3. Calcium homeostasis
• Maintenance of calcium and phosphate homeostasis is
under the influence of two polypeptide hormones;
• parathyroid hormone(PTH)
• calcitonin (CT),
• as well as a sterol hormone, 1,25 dihydroxy cholecalciferol
(1,25 (OH)2D3. (calcitriol)
5. Control of PTH secretion
• Under influence of serum Ca2+
• Increased levels = -ve FB via
CaSR
• Low levels = low CaSR activity
• Calcitriol: negative feedback, via
vit D receptor prevents gene
expression
• normal levels 10-55 pg/ml
6. Pathophysiology of parathyroid hormone
• The pathophysiology of the PTH system will include the following:-
1.excess of PTH;
2.a deficiency of PTH;
3. target tissue resistance to PTH.
8. Primary hyperparathyroidism
• over secretion of PTH by one or more parathyroid glands.
• Usually due to combination of
• decreased sensitivity to calcium, (decreased functional CaSRs)
• or an increase in parathyroid cell mass, or both.
• Demographics
• 5-50 per 10,000 individuals.
• common after 40 years
• female-to-male ratio of 3:1.
9. 1° hyperPTH cont.
causes
• Glandular adenomas – 89%. Usually solitary. Multiple <2%
• Gland hyperplasia – about 6%. Usually all 4
• Carcinomas – rare.
• Familial syndromes – part of MEN 1 and MEN 2a syndromes
10. 1° hyperPTH cont.
clinical consequences
• Presents with features of
hyperCa2+
• Skeletal syndrome
• Renal syndrome
• Gastrointestinal syndrome
• other
11. 1° hyperPTH cont.
skeletal presentation
• Osteitis fibrosa cystica
• Due to osteoclastic activity – bone
demineralization
• Presentation with bone pain
• Subperiosteal bone resorption ,
brown tumours on xray
14. Secondary hyperparathyroidsm
• compensatory hyperfunctioning of the parathyroid glands
• caused by hypocalcemia or peripheral resistance to
parathyroid hormone (pseudohypoparathyroidsm)
• Hyperplasia of parathyroid glands
• Commonly due to renal failure, esp with poor nutrition and
advanced age
• Other causes:
• calcium malabsorption,
• vitamin D deficiency, or deranged vitamin D metabolism
16. 2° HPT cont.
clinical presentation
• Similar to 1° hyperPTH but milder
• Nephrolithiasis and calcinosis less common.
• Renal osteodystrophy with generalized osteopenia and multiple
pathological #’s
• Osteodystrophy causes bone pain, proximal muscle weakness
• MX: addressing underlying issue
17. Tertiary hyperparathyroidism
• Occurs post secondary hyperparathyroidism (HPT) in which the
glandular hyperfunction and hypersecretion continue despite
correction of the underlying abnormality,
• Seen post renal transplant
• development of autonomous (unregulated) function after sustained
stimulation.
• MX; parathyroidectomy
18. PTHrP
• PTH like activity via PTH 1 receptors
• Role in embryology
• Commonest cause of hyper Ca2+
in non mets solid tumours
• AKA humoral hypercalcemia of malignancy (HHM)
• Upto 80% of all hyper Ca2+
in Ca
• Commonly breast, lung, renal, ovarian SCC
19.
20. Hypoparathyroidism
• Parathyroid gland hypofunction.
• Hallmark: low PTH, serum Ca2+
with high Po4-
• Prevelence after 45yrs
• M:F - 1:3
• Affects 22 per 100,000 people
• 1° hypoPT – related to gland pathology
• 2° hypoPT – a physiologic state secondary hypercalcemia.
26. Hypoparathyroidism cont.
Mx
• Control of calcium levels
• Calcium suppliments and vitamin D.
• Recombinant human parathyroid hormone (rhPTH[1-84], Natpara)
-adjunct to calcium and vitamin D
28. quiz
• A 52-year-old female presents with nausea, fatigue, muscle
weakness,
and intermittent pain in her left flank.
• Laboratory examination reveals an increased serum calcium and a
decreased serum phosphorus.
• The patient’s plasma parathyroid hormone levels are increased, but
parathyroid hormone related peptide levels are within normal limits.
Urinary calcium is increased, and microhematuria is present. The
patient’s
abnormality is most likely caused by
a. Primary hyperparathyroidism
b. Primary hypoparathyroidism
c. Pseudohypoparathyroidism
d. Secondary hyperparathyroidism
e. Secondary hypoparathyroidism
The development of renal insufficiency in individuals with hypercalcemia is related to the degree and duration of hypercalcemia.
Mild hypercalcemia is rarely associated with renal insufficiency. In randomized trials of two to three years duration, there is little evidence that renal function deteriorates in patients with mild chronic hypercalcemia due to hyperparathyroidism. (See &quot;Management of primary hyperparathyroidism&quot;, section on &apos;Biochemical abnormalities&apos; .)
Higher elevations in the serum calcium concentration (serum calcium values of 12 to 15 mg/dL [3 to 3.75 mmol/L]) can lead to a reversible fall in glomerular filtration rate that is mediated by direct renal vasoconstriction and natriuresis-induced volume contraction [ 13,14 ].
Long-standing hypercalcemia and hypercalciuria may lead to calcification, degeneration, and necrosis of the tubular cells, and eventual tubular atrophy and interstitial fibrosis and calcification (nephrocalcinosis). Nephrocalcinosis, a condition observed in over one-half of hypercalcemic patients with renal insufficiency, is the most common cause of chronic kidney disease in sarcoidosis. In comparison, nephrocalcinosis appears to be uncommon in patients with primary hyperparathyroidism [ 15 ]. (See &quot;Renal disease in sarcoidosis&quot;, section on &apos;Hypercalciuria and hypercalcemia&apos;and &quot;Nephrocalcinosis&quot; .)
Proposed mechanisms for the development of pancreatitis include deposition of calcium in the pancreatic duct and calcium activation of trypsinogen within the pancreatic parenchyma [ 8-10 ]. In rats, acute hypercalcemia causes a dose-dependent increase in serum amylase and morphologic characteristics of acute pancreatitis [ 9 ].
Peptic ulcer disease has been described in patients with hypercalcemia due to primary hyperparathyroidism [ 4 ] and may be caused by calcium-induced increases in gastrin secretion. In patients with MEN1 with coexisting Zollinger-Ellison syndrome and hyperparathyroidism, parathyroidectomy alone has led to a significant reduction in serum gastrin concentrations and acid secretion [ 11 ].
Acute hypercalcemia directly shortens the myocardial action potential, which is reflected in a shortened QT interval
High po4, low ca and gland hyperplasia
In 1942, Fuller Albright first introduced the term pseudohypoparathyroidism to describe patients who presented with PTH-resistant hypocalcemia and hyperphosphatemia along with an unusual constellation of developmental and skeletal defects, collectively termed Albright hereditary osteodystrophy (AHO).
Failing kidneys do not convert enough vitamin D to its active form, and they do not adequately excrete phosphate. When this happens, insoluble calcium phosphate forms in the body and removes calcium from the circulation
This hyperphosphatemia causes decreased production of 1,25 de(oh)cholecaciferol
Low vit D3 causes reduced absorption of calcium and further inc in PTH
Decreased clearance by damaged glomeruli
Autoimmune - against the gland or CaSR
Dev’t - X-linked or in autosomal recessive hypoparathyroidism
DiGeorges syndrome It is assoc wit congenital cardivascular malformations esp. Aortic arch.
Moderate hypermagnesemia can inhibit the secretion of parathyroid hormone, leading to a reduction in the plasma calcium concentration
Infiltration - Haemosiderosis, breast mets