A. Introduction

1. Incidence increased mainly due to routine screening of serum calcium
   1. 100,000 new cases per year in USA (1:1000 to 1:2000 persons)
   2. Most patients are asymptomatic, at least initially [3]
   3. Female : Male ~2:1
2. Post-menopausal women are disproportionately affected (unclear reasons)
3. Parathyroid Hormone (PTH)
   1. Released in response to decreased serum [Ca2+]
   2. Causes osteoclast activity with release of Ca2+ and PO42- from bone
   3. Causes increased renal conversion of 25-OH Vitamin D to 1a,25 dihydroxy-Vitamin D
   4. Stimulates increased renal tubular Ca2+ resorption
4. PTH related peptide (PTHRP)
   1. Usually produced by tumors
   2. Binds to Type 1 PTH receptor and induces similar activity
   3. May be important during embryonic development
5. Asymptomatic HPT [3]
   1. Increasing incidence with general calcium screening
   2. Most patients with <11mg/dL serum calcium
   3. Most patients with 1.5-2.0X elevations of PTH (normal levels 65pg/mL)
   4. Assess for bone loss, kidney stones, or easy fatigability

B. Etiology of Primary HPT

1. Single Ademonas in 80-85% of Primary HPT
   1. Monoclonal or oligoclonal tumors
   2. Likely that two or more genes have mutated
   3. Somatic mutation of MEN1 gene (tumor suppressor) in ~20% of cases
   4. Small minority of single adenomas have activating mutations of Cyclin D1 (CCND1) gene
   5. Nearly all adenomas have overexpression of Cyclin D1
   6. Abnormal cells have deficient sensitivity to inhibition by Ca2+
2. Polyglandular hyperplasia in 14-19% (all glands involved)
3. Parathyroid carcinoma: ~1% primary HPT cases
4. Monoclonal Gammopathy [4]
   1. ~10% of patients with primary HPT have a monoclonal gammopathy
   2. Of these, 20% had indolent myeloma
   3. 80% have monoclonal gammopathy of undetermined significance (MGUS)
   4. Serum protein electrophoresis should be performed on patients with primary HPT
5. Familial Hypocalciuric Hypercalcemia [1,5]
   1. Autosomal dominant
   2. Caused by monoallelic inactivating germ-line mutations of calcium sensing receptor gene
   3. Hypercalcemia persists after subtotal parathyroidectomy (surgery is contraindicated)
   4. Normal serum PTH levels
   5. Multiple, minimally enlarged parathyroid glands present
6. Neonatal (Familial) Severe Primary HPT
   1. Rare autosomal recessive syndrome
   2. Usually due to homozygous inactiving germ-line mutations of calcium sensing receptor gene
   3. Very high serum PTH levels
   4. Multiple enlarged glans
   5. Marked hypercalcemia with Ca2+ usually >16mg/dL
7. Hyperparathyroidism - Jaw Tumor (HPT-JT) Syndrome [6]
   1. Due to mutations in HRPT2 gene which encodes parafibromin protein
   2. Rare autosomal dominant cause of HTP and parathyroid carcinomas
   3. Includes ossifying fibromas of mandible and maxilla
   4. Various cystic and neoplastic renal abnormalities
8. Rarely, HPT is a component of MEN Syndromes
   1. MEN I: pituitary adenoma, parathyroid hyperplasia, pancreatic neoplasm
   2. MEN IIa: medullary CA of thyroid, pheochromocytoma, parathyroid hyperplasia

