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Microsoft word - primaryhyperparathyroid
By Associate Professor Terry Diamond,
Department of Endocrinology,
University of New South Wales What is Primary Hyperparathyroidism?
This is a syndrome comprising of an overproduction of
parathyroid hormone (PTH) by one or more abnormal
parathyroid glands resulting in hypercalcaemia (an elevated
serum calcium level). Normal Parathyroid Anatomy:
The parathyroid glands are four small glands located in the neck
near the thyroid gland and are responsible for maintaining
normal serum calcium levels. Usually, 4 parathyroid glands
develop, although approximately 10% of people may have 2, 3,
or 5 glands. The superior glands are typically located on the
posterior aspect of the upper thyroid, whereas the location of the
inferior glands is more variable (posterior to, or located in the
thyroid gland, along the carotid sheath, or attached to the
thymus or even in the chest).
Normal Parathyroid Physiology: All parathyroid glands
constantly monitor serum calcium
concentration. This is acieved by a complex sensing mechanism
(calcium-ion sensing receptor) in the parathyroid cells that
respond to changes in serum calcium concentration. This is a
very sensitive mechanism occurring in all normal parathyroid
aiming to maintain normal
serum calcium 'setting' of
between 2.1 and 2.65 mmol/L This is essential for normal bone
metabolism, muscle and nerve physiology. In the nonpathologic
state, PTH secretion increases in response to low serum calcium
concentrations, thereby enhancing calcium gut and kidney
reabsorption and osteoclastic bone resorption.
Absorb Ca++ and PO —
in Small Intestine
1,25 (0H)2 D3
Maintain Serum Calcium
Abnormal Parathyroid Physiology:
Usually one, or sometimes all four parathyroid glands become
abnormal and lose their calcium sensing ability thereby
secreting too much PTH without paying attention to the serum
calcium concentration. With primary hyperparathyroidism, an
increased PTH secretion by pathological gland(s) result in an
increased reabsorption of calcium from the gut/kidneys and
increased bone resorption. Even though the serum calcium level
rises, the abnormal parathyroid(s) continue to secrete PTH in an
uncontrolled manner resulting in hypercalcaemia. Defining Primary Hyperparathyroidism: Hyper-parathyroid-ism
= condition of too much
parathyroid gland activity hyper = too much
parathyroid = parathyroid gland
ism = a disease or condition
This is a primary disorder of the parathyroids affecting one, two
or all four glands, whereby an autonomous secretion of PTH
results in elevated serum PTH and calcium concentrations
. Who will get Primary Hyperparathyroidism?
The incidence of primary hyperparathyroidism is
approximately 25-30 cases per 100,000 people. In individuals
aged 15-65 years, the incidence increases to 70-150 cases per
100,000 people. Young people do get parathyroid disease, but
this is rare in childhood.
Incidence of primary hyperparathyroidism in women is 2-
3 times the incidence in men. Age:
The average patient age at diagnosis is 55 years. The
incidence peaks in those aged 40-70 years.
What causes Primary Hyperparathyroidism?
The most common cause is the development of a benign
tumor in one of the parathyroid glands
. This enlargement of
one parathyroid gland is called a parathyroid adenoma
accounts for about 97 percent of all patients with primary
hyperparathyroidism. They will also have three normal
parathyroid glands. Approximately 3 percent of all patients with
primary hyperparathyroidism will have an enlargement of all
four parathyroid glands, a term called parathyroid
In this instance, all of the parathyroid glands
become enlarged and produce too much parathyroid hormone.
This condition may be associated with long-term Lithium
therapy (for psychosis), previous ionising radiation to the head
and neck and rarely, as a familial tumour syndrome. Patients
with primary hyperparathyroidism may rarely have two
parathyroid adenomas (0.5%) and two normal glands.
Parathyroid carcinoma is very, very, very rare (<0.05%). What symptoms occur with Primary
Hyperparathyroidism causes symptoms in almost
, but sometimes they are quite subtle.
Since hyperparathyroidism was first described in 1925, the
“classical” symptoms have become known as
1. moans (psychological and neurological effects), 2. groans (abdominal ulcer pains), 3. stones (kidneys), and 4. bones (fractures).
