PARADOXICAL ELEVATION OF GROWTH HORMONE IN ACTIVE CHRONIC HEPATITIS

1035

is less clear. Brooks and Prunty 11 showed that large doses of 17 (X-ethyl-19-nortestosterone brought about a fall in the excretion of total 17-oxosteroid and dehydroepiandrosterone. Huis in’t Veld et al.12 found that 17 (X-methyl-19-nortestosterone (a compound with marked progestational activities) caused a fall in the excretion of urinary 17-oxosteroids in men, and Feldman and Carter 13 showed the same thing in oophorectomised or postmenopausal women with breast cancer. However, Mauvais-Jarvis et al.14 found that 10 days’ treatment with ’Lyndiol’ had no significant effect on the excretion of androsterone and aetiocholanolone but that dehydroepiandrosterone excretion increased in some women. There are other scattered reports, but the problem is that dosages and duration of treatment vary considerably and in many instances the steroidal substances were administered to women with a variety of illnesses. In the present study, the fact that the type of pill and the duration of treatment were not recorded may be an advantage in that the results represent what occurs in the generality of women rather than in individual cases under artificial conditions. There has been some speculation concerning the possible effects of contraceptive pills on the incidence of breast cancer .15 Bulbrook and Hayward and Bulbrook et al .16 found that both 17-oxosteroid and 17-OHc.s.-excretion tended to be subnormal in 10 of 21 women in whom breast cancer was subsequently diagnosed. The subnormal amounts of these steroids excreted by the 10 women in the preclinical phase of breast cancer are similar to those excreted by normal women taking contraceptive pills. However, the levels of the plasma precursors of the urinary compounds might be expected to be very different in the two groups since the contraceptive pill would

terone

alter steroid secretion, protein binding, metabolism, and urinary excretion. For this reason, current results in the Guernsey study give no information about the possible effects of the pill on the incidence of breast cancer. REFERENCES

Bulbrook, R. D., Hayward, J. L. Lancet, 1967, i, 519. Peterson, R. E. Recent Prog. Horm. Res. 15, 231. Layne, D. S., Meyer, C. J., Vaishwanar, P. S., Pincus, G. J. clin. Endocr. Metab, 1962, 22, 107. 4. Musa, B. U., Doe, R. P., Seal, U. S. ibid. 1967, 27, 1463. 5. Van de Wiele, R. L., MacDonald, P. C., Gurpide, E., Lieberman S. Recent Prog. Horm. Res. 1963, 19, 275. 6. Forchielli, E., Rao, G. S., Sarda, I. R., Gibree, N. B., Pochi, P. E., Strauss, J. S., Dorfman, R. I. Acta endocr., Copenh. 1965,

1. 2. 3.

7.

8.

9. 10.

11. 12. 13.

50, 51. Vermeulen, A. in Androgens in Normal and Pathological Conditions, International Congress Series no. 101 (edited by A. Vermeulen and D. Exley); p. 71. Amsterdam, 1966. Alder, A., Burger, H., Davis, J., Dulmanis, A., Hudson, B., Sarfaty, G., Straffon, W. Br. med. J. 1968, i, 28. Pearlman, W. H., Crepy, O. J. biol. Chem. 1967, 242, 182. Bird, C. E., Green, R. N., Clark, A. F. J. clin. Endocr. Metab. 1969, 29, 123. Brooks, R. V., Prunty, F. T. G. J. Endocr. 1957, 15, 385. Huis in’t Veld, L. G., Louwerebs, B., Spey, P. A. F. Acta endocr., Copenh. 1960, 33, 388. Feldman, E. B., Carter, A. C. J. clin. Endocr. Metab. 1960, 20, 842.

14.

Mauvais-Jarvis, P., Jayle, M. F., Decourt, J., Louchart, J., Truffert, J. Acta endocr., Copenh. 1965, 50, 133. 15. Hertz, R. Int. J. Fert. 1968, 13, 273. 16. Bulbrook, R. D., Hayward, J. L., Allen, D. S. in Hormonal Aspects in the Epidemiology of Human Breast Cancer (edited by J. H. De Bussy); p. 163. Amsterdam, 1969.

