13. Parathyroid Hormone:
• parathyroid Hormone Structure and Synthesis PTH is an 84-amino-acid
single-chain peptide. The amino acid portion, PTH(1–34), is
highly conserved and is critical for the biologic actions of the
molecule. The PTH gene is located on chromosome 11.
• PTH is initially synthesized as a larger molecule ( preproparathyroid
hormone, consisting of 115 amino acids), which is then reduced in
size by a second cleavage ( proparathyroid hormone, 90 amino
acids) before secretion as the 84-amino-acid peptide.
• Transcriptional suppression of the PTH gene by calcium is nearly
maximal at physiologic calcium concentrations.
• Hypocalcemia increases transcriptional activity within hours.
1,25(OH) 2 D 3 strongly suppresses PTH gene transcription.
14. Parathyroid Hormone
• Regulation of PTH Secretion
• PTH secretion increases steeply to a maximum value of five times the basal rate of
secretion as calcium concentration falls from normal to the range of 7.5–8.0 mg/ dL .
• The ionized fraction of blood calcium is the important determinant of hormone secretion.
• ECF calcium controls PTH secretion by interaction with a calcium sensor, a G protein–
coupled receptor (GPCR) for which Ca 2+ ions act as the ligand .
• Stimulation of the receptor by high calcium levels suppresses PTH secretion. The receptor
is present in parathyroid glands.
• Point mutations associated with loss of function cause a syndrome FHH resembling
hyperparathyroidism but with hypocalciuria . On the other hand, gain-of-function mutations
cause a form of hypocalcemia resembling hypoparathyroidism .
• Metabolism -
• Secreted PTH has a half-life of 2 to 4 minutes. In the liver, PTH is metabolized into the
active N-terminal component and the relatively inactive C-terminal fraction. The C-terminal
component is excreted by the kidneys .Much of the proteolysis of hormone occurs in the
liver and kidney.
15. Calcitonin and Vitamin D
• Calcitonin and Vitamin D Calcitonin is produced by thyroid C cells and functions as
an antihypercalcemic hormone by inhibiting osteoclast -mediated bone resorption
• . Calcitonin production is stimulated by calcium and catecholamines ,
cholecystokinin , and glucagon.
• At the kidney, calcitonin increases phosphate excretion by inhibiting its
reabsorption .
• Calcitonin plays a minimal, if any, role in the regulation of calcium levels in
humans. However, it is very useful as a marker of MTC and in treating acute
hypercalcemic crisis.
• Vitamin D refers to vitamin D2 and vitamin D3 , both of which are produced by
photolysis of naturally occurring sterol precursors.
• Vitamin D 2 is available commercially, whereas vitamin D 3 is the most important
physiologic compound .
• Vitamin D is metabolized in the liver to its primary circulating form, 25-
hydroxyvitamin D. Further hydroxylation in the kidney results in 1,25-dihydroxy
vitamin D, which is the most metabolically active form of vitamin D.
• Vitamin D stimulates the absorption of calcium and phosphate from the gut and
the resorption of calcium from the bone.
16. Hyperparathyroidism
Hyperfunction of the parathyroid glands may be classified as primary,
secondary, or tertiary.
• PHPT arises from increased PTH production from abnormal
parathyroid glands and results from a disturbance of normal
feedback control exerted by serum calcium.
• Elevated PTH levels may also occur as a compensatory response to
hypocalcemic states resulting from chronic renal failure or GI
malabsorption of calcium.
• This secondary HPT can be reversed by correction of the underlying
problem (e.g., kidney transplantation for chronic renal failure).
• However, chronically stimulated glands may occasionally become
autonomous, resulting in persistence or recurrence of
hypercalcemia after successful renal transplantation, resulting in
tertairy HPT.
17. Primary Hyperparathyroidism
• PHPT is a common disorder, affecting 100,000 individuals
annually in the United States.
• PHPT occurs in 0.1 to 0.3% of the general population and is
more common in women (1:500) than in men (1:2000).
