Hyperparathyroidism
•
The symptomatic presentation may vary but the increased use of auto
analysers has resulted in ‘asymptomatic’ hypercalcaemic patients being
the largest group.
• A corrected serum calcium concentration above the upper limit of normal
and a simultaneous elevation of serum parathyroid
hormone level are mandatory for the diagnosis.
•
Surgery should only be performed by an experienced parathyroid surgeon.
Long-term follow-up is essential as there is a
significant increase in risk of death from cardiovascular disease.
•
Primary hyperparathyroidism, which is an un stimulated and inappropriately
high parathyroid hormone secretion for the concentration of plasma ionised
calcium, and is due to adenoma or hyperplasia, and very rarely carcinoma.
A
single adenoma is the commonest finding (multiple in 6 per cent). The whole
gland is usually considerably enlarged, darker in colour, firmer and more
vascular than normal; in some a rim of normal parathyroid tissue may be seen
surrounding the adenoma. The histological appearances are the same as in
hyperplasia, with a predominance of chief and water-clear cells. Carcinoma of
the parathyroids is extremely rare, less than 1 per cent. It tends to invade
locally and recur after operation. Blood-borne metastases have been described.
•
Secondary hyperparathyroidism is associated with chronic renal failure or
malabsorption syndromes. The stimulus for the hyperplasia is chronic
hypocalcaemia. All four glands are involved.
•
Tertiary hyperparathyroidism is a further stage in the development of
reactive hyperplasia where autonomy occurs as the parathyroids no longer respond
to physiological stimuli.
Cinical
features
Hyperparathyroidism, rarely found in the first
decade of life, is commoner in women than men, and most commonly found between
the ages of 20 and 60 years. The clinical features vary enormously, even when
the biochemical changes are similar.
Asymptomatic
cases
The most common presentation is the detection
of unsuspected and asymptomatic hypercalcaemia by routine biochemical screening.
Bones, stones,
abdominal groans and psychic moans’
Only 50 per cent of patients suffer from any
of these.
Nonspecific
symptoms
Nonspecific symptoms include muscle weakness,
thirst, polyuria, anorexia and weight loss — a challenge to the astute
clinician!
Bone disease
Renal stones
Hyperparathyroidism must be considered in
every patient presenting with renal tract stone or nephrocalcinosis (Fig. 45.5),
and even in those cases of renal colic where no stone can be
demonstrated.
Dyspeptic cases
Patients with nausea, vomiting and anorexia
are relatively common. Peptic ulcer and pancreatitis are not infrequently found
in association with hyperparathyroidism, but the relationship is not as yet
fully understood.
Psychiatric
cases
Psychiatric cases are not uncommon; women,
complaining of tiredness, listlessness and with obvious personality changes,
Clinical
examination and investigation
Clinical examination may be unrewarding but
the cause of dehydration or confusion may be found in the eyes. Corneal
calcification may be detected.
It begins on the lateral and medial borders of the limbus (which distinguishes
it from arcus senilis) and is best seen through a hand lens by the light of a
bright torch reflected off the iris. Less common is band
keratopathy in which a transverse band of calcification forms across the
front of the cornea, and conjunctival
calcification where redness of the eye also occurs. Hypertension may be
present in up to 50 per cent of cases. There may be electrocardiographic changes
with a shortened QT interval, primarily by an effect on the length of the S—T
segment. A parathyroid adenoma is very seldom palpable in the neck. The
diagnosis is confirmed with the following biochemical findings:
•
elevation of serum calcium (upper limit of normal 2.6 mmol/litre). Serum
calcium occurs as calcium ions complexed to citrate and bound to albumin.
Therefore the serum albumin concentration should be known in order to apply a
correction factor: corrected serum calcium (mmol/litre) = measured serum Ca (mmol/litre)
+ (40 —A) x 0.02, where A = serum albumin (g/litre);
•
diminution of serum phosphorus (lower limit of normal 0.8 mmol/litre);
•
increased excretion of calcium in the urine (upper limit of normal 62
mmol per 24 hours for females, 75 mmol for males);
•
elevation of the serum alkaline phosphatase in cases with bone disease;
•
elevation of serum parathormone concentration.
The
diagnosis of hyperparathyroidism largely depends on confirmed hypercalcaemia,
exclusion of other causes of hypercalcaemia (see below) and a raised
parathormone level. Present day immunoradiometric assays (upper limit of normal
varies according to the laboratory) for biologically active intact parathormone
are highly reliable and a raised level is even more reliable. Detectable levels
of parathormone within the normal range, in the presence of hypercalcaemia, are
suggestive of the diagnosis.
Preoperative localisation
Provided the surgeon is experienced in
parathyroid surgery, preoperative localisation tests may do little to enhance
the ability to detect 95 per cent of
abnormal glands at surgery. However, a multimodal approach combining
thallium—technetium isotope scanning, neck ultrasonography and magnetic
resonance imaging (MRI) may yield precise information which will clearly
facilitate surgery and reduce unnecessary dissection of tissue. Localisation
tests are particularly indicated before re-exploration when the initial
operation has failed, but may also be helpful to less experienced surgeons.
•
The simplest localisation test is an ultrasonic scan but results vary
according to the skill and experience of the investigator.
• Computerised tomography is of most value in localising a lesion in the
mediastinum rather than the neck.
•
Thallium—technetium isotope subtraction imaging may locate up to 90 per
cent of parathyroid adenomas before surgery (Fig. 45.6).
Like ultrasonography, subtraction scintigraphy is more accurate the larger
the adenoma, and is inaccurate in parathyroid hyperplasia.
•
MRI is improving rapidly with some centres reporting up to 64 per cent
detection prospectively. A low signal is obtained from the parathyroid glands on
a T1-weighted image while a T2-weighted image appears in early
studies to produce good contrast resolution from the surrounding tissues.
•
Invasive techniques such as selective angiography and selective venous
sampling may be helpful in locating an abnormally situated gland after a failed
initial exploration.
Differential
diagnosis
Other causes of hypercalcaemia must be
remembered and excluded. They are:
•
carcinoma with endocrine secretion (bronchus, kidney and ovary);
•
multiple myeloma;
•
vitamin D intoxication;
•sarcoidosis;
•thyrotoxicosis;
•immobilisation;
•
medication: thiazide diuretics, lithium.
The
differential diagnosis presents no problem
if the parathormone level is estimated. In none of the above-mentioned
conditions will parathormone be detectable in the blood.
Treatment
The only corrective treatment is surgical
removal of the overactive gland or glands. In symptomatic patients, the
indications for operation are clearcut. Many patients, however, in whom
hypercalcaemia has been discovered incidentally, are not overtly symptomatic and
a decision in favour of operation is more difficult.
Preoperative
treatment is not usually necessary except in acute cases, when rapid correction
of dehydration and electrolyte imbalance is necessary, with a careful daily
check on the serum calcium. Drugs used would have been discussed earlier.
A
recent international survey of operative strategy shows that the approach is
changing. Removal of the adenoma with biopsy of the other glands has been
supplanted by removal of the adenoma, a peroperative histological diagnosis and
then biopsy of one normal gland. If the peroperative biopsy is that of a
hyperplastic gland, then removal of all four glands with auto transplantation is
indicated. Approximately 90 per cent of cases of primary hyperparathyroidisrn
are associated with single-gland disease (adenoma). Ten per cent of cases are
associated with multiple-gland disease, either hyperplasia or more than one
adenoma. Adenomas, single or multiple, are removed.
In
approximately 10 per cent of cases even the most experienced surgeon in this
field may find difficulty in locating a parathyroid adenoma.
Parathyroid
tissue can be successfully autotransplanted into the arm, a useful technique to
avoid repeated potentially difficult explorations of the neck. The indications
are tertiary hyperparathyroidism in patients undergoing chronic renal dialysis,
and recurrent hyperparathyroidism. The technique is to excise all of the
parathyroid tissue from the neck and to implant eight 1-mm3 fragments
into a pocket in the forearm muscle mass, marking the site with nonabsorbable
sutures. Postoperative vitamin D and calcium replacement therapy is required for
varying periods. Recurrent hypercalcaemia is an indication for exploration of
the implantation site and to excise further parathyroid tissue.
Prognosis
With successful surgery in severe cases, bones
will recalcify and pseudotumours resolve. Renal stones will not disappear, but
the incidence of recurrence after surgical removal is reduced and deterioration
in renal function is prevented. Psychiatric patients show an early and often
remarkable recovery. Many patients who are not overtly symptomatic
beforehand are aware of an improvement in
well-being after correction of hypercalcaemia. In a small minority of cases,
hyperparathyroidism recurs after several years and may warrant further surgery.
In some of these, autotransplantation (above) offers reasonable prospects of
control; Wells has reported excellent results when auto transplantation has been
used for recurrent and familial hyperparathyroidism.
Hypertension
associated with hyperparathyroidism is common, but the mechanism is unclear.
Long-term
survival has been studied in 900 patients in Sweden. Despite successful surgery
for primary hyperparathyroidism, the risk of premature death from
cardiovascular and malignant diseases remained significant. Thus long-term
follow-up is important as this indicates that primary hyperparathyroidism
causes damage that is not reversed by surgery.
Patients
with persistent and recurrent primary hyperparathyroidism are a difficult
management problem. For patients in whom initial exploration fails, reoperation
is associated with a higher morbidity and a greater chance of failure. Accurate
diagnosis and review of the initial pathology are essential, a family history of
multiple endocrine neoplasia should be excluded, together with occult
malignancy. Preoperative venous sampling of the neck and thorax is particularly
valuable in localising a missed adenoma which is the most common cause of
failure at the first operation.
Mild
asymptomatic hypercalcaemia is a relative contraindication to further surgery
but regular follow-up is mandatory. With an experienced surgeon, up to 90 per
cent of missed lesions may be found but persistent postoperative hypocalcaemia
may occur in up to 10 per cent of patients and recurrent laryngeal nerve injury
is seen in about 6 per cent.
Parathyroid
carcinoma
Parathyroid carcinoma is a rare condition to
be considered when a high serum calcium is associated with a palpable lump in
the neck. At operation it has a characteristic grey—white colour and is
adherent because of local invasion of adjacent soft tissue. The best results are
obtained by early recognition, avoiding rupture of the tumour capsule, and
aggressive surgical management including ipsilateral thyroid lobectomy. Surgical
clips should be used to outline the tumour bed for postoperative radiotherapy.
Multiple
endocrine neoplasia syndrome — APUD cells
Always consider that a patient with
hyperparathyroidism may also have multiple endocrine adenomas. The cells
involved, irrespective of the site, have the common chemical characteristics of
amine precursor uptake and decarboxylation and are thus known as APUD cells.
The disorder is inherited as an autosomal dominant, the manifestations in any
one family tend to be similar and all members of the family should be
investigated.
Type I
This most common variant involves the
parathyroid glands (90 per cent), pancreatic islets (80 per cent), pituitary (65
per cent), thyroid and adrenal cortex. There is hyperplasia of the
parathyroid glands and a chromophobe adenoma of the pituitary which may result
in increased prolactin production or acromegaly. The pancreatic tumour may
produce gastrin (the Zollinger—Ellison syndrome) or insulin, glucagon,
somatostatin or vasoactive intestinal peptide (VIP) causing watery diarrhoea.
Treatment is surgical excision.
Type IIa
A genetic abnormality located on chromosome 10
has been identified in MEN type ha syndrome. Fifty per cent have parathyroid
hyperplasia. The associated lesions may be a medullary carcinoma of thyroid,
which produces calcitonin, and a phaeochromocytoma. The latter should be
excluded or be the first priority for treatment before exploration of the neck
(see also Chapter 44).
This is differentiated from type IIa because
of additional neurological abnormalities. Mucosal neuromas produce ‘lumpy and
bumpy’ lips (Fig. 44.42) or eyelids, and there is a characteristic Marfanoid
facial appearance. Megacolon and ganglioneuromatosis are also - found (see also
Chapter 44).