal or somewhat subnormal. At this time the histaminase content of the blood, however, is greatly increased (Marcou, Athanasiu-Vergu, Chiriceanu, Cosma, Gingold & Parhon, 1938; Werle & Effkemann, 1940; Zeller & Birkhaiuser, 1940; Ahlmark, 1944; Swanberg, 1950). As far as our results show, there is no change in the

6 HISTAMINE IN HUMAN SKIN 291 skin histamine content of patients with benign tumours, but there are some indications that patients with malignant growth, if they are not hyperthyroid or treated with large doses of thyroid, have a somewhat lower histamine content in their skin than normal people. However, more cases must be examined to be certain about this finding. If it should prove to be true that malignant growth is generally associated with a subnormal histamine content of skin, the question would be whether this is an effect of the malignancy, especially as the low histamine content was found mostly in mor'- advanced cancer cases, or whether low skin histamine favours the occurrence of malignant growth. The finding that thyroid activity apparently increases the histamine content of the human skin is in agreement with observations obtained in animals. Goltz & Dragstedt (1940) found that, in rats, the normal mean histamine content of skin (region not stated) was 11-5, and increased to 21-2,ug/g in hyperthyroidism produced by subcutaneous injections of thyroid hormone and decreased to 6-4,ug/g after thyroidectomy. There was some indication of similar changes in the histamine content of liver and lung, but the great individual variations in histamine content of these tissues made it impossible to make certain conclusions. Hoffmann & Hoffmann (1944) also found that, in rats in which hyperthyroidism was produced, the histamine content of the stomach wall and skeletal muscle was increased. It thus appears that the histamine content of at least some tissues is influenced by the thyroid and increases with hyper- and decreases with hypo-activity of the thyroid. Recently it has been shown that there is a positive correlation between mast cell population of a tissue and its histamine content (Riley & West, 1953; Graham, Lowry, Wahl & Priebat, 1953; Riley, 1954), although not all histamine is assumed to reside in these cells. We do not know to what extent the changes produced by the thyroid hormone reflect changes in the mast cell population of the tissues examined. SUMMARY 1. The histamine content of human skin samples from forty-nine patients was examined. The skin was taken from the abdomen (thirty-seven samples), breast (seven samples), and neck (five samples). The histamine equivalent varied between 1-8 and 26-7,ug/g (mean 8x8 vg/g). 2. The histamine content of the skin at the end of pregnancy is either normal or somewhat reduced. 3. Hyperthyroidism and administration of thyroid hormone seem to increase, hypothyroidism to decrease the histamine content of the skin. 4. Benign growth (fibroids) does not influence the histamine content of skin, but there is an indication that advanced malignant growth of the breast is often associated with a subnormal histamine content of skin.

7 292 W. FELDBERG AND A. A. LOESER 5. Deep X-ray or radium treatment seems greatly and permanently to reduce the histamine content of the exposed skin. We should like to make grateful acknowledgement to Mr J. Piercey, Thyroid Unit, New End Hospital, Hampstead, for providing us with skin samples from patients with thyroid disorders. REFERENCES AHLMARK, A. (1944). Studies on the histaminolytic power of plasma, with special reference to pregnancy. Acta phy8iol. 8cand. 9, Suppl. 28. FELDBERG, W. & MILES, A. A. (1952). Regional variations of increased permeability of skin capillaries induced by a histamine liberator and their relation to the histamine content of the skin. J. Phy8iol. 120, GOLTz, F. R. & DRAGSTEDT, C. A. (1940). Effect of thyroidectomy and experimental hyperthyroidism upon histamine content of rat tissues. Proc. Soc. exp. Biol., N. Y., 45, GRAHAM, T., LowRY, 0. H., WARTL, N. & PRIEBAT, M. K. (1953). Localization of tissue histamine in mast cells. Abstr. XIX int. physiol. Congr. p HAIais, K. E. (1927). Observations upon a histamine-like substance in skin extracts. Heart, 14, HOFFMANN, F. & HOFFMANN, E. J. (1944). Nuevos conceptos fisiopatologicos de la hipertireosis. Publ. In8t. Fi8iol. Chile. LOESER, A. A. (1953). Endocrines in the treatment of cancer. Brit. med. J. 1, LOESER, A. A. (1954a). A new therapy for the prevention of postoperative recurrences in genital and breast cancer. (A six year study of prophylactic thyriod treatment). In La Prophylaxie in Gynaecology. Int. Congr. Gynaecol., Geneva, p LOESER, A. A. (1954b). Cancer and hormones. Tran8. med. Soc. Lond. (in the Press). MxRcou, I., ATHANASIU-VERGU, E., CHIRICEANU, D., COSMA, G., GINGOLD, N. & PARHON, C. C. (1938). Sur la r6le physiologique de l'histamine. Pr. med. 46, RILEY, J. F. (1954). The riddle of the mast cells. A tribute to Paul Ehrlich. Lancet, 266, RILEY, J. F. & WEST, G. B. (1953). The presence of histamine in tissue mast cells. J. Phy8iol. 120, SMITH, A. N. (1953). Release of histamine by the histamine liberator compound 48/80 in cats. J. Phy8iol. 121, SWANBERG, H. (1950). Histaminase in pregnancy, with special reference to its origin and formation. Acta physiol. 8cand. 23, Suppl. 79. WERLE, E. & EFFKEMANN, G. (1940). tber die histaminzerstorende Fihigkeit des Schwangerenblutes. Arch. Gynaek. 170, ZELLER, E. A. & BIRKHXUSER, H. (1940). Vber eine in vitro-schwangerschaftsreaction. Schweiz. med. W8chr. 70,