PARADOXICAL ELEVATION OF GROWTH HORMONE IN ACTIVE CHRONIC HEPATITIS MERVYN D. BECKER* G. C. COOK† A. D. WRIGHT‡

Departments of Medicine, Royal Free Hospital and Royal Postgraduate Medical School, London A

paradoxical elevation of growth hormone in response to oral and intravenous glucose has been found in eight of fourteen patients with active chronic hepatitis. The degree of elevation of growth hormone and also of an associated hyperinsulinæmia were more apparent in the patients with advanced liver disease. Possible causes of the growth hormone elevation in these patients are a decreased degradation-rate of the hormone, hypoproteinæmia, and hyperœstrogenæmia. None of these explanations seems satisfactory. Glucose tolerance was not appreciably affected by the degree of activity of the liver disease or by corticosteroid therapy. Summary

Introduction HYPERINSULIN1F,MIA and insulin resistance have previously been reported in chronic liver disease.1 The mechanism of the insulin resistance is not understood, but may be due to the presence of an insulin

antagonist, possibly growth hormone. We have investigated the interrelationships between glucose, growth hormone, and insulin in patients with active chronic hepatitis. Patients and Methods

gives the clinical and laboratory details of the patients investigated. The diagnosis of active chronic hepatitis was clearly established on clinical, biochemical, and histological grounds. No patient was obese or gave a family history of diabetes mellitus. Seven were receiving 10-30 mg. prednisolone daily and seven

Table fourteen

had

i

never

received corticosteroids.

Serum

urea

and

electrolytes were normal. A normal (control) group consisting of one healthy male, and three healthy females was also investigated. The mean body-weights of the patients and controls were 61 and 60 kg., respectively. The patients were divided into an early, moderate, and advanced group on the basis of activity of the liver disease and the duration of the illness. They all had a high serumaspartate-transaminase. The five early cases had had symptoms for less than 2 years, and the liver biopsy showed piecemeal necrosis but no evidence of cirrhosis. The five moderate cases had similar clinical, biochemical and histological features but had had symptoms for 2 years or more. The four advanced cases all had established cirrhosis on liver biopsy, ascites, and a low serum-albumin. Each patient and control received a 300 g. carbohydrate diet for 3 days, and was then given intravenous (LV.G.T.T.) and oral (O.G.T.T.) glucose-tolerance tests, in random order at an interval of 1-3 days. All tests were performed after an overnight fast, between 8.30 P.M. and 9.30 A.M. The patients and controls were in bed throughout the tests. * Present address: 3081 Lake Hollywood Drive, Los Angeles 90028, California, U.S.A. &dag er; Present address: Department of Medicine, University of Zambia, P.O. Box 2379, Lusaka, Zambia. ‡ Present address: Department of Medicine, McMaster University, Hamilton, Ontario, Canada

1036 TABLE I--CLINICAL AND LABORATORY DETAILS OF THE PATIENTS WITH ACTIVE CHRONIC HEPATITIS

*

Normal upper limit 17

For the I.V.G.T.T., 0-5 g. glucose per kg. body-weight was injected into an antecubital vein in 2-3 minutes; venous and capillary blood-samples were taken before and 10, 20, 30, 40, 50, and 60 minutes after the start of the injection. For the o.G.T.T., 0-75 g. glucose per kg. body-weight was given as a 15% w/v solution. Venous and capillary blood-samples were taken at 0, 15, 30, 45, 60, 90, 120, 150, and 180 minutes. To ascertain the specificity of the growth-hormone response during the I.V.G.T.T., two patients with active chronic hepatitis and one control were given a continuous infusion of saline solution for 30 minutes before receiving the intravenous glucose; they were unaware of the time the saline infusion ended and the glucose was injected. Capillary glucose was determined by a glucose-oxidase method.3 Plasma-immunoreactive-insulin (I.R.I.) was measured by a radioimmunological assay.4 Serum-growthhormone was determined by a radioimmunoassay, using a modification of the method of Hartog et al. 6; the results are expressed as ng. per ml. using Medical Research Council reference standard A. All estimations were done in

i.u.

per litre.

rise at 45 minutes. Differences between the advanced and control groups were significant at 0 and 90 (P<0-05) and 120 and 150 (P<0-02) minutes, and those between the moderate and control groups at The mean 90, 120, and 150 minutes (P<0-05). concentrations for the early group were higher than for the control group but the differences were not significant. The early group was significantly different 120 from the advanced group at 90 (P<0-05), (P<0-02), and 150 (P<0-02) minutes. Four of the

eight patients (two advanced, one moderate, and one early) who were receiving corticosteroids had an abnormal elevation of growth hormone. The mean concentration of growth hormone in the corticosteroid and untreated groups was similar and in both this was higher than in the control group.

duplicate. The criterion for the diagnosis of diabetes mellitus was abnormal O.G.T.T.l This was considered to be impaired if either the fasting blood-glucose was greater than 85 mg. per 100 ml. or the 120-minute concentration was above 115 mg. per 100 ml. The response was considered abnormal if there was a rise before 60 minute in the o.G.T.T., or before 30 minutes in the I.V.G.T.T.6 The disappearancerate (k) for glucose was calculated for all I.V.G.T.T.’ Paradoxically, responses of growth hormone are defined as elevations when there is normally a suppression. an

Results Growth hormone Response to Oral Glucose Fig. 1 summarises the growth-hormone response during the o.G.T.T. The control group had a fasting level of less than 6 ng. per ml., suppression to less than 4 ng. per ml. during the 15-120 minute period, and an elevation to 50 ng. per ml. at 120-180 minutes. The response in eight of the fourteen patients was abnormal. The four advanced and two of the moderate

had paradoxical elevations; of the two early cases with an abnormal response, one (a male), did not show a normal suppression, and the other had a

cases

Fig. 1-Growth-hormone response during O.G.T.T., in the early, moderate, and advanced groups.

1037

three moderate, and one early cases; one male patient, an early case, did not show a normal suppression. The advanced group was significantly different from the control group at 0, 40 (P<0.05), 50 (P<0-02), and 60 (p<0’02) minutes. The advanced group was also significantly different from the early and moderate minutes. Growth groups at 50 and 60 (P<0-02) hormone in the early and moderate groups remained higher than normal throughout the test but on no occasion was the difference significant. The mean concentrations of serum-growth-hormone in the corticosteroid and untreated groups were similar, but were elevated when compared with the controls. There was a good association in the growth-hormone response between the I.V.G.T.T. and O.G.T.T.; seven

Fig. 2-Growth-hormone response during I.V.G.T.T., in the early, moderate, and advanced groups.

Growth-hormone Response to Intravenous Glucose Fig. 2 summarises the growth-hormone response during the I.V.G.T.T. The control group had a fasting level of less than 6 ng. per ml., suppression below 4 ng. per ml. between 10 and 40 minutes, and a slight rise beginning at 50 minutes. The response was abnormal in eight of the fourteen patients. Paradoxical elevations were found in three advanced, Fig. 4-Glucose The mean ± interval.

response S.E.M.

during the O.G.T.T. and I.V.G.T.T.

is shown for each group

at

who had an abnormal response in also abnormal in the other.

patients

Fig. 3-Insulin The mean ± interval.

response S.E.M.

during

the O.G.T.T. and I.V.G.T.T.

is shown for each group

at

each time

each time

one were

Insulin Response to Oral and Intravenous Glucose Fig. 3 summarises the results. During both O.G.T.T. and I.V.G.T.T. the early, moderate, and advanced groups had higher mean concentrations of insulin than did the controls. During the o.G.T.T., the differences between the advanced and control groups were significant at 0 and 120 (P<0.05), 150 (P<0-02), and 180 (P<0-05) minutes. During the I.V.G.T.T. the advanced group was significantly different from the control group at 0 and 60 (P<0-05) minutes. both the corticosteroid and untreated tests, During had mean insulin concentrations than groups higher did the controls; the corticosteroid group had the highest values. During the o.G.T.T. both corticosteroid and untreated groups were significantly different from the control group at 0, 90, and 180 (P<0-05) minutes. The corticosteroid group was significantly different from the untreated group at 15 and 60 (P<0-05) minutes. There was no significant difference between the untreated and control groups. Glucose Response to Oral and Intravenous Glucose Fig. 4 summarises the results. The patients with

1038 active chronic

hepatitis had

a

slightly higher

mean

fasting glucose concentration than did the controls. There was, however, no significant association between impairment of glucose tolerance and the activity of the liver disease

or

corticosteroid

treatment.

Four

patients (28%) had an impaired O.G.T.T.; two advanced, one moderate, and one early case; the early and one advanced case were receiving corticosteroids. The mean k values during the l.v.G.T.T. were: control group 1-89, early group 1-31, moderate group 1-10, and advanced group 1-27% per minute. The k value for the corticosteroid group was 1-41, and the untreated group 1-31% per minute. Saline Infusion before Intravenous Glucose Table n summarises the results. The two patients with active chronic hepatitis had an elevated growthTABLE II-GROWTH-HORMONE RESPONSE DURING SALINE INFUSION AND I.V.G.T.T., IN TWO PATIENTS WITH ACTIVE CHRONIC

HEPATITIS,

AND ONE CONTROL

hormone level during the saline infusions and this strikingly increased after intravenous glucose. The control had low values throughout. Discussion

A paradoxical elevation of growth hormone in active chronic hepatitis, which seems to become more striking as the liver disease progresses, has been demonstrated. The cause of this is not clear. Growth hormone given to healthy subjects can augment the insulin response during a glucose-tolerance test.88 Acromegalic patients also have an exaggerated insulin response during a glucose tolerance test.9 The rise of growth hormone in our patients lagged behind the rise in insulin concentrations; it therefore seems unlikely that growth hormone was responsible for stimulating insulin release. When insulin and glucose are given simultaneously to healthy individuals there is no rise in growth hormone 10; it also seems unlikely therefore that insulin is the stimulus for growth-hormone release. Growth-hormone levels did not change dramatically during the saline infusions. This excludes the possibility that adrenergic stimuli in response to stress is the mechanism responsible for the elevated concentrations.1l,12 To determine whether the growth-hormone response in active chronic hepatitis was specific for that disease, three patients with other liver disease were investigated. An 18-year-old female with schistosomiasis and a 42-year-old male with cirrhosis and a primary hepatocellular carcinoma, had an abnormal growth-hormone response to glucose. A further patient with primary biliary cirrhosis, however, responded normally. There was no evidence that corticosteroid-treated patients had a suppressed growth-hormone response, as has been previously

reported.5,13-15

Decreased degradation of growth hormone in our patients with progressive liver disease could explain the high fasting concentrations, but not the rapid elevation in response to glucose. Hypoproteinasmic states (e.g., kwashiorkor and uraemia) are associated with low serum-albumin and elevated fasting growthhormone concentration.16,17 Our four advanced cases of active chronic hepatitis, with cirrhosis and ascites, had low serum-albumin concentrations. However, the other four patients with an elevated growthhormone response had normal serum-albumin values. Growth-hormone concentrations are elevated in the presence of hyperoestrogenxmia, and that was the explanation given by Hernandez et a1.18 for the elevated fasting concentrations in four of five active cirrhotics; and one inactive cirrhotic had a progressive rise of growth hormone during a glucose-tolerance test. CEstrogen administration to males produces high ambulatory growth-hormone concentrations comparable to those in females, but a normal suppression occurs in response to glucose. 19 Two of our female patients who were postmenopausal had a striking rise of growth hormone; postmenopausal women have growth hormone concentrations below those for ambulatory premenopausal females.19 It is also clear that oestrogens can increase the growth-hormone response to some physiological stimuli. In patients with a paradoxical rise of growth hormone in Turner’s syndrome, oestrogen administration during an I.V.G.T.T. further increased the response in two of three patients and decreased the insulin concentrations in two.2o The effect of insulin and growth hormone infused simultaneously on glucose uptake in the forearm tissue, is to counteract the effect of the other on glucose uptake.21 Thissituation might well exist in our patients. A paradoxical growth-hormone response to hyperglycaEmia has previously been reported in acromegaly,22 acute intermittant porphyria,23 cerebral tumours,24 prediabetic males,25 premature infants,26 post-myocardial infarction,27 Turner’s syndrome,20 and uraemia,17,28 However, of these groups only the uraemic patients had hyperinsulinsemia and elevated growth-hormone concentrations in response to

glucose. Impairment of glucose tolerance

was

mild, and

did not seem to be worse in the corticosteroid than the untreated group. The plasma-insulin concentrations did not correlate with the activity or duration of the liver disease, although in the I.V.G.T.T. there was a tendency for the advanced cases to have the highest insulin concentrations. The corticosteroidtreated patients had higher insulin levels, as was expected.29There was no initial lag in insulin release as is seen in prediabetic and diabetic patients. We thank Prof. R. Luft, Prof. Russell Fraser, Dr. N. McIntyre, Dr. P. Sonksen, and Dr. J. Fevery for their assistance, and Miss J. Jacobson for technical help. Requests for reprints should be addressed to the Department of Medicine, Royal Free Hospital, Grays Inn Road, London W.C.I. REFERENCES 1. 2.

Megyesi, C., Samols, E., Marks, V. Lancet, 1967, ii, 1051. Sherlock, S. Diseases of the Liver and Biliary System;

Oxford, 1968. 3. Marks, V. Clin. Chim. Acta, 1959, 4, 395. 4. Hales, C. N., Randle, P. J. Biochem. J. 1963, 88, 137.

p. 425.

’

1039

RADIOACTIVE IODINE UPTAKE BY THYROID OF BREAST-FED INFANTS AFTER MATERNAL BLOOD-VOLUME MEASUREMENTS E. P. BLAND M. F. DOCKER

J. SELWYN CRAWFORD R. F. FARR

Birmingham Maternity Hospital and Department of Physics, United Birmingham Hospitals Summary

Investigations of

two

patients have

shown that when routine blood-volume

studies, using serum-albumin labelled with iodine-125 done on a mother at the time of delivery, a considerable amount of radioactive iodine may be transmitted to the infant in the breast-milk. This is likely to increase by a factor of 10 the risk that the child will subsequently develop cancer of the thyroid. are

Introduction

of blood lost and the change in circulating blood-volume in relation to surgery is a valuable index to efficient supportive therapy. Several workers 1-3 have found that blood-loss at caesarean section tends to be considerably greater than estimates based upon clinical impression had led many obstetricians (and anaesthetists) to expect. When the new KNOWING the

amount

Birmingham Maternity Hospital decided to include

was

opened

we

of blood-loss and preand in our battery blood-volumes operative postoperative

5. 6.

7. 8. 9. 10. 11.

12.

measurement

Hartog, M., Gaafar, M. A., Fraser, R. Lancet, 1964, ii, 376. Hunter, W. M., Willoughby, J. M. T., Strong, J. A. J. Endocr. 1968, 40, 297. Cook, G. C. Metabolism, 1968, 17, 1073. Luft, R. New Engl. J. Med. 1968, 279, 1086. Luft, R., Cerasi, E. Acta endocr., Copenh. 1967, suppl. no. 124, p. 9. Mintz, D. H., Finster, J. L., Taylor, A. L., Fefer, A. Am. J. Med. 1968, 45, 187. Czarny, D., James, V. H. T., Landon, J., Greenwood, F. C. Lancet, 1968, ii, 126. Blackard, W. G., Heidingsfelder, S. A. J. clin. Invest. 1968, 47, 1407.

13. 14. 15. 16. 17.

18. 19.

Frantz, A. G., Rabkin, M. T. New Engl. J. Med. 1964, 271, 1375. Martin, M. M., Gaboardi, F., Podolsky, S., Raiti, S., Calcagno, P. L. ibid. 1968, 279, 273. Sheikholislam, B. M., Lamb., E. A., Lebovitz, H. E., Stempfel, R. J. Pediat. 1966, 69, 970. Pimestone, B., Barbezat, G., Hansen, J. D. L., Murray, P. Lancet, 1967, ii, 1333. Wright, A. D., Lowy, C., Fraser, T. R., Spitz, I. M., Rubenstein, A. H., Bersohn, I. ibid. 1968, ii, 798. Hernandez, A., Zorrilla, E., Gershberg, H. J. Lab. clin. Med. 1969, 73, 25. Frantz., A. G., Rabkin, M. T. J. clin. Endocr. Metab. 1965, 25, 1470.

