Download Calcitonin in Man

12 October 1968
Leading Articles
institutions is an old craft, at which the British are said to
excel. Sometimes, however, it is better to be less spectacular
and adapt the old tradition to the new circumstances, and this
the College is doing with notable success. But among today's circumstances is an increasing intrusion of politics and
bureaucracy on medicine. Professional institutions have a
special duty to see that professional initiatives remain where
they belong. Fortunately the College has a long experience
to draw upon.
Hypnosis in Medicine
Though in 1955 a B.M.A. subcommittee on the medical use
of hypnosis' reported that " hypnosis is of value and may be
the treatment of choice in some cases of so-called psychosomatic disorder and psychoneurosis," it cannot yet be said
that it has a clearly defined place in the management of the
physically ill. This is probably a consequence of the dearth
of adequate research into the efficacy of hypnotherapy in
various disorders-quite apart from the aura of Mesmer and
the music-hall which still surrounds the subject. The controlled trial of hypnotherapy in a large series of patients with
asthma, organized by the Research Committee of the British
Tuberculosis Association and reported at page 71 of the
B.M.7. this week, is therefore welcome.
Hypnosis is a useful method of inducing anaesthesia for
surgery and childbirth,2 but its ability to induce physical
changes is most easily seen in the response of certain skin
disorders-for example, warts3 and ichthyosis.45 Other medical conditions in which hypnotherapy has been reported to be
effective include peptic ulcer," post-gastrectomy dumping
syndrome,7' migraine," and unstable diabetes.'0 These are
all disorders of function, though with a physical basis, and
usually have a prominent emotional component also.
Asthma exemplifies this type of disorder, and hypnotherapy
is reported to have benefited patients who suffer from itll-13
even those in severe status asthmaticus.'4 Hypnotherapy may
improve patients with asthma in two distinct waysl'-through
physiological improvement (decreasing airways resistance)
and through psychological improvement (decreasing awareness of airways resistance). In the British Tuberculosis
Subcommittee of the Psychological Medicine Group Committee of the
British Medical Association. Brit. med. 7. Suppl., 1955, 1, 190.
2 Mason, A. A., in General Anaesthesia, ed. F. T. Evans and T. C. Gray,
vol. 2, ch. 29, 1959, London.
3
Sinclair-Gieben, A. H. C., and Chalmers, D., Lancet, 1959, 2, 480.
Mason, A. A., Brit. med. 7., 1952, 2, 422.
Schneck, J. M., Dis. nerv. Syst., 1954, 15, 211.
' Moody, H., Brit. 7. med. Hyp., 1953, 5, 23.
' Dorcus, R. M., and Goodwin, P., 7. clin. exp. Hypnos., 1955, 3, 200.
Leonard, A. S., Papermaster, A. A., Fargo, N. D., and Wangensteen,
0. H., 7. Amer. med. Ass., 1957, 165, 1957.
' Horan, J. S., 7. clin. exp. Hypnos., 1953, 1, No. 4, 7.
1I Raginsky, B. B., in Hypnosis in Modern Medicine, 2nd. ed., ed. J. M.
Schneck. 1959. Springfield, Ill.
" Edwards, G., Brit. med. 7., 1960, 2, 492.
12
Maher-Loughnan, G. P., Macdonald, N., Mason, A. A., and Fry, L.,
Brit. med. 7., 1962, 2, 371.
" Marchesi, C., Brit. 7. med. Hypnot., 1949, 1, p. 14.
" Sinclair-Gieben, A. H. C., Brit. med. 7., 1960, 2, 1651.
Brenman, M., and Gill, M. M., Hypnotherapy: A Survey of the
Literature, 1947, London.
16 Kroger, W. S., Clinical and Experimental Hypnosis in Medicine, Dentistry, and Psychology, 1963. Philadelphia.
17 West, L. J., 7. amer. med. Ass., 1960, 172, 672.
Halliday, A. M., and Mason, A. A., 7. Neurol. Neurosurg. Psychiat.,
1964, 27, 300.
B~
67
Association's study pulmonary function tests did not give
different results in the hypnotherapy and control groups,
though there was a significantly greater trend towards
improvement over the year in females in the hypnotized
group. Nevertheless independent clinical assessors detected
marked improvement in a higher proportion of the hypnotized
group.
The most important factor in the response to hypnotherapy
appears to be the depth of trance achieved by the subject. 12
About 10% of people are resistant to hypnosis and only
10-20% are capable of reaching the deepest level of trance,
characterized by spontaneous amnesia and response to posthypnotic suggestion. The latter capacity declines with age.'5
In the British Tuberculosis Association's trial 97% of the
patients were satisfactorily hypnotized, probably because they
strongly wanted to be relieved of their disease, but only 6%
achieved a state of deep trance. In addition to the patient's
susceptibility the skill of the therapist is relevant, a fact
demonstrated in this trial. Other factors said to be associated
with a good response to hypnosis are age below 30 years, illness of less than 20 years' duration, mild degree of the illness,
and some particular emotional trigger.'2 None of these was
confirmed in the present trial.
