- Email: [email protected]
ORAL ZINC SULPHATE IN LEG ULCERS
1069
of 25 ng. per ml. It is interesting that the paradoxical secretion of growth hormone, which happened in ten of the control children at the peak of their hyperglycxmia (1/2 hour after glucose), which we ascribe to a stress response, was not seen in any of the obese children. The failure of the growth-hormone response in the obese children was striking (fig. 2). Only one fasting observation exceeded the sensitivity level of the assay of 1 ng. per ml. In the control children thirteen of the twenty-four had measurable fasting values with a mean of 5-3 ng. per ml. Only two of the sixteen obese children showed responses comparable to the controls with maximum growth-hormone levels rising to 13 and 25 ng. per ml. Two showed a low-normal response with levels of 7 and 8 ng. per ml. In the remaining twelve the responses were clearly subnormal. Eight of these children had undetectable levels of growth hormone throughout the a mean
test.
Discussion Our results suggest that most obese children do not produce growth hormone in response to oral glucose. In obese adults, reports on the response to insulininduced hypoglycaemia have been conflicting. Roth et al. (1963) reported that obese adults, in contrast to the non-obese, showed little or no rise in growthhormone secretion after prolonged fasting or after physical exercise; and these workers also noted subnormal growth-hormone responses during the prolonged glucosetolerance test, but normal responses after intravenous insulin. Beck et al. (1964), however, found that growthhormone response to insulin-induced hypoglycxmia was often impaired in obese adults, as did Pearson et al. (1964). The diminished responsiveness of obese children to oral glucose is difficult to explain. The stimulus to growth-hormone secretion after an oral glucose load is thought to be the fall in glucose level in the postabsorptive phase. The response failure cannot, however, be related to the reduced glucose tolerance seen in some of the children. Though blood-glucose levels did not return to fasting levels until 1 hour after the control children, the rate of fall of blood-glucose and the levels 4 hours after glucose were similar in both groups. In fact the mean blood-glucose level of the obese children fell through a greater range than that of the control group. Even where the glucose tolerance was completely normal, there was no growth-hormone response. The response to the normal energy-feedback mechanism controlled by glucose concentration is impaired in the obese individual. The absence of growth hormone peaks 30 minutes after glucose in our obese children suggests that their response to stress is also reduced, and this is supported by a report of subnormal growth-hormone responses to insulin-induced
hypoglycsemia (Croughs Abnormality of the energy-feedback
et al. 1968). mechanism and reduced response to stress does not necessarily imply failure of the nycthemeral secretion phases described in normal children by Hunter and Rigal (1966). The demonstration of reduced diurnal secretion in experimental obesity in adults by Sims and Horton (1968) suggests, however, that this form of secretion may also be reduced in the overweight child. Obese children secrete less growth hormone than do children of normal weight, but their growth velocity, far from being impaired, is often accelerated. How then is growth maintained in the presence of plasma-levels of growth hormone which usually signify growth-hormone
deficiency ? Paulsen et al. (1968) have reported increased secretion of insulin in the obese child, both in the fasting state and in response to oral glucose, and we have confirmed this in our obese children. Both insulin and growth hormone have anabolic activity, and both are responsible for transfer of aminoacids into the cell. If the anabolic activity of the two hormones is synergistic then the high insulin secretion in the obese child may be sufficient to promote normal growth despite low growthhormone secretion. Stimmler et al. (1967) and Hunter et al. (1967) advocated the prolonged glucose-tolerance test as a satisfactory method of assessing growth-hormone secretion in children. In the short-stature obese child failure to respond may be the result of obesity rather than growthhormone deficiency, and some other method-e.g., the nitrogen-retention test (Brown et al. 1967)-may have to be used. We thank Prof. D. V. Hubble, Prof. C. M. Anderson, and the consultants of the Birmingham Children’s Hospital for permission to investigate their patients; Sister Hilda Jukes, Miss Bernice Morris, and Mr. Geoffrey Holder for laboratory assistance; Miss Lynette Fisher-Jones for typing this manuscript; and the Children’s Hospital department of medical illustration. Requests for reprints should be addressed to C.G.T. REFERENCES
Beck, P., Koumans, J. H., Winterling, C. A., Stein, F., Daughaday, W. H., Kipnis, D. M. (1964) J. Lab. clin. Med. 64, 654. Brown, G. A., Stimmler, L., Lines, J. G. (1967) Archs Dis. Childh. 42, 239. Croughs, W., Schopman, W., Tiddens, H. A. (1968) Helv. pœdiat. Acta, 23, 464. Discombe, G. (1963) J. clin. Path. 16, 170. Hartog, M., Gaafar, M. A., Meisser, B., Fraser, R. (1964) Br. med. J. ii, 1229. Hunter, W. M., Rigal, W. M. (1966) J. Endocr. 34, 147. Wolfsdorf, J., Farquhar, J., Rigal, W. M. (1967) Lancet, ii, 1271. Jackson, D., Grant, D. B., Clayton, B. E. (1968) ibid. ii, 373. Lancet (1969) i, 85. Parker, M. L., Hammond, J. M., Daughaday, W. H. (1967) J. clin. Endocr. Metab. 27, 1129. Paulsen, E., Richenderfer, L., Ginsberg-Fellner, F. (1968) Diabetes, 17, 261. Pearson, O. H., Stratman, S. M., Spector, S., Yen, S. (1964) Proceedings of the 46th Meeting of the Endocrine Society (San Francisco, 1964); p. 65 (abstract 85). Roth, J., Glick, S. M., Yalow, R. S., Berson, S. A. (1963) Metabolism, 12, —
577.
(1964) Diabetes, 13, 355. Sims, E. A., Horton, E. S. (1968) Am. J. clin. Stimmler, L., McArthur, R. G., Brown, G. —
—
—
—
Nutr. 21, 1455. A. (1967) Can. med. Ass.
J. 97, 1159. Archs Dis. Childh. Tanner, J. M., Whitehouse, R. H., Takaishi, M. (1966) 41, 454, 613.
ORAL ZINC SULPHATE IN LEG ULCERS
S. LATAFAT HUSAIN* FROM
THE
HOSPITAL,
DEPARTMENT OF DERMATOLOGY, SOUTHERN GENERAL AND THE UNIVERSITY DEPARTMENT OF DERMATOLOGY, WESTERN INFIRMARY, GLASGOW
A hundred and four inpatients of various ages with ulcers of the lower limb were included in a controlled trial of oral zinc sulphate. Identical capsules containing 220 mg. of lactose (placebo) or zinc sulphate were given three times a day to equal numbers of controls and treated patients. Ulcers healed more quickly in the treatment group. The ulcers of the treatment group healed in 32 on average, as against 77 days for the control group. There was no significant dependence on age or sex. Mild diarrhœa in three patients was the only toxic effect of zinc-sulphate therapy. Oral zinc sulphate would seem to have a place in the treatment of chronic leg ulcers which do
Sum ary
not
respond
to
topical
treatment.
Prolonged
*Present address: Department of Dermatology, C.4.
or
repeated
Royal Infirmary, Glasgow
1070
should, however, be avoided since not enough is known about the side-effects of systemic zinc salts. courses
Introduction
THERAPEUTIC agents recommended for topical use in the treatment of chronic leg ulcers are legion, and this itself suggests that none is entirely satisfactory. Many workers (Wright 1931, Bisgaard 1948, Anning 1954, Fergusson and Logan 1961) agree that bed rest and attention to the underlying vascular lesion are essential in the management of such cases; Most leg ulcers take around 11 weeks to heal completely, irrespective of treatment (Fergusson and Logan 1961, Cockrane 1961, Lorch 1961, Haegar 1964, Munro-Ashman and Wells 1968). Pories et al. (1967a, b) found that oral zinc sulphate accelerated wound healing after the excision of pilonidal sinuses, and this stimulated interest in the application of this therapy to leg ulcers of various types. The results of a pilot investigation in sixteen cases of chronic ulcers of the lower limb treated with systemic zinc sulphate seemed to warrant a controlled trial. Patients and Methods and One hundred four patients, of various ages, with ulcers of the lower limb were admitted to the dermatological wards. Each patient received the same form of topical therapy depending on the severity of the ulcer (i.e., 12-5-25% aqueous solution of sodium sulphate, oily lotion of calamine, or eusol dressings) during their stay in the hospital. Although it was impossible to standardise bed rest for each patient, every effort was made to TABLE
I-DISTRIBUTION OF PATIENTS ACCORDING TO AGE AND SEX
ensure that maximum bed rest was achieved. Every effort was made to ensure that ulcers of similar sizes and appearance fell in approximately equal numbers in the treated and control groups. Capsules containing 220 mg. lactose (placebo) or 220 mg. zinc sulphate B.P. were prepared by the pharmacy departments. These had been labelled A or B, but I did not know which was which. Equal numbers of patients were allocated to treatment or control groups (table i). The average age of the control group was 62-05 years; the average age of the treatment group was 60-34 years. The dosage was one capsule three times daily, half an hour after meals. Two methods were used in the weekly assessment of the ulcers. In the early stages, when the ulcers had some depth, their volume was measured by the amount of hydrocolloid gel (’ Tissutex ’) required to fill them (Pories et al. 1967a, b). As the ulcers began to heal and became shallower, and also in the large superficial ulcers, this method was unsatisfactory, so a second method was used. The ulcer outline was traced on to transparent paper, and the tracing was transferred to graph paper. The areas was then measured in sq. mm. by counting the small squares (Fergusson and Logan 1961). The ulcer was considered to be healed when there was no scab formation. Samples of venous blood were taken for the estimation of serum-zinc before treatment, after 2 weeks during the treatment, and a week after the ulcer had healed. Unfortunately, the trial ceased to be double-blind after 16 patients had been treated; it became clear that capsule B contained zinc sulphate because
Time to complete healing in relation
to age.
the patients who were receiving it showed a striking rise in serum-zinc at the second estimation during treatment. Serumzinc levels were estimated during treatment to ensure that the patients were taking the capsules regularly.
Results
The ulcers of the treated group healed more quickly than those of the control group. This clinically significant increase in wound healing produced by zinc sulphate was substantiated by the statistical analysis. The ulcers of the treated group healed in 32-3 (±1-662) days (mean) and those of the control group took days±s.E. 77.19 (±4-321) days. This was extremely significant on Mann-Whitney V test (P < 0 -001). The ulcers of patients who were on zinc sulphate healed 44-89 days sooner than the patients in the control group. The ranges for the total number of days required for healing were 12-71 days for the treatment group and 35-232 days for the controls. Out of 104 patients (52 patients in control group) with ulcers only 3 took more than 150 days to heal completely. Time to complete healing was independent of age (see figure), and there was no significant difference between the rate of healing of males and females for either preparation (controls, t=0055, D.F.=50; treated, t=0-998, D.F.=
days s.E.
50) (table 11). serum-zinc estimation in the
pilot-study g./ml.±s.E. 1.015 (±0-0406) g. per ml. at the first estimation, .g./ml.S.E. 1.886 (±0-2405) g. per ml. during treatment, and (Lg./ml. 1-282 (±0-1149) g. The
mean
cases was
per ml. after treatment. The average surface area of the ulcers was 4290 sq. mm. in the control group and 4830 sq. mm. in the treatment group, and the healing-rates were 90 sq. mm. per day and 421-& sq. mm. per day, respectively. TABLE II-AVERAGE NUMBER OF DAYS REQUIRED FOR COMPLETE HEALING IN MALES AND FEMALES
1071 Discussion
"Leg ulcers present a difficult therapeutic problem and both patients and doctors tend to accept the presence of an ulcerated leg with a grim stoicism born of years of unsuccessful treatment" (Rivlin 1958). If this attitude prevails, the chronically disabled patient may not seek treatment again unless given the stimulus of new hope. Topical antibiotics and other preparations have been used in the treatment of leg ulcers, as have eusol soaks (Fergusson and Logan 1961), silver spray plus aluminium foils (Haeger 1965), and firm pressure bandages or soft medicated bandages. Diuretics to reduce the oederna were advocated by Fox (1962) and grafting and " disobliteration " was recommended by Irvine et al. (1965) for arterial ulcers. However, it is difficult
to assess the effects of these many forms of treatment on the healing-rate of leg ulcers due to their multifactorial xtiology and the difference in size and depth of these ulcers. Zinc is an essential element in nutrition and is a constituent of most foods. Zinc salts are sometimes given by mouth for their properties as reflex emetics but they are mainly used topically as mild astringent and disinfectants (Extra Pharmacopaeia 1967), and several topical preparations containing zinc salts are used for the treatment of leg ulcers. Radioisotope studies have shown that zinc-65 becomes incorporated into the red blood-cells, where it is closely associated with metalloenzymes (Tucker and Salmon 1955, Vallee 1959, Underwood 1962). Zinc is preferentially concentrated in healing tissue (Savlov et al. 1962) probably due to a shift of zinc from plasma into the formed elements of blood (Ross et al. 1958, Graig and Siegel 1960, Rubini et al. 1961, Spencer et al. 1966). Although the clinical appearance of the ulcers varied from patient to patient initially, it was quite clear that, after 2-3 weeks’ treatment with local therapy combined with zinc sulphate systemically, the ulcers were cleaner and showed healthy granulation tissue. There was also a striking reduction in the purulent exudate. On the other hand, the control group showed only slight improvement, granulation tissue was not quite so evident, and a purulent exudate was invariably present. During the ensuing weeks, up to the time of complete healing, the zinc-sulphate group seemed clinically to show more rapid epithelialisation than the control group. This trial was done on inpatients because not enough is known about the side-effects of zinc salts given by mouth. This point was carefully explained to all the patients before the trial started. However, apart from three patients who had mild diarrhoea, which quickly cleared up on discontinuing the treatment, I saw no clinical evidence of drug toxicity. Nevertheless the period of treatment in some patients was short, and a cumulative toxic effect in patients on prolonged or repeated courses of zinc sulphate cannot be excluded. Although bed rest combined with topical therapy will, in most cases, result in healing of chronic leg ulcers (Fergusson and Logan 1961), I believe that systemic therapy with zinc sulphate has a place in the management of these patients. In this trial, bed rest and topical therapy were used, in addition to oral zinc, so it is difficult to predict the effect of zinc sulphate on ambulant patients, but at least treatment with zinc sulphate can be considered a useful adjuvant .therapy in the management of chronic leg ulcers. Until more information is available, however, prolonged therapy and repeated courses for recurrent ulceration should be avoided.
I thank Prof. J. A. Milne and Dr. W. B. McKenna for encourageand advice, Dr. R. L. Cormie and Dr. W. N. Morley for allowing me to include their cases, Dr. W. H. Lyle, Dista Laboratories, Liverpool, for the estimation of serum-zinc, Mr. R. A. Elton for statistical analysis, and my colleagues and the nursing staff for their ment
cooperation. REFERENCES
Anning, S. T. (1954) Leg Ulcers. London. Bisgaard, H. (1948) Ulcers and Eczema of Legs. Copenhagen. Cockrane, G. M. (1961) Practitioner, 187, 787. Extra Pharmacopœia (1967) London. Fergusson, A. G., Logan, J. C. P. (1961) Br. med. J. i, 871. Fox, D. D. (1962) ibid. ii, 1370. Graig, F. A., Siegel, E. (1960) Pro. Soc. exp. Biol. Med. 104, 391. Haeger, K. (1964) Acta chir. scand. 128, 140. — (1965) ibid. 130, 592. Irvine, W. T., Williams, E. J., Plessas, S. N. (1965) Br. med. J. i, 1147. Lorch, D. M. (1961) Practitioner, 187, 67. Munro-Ashman, E. J. E., Wells, R. S. (1968) Br. J. clin. Pract. 22, 129. Pories, W. J., Henzel, J. H., Rob, C. G., Strain, W. H. (1967a) Lancet, i, 121. (1967b) Ann. Surg. 165, 432. Rivlin, S. (1958) Lancet, i, 1363. Ross, J. F., Ebaugh, F. G. Jr., Talbot, T. R. Jr. (1958) Tr. Ass. Am. Physns. 71, 322. Rubini, M. E., Montalvo, G., Lockhart, C. P., Johnson, C. R. (1961) Am. J. Physiol. 200, 1345. Savlov, E. D., Strain, W. H., Huegin, F. (1962) J. surg. Res. 2, 209. Spencer, H. Rosoff, B., Lewin, I. (1966) Zinc Metabolism (edited by A. S. Prasad). Springfield, Illinois. Tucker, H. F., Salmon, W. D. (1955) Proc. Soc. exp. Biol. Med. 88, 613. Underwood, E. J. (1962) Trace Elements in Human and Animal Nutrition. —
—
—
—
New York.
Vallee, B. L. (1959) Physiol. Rev. 39, Wright, A. D. (1931) Lancet, i, 457.
443.
PREDICTION OF MALIGNANCY IN SOLITARY THYROID NODULES LEIGH W. KENDALL
ROBERT E. CONDON
SURGERY, UNIVERSITY OF ILLINOIS MEDICINE, CHICAGO, ILLINOIS
FROM THE DEPARTMENT OF COLLEGE OF
reliability of radioiodine scanning and physical characteristics of the nodule as indicators of malignancy in patients with clinically solitary thyroid nodules, a survey was made of five years’ experience of patients operated on for thyroid disease at a university teaching hospital in the Mid-West goitre belt. The incidence of malignancy in the 91 patients with solitary nodules was 20·9%. Of these 91, hypofunction (" cool" or cold ") was diagnosed on radioiodine scanning in 83% of benign nodules and 75% of malignant nodules. This test was of no value in differential diagnosis. Similarly, the physical characteristics of the nodule and other findings on physical examination did not reliably differentiate between benign and malignant solitary nodules. It is advised that solitary thyroid nodules Sum ary
To evaluate the
"
should be excised. Introduction EVALUATION of patients who have solitary nodules of the thyroid gland continues to be a clinical problem. Although the great majority of such nodules are benign, a significant minority harbour a carcinoma. Preoperative identification of nodules which are likely to contain cancer is important, since the advice given to the patient and the operative approach may be modified if the surgeon strongly " suspects that cancer is present. The finding of a cool " " or cold " nodule on radioiodine scanning of the thyroid gland is said to be associated with an increased incidence of thyroid cancer (Cope et al. 1949, Dobyns et al. 1949, Rawson et al. 1949, Perlmutter et al. 1954, Johnson and Bierwaltes 1955, Perlmutter and Slater 1956, Groesbeck 1959, Meadows 1962). Similarly, certain symptoms and
of 25 ng. per ml. It is interesting that the paradoxical secretion of growth hormone, which happened in ten of the control children at the peak of their hyperglycxmia (1/2 hour after glucose), which we ascribe to a stress response, was not seen in any of the obese children. The failure of the growth-hormone response in the obese children was striking (fig. 2). Only one fasting observation exceeded the sensitivity level of the assay of 1 ng. per ml. In the control children thirteen of the twenty-four had measurable fasting values with a mean of 5-3 ng. per ml. Only two of the sixteen obese children showed responses comparable to the controls with maximum growth-hormone levels rising to 13 and 25 ng. per ml. Two showed a low-normal response with levels of 7 and 8 ng. per ml. In the remaining twelve the responses were clearly subnormal. Eight of these children had undetectable levels of growth hormone throughout the a mean
test.
Discussion Our results suggest that most obese children do not produce growth hormone in response to oral glucose. In obese adults, reports on the response to insulininduced hypoglycaemia have been conflicting. Roth et al. (1963) reported that obese adults, in contrast to the non-obese, showed little or no rise in growthhormone secretion after prolonged fasting or after physical exercise; and these workers also noted subnormal growth-hormone responses during the prolonged glucosetolerance test, but normal responses after intravenous insulin. Beck et al. (1964), however, found that growthhormone response to insulin-induced hypoglycxmia was often impaired in obese adults, as did Pearson et al. (1964). The diminished responsiveness of obese children to oral glucose is difficult to explain. The stimulus to growth-hormone secretion after an oral glucose load is thought to be the fall in glucose level in the postabsorptive phase. The response failure cannot, however, be related to the reduced glucose tolerance seen in some of the children. Though blood-glucose levels did not return to fasting levels until 1 hour after the control children, the rate of fall of blood-glucose and the levels 4 hours after glucose were similar in both groups. In fact the mean blood-glucose level of the obese children fell through a greater range than that of the control group. Even where the glucose tolerance was completely normal, there was no growth-hormone response. The response to the normal energy-feedback mechanism controlled by glucose concentration is impaired in the obese individual. The absence of growth hormone peaks 30 minutes after glucose in our obese children suggests that their response to stress is also reduced, and this is supported by a report of subnormal growth-hormone responses to insulin-induced
hypoglycsemia (Croughs Abnormality of the energy-feedback
et al. 1968). mechanism and reduced response to stress does not necessarily imply failure of the nycthemeral secretion phases described in normal children by Hunter and Rigal (1966). The demonstration of reduced diurnal secretion in experimental obesity in adults by Sims and Horton (1968) suggests, however, that this form of secretion may also be reduced in the overweight child. Obese children secrete less growth hormone than do children of normal weight, but their growth velocity, far from being impaired, is often accelerated. How then is growth maintained in the presence of plasma-levels of growth hormone which usually signify growth-hormone
deficiency ? Paulsen et al. (1968) have reported increased secretion of insulin in the obese child, both in the fasting state and in response to oral glucose, and we have confirmed this in our obese children. Both insulin and growth hormone have anabolic activity, and both are responsible for transfer of aminoacids into the cell. If the anabolic activity of the two hormones is synergistic then the high insulin secretion in the obese child may be sufficient to promote normal growth despite low growthhormone secretion. Stimmler et al. (1967) and Hunter et al. (1967) advocated the prolonged glucose-tolerance test as a satisfactory method of assessing growth-hormone secretion in children. In the short-stature obese child failure to respond may be the result of obesity rather than growthhormone deficiency, and some other method-e.g., the nitrogen-retention test (Brown et al. 1967)-may have to be used. We thank Prof. D. V. Hubble, Prof. C. M. Anderson, and the consultants of the Birmingham Children’s Hospital for permission to investigate their patients; Sister Hilda Jukes, Miss Bernice Morris, and Mr. Geoffrey Holder for laboratory assistance; Miss Lynette Fisher-Jones for typing this manuscript; and the Children’s Hospital department of medical illustration. Requests for reprints should be addressed to C.G.T. REFERENCES
Beck, P., Koumans, J. H., Winterling, C. A., Stein, F., Daughaday, W. H., Kipnis, D. M. (1964) J. Lab. clin. Med. 64, 654. Brown, G. A., Stimmler, L., Lines, J. G. (1967) Archs Dis. Childh. 42, 239. Croughs, W., Schopman, W., Tiddens, H. A. (1968) Helv. pœdiat. Acta, 23, 464. Discombe, G. (1963) J. clin. Path. 16, 170. Hartog, M., Gaafar, M. A., Meisser, B., Fraser, R. (1964) Br. med. J. ii, 1229. Hunter, W. M., Rigal, W. M. (1966) J. Endocr. 34, 147. Wolfsdorf, J., Farquhar, J., Rigal, W. M. (1967) Lancet, ii, 1271. Jackson, D., Grant, D. B., Clayton, B. E. (1968) ibid. ii, 373. Lancet (1969) i, 85. Parker, M. L., Hammond, J. M., Daughaday, W. H. (1967) J. clin. Endocr. Metab. 27, 1129. Paulsen, E., Richenderfer, L., Ginsberg-Fellner, F. (1968) Diabetes, 17, 261. Pearson, O. H., Stratman, S. M., Spector, S., Yen, S. (1964) Proceedings of the 46th Meeting of the Endocrine Society (San Francisco, 1964); p. 65 (abstract 85). Roth, J., Glick, S. M., Yalow, R. S., Berson, S. A. (1963) Metabolism, 12, —
577.
(1964) Diabetes, 13, 355. Sims, E. A., Horton, E. S. (1968) Am. J. clin. Stimmler, L., McArthur, R. G., Brown, G. —
—
—
—
Nutr. 21, 1455. A. (1967) Can. med. Ass.
J. 97, 1159. Archs Dis. Childh. Tanner, J. M., Whitehouse, R. H., Takaishi, M. (1966) 41, 454, 613.
ORAL ZINC SULPHATE IN LEG ULCERS
S. LATAFAT HUSAIN* FROM
THE
HOSPITAL,
DEPARTMENT OF DERMATOLOGY, SOUTHERN GENERAL AND THE UNIVERSITY DEPARTMENT OF DERMATOLOGY, WESTERN INFIRMARY, GLASGOW
A hundred and four inpatients of various ages with ulcers of the lower limb were included in a controlled trial of oral zinc sulphate. Identical capsules containing 220 mg. of lactose (placebo) or zinc sulphate were given three times a day to equal numbers of controls and treated patients. Ulcers healed more quickly in the treatment group. The ulcers of the treatment group healed in 32 on average, as against 77 days for the control group. There was no significant dependence on age or sex. Mild diarrhœa in three patients was the only toxic effect of zinc-sulphate therapy. Oral zinc sulphate would seem to have a place in the treatment of chronic leg ulcers which do
Sum ary
not
respond
to
topical
treatment.
Prolonged
*Present address: Department of Dermatology, C.4.
or
repeated
Royal Infirmary, Glasgow
1070
should, however, be avoided since not enough is known about the side-effects of systemic zinc salts. courses
Introduction
THERAPEUTIC agents recommended for topical use in the treatment of chronic leg ulcers are legion, and this itself suggests that none is entirely satisfactory. Many workers (Wright 1931, Bisgaard 1948, Anning 1954, Fergusson and Logan 1961) agree that bed rest and attention to the underlying vascular lesion are essential in the management of such cases; Most leg ulcers take around 11 weeks to heal completely, irrespective of treatment (Fergusson and Logan 1961, Cockrane 1961, Lorch 1961, Haegar 1964, Munro-Ashman and Wells 1968). Pories et al. (1967a, b) found that oral zinc sulphate accelerated wound healing after the excision of pilonidal sinuses, and this stimulated interest in the application of this therapy to leg ulcers of various types. The results of a pilot investigation in sixteen cases of chronic ulcers of the lower limb treated with systemic zinc sulphate seemed to warrant a controlled trial. Patients and Methods and One hundred four patients, of various ages, with ulcers of the lower limb were admitted to the dermatological wards. Each patient received the same form of topical therapy depending on the severity of the ulcer (i.e., 12-5-25% aqueous solution of sodium sulphate, oily lotion of calamine, or eusol dressings) during their stay in the hospital. Although it was impossible to standardise bed rest for each patient, every effort was made to TABLE
I-DISTRIBUTION OF PATIENTS ACCORDING TO AGE AND SEX
ensure that maximum bed rest was achieved. Every effort was made to ensure that ulcers of similar sizes and appearance fell in approximately equal numbers in the treated and control groups. Capsules containing 220 mg. lactose (placebo) or 220 mg. zinc sulphate B.P. were prepared by the pharmacy departments. These had been labelled A or B, but I did not know which was which. Equal numbers of patients were allocated to treatment or control groups (table i). The average age of the control group was 62-05 years; the average age of the treatment group was 60-34 years. The dosage was one capsule three times daily, half an hour after meals. Two methods were used in the weekly assessment of the ulcers. In the early stages, when the ulcers had some depth, their volume was measured by the amount of hydrocolloid gel (’ Tissutex ’) required to fill them (Pories et al. 1967a, b). As the ulcers began to heal and became shallower, and also in the large superficial ulcers, this method was unsatisfactory, so a second method was used. The ulcer outline was traced on to transparent paper, and the tracing was transferred to graph paper. The areas was then measured in sq. mm. by counting the small squares (Fergusson and Logan 1961). The ulcer was considered to be healed when there was no scab formation. Samples of venous blood were taken for the estimation of serum-zinc before treatment, after 2 weeks during the treatment, and a week after the ulcer had healed. Unfortunately, the trial ceased to be double-blind after 16 patients had been treated; it became clear that capsule B contained zinc sulphate because
Time to complete healing in relation
to age.
