Endocrinology parathyroid gland

Endocrinology-Parathyroid gland

Parathyroid functionPlasma calcium (Ca) regulation a. Parathyroid hormone (PTH): secreted in response to low

serum Ca; induces osteoclasts to reabsorb bone and increases plasma Ca; induces kidneys to increase conversion of 25-(OH) vitamin D to 1,25-(OH)2 vitamin D, decreases phosphate reabsorption, and increases distal tubule Ca reabsorption for net increase in plasma Ca

b. 1,25-(OH)2 vitamin D: metabolite of dietary vitamin D; production in kidneys increases with PTH secretion; increases intestinal Ca21 absorption; increases renal proximal tubule phosphate reabsorption (in opposition to PTH-inducedphosphate wasting)

c. Calcitonin: secreted by thyroid parafollicular cells; inhibits bone reabsorption

•Nephrotic syndrome hypoalbuminuria total calcium decrease ionized calcium normal.albumin decrease 1 unit lead to decrease calcium by 0.8.

•Hypocalcemia need to adjust albumin!!•ESRD phosphate cant excrete increase

phosphate level acc by decrease calcium level. (secondary hyperPTH)

Hypercalcemia-etiology•MCC primary hyperPTH•Malignancy#2-PTH like peptide(squamous cell lung/esophagus) cancer-Bone metastasis (multiple myeloma,breast cancer)•Sarcoidosis (activate vit d through the

macrophage/granuloma,esp during summer when they exposed to sun)RX: prednisone(different from other etiolgy)

Etiology hypercalcemina• Prolong immobilization (MC seen in geriatic

patient)(hypercalcemia of immobilization)• Hyperthyroidism(activate osteoclast increase

serum calcium )• Familial hypocalciuric hypercalcemia(DX:look

for calcium in urine)• Drugs (HCTZ,lithium)• Paget disease• Acidosis(increase free calcium due to albumin

buffer acidosis,increase binding of Hydrogen and albumin which displace calcium from albumin.)

Clinical symptoms• Acute, symptomatic hypercalcemia presents with

confusion, stupor, lethargy,and constipation.• Cardiovascular-Short QT syndrome and hypertension• Bone lesions- Osteoporosis• Renal- Nephrolithiasis- Diabetes insipidus- Renal insufficiency

Management of hypercalcemia•IV fluid normal saline (#1) if develop

edema or fluid overload add furosemide(only used after hydration are severe case!!)

•Calcitonin•Biphosphanides(pamidronate)(long

acting) keep calcium low ,it takes 24-48h to start working.

•A patient with severe hypercalcemia. First line treatment IVF.If still hypercalcemia add calcitonin which will wear off after two days) biphosphanides (takes 2 days to maximally working)

•If pt is mild hypercalcemia treat with biphosphanides.

A 75-year-old man with a history of malignancy is admitted with lethargy, confusion,and abdominal pain. He is found to have a markedly elevated calcium level.After 3 liters of normal saline and pamidronate, his calcium level is still markedly elevated the following day. What is the most appropriate next step in management?a. Calcitoninb. Zolendronic acidc. Plicamycind. Galliume. Dialysisf. Cinacalcet

•Answer: A. Calcitonin inhibits osteoclasts. The onset of action of calcitonin is very rapid, and it wears off rapidly. Bisphosphonates take several days to work.

•Plicamycin and gallium are older therapies for hypercalcemia that no longer have any place in management. When they are given as choices for therapy, plicamycin and gallium are always wrong.

• Zolendronic acid is a bisphosphonate and does not add anything to the use of Pamidronate.

•Cinacalcet is an inhibitor of PTH release. If the hypercalcemia isfrom malignancy, PTH should already be maximally suppressed.

• Dialysis would be used only for those in renal failure.

Hyperparathyroidism•55-year-old woman has hypercalcemia

discovered as an incidental finding during normal routine physicial examination. A hand radiograph is shown

HyperPTH - Introduction

• Increased parathyroid hormone (PTH) production that may be of primary, secondary or tertiary causes

Pathophysiology• PTH indirectly stimulates osteoclasts by binding to its

receptor on osteoblasts, inducing RANK-L and M-CSF synthesis

Epidemiology• occurs in 0.1% of the population• 90% result form a single adenoma• remaining 10% from parathyroid hyperplasia• parathyroid carcinoma accounts for less than 1% of

all cases

Classification Primary• typically the result of hypersecretion of PTH by a parathyroid

adenoma/hyperplasia may result in osteitis fibrosa cystica breakdown of bone common involves the jaw

