PARATHYROID GLANDS
The calcium crew
The Parathyroids are 4 pea-sized glands located behind the Thyroid. Its only job is to regulate calcium levels. The predominant cell is the Chief Cell, which releases pulses of parathyroid hormone (PTH) when it senses low calcium. Physiologic levels of PTH will raise calcium and lower phosphate. PTH mostly works on the kidneys, increasing Ca reabsorption in the DCT, and decreasing P reabsorption in the PCT. It also activates the 1a-Hydroxylase enzyme, which turns on Vitamin D. Pulsatile PTH promotes osteoblasts (bone growth). But continuous PTH promotes osteoclasts (bone resorption) by increasing RANKL and decreasing OPG.
PTH tells calcium to “Please Try Harder”
HYPOPARATHYROIDISM
Hypoparathyroidism is a state of low PTH activity.
PRIMARY HYPOPARATHYROIDISM is when the parathyroid glands stop working, resulting in low levels of PTH. The most common cause is PT gland injury during thyroid surgery. Less common causes include autoimmune attack or DiGeorge Syndrome. It results in hypocalcemia. Signs of hypocalcemia include tetany (Trousseau), twitches (Chvostek), hyperreflexia, weakness and perioral tingling.
PSEUDO-HYPOPARATHYROIDISM is a state of PTH resistance. The MOA is complicated as hell, but here goes nothing. So it begins with mom. Due to “imprinting,” you inherit a certain mutation from her. The mutation leads to a defective Gs protein alpha subunit, and that causes PTH resistance. And that leads to hypocalcemia. So it’s as if the patient has low PTH, even though their serum levels may be normal or high. It also presents with a constellation of skeletal defects known as Albright Hereditary Osteodystrophy: developmental delay, obese, short stature and shortened 4th and 5th digits (“knuckle, knuckle, dimple, dimple” sign).
PSEUDO-PSEUDO-HYPOPARATHYROIDISM is quite the mouthful. It occurs when you inherit the defective Gs alpha subunit from dad. It leads to Albright Hereditary Osteodystrophy, but with completely normal labwork (no PTH resistance, no hypocalcemia). Pretty low yield.
HYPERPARATHYROIDISM
Hyperparathyroidism is a state of high PTH activity.
PRIMARY HYPERPARATHYROIDISM is due to an adenoma that makes PTH. PTH leads to hypercalcemia (stones, thrones, bones, groans, psychiatric overtones) and hypophosphatemia. On an EKG, hypercalcemia causes QT interval shortening (the interval goes in the opposite direction of the calcium). This condition results in a specific kind of bone loss called Osteitis Fibrosa Cystica (Brown Tumor) where overactive pockets of osteoclasts will chew away round lesions of bones (depositing hemosiderin from hemorrhages, hence “brown”). Treat with surgery.
SECONDARY HYPERPARATHYROIDISM refers to high PTH due to a chronic disease state, principally chronic kidney disease (CKD). In CKD, the kidney is damaged, so PTH can no longer work there, plus it can’t activate vitamin D there any longer. All of this leads to pretty bad hypocalcemia. That stimulates the PT glands to make a lot of PTH. Keep in mind that the PT glands are *perfectly healthy* with secondary hyperparathyroidism, they’re just following normal feedback patterns! Without the kidneys or vitamin D, PTH has to get its calcium from the bones. This leads to pretty nasty bone resorption, as well as hyperphosphatemia. This condition is called renal osteodystrophy, and it’s a big deal in the CKD world. Most CKD patients have to take calcium supplements, phosphate binders, calcimimetics and/or calcitriol to prevent it.
TERTIARY HYPERPARATHYROIDISM is when someone “cuts the breaks” on the PT glands. This is seen after years and years of secondary hyperparathyroidism. Eventually the PT glands get used to making so much PTH that they become autonomous and create a maximal amount of PTH all the time! Associated with very high levels of PTH and Ca (but low Phos).
PARANEOPLASTIC HYPERPARATHYROIDISM - some squamous cell cancers secrete PTH-related-peptide (PTHrp). This is particularly common with squamous cell lung cancer. PTHrp has all the effects of PTH, but our lab assays often don’t detect it, so there’s a deceptively low PTH level.
Brown tumors of Osteitis Fibrosa Cystica due to Hyperparathyroidism
VITAMIN D
RICKETS is the pediatric bone disease from severe Vitamin D Deficiency. They experience bone deformities (genu varum, or bowlegs) and bone pain. It's exacerbated by low sun exposure or dark skin. They have hypocalcemia and hypophosphatemia. Treat with oral Vitamin D supplements. But if the supplements don’t work, then they probably just have a mutation in 1a-Hydroxylase.
OSTEOMALACIA is the adult bone disease from severe Vitamin D Deficiency. Patients have bone pain and weakness, and they’re prone to pseudofractures. It’s most commonly seen in people with CKD.
VITAMIN D DEFICIENCY is a largely asymptomatic condition found in adults. There were many purported benefits of Vitamin D supplementation espoused during the 1990s and 2000s, but more recent evidence has cast doubt on that. For now, I would leave Vitamin D supplements to snake oil salesmen like Dr. Oz.
VITAMIN D EXCESS is occasionally seen whenever there are granulomas, for example with sarcoidosis. The macrophages in the middle of the granuloma secrete a1-hydroxylase.
