Hypoparathyroid disorders

1
Hypoparathyroid disorders

• ? ? ? ? ?
• Marx, Stephen J.
• The New England Journal of Medicine
• Volume 343(25) 21 December 2000   pp 1863-1875

2
Outline

• Case Report
• Introduction
• Structure and Actions of PTH
• Measurement of PTH in Serum
• Diagnosis and Causes
• Damage to the Parathyroid Glands from Surgery
• Developmental Defects in the Parathyroid Glands
• Autoimmune Hypoparathyroidism
• Defects in the PTH Molecule
• Defective Regulation of PTH Secretion
• Treatment of Hypoparathyroidism
• Calcium and Vitamin D Analogues
• Parathyroid-Tissue Transplantation or PTH
• Genetic Disorders of PTH Action
• Defects of the Type 1 PTH Receptor
• Jansen's Chondrodystrophy
• Blomstrand's Chondrodystrophy
• Defects of the Stimulatory Guanine-Nucleotide-Bind
  ing Protein
• Pseudohypoparathyroidism Type 1a

3
Trousseau's Sign (1)

• A 51 Y/O woman with mild HTN for which she was
  taking a beta-adrenergic antagonist and a
  thiazide diuretic was sent to ER because of
  hypocalcemia (serum calcium 5.4 mg/dl) in an
  outpatient clinic earlier in the day. She
  described a five-day history of worsening
  paresthesias in her arms and legs and a one-day
  history of cramps in her hands and facial
  muscles. She had also had diarrhea intermittently
  for two wks. She reported no alcohol ingestion.
• P.E. revealed mild hyperreflexia, Chvostek's
  sign, and Trousseau's sign, as evidenced by
  changes in the patient's right hand (Panel A) 90
  seconds after insufflation of the BP cuff to 10
  mm Hg above systolic pressure (Panel B).

4
Trousseau's Sign (2)

• Lab. studies showed hypocalcemia, hypomagnesemia,
  normal serum albumin, phosphate, and Cr, and a
  high serum PTH.
• The patient's symptoms, signs, and biochemical
  abnormalities resolved after the IV
  administration of calcium and magnesium, and she
  was subsequently treated with oral calcium and
  magnesium.
• The hypocalcemia was attributed to hypomagnesemia
  resulting from both an insufficient intake of
  magnesium and magnesium wasting owing to diarrhea
  and thiazide therapy.

NEJM. Volume 343(25)  21 December 2000  p 1855
5
Introduction(1)

• The four parathyroid glands, through the
  secretion of PTH, regulate serum calcium and bone
  metabolism. Serum calcium regulate PTH secretion
  high concentrations inhibit secretion by
  parathyroid glands of PTH and low concentrations
  stimulate it.
• Low or falling serum calcium act within seconds
  to stimulate PTH secretion, initiated by means of
  a calcium-sensing receptor on the surface of the
  parathyroid cells.
• This receptor is a heptahelical molecule, like
  the receptors for light, odorants,
  catecholamines, and many peptide hormones.

6
Introduction(2)

• PTH secretion is 50 of the maximal level at a
  serum ionized calcium of 4 mg/dl (1 mmol/l) this
  is considered the calcium set point for PTH
  secretion.
• A slower regulation of PTH secretion occurs over
  a period of hours as a result of cellular changes
  in PTH messenger RNA (mRNA).
• Vitamin D and its metabolites 25-OH vit D and
  1,25-(OH)2D, acting through vitamin D receptors,
  decrease the level of PTH mRNA, and hypocalcemia
  increases it.

7
Introduction(3)

• The slowest regulation of PTH secretion occurs
  over days or even months and reflects changes in
  the growth of the parathyroid glands.
• Metabolites of vitamin D directly inhibit the
  mass of parathyroid cells hypocalcemia
  stimulates the growth of parathyroid cells
  independently of the contrary action of vitamin D
  metabolites.
• Disruptions in these processes cause
  hyperparathyroidism or hypoparathyroidism.

