- Email: [email protected]
Metabolism of Iodotyrosines
611
LEADING ARTICLES
THE LANCET LONDON:
SATURDAY, SEPT. 22,
Metabolism of
1956
Iodotyrosines
RECENT research has embroidered, but not radically kanged. HARINGTON’S now classical concept 1 of the blosynthesis of thyroid hormone. The first step is thought to be the iodination of tyrosine radicals, within the thyroglobulin molecule, to form iodotyrosines. Some of these then couple to give thyroxine. But only a proportion can do so, depending on their spatial position within the thyroglobulin molecule. When the thyroglobulin molecule is later hydrolysed by the protease known to be present in the gland,
and
di-iodotyrosines must be released, as well as the active hormonal products, thyroxine and tripodothyronine. Yet only the two last compounds Mono- and di-iodotyrosine .’.ppear in the blood. since ,lpparentlv disappear, only traces of the free be found the gland. The can within compounds of the was solved mystery vanishing iodotyrosines by ROCHE and his colleagues,2 who discovered an enzyme .ll the thyroid which has the property of liberating from mono- and di-iodotyrosine. This deiodinase acts only on iodotyrosines ; it has no action on thyroxine or any of the other iodinated thyronines. Since it is activated by thyroid-stimulating hormone and depressed by thyroxine,3 it is likely to have an important part to play in the economy of the thyroid. It- presumed function is the conservation of iodine, which would otherwise be lost to the thyroid if it was allowed to escape in the form of iodotyrosines. Even mono-
if these substances were deiodinated elsewhere in the body. only about half the iodine contained in them would find its way back to the thyroid as iodide, the rest being excreted in the urine. Since a large propor1l0n ofthe iodine in thyroglobulin is contained in radicals, the amount which could be lost, in the absence of the deiodinating enzyme, would be considerable. Even in areas where there is no goitre the intake of iodine in the diet is not more than barely adequate. It is therefore to ’- expected that the absence of the deiodinating would result in the signs of iodine deficiency, first by the development of a hyperplastic goitre Idter Thi, expectation has now been verified by STANBURY and his colleagues,4 working in Professor QuERiDO’s laboratory at Leyden. They have described 3 cases goitre with hypothyroidism which appear to be
by hypothyroidism.
explained by presuming
a
congenital
of the deiodinase. After giving these patients labelled with 131I, mono- and di-iodotyrosine *-.- identified in the blood and urine. This showed ’:...1 the deiodinating enzyme was either absent or - ’ doing job properly. This would not necessarily
its
1. 2.
C. R. Proc. roy. Soc. B. 1944, 132, 223. Michel, R., Michel, O., Lissitzky, S. Biochim. biophys.
Harington,
Roche, J.
9, 161. R., Amer. J. Med. 1956, 20, 670. Stanbury, J. B., Meijer, J. W. A., Kassenaar, A. A. H. Endocrin. 1956, 16, 848.
be a serious matter for the patients if they could split off the iodine elsewhere in the body, since about half of it would then find its way back to the thyroid. But they were not able to do so, for when labelled di-iodotyrosin.6 was given intravenously it appeared almost entirely unchanged in the urine. This is in sharp contrast to what happens in normal people who can split off all the iodine from administered diiodotyrosine. Similarly, when mono-iodotyrosine was given to the 3 goitrous patients, the bulk of it appeared in the urine either unchanged or in the form of unidentified iodine-containing substances. The clinical features in these 3 cases can probably be explained by the assumption that the patients had no deiodinating enzyme either in the thyroid or elsewhere in the body. The loss of iodine resulting from continual excretion of iodotyrosines in the urine might well be sufficient to prevent the formation of thyroid hormone in adequate amounts, even by enlarged and hyperplastic
glands.
brothers. The 3rd was but 4 of her own relatives 2, had goitres. These were investigated, together with a 5th unaffected member of the family. These 5 were able to deiodinate intravenous di-iodotyrosine, but less efficiently than normal subjects. It is a fair guess that the defect was enough to stimulate goitre formation and that the enlarged thyroid was then able to make sufficient hormone, in spite of its handicap, to avoid clinical hypothyroidism. The cases studied by STANBURY et al. were too few to permit deductions about genetics. A biochemical defect of this sort is, however, likely to be genetically determined, and it is tempting to consider the possibility that the 3 patients with the full defect represent homozygotes, while the relatives with goitre, but no hypothyroidism, may be heterozygotes. Much more work would be needed to test this idea, but it is interesting as a possible explanation of the far from negligible number of goitres which appear in areas where the supply of iodine is apparently adequate. Although the supposed homozygotes, with complete lack of deiodinase, are obviously rare, it is quite possible for the beterozygotes These speculations are to be relatively common. a ahead of the evidence, but they running long way that it be worth applying the techniques suggest might al. to the investigation of developed by STANBURY et other cases of non-endemic goitre.
Of the 3
patients,
2
were
not related to the other
Undescended Testis THE lack of accurate information on postnatal descent of the testis has lately been emphasised by He followed up 1700 male infants first SCORER.12 seen at a maternity unit and compared his figures for incomplete descent at the end of the first year of life with those for the adult population, as calculated by SOUTHAM and COOPER.3 Their estimate for the general population was near to SCORER’S observed prevalence in infants, and from this he concludes that " it seems likely that complete descent of the testicles does not occur after the age of three months." If this is true, it is an important piece of information and may lead to a change of views on the best time for - treating the undescended testis. But to accept
Acta, 1952,
3. 4.
Michel,
J. clin.
1. Scorer, C. G. Arch. Dis. Childh. 1956, 31, 198. 2. Scorer, C. G. Brit. J. Urol. 1955, 27, 374. 3. Southam, A. H., Cooper, E. R. A. Lancet, 1927, i, 805.
