PARATHYROID

HORMONE

Presented by : Rabina Ramtel

MSc. Clinical Biochemistry
2nd year
OUTLINE
 Introduction of Parathyroid gland

 Anatomy

 Physiology
 Action of parathyroid hormone on different organs

 Measurement of PTH

 Disorders associated with parathyroid gland

 Summary
 HISTORY
 The parathyroid gland was first recognized in 1850 by Richard Owen
during a dissection of an Indian rhinoceros at the London Zoo.

 The credit for the discovery of the parathyroid has, however, been
given to the Uppsala anatomist Ivar Sandström, who was the first to
demonstrate the gland in man.

 His dissection studies were undertaken between 1877 and 1880,

when he still was a medical student in Uppsala.

 Ivar Sandström, the man behind the discovery of the parathyroid

gland, often called the last anatomical discovery, was a
disharmonious person with psychiatric problems and he committed
suicide in 1889 at the age of 37 years.
ANATOMY
• Yellowish–brown, ovoid
bodies
• Four in number

• Measuring about 6mm in length,

4mm in breadth, 2mm in thickness

• Weighs about 50 mg

• Superior ones are more constant in position and lie

at the middle of the posterior border of the thyroid
gland

• Inferior ones lies close to the inferior poles of the

thyroid gland
VASCULAR AND NERVE SUPPLY
HISTOLOGY
PHYSIOLOGY
 Secretes parathyroid hormone (parathormone)

 Essential for the maintenance of blood calcium level within a very

narrow critical level.

 Maintenance of blood calcium level is necessary because calcium is

an important inorganic ion for many physiological functions.
BIOSYNTHESIS
REGULATION OF PTH GENE EXPRESSION
REGULATION OF PTH GENE EXPRESSION,
SECRETION, AND PARATHYROID CELL
PROLIFERATION
REGULATION OF PTH GENE EXPRESSION,
SECRETION, AND PARATHYROID CELL
PROLIFERATION
 Parathyroid synthesizes and secretes PTH unless it is restrained by the
parathyroid calcium receptor (CaR) which senses serum [Ca2+] levels.
 A low serum calcium leads to decreased activation of the CaR and thus
increased PTH mRNA stability and levels, PTH secretion, and parathyroid
cell proliferation.
 A high serum Phosphate and chronic kidney disease (CKD) lead to similar
changes in all these parameters.
 PTH mRNA stability is regulated by the balanced interactions of the
protective parathyroid trans-acting factors AUF1 and Unr and the decay
promoting protein KSRP, that bind to a defined cis element in the PTH
mRNA 3′-UTR.
 These interactions are regulated by the peptidylprolyl cis/trans isomerase
Pin1.
 1,25D decreases PTH gene transcription and parathyroid cell proliferation.
 Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that
decreases PTH gene expression and secretion.
 MECHANISM OF PTH ACTION

Fig: Signaling pathways induced by the activation of the parathyroid hormone receptor.
BIOLOGICAL ACTIONS OF PTH
The primary function of PTH is to maintain the ECF calcium
concentration within a narrow normal range.

Direct action of PTH:

 On bone

 On kidney
 Increase calcium reabsorption
 Decrease phosphate reabsorption
 Stimilate activation of vitamin D

Indirect action of PTH

 On the intestine
ACTION OF PTH ON BONE
ACTION OF PTH ON BONE
 Slow phase
 Slow phase of calcium resorption from bone is due to the activation
of osteoclasts by PTH.

 When osteoclasts are activated, some substances such as proteolytic

enzymes, citric acid and lactic acid are released from lysosomes of
these cells.

 Allthese substances digest or dissolve the organic matrix of the bone,

releasing the calcium ions.

 The calcium ions slowly enter the blood.

 PTH increases calcium resorption from bone by stimulating the

proliferation of osteoclasts also.
ACTION OF PTH ON BONE
 Rapid phase
 Rapid phase occurs within minutes after the release of PTH from
parathyroid glands.

 Immediately after reaching the bone, PTH gets attached with the
receptors on the cell membrane of osteoblasts and osteocytes.

 Thehormone-receptor complex increases the permeability of

membranes of these cells for calcium ions.

