Hyperparathyroidism

1
Hyperparathyroidism

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

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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.

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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

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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

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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.

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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.

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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.

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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.

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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.

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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

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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

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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

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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.

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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.

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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.

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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.

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Physical Exam.

• Secondary hyperparathyroidism
• Skeletal deformity
• Decreased muscle tone
• Bone pain on palpation
• Short stature

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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.

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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.

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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.

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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.

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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

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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.

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Eitiology

• MEN type II is also associated with
  hyperparathyroidism

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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.

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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.

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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.

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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

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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

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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.

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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

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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.

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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.

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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.

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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).

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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.

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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.

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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) .

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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.

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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

• Thank You