8
Structure and Actions of PTH (1)

• PTH is stored and secreted mainly as an
  84-amino-acid peptide. A synthetic amino-terminal
  fragment, PTH (1-34), is fully active
  modifications at the amino terminal, particularly
  at the first two residues, can abolish its
  biologic activity.
• The effects of PTH on mineral metabolism are
  initiated by the binding of PTH to type 1 PTH
  receptor in the target tissues. PTH thereby
  regulates large calcium fluxes across bone,
  kidneys, and intestines( Figure 1).

9
Structure and Actions of PTH (2)

• Another PTH receptor (type 2) has been found in
  the brain and intestines. Its main ligand is a
  peptide different from PTH the functions of this
  receptor are not known.
• PTH-related peptide is a distant homologue of PTH
  and is not a true hormone. It is synthesized in
  cartilage and in many more tissues than is PTH,
  and its secretion is not regulated by serum
  calcium.Its local release activates the type 1
  PTH receptor, and its affinity for this receptor
  is similar to that of PTH ( Figure 1).

10
Measurement of PTH in Serum (1)

• Measurements of serum calcium, PTH, 25-OH vitD,
  and 1,25-(OH)2D are used regularly in the
  diagnosis and treatment of hyperparathyroidism
  and hypoparathyroidism only the measurement of
  serum PTH is covered here.
• Serum calcium should usually be measured at the
  same time as serum PTH since the ionized
  fraction of serum calcium is the biologically
  active form, it is a more useful index of
  hyperparathyroidism and hypoparathyroidism than
  are other indexes of calcium in serum. It is
  therefore the preferred form of serum calcium to
  measure.

11
Measurement of PTH in Serum (2)

• Current assays for serum PTH are two-site assays
  designed to detect both amino-terminal and
  carboxy-terminal epitopes of the peptide. The
  better assays are those that are well
  standardized, do not cross-react with PTH-related
  peptide, and are sufficiently sensitive that
  normal values can be distinguished from subnormal
  values ( Figure 2).
• PTH molecules that are reactive in these two-site
  immunoassays are considered "intact," but some
  have no bioactivity.

12
Measurement of PTH in Serum (3)

• A loss of only six amino acids to yield PTH
  (7-84) eliminates all bioactivity but does not
  affect the immunoreactivity measured in most or
  all of these assays.In fact, about half of the
  PTH detected with these assays in chronic renal
  disease is biologically inactive.
• Measurements of PTH can help characterize
  parathyroid tumors. PTH can be measured in fluid
  obtained from a lesion by FNA (usually guided
  ultrasonographically) or in serum from the veins
  of neck and mediastinum, catheterized
  selectively. Results can be obtained in 10-15
  mins allow physicians to assess the completeness
  of removal of hyperfunctioning parathyroid tissue
  during operation.

13
Introduction

• Hypoparathyroidism can cause hypocalcemia with
  consequent paresthesias, muscle spasms (i.e.,
  tetany), and seizures, especially when it occurs
  rapidly.
• In contrast, chronic hypoparathyroidism generally
  causes hypocalcemia so gradually that the only
  symptom may be visual impairment from cataracts
  caused by years of hypoparathyroidism.

14
Diagnosis and Causes

• Like hyperparathyroidism, hypoparathyroidism is
  diagnosed on the basis of measurements of serum
  calcium and PTH ( Figure 2).
• The causes of hypoparathyroidism are diverse,
  representing disruptions of one or more of the
  steps in the development and maintenance of PTH
  secretion.

15
Damage to the Parathyroid Glands from Surgery

• Injury to or removal of the parathyroid glands
  during neck surgery is the most common cause of
  acute or chronic hypoparathyroidism.

16
Developmental Defects in Parathyroid Glands (1)

• Agenesis of the parathyroid glands occurs in
  infants with DiGeorge syndrome (and the closely
  related velocardiofacial syndrome).
• The manifestations include incomplete development
  in the branchial arches, resulting in varying
  degrees of parathyroid and thymic hypoplasia,
  conotruncal cardiac defects, facial
  malformations, and learning disability.