 It
accelerates the calcium pump mechanism, so that calcium ions
move out of these bone cells and enter the blood at a faster rate.
 ACTION OF PTH ON KIDNEY

PTH

Vitamin D
ACTION OF PTH ON KIDNEY
MODULATION OF CALCIUM AND PHOSPHATE
REABSORPTION
Factor Nephron site Mechanism Effect
PTH DCT TRPV5 channels Calcium
reabsorption
and phosphate
excretion
Proximal tubule NHE-3 transporters

PTH
plasma Ca 2+
Thick ascending limb CaSR

Factor Nephron site Mechanism Effect

PTH Proximal tubule Na/Pi symporter

FGF-23 Proximal tubule Na/Pi symporter

Pi intake Proximal tubule Na/Pi symporter

ACTION OF PTH ON INTESTINE
SUMMARY OF PTH ACTION
REGULATION OF PTH RELEASE

release Hypocalcemia
Hyperphosphatemia
Catecholamines

release Hypercalcemia
Vitamin D
Severe hypomagnesemia
REGULATION OF PTH BY
FEEDBACK MECHANISM
REGULATION OF PTH
PARATHYROID HORMONE RELATED PROTEIN

PTHrP is derived from a

gene on chromosome 12

brain, pancreas, heart, lung,

mammary tissue, placenta, endothelial
cells, and smooth muscle

PTH and PTHrP are product of different

genes but exhibit considerable functional and
structural homology
 Functions of Parathyroid Hormone-Related Protein

• PTH-like actions associated with the humoral hypercalcemia of malignancy.

• In this pathologic entity, PTHrP acts as a hormone; secreted from the tumor into
the blood stream and then acts on bone and kidney to raise calcium levels

PTHrP acts as a calciotropic hormone during fetal life and in lactation

• Secretion of PTHrP from the breast into the bloodstream leads to an increase in
bone resorption.

• Calcium then activates the CASR in breast tissue, increases the movement of
calcium into milk, and downregulates expression of PTHrP in the breast

• synthesized in response to stretch in the smooth muscle of blood vessels,

gastrointestinal tract, uterus, and bladder, and it acts in an autocrine fashion to
relax the smooth muscle.

• Exhibits antiproliferative effects in adults by regulating epidermal and hair follicle

cell growth as well as inhibiting angiogenesis.
HETEROGENEITY OF CIRCULATING PTH
 C-forms of circulating PTH
 Carboxyl-terminal (C) fragments missing the amino-terminal (N) structure
of PTH(1–84) 80% of circulating PTH in normal individuals and up to 95%
in renal failure patients.

 C-PTH fragments are acutely regulated in the circulation by ionized calcium

concentration.

 Hypocalcemia favors the output of PTH(1–84) over that of C-PTH

fragments, decreasing the C-PTH fragments/PTH(1–84) ratio to its lowest
value.

 While inhibiting PTH secretion, hypercalcemia favors the output of C-PTH

fragments over that of PTH(1–84), increasing the C-PTH fragments/
PTH(1–84) ratio to its highest value.

 C-PTH fragments do not interact with the type I PTH/PTHrP receptor nor do
they directly influence cAMP.
 N- forms of circulating PTH
 Distinct from PTH(1–84)

 4–8% of the immunoreactivity detected by a third-generation

PTH assay in normal individuals and up to 15% in renal failure
patients.

 overproduced in severe primary or secondary

hyperparathyroidism, as well as in parathyroid cancer.

 Itsrole in PTH physiology as well as its biological activity

remain obscure
EFECTS OF (1-84)PTH AND (7-84)PTH ON SKELETON.
EFECTS OF PTH FRAGMENTS ON THE
KIDNEY.
EFFECT OF PTH FRAGMENT ON THE
CARDIOVASCULAR SYSTEM
MEASUREMENT OF PTH

 PTH can be measured in the blood in several

different forms:
 intactPTH;
 N-terminal PTH;
 mid-molecule PTH, and
 C-terminal PTH,
different tests are used in different clinical situations.
METHODS OF ASSAYING PTH FRAGMENTS
• 1st Described in 1963,
• Used a single antibody to
recognize (1-84)pth,
abundant inactive mid pth
and C- pth fragments

• 2nd Developed in 1987,

• two antibodies a solid-phase
capture antibody directed
against the C-terminus, and a
labeled detection antibody
raised against the N-terminus
(amino acids 1-34), or vice
versa.