• Increased PTH production leads to hypercalcemia via
increased GI absorption of calcium, increased production of
vitamin D3 , and reduced renal calcium clearance.
• PHPT is characterized by increased parathyroid cell
proliferation and PTH secretion that is independent of
calcium levels.
18. Etiology
• The exact cause of PHPT is unknown-
• 1 Exposure to low-dose therapeutic ionizing radiation .
• 2 Familial predisposition account for some cases.
• 3 Declining renal function with age as well as alteration in the sensitivity of parathyroid glands to
suppression by calcium.
• 4 Lithium therapy has been known to shift the set point for PTH secretion in parathyroid cells,
thereby resulting in elevated PTH levels and mild hypercalcemia . Lithium stimulates the growth of
abnormal parathyroid glands in vitro and also in susceptible patients in vivo.
• 5 PHPT results from the enlargement of a single gland or parathyroid adenoma in approximately
80% of cases, multiple adenomas or hyperplasia in 15 to 20% of patients, and parathyroid
carcinoma in 1% of patients.
• - When more than one abnormal parathyroid gland is identified preoperatively or
intraoperatively , the patient has hyperplasia (all glands abnormal) until proven otherwise.
• -Genetics-Most cases of PHPT are sporadic. However, PHPT also occurs within the spectrum of a
number of inherited disorders such as MEN1, MEN2A, isolated familial HPT, and familial HPT with
jaw- tumor syndrome. All of these syndromes are inherited in an autosomal dominant fashion.
19. MEN-1
•
PHPT is the earliest and most common manifestation of MEN1 and
develops in 80 to 100% of patients by age 40 years old.
• These patients also are prone to pancreatic neuroendocrine tumors
and pituitary adenomas and, less commonly, to adrenocortical
tumors , lipomas , skin angiomas , and carcinoid tumors of the
bronchus, thymus, or stomach.
• Prolactinomas occur in 10 to 50% of MEN1 patients and constitute
the most common pituitary lesion.
• MEN1 has been shown to result from germline mutations in the
MEN1 gene, a tumor -suppressor gene located on chromosome
11q12-13 which encodes menin , a protein that is postulated to
interact with the transcription factors .
20. MEN2A and other syndromes:
• HPT develops in about 20% of patients with MEN2A and
generally is less severe.
• MEN2A ( Sipple syndrome) , is characterized by
pheochromocytoma , medullary carcinoma, and
parathyroid hyperplasia. MEN2A is caused by germline
mutations of the RET proto-oncogene located on
chromosome 10.
• Patients with the familial HPT with jaw- tumor syndrome
have an increased predisposition to parathyroid carcinoma.
This syndrome maps to a tumor -suppressor locus HRPT2 ,
on chromosome 1.
• Patients belonging to isolated HPT kindreds also appear to
demonstrate linkage to HRPT2 .l]
21. Genetics
• Approximately 25 to 40% of sporadic parathyroid adenomas and
some hyperplastic parathyroid glands have mutation at 11q 13, the
site of the MEN1 gene.
• The parathyroid adenoma 1 oncogene ( PRAD1 ), which encodes
cyclin D1, a cell cycle control protein, is overexpressed in about 18%
of parathyroid adenomas.
• Other chromosomal regions deleted in parathyroid adenomas
include 1p, 6q, 15q, 16p and 19p.
• Sporadic parathyroid cancers are characterized by uniform loss of
the tumor -suppressor gene RB , which is involved in cell cycle
regulation, and 60% have HRPT2 mutations.
• These alterations are rare in benign parathyroid tumors and may
have implications for diagnosis. The p53 tumor -suppressor gene is
also inactivated in a subset (30%) of parathyroid carcinomas.
22. Clinical Manifestations
• Patients with PHPT formerly presented with the
"classic" pentad of symptoms (i.e., kidney stones,
painful bones, abdominal groans, psychic moans, and
fatigue overtones).
• Currently, most patients present with weakness,
fatigue, polydipsia , polyuria , nocturia , bone and joint
pain, constipation, decreased appetite, nausea,
heartburn, pruritus , depression, and memory loss.
• Furthermore, these symptoms and signs improve in
most, but certainly not all, patients after
parathyroidectomy . Truly "asymptomatic" PHPT
appears to be rare, occurring in <5% of patients.
23. Renal Disease
• Approximately 80% of patients with PHPT have some degree of renal
dysfunction or symptoms.
• Kidney stones were previously reported in up to 80% of patients but now
occur in about 20 to 25%.
• The calculi are typically composed of calcium phosphate or oxalate.
• Nephrocalcinosis , which refers to renal parenchymal calcification, is found
in <5% of patients and is more likely to lead to renal dysfunction.
• Chronic hypercalcemia also can impair concentrating ability, thereby
resulting in polyuria , polydipsia , and nocturia . Hypertension is reported
to occur in up to 50% of patients with PHPT.
• Hypertension appears to be more common in older patients and
correlates with the magnitude of renal dysfunction and, in contrast to
other symptoms, is least likely to improve after parathyroidectomy
24. Bone Disease
• Bone disease, including osteopenia , osteoporosis, and osteitis fibrosa
cystica , is found in about 15% of patients with PHPT.
• Increased bone turnover, as found in patients with osteitis fibrosa cystica ,
can be determined by an elevated blood alkaline phosphatase level.
• Advanced PHPT with osteitis fibrosa cystica now occurs in <5% of patients.
• It has pathognomonic radiologic findings, which are best seen on x-rays of
the hands and are characterized by subperiosteal resorption (most
apparent on the radial aspect of the middle phalanx of the second and
third fingers), bone cysts, and tufting of the distal phalanges .
• The skull also may be affected and appears mottled with a loss of
definition of the inner and outer cortices.
• Brown or osteoclastic tumors and bone cysts also may be present.
• Severe bone disease, resulting in bone pain and tenderness and/or
pathologic fractures, is rarely observed nowaday
25. Bone Disease
• Reductions of bone mineral density (BMD) with osteopenia and
osteoporosis are more common.
• Patients with normal serum alkaline phosphatase levels almost
never have clinically apparent osteitis fibrosa cystica .
• HPT typically results in a loss of bone mass at sites of cortical bone
such as the radius and relative preservation of cancellous bone such
as that located at the vertebral bodies.
• Patients with PHPT, however, also may have osteoporosis of the
lumbar spine that improves dramatically following
parathyroidectomy .
• Fractures also occur more frequently in patients with PHPT, and the
incidence of fractures also decreases after parathyroidectomy .
• Bone disease correlates with serum PTH and vitamin D levels.
26. Gastrointestinal Complications
• PHPT has been associated with peptic ulcer
disease.
• An increased incidence of pancreatitis also has
been reported in patients with PHPT, although
this appears to occur only in patients with
profound hypercalcemia (Ca 2+ ≥12.5 mg/ dL ).
• Patients with PHPT also have an increased
incidence of cholelithiasis , presumably due to an
increase in biliary calcium, which leads to the
formation of calcium bilirubinate stones.
27. Neuropsychiatric Complications
• Severe hypercalcemia may lead to various neuropsychiatric
manifestations such as florid psychosis, obtundation , or
coma.
• In mild hypercalcemia symptoms such as depression,
anxiety, and fatigue are more commonly observed.
• The etiology of these symptoms is not known. Studies
demonstrate that levels of certain neurotransmitters
(monoamine metabolites 5-hydroxyindoleacetic acid and
homovanillic acid) are reduced in the cerebrospinal fluid of
patients with PHPT when compared to controls.
• Electroencephalogram abnormalities also occur in patients
with primary and secondary HPT and normalize following
parathyroidectomy .
