HyperparathyroidismHyperparathyroidismSarah Rodriguez, MDSarah Rodriguez, MD

Shawn Newlands, MD, PhDShawn Newlands, MD, PhDUniversity of Texas Medical BranchUniversity of Texas Medical Branch

Grand Rounds PresentationGrand Rounds PresentationFebruary 2006February 2006

PTH/Calcium HomeostasisPTH/Calcium HomeostasisLow circulating serum Low circulating serum

calcium calcium concentrations concentrations stimulate the stimulate the parathyroid glands to parathyroid glands to secrete PTH, which secrete PTH, which mobilizes calcium mobilizes calcium from bones by from bones by osteoclastic osteoclastic stimulation. PTH also stimulation. PTH also stimulates the stimulates the kidneys to reabsorb kidneys to reabsorb calcium and to calcium and to convert 25-convert 25-hydroxyvitamin D3 hydroxyvitamin D3 (produced in the (produced in the liver) to the active liver) to the active form, form, 1,25-1,25-dihydroxyvitamin D3, dihydroxyvitamin D3, which stimulates GI which stimulates GI calcium absorption. calcium absorption. High serum calcium High serum calcium concentrations have concentrations have a negative feedback a negative feedback effect on PTH effect on PTH secretion.secretion.

PTHPTH Renal effects (steady state maintenance)Renal effects (steady state maintenance)

– Inhibition of phosphate transportInhibition of phosphate transport– Increased reabsorption of calciumIncreased reabsorption of calcium– Stimulation of 25(OH)D-1alpha-hydroxylaseStimulation of 25(OH)D-1alpha-hydroxylase

Bone effects (immediate control of blood Ca)Bone effects (immediate control of blood Ca)– Causes calcium bone release within minutesCauses calcium bone release within minutes– Chronic elevation increases bone remodeling and Chronic elevation increases bone remodeling and

increased osteoclast-mediated bone resorptionincreased osteoclast-mediated bone resorption– However, PTH administered intermittently However, PTH administered intermittently

has been shown to increase bone formation has been shown to increase bone formation and this is a potential new therapy for and this is a potential new therapy for osteoporosisosteoporosis

HypercalcemiaHypercalcemiaI.Parathyroid-relatedI.Parathyroid-related

-Primary hyperparathyroidism-Primary hyperparathyroidism-Lithium therapy-Lithium therapy-Familial hypocalciuric hypercalcemia-Familial hypocalciuric hypercalcemia

II. Malignancy-relatedII. Malignancy-related-Solid tumor with metastases (breast)-Solid tumor with metastases (breast)-Solid tumor with humoral mediation of hypercalcemia (lung, kidney)-Solid tumor with humoral mediation of hypercalcemia (lung, kidney)-Hematologic malignancies (multiple myeloma, lymphoma, -Hematologic malignancies (multiple myeloma, lymphoma, leukemia)leukemia)

III. Vitamin D-relatedIII. Vitamin D-related-Vitamin D intoxication-Vitamin D intoxication-↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases-↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases-Idiopathic hypercalcemia of infancy-Idiopathic hypercalcemia of infancy

IV. Associated with high bone turnoverIV. Associated with high bone turnover-Hyperthyroidism-Hyperthyroidism-Immobilization-Immobilization-Thiazides-Thiazides-Vitamin A intoxication-Vitamin A intoxication

V. Associated with renal failureV. Associated with renal failure-Severe secondary hyperparathyroidism-Severe secondary hyperparathyroidism-Aluminum intoxication-Aluminum intoxication-Milk-alkali syndrome-Milk-alkali syndrome

**Primary hyperparathyroidism and cancer account for 90% of cases of hypercalcemia

Primary HyperparathyroidismPrimary Hyperparathyroidism

Estimated incidence is 1 case per 1000 men and 2-Estimated incidence is 1 case per 1000 men and 2-3 cases per 1000 women3 cases per 1000 women– Incidence increases above age 40Incidence increases above age 40– Most patients with sporadic primary Most patients with sporadic primary

hyperparathyroidism are postmenopausal hyperparathyroidism are postmenopausal women with an average age of 55 yearswomen with an average age of 55 years