• 3rd launched in 1999,

• Used an anti -C- terminal
Ab similar to that of 2nd
gen and an anti - N-
terminal Ab directed
toward the 1st amino
acids (1-4) of the
peptide , had no rxn to
the (7-84) pth fragment
4th generation assay
OXIDATION OF PTH

Oxidized hPTH was analyzed

by high resolution nano-
liquid chromatography
coupled to ESI-FTT tandem
mass spectrometry (nanoLC-
ESI-FT-MS/MS) directly and
after proteolytic cleavage.
REFERENCE INTERVALS
 Reference intervals for PTH vary greatly with the method used.
Typical reference intervals are as follows:

 Intact
PTH(1st generation) : 10 to 65 pg/mL or 1.1to 6.8pmol/L
 PTH(1-84) (2nd generation) : 60 to 40 pg/mL or 0.6 to 4.2
pmol/L

 Interpretation of PTH concentrations should take into account

the patient’s circulating calcium concentration at the time of
sampling.
Intact PTH concentrations vary with age
 low or normal during pregnancy,

 lower in fetuses and umbilical cord blood,

 increasedduring the first few days of life, in response to neonatal

hypocalcemia.

 similar concentration in children and adult

 In healthy adults, circulating concentrations of intact PTH

increase with age.

 Intact PTH is secreted in a pulsatile fashion with an overall

circadian rhythm characterized by a nocturnal rise.
MEASUREMENT OF PARATHYROID HORMONE
RELATED PROTEIN (PTHRP)

 Can be done by
 competitive immunoassays
 noncompetitive immunoassays

 Reference Interval
PTHrP: 1.3 pmol/L or less.

 PTHrP concentrations in healthy persons are dependent on both the

assay and the specimen collection, varying from undetectable to up
to 5 pmol/L.
 With sensitive noncompetitive immunoassays, concentrations of up
to approximately 1 to 2 pmol/L have been reported in normal
subjects.
DISORDERS ASSOCIATED WITH PARATHYROID
HORMONE

Hyperparathyroidism
 Excessive secretion of parathyroid hormone
 Characterized by hypercalcaemia

Clinical Features
 Older women, >40 years of age.

 Renal calculi or renal calcification – occurs in 20% of patients,

polyuria (‘renal stones’). Hypertension can result from renal
impairment
 Bone pain or deformity, Osteitis fibrosa cystica (brown tumors) – bone
lesions from Ca resorption; characteristic of hyperparathyroidism,
pathological fractures (‘painful bones’).
 Muscle weakness, anorexia, intestinal atony, psychosis (‘psychic
moans’).
 Peptic ulceration and pancreatitis (‘abdominal groans’).
Diagnosis

 Laboratory
 Elevated PTH in the setting of hypercalcaemia.
 Serum calcium ↑, ↓ phosphate and elevated alkaline phosphatase.

 Imaging
 High-resolution ultrasound.
 99m
Tc sestamibi scintigraphy ± sestamibi-single photon emission computed
tomography (SPECT).
 CT and MRI scanning.
 DXA scans for bone density measurement

Types of hyperparathyroidism
• Primary hyperparathyroidism (PHPT).
• Secondary hyperparathyroidism
• Tertiary hyperparathyroidism
PRIMARY HYPERPARATHYROIDISM
Disorder of calcium, phosphorous and bone
metabolism resulting form the increased secretion of
parathyroid hormone

Etiology
• parathyroid benign adenoma (75%)
• parathyroid hyperplasia (20%)
• Hereditary syndromes such as multiple endocrine
neoplasia syndrome(MENs)

Dx: ↑ Ca, ↓ PO4−; Cl− to PO4− ratio >

33; ↑ renal cAMP; HCO3− secreted in
urine
Genetic disorder causing hyperparathyroid like syndromes

Familial Hypocalciuric Hypercalcemia FHH (also called familial benign

hypercalcemia)
 is inherited as an autosomal dominant trait

 Most cases are caused by an inactivating mutation in a single allele of the

CaSR leading to inappropriately normal or even increased secretion of
PTH

 Other forms of FHH are caused either by heterozygous mutations in

GNA11 (encoding Gα11)(FHH2), or by mutations in AP1A1 (FHH3).

 The primary defect is abnormal sensing of the blood calcium by the

parathyroid gland and renal tubule, causing inappropriate secretion of
PTH and excessive reabsorption of calcium in the distal renal tubules
Jansen’s Disease

 Activating mutations in the PTH/PTHrP receptor (PTH1R) have been

identified as the cause of this rare autosomal dominant syndrome.

 The mutations lead to constitutive activation of receptor which is

sufficient to cause the disease.