Secondary• secondary parathyroid hyperplasia as compensation from

hypocalcemia or hyperphosphatemia,↓ gut Ca2+ absorption, ↑ phosphorous

associated conditions 1. chronic renal disease renal disease causes hypovitaminosis leads to ↓ Ca2+ absorption 2. renal osteodystrophy bone leisons due to secondary hyperparathyroidism

Tertiary parathyroid glands become dysregulated after secondary hyperparathyroidism secrete PTH regardless of Ca2+ level

  Serum Ca Serum Phos Serum PTH

Primary ↑ ↓ ↑

Secondary normal or ↓ ↑ ↑

Tertiary ↑ ↑ ↑

Presentation•often asymptomatic•hypercalcemia• weakness•kidney stones ("stones")•bone pain ("bones")•GIT:constipations ("groans")•uncommon cause of secondary

hypertension•CNS:Mental status change(psychiatric

overtones)

slower manifestations such as:•• Osteoporosis•• Nephrolithiasis and renal insufficiency•• Muscle weakness, anorexia, nausea,

vomiting, and abdominal pain•• Peptic ulcer disease (calcium stimulates

gastrin)

EvaluationSerology• primary hypercalcemia, ↑ PTH• secondary hypocalcemia/normocalcemia , ↑ PTH• malignancy ↓ PTH• ↑ alkaline phosphatase• normal anion gap metabolic acidosis• ↓ renal reclamation of bicarbonateUrinalysis• primary hypercalciuria (renal stones), ↑ cAMPRadiograph• cystic bone spaces ("salt and pepper"),often in the skull• loss of phalange bone mass, ↑ concavity (see key

image of this topic)EKG• shortened QT

•Bone x-ray is not a good test for bone effects of high PTH. DEXA densitometry is better.

•Preoperative imaging of the neck with sonography or nuclear scanning may be helpful in determining the surgical approach.

Treatment•Surgical removal of the involved parathyroid

glands is the standard of care.•When surgery is not possible, give cinacalcet•Acute hypercalcemia IV fluids,Loop diuretics•Symptomatic hypercalcemia is treated

surgically treat with parathyroidectoy•complications include post-op hypocalcemiamanifests as numbness, tingling, and muscle cramps should be treated with IV calcium gluconate

In primary hyperPTH,surgery is indicated if any of the following are present:

•Symptomatic hypercalcemia•Calcium>11.5•Renal insufficiency•Age<50•Nephrolithiasis•Osteoporosis

A 45-year-old male undergoes a parathyroidectomy following the passage of two renal stones in a 12-month period. A single parathyroid adenoma is removed. Two days following surgery, the patient reports numbness and tingling around his mouth and lips and muscle cramps. What is the most appropriate next step in the management of this patient?

1. IV calcium gluconate 2. Vitamin D supplementation 3. IV potassium phosphate 4. Surgical neck re-exploration 5. Observation

• PREFERRED RESPONSE ▼ 1• This patient's presentation is consistent with postoperative

hypocalcemia. Treatment with IV calcium gluconate is appropriate.

• Postoperative hypocalcemia is common following successful parathyroidectomy. If hypocalcemia is asymptomatic, no treatment is necessary. Symptoms of hypocalcemia generally appear 2 to 4 days following surgery and are initially treated with IV calcium gluconate, or, if symptoms are mild, oral calcium such as calcium lactate, calcium carbonate, or calcium gluconate. For symptoms that occur earlier than two days or are asymmetric, one should be suspicious of other causes.

• French et al. describe the clinical manifestations of hypocalcemia. “Clinical manifestations of hypocalcemia correlate with both the magnitude and acuity of fall in serum levels. In general, symptoms occur at an ionized calcium concentration of 2.8 mg/dL (0.7 mmol/L) and include circumoral paresthesias, muscle cramps, muscle weakness, myalgias, dysphagia, irritability, depression, and confusion.”

• Incorrect answers:• Answer 2: Vitamin D supplementation is

indicated in cases where symptoms persist despite IV calcium gluconate therapy.

• Answer 3: Potassium phosphate is used to treat hypophosphatemia.

• Answer 4: Surgical neck re-exploration is not indicated in this patient.

• Answer 5: Observation is indicated in asymptomatic hypocalcemia. It would not be appropriate in this situation.

A 62-year-old female presents to general medical clinic for health maintenance. She is due for a colonoscopy but before she schedules it, she would like to have a full exam. She has no complaints and no significant past medical history. She has been in good health for most of her life. Vital signs are stable. Her physical examination is benign. Routine labs reveal a calcium of 11.2 mg/dL. What is the next step in management? Topic Review Topic

1. Order PTH2. Order PTH related peptide3. Reorder serum calcium4. Order ACE5. Order a chest radiograph

• PREFERRED RESPONSE ▼ 3• In a patient with asymptomatic hypercalcemia the first test should

be to confirm hypercalcemia with a second serum calcium. If this test returns positive, then a PTH level is the next step in management. If the hypercalcemia were severe or there were symptoms in this patient the management would be: 1. IV fluids, 2. Loop diuretics (furosemide) 3. Calcitonin then 4. Bisphosphonates (long term management). Often times only IV fluids and a loop diuretic are needed.

• The clinical features of hypercalcemia include the classic stones (kidney stones), bones (aches and pains), groans (constipation), and psychiatric overtones (depression and mood liability). However, this patient presents without these clinical features, and thus a reasonable next step would be to confirm the hypercalcemia. Recall the various causes of hypercalcemia. The broad differential includes endocrinopathies, malignancies, and pharmacologic causes. Endocrinopathies include hyperparathyroidism. Malignancies include any metastatic cancers to the bone, multiple myeloma, and PTH-like peptide producing cancers such as squamous cell lung cancer. Pharmacologic causes include Vitamin D, milk-alkali syndrome, and certain medications such as thiazides, and lithium. Other less common causes are sarcoidosis and familial hypocalciuric hypercalcemia.

• Incorrect Answers:• Answer 1: Ordering a parathyroid level would be

reasonable in a patient who presents with hypercalcemia and the cardinal clinical features.

• Answers 2 and 5: These choices are reasonable in the workup where hypercalcemia of malignancy is expected.

• Answer 4: An ACE would be a reasonable step in a patient with hypercalcemia and some features of sarcoidosis. Since the ACE is a very sensitive but not highly specific test for sarcoidosis, other workup would also be indicated including chest radiograph.

Hypocalcemia-etiology1. Acquired (surgical removal #1)2. vitamin D deficiency-renal failure-intestinal malabsorption(crohn disease,celiac sprue,pancreatitis)-not enough sunlight3.) Hypomagnesium-Magnesium is necessary for PTH to be released from the gland. Low magnesium levels also lead to increased urinary loss of calcium.4.)Hyperphosphatemia5.)Drug: loop diuretics ,alendronate ,phenytoin , foscarnet

Other Causes

•Other causes include genetic disorders, fat malabsorption, and low albumin states. For every point decrease in albumin, the calcium level decreases by 0.8.

•Low albumin causes a decrease in total calcium,but the free calcium level is normal; hence, no symptoms.

Presentation

Signs of neural hyperexcitability in hypocalcemia:• Chvostek sign (facial nerve hyperexcitability)• Carpopedal spasm• Perioral numbness• Mental irritability• Seizures• Tetany (Trousseau sign)

Diagnostic Tests

•EKG shows a prolonged QT that may eventually cause arrhythmia.

•Slit lamp exam shows early cataracts.

Treatment

•Replace calcium and vitamin D. This is done orally if symptoms are mild or absent and intravenously if symptoms are severe.

•Acute stage of hypocalcemia: calcium gluconate IV.

•Maintenance therapy: oral calcium 2-4g per day,vitamin D.

•For ESRD:hyperphosphatemia -diet restriction and phosphate binders(CaCO3/Al3OH2)

Hypoparathyroidism•A 33-year-old woman with a total

thyroidectomy for papillary carcinoma of the thyroid, is noted to have carpal spasm when her blood pressure is taken and facial muscle contractions with tapping over the facial nerve.

  Serum Ca Serum Phos PTH Common Cause

Hyperparathyroidism ↑ ↓ ↑ adenoma

Hypoparathyroidism ↓ ↑ ↓ parathyroidectomy

Ectopic PTH ↑ ↓ ↓ malignancy

Vit D malabsorption ↓ ↓ ↑ celiac disease, other GI isease

hypo vit D with no phosphate excretion

from the kidney.↓ ↑ ↑ renal failure, pseudo

hypoparathyroidism

• A 56-year-old woman is in the ER after a seizure. Although suffering from some continued confusion, she keeps pointing at the area around her mouth and saying that it feels "funny." Her husband states that she has a history of osteoarthritis and thyroid cancer, for which she underwent a total thyroidectomy one month ago. As far as he knows, she has no family history of epilepsy. Her exam is notable for 3+ reflexes in her upper and lower extremities. After applying a blood pressure cuff to her arm for 3 minutes, her hand looks like Figure A. Which laboratory abnormality is her blood work most likely to reveal?