Although most people with primary hyperparathyroidism claim
to feel well when the diagnosis is made, the majority of these
will actually say they feel better after the problem has been
cured. Many patients who thought they were asymptomatic
preoperatively will claim to sleep better at night, be less
irritable, and find that they remember things much easier than
they could when their calcium levels were high. In some
studies, as many as 92% of patients claim to feel better after
removal of a diseased parathyroid gland, even when only
75% claim they felt "bad" before the operation. Classical Symptoms
When the serum calcium exceeds the routine elevations (> 2.65
mmol/L) seen in primaryhyperparathyroidism,
“hypercalcaemic” symptoms can include:
• loss of appetite
• frequent urination
• muscle weakness
• joint pain
When the serum calcium becomes very high (usually >3
mmol/L), more severe symptoms include:
• abdominal pain
• memory loss
• depression Potential Dangers of “missed” or untreated
• Osteoporosis and osteopenia
• Bone fractures
• Kidney stones
• Peptic ulcers
• Nervous system complaints
The incidence of these problems depends primarily on the
duration of the disease and its severity. Patients with
longstanding and persistently elevated serum PTH can develop
significant skeletal and renal abnormalities. This problem is
even more of a concern in older patients. Everybody will lose
bone density, which is progressive.
The constant filtering of
large amounts of calcium will cause the deposition of calcium
within the renal tubules and can lead to kidney failure. Diagnosis of Primary Hyperparathyroidism:
This disorder is confirmed by routine blood test. These include elevated serum calcium and an “inappropriately”
elevated serum PTH concentration.
Additional testing is indicated to exclude other conditions
causing hypercalcaemia and for decision-making regarding
• Blood test
– Serum urea and creatinine (to assess
• Urine test
– 24 Hour urine calcium (to exclude a rare
condition of low calcium excretion or familial hypocalciuric hypercalcaemia) and creatinine clearance (to assess kidney function).
• Abdominal ultrasound
-- In some cases imaging of
the kidneys (to exclude stone formation) and pancreas (to exclude pancreatitis) is required.
• Skeletal X-Rays and Bone density test
determine the detrimental effect of prolonged PTH on the skeleton.
• Parathyroid imaging with Technetium 99m
SESTAMIBI scan –
This is a radiolabelled nuclear
medicine scan (MIBI) of the thyroid that preferentially
localises a single abnormal parathyroid adenoma that
may be amenable to minimally invasive parathyroid
surgery. The Sestamibi scan with computerised
tomography (SPECT), is the most specific test.
Treatment of Primary Hyperparathyroidism:
Types of physicians
Physicians who treat primary hyperparathyroidism include
endocrinologists (internists who specialise in hormonal and
metabolic disorders) and surgeons who specialise in endocrine
surgery. Surgery for Primary Hyperparathyroidism:
At present, the only known cure for primary
hyperparathyroidism is surgical removal of the abnormal
. There are specific guidelines to help
determine who should have surgery. The decision requires
careful evaluation and individual assessment.
Current parathyroid surgery is largely based on the findings of
the MIBI scan, whether positive or negative. A positive scan
facilitates the removal of a single parathyroid adenoma by
minimally invasive parathyroid surgery.
“MIBI” positive adenoma
"Minimally invasive parathyroidectomy
This is performed in select medical centers by experienced
parathyroid surgeons. The MIBI scan localises the presence of a
single or rarely double parathyroid adenoma. Surgery can be
performed under general, regional, or local anesthesia. The operation is successful in over 95 percent of cases. Serious complications are uncommon. Surgery usually leaves a thin, faint horizontal scar about 1-2 cm long in the lower neck. The findings of a normal serum PTH concentration measured immediately post surgery is confirmatory evidence of cure.
Minimally invasive parathyroid surgery via a small incision. Parathyroid Neck Exploration:
Individuals who have a negative MIBI scan or who are
suspected of having multigland disease (more than one
abnormal parathyroid gland) are candidates for parathyroid neck
exploration by an experienced parathyroid surgeon. Several
non-invasive tests (ultrasound, computerised tomography,
magnetic resonance imaging, positron emission tomography) are
available for locating the abnormal parathyroid gland(s), but
these are usually reserved for failed operations.
In order to assure control of affected glands a thorough neck
exploration is mandatory. This includes both sides of the neck
from the carotid bifurcation to the superior mediastinum.