>80% of cases are caused by a solitary parathyroid >80% of cases are caused by a solitary parathyroid adenomaadenoma

Approximately 10% are caused by “double Approximately 10% are caused by “double adenoma”adenoma”

Primary HPT: Clinical FeaturesPrimary HPT: Clinical Features Symptomatic:Symptomatic:

– Osteitis fibrosa cysticaOsteitis fibrosa cystica– NephrolithiasisNephrolithiasis– Pathologic fracturesPathologic fractures– Neuromuscular diseaseNeuromuscular disease– Life-threatening Life-threatening

hypercalcemiahypercalcemia– ?Peptic Ulcer Disease?Peptic Ulcer Disease

?Asymptomatic:?Asymptomatic:– FatigueFatigue– Subjective muscle weaknessSubjective muscle weakness– DepressionDepression– Increased thirstIncreased thirst– PolyuriaPolyuria– ConstipationConstipation– Musculoskeletal aches and Musculoskeletal aches and

painspains

Work-UpWork-Up

Intact PTH and chemistry panelIntact PTH and chemistry panel– PTH elevated despite elevated serum calciumPTH elevated despite elevated serum calcium– Serum phosphate in the low-normal to mildly decreased rangeSerum phosphate in the low-normal to mildly decreased range– Look at the serum creatinine to evaluate for CRI/CRFLook at the serum creatinine to evaluate for CRI/CRF

Rule out lithium or thiazide useRule out lithium or thiazide use 24-hour urine calcium excretion24-hour urine calcium excretion

– Used to rule out familial hypocalciuric hypercalcemiaUsed to rule out familial hypocalciuric hypercalcemia– Values below 100mg/24 hours or a calcium creatinine Values below 100mg/24 hours or a calcium creatinine

clearance ratio of <0.01 are suggestive of FHHclearance ratio of <0.01 are suggestive of FHH Wrist, spine and hip DEXAWrist, spine and hip DEXA Consider KUB, IVP or CT to evaluate for kidney stonesConsider KUB, IVP or CT to evaluate for kidney stones Ionized calcium versus serum calcium—the debate rages Ionized calcium versus serum calcium—the debate rages

on….on….– CORRECTED SERUM CALCIUMCORRECTED SERUM CALCIUM

Serum calcium (mg/dL)+(0.8X[4-albumin (g/dL)])Serum calcium (mg/dL)+(0.8X[4-albumin (g/dL)])

CA/CRT ratio: (24 hr urine calciumXserum crt)/(24 hr urine crtXserum calcium)

Surgical CandidacySurgical Candidacy Symptomatic primary HPTSymptomatic primary HPT NIH Consensus Development Panel 2002 Revised NIH Consensus Development Panel 2002 Revised

Guidelines [if any of the following are met]Guidelines [if any of the following are met]– Serum calcium greater than 1mg/dL above the upper Serum calcium greater than 1mg/dL above the upper

limit of the reference rangelimit of the reference range– 24 hour urine calcium greater than 400 mg24 hour urine calcium greater than 400 mg– Creatinine clearance reduced by more than 30% Creatinine clearance reduced by more than 30%

compared with age-matched subjectscompared with age-matched subjects– Bone density at the lumbar spine, hip, or distal radius Bone density at the lumbar spine, hip, or distal radius

more than 2.5 SD below peak bone massmore than 2.5 SD below peak bone mass– Age under 50Age under 50– Patients for whom medical surveillance is not desirable Patients for whom medical surveillance is not desirable

or possibleor possiblecreatinine clearance (mL/min) = creatinine clearance (mL/min) = ((urine creatinine in mg/dL) * (urine ((urine creatinine in mg/dL) * (urine volume in mL)) / ((plasma creatinine volume in mL)) / ((plasma creatinine in mg/dL) * (time period in minutