Secondary Hyperparathyroidism

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Secondary Hyperparathyroidism

• Chou Chien Wen M.D.
• Endocrine and Metabolism Section
• Chi-Mei Medical Center
• 7 Nov 2003

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Case Report

• Name ??x?
• Chart No 14117599
• Sex female
• Age6 Jan 1994 (49 y/o)
• Cause of Renal failure Polycystic kidney
• Duration of HD 5 yrs

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Clinical Course
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Medication History

• Before 92-6-30
• FA 1 qd
• Vit BC 1 qd
• Calcium Carbonate 1 tid
• AH 2 tid
• EPREX 2000 IU/0.5 cc IM stat
• Lopid 1 tid for CH 237 TG 869
• After then
• D C Calcium Carbonate

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Image Study

• Parathyroid echo 92-10-16
• Parathyroid hyperplasia, both lower pole
• CT scan of neck 92-10-30
• Bilateral parathyroid hyperplasia or adenoma,
  lower pole
• RT 1 cm LT 0.6 cm

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Stage of Chronic Kidney Disease
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Major Features of Abnormalities in Mineral
Metabolism in Kidney Failure

• Hypoclacemia
• Secondary hyperparathyroidism
• Hyperphosphatemia
• Defective intestinal absorption of calcium
• Altered vitamin D metabolism
• Bone disease
• Soft-tissue calcification including coronary
  arteries and cardiac valves calcification
• Altered handling of phosphate, calcium and
  magnesium by the kidney
• Pruritus
• Proximal myopathy
• Skin ulceration and soft-tissue necrosis

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Three factors are central to its development

• The first, reduced renal synthesis of
  1,25-dihydroxyvitamin D (calcitriol)
• As the disease progresses, renal phosphate
  clearance and net calcium balance become
  inadequate to maintain serum phosphorus and
  ionized calcium levels within an optimal range.
• The synthesis and release of PTH are stimulated
  by a low serum calcium level, reduced inhibitory
  activity of calcitriol, and an elevated serum
  phosphate level.
• progressive increase in the mass of the
  parathyroid gland and, often, a benign,
  tumor-like growth.
• In its extreme form, severe hyperparathyroidism
  becomes unresponsive to medical treatment, and
  necessitates parathyroidectomy

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Biological Consequences of Vitamin D Deficiency
and its Metabolism

• Shift in set-point of calcium for the parathyroid
  gland
• Secondary hyperparathyroidism
• Skeletal resistance to the calcemic action of PTH
• Impaired mineralization of osteoid
• Abnormalities in formation and maturation of
  collagen
• Retarded growth in uremic children
• Defective intestinal absorption of calcium and
  phosphorus
• Abnormalities in the structural integrity of the
  intestinal mucosa
• Proximal myopathy

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Ca and Vitamin D Supplement

• The early administration of calcium supplements
  or vitamin D attenuates the development and
  progression of hyperparathyroidism
• If not closely monitored, though, vitamin D
  administration may lead to hypercalcemia because
  of the prolonged half-life of native vitamin D.
• More active vitamin D derivatives and analogues
  with shorter half-lives primarily calcitriol
  and alfacalcidol have been used for the past
  two decades.
• Their administration results in a prompt
  reduction in the plasma levels of intact PTH in
  patients undergoing hemodialysis who have severe
  forms of secondary hyperparathyroidism

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Recommended Supplement for Vit D Deficiency
/Insufficiency in Patients with CKD Stages 3 and 4
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Serum Levels of PTH, Ca and P required for
Initiation of Oral Vitamin D sterol Therapy, and
Recommended Initial Doses in Patients with Stages
3 and 4
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Recommended Initial Dosing for Vitamin D sterols
by Serum levels of Intact PTH, Ca, P and Ca-P
Product
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Frequency of measurement of PTH and Ca/P by Stage
of CKD
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Target Range of Intact Plasma PTH by Stage of CKD
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Side Effects of Vitamin D Derivatives

• including hypercalcemia and hyperphosphatemia
  and, as a result, a high level of the
  calciumphosphate product.
• soft-tissue calcification, particularly vascular
  calcification, a key factor underlying the
  accentuated risk of CVD in patients with CKD
• prolonged administration of high doses of
  calcitriol or alfacalcidol is associated with
  adynamic bone disease, as is the administration
  of high doses of calcium-containing phosphate
  binders.
• These adverse outcomes have prompted the
  development of novel, "nonhypercalcemic" vitamin
  D analogues (Figure 1).
• Three of these analogues have recently been
  marketed 19-nor-1,25-dihydroxyvitamin D2
  (paricalcitol), 1 -hydroxyvitamin D2
  (doxercalciferol), and 22-oxacalcitriol.

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Figure 1. Chemical Structures of Calcitriol and
the Newer Vitamin D Analogues.
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Differential actions of vitamin D analogues

• The affinity of 22-oxacalcitriol for the vitamin
  Dbinding protein is less than 1 percent that of
  calcitriol.
• In contrast, both paricalcitol and
  doxercalciferol have binding affinities
  equivalent to that of calcitriol.
• Vitamin Dbinding protein enhances the half-life
  of vitamin D derivatives in the circulation, an
  effect that probably decreases their tissue
  accessibility.
• Altered binding affinity for the vitamin D
  receptor has also been reported.
• The affinity of 22-oxacalcitriol for the receptor
  is one eighth that of calcitriol, and the
  affinities of paricalcitol and doxercalciferol
  are similar.
• Paricalcitol down-regulates the expression of
  vitamin D receptor in the intestine, whereas
  calcitriol up-regulates it.
• Vitamin D analogues may act differently from
  calcitriol in inducing conformational changes in
  the vitamin D receptor and modulating its binding
  to vitamin Dresponsive elements to affect the
  transcription of numerous genes.

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Calcimimetic agents and secondary
hyperparathyroidism rationale for use and
results from clinical trials.

• Calcimimetic agents are small organic molecules
  that act as allosteric activators of the calcium
  sensing receptor (CaSR).
• In parathyroid cells, they lower the threshold
  for receptor activation by extracellular calcium
  ions and diminish parathyroid hormone (PTH)
  secretion.
• Calcimimetic compounds thus represent a novel way
  of controlling excess PTH secretion in clinical
  disorders such as secondary hyperparathyroidism
  (SHPT) due to chronic renal failure.
• Clinical trials have documented that the
  calcimimetic agent cinacalcet hydrochloride
  effectively lowers plasma PTH levels without
  increasing serum calcium or phosphorus
  concentrations in adult hemodialysis patients
  with SHPT.
• Serum phosphorus levels and values for the
  calcium-phosphorus ion product in serum often
  decline as plasma PTH levels fall during
  treatment.
• Experimental evidence suggests that calcimimetic
  agents may also impede the development of
  parathyroid gland hyperplasia, an integral
  component of SHPT due to chronic renal failure.
• Calcimimetic agents have considerable potential,
  therefore, as part of new therapeutic strategies
  for SHPT.

Goodman WG. Pediatr Nephrol. 2003 Oct 28
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Survival of Patients Undergoing Hemodialysis with
Paricalcitol or Calcitriol Therapy

• paricalcitol was associated with a lower
  mortality rate over the 36-month follow-up period
  (18.0 percent) than calcitriol (22.3 percent).
• This difference of 4 to 5 percentage points in
  yearly mortality rates was most evident for the
  cardiovascular end points.
• A difference in the final calciumphosphate
  product value does not appear to explain the
  outcomes of the study.

N Engl J Med 2003 349446-456, Jul 31, 2003.
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Potential medical Uses of Calcium Receptor
Modulators

• Parathyroids
• Inherited parathyroid disorders
• Primary hyperparathyroidism
• Secondary hyperparathyroidism
• Parathyroid carcinomatosis
• Surgical parathyroidectomy failure
• Ectopic parathyroid gland localization
• Parathyromatosis
• Parathyroid surgery refusal
• Surgical contraindication
• Cardiovascular
• Arterial hypertension
• Calciphylzxis
• Renal
• Diuretic
• Slow progressive chronic renal failure

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Factors That May Predispose to Soft-Tissue
Calcification in Stages 4 and 5 CKD

• Hyperphosphatemia
• An increase in serum calcium-phosphorus product
• Secondary hyperparathyroidism
• Local tissue injury
• A rise in local pH of tissue
• Removal of calcification inhibitors by dialysis
• Excessive calcium intake

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Subtotal parathyroidectomy a possible treatment
for calciphylaxis.

• Calciphylaxis is a rare disorder in patients with
  chronic renal failure that is characterized by
  ischemic necrotic skin lesions.
• The prognosis is grave and mortality is high
  (80).
• The precise mechanism of calciphylaxis is still
  unknown, but in addition to chronic renal
  failure, elevated parathyroid hormone levels
  appear to play a role.
• The role of parathyroidectomy in treating
  affected patients is questionable.
• In this article, we describe the case of a
  patient with chronic renal failure who developed
  rapidly progressive subcutaneous calcifications
  and ulcerations in the lower extremities.
• These lesions regressed following subtotal
  parathyroidectomy.

Bahar G Ear Nose Throat J. 2003 May82(5)390-3.