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Hyperparathyroidism

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Title: Hyperparathyroidism


1
Hyperparathyroidism
  • Prepared by Dr. Lami Salah
  • Moderator Dr. A. Hamam

2
Parathyroid Hormone (PTH)
  • Is an 84 aminoacid chain, but its biologically
    activity resides in the first 34 residues.
  • In the parathyroid gland, a Pre-Pro-PTH are
    synthesized
  • Pre-Pro-PTH is converted to Pro-PTH and Pro-PTH
    converted to PTH.
  • When serum Calcium level falls, signal is
    transduced through calcium sensing receptors, and
    secretion of PTH increased.

3
Parathyroid Hormone (PTH)
  • The calcium sensing receptor
  • regulate the secretion of PTH and the
    reabsorption of calcium by renal tubules in
    response to alteration in serum calcium
    concentration.
  • The gene for the receptor is located on the
    chromosome 3.
  • Loss of function mutations results in an increase
    in the set point with respect to serum calcium,
    resulted in hypercalcemia and in the conditions
    of Familial hypocalciuric Hypercalcemia and
    Neonatal Severe Hyperparathyroidism

4
Parathyroid Hormone (PTH)
  • The calcium sensing receptor
  • Gain of function mutations result in depressed
    secretion of PTH in response to hypocalcemia,
    leading to syndrome of Familial Hypocalcemia with
    Hypercalciuria

5
Parathyroid Hormone related peptide (PTHrP)
  • Is homologous to PTH only in the first 13 aa of
    its amino terminus, 8 of which are identical to
    PTH.
  • Its gene is on the short arm of chromosome 12 and
    that of PTH is on the short arm of chromosome 11.
  • PTHrP, like PTH, activates PTH receptors in
    kidney and bone cells.
  • It is produced in almost every type of cells in
    the body, including every tissue of the embryo at
    certain stage of development.

6
Parathyroid Hormone related peptide (PTHrP)
  • Inactivating mutation of the receptor for
    PTH/PTHrP results in lethal bone disorder
    charaterized by short limbs and markedly advanced
    bone maturation known as Blomstrand
    Chondrodysplasia.

7
Definition
  • Hyperparathyroidism describes proliferation of
    the parathyroid hormone (PTH)secreting cells, or
    chief cells, in one or more of the 4 parathyroid
    glands.
  • The cause may be due to a genetic mutation, as in
    primary hyperparathyroidism, or to a variety of
    underlying conditions that produce secondary
    hyperparathyroidism due to hypocalcemia, such as
    intestinal malabsorption, or high serum
    phosphorus levels, such as with chronic renal
    failure.

8
Definition
  • Tertiary hyperparathyroidism usually exists in
    situations of secondary hyperparathyroidism.
    Tertiary hyperparathyroidism occurs when
    parathyroid hyperplasia becomes so severe that
    removal of the underlying cause does not
    eliminate the stimulus for PTH secretion and
    hypertrophic chief cells become autonomous.

9
Pathophysiology
  • While the exact mechanism causing increased PTH
    secretion is not certain, a loss of sensitivity
    of these proliferating chief cells to normal
    extracellular calcium concentrations occurs.
  • In 1996, Kifor et al showed that the parathyroid
    cell surface G proteincoupled calcium-sensing
    receptor is reduced by approximately 50 in
    parathyroid adenoma cells as compared to normal
    parathyroid controls.

10
Pathophysiology
  • This reduction is associated with an increased
    amount of circulating calcium, which is required
    to suppress PTH secretion.
  • The reduction may be caused by genetic mutation
    (eg, familial hypocalciuric hypercalcemia,
    neonatal severe hyperparathyroidism), multiple
    endocrine neoplasia (MEN), or conditions that
    would normally stimulate compensatory PTH
    secretion

11
Pathophysiology
  • Conditions include calcium or vitamin D
    malabsorption, accumulation of phosphate with
    inability to excrete it (eg, chronic renal
    failure), and uremia.
  • In addition, some genetic mutations have been
    described in primary hyperparathyroidism,
    including relocation of the PTH gene to a site
    next to an oncogene.
  • Loss of one copy of a tumor suppressor gene on
    chromosome 11 has also been reported in some
    patients with multiple endocrine neoplasia type 1
    (MEN I) syndrome