28. Other Features
• PHPT also can lead to fatigue and muscle weakness, which
is prominent in the proximal muscle groups. Although the
exact etiology of this finding is not known, muscle biopsy
studies show that weakness results from a neuropathy,
rather than a primary myopathic abnormality.
• Patients with HPT also have an increased incidence of
chondrocalcinosis , gout, and pseudogout , with deposition
of uric acid, calcium, pyrophosphate crystals in the joints.
• Calcification at ectopic sites such as blood vessels, cardiac
valves, and skin also has been reported, as has hypertrophy
of the left ventricle independent of the presence of
hypertension
29. Physical Findings
• Parathyroid tumors are seldom palpable, except in patients with
profound hypercalcemia .
• A palpable neck mass in a patient with PHPT is more likely to be
thyroid in origin or a parathyroid cancer.
• Patients also may demonstrate evidence of band keratopathy , a
deposition of calcium in Bowman's membrane just inside the iris of
the eye.
• This nonspecific condition generally is caused by chronic eye
diseases such as uveitis , and glaucoma, but also may occur in the
presence of conditions associated with high calcium or phosphate
levels.
• Fibro-osseous jaw tumors , and or the presence of familial disease
in patients with PHPT and jaw tumors , if present, should alert the
physician to the possibility of parathyroid carcinoma.
37. Medical management
• A number of medical therapies such as selective
estrogen receptor modifiers and bisphosphonates have
been used to successfully lower serum calcium and
increase BMD in patients with PHPT.
• More recently, calcimimetics (modifiers of the
sensitivity of the CASR) have been used in randomized,
multicenter controlled trials and have been shown to
decrease both serum calcium and PTH levels in both
symptomatic and asymptomatic PHPT patients.
Although these therapies show promise, long-term
outcome data are lacking, and their routine use is not
advocated at this time.
38.
39.
40. Localization studies:
• Single-photon emission computed
tomography(SPECT), particularly when used
with CT, has been shown to be superior to
other nuclear medicine–based imaging
41.
42.
43. Parathyroidectomy
• Parathyroidectomy
• Unilateral parathyroid exploration
• Radio-guided parathyroidectomy
• Total endoscopic parathyroidectomy
• Minimally invasive parathyroidectomy
• Autotransplantation For patients with hyperplasia, a
titanium clip is placed across the most normal gland.
• Sternotomy- A sternotomy is usually not recommended
at the initial operation, unless the calcium level is >13
mg/ dL
44. Complications of Parathyroid Surgery
• Transient and permanent vocal cord palsy and
hypoparathyroidism.
• Patients with symptomatic hypocalcemia or
those with calcium levels <8 mg/ dL are
treated with oral calcium supplementation (up
to 1 to 2 g every 4 hours). 1,25-dihydroxy
vitamin D [ calcitriol ( Rocaltrol ) 0.25 to 0.5 g
bid] .
45. Parathyroid Carcinoma
• Accounts for approximately 1% of PHPT cases.
• Suspected preoperatively by the presence of
severe symptoms, serum calcium levels >14
mg/ dL , significantly elevated PTH levels (5 x
normal), and a palpable parathyroid gland.
• Local invasion is most common; approximately
15% of patients have lymph node metastases
and 33% have distant metastases at
presentation.
46. Parathyroid Carcinoma
• Prophylactic neck dissection is not advised
because it is associated with an increased risk of
complications and does not appear to have a
significant impact on survival.
• Reoperation is indicated for locally recurrent or
metastatic disease to control hypercalcemia .
• Radiation and chemotherapy may be considered
in patients with unresectable disease.
47. Familial Hyperparathyroidism
• Generally have a higher incidence of multiglandular disease,
supernumerary glands, and recurrent or persistent disease.
• Warrant a more aggressive approach and are not candidates for
various focused surgical approaches.
• Preoperative sestamibi scan and ultrasound can be obtained in
patients with inherited HPT to identify potential ectopic glands.