the patients who were receiving it showed a striking rise in serum-zinc at the second estimation during treatment. Serumzinc levels were estimated during treatment to ensure that the patients were taking the capsules regularly.
Results
The ulcers of the treated group healed more quickly than those of the control group. This clinically significant increase in wound healing produced by zinc sulphate was substantiated by the statistical analysis. The ulcers of the treated group healed in 32-3 (±1-662) days (mean) and those of the control group took days±s.E. 77.19 (±4-321) days. This was extremely significant on Mann-Whitney V test (P < 0 -001). The ulcers of patients who were on zinc sulphate healed 44-89 days sooner than the patients in the control group. The ranges for the total number of days required for healing were 12-71 days for the treatment group and 35-232 days for the controls. Out of 104 patients (52 patients in control group) with ulcers only 3 took more than 150 days to heal completely. Time to complete healing was independent of age (see figure), and there was no significant difference between the rate of healing of males and females for either preparation (controls, t=0055, D.F.=50; treated, t=0-998, D.F.=
days s.E.
50) (table 11). serum-zinc estimation in the
pilot-study g./ml.±s.E. 1.015 (±0-0406) g. per ml. at the first estimation, .g./ml.S.E. 1.886 (±0-2405) g. per ml. during treatment, and (Lg./ml. 1-282 (±0-1149) g. The
mean
cases was
per ml. after treatment. The average surface area of the ulcers was 4290 sq. mm. in the control group and 4830 sq. mm. in the treatment group, and the healing-rates were 90 sq. mm. per day and 421-& sq. mm. per day, respectively. TABLE II-AVERAGE NUMBER OF DAYS REQUIRED FOR COMPLETE HEALING IN MALES AND FEMALES
1071 Discussion
"Leg ulcers present a difficult therapeutic problem and both patients and doctors tend to accept the presence of an ulcerated leg with a grim stoicism born of years of unsuccessful treatment" (Rivlin 1958). If this attitude prevails, the chronically disabled patient may not seek treatment again unless given the stimulus of new hope. Topical antibiotics and other preparations have been used in the treatment of leg ulcers, as have eusol soaks (Fergusson and Logan 1961), silver spray plus aluminium foils (Haeger 1965), and firm pressure bandages or soft medicated bandages. Diuretics to reduce the oederna were advocated by Fox (1962) and grafting and " disobliteration " was recommended by Irvine et al. (1965) for arterial ulcers. However, it is difficult
to assess the effects of these many forms of treatment on the healing-rate of leg ulcers due to their multifactorial xtiology and the difference in size and depth of these ulcers. Zinc is an essential element in nutrition and is a constituent of most foods. Zinc salts are sometimes given by mouth for their properties as reflex emetics but they are mainly used topically as mild astringent and disinfectants (Extra Pharmacopaeia 1967), and several topical preparations containing zinc salts are used for the treatment of leg ulcers. Radioisotope studies have shown that zinc-65 becomes incorporated into the red blood-cells, where it is closely associated with metalloenzymes (Tucker and Salmon 1955, Vallee 1959, Underwood 1962). Zinc is preferentially concentrated in healing tissue (Savlov et al. 1962) probably due to a shift of zinc from plasma into the formed elements of blood (Ross et al. 1958, Graig and Siegel 1960, Rubini et al. 1961, Spencer et al. 1966). Although the clinical appearance of the ulcers varied from patient to patient initially, it was quite clear that, after 2-3 weeks’ treatment with local therapy combined with zinc sulphate systemically, the ulcers were cleaner and showed healthy granulation tissue. There was also a striking reduction in the purulent exudate. On the other hand, the control group showed only slight improvement, granulation tissue was not quite so evident, and a purulent exudate was invariably present. During the ensuing weeks, up to the time of complete healing, the zinc-sulphate group seemed clinically to show more rapid epithelialisation than the control group. This trial was done on inpatients because not enough is known about the side-effects of zinc salts given by mouth. This point was carefully explained to all the patients before the trial started. However, apart from three patients who had mild diarrhoea, which quickly cleared up on discontinuing the treatment, I saw no clinical evidence of drug toxicity. Nevertheless the period of treatment in some patients was short, and a cumulative toxic effect in patients on prolonged or repeated courses of zinc sulphate cannot be excluded. Although bed rest combined with topical therapy will, in most cases, result in healing of chronic leg ulcers (Fergusson and Logan 1961), I believe that systemic therapy with zinc sulphate has a place in the management of these patients. In this trial, bed rest and topical therapy were used, in addition to oral zinc, so it is difficult to predict the effect of zinc sulphate on ambulant patients, but at least treatment with zinc sulphate can be considered a useful adjuvant .therapy in the management of chronic leg ulcers. Until more information is available, however, prolonged therapy and repeated courses for recurrent ulceration should be avoided.