12
Pathophysiology
  • PTH indirectly stimulates bone resorption by
    attaching to the osteoblast PTH receptor, which
    then signals the osteoblast to produce a variety
    of substances, among them proinflammatory
    cytokine interleukin-6 and osteoclast
    differentiating factor, both of which can
    stimulate osteoclast differentiation and
    proliferation.
  • The osteoblast also acts as a brake on
    osteoclastic activity by producing
    osteoprotegerin. Exactly how the osteoblast
    governs osteoclastogenesis is not fully
    understood

13
Mortality/Morbidity
  • The morbidity from primary hyperparathyroidism is
    most often due to hypercalcemia.
  • This can take the form of bradycardia and heart
    block and dehydration due to polyuria, nausea,
    vomiting, and poor fluid intake. Pancreatitis has
    also been reported.
  • Other causes of morbidity observed with primary
    hyperparathyroidism may be due to effects of
    associated tumors, such as jaw tumors or Wilms
    tumor.
  • Morbidity from secondary hyperparathyroidism
    usually involves demineralization of bones with
    subsequent pain, fracturing, or deformity.

14
History
  • Primary hyperparathyroidism
  • Most commonly, patients present without symptoms.
    Hyperparathyroidism may be diagnosed in an
    otherwise asymptomatic patient by incidental
    discovery during routine blood chemistry analysis
    of hypercalcemia.
  • Symptoms of early disease, when present, are
    specific to hypercalcemia.
  • They include muscle weakness, depression,
    increased sleepiness, nausea, vomiting, acute
    abdominal pain (which might be the result of
    pancreatitis), constipation, and polydipsia.
  • Frequent and occasionally painful urination and
    dysuria and/or back pain may be observed, the
    latter from nephrolithiasis.

15
History
  • Secondary hyperparathyroidism
  • Patients with secondary hyperparathyroidism
    usually present with a history of underlying
    disease such as renal or intestinal conditions.
  • Symptoms are musculoskeletal in nature, including
    bone pain, muscle weakness, and previous
    fracture.

16
Physical Exam.
  • Primary hyperparathyroidism
  • Signs of dehydration due to hypercalcemia, such
    as tenting of skin, prolonged capillary refill
    time, and dry mucous membranes.
  • Bradycrardia. With or without irregular
    heartbeat.
  • Decreased muscle tone and somnolence.

17
Physical Exam.
  • Secondary hyperparathyroidism
  • Skeletal deformity
  • Decreased muscle tone
  • Bone pain on palpation
  • Short stature

18
Eitiology
  • Primary hyperparathyroidism - Genetic mutation.
  • Secondary hyperparathyroidism - May develop as a
    response to hypocalcemia caused by intestinal
    disease resulting in calcium and vitamin D
    malabsorption .
  • Chronic renal insufficiency
  • Insufficient vitamin D and calcium intake
    Insufficient intake in children may cause
    rickets. rickets are a major cause of secondary
    hyperparathyroidism in developing countries,
    especially those countries in which children are
    kept out of the sun while parents work.

19
Eitiology
  • Iatrogenic causes Iatrogenic causes, such as
    lithium administration, may decrease the ability
    of circulating levels of calcium that are within
    the reference range to suppress PTH secretion.
    The mechanism for this is not presently clear.
  • Cholestatic liver disease Contrary to previous
    belief, not all children with chronic cholestatic
    liver disease have secondary hyperparathyroidism.
    Many of these patients, as well as adults with
    chronic liver disease, have levels of PTH within
    the reference range.

20
Eitiology
  • Neonatal severe hyperparathyroidism symptoms
    develop shortly after birth and consist of
    anorexia, irritability, lethargy, constipation,
    and failure to thrive.
  • Radiograph reveal subperiosteal bone resorption,
    osteoparosis, and pathological fractures.
  • Symptoms maybe mild, resolving without treatment
    or may have rapidly fatal course if diagnosis and
    treatment are delayed.

21
Eitiology (Neonatal severe hyperparathyroidism)
  • Histologically the parathyroid gland show diffuse
    hyperplasia.
  • Infants maybe homozygous or heterzygous for the
    mutation in Ca sensing receptor gene, where is
    most idividual with one copy of this mutation
    exhibit autosomally dominant familial
    hypocalciuric hypercalcemia.

22
Eitiology
  • MEN type I
  • Is an autosomal dominant disorder characterized
    by hyperplasia or neoplasia of the endocrine
    pancreas, the anterior pituitary, and Parathyroid
    glands.
  • Mostly hyperparathyroidism is the presenting
    manifestation. But rarely occur in children below
    18 years of age.
  • The gene of MEN type I is on chromosome 11

23
Eitiology
  • Hyperparathyroidism/jaw tumor syndrome
  • AD disorder characterized by parathyroid adenoma
    and fibro-osseous jaw tumors.
  • Affeced patients may also have polcystic kidney
    disease, renal hamartomas and Wilms tumor.

24
Eitiology
  • MEN type II is also associated with
    hyperparathyroidism

25
Eitiology
  • Transient Neonatal Hyperparathyroidism
  • Has occurred in a few infants born to mothers
    with hypoparathyroidism.
  • The cause of the condition is chronic
    intrauterine exposure to hypocalcemia with
    resultant hyperplasia of the fetal parathyroid
    glands
  • The newborn manifestations involve the bone
    primarily and healing occur between 4 and 7
    months of age.

26
Lab Studies
  • One key difference between primary and secondary
    hyperparathyroidism is that patients with primary
    disease are always hypercalcemic, while those
    with secondary disease are almost always
    normocalcemic.
  • For blood studies, serum calcium concentrations
    and immunoreactive PTH levels using
    immunoradiometric assay (IRMA) to detect intact
    PTH molecules are most important.
  • These can be used to distinguish primary from
    secondary hyperparathyroidism.
  • In primary disease, high levels of calcium and
    PTH are observed, while in secondary disease,
    levels of calcium are within the reference range
    and levels of PTH are high.

27
Lab Studies
  • Serum levels of phosphorus are not always helpful
    with respect to diagnosis.
  • Serum phosphorus levels in primary
    hyperparathyroidism are mainly in the low-normal
    range.
  • Serum levels in secondary hyperparathyroidism due
    to renal failure serum phosphorus levels are
    elevated because of the inability of the kidney
    to excrete phosphorus.
  • In the absence of dialysis therapy, phosphorus
    levels are elevated.

28
Imaging Studies
  • Radiography
  • The value of skeletal radiographs in diagnosis of
    primary hyperparathyroidism is questionable
    because relatively few cases exhibit stigmata of
    hyperparathyroidism.
  • Radiographs may be useful in defining the extent
    of damage in secondary hyperparathyroidism.
  • Radiographs reveal the following in some cases of
    primary and most cases of secondary
    hyperparathyroidism
  • Multiple areas of subperiosteal bone resorption
    of the distal phalanges
  • Tapering of the clavicles
  • Brown tumors of the long bones and a
    salt-and-pepper appearance of the skull

29
Imaging Studies
  • Bone densitometry
  • Another way to monitor the severity of bony
    involvement is with bone densitometry, determined
    by dual energy x-ray absorptiometry (DEXA). This
    technique can be used to quantify bone mineral
    content of a specific region in g, bone area in
    cm2, and density in g/cm2.
  • This is an areal or 2-dimensional measurement,
    but it can be followed longitudinally to evaluate
    the severity of the effect on bone and the
    effectiveness of therapy.

30
Imaging Studies
  • Many patients with severe primary
    hyperparathyroidism have reduced bone mineral
    density at multiple sites

31
Cont.
  • Other Tests
  • The only other tests of value are those that are
    used to diagnose the underlying cause of
    secondary hyperparathyroidism, associated genetic
    defects, or tumors accompanying primary
    hyperparathyroidism.
  • Procedures
  • No diagnostic procedures are pertinent to
    diagnosis, except those that are used to diagnose
    an underlying disease in secondary
    hyperparathyroidism.

32
Medical Care
  • Medical management of primary hyperparathyroidism
    is not satisfactory because no agents presently
    exist that can produce either sustained blockage
    of PTH release by parathyroid glands or sustained
    blockage of hypercalcemia.
  • However, research is currently underway to
    develop calcimimetics, which can stimulate
    up-regulation of parathyroid calcium-sensing
    receptor and potentially blunt abnormally
    increased PTH secretion.
  • In addition, human osteoprotegerins, which can
    block PTH-induced hypercalcemia, are also
    undergoing clinical studies.

33
Medical Care
  • For secondary hyperparathyroidism that occurs
    with chronic renal failure, parenteral
    administration of calcitriol is helpful however,
    this manner of administration is feasible only
    for those patients receiving hemodialysis.
  • For those individuals receiving therapy with
    peritoneal dialysis, oral administration of
    calcitriol is the only alternative. This route of
    administration may not be as effective as the
    intravenous route however, some preliminary
    clinical trials have been conducted for
    calcimimetics in this condition, as well as in
    primary hyperparathyroidism. Early results are
    encouraging.

34
Medical Care
  • For other forms of secondary hyperparathyroidism,
    such as that resulting from chronic cholestatic
    liver disease, no standard treatment guidelines
    exist.
  • Therefore, treatment should be aimed at
    ameliorating the underlying condition and
    supplying sufficient dietary calcium, phosphorus,
    vitamin D, and magnesium.
  • This ensures that hyperparathyroidism is not
    exacerbated by nutritional insufficiency.

35
Medical Care
  • The treatment of acute severe hypercalcemia
    (serum calcium level gt14.0 mg/dL), which may or
    may not result from hyperparathyroidism, would
    include hydration with isotonic sodium chloride
    solution to restore extracellular fluid volume
    that may be depleted secondary to vomiting and to
    induce calciuresis.
  • Consider the addition of loop diuretics, such as
    furosemide, only after normal hydration is
    restored.
  • In extreme cases, either hemodialysis or
    peritoneal dialysis with low or zero calcium
    dialysate could be employed.

36
Medical Care
  • Although not routinely used in pediatrics, more
    studies are demonstrating that the
    bisphosphonates, antiresorptive agents, can be
    safely used in children and may lower serum
    calcium levels by decreasing bone resorption.
  • Also, mobilization should be encouraged to
    prevent the hypercalcemia that occurs secondary
    to bed rest.

37
Surgical Care
  • Parathyroidectomy
  • For primary hyperparathyroidism, subtotal or
    total parathyroidectomy is the treatment of
    choice, depending on the number of glands
    involved with tumors.
  • Parathyroidectomy can result in reference range
    serum calcium levels, an increase in bone mineral
    density, and successful prevention of kidney
    stones.
  • Also, in uremic patients, subtotal or total
    parathyroidectomy is an option when medical
    management with calcitriol or one of its analogs
    is unsuccessful or when tertiary
    hyperparathyroidism that is independent of
    external feedback develops

38
Surgical Care
  • Surgical complications
  • Postoperative complications include transient
    hypocalcemia because parathyroids regain their
    sensitivity to circulating calcium.
  • Hungry bone syndrome, a prolonged period of
    hypocalcemia, can occur postoperatively in those
    cases of primary hyperparathyroidism that
    demonstrated significant bone demineralization.
    Bones reaccumulate calcium at the expense of
    circulating levels.
  • Finally, as in thyroid surgery, a risk of damage
    to the recurrent laryngeal nerve resulting in
    permanent hoarseness of the voice exists.

39
Diet
  • No strict dietary requirements are necessary for
    management of primary hyperparathyroidism.
  • For secondary hyperparathyroidism, dietary
    management depends on the underlying disease
    state.
  • For renal disease, phosphate may be restricted
    depending on the success of dialysis treatment or
    oral phosphatebinding therapy.
  • For liver disease or malabsorptive syndromes,
    oral or intravenous supplementation of calcium,
    phosphate, magnesium, and vitamin D would be
    helpful to minimize inadequacy of these nutrients
    caused by malabsorption or other loss.

40
Treatment
  • Vitamin D analogs
  • These agents regulate serum calcium levels via
    actions on calcium and phosphorus metabolism at
    intestinal, renal, and skeletal sites.
  • The kidney appears to play a central role in this
    system. It produces calcitriol (ie,
    1,25-dihydroxyvitamin D, the primary active
    metabolite of vitamin D3), which acts on distal
    organs, and at the same time is the target organ
    for PTH, calcitonin, and possibly calcitriol.
  • Calcitriol is administered to help suppress
    excessive PTH release and blunt the
    hyperparathyroid response to chronic renal
    failure.

41
Treatment (Vitamin D analogs )
  • Calcitriol (Calcijex, Rocaltrol)
  • Used in attempted suppression of PTH secretion
    stimulated by inability of the kidneys to excrete
    phosphate, with its consequent accumulation in
    blood.
  • Increases calcium levels by promoting absorption
    of calcium in the intestines and retention in the
    kidneys.
  • Has not been tried in patients with other causes
    of secondary hyperparathyroidism.

42
Treatment (Vitamin D analogs )
  • Dose
  • 0.01-0.04 mcg/kg/d POIV dose is not established
    not to exceed adult dose.
  • Precautions
  • Maternal hypersensitivity to vitamin D during
    pregnancy may lead to Williams syndrome growth
    arrest may result in children fed ergocalciferol
    1800 U/d major precaution involves monitoring to
    avoid hypercalcemia

43
Treatment
  • Isotonic crystalloids
  • Sodium chloride 0.9 fluid is used to supply
    intravenous hydration to replace fluids lost by
    emesis for patients with acute hypercalcemia of
    any etiology.

44
Treatment
  • Loop diuretics
  • Once hydration has been established, use of a
    diuretic (eg, furosemide) can help increase
    calciuresis without adding to the dehydration
    caused by hypercalcemia.
  • Furosemide (Lasix) -- Increases excretion of
    water by interfering with chloride-binding
    cotransport system, which in turn inhibits sodium
    and chloride reabsorption in the ascending loop
    of Henle and the distal renal tubule.

45
Treatment (Loop diuretics )
  • Dose
  • 1 mg/kg IV may cautiously increase dose by 1
    mg/kg q2h not to exceed 6 mg/kg/dose

46
Treatment
  • Bisphosphonates
  • Bisphosphonates are antiresorptive agents that
    are used to help preserve bone mass. They are
    available in oral and parenteral forms.
  • The inhibition of bone resorption produces a
    hypocalcemic effect.
  • Used in the management of conditions associated
    with increased bone resorption (eg, osteoporosis,
    Paget disease of bone, management of
    hypercalcemia especially that associated with
    malignancy).

47
Treatment (Bisphosphonates)
  • In case of acute hypercalcemia with vomiting,
    parenteral therapy is recommended. By reducing
    bone resorption, a calcium-lowering effect in the
    blood may occur.

48
Tretment (Bisphosphonates)
  • Pamidronate (Aredia)
  • IV bisphosphonate that acts as an antiresorptive
    agent.
  • Inhibits normal and abnormal bone resorption.
  • Appears to inhibit bone resorption without
    inhibiting bone formation and mineralization.
  • Currently accepted uses include the treatment of
    hypercalcemia associated with neoplasms and
    metastases as well as for treatment of Paget
    disease.

49
Pamidronate (Aredia) cont.
  • This category of drugs is not approved for the
    treatment of hypercalcemia secondary to
    hyperparathyroidism, but in practice can be used
    for this as well as in the management of
    postmenopausal osteoporosis.
  • Now being used in pediatrics to treat
    osteogenesis imperfecta and idiopathic juvenile
    osteoporosis.
  • Preliminary study results on its use to prevent
    bone loss following severe burns appear
    promising.

50
Tretment (Bisphosphonates)
  • Dose
  • Not established some studies have used 1.5
    mg/kg/dose IV infused over 8 h not to exceed 90
    mg/dose prepare IV by mixing 1 L of dextrose 5
    and water
  • Precautions
  • Monitor hypercalcemia-related parameters, such as
    serum levels of calcium, phosphate, magnesium,
    and potassium once treatment begins.
  • adequate intake of calcium and vitamin D is
    necessary to prevent severe hypocalcemia.
  • caution when administering bisphosphonates in
    patients with active upper GI problems (eg,
    gastric irritation, nausea, GI pain) .

51
Further Outpatient Care
  • Further inpatient care depends on the nature of
    the diagnosis and why the patient was admitted.
  • For a parathyroidectomy, the patient's serum
    calcium level must be monitored postoperatively
    to determine if any evidence of transient
    postoperative hypocalcemia or hungry bone
    syndrome exists.
  • Monitor wound healing and observe for damage to
    the recurrent laryngeal nerve.

52
Further Outpatient Care
  • Because management is often medical for secondary
    hyperparathyroidism, further care depends on
    efforts to control the underlying problem,
    thereby improving hyperparathyroidism management
    also often involves initial use of calcitriol to
    find the appropriate dose for maintenance of the
    patient.

53
Further Outpatient Care
  • Outpatient care for postparathyroidectomy
    patients involves continued monitoring of serum
    calcium levels (if low at discharge) and
    observation of wound healing.
  • Furthermore, care should include treatment of
    accompanying tumors, such as in MEN I.
  • For secondary hyperparathyroidism, outpatient
    care includes management and control of the
    underlying condition.

54
Complications
  • Complications of primary hyperparathyroidism
    include consequences of hypercalcemia such as
    nephrolithiasis, dehydration, and cardiac
    arrhythmias.
  • Complications of secondary hyperparathyroidism
    are mainly skeletal and involve fractures,
    decreased bone density, bone pain, and muscle
    weakness.

55
Prognosis
  • For primary hyperparathyroidism,
    parathyroidectomy should be curative if the
    condition occurs in isolation. However, if it is
    associated with other tumors, then prognosis
    depends on the management of accompanying tumors.
  • For secondary hyperparathyroidism, prognosis
    depends entirely on the success of the physician
    or surgeon in managing the primary disease
    process.

56
Patient Education
  • Patients with primary hyperparathyroidism must
    understand the following
  • Location and function of parathyroid gland and
    parathyroid hormone.
  • Effects of hypercalcemia on the body (eg,
    arrhythmia, stones, bone demineralization,
    increased fracture risk).
  • Lack of success in managing primary
    hyperparathyroidism medically, need for surgical
    consultation, and possible removal of one or more
    parathyroid glands.

57
Patient Education
  • Patients with secondary hyperparathyroidism must
    understand the following
  • The mechanism by which the underlying condition
    causes secondary hyperparathyroidism
  • Effects on the body (eg, bone pain, bone
    demineralization, increased fracture risk, muscle
    weakness)
  • Proper management of secondary hyperparathyroidism
    in each individual case

58
Medical/Legal Pitfalls
  • Inasmuch as primary hyperparathyroidism may be
    asymptomatic, mild hypercalcemia found
    incidentally on a screening test of serum
    electrolytes may not be pursued diagnostically.
    Failure to repeat the serum calcium determination
    and to thus detect consistent elevation of serum
    calcium concentration would result in failure to
    diagnose the condition as primary
    hyperparathyroidism.

59
Medical/Legal Pitfalls
  • Conversely, symptoms such as nausea, vomiting,
    and constipation, while characteristic of
    hypercalcemia, may cause physicians to pursue
    other diagnostic possibilities. Failure to check
    serum calcium levels in children presenting with
    nausea and vomiting may lead to a missed
    diagnosis of primary hyperparathyroidism

60
Medical/Legal Pitfalls
  • Failure to diagnose an underlying cause for
    hypercalcemia, such as renal failure or
    malignancy, is another medicolegal pitfall.
  • Physicians should be aware of the possibility of
    MEN in cases of familial hyperparathyroidism due
    to adenomas. Careful family history must be taken
    for hypercalcemia, parathyroid adenomas,
    Zollinger-Ellison syndrome, and other
    MEN-associated problems. The family should be
    counseled accordingly if history is positive.

61
Special Concerns
  • Pediatrics Because of the high frequency of
    gastrointestinal symptoms, such as abdominal pain
    and constipation, among school-aged children and
    adolescents, checking blood ionized calcium
    concentration as part of a routine workup of the
    above-mentioned symptoms is prudent.

62
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