• A bilateral cervical thymectomy , regardless of the results of
localization studies.
• Both subtotal parathyroidectomy and total parathyroidectomy with
autotransplantation are appropriate and parathyroid tissue also
should be cryopreserved .
48. Parathyromatosis
• Parathyromatosis is a rare condition characterized by the
finding of multiple nodules of hyper-functioning
parathyroid tissue throughout the neck and mediastinum ,
usually following a previous parathyroidectomy .
• The true etiology of parathyromatosis is not known. It is
postulated to arise either from overgrowth of congenital
parathyroid rests or seeding at surgery from rupture of
parathyroid tumors or subtotal resection of hyperplastic
glands.
• Parathyromatosis represents a rare cause of persistent or
recurrent HPT and can be identified intraoperatively .
• Aggressive local resection of these deposits can result in
normocalcemia but is rarely curative.
49. Secondary Hyperparathyroidism
• Secondary HPT commonly occurs in patients with chronic renal failure but
also may occur in those with hypocalcemia secondary to inadequate
calcium or vitamin D intake, or malabsorption .
• The pathophysiology of HPT in chronic renal failure is complex and
appears to be related to hyperphosphatemia (and resultant hypocalcemia
), deficiency of 1,25-dihydroxy vitamin D due to loss of renal tissue, low
calcium intake, decreased calcium absorption. Patients generally are
hypocalcemic or normocalcemic . Aluminum hydroxide, which often was
used as a phosphate binder, has been shown to contribute to the
osteomalacia observed in this disease. These patients generally are
treated medically with a low-phosphate diet, phosphate binders,
adequate intake of calcium and 1,25-dihydroxy vitamin D and a high
calcium, low- aluminum dialysis bath.
• Calcimimetics have been shown to control parathyroid hyperplasia and
osteitis fibrosa cystica associated with secondary HPT and to decrease
plasma PTH and total and ionized calcium levels in humans.
50. Secondary Hyperparathyroidism
• Surgical treatment was traditionally
recommended for,
1 patients with bone pain, pruritus , and
2 a calcium-phosphate product ≥70,
3 calcium >11 mg/ dL with markedly elevated PTH,
4 calciphylaxis ,
5 progressive renal osteodystrophy , and soft tissue
calcification and tumoral calcinosis , despite
maximal medical therapy.
51. Tertiary Hyperparathyroidism
• Generally, renal transplantation is an excellent method of treating
secondary HPT, but some patients develop autonomous parathyroid gland
function i,e . Tertiary HPT.
• Tertiary HPT can cause problems similar to PHPT, such as pathologic
fractures, bone pain, renal stones, peptic ulcer disease, pancreatitis, and
mental status changes.
• The transplanted kidney is also at risk.
• Operative intervention is indicated for symptomatic disease or if
autonomous PTH secretion persists for >1 year after a successful
transplant.
• Subtotal or total parathyroidectomy with autotransplantation and an
upper thymectomy .
• All parathyroid glands be identified and subtotal parathyroidectomy be
performed as long-term follow-up studies show that limited excisions in
these patients are associated with an up to fivefold increased risk of
recurrent or persistent disease.
52. Hypoparathyroidism
• Is an endocrine disorder in which hypocalcemia and
hyperphosphatemia are the result of a deficiency in
PTH secretion or action.
• The parathyroid glands may be congenitally absent in
DiGeorge syndrome, an autosomal dominant form
involving microdeletions of chromosome 22q11.2 has
been described which also is characterized by lack of
thymic development and, cardiovascular, facial, and
other developmental defects, and most patients die in
early childhood with severe infections, hypocalcemia
and seizures, or cardiovascular complications
53. Hypoparathyroidism
• It can occur as part of a multiglandular endocrine
deficiency syndrome (type 1) characterized most commonly
by hypoparathyroidism , adrenal insufficiency, and
mucocutaneous candidiasis .
• By far, the most common cause of hypoparathyroidism is
thyroid surgery , particularly total thyroidectomy with a
concomitant central neck dissection. Patients often develop
transient hypocalcemia due to ischemia of the parathyroid
glands; permanent hypoparathyroidism is rare.
• Hypoparathyroidism also may occur after parathyroid
surgery, which is more likely if patients undergo a subtotal
resection or total parathyroidectomy with parathyroid
autotransplantation.
54. Conditions Causing Hypocalcemia
• Hypoparathyroidism -Surgical
Neonatal
Familial
Heavy metal deposition
Magnesium depletion
Resistance to the action of PH
Pseudohypoparathyroidim
Renal failure
Medications— calcitonin , bisphosphonates ,
mithramycin
55. Conditions Causing Hypocalcemia
• Failure of normal 1,25-dihydroxy vitamin D
production
• Resistance to the action of 1,25-dihydroxy
vitamin D
• Acute complex
formation or deposition of calcium
Acute hyperphosphatemia
Acute pancreatitis
Massive blood transfusion (citrate overload)
56. Clinical features
• Patients initially develop circumoral and fingertip numbness and
tingling.
• Mental symptoms include anxiety, confusion, and depression.
• Physical examination reveals positive Chvostek's sign (contraction
of facial muscles elicited by tapping on the facial nerve anterior to
tragus of the ear) and Trousseau's sign ( carpopedal spasm which is
elicited by occluding blood flow to the forearm with a blood
pressure cuff for 2 to 3 minutes).
• Erb`s sign – increased electric excitability of the muscles.
• Tetany , which is characterized by tonic- clonic seizures, carpopedal
spasm, and laryngeal stridor , may prove fatal and should be
prevented.
57. Treatment
• Most patients with postoperative
hypocalcemia can be treated with oral calcium
and vitamin D supplements;
• IV calcium infusion is rarely required except in
patients with preoperative osteitis fibrosa
cystica .
• IV calcium gluconate infusion for the
treatment of moderate to severe
hypocalcemia
58. Pseudohypoparathyroidism
• PHP is a hereditary disorder characterized by
symptoms and signs of hypoparathyroidism ,
typically in association with distinctive skeletal
and developmental defects.
• The hypoparathyroidism is due to a deficient
end-organ response to PTH.
• Hyperplasia of the parathyroids , a response
to hormone resistance, causes elevation of
PTH levels.
59. Pseudohypoparathyroidism
• Patients have low calcium and high phosphate
levels, as with true hypoparathyroidism . PTH
levels, however, are elevated, reflecting
resistance to hormone action.
• AHO, consisting of short stature, round face,
skeletal anomalies ( brachydactyly ), and
heterotopic calcification is seen in PHP-Ia.
• Response of Urinary cAMP to PTH is low in
Type-l and normal in Type 2.
60. Genetics
• Multiple defects have now been identified in the
GNAS-1 gene in PHP- Ia and PPHP patients.
• This gene, which is located on chromosome 20q13,
encodes the stimulatory G-protein subunit G s α .
• PHP- Ia and PPHP, have an inheritance pattern
consistent with gene imprinting —only females, can
transmit the full disease with hypocalcemia .
• In the renal cortex, it is postulated that only the
maternal allele is normally active (independent of any
mutation).
• Maternal gene imprinting- PHP-la.
• Paternal gene imprinting- PPHP.
61. Pseudohypoparathyroidism
• Ellsworth-Howard test- Measurement of serum and urinary
phosphorus after intravenous administration of parathyroid
extract (200U); used in the diagnosis
of Pseudohypoparathyroidism .
• Normally -5 fold increase in urinary phosphorus excretion.
• Hypoparathyroidism -10 fold increase in urinary
phosphorus excretion.
• Pseudohypoparathyroidism - <2 fold increase in urinary
phosphorus excretion.
• Treatment Similar to that of hypoparathyroidism , except
that the doses of vitamin D and calcium are usually lower
than those required in true hypoparathyroidism .