LEADING ARTICLES
THE LANCET LONDON:
SATURDAY, SEPT. 22,
Metabolism of
1956
Iodotyrosines
RECENT research has embroidered, but not radically kanged. HARINGTON’S now classical concept 1 of the blosynthesis of thyroid hormone. The first step is thought to be the iodination of tyrosine radicals, within the thyroglobulin molecule, to form iodotyrosines. Some of these then couple to give thyroxine. But only a proportion can do so, depending on their spatial position within the thyroglobulin molecule. When the thyroglobulin molecule is later hydrolysed by the protease known to be present in the gland,
and
di-iodotyrosines must be released, as well as the active hormonal products, thyroxine and tripodothyronine. Yet only the two last compounds Mono- and di-iodotyrosine .’.ppear in the blood. since ,lpparentlv disappear, only traces of the free be found the gland. The can within compounds of the was solved mystery vanishing iodotyrosines by ROCHE and his colleagues,2 who discovered an enzyme .ll the thyroid which has the property of liberating from mono- and di-iodotyrosine. This deiodinase acts only on iodotyrosines ; it has no action on thyroxine or any of the other iodinated thyronines. Since it is activated by thyroid-stimulating hormone and depressed by thyroxine,3 it is likely to have an important part to play in the economy of the thyroid. It- presumed function is the conservation of iodine, which would otherwise be lost to the thyroid if it was allowed to escape in the form of iodotyrosines. Even mono-
if these substances were deiodinated elsewhere in the body. only about half the iodine contained in them would find its way back to the thyroid as iodide, the rest being excreted in the urine. Since a large propor1l0n ofthe iodine in thyroglobulin is contained in radicals, the amount which could be lost, in the absence of the deiodinating enzyme, would be considerable. Even in areas where there is no goitre the intake of iodine in the diet is not more than barely adequate. It is therefore to ’- expected that the absence of the deiodinating would result in the signs of iodine deficiency, first by the development of a hyperplastic goitre Idter Thi, expectation has now been verified by STANBURY and his colleagues,4 working in Professor QuERiDO’s laboratory at Leyden. They have described 3 cases goitre with hypothyroidism which appear to be
by hypothyroidism.
explained by presuming
a
congenital
of the deiodinase. After giving these patients labelled with 131I, mono- and di-iodotyrosine *-.- identified in the blood and urine. This showed ’:...1 the deiodinating enzyme was either absent or - ’ doing job properly. This would not necessarily
its
1. 2.
C. R. Proc. roy. Soc. B. 1944, 132, 223. Michel, R., Michel, O., Lissitzky, S. Biochim. biophys.
Harington,
Roche, J.
9, 161. R., Amer. J. Med. 1956, 20, 670. Stanbury, J. B., Meijer, J. W. A., Kassenaar, A. A. H. Endocrin. 1956, 16, 848.
be a serious matter for the patients if they could split off the iodine elsewhere in the body, since about half of it would then find its way back to the thyroid. But they were not able to do so, for when labelled di-iodotyrosin.6 was given intravenously it appeared almost entirely unchanged in the urine. This is in sharp contrast to what happens in normal people who can split off all the iodine from administered diiodotyrosine. Similarly, when mono-iodotyrosine was given to the 3 goitrous patients, the bulk of it appeared in the urine either unchanged or in the form of unidentified iodine-containing substances. The clinical features in these 3 cases can probably be explained by the assumption that the patients had no deiodinating enzyme either in the thyroid or elsewhere in the body. The loss of iodine resulting from continual excretion of iodotyrosines in the urine might well be sufficient to prevent the formation of thyroid hormone in adequate amounts, even by enlarged and hyperplastic
glands.
brothers. The 3rd was but 4 of her own relatives 2, had goitres. These were investigated, together with a 5th unaffected member of the family. These 5 were able to deiodinate intravenous di-iodotyrosine, but less efficiently than normal subjects. It is a fair guess that the defect was enough to stimulate goitre formation and that the enlarged thyroid was then able to make sufficient hormone, in spite of its handicap, to avoid clinical hypothyroidism. The cases studied by STANBURY et al. were too few to permit deductions about genetics. A biochemical defect of this sort is, however, likely to be genetically determined, and it is tempting to consider the possibility that the 3 patients with the full defect represent homozygotes, while the relatives with goitre, but no hypothyroidism, may be heterozygotes. Much more work would be needed to test this idea, but it is interesting as a possible explanation of the far from negligible number of goitres which appear in areas where the supply of iodine is apparently adequate. Although the supposed homozygotes, with complete lack of deiodinase, are obviously rare, it is quite possible for the beterozygotes These speculations are to be relatively common. a ahead of the evidence, but they running long way that it be worth applying the techniques suggest might al. to the investigation of developed by STANBURY et other cases of non-endemic goitre.
Of the 3
patients,
2
were
not related to the other
Undescended Testis THE lack of accurate information on postnatal descent of the testis has lately been emphasised by He followed up 1700 male infants first SCORER.12 seen at a maternity unit and compared his figures for incomplete descent at the end of the first year of life with those for the adult population, as calculated by SOUTHAM and COOPER.3 Their estimate for the general population was near to SCORER’S observed prevalence in infants, and from this he concludes that " it seems likely that complete descent of the testicles does not occur after the age of three months." If this is true, it is an important piece of information and may lead to a change of views on the best time for - treating the undescended testis. But to accept
Acta, 1952,
3. 4.
Michel,
J. clin.
1. Scorer, C. G. Arch. Dis. Childh. 1956, 31, 198. 2. Scorer, C. G. Brit. J. Urol. 1955, 27, 374. 3. Southam, A. H., Cooper, E. R. A. Lancet, 1927, i, 805.