 Hypercalcemia and hypophosphatemia with undetectable or low PTH

levels are typically observed
FIGURE: Illustration of some genetic mutations that alter calcium metabolism by effects on the
parathyroid cell or target cells of parathyroid hormone (PTH) action

Harrison’s principle of internal medicine

SECONDARY HYPERPARATHYROIDISM

 Hyperplasia of the gland in response to hypocalcaemia (e.g. in chronic

renal failure).

 Characterized by ↑ PTH in response to low Ca

 Cause - Resistance to the normal level of PTH is a major factor

contributing to the development of hypocalcemia, which, in turn, is a
stimulus to parathyroid gland enlargement

 an increase of FGF23 production by osteocytes (and possibly osteoblasts)

in bone occurs well before an elevation in PTH is detected.

 FGF23 is a potent inhibitor of the renal 1-alpha hydroxylase and the

FGF23-dependent reduction in 1,25(OH)2 vitamin D seems to be an
important stimulus for the development of secondary HPT

 also in those with osteomalacia due deficiency of vitamin D action and

PHP (deficient response to PTH downstream of PTHR1).
TERTIARY HYPERPARATHYROIDISM

 Autonomous secretion of parathormone even after the removal of

secondary stimulus (e.g. after renal transplantation).

 MEN syndromes (type I (parathyroid adenoma, pancreatic islet cell

tumours, pituitary adenoma) and type II (parathyroid adenoma, medullary
thyroid cancer, phaeochromocytoma) and ectopic parathormone
production (e.g. from small cell lung cancer).
HYPOPARATHYROIDISM

A deficiency of parathyroid hormone

Causes
 acute or chronic

 idiopathic (autoimmune genetic disorder or the congenital absence of the

parathyroid glands)
 Acquired (accidental removal of or injury to the parathyroid glands,
massive neck irradiation, sarcoidosis, amyloidosis, tuberculosis,
neoplasms, or trauma.)
 Acquired, reversible hypoparathyroidism (hypomagnesemia-induced
impairment of hormone synthesis and release, from suppression of normal
gland function due to hypercalcemia, or from delayed maturation of
parathyroid function).
 effects of hypoparathyroidism are usually correctable with replacement
therapy.
 Mild hypoparathyroidism may be asymptomatic, but it usually produces
hypocalcemia and high serum phosphate levels that affect the central
nervous system (CNS) as well as other body systems.

 long-term hypocalcemia may result, cataracts and basal ganglion

calcifications, are irreversible.

 In the chronic form, hypoparathyroidism typically causes neuromuscular

irritability, increased deep tendon reflexes, Chvostek’s sign
(hyperirritability of the facial nerve, producing a characteristic spasm when
it’s tapped), dysphagia, organic brain syndrome, psychosis, mental
deficiency in children, and tetany.

 DiGeorge syndrome, or the velocardiofacial syndrome: an autosomal

dominant form involving microdeletions of chromosome 22q11.2 in which
there is defect in development of thymus and parathyroid gland
PTH INEFFECTIVE
 Occurs when the PTHR1–signaling protein complex is defective
 when PTH action to promote calcium absorption from the diet via
the synthesis of 1,25(OH)2 D is insufficient because of vitamin D
deficiency or because vitamin D is ineffective (defects in vitamin D
receptor or vitamin D synthesis);
 or in CKD in which the calcium-elevating action of PTH is
impaired
PSEUDOHYPOPARATHYROIDISM(PHP)
 PHP refers to a group of distinct inherited disorders

 PHP resembles hypoparathyroidism and is manifested by hypocalcemia and

hyperphosphatemia, yet elevated PTH levels.

 The cause of the disorder is defective PTH-dependent activation of the

stimulatory G protein complex or the downstream effector protein kinase A,
resulting in failure of PTH to increase intracellular cAMP or to respond to
elevated cAMP levels

 Hyperplasia of parathyroid is seen due to, a response to hormone-resistant

hypocalcemia

 Patients affected by PHP characterized by symptoms and signs of

hypocalcemia in association with distinctive skeletal and developmental
defects.
PARATHYROID HORMONE VERSUS
CALCITONIN
SUMMARY
REFERENCES
 Richard S.Snell. Clinical Anatomy for Medical Students
 Tietz Textbook Clinical Chemistry and Molecular
Diagnostics. 5th edition
 Harrison’s principle of internal medicine. 19th edition.
 William J. Marshall. Clinical biochemistry and metabolic
aspects. 3rd edition
 Giovanni Lombardi et. al. Physical Activity-Dependent
Regulation of Parathyroid Hormone and Calcium-
Phosphorous Metabolism
 Guyton and Hall. Text book of medical physiology. 11 th
edition.