Download Primary Hyperparathyroidism

Course in Endocrinology, Year 4, HUJI, 31/10/2013
PTH related disorders
Simona Glasberg, MD
Neuroendocrine Tumors Unit,
Endocrinology & Metabolism Service,
Hadassah-Hebrew University Medical Center,
Jerusalem, Israel
Introduction -The parathyroid glands
 small endocrine glands in the neck that produce parathyroid
hormone (PTH).
 humans usually have four parathyroid glands, located in variable
manner on the posterior surface of the thyroid gland, or, in rare
cases, within the thyroid gland itself or in the chest (mediastinum) or
even the thymus.
 control the amount of Ca in the blood and within the bones.
Parathyroid hormone- physiology
The primary function of PTH is to maintain the
extracellular fluid (ECF) calcium concentration
within a narrow normal range.
PTH acts
 directly on bone (Ca resorbtion)
and kidney (Ca re-absorption)
 indirectly on the intestine through
its effects on synthesis of 1,25(OH)-D
increase
serum
Ca
in turn, PTH production is closely regulated by
the concentration of serum ionized calcium
and vitamin D.
 Calcium (through the Ca-SR) and vitamin
D (through its nuclear receptor)- reduce
PTH release and synthesis.
Hyperparathyroidism (HPT)
 excess production of PTH
 is a common cause of hypercalcemia
 is usually the result of autonomously functioning
adenomas, or hyperplasia.
 Hypocalcaemia, as might be induced by calciumdeficient diets, is counteracted by an increased
secretion of PTH 
(1) increased rate of dissolution of bone mineral 
increased flow of calcium from bone into blood
(2) reduced renal clearance of calcium, returning
more of the calcium filtered at the glomerulus into
ECF  Immediate control
(3) increased efficiency of calcium absorption in
the intestine by stimulated production of
1,25(OH)2D  Steady state
PTH actions on kidneys
Inhibition of phosphate absorbtion
(proximal tubule)
Augmentation of calcium reabsorbtion
(distal tubule)
Stimulation of the renal 25- (OH) D3 1alpha-hydroxylase.
As much as 12 mmol (500 mg) calcium is
transferred between the ECF and bone each
day
PTH acts as a homeostatic hormone to
preserve calcium concentration in blood
at the cost of bone demineralization.
PTH actions on bone
 PTH-mediated changes in bone calcium release
can be seen within minutes.
 The chronic effects of PTH are to:
 increase the number of bone cells, both osteoblasts
and osteoclasts, and to increase the remodeling of
bone
 Continuous exposure to elevated PTH (as in
hyperparathyroidism) leads to increased
osteoclast- mediated bone resorption.
PTH actions on bone, cont.
 However, the intermittent administration of PTH,
elevating hormone levels for 1–2 hours each day, leads
to a net stimulation of bone formation rather than
bone breakdown.
 Striking increases, especially in trabecular bone in the
spine and hip, have been reported with the use of PTH
in combination with estrogen.
 PTH(1-34) (teriparatide, Forteo Eli Lilly) as
monotherapy caused a highly significant reduction in
fracture incidence in a worldwide placebo-controlled
trial.
PTH actions on bone - how it works?
 Osteoblasts (or stromal cell precursors), which have
PTH/PTHrP receptors, are crucial to this bone-forming
effect of PTH.
 Osteoclasts, which mediate bone breakdown, lack such
receptors. PTH-mediated stimulation of osteoclasts is
indirect, acting in part, through cytokines released from
osteoblasts to activate osteoclasts
 In experimental studies of bone resorption in vitro,
osteoblasts must be present for PTH to activate
osteoclasts to resorb bone
PTH - Structure
 PTH is an 84-amino-acid single-chain peptide. The aminoterminal portion, PTH(1–34), is critical for the biologic actions
of the molecule.
PTH - Biosynthesis, Secretion,
and Metabolism
 Hypocalcemia  Minutes  secretion of
preformed hormone.
 Sustained hypocalcemia  Hours  PTH
mRNA expression  Days  cellular
replication
increase gland mass.
PTH - Secretion
 PTH secretion increases steeply to a maximum
value of about five times the basal rate as
calcium concentration falls from normal to the
range of 1.9–2 mmol/L (7.5–8 mg/dL) (measured
as total calcium).
Severe intracellular magnesium deficiency
impairs PTH secretion.
PTH - availability
 Rapid (minutes) changes in PTH availability
depends on the proteolytic destruction of
preformed hormone (posttranslational regulation of
hormone production)
 High calcium increases
 Low calcium inhibit
Ca
the proteolytic
destruction of PTH
stores.