I thank Prof. J. A. Milne and Dr. W. B. McKenna for encourageand advice, Dr. R. L. Cormie and Dr. W. N. Morley for allowing me to include their cases, Dr. W. H. Lyle, Dista Laboratories, Liverpool, for the estimation of serum-zinc, Mr. R. A. Elton for statistical analysis, and my colleagues and the nursing staff for their ment
cooperation. REFERENCES
Anning, S. T. (1954) Leg Ulcers. London. Bisgaard, H. (1948) Ulcers and Eczema of Legs. Copenhagen. Cockrane, G. M. (1961) Practitioner, 187, 787. Extra Pharmacopœia (1967) London. Fergusson, A. G., Logan, J. C. P. (1961) Br. med. J. i, 871. Fox, D. D. (1962) ibid. ii, 1370. Graig, F. A., Siegel, E. (1960) Pro. Soc. exp. Biol. Med. 104, 391. Haeger, K. (1964) Acta chir. scand. 128, 140. — (1965) ibid. 130, 592. Irvine, W. T., Williams, E. J., Plessas, S. N. (1965) Br. med. J. i, 1147. Lorch, D. M. (1961) Practitioner, 187, 67. Munro-Ashman, E. J. E., Wells, R. S. (1968) Br. J. clin. Pract. 22, 129. Pories, W. J., Henzel, J. H., Rob, C. G., Strain, W. H. (1967a) Lancet, i, 121. (1967b) Ann. Surg. 165, 432. Rivlin, S. (1958) Lancet, i, 1363. Ross, J. F., Ebaugh, F. G. Jr., Talbot, T. R. Jr. (1958) Tr. Ass. Am. Physns. 71, 322. Rubini, M. E., Montalvo, G., Lockhart, C. P., Johnson, C. R. (1961) Am. J. Physiol. 200, 1345. Savlov, E. D., Strain, W. H., Huegin, F. (1962) J. surg. Res. 2, 209. Spencer, H. Rosoff, B., Lewin, I. (1966) Zinc Metabolism (edited by A. S. Prasad). Springfield, Illinois. Tucker, H. F., Salmon, W. D. (1955) Proc. Soc. exp. Biol. Med. 88, 613. Underwood, E. J. (1962) Trace Elements in Human and Animal Nutrition. —
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443.
PREDICTION OF MALIGNANCY IN SOLITARY THYROID NODULES LEIGH W. KENDALL
ROBERT E. CONDON
SURGERY, UNIVERSITY OF ILLINOIS MEDICINE, CHICAGO, ILLINOIS
FROM THE DEPARTMENT OF COLLEGE OF
reliability of radioiodine scanning and physical characteristics of the nodule as indicators of malignancy in patients with clinically solitary thyroid nodules, a survey was made of five years’ experience of patients operated on for thyroid disease at a university teaching hospital in the Mid-West goitre belt. The incidence of malignancy in the 91 patients with solitary nodules was 20·9%. Of these 91, hypofunction (" cool" or cold ") was diagnosed on radioiodine scanning in 83% of benign nodules and 75% of malignant nodules. This test was of no value in differential diagnosis. Similarly, the physical characteristics of the nodule and other findings on physical examination did not reliably differentiate between benign and malignant solitary nodules. It is advised that solitary thyroid nodules Sum ary
To evaluate the
"
should be excised. Introduction EVALUATION of patients who have solitary nodules of the thyroid gland continues to be a clinical problem. Although the great majority of such nodules are benign, a significant minority harbour a carcinoma. Preoperative identification of nodules which are likely to contain cancer is important, since the advice given to the patient and the operative approach may be modified if the surgeon strongly " suspects that cancer is present. The finding of a cool " " or cold " nodule on radioiodine scanning of the thyroid gland is said to be associated with an increased incidence of thyroid cancer (Cope et al. 1949, Dobyns et al. 1949, Rawson et al. 1949, Perlmutter et al. 1954, Johnson and Bierwaltes 1955, Perlmutter and Slater 1956, Groesbeck 1959, Meadows 1962). Similarly, certain symptoms and