Specific treatment algorithms exist. A single adenoma is first
biopsied and if found to be hypercellular parathyroid tissue then
one more gland is biopsied. If the biopsy of the sercond gland
proves to be normal then the diagnosis of an adenoma is made
and the adenoma is resected. If the second biopsy reveals
hypercellular parathyroid or if diffusely enlarged glands are
seen, the process is most likely hyperplasia. In this case three
glands and a portion of the fourth are excised (called 31/2 gland parathyroidectomy). A well vascularised remnant is left to provide some parathyroid function.
Parathyroid autotransplantation is reserved for patients in whom
all four parathyroid glands are affected (important in familial
tumor syndromes and Multiple Endocrine Neoplasia) or who
need repeat surgery resulting in the removal of all or excessive
amounts of parathyroid tissue. This can result in
hypoparathyroidism, or the production of too little PTH. To
prevent this, parathyroid autotransplantation is performed. All
parathyroid tissue in the neck is removed, and a small amount is
transplanted to the forearm where it can remain and perform its
function of producing parathyroid hormone for the body. Indications for parathyroidectomy:
The National Institute of Health in USA has outlined a
number of indications for parathyroid surgery in
patients with primary hyperparathyroidism
a. Serum calcium > 2.90 mmol/l. b. Life threatening hypercalcaemia eg. neurological
complications (dehydration), acute pancreatitis, active peptic ulcer disease etc.
c. Renal disease (nephrocalcinosis, hypercalciurea >10
mmol/day or creatinine clearance < 30% below normal).
d. Bone density (t-score < -2.5 at any site) e. Patient’s age: < 50 years
Is there an alternative to surgery for Primary
Patients who on routine testing are found to have a mildly elevated serum calcium concentration (2.65-
2.75 mmol/L) may be treated conservatively.
–If surgery is not to be performed, these patients
should be monitored regularly with serum calcium every 6 months and 24 hour urinary calcium excretion and bone density every 12 months. Most patients do not get worse over years of follow-up care.
• Estrogen and bisphosphonate therapies
-- This treatment
may reduce some of the PTH effects of the disease, but will not directly control glandular overactivity. Estrogen and alendronate (fosamax) are important therapies for women with osteoporosis and primary hyperparathyroidism. These agents may increase bone densities by 4-6% over 2 years in this cohort.
Prognosis Removing the abnormal parathyroid gland(s) cures
Kidney stones do not tend to recur. In patients
with osteoporosis/osteopaenia, bone densities may increase by
as much as 20% over 1 to 4 years. However, nonspecific
symptoms such as weakness and easy fatigability are not always
eliminated. Recent data suggests that curing primary
hyperparathyroidism may improve abnormal fat (lipid) and
glucose metbolism thereby improving insulin resistance and
reduce the risk of heart disease.
Important Facts about Primary
1. It is never
normal to have elevated serum calcium.
2. Almost all patients with elevated serum calcium will have
a single abnormal parathyroid gland. Your doctor may look for other causes. but you will end up with parathyroid disease.
3. The one abnormal parathyroid gland is a tumor. It is a
benign tumor (almost never cancer), but it is a tumor.
4. Most parathyroid tumors vary in size between an olive and
a grape. The size doesn't matter. just how much PTH it
produces and how much calcium it is taking out of your bones.
5. An expert in parathyroid surgery can fix this problem in
6. Selecting your surgeon is the most important step, since
the outcomes (cure rates and complications) are directly related to surgeon’s experience.
7. Removing the abnormal parathyroid tumor will cure the
hyperparathyroidism and will normalise the serum calcium concentration WITHIN HOURS.
8. Removing the parathyroid tumor will change the patient's
life. It can make you feel 10 years younger, and literally, change your life.
The question begs “Why not undergo parathyroid
surgery for primary hyperparathyroidism?”
Albright F, Reifenstein EC: Clinical hyperparathyroidism. In: The
Parathyroid Glands and Metabolic Bone Disease: Selected Studies. 1948:
Bilezikian JP, Silverberg SJ. Asymptomatic priamry
hyperparathyroidism. N Engl J Med 2004;350:1746-51.
Silverberg SJ: Natural history of primary hyperparathyroidism.
Endocrinol Metab Clin North Am 2000 Sep; 29(3): 451-64.
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The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma Randolph Malone, MD*; Craig LaForce, MD†; Sai Nimmagadda, MD‡; Lynne Schoaf, RN§; Karen House, MS§; Anna Ellsworth, BS§; and Paul Dorinsky, MD§ Background: For children older than 5 years with asthma who remain symptomatic despite inhaled corticosteroid (ICS) th