PTH
Ca++ sensing receptor (CaSR)
 a G protein-coupled receptor (GPCR).
 serves for the ECF calcium control of PTH secretion.
 its stimulation by high Ca levels suppresses PTH secretion.
 is present in PT glands and the calcitonin-secreting cells of the
thyroid (C cells), as well as in other sites such as brain and kidney.
CaSR - mutations
 Heterozygous point mutations associated with loss-offunction cause the syndrome of FHH, in which the
blood calcium abnormality resembles that observed in
hyperparathyroidism but with hypocalciuria.
 Heterozygous gain-of-function mutations cause a form
of hypocalcemia resembling hypoparathyroidism.
PTH - Metabolism
 Most of the proteolysis of hormone occurs in the
liver and kidney.
PTHrP (Parathyroid hormone-related
protein)
Same receptor as PTH
Important in fetal life
PTHrP
 Most cell types produce PTHrP, including brain, pancreas,
heart, lung, mammary tissue, placenta, endothelial cells, and
smooth muscle.
 PTHrP is responsible for most instances of hypercalcemia of
malignancy - a syndrome that resembles HPT but without
elevated PTH levels.
 In fetal animals, PTHrP directs transplacental calcium
transfer, and high concentrations of PTHrP are produced in
mammary tissue and secreted into milk, but the biologic
significance of the very high concentrations of this hormone
in breast milk is unknown.
 in adults
 PTHrP appears to have little influence on calcium
homeostasis
 in disease states (e.g., large tumors, especially of the
squamous cell type as well as renal cell carcinomas),
there is massive overproduction of PTHrP and
hypercalcemia.
Calcitonin
 Antagonist to PTH
 Limited physiologic significance in humans (no
need for replacement)
 Tumor marker – MTC
 Adjunctive treatment in severe hypercalcemia and
in Paget's disease of bone
 Calcitonin from salmon, which is used
therapeutically, is 10–100 times more potent than
mammalian forms in lowering serum calcium
Hypercalcemia
I. Parathyroid-related
II. Malignancy-related
 Primary Hyperparathyroidism  Solid tumor with bone
metastases (breast)
1. Adenoma(s)
 Solid tumor with humoral
2. Hyperplasia (MEN)
mediation of
3. Carcinoma
hypercalcemia (lung,
 Lithium therapy
kidney)
 Familial hypocalciuric
 Hematologic malignancies
hypercalcemia (FHH)
(multiple myeloma,
lymphoma, leukemia)
Hypercalcemia
III. Vitamin D - related
IV. High bone turnover
 Vitamin D intoxication
 Hyperthyroidism
 1,25(OH)2D: sarcoidosis
and other granulomatous
diseases
 Immobilization
 Idiopathic hypercalcemia
of infancy
 Vitamin A intoxication
 Thiazides
False positive Hypercalcemia
hemoconcentration during blood collection
 elevation in serum proteins such as albumin
No need for fasting
Hypercalcemia - Clinical features
 Asymptomatic  usually due to PHPT.
 Malignancy-associated hypercalcemia 
the disease is usually not occult
 The interval between detection of
hypercalcemia and death, especially without
vigorous treatment, is often <6 months.
Hypercalcemia - Signs & symptoms
Fatigue
Depression
Mental confusion
Anorexia, nausea,
vomiting
Constipation
Reversible renal
tubular defects
Increased urination
A short QT interval
in the ECG
Cardiac
arrhythmias
Hypercalcemia - Signs & symptoms
 More common at calcium levels >2.9–3 mmol/L
(11.5–12 mg/dL)
 >3.2 mmol/L (13 mg/dL), calcification in kidneys,
skin, vessels, lungs, heart, and stomach occurs
and renal insufficiency may develop, particularly if
blood phosphate levels are normal or elevated due
to impaired renal function.
 Severe hypercalcemia, usually defined as 3.7–4.5
mmol/L (15–18 mg/dL), can be a medical
emergency; coma and cardiac arrest can occur.
Primary
Hyperparathyroidism
(PHPT)
PHPT - Natural history & incidence
 High PTH, Hypercalcemia, hypo-phosphatemia.
 Patients may present with multiple signs and symptoms,
including recurrent nephrolithiasis, peptic ulcers, mental
changes, and, less frequently, extensive bone resorption.
 The diagnosis is frequently made in patients who have
no symptoms and minimal, if any, signs of the disease
other than hypercalcemia and elevated levels of PTH.