Lindsten, J., Cerasi, E., Luft, R., Hultquist, G. Acta endocr., Copenh. 1967, 56, 107. 21. Rabinowitz, D., Merimee, T. J., Burgess, J. A. Diabetes, 1966, 15, 905. 22. Earll, J. M., Sparks, L. L., Forsham, P. H. J. Am. med. Ass. 1967, 201, 628. 23. Perlroth, M. G., Tschudy, D. P., Waxman, A., Odell, W. D. Metabolism, 1967, 16, 87. 24. Beck, P., Parker, M. L., Daughaday, W. H. J. clin. endocr. Metab. 1966 26, 463. 25. Boden, G., Soeldner, J. S., Gleason, R. E., Marble, A. J. clin. Invest. 1968, 47, 729. 26. Cornblath, M., Parker, M. L., Reisner, S. H., Forbes, A. E., Daughaday, W. H. J. clin. Endocr. Metab. 1965, 25, 209. 27. Lebovitz, H. E., Shultz, K. T., Matthews, M. E., Scheele, R. Circulation, 1969, 39, 171. 28. Horton, E. S., Johnson, C., Lebovitz, H. E. Ann. intern. Med. 1968, 68, 63. 29. Perley, M., Kipnis, D. M. New Engl. J. Med. 1966, 274, 1237.

20.

of patient-monitoring routines. The methods andresults will be described elsewhere, but it is necessary to point out here that, in order to assess the degree of accuracy of blood-volume estimates, we made preoperative and postoperative measurements in several cases of postpartum sterilisation (P.P.s.), since only rarely is more than 200 ml. of blood lost at this operation. Blood-volume was assessed with the aid of the Pitman model 125 blood-volume computer. Solutions containing approximately 5 uCi of iodine-125 were given by intravenous injection immediately before operation and about 1 hour after the end of operation. We recognised the need for caution in using radioactive materials in obstetric medicine, and at the outset our concern was that a significant amount of iodine-125 might reach the infant by the transplacental route. However, a review of published work on the use of iodine isotopes for placental localisation 4,5 and consultation with the Medical Research Council satisfied us that the administration of 5 uCi to the mother before delivery would not pose a hazard to the infant, and we had no reservations about the inaugurating the monitoring service. Some time after the initiation of the service, our attention was drawn to a paper by Czerniak et al.6 referring to the presence of radioactive iodine in the colostrum and the milk of mothers who, just before labour and delivery, had been given iodine-131 as a test of thyroid function. Further search of the literature revealed that Miller and Weetch and Weaver et awl. had referred to the hazard to breast-feeding infants of administering radioactive iodine to the mother. We felt that this matter required immediate investigation. Before we made this decision, four patients (two undergoing cxsarean section and two undergoing P.P.s.) had breast-fed their infants after being given iodine-125: the necessary instruments became available to us shortly after a fifth breastfeeding mother had been delivered by section and our sixth case in this category had a P.P.s. on a date when we were ready to undertake a full investigation. The first patient received a dose of 10 uCi, the second received 6 uCi, in both cases the dose was given in two

equal portions. Investigation The first patient started to feed her child 3 days after administration of the radioiodine, the second was already feeding at the time of administration. Measurements were done on 5 ml. samples of milk taken at frequencies varying from one to five per day. An automatic sample changing gamma-counter was used to measure the concentration of radioactive iodine present in the milk. The figure shows that the concentrations of iodine in the first milk received by the infants were 0-7 and 0-15 uCi per litre, respectively. In case 1 the concentration fell exponentially, the peak concentration having been passed when feeding was commenced. In case 2 the concentration reached a maximum 24 hours after the operation, the peak concentration being 0-3 uCi per litre; thereafter the concentration fell exponentially. Using data obtained over the 8 days that the patients were available for observation, and assuming that the infants received five feeds per day, each of 60 ml., it was possible to show by extrapolation that the total intake would be 0-5 .uCi in the first case and 0-6,uCi in the second. We tried to assess the amount of iodine present in the