Disorders of Calcium Metabolism: Hypercalcemia

Steven Chessler, MD, Ph.D. March-April, 2018

Internal Medicine noon conference

(F5)

History and Physical A 45 year-old female consults you because of a low bone mineral density (BMD). She relates that she availed herself of a free screening test of her BMD. The results indicated that she had osteopenia, so she called your office for an appointment. The checklist that she filled out indicates that she is in good health and on no medications. She looks well and the physical is unrevealing. Laboratory Her routine laboratory evaluation is essentially normal, including normal renal function, except for a serum calcium of 10.6, where 10.5 is the upper limit of normal. A DEXA reveals normal bone mineral density. What labs would you order to

follow-up on the Ca++?

History and Physical A 45 year-old female consults you because of a low bone mineral density (BMD). She relates that she availed herself of a free screening test of her bone mineral density (BMD). The results indicated that she had osteopenia, so she called your office for an appointment. The checklist that she filled out indicates that she is in good health and on no medications. She looks well and the physical is unrevealing. Laboratory Her routine laboratory evaluation is essentially normal, including normal renal function, but includes a serum calcium of 10.6, where 10.5 is the upper limit of normal. A DEXA reveals normal bone mineral density What labs would you order to

follow-up on the Ca++?

Results

PTH (at same time): 42 pg/ml (nl: 11-54)

Repeat Ca++: 10.8 Albumin: 4 mg/dl Phos: 3 mg/dl (2.5-4.0)

After verifying the lab results thus far, which would be the best test to help confirm the most likely diagnosis and avoid possible unnecessary treatment?

A. 1,25-dihyroxyvitamin D

B. 25-hydroxyvitamin D

C. Spot urine Ca++

D. 24 hour urine Ca++

E. PTHrP

• Twenty-four-hour urine for calcium will help in the differential diagnosis of FHH. If marked hypercalciuriais present (ie, > 400 mg/d), a more complete urinary biochemical stone profile should be considered. In the presence of abnormal findings indicating increased calcium-containing stone risk and marked hypercalciuria, a guideline for surgery is met.

Answer is D:

24 hour urine is 114 mg/24 hours. (normal 100-300)

Best single next step to help establish diagnosis?

A. Family history

B. Sestamibi imaging of parathyroid glands

C. Surgical exploration of parathyroid glands

D. TSH and free T4

24 hour urine is 450 mg/24 hours (normal 100-300). Also, there is no history of renal stones, fracture, mental status changes or other symptoms. Most appropriate therapy (per current guidelines)?

A. Cinacalcet

B. Parathyroid surgery

C. Alendronate

D. Either parathyroid surgery or monitoring over time

E. Monitoring over time

Same case, but now result is:

Measurement Result Serum calcium (>upper limit of nl.) 1.0 mg/dL (0.25 mmol/L) Skeletal A. BMD by DXA: T-score <-2.5 at

lumbar spine, total hip, femoral neck, or distal 1/3 radius

B. Vertebral fracture Renal A. Creatinine clearance <60 cc/min

B. 24-h urine for calcium >400 mg/d and increased stone risk by biochemical stone risk analysis

C. Presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound, or CT

Age, y <50

Primary Hyperparathyroidism: Management Guidelines (2013) surgery recommended if:

Hypercalcemia/hyperparathyroidism: clinical signs

• GI: – Nausea, vomiting, abdominal pain – Constipation

• Renal:

– Polyuria, dehydration – Renal failure – Nephrolithiasis

• Neurological – Fatigue – Confusion – Depression – Stupor, coma

• Skeletal – Bone pain and tenderness – Spontaneous fracture (compression fx’s)

Hypercalcemia/hyperparathyroidism: clinical signs

• Neuromuscular – Muscle weakness, hypotonia

• Cardiovascular – Hypertension – Short QT interval

Hyperparathyroidism/Hypercalcemia – signs/symptoms

Hypercalcemia: major causes • Primary hyperparathyroidism (PHPT) • Malignancy • Others

Hyperparathyroidism: causes • Primary

– Adenoma (90%) – Multiple gland enlargement (10%)

• MEN 1 • MEN 2A • Familial hyperparathyroidism

– Carcinoma (<1%) – Familial benign hypercalcemia (FBH)

• Secondary (normo- or hypocalcemic) – Renal failure – Vitamin D deficiency

Primary hyperparathyroidism

• Affects approximately 100,000 patients a year.

• Prevalence: 0.1 to 0.3% of the general population.

• More common in women (1:500) than in men (1:2000).

• Patients with single adenoma (~90%): minimally invasive surgery

Sestamibi imaging ~90% sensitive, ~98% specific

Minimally invasive = incision length < 2.5 cm

Intraoperative PTH testing confirms biochemical cure

Malignant hypercalcemia: major causes

• PTHrP - mediated – Breast carcinoma – Squamous carcinoma (lung, head & neck,

esophagus) – Renal carcinoma

• Cytokine/osteoclast activating factor - mediated – Myeloma (lymphoma, leukemia)

• Tumor production of calcitriol – Lymphoma

Hypercalcemia: other causes

• Drugs: – Vitamin D – Calcium carbonate (milk alkali syndrome) – Lithium – Thiazide diuretics – Vitamin A

• Sarcoidosis, other granulomatous disorders • Hyperthyroidism

1. Calcium and phosphorus 2. Bone 3. Vitamin D 4. Parathyroid Hormone 5. Calcitonin

REVIEW, Ca++ metabolism:

PTH, Vitamin D and Calcium homeostasis

• Three definable fractions of calcium in serum: – Ionized calcium 50% – Protein-bound calcium 41%

• 90% bound to albumin – Calcium complexed to serum

constituents 9% • Citrate and phosphate

Extracellular Calcium

Calcium turnover

Renal Excretion

• The kidneys account for the bulk of regulated calcium excretion

• Three distinct locations along the renal tubule are involved

• The regulation of calcium excretion at each of the three renal sites is different

Renal Excretion

• Proximal convoluted tubule – Accounts for 70% of

calcium reabsorption – Mainly paracellular

pathway

Renal Excretion • Proximal convoluted

tubule

• Thick ascending limb of loop of Henle 20 % of calcium reabsorption

Calcium sensing receptor (CaSR)

Caskey F J , Pickett T M Nephrol. Dial. Transplant. 2005;20:1752-1755

FHH, FBH (familial benign/hypocalciuric hypercalcemia)

Renal Excretion

• Proximal convoluted tubule • Thick ascending limb

• Distal convoluted tubule – PTH regulation – 8% of calcium

reabsorption

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1. Calcium and phosphorus

2. Bone 3. Vitamin D 4. Parathyroid Hormone 5. Calcitonin

PTH, Vitamin D and Calcium homeostasis

20-25

Calcium Regulation: Bone Exchange

• Bone is dynamic and is constantly remodeled

• Calcium is exchanged between blood and bone daily (roughly 400 mg/day); 10% of skeleton per year

• Ongoing remodeling allows bone to store and release calcium as needed to help maintain homeostasis

Normal bone remodeling cycle

Case: Man With Lethargy, Fatigue and Weakness

• 60 yr old male presents with complaints of fatigue and weakness over 1 month.

• PMHx: Negative; no history CHF or kidney disease • PE: significant for memory and cognitive

defects • Lab: Ca 15.0 mg/dL PO4 2.3 mg/dL

Most likely cause of hypercalcemia? A) Vitamin D intoxication

B) Granulomatous disease

C) Malignancy

D) Acute hyperparathyroidism

E) Chronic hyperparathyroidism

60 yr old male presents with complaints of fatigue and weakness over 1 month. Renal function is normal. PMHx: Negative; no history CHF or kidney disease PE: significant for memory and cognitive defects Lab: Ca 15.0 mg/dL, PO4 2.3 mg/dL

Severe hypercalcemia: • Principles of therapy

– Expand ECF volume – Increase urinary calcium excretion – Decrease bone resorption

• Indications for therapy – Symptoms of hypercalcemia – Plasma [Ca] >15 mg/dl

After admission, the patient becomes increasingly obtunded. How do you treat?

Hypercalcemia - Treatment

– NS bolus to restore volume; then 100 – 200 ml/hr – Bisphosphonates (onset 24-48 hrs) – Calcitonin 4 – 8 IU q6-8 hrs (onset immediate,

resistance develops in 24-48 hrs) – [Mg and K prn]

Despite having administered zoledronic acid (4 mg IV), hypercalcemia is not brought under adequate control.

The best option for prolonged control is now to add: A) A drug targeting the calcium-sensing receptor (CaSR).

B) Pamidronate

C) A loop diuretic

D) A drug targeting the calcitonin receptor

E) A drug targeting RANK ligand (RANKL)

Rank Ligand (RANKL) and osteoprotegerin (OPG) balance bone loss and formation

• RANKL is a key inducer of osteoclast formation

• By binding with RANKL, OPG (or denosumab) prevents RANKL Ligand from binding with RANK on the surface of osteoclasts and their precursors.

1. Calcium and phosphorus 2. Bone

3. Vitamin D 4. Parathyroid Hormone 5. Calcitonin

PTH, Vitamin D and Calcium homeostasis Lecture outline

Hormonal control of Ca2+

• Parathyroid hormone (PTH) stimulates 1,25-(OH)2-Vitamin D synthesis.

• The first hydroxylation reaction takes place in the liver yielding 25-hydroxyl D

• Second hydroxylation reaction takes place in the kidney yielding 1,25(OH)2-D3 (calcitriol; 1,25-dihydroxy-vitamin D).

• Sarcoidosis, other granulomatous disorders, certain malignancies (lymphoma) can also produce 1,25(OH)2-D3

Synthesis of Vitamin D

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REGULATION OF RENAL 1α-HYDROXYLASE PRODUCTION

Stimulates PTH Low calcium Low phosphate Calcitonin

Inhibits 1,25(OH)2D3

High calcium High phosphate

Case: A 36 yo African-American male with a 5 month history of cough and dyspnea is found to have a calcium level of 10.9 mg/dl (normal < 10.6). His only medication is an albuterol MDI. He smokes 1-2 packs per day. He is thin and ill-appearing. Physical exam is only notable for lungs having scattered crackles bilaterally and cervical lymphadenopathy.

Laboratory results: Albumin— 4 mg/dL (normal) Creatinine: 1.0 mg/dL Repeat Ca++: 10.8 mg/dL (8.5-10.5 mg/dL) Phosphate: 4.5 mg/dL (2.5-4.4 mg/dL) PTH: 9 pg/ml (11-54 pg/ml) 25-hydroxyvitamin-D: 25 ng/ml (30-74 ng/ml)

The cause of the hypercalcemia will most likely be revealed by: A. Measurement of 24 hour urine calcium B. Measurement of serum PTHrP C. Measurement of serum 1,25-dihydroxyvitamin-D D. Sequencing of the gene encoding the CaSR

Answer: C (has sarcoid or TB so measure 1,25-dihydroxyvit.-D) From: UpToDate, Diagnostic approach to hypercalcemia: “Measurement of the serum phosphate concentration and urinary calcium excretion also may be helpful in selected cases. Hyperparathyroidism and humoral hypercalcemia of malignancy (due to PTH-related protein) may be associated with frank hypophosphatemia or low-normal serum phosphate levels resulting from inhibition of renal proximal tubular phosphate reabsorption. In comparison, the serum phosphate concentration is normal or elevated in granulomatous diseases, vitamin D intoxication, immobilization, thyrotoxicosis, milk-alkali syndrome, and metastatic bone disease.“

Summary: vitamin D action

• Main action of 1,25-(OH)2-D is to stimulate absorption of Ca2+ (and phosphate) from the intestine.

also: • acts on osteoblasts to increase RANKL and thus

activate osteoclasts to increase Ca++ resorbtion. • is necessary for proper bone formation.

1. Calcium and phosphorus 2. Bone 3. Vitamin D

4. Parathyroid Hormone 5. Calcitonin

PTH, Vitamin D and Calcium homeostasis

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Parathyroid Hormone

Calcium regulates

PTH secretion

via a CaSR

PTH and calcium+phosphate homeostasis

1. Calcium and phosphorus 2. Bone 3. Vitamin D 4. Parathyroid Hormone

5. Calcitonin

PTH, Vitamin D and Calcium homeostasis Lecture outline

Calcitonin • Decreases plasma Ca2+ and phosphate

concentrations, mainly by decreasing bone resorption.

• Synthesized and secreted by the parafollicular cells (aka C cells) of the thyroid gland.

• Release stimulated by hypercalcemia and inhibited by hypocalcemia

Slide credit: Dale Buchanan Hales Ph.D.

• Calcitonin rapidly inhibits osteoclast activity o causes inhibition of osteoclast motility, alterations in

cell morphology and osteoclast inactivation.

• Kidneys o inhibits calcium reabsorption (increases excretion) o also increases phosphorus excretion

• Role in calcium homeostasis unclear

Calcitonin effects

Hormone Effect on bones Effect on gut Effect on kidneys

Parathyroid hormone increase Ca++, decrease PO4 levels in blood

Promotes resorption

Indirect effects via increase in calcitriol from 1-hydroxylation

Promotes Ca++ reabsorption and PO4 excretion, activates 1-hydroxylation

Calcitriol (vitamin D) Ca++, PO4 levels increase in blood

(↑RANKL→bone resportion)

Increases Ca++ and PO4 absorption

No direct effects

Calcitonin Inhibits resorption

No direct effects Promotes Ca++ and PO4 excretion

Hypocalcemia: clinical signs

• Paresthesias • Tetany (carpopedal spasm) • Trousseau’s, Chvostek’s signs • Seizures • Chronic: cataracts, basal ganglia Ca

Trousseau’s sign

Hypocalcemia: causes • Hypoparathyroidism

– Surgical (thyroid, parathyroid surgery) – Autoimmune – Magnesium deficiency

• PTH resistance (pseudohypoparathyroism)

• Vitamin D deficiency • Vitamin D resistance

• Other: renal failure, pancreatitis, tumor lysis

END