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4.
Definition and classification of the hyperparathyroid The hyperfunction
of one or more parathyroid glands produces the clinic syndrome known
as hyper-para-thyroidism (IPT), which, depending on the calcemia levels,
is classified as: primary (IPTp) and secondary (IPTs). The two forms
also differentiate because of their distinct therapeutic implications.
An abnormal growth of parathyroid glands does not result in a compressive
process on the surrounding tissues, as in the case of other endocrine
glands (hypophysis, thyroid), but manifests itself through an increased
incretion of PTH with hypercalcemia having an asympto-matic course for
several years. IPTp distinguishes itself for the presence of circulating
levels of calcium touching the higher limits of the normal range or
definitely high values associated with (inadequately) high PTH levels.
IPTp has a 1:1000 impact increasing with age, to a larger extent between
40 and 65 years and three times as much in post-menopausal women than
in men of the same age. It may occur in a sporadic or in a familial
form (Table I).
The excessive production of PTH in IPTp may be supported by an adenoma
(85-87% of cases), by hyperplasia (12-15% of cases) or by a carcinoma
of the parathyroid glands (<1% of cases), which give rise to clinic
presentations which cannot be distinguished from one another. The parathyroid
adenoma generally is a solitary, benign, tumour of the parathyroid tissue
and most adeno-mas are marked by hyperfunction. The familial forms are
generally hyperplastic or in any case involve a number of parathyroid
glands.
The
ectopic production of PTH by a non-parathyroid neoplasia miming the
picture of IPTp is very rare (less than ten cases described in literature
to date). IPTs is a compensatory - and therefore appropriate - response
to a reduced level of circulating calcium, though excess PTH may reach
such high levels that it can produce a number of compli-cations.
A typical example of IPTs is represented by intestinal pathologies associated
with malabsorption or with a severe vitamin D deficiency.
Another
major condition brought about by IPTs is chronic renal insufficiency.
In such patients, even in the event of slight reductions in renal function,
the para-thyroid histologic changes and the increase in circulating
PTH are amongst the earlier metabolic alterations of mineral metabolism.
In the event of renal insufficiency, a whole range of factors contributes
to the alteration of the normal secretion of PTH, such as reduced circulating
levels of 1,25(OH)2D3, the retention of phosphates and related hypocalcemia
and the resistance of bones to the action of PTH.
The histologic lesions of IPTs are represented by a vast hyperplasia
of chief cells, which in time may develop into nodules.
This
variation may be associated with the development of a certain degree
of secretory autonomy, which may lead to tertiary hyper-parathyroidism
(IPTt) with hyper-calcemia. 5. Familial forms of primary hyperthyroidism
Specialists should be able to suspect and detect familial cases in order
not to make therapeutic mistakes and to direct their therapeutic choices
within a family.
The
type 1 multiple endocrine neoplasia (MEN 1) is a syndrome marked by
hyperplasia of the parathyroid glands, neoplasias of the adeno-hypophysis
(more often prolactinomas) and of the endocrine component of the gastroenteric
tract (the most frequent are gastrinomas and insulinomas).
It rarely exists in a sporadic form, whereas the more frequent familial
form has an autosomal dominant transmission with complete penetrance
and variable expressiveness.
Therefore,
with a parent suffering from this syndrome, there is a 50% probability
of transmitting the pathology to a son or daughter.
IPTp represents in 80-90% of cases the first clinic manifestation and
in all cases it manifests itself by the age of 50.
It is an IPT supported by hyperplasia of all the parathyroid glands,
even though with an involvement which is asynchronous in time and asymmetrical
in size (picture 6). The average age of onset of the IPTp associated
with this syndrome is around 20-25 years, versus the average of 55 years
in sporadic forms.
It is therefore the young age of inset which should lead to the suspicion
of a familial form. Recently, the gene MEN1 (chromosome 11) has been
cloned. This is a gene made up of 10 exons, 9 of which code for a 2.8
Kb transcript.
Its
product, menin, has no features in common with any of the previously
known proteins and interacts directly with the transcription factor
JunD, by repressing the JunD-dependent transcriptional activation.
Various
types of mutations are descri-bed: "frame-shift" (DNA reading code shift),
"in-frame" deletions, "missense" and "non-sense" with consequent loss
of the menin function.
It
has been demonstrated that there is no correlation between mutation
and clinic phenotype. To this day, the mutations described are over
200 for these patients.
The possibility of having a mutational analysis of the gene represents
a useful diagnostic method available to verify possible transmission
to the progeny.
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