Ueda2016 hyperparathyroidism - mohamed mashahit

1. Hyperparathyroidism
Prof
Mohameed Mashahit

2. Objectives
• To Review:
• The parathyroid glands
• Pathophysiology of hyperparathyroidism
• Clinical Presentation
• Diagnosis
• Treatments

3. Hypercalcemia is a common metabolic abnormality seen in
approximately 5% of hospitalized individuals.
The Canadian Journal of Diagnosis / February 2006/Aliya Khan

4. The Parathyroid Glands
• History:
• The parathyroid glands were first discovered in the
Indian Rhinoceros by Richard Owen in 1850.
• The glands were first discovered in humans by Ivar
Viktor Sandström, a Swedish medical student, in
1880.
• It was the last major organ to be recognized in
humans.

5. Parathyroid Gland:
Ectopic locations are seen in 4- 16% - the parathyroid glands might also be
found in the carotid sheath, anterior mediastinum, and intrathyroidal tissue.

6. Atlas of Microscopic Anatomy: Section 15 - Endocrine Glands

7. 115-AAC
trypsin-like protease
90-AAC
84-AAC
PTH is an 84-amino acid polypeptide (chain) derived from a prohormone
The biosynthetic process is estimated to take less than one hour.
BASIC BIOLOGY OF MINERAL METABOLISM, F. Richard Bringhurst
Packaged

8. Parathyroid hormone:
 84 amino acid peptide
 Recognized by PTH-1 receptor and then acts on target organs to
master calcium homeostasis
 70% metabolized by the liver and 20% by kidneys;
 Half life of 2 minutes

9. Functions of PTH
• Chief cells – produce PTH
• PTH = Main regulator of calcium homeostasis in the body
• Ionised calcium – tightly regulated for optimum function of
cell signalling, neural function, muscular function, and bone
metabolism , blood coagulation . etc
• PTH responds to changes in circulating ionised
calcium via the calcium-sensing receptor (CaSR)
located on the surface of the chief cells

10. Parathyroid Hormone
Receptors
• PTH acts by binding to its receptor(PTH1R and
PTH2R)
• Both are members of the G Protein coupled receptor family
• PTH-1R receptor binds PTH and PTHrP with equal affinity.
• Regulates calcium homeostasis through activation
of adenylate cyclase and phospholipase C
• mostly expressed in bone and kidney
• PTH2R selectively binds PTH only.
• PTH2R expressed heavily in the brain,
pancreas, endothelium
Uptodate: Parathyroid Hormone andAction

11. Calcium sensing receptors
• CaSR expressed in parathyroid, thyroid C cells and kidney.
•Activation of the CaSR by increased extracellular Ca2+ inhibits
parathyroid hormone (PTH) secretion, stimulates calcitonin secretion,
and promotes urinary Ca2+ excretion, and thereby maintains the
extracellular Ca2+ at the normal level

12. •HYPERPARATHYROIDISM

13. Causes of Hyperparathyroidism
Primary Secondary- In
response to
hypocalcemia
Tertiary
•Parathyroid Adenoma,
Hyperplasia, Carcinoma
•MEN 1 or MEN 2a
•Familial hypocalciuric
hypercalcemia
•Hyperparathyroid-jaw
tumor (HPT-JT)
syndrome
•Familial isolated
hyperparathyroidism
(FIHPT)
•Renal Failure
-Impaired calcitriol
production
-Hyperphosphatemia
•Decreased calcium
-Low oral intake
-Vit D deficiency
-Malabsoption
-renal calcium loss –
lasix
•Inhibition of bone
resorption
-Bisphophonates
-Hungry Bone Syndrome
•Autonomous hypersecretion
of parathyroid hormone
-chronic secondary
hyperparathyroidism
-After renal transplantation

14. Primary Hyperparathyoidism –
Epidemiology
• PHPT - most common cause of hypercalcemia in the outpatient
clinical setting
• Prevalence ranges from 1 to 4 per 1000 people
• Female-to-Male ratio: 2:1 to 3:1
• Incidence increases with age
• Postmenopausal women have an incidence 5x higher than the general
population
Canadian Family Physician February 2011 vol. 57 no. 2 184-189

15. 1- Parathyroid adenoma or carcinoma
• Single gland adenoma: 75-85%
• Multigland adenoma
• 2 glands: 2-12%
• 3 glands: <1-2%
• 4 or > glands: 1-15%
• Parathyroid carcinoma: 1%
Lancet 2009; 374: 145–58

16. Lower pole adenomas are
more common than are
upper pole adenomas; sizes
range from 1 cm to 3 cm
and weights from 0·3 g to
5 g; may be more than 25g.
Parathyroid adenoma
Lancet 2009; 374: 145–58
Largest reported weighted 120g
Largest number was 8

17. Causes
• Exact cause of primary hyperparathyroidism is unknown
• Ionizing radiation maybe associated
• Irradiation for acne -?2·3-fold increase
• Survivors of an atomic bomb - 4-fold increase
• Present doses of radioactive iodine for thyrotoxicosis
do not increase the incidence of primary
hyperparathyroidism
Lancet 2009; 374: 145–58

18. 2- Rare Familial Disorders
• Multiple endocrine neoplasia (MEN) type 1 –MEN1 gene mutation
(Parathyroid, pituitary, pancreatic)
• MEN type 2A syndromes –RET gene mutation (Parathyroid, Pheo,
MTC)
• Familial hypocalciuric hypercalcemia (FHH)- autosomal dominant-
inactivating mutation of the CaSR gene
• Familial hyperparathyroidism–jaw tumour syndrome- HRPT2 gene;
Autosomal dominant
• Familial isolated hyperparathyroidism

19. FHH PHPT
Mechanism (CaSR gene on Chr 3) –
makes PTHR less sensitive to
calcium - higher serum
calcium level is required to
reduce PTH secretion
PTH Adenoma, Hyperplasia,
carcinoma
Fhx + Autosomial Dominant + rare syndromes
PTH Mildly high in 15-20% High normal – high
Urine Calcium /Magnesium Low Normal – high
FECa ; sensitivity 85%,
specificity 88%, PPV 85%
<1% >1%
Symptoms - +/-
Management Conservation Parathyroidectomy
Plasma albumin-adjusted
calcium (mmol/L)
2.55-3.5 2.55-4.5
Age/sex <40; women = male >50; mainly women

20. Clinical Presentation of PHPT
• Possible presentations:
• Asymptomatic Incidental hypercalcemia – 70-80%
• In most patients, mean serum calcium < 0.25 mmol/L above the
ULN range
• Normocalcemic hyperparathyroidism
• Usually present for evaluation of low BMD, osteoporosis, or fragility
fractures
• Symptomatic hypercalcemia

21. Symptoms of Hypercalcemia
• Stones
• Bones
• Groans
• Psychiatric
Moans

22. Renal Manifestations
• Nephrolithiasis 15-20%
• Nephrocalcinosis
• Polyuria
• Renal insufficiency
• Acute hypercalcaemic
crisis with nephrogenic
diabetes insipidus and
dehydration seen when
calcium greater than
3·0 mmol/L

23. Psychic Moans:
• Neuropsychiatric: lethargy,
decreased cognitive and social
function, depressed mood,
psychosis, and coma in those
with severe
hypercalcemia.
• Neuromuscular: weakness and
myalgia

24. Gastrointestinal Manifestations
• Commonly
• constipation, nausea, vomiting, anorexia
• Uncommon, but serious:
• PUD orAcute pancreatitis
• Mechanism:
• PTH stimulates gastrin secretion (PUD), decreases peristalsis, and
increases the calcium- phosphate product with calcium-phosphate
deposition and obstruction in pancreatic ducts
Uptodate: Clinical manifestations of primary
hyperparathyroidism

25. Bone Manifestations
• Bony pain
• Low bone mineral density – most at cortical sites
• Fragility fractures
• Rarely PHPT bone disease – osteitis fibrosa cystica- <5 percent
of patients
• Proximal muscle weakness due to type II muscle fibre atrophy can be
seen in association with severe bone disease (osteitis fibrosa cystica).
Uptodate: Clinical manifestations of primary
hyperparathyroidism

26. subperiosteal resorption

27. Cardiovascular:
- Shortened QT interval
- HTN – hypercalcemia causes vasoconstriction
- Arrhythmias in severe hypercalcemia
- Deposition of calcium on valves, in coronaries, and
myocardium

28. Other Manifestations
• Arthralgia, synovitis, arthritis
• HPT associated with increased crystal deposition from calcium
phosphate, calcium pyrophosphate (pseudogout), and uric
acid (gout)
• Band Keratopathy – Calcium phosphate precipitation in
medial and limbic margins of cornea

29. Diagnosis
• Repeat calcium to confirm, correct for lowAlbumin
• Ionized Calcium: may be more helpful in some conditions
• Check PTH – rule in PHPT if frankly elevated PTH
concentration or normal PTH level with hypercalcemia
• Supporting findings: low P04,high Cl, high urine pH
(>6), high ALP

30. • Address DDX hyperparathyroidism and hypercalcemia
• Multiple endocrine neoplasia (MEN) type 1 –MEN1 gene
mutation
• -MEN type 2A syndromes –RET gene mutation
• -Familial hypocalciuric hypercalcemia (FHH)
• Familial hyperparathyroidism–jaw tumour syndrome- HRPT2
gene;Autosomal dominant
• -Familial isolated hyperparathyroidism
• Teritiary HPT
• Medications , as frusimide and lithium
• Two most common causes are Primary HPT and Cancer-
related hypercalcemia (PTH related protein mediated,
or directly via bony lesions)

31. Differences between PTHrP and PTH
Intact
PTH
PTHrP 1,25VitD Calcium
Primary
HPT
High Low High High
PTHrP
malignancy
Low High Low High

32. Localize
• Localization: technetium 99m–labeled sestamibi scanning,
ultrasound, CT, MRI, and PET. Used to aid surgery.
**Imaging should not be used to establish the
diagnosis of PHPT or to screen patients for
surgical referral**
• Gold standard: a four gland parathyroid exploration

33. Sestamibi scintigraphy
• 99mTc-sestamibi is taken up by the mitochondria in
thyroid and parathyroid tissue; however, the radiotracer
is retained by the mitochondria-rich oxyphil cells in
parathyroid glands longer than in thyroid tissue
• Planar images obtained after injection of 99mTc-
sestamibi and again at 2 hours to identify foci of
retained radiotracer activity consistent with
hyperfunctioning parathyroid tissue.
Uptodate: Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism

34. Management

35. Acute Management of Hypercalcemia
• Avoid thiazides, lithium, volume depletion, prolonged bed rest,
or inactivity, and high calcium diet (>1g/day)
• Rehydration!!!
• Calcitonin +/- cinacalcet can also be of value in the short
term to maintain a reduction of calcium
• If surgery planned within a few days,AVOID IV
bisphosphonates because post op hypocalcemia risk

36. Parathyroidectomy
• Definitive therapy
• Surgical techniques: total open parathyroidectomy or a
minimally invasive procedure with or without the use
of intraoperative PTH assays
• Only a subgroup of people with asymptomatic PHTP
benefit from surgery

37. Guidelines for parathyroid surgery in patients with
asymptomatic PHPT

38. Results after Surgery
• Calcium, phosphate, and urine calcium return to normal quickly
• PTH levels fall by 50% within the first 10-15 min
• Indicators of bone resorption normalise quicker than formation
(ALP). Bone turnover returns to normal within 6 – 12 months
• Osteoblast > osteoclast activity, resulting in a substantial
improvement in bone mineral density – greatest at hip and spine

39. Silverberg, NEJM 1999
8% after
1yr
(P=0.05)
12%
after 10
years
(P=0.03)
6% after
1 year
(P=0.00
2)
14 %
after 10
years
(P=0.00
2)

40. Cardiac/Renal Outcomes
• Cardiac Outcomes:
• Longterm hypertension control not improved
• Left ventricular hypertrophy decreases after surgery
in some
• slower the progression of aortic and mitral valve
calcification
• Renal Outcomes:
• Kidney stones are reduced in frequency amongst
those with a history of kidney stones

41. Mollerup CL. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid
surgery: controlled retrospective follow up study. Bmj, 325:807,2002.

42. Medical Management for
those NOT candidates for
parathyroidectomy

43. DRUGS USED
• CALCIMIMETICS
• HRT
• SERMS
• BISPHOSPHONATES

44. Calcimimetics
• Drugs that mimics calcium circulating in the blood so can trick
the parathyroid gland to release less parathormone .
• FDA approved for CKD and cancer . Mainly ..
• Some doctors prescribe it for primary PHPT if surgery is not
feasible
• Sensipar ( cinacalcet )
• The most common side effects are bone and muscle aches ,
diarrhea , respiratory tract infection

45. Medical Management
• Focused on goals:
• Improving BMD as most are postmenopausal women – HRT,
SERMS, Bisphosphonates
HRT:
• significant reduction in calcium (0·1–0·3 mmol/L)
• 4–8% increase in BMD at trabecular and cortical
sites
Orr-Walker BJ. Effects of hormone replacement therapy on bone mineral density in
postmenopausal women with primary hyperparathyroidism: four-year follow-up and
comparison with healthy postmenopausal women. Arch Intern Med 2000;
160: 2161–66.

46. 42 Postmenopausal
women with mild
PHPT, a 2-yr
randomized, placebo-
controlled trial.
1.3% ±0.4%;P = 0.004
5.2% ±1.4%;P = 0.002
GreyAB. 1996 Effect of hormone replacement therapy on bone mineral density
in postmenopausal women with mild primary hyperparathyroidism.
A randomized, controlled trial.Ann Intern Med 125:360 –368
3.6%
6.6%

47. SERMS
• A small, placebo-controlled, randomized trial reported the effects of
raloxifene (60 mg/d) on serum calcium and phosphorus over 2
months in postmenopausal women with PHPT
• calcium declined significantly by 2 months in the raloxifene-treated
women. No changes in PTH,
J Clin Endocrinol Metab, February 2009, 94(2):373–381

48. Bisphosphonates
• Pamidronate in patients with mild PHPT- Infusions (30 mg)
10 patients in a randomized crossover study and were effective
in reducing serum calcium from 2.72 to 2.49 mmol/liter after
1 wk.
• Short-term treatment with risedronate was effective in
lowering serum calcium in individuals with mild PHPT; no
long term study
• Alendronate most extensively evaluated in individuals with
PHPT.
• Data from the RCT have consistently shown that
alendronate decreases bone turnover and increases BMD at
the lumbar spine and proximal femur in PHPT.

50. Summary
• Primary hyperparathyroidism is one of the most common
endocrine disorder
• Asymptomatic disease is common, and severe disease with renal
stones and metabolic bone disease arises less frequently.
• Primary hyperparathyroidism can be cured by
parathyroidectomy for those with symptomatic hypercalcemia
and a subgroup of asymptomatic patients
• Medical options for treating the skeletal complications of PHPT
include bisphosphonates, HRT, and raloxifene AND
RECENTLY CACIMIMETICS

51. Thank you

52. How do PTHrP and PTH differ?
• PTHrP has 3 protein forms: 139, 141, 173 amino acids
• First 139 AA are the most common among all 3 forms
• 8 of first 13N-terminalAA are same as intact PTH (1-84),
therefore PTHrP and PTH can stimulate the same receptors
• But, different effects on 1,25(OH)2D
• Continuous secretion of PTHrP by tumors downregulates
receptors that stimulate 1 alpha hydroxylase  decreased
enzyme decreased 1,25(OH)2D
• Higher levels of Calcium may also decrease 1,25(OH)2D

53. Approach
• PHPT: elevated intact PTH or at the high end of the normal
range in the setting of elevated total calcium
• Repeat measurements (usually 2- 3), check PO4 (low-normal),
ALP (high)
• Further laboratory testing is to rule out other causes of
hypercalcemia.
• Distinguish FHH from PHTP– 24h urine and FECa
• Correct levels of 25(OH)D if present may cause a false positive
• Renal function tests r/o secondary causes
• Consider genetic testing if Fhx of MEN syndrome

55. Will surgery decrease future fractures?
• Retrospective cohort study of 1569 patients with
PHPT(452 of whom had had a parathyroidectomy):
• Reported a significant increase in 10-year fracture-free survival,
mainly hip fractures after parathyroidectomy (59% vs 73%)
• Parathyroidectomy decreased the 10-year hip fracture rate by 8% (P =
.001) and the upper extremity fracture rate by 3%
(P = .02)
VanderWalde LH.The effect of parathyroidectomy on bone fracture
risk in patients with primary hyperparathyroidism. Arch Surg 2006; 141: 885–89.