The manifestations may be subtle, and the disease may
have a benign course for many years or a lifetime.
PHPT - Incidence
 The incidence is 1 in 800 people. This rate is much higher in
women over 50: 1 in 250.
 The disease has a peak incidence between the third and
fifth decades but occurs in young children and in the elderly.
 At young ages, hyperparathyroidism is often caused by a
familial hyperparathyroidism syndromes.
 has been reported in patients with a history of irradiation to
the head and neck (eg, for the treatment of childhood
malignancy, for the treatment of benign conditions, or after
nuclear power plant accidents).
PHPT - Etiology
 Most often - isolated adenomas
 Hyperplasia - in hereditary syndromes such as
MEN syndromes.
 Carcinoma < 1%
Solitary Adenomas
A single abnormal gland is the cause of PHPT
in ~85%
Double adenomas are reported.
Hereditary Syndromes and
Multiple Parathyroid Tumors
 In ~15% of patients, all glands are hyperfunctioning
(parathyroid hyperplasia) - usually hereditary and associated
with other endocrine abnormalities.
 MEN 1 (Wermer's syndrome): hyperparathyroidism ,tumors of the
pituitary and pancreas.
 MEN 2A: pheochromocytoma, MTC, PHPT
 MEN 2B usually lacks hyperparathyroidism; has additional
associated features such as multiple neuromas.
 The hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs in
families with parathyroid tumors (sometimes carcinomas) in
association with benign jaw tumors - often termed non-syndromic
familial isolated hyperparathyroidism (FIHP).
Adenomas - Pathology
 Most often located in the inferior parathyroid
glands
 6 -10% ectopic: thymus, thyroid, pericardium,
or behind the esophagus.
 Usually 0.5–5 g in size but may be as large as
10–20 g (normal glands weigh 25 mg on
average).
 Chief cells are predominant in both hyperplasia
and adenoma.
Parathyroid carcinoma
 Often not aggressive. Long-term survival without recurrence
is common if at initial surgery the entire gland is removed
without rupture of the capsule.
 Recurrent parathyroid carcinoma is usually slow-growing with
local spread in the neck, and surgical correction of recurrent
disease may be feasible.
 The diagnosis of carcinoma is often made in retrospect. HPT
from a parathyroid carcinoma is usually more severe
clinically.
Genetic Defects Associated with
Hyperparathyroidism
 Mutations in the Menin tumor suppressor gene (MEN1) .
 Over 1300 mutations have been reported to date.
 The MEN1 phenotype is inherited via an autosomal-dominant
pattern and is associated with neoplasms of the pituitary
gland, the parathyroid gland, and the pancreas.
Crystal Structure of Human Menin
Genetic Defects Associated with
Hyperparathyroidism, cont.
 Retinoblastoma (Rb) gene
 a tumor-suppressor gene located on chr 13q14, initially
associated with retinoblastoma, but implicated in other
neoplasias, including parathyroid carcinoma
 HRPT2 gene
 sporadic parathyroid carcinomas frequently have HRPT2
mutations.
 some patients with apparently sporadic parathyroid
carcinoma carry germ-line mutations in HRPT2 and may
have the HPT-JT syndrome or a phenotypic variant.
 RET encodes a tyrosine kinase type receptor;
 specific inherited germ-line mutations lead to a
constitutive activation of the receptor- MEN 2
PHPT - Signs and symptoms
 In series in which patients are followed without operation, as
many as 80% are classified as without symptoms.
 Kidney involvement, due either to deposition of calcium in
the renal parenchyma or to recurrent nephrolithiasis, was
present in 60–70% of patients prior to 1970.
 With earlier detection, renal complications occur in <20% of patients in
many large series. Renal stones are usually composed of either
calcium oxalate or calcium phosphate.
 In occasional patients, repeated episodes of nephrolithiasis
or the formation of large calculi may lead to urinary tract
obstruction, infection, and loss of renal function.
Nephrocalcinosis may also cause decreased renal function
and phosphate retention.
PHPT - Bone involvement
 The distinctive bone manifestation is osteitis fibrosa
cystica, which occurred in 10–25% of patients in series
reported 50 years ago.
 Histologically, the pathognomonic features are:
 an increase in the giant multinucleated osteoclasts in scalloped areas
on the surface of the bone (Howship's lacunae)
 replacement of the normal cellular and marrow elements by fibrous
tissue.
 X-ray changes include resorption of the phalangeal tufts and
replacement of the usually sharp cortical outline of the bone
in the digits by an irregular outline (subperiosteal resorption).
 In recent years, osteitis fibrosa cystica is very rare, due
to the earlier detection of the disease.
Cortical bone density is reduced while
trabecular (cancellous) bone density,
especially in the spine, is relatively
preserved (distal radius…)
PHPT - Neurologic
manifestations
 Neuropsychiatric
 Neuromuscular- proximal muscle
weakness, easy fatigability, and atrophy of
muscles, complete regression of
neuromuscular disease after surgical
correction of the hyperparathyroidism
PHPT – GIT manifestations
 Sometimes subtle and include vague
abdominal complaints and disorders of the
stomach and pancreas
 MEN 1 - duodenal ulcer may be the result of
associated pancreatic tumors that secrete
excessive quantities of gastrin (ZES)
 Pancreatitis has been reported in association
with hyperparathyroidism, but the incidence
and the mechanism are not established.
Asymptomatic PHPT (APHPT)
Biochemically confirmed hyperparathyroidism
(elevated or inappropriately normal PTH levels
despite hypercalcemia) with the absence of
signs and symptoms typically associated with
more severe hyperparathyroidism such as
features of renal or bone disease.
APHPT - Issues of concern
 Potential for cardiovascular deterioration
 The presence of subtle neuropsychiatric symptoms
 Longer-term status of skeletal integrity in patients
not treated surgically.
 The current consensus is that medical monitoring
rather than surgical correction of
hyperparathyroidism may be justified in certain
patients.
 The evidence of eventual (>8 years) deterioration
in BMD after a decade of relative stability.
Guidelines for Surgery in APHPT
Parameter
Guideline
Serum calcium (above normal)
>1 mg/Dl
24-h urinary Ca
No indication


Creatinine clearance
<60 mL/min
Bone density
T score <–2.5 at Any of 3 sites
Age
<50
Guidelines for Monitoring in APHPT
Parameter
Guideline
Serum calcium
Annually
24-h urinary calcium
Not recommended
Creatinine clearance
Not recommended
Serum creatinine
Annually
Bone density
Annually (3 sites)
APHPT - Diagnosis
Elevated PTH level
Asymptomatic hypercalcemia
Phosphate is usually low but may be normal,
especially if renal failure has developed
Treatment: PHPT
 Surgical excision of the abnormal parathyroid
tissue is the definitive therapy for this disease.
 The conventional parathyroidectomy procedure
was neck exploration with general anesthesia; this
procedure is being replaced in many centers,
whenever feasible, by an outpatient procedure with
local anesthesia, termed minimally invasive
parathyroidectomy.
 Parathyroid exploration is challenging and should
be undertaken by an experienced surgeon
 US
 Preoperative 99mTc sestamibi scans with singlephoton emission CT (SPECT) are used to predict
the location of an abnormal gland
 Intraoperative sampling of PTH before and at 5minute intervals after removal of a suspected
adenoma to confirm a rapid fall (>50%) to normal
levels of PTH.
Multiple-gland hyperplasia
 Two schemes have been proposed for surgical management.
 One is to totally remove three glands with partial excision of the
fourth gland; care is taken to leave a good blood supply for the
remaining gland.
 Other surgeons advocate total parathyroidectomy with immediate
transplantation of a portion of a removed parathyroid gland into
the muscles of the forearm, with the view that surgical excision is
easier from the ectopic site in the arm if there is recurrent
hyperfunction.
 In a minority of cases, if no abnormal parathyroid glands are
found in the neck, the issue of further exploration must be
decided. There are documented cases of five or six parathyroid
glands and of unusual/ectopic locations for adenomas such as in
the mediastinum.
 When a second parathyroid exploration is indicated, the minimally
invasive techniques for preoperative localization such as
ultrasound, CT scan, and isotope scanning are combined with
venous sampling and/or selective digital arteriography in one of
the centers specializing in these procedures.
 Intraoperative monitoring of PTH levels by rapid PTH
immunoassays may be useful in guiding the surgery
 long-term cures have been achieved with selective embolization
or injection of large amounts of contrast material into the endarterial circulation feeding the parathyroid tumor.
Post-op
 A decline in serum calcium occurs within 24 hours after
successful surgery.
 Usually blood calcium falls to low-normal values for 3–5 days
until the remaining parathyroid tissue resumes full hormone
secretion.
 Acute postoperative hypocalcemia is likely only if
 severe bone mineral deficits are present
 injury to all the normal parathyroid glands occurs during surgery.