17
Developmental Defects in Parathyroid Glands (2)

• Both syndromes are associated with rearrangements
  and microdeletions affecting an unknown gene or
  genes on the long arm of chromosome 22. Any
  resultant defect should be treated, depending on
  its severity.
• Isolated agenesis of the parathyroid glands in
  one family has been attributed to a recessive
  deletion in the gene on chromosome 6 that
  normally encodes a transcription factor.

18
Autoimmune Hypoparathyroidism

• It is a prominent component of autoimmune
  polyglandular syndrome type 1, also known as
  autoimmune polyendocrinopathy-candidiasis-ectoderm
  al dystrophy syndrome. It looks like other
  manifestations of the syndrome, occurs during
  childhood for this reason and because of such
  associated abnormalities as hypoadrenalism and
  intestinal malabsorption, the hypoparathyroidism
  may be difficult to treat.
• The syndrome is inherited as an autosomal
  recessive trait and is caused by mutations in an
  autoimmune regulator gene (AIRE) with a known
  sequence but an unknown function.

19
Defects in the PTH Molecule

• A few cases of familial hypoparathyroidism have
  been described in which the cause was a mutation
  in the gene for PTH that resulted in the
  synthesis of a defective PTH molecule and
  undetectable amounts of PTH in serum.

20
Defective Regulation of PTH Secretion

• Hypocalcemia and hypercalciuria are the chief
  features of autosomal dominant hypercalciuric
  hypocalcemia, which is caused by activating
  mutations of parathyroid and renal
  calcium-sensing receptor. These mutations cause
  excessive calcium-induced inhibition of PTH
  secretion.
• The hypocalcemia is usually mild and
  asymptomatic. When it is mild, it should be
  treated cautiously, if at all, because raising
  serum calcium further increases urinary calcium
  excretion and may cause nephrocalcinosis.

21
Treatment of Hypoparathyroidism

• Calcium and Vitamin D Analogues
• Parathyroid-Tissue Transplantation or Parathyroid
  Hormone

22
Calcium and Vitamin D Analogues (1)

• The main treatments available for acute or
  chronic hypoparathyroidism are calcium salts,
  vitamin D or vitamin D analogues, and drugs that
  increase renal tubular reabsorption of calcium
  (i.e., thiazides) ( Table 2). The PTH-dependent
  renal production of 1,25-(OH)2 D is deficient in
  all hypoparathyroid states. Therefore, therapy
  with a vitamin D analogue is used to ensure that
  there is a steady serum concentration of an
  active vitamin D analogue.
• If PTH is absent or nonfunctional, its
  hypocalciuric action cannot occur therefore,
  raising the serum calcium may cause
  hypercalciuria, nephrolithiasis, and renal
  damage.

23
Calcium and Vitamin D Analogues (2)

• Pts in whom hypocalcemia develops suddenly - for
  example, after neck surgery - are best treated
  with IV calcium and with oral or IV calcitriol.
  Chronic hypocalcemia should be treated with oral
  calcium and either calcitriol or vitamin D. The
  efficacy of treatment may vary, such as
  autoimmune polyglandular syndrome type 1, are
  best treated with vitamin D analogues that have a
  short half-life.
• Calcitriol raises serum calcium within 1 or 2
  days after treatment begins, and its action
  dissipates equally rapidly the action of vitamin
  D begins and dissipates over a period of 2 to 4
  wks.

24
Parathyroid-Tissue Transplantation or PTH (1)

• Transplantation of parathyroid tissue is
  appealing but rarely possible. A parathyroid
  allograft would require immunosuppression and
  more dangerous than the disease it was meant to
  treat.
• Parathyroid autografts are sometimes placed in
  forearm and consist of either fresh parathyroid
  tissue or removed earlier and cryopreserved.
• Indication for a parathyroid autograft is a high
  likelihood of postoperative hypoparathyroidism.
• As many as half of these grafts fail, and among
  those that survive and function, the potential
  for late autograft-mediated recurrences of
  hyperparathyroidism is substantial, since the
  parathyroid tissue used for the graft was
  abnormal.

25
Parathyroid-Tissue Transplantation or PTH (2)

• Pts with hypoparathyroidism have been treated
  successfully with synthetic human PTH (1-34)
  given subcutaneously once daily.
• The increase in urinary calcium excretion in
  these pts was smaller than that which occurs in
  pts treated with calcium and calcitriol or
  vitamin D.
• However, synthetic human PTH (1-34) is not
  currently available.

26
Genetic Disorders of Parathyroid Hormone Action

• Hereditary defects in parathyroid hormone action
  are rare but informative. Each confirms the role
  of an important signaling molecule.
• To some extent, these states mimic disorders of
  parathyroid hormone excess or deficiency.

27
Defects of the Type 1 PTH Receptor

• Two defects with opposite effects on type 1 PTH
  receptor have a surprisingly similar effect on
  bone growth.

28
Jansen's Chondrodystrophy

• It is characterized by short limbs, mild
  hypercalcemia, and low serum PTH.
• It is caused by activating mutations of the type
  1 PTH receptor and is inherited as an autosomal
  dominant trait.
• It is associated with increased proliferation and
  delayed maturation of chondrocytes, which may
  weaken growth plates, thereby causing the short
  limbs.

29
Blomstrand's Chondrodystrophy

• It is characterized by growth impairment,
  primarily in the form of short limbs.
• It has been lethal prenatally, and therefore the
  regulation of serum calcium has not been
  evaluated in vivo.
• It is caused by inactivating mutations of the
  type 1 PTH receptor and is inherited as an
  autosomal recessive trait. The growth plates show
  accelerated calcification and a near-absence of
  proliferating chondrocytes.

30
Defects of the Stimulatory Guanine-Nucleotide-Bind
ing Protein

• PTH signaling in cells is mediated by the type 1
  PTH receptor, which then acts on a stimulatory
  guanine-nucleotide-binding (Gs) protein, which is
  composed of three subunits (alpha, beta, and
  gamma).
• The Gs(alpha) subunit (encoded by the GNAS1 gene)
  mediates cyclic AMP stimulation by PTH and by
  several other peptide hormones, including
  thyrotropin.

31
Pseudohypoparathyroidism Type 1a

• Pseudohypoparathyroidism type 1a is characterized
  by short stature and other skeletal
  abnormalities, which are known collectively as
  Albright's hereditary osteodystrophy, as well as
  hypocalcemia and high serum PTH.
• It is caused by inactivating mutations in the
  (alpha) subunit of Gs) and is inherited as an
  autosomal dominant trait. Many pts have
  resistance not only to PTH but also to
  thyrotropin.

32
Pseudo-pseudohypoparathyroidism

• It occurs in families with pseudohypoparathyroidis
  m type 1a.
• It consists of a combination of inactivating
  mutations of GNAS1 and Albright's osteodystrophy
  without the resistance to multiple hormones that
  characterizes pseudohypoparathyroidism.
• The hormone resistance is suppressed when the
  mutated GNAS1 gene is inherited from the father
  (i.e., paternal imprinting, or suppression, of
  the mutant copy occurs in selected tissues).

33
Pseudohypoparathyroidism Type 1b

• It is characterized by isolated resistance to PTH
  without the accompanying Albright's
  osteodystrophy. It is associated with defective
  methylation within GNAS1, which is most likely
  caused by a mutation in or near GNAS1.
• Hypocalcemia in pseudohypoparathyroidism type 1a
  or 1b should be treated in the same way as it is
  in true hypoparathyroidism.

34
Conclusions

• Despite a confusing disease nomenclature that is
  a remnant of past eras, substantial insight has
  been gained into many disorders of the
  parathyroid axis. With the advent of reliable and
  specific assays for PTH, the diagnosis of
  parathyroid dysfunction has become much easier.
• Treatments are generally satisfactory and are
  logically related to the defects in the
  parathyroid gland or to their expression in the
  target organs. Controversies persist, however,
  particularly about the treatment of primary
  hyperparathyroidism.