• 1. Low phosphorous• 2. Low ionized calcium• 3. Low magnesium• 4. High 25-hydroxyvitamin D• 5. High PTH

• PREFERRED RESPONSE ▼ 2• A post-thyroidectomy patient presenting with seizure, circumoral

paresthesias, hyperreflexia, and carpopedal spasm (Trousseau's sign) most likely has hypoparathyroidism, which causes low ionized calcium.

• Hypoparathyroidism is a rarer endocrine disorder than hyperparathyroidism. It most commonly occurs after thyroid, parathyroid, or other neck surgery. Other causes include autoimmune disease (specifically, autoimmune polyendocrine syndrome type 1), radiation neck therapy, genetic syndromes (including DiGeorge syndrome), mitochondrial disorders, and infiltrative disorders (e.g., Wilson's disease, hemochromatosis). Post-thyroid surgery, transient hypoparathyroidism occurs in 7-46% of patients while the condition is permanent in closer to 1%.

• abnormal calcium levels are the most common presentation. Aside from re-measuring the calcium level, other important levels include: intact parathyroid hormone levels, albumin, creatinine, magnesium, and calcitriol. Management of hypoparathyroidism includes calcium gluconate, calcitriol supplementation, and close monitoring.

• Figure A depicts a positive Trousseau's sign, which is found in hypocalcemia after applying a blood pressure cuff to the arm for at least 3 minutes. The absence of blood flow combined with low calcium induces spasm of the hand and forearm.

• Illustration A shows the anatomy of the parathyroid glands in relation to the thyroid gland, illuminating why hypoparathyroidism is often a result of thyroid surgery.

• Illustration B shows the normal role of PTH in calcium regulation in the body.

•Incorrect answers:•Answer 1: Phosphorous levels are high in

hypoparathyroidism.•Answer 3: Magnesium levels are normal in

hypoparathyroidism.•Answer 4: 25-hyroxyvitamin D levels are

normal in hypoparathyroidism. Notably, 1,25 dihydroxyvitamin D (calcitriol) levels are usually low in hypoparathyroidism, since PTH simulates conversion of 25-hyroxyvitamin D to 1,25 dihydroxyvitamin D.

•Answer 5: PTH levels are low in hypoparathyroidism.

Pseudohypoparathyroidism

• Rare genetic disorder Mechanism• PTH resistance• decreased target cell response to

PTH

Classification• Type 1a - Albright hereditary osteodystrophy • defect in GNAS1 (Gsα protein)• defective gene from mother• upstream defect • proximal to formation of cAMP• skeletal defects• short 4th, and 5th metacarpals and metatarsals or short 4th metacarpal

only • "knuckle, knuckle, dimple, dimple" sign on closed fist• differentials• Turner syndrome• short 4th metacarpal only • "knuckle, knuckle, dimple, knuckle"• Down syndrome• short middle phalanx• brachydactyly• exostoses• round facies • obesity • short stature• diminished intelligence•

•Type 1b• defect in GNAS1 (Gsα protein)• normal appearance• Type 2• unknown gene defect• downstream defect• distal to formation of cAMP• normal appearance

Symptom

• symptoms of hypocalcemia• paresthesia • fingertip, toes, perioral• abdominal pain, biliary colic• muscle cramps, tetany• dyspnea (laryngospasm, bronchospasm)• convulsions• mental status changes • anxiety, fatigue, mood swings

Laboratory• high PTH• low calcium• high phosphate• low vit D• Ellsworth-Howard test• method to differentiate type 1 and type 2 by

administering exogenous PTH • Type 1 will show no increase in urinary cAMP

and phosphate• Type 2 will show increased excretion of

urinary cAMP and phosphate

Pseudohypoparathyroidism1. Hypocalcemia resulting from tissue nonresponsiveness to PTH2. Associated with developmental and skeletal abnormalities (e.g., Albright hereditary osteodystrophy)3. H/P : symptoms of hypocalcemia, short stature, seizures, poor mental developmentin children4. Labs : decreased Ca21, increased phosphate, increased PTH; administration ofPTH causes no change in serum or urine Ca215. Treatment : Ca and vitamin D supplementation