 In general, there are few problems encountered in patients
with uncomplicated disease such as a single adenoma (the
clear majority), who do not have symptomatic bone disease
nor a large deficit in bone mineral, who are vitamin D and
magnesium sufficient, and who have good renal and
gastrointestinal function.
Hypocalcemia
 The extent of postoperative hypocalcemia varies with the surgical
approach. If all glands are biopsied, hypocalcemia may be
transiently symptomatic and more prolonged.
 Hypocalcemia is more likely to be symptomatic after second
parathyroid explorations, particularly when normal parathyroid
tissue was removed at the initial operation and when the
manipulation and/or biopsy of the remaining normal glands are
more extensive in the search for the missing adenoma.
Hypocalcemia
 muscle twitching, a general sense of anxiety, and
positive Chvostek's and Trousseau's signs coupled
with serum calcium consistently <2 mmol/L (8
mg/dL).
 parenteral calcium replacement should be instituted
when hypocalcemia is symptomatic.
 The rate and duration of IV therapy are determined by the
severity of the symptoms and the response of the serum
calcium to treatment.
 Calcitriol…
 Hypomagnesemia should be corrected
PHPT - Medical Management
 When surgery is not selected, or not medically
feasible
 It has been established that bisphosphonate
increase bone mineral density significantly without
changing serum calcium
 Calcimimetics (Cinacalcet (Sensipar) mimics
calcium at the PTH receptor) lower PTH secretion,
lower calcium but do not affect bone mass density
(BMD).
Other ParathyroidRelated Causes of
Hypercalcemia
Lithium
 Lithium, used in the management of bipolar depression
and other psychiatric disorders, causes hypercalcemia
in ~10% of treated patients.
 The hypercalcemia is dependent on continued lithium
treatment, remitting and recurring when lithium is
stopped and restarted.
 long-standing stimulation of parathyroid cell replication
by lithium may predispose to development of
adenomas (as is documented in secondary
hyperparathyroidism and renal failure).
 Fortunately, there are usually alternative medications
for the underlying psychiatric illness.
 Parathyroid surgery should not be recommended
unless hypercalcemia and elevated PTH levels
persist after lithium is discontinued.
Familial hypocalciuric
hypercalcemia (FHH)
 Autosomal dominant trait.
 Affected individuals are discovered because of
asymptomatic hypercalcemia.
 Caused by an inactivating mutation in a single allele of
the calcium sensing receptor
 inappropriately normal or even increased secretion of
PTH
FHH - Pathophysiology
 The primary defect is abnormal sensing of the
blood calcium by the parathyroid gland and renal
tubule, causing inappropriate secretion of PTH and
excessive renal reabsorption of calcium.
 Many different inactivating mutations in the
calcium-sensing receptor have been identified in
patients with FHH.
 These mutations lower the capacity of the sensor
to bind calcium, and the mutant receptors function
as though blood calcium levels were low;
excessive secretion of PTH occurs from an
otherwise normal gland
 Patients with FHH have >99% renal calcium reabsorption.
The hypercalcemia in FHH is often detectable in the first
decade of life
 PTH may be elevated in FHH, but the values are usually
normal or lower for the same degree of calcium elevation in
patients with PHPT.
 Parathyroid surgery performed in a few patients with FHH
before the nature of the syndrome was understood led to
permanent hypoparathyroidism; nevertheless, hypocalciuria
persisted, establishing that hypocalciuria is not PTHdependent (now known to be due to the abnormal calciumsensing receptor in the kidney).
 In those patients inadvertently operated upon, the parathyroids
appeared normal or moderately hyperplastic.
 Few clinical signs or symptoms are present in patients with FHH,
and other endocrine abnormalities are not present.
 Most patients are detected as a result of family screening after
hypercalcemia is detected in a proband.
 Parathyroid surgery is not appropriate
 Rare cases of acquired hypocalciuric hypercalcemia are reported
due to antibodies against the Ca-SR.
 They appear to be a complication of an underlying autoimmune disorder and
respond to therapies directed against the underlying disorder.
Jansen’s disease (Jansen's
metaphyseal chondrodysplasia)
 A rare AD syndrome: less than 20 reported cases worldwide
 Activating mutations in the PTH/PTHrP receptor (PTH1R)
 Short-limbed dwarfism due to abnormal regulation of
chondrocyte maturation in the growth plates of the bone.
 Numerous abnormalities
 multiple cystic resorptive areas in bone resembling those seen in
severe hyperparathyroidism.
 Hypercalcemia and hypophosphatemia with undetectable or low
PTH levels are typically seen..