The B.M.A. subcommittee' described hypnosis in the
following terms: " A temporary condition of altered attention
in the subject which may be induced by another person and
in which a variety of phenomena may appear spontaneously
or in response to verbal or other stimuli. These phenomena
include alterations in consciousness and memory, increased
susceptibility to suggestion, and the production in the subject
of responses and ideas unfamiliar to him in his usual state of
mind. Further, phenomena such as anaesthesia, paralysis and
rigidity of muscles, and vasomotor changes can be produced
and removed in the hypnotic state." The mechanism through
which these various phenomena are effected remains a matter
for speculation. Purely psychological hypotheses are being
supplemented by attempted explanation in terms of brain
physiology.'6 It is suggested'7 that the altered attention is
mediated by the ascending reticular activating system and its
cortical connexions by a process of attenuation of the sensory
input. But the fact that normal cortical potentials are
recorded after appropriate stimuli in persons with hypnotically induced anaesthesia and deafness'8 indicates that
attenuation of sensory messages does not occur below the
cerebral cortex. Though a satisfactory explanation is still
awaited, hypnotherapy can be used empirically with benefit
to patients, as the British Tuberculosis Association's trial
shows. It is to be hoped that more physicians will be
encouraged to explore its possibilities.
Calcitonin in Man
In 1962 D. H. Copp' and colleagues reported a new hormone,
calcitonin, which lowers the concentration of calcium in the
blood. Since then porcine calcitonin has been synthesized,2 3
human calcitonin isolated, and its amino-acid composition
determined.4 Synthetic human calcitonin is therefore likely
to become available.
Calcitonin is secreted by " C " cells,5 which are embryologically derived from the last branchial pouch. These cells
12 October 1968
68
Leading Articles
are found mainly in the thyroid gland of mammals and the
ultimobranchial body of non-mammals.' In man calcitonin
has also been found in parathyroid and thymus tissue,7 so
that complete deficiency of calcitonin in association with
absence of thyroid is unlikely.
Hypercalcaemia is the stimulus for release of calcitonin,l 8
and its hypocalcaemic and hypophosphataemic action' is due
to inhibition of bone resorption.9 When the rate of bone
resorption is high, as in generalized Paget's disease, small
doses of calcitonin lower the blood calcium.'0 However, in
normal adult man bone is resorbed at a relatively low rate,
and even large single intravenous injections of calcitonin do
not cause hypocalcaemia."l An action of calcitonin on the
kidney causing increased excretion of phosphate has been
reported in man'2 and animals," but the significance of this
finding is not yet understood.
A substance with calcitonin-like activity may now be extracted from normal human plasma." It causes hypocalcaemia
and hypophosphataemia in the assay rat, has a log-dose
response curve identical to purified porcine calcitonin, and
inhibits resorption of bone in tissue culture. Though proof
is lacking, the material is probably calcitonin. A rough
estimate of the secretion rate of calcitonin in adults is between
100 and 1,000 Medical Research Council units per 24 hours.'5
If this extracted calcitonin is biologically active, then it is
reasonable to suggest that it is acting to oppose the bone-
resorptive
action of parathyroid hormone. It is possible,
therefore, that the effect of parathyroid hormone on absorption of calcium from the gut" in the maintenance of a normal
serum calcium is more important than previously realized.
So far only medullary carcinoma of the thyroid has been
shown to secrete excessive amounts of calcitonin.'7-" This
tumour originates from C cells,20 and its study might reasonably be expected to shed some light on the effects of
excessive production of calcitonin. Three of the cases
E. C., Cheney, B. A., Davidson, A. G. F.,
and Henze, K. G., Endocrinology, 1962, 70, 638.
Neher, R., Riniker, B., Zuber, H., Rittel, W., and Kahnt, F. W., Helv.
Copp, D. H., Cameron.
2
chim. Acta,
Brit. med.
1968, 51,
917.
7.,
1968, 3, 3.
Riniker, B., et al., HeIv. chim. Acta, in press.
Pearse, A. G. E., Proc. roy. Soc., B, 1966, 164, 478.
' Pearse, A. G. E., in Calcitonin: Proceedings of Symposium on Thyrocalcitonin and C cells, p. 98, ed. S. Taylor, London, 1968.
Galante, L., et al., Lancet, 1968, 2, 537.
' Kumar,
A., Foster, G. V., and
M.
480.
MacIntyre, I., Lancet, 1963, 2,
Friedman, J., and Raisz, L. G., Science, 1965, 150, 1465.
'° Bijvoet, 0. L. M., van der Sluys Veer, J., and Jansen, A. P., Lancet,
1968, 1, 876.
Singer, F. R., et al., Calc. Tiss. Res., 1968, 2, Suppl., Abstract 20.
Ardaillou, R., Vuagnat, P., Milhaud, G., and Richet, G., Nephron,
1967, 4, 298.
3 Robinson,
C.
J., Martin,
T.
J.,
and
83.
I' Gudmundsson,
T.
V.,
et
al.,
MacIntyre, I., Lancet, 1966, 2,
Caic. Tiss.
stract 17.
Res., 1968, 2, Suppi., Ab-
'° MacIntyre, I., unpublished.
Spencer, H., Lewin, I., and Samachson, J., Proceedings of the Third
International Congress of Endocrinology, 1968.
Excerpta Medica,
Abstract No. 157.
In press.
"Milhaud, G., Moukhtar, M. S., Bourichon, J., and Petault, A. M.,
Sci.
C. R. Acad.
5.
(Pans), 1965, 261,
"Melvin, K. E. W., and Tashjian, A. H., jun., Proc. nat. Aced.
1216.
(Wash.), 1968,
" Cunliffe, W. J., et al., Lancet,
2, 63.
4513,
S9,
Sci.
1968,
Williams,
20
E.
19, 103.
21
Fraser, D.,
Kooh,
Res., 1968,
22
Tashjian,
Sci.
A.
S.
W., Chan, A. M., and Cherian, A. G., Caic. Tiss.
2, Suppl.
Abstract
H., Jr., Frantz,
A.
(Wash.), 1966, 56, 1138.
2S Walker,
2
D., Brown, C. L., and Doniach, I., 7. clin. Path., 1966,
D.
G.,
Endocrinology,
52.
G., and Lee, J. B., Proc.
nat.
Acad.
1966, 79, 836.
Foster, G. V., Joplin, G. F.,
Slack, E., Lancet, 1966, 1, 107.
MacIntyre,
I., Melvin,
K. E.
W.,
and
hLurs
MEDC AL IOJ RNL
described in the B.M.J. this week by Dr. M. Tubiana and
colleagues and three more previously reported'8 19 have
included data on serum-calcium levels in association with
excessive secretion of calcitonin. Three patients were normocalcaemic, two (Cases 1 and 4 in the present report) were
mildly hypercalcaemic, and one was hypocalcaemic.
The absence of any consistent effect on the serum calcium
is at first sight difficult to understand. There are three
possibilities. Firstly, the calcitonin from the C cell tumour
may be biologically inactive in man. Secondly, excess calcitonin may be compensated by an increase in secretion of
parathyroid hormone. Thirdly, the serum calcium may be
normal when bone resorption rates are reduced if dietary
calcium is adequate.
No evidence is available to confirm or refute the first suggestion, and assays of parathyroid hormone have been reported
in only one patient.'8 This patient, who was hypocalcaemic
and had widespread metastases and diarrhoea, showed a fourfold increase in the assay level. Dietary calcium was probably
inadequate or unavailable and was likely to have been responsible for the hypocalcaemia in the presence of a reduced rate
of bone resorption. The parathyroid glands in another
patient'9 were macroscopically and histologically normal, and
urinary excretion of phosphate was in the low normal range.
Secondary hyperparathyroidism in this patient is therefore
unlikely.
If calcitonin secreted by these tumours diminishes resorption of bone, then normal values of serum calcium would
depend largely on absorption of calcium from the gut. That
this situation may occur is suggested in a recent report2l
describing a case of osteopetrosis in a growing child in whom
restriction of dietary calcium led to severe hypocalcaemia.
Resorption of bone, therefore, may not always play a significant part in maintaining the correct level of serum calcium.
The hypercalcaemia noted in cases 1 and 4 of the present
report is more difficult to explain, but we are not told how
many calcium estimations these figures represent nor at what
time of day blood was taken. In the absence of bone as a
buffer for ingested calcium, fluctuations in serum calcium
values might be expected.
The recent recognition of medullary carcinoma of the
thyroid as a new endocrine disease has certain practical consequences. Firstly, the diagnosis may be confirmed and the
results of therapy followed by serial assays of plasma
calcitonin. Secondly, prophylactic thymectomy may be considered when the tumour is still apparently localized to the
thyroid, because the frequent appearance of the disease in
the mediastinum may represent further primary tumour sites
rather than metastases.
Little is known about abnormalities of calcitonin secretion
in other diseases. The thyroid gland in pseudohypoparathyroidism has been reported to contain increased calcitonin
levels22 and there is some evidence from animal studies that
thyroidal C cells are increased in osteopetrosis.2' But determinations of plasma calcitonin are required before any
definite conclusion may be drawn.
The therapeutic use of calcitonin is still in an experimental
stage. It is known to be active in man,2' and large doses may
turn out to be the safest and most effective treatment of
hypercalcaemia due to increased resorption of bone. It may
also help in the treatment of Paget's disease, osteoporosis,
and possibly malignant metastases in bone. So far only
porcine calcitonin has been used in man, and the effectiveness
of the human material awaits confirmation.