C. Symptoms

1. Bone Changes
   1. Pain and Pathologic Fractures
   2. Demineralization and fibrosis - especially in cortical bone (such as distal radius)
   3. Severe Disease: bone changes called ostetis fibrosa cystica
   4. Even "mild" cases have demonstrable reduction in bone mineral density
2. Osteitis Fibrosa Cystica
   1. Due to resorption, abnormal metabolism
3. Effects on Joints
   1. Chondrocalcinosis (~10% of patients)
   2. Pseudogout
4. Vitamin D (25-OH-VitD) Insufficiency or Frank Deficiency
   1. Common in patients with mild hyperparathyroidism
   2. May exacerbate bone disease (osteopenia) in these patients
5. Renal Disease
   1. Hypersecretion of calcium leading to renal stone formation
   2. Nephrocalcinosis (paranchymal calcium / phosphate deposition) and renal colic
   3. Reduced glomerular filtration rate (creatinine clearance)
   4. Calcium induced diuresis with thirst, polyuria, dehydration
6. Neurologic and Psychiatric
   1. Weakness due to muscle dysfunction
   2. Depression, apathy, fatigue, lethargy
   3. Rarely, may progress to confusion, delirium, obtundation
   4. Fahr's Disease - rare neurodegeneration of symmetric basal ganglia calcifications; idiopathic or associated with hypercalcemic and other disorders [10]
7. Gastrointestinal
   1. Peptic Ulcer Disease
   2. Pancreatitis - 10-15% of patients with HPT [7]
   3. Abdominal Pain (cramping) and Constipation
   4. Cholelithiasis - colicky pain
8. Cardiovascular Disease
   1. Hypertension (20-60%)
   2. High incidence of LVH (likely from hypertension)
   3. Calcific deposition in myocardium and L sided valves
   4. Shortened QT interval (hypercalcemia)
9. "Normocalcemic" Hyperparathyroidism
   1. Minority of cases of true hyperparathyroidism have normal serum calcium levels
   2. Some cases due to abnormally low serum albumin levels
   3. Vitamin D deficiency or acidosis may mask hypercalcemia
   4. In most of these cases, ionized serum calcium is high though total levels normal
10. Mnemonic for hyperparathyroidism/hypercalcemia: "bones, stones, and groans"

D. Classification Based on Calcium Levels

1. Serum ionized Ca2+ levels are more important than total Ca2+ for severity determination
2. Typically, total corrected Ca2+ is used
   1. This is Total serum Ca2+ value added to:
   2. Corrected Ca2+: 0.8mg/dL Ca2+ for every 1gm/dL serum albumin below 4gm/dL
   3. This correction can be used in place of ionized Ca2+, which is difficult to measure
3. Severe HPT: Ca2+ > 12.0mg/dL; ~1% of patients
4. Moderate HPT: Ca2+ > 11.0mg/dL; ~30% of patients
5. Mild HPT with disease manifestations: Ca2+ <11.0mg/dL; ~40% of patients
6. Mild HPT, without disease complications: ~30% of patients [3]
7. High risk of progression of asympatomic HPT in younger persons
8. ~30% of HPT patients will have abnormally low serum phosphate levels

E. Differential Diagnosis of Hypercalcemia

1. Hyperparathyroidism
   1. Primary HPT is a fairly common cause of hypercalcemia
   2. Secondary HPT usually begins as a response to hypocalcemia
2. Carcinomas
   1. Ectopic PTH-like peptide (PTHRP)
   2. Especially squamous cell (lung, larynx, skin)
3. Thiazide Diuretics
   1. Thiazides inhibit Ca2+ renal secretion
   2. In general, HPT must be present along with these drugs
4. Elevated Levels of Vitamin D
   1. Vitamin D Intoxication and Milk Alkali Syndrome
   2. Lymphoma - increased production of dihydroxyvitamin D (DHVD)
   3. Granulomatous reactions - increased production of dihydroxyvitamin D (DHVD)
5. Granulomatous Inflammatory Responses
   1. Sarcoidosis
   2. Crohn's disease
   3. Infectious Agents: tuberculosis, bartonella (Cat Scratch), fungal infections
6. Hyperthyroidism: increased bone turnover

F. Evaluation

1. History and physical targeted to symptoms
2. Serum electrolytes and renal function
3. Serum calcium, phosphate and albumin levels - frequently
4. 24-Hour urinary calcium excretion -initially only
5. Bone densitometry to rule out osteoporosis - and at least annually
6. Preoperative localization of parathyroid adenomas
   1. Ultrasound or computerized tomographic scan of limited utility
   2. Tc99-MIBI-pertechnetate with SPECT scanning can be used reliably [8]

G. Treatment

1. Treatment is necessary in a minority of patients [9]
   1. Watchful waiting in most patients with mild or asymptomatic disease
   2. Surgery should be offerred to patients with symptoms or signs of disease
   3. Surgery is clearly beneficial in such patients
2. Indications for Treatment of Asymptomatic Primary HPT [1]
   1. Surgery recommended for the following:
   2. Serum calcium >1mg/dL (0.25 mM) above upper limit of normal
   3. Urinary calcium excretion >400mg/4 hours
   4. Impaired renal function (creatinine clearance 30% below expected level)
   5. Bone mineral density T-score less than -2.5
   6. Age <50 years
   7. Followup likely unreliable
3. Treat Hypercalcemia (acutely) As Needed
   1. Fluids are critical - correct vascular volume depletion
   2. Addition of loop diuretic recommended to increase calcium excretion
   3. Bisphosphonates as needed
   4. Subcutaneous calcitonin
   5. Low calcium diet in many cases (at least initially)
4. Reduction in calcium intake may be helpful
   1. This is most likely true in persons with elevated serum vitamin D (DHVD)
   2. Persons with normal serum DHVD may liberalize calcium intake cautiously
   3. Bisphosphonates with normal calcium intake may be optimal (prevent osteoporosis)
5. Bone Disease
   1. Hormone replacement therapy improves bone mineral density (BMD) in mild disease
   2. Nearly all women with primary hyperparathyroidism should be on some estrogen
   3. An oral bisphosphonate such as alendronate (Fosamax®) may also reduce bone disease
   4. Intravenous bisphosphonates (such as pamidronate) may be considered
   5. Nasal calcitonin (Miacalcin®) could also be used, though efficacy not proved in HPT
6. Consider evaluation for MEN syndromes
7. Calcium-Sensing Receptor Agonists [3,11,12]
   1. Cinacalcet (Sensipar®) is FDA approved for treatment of secondary HPT due to renal failure and for treatment of hypercalcemia due to parathyroid carcinoma
   2. Cinacalcet has shown good activity in primary HPT
   3. Cinacalcet can be used to normalize PTH levels in patients with renal failure
   4. PTH reduction with cinacalcet in dialysis patients accompanied by 8-15% reduction in calcium - phosphate product Ca-P product
   5. Initial dose is 30mg once daily for 2-4 weeks, then titrate up to 90mg qd [11]

H. Surgical Resection [9]

1. Only ~20-25% of patients with HPT will meet criteria for (benefit from) surgery
2. Indications for surgical resection of adenoma or hyperplastic glands
   1. Moderately or markedly elevated serum calcium:
   2. For example, a calcium level of 11.5mg/dL or greater (with normal albumin)
   3. History of an episode of life-threatening hypercalcemia
   4. Reduced creatinine clearance (such as 30% ore more below expected)
   5. Presence of kidney stone(s) on abdominal radiograph
   6. Markedly elevated 24-hour urine calcium excretion (usually >400mg/24 hours)
   7. Substantially reduced bone mass (>2 SD below mean) on DEXA scan
   8. Age of patients <50 years old (concern about long term effects of HPT)
3. Preparation for Surgery
   1. Pre-operative radiographic evaluation is not indicated for initial surgery
   2. Localization of high-PTH gland(s) is not necessary before surgery in most cases
   3. Gland localization may be useful in patients who have failed initial surgery
   4. Hypocalcemia (with tetany) is very common post-surgery
4. Successful in >85% of cases at reducing PTH and hypercalcemia
   1. Clearly improves bone density
   2. Eliminates risk of kidney stones
   3. Reduces need for careful monitoring of calcium levels
5. Post-Operative Course
   1. Most patients have a transient episode of hypocalcemia due to "stunned" glands
   2. If overt skeletal disease is present, than "hyngry bone" syndrome may occur
   3. Hungry Bone Syndrome - rapid deposition of calcium and phosphorus into bone
   4. Late post-surgical hypoparathyroidism may also occur
6. In 10-15% of cases, patient will remain hyperparathyroid and/or hypercalcemic
   1. Radiographic imaging is recommended in these patients
   2. Ultrasound, CT, and/or nuclear medicine scans are used to locate abnormal gland(s)

References

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2. Mark SJ. 2000. NEJM. 343(25):1863
3. Bilezikian JP and Silverberg S. 2004. NEJM. 350(17):1746
4. Arnulf B, Bengoufa D, Sarfati E, et al. 2002. Arch Intern Med. 162:464
5. Brown EM, Pollak M, Seidman CE, et al. 1995. NEJM. 333(4):234
6. Shattuck TM, Valimaki S, Obara T, et al. 2003. NEJM. 349(18):1722
7. Mergener K and Ballie J. 1997. Lancet. 350(9088):1379
8. Moka D, Voth E, Dietlein M, et al. 2000. Am J Med. 108(9):733
9. Silverberg SJ, Shane E, Jacobs TP, et al. 1999. NEJM. 341(17):1249
10. Morgante L, Trimarchi F, Benvenga S. 2002. Lancet. 359(9308):759
11. Cinacalcet. 2004. Med Let. 46(1192):80
12. Block GA, Martin KJ, de Rancisco ALM, et al. 2004. NEJM. 350(15):1516