Parathyroid Pathology

Question 1

What are the three broad categories of hyperparathyroidism? What is the major cause of each?

Answer 1

• primary, secondary, and tertiary
• primary: excess PTH due to an issue with the parathyroid gland(s) itself; most common cause is a parathyroid adenoma
• secondary: excess PTH in the setting of normal parathyroid glands; most commonly due to chronic hypocalcemia caused by chronic renal failure
• tertiary: autonomous PTH secretion that can occur after prolonged secondary hyperparathyroidism, and continues even once the secondary hyperparathyroidism is resolved

Question 2

What is primary hyperparathyroidism? What can cause it? How do patients present? How do we treat it?

Answer 2

• primary hyperparathyroidism is mainly due to a parathyroid adenoma (more than 80-95% of cases); other causes include parathyroid hyperplasia (5-10%) and parathyroid carcinoma (1%)
• most often, it presents as asymptomatic hypercalcemia; however, symptoms include: nephrolithiasis, nephrocalcinosis (metastatic calcification), constipation, hyporeflexia, lethargy, polyuria, polydipsia, peptic ulcer disease, acute pancreatitis, and osteitis fibrosa cystica
• patients present with “painful bones, renal stones, abdominal groans, and psychiatric overtones”
• treat with surgical resection of the affected gland

Question 3

What is a very rare cause of primary hyperparathyroidism? What do we find on lab tests?

Answer 3

• familial hypocalciuric hypercalcemia (FHH)
• this genetic condition is characterized by an inactivating mutation of the Ca2+ sensory receptors on parathyroid cells, resulting in an inability to properly read the Ca2+ levels and triggering constitutive PTH secretion; the mutations also result in a decreased ability of the kidneys to excrete Ca2+
• lab: raised PTH, decreased urine Ca2+, raised serum Ca2+

Question 4

Which syndromes are associated with primary hyperparathyroidism? What is each also known as? What does each syndrome cause?

Answer 4

• MEN1 and MEN2a
• MEN syndromes are autosomal dominant and characterized by multiple endocrine neoplasms occurring at a younger age and with a high rate of recurrence
• MEN1: (AKA Wermer syndrome) parathyroid tumors, pituitary tumors, pancreatic endocrine tumors (Z-E syndrome, inuslinomas)
• MEN2a: (AKA Sipple syndrome) parathyroid hyperplasia, thyroid medullary carcinoma, pheochromocytoma
• (MEN2b: thyroid medullary carcinoma, pheochromocytoma, oral involvement)

Question 5

What is osteitis fibrosa cystica?

Answer 5

• this is a complication/presentation of primary hyperparathyroidism
• the excessive bone resorption (osteoclastic activity) results in a thinned cortex and fibrous tissue in the marrow
• begins as osteoporosis and then micro fractures begin to develop followed by micro hemorrhages and the formation of “brown tumors”

Question 6

What lab findings do we see in primary hyperparathyroidism?

Answer 6

• raised PTH
• hypercalcemia and hypophosphatemia (the opposite occurs in secondary hyperparathyroidism)
• raised urinary cAMP (because the hormone is stimulating renal cells via the adenylyl cyclase/cAMP mechanism)
• raised ALP (despite the net bone resorption, osteoblast activity is also increased by PTH, so ALP will increase)
• raised vitamin D
• (note that in an adenoma, the normal 3 glands undergo atrophy; in parathyroid hyperplasia, all 4 are usually involved)

Question 7

What is secondary hyperparathyroidism? What causes it (give a specific mechanism)? How do patients present?

Answer 7

• secondary hyperparathyroidism is excess PTH secretion in the setting of chronic hypocalcemia (the parathyroids are normal); most commonly it is due to chronic renal failure
• in chronic renal failure, there is decreased vitamin D activation, leading to decreased Ca2+ gut absorption; in addition, phosphate secretion is reduced and the increased serum phosphate will bind to the free ionized Ca2+, further decreasing the serum Ca2+
• patients may present with mild HYPOcalcemia (hyperreflexia, muscle cramps, tingling, numbness)

Question 8

What lab findings do we see in secondary hyperparathyroidism?

Answer 8

• raised PTH
• HYPOcalcemia, HYPERphosphatemia (the opposite occurs in primary hyperparathyroidism)
• raised ALP
• (all 4 glands undergo hyperplasia)

Question 9

What is tertiary hyperparathyroidism? What causes it? What lab findings do we see?

Answer 9

• this is autonomous hyperparathyroidism that results from chronic renal disease (it follows secondary hyperparathyroidism once the glands “get used to” constantly secreting PTH)
• lab: hypercalcemia and very high PTH levels

Question 10

What causes hypoparathyroidism? How do patients present? What are two major clinical signs of hypoparathyroidism? What lab findings do we see?

Answer 10

• hypoparathyroidism is caused by autoimmune damage, surgical excision, or congenital abnormalities (DiGeroge syndrome), resulting in deficient parathyroid tissue
• patients present with hypocalcemia: hyperreflexia and muscle cramps (tetany), tingling and numbness (especially near the peri-oral area as an early sign)
• major clinical signs are Chvostek sign (tapping the facial nerve triggers facial muscle contraction) and Trousseau sign (inflating the BP cuff triggers carpal spasms)
• lab: low PTH, hypocalcemia, hyperphosphatemia

Question 11

What is pseudohypoparathyroidism? What causes it? What is another name for this disease? What physical features is this disease associated with? What lab findings do we see?

Answer 11

• this is hypocalcemia due to end-organ resistance to PTH
• the resistance is caused by an A.D. mutation of the Gs GPCR involved in renal responsiveness to PTH
• AKA Albright hereditary osteodystrophy
• patients have a short stature and shortened 4th and 5th digits (called the “knuckle knuckle dimple dimple” sign)
• lab: RAISED PTH (hence “pseudo”), hypocalcemia, hyperphosphatemia
• kidneys are not responding to PTH, so PTH secretion is increased; despite this, Ca2+ levels are low because of the inability to elicit a response

Question 12

What is humoral hypercalcemia of malignancy? What is the major cause? What lab findings do we see?

Answer 12

• this is hypercalcemia due to ectopic secretion of PTH
• major cause is lung carcinoma that secretes PTHrp (PTH related peptide) that functions like PTH
• lab: decreased PTH (because the PTHrp is raising Ca2+ levels, which will inhibit PTH secretion), hypercalcemia, hypophosphatemia, raised vitamin D, raised urinary cAMP

Question 13

How can sarcoidosis result in hypercalcemia?

Answer 13

• macrophages in the granulomas in sarcoidosis actually synthesize 1-alpha-hydroxylase (the renal activating enzyme for vitamin D)
• this results in overactive vitamin D, leading to hypercalcemia

Question 14

Why does HYPOcalcemia cause tetany and numbness?

Answer 14

• hypocalcemia is a lowered serum Ca2+ concentration; the intracellular concentration is still normal
• the loss of Ca2+ outside the cell results in a lowered threshold potential and promote sodium influx, so muscle and nerve fibers depolarize more quickly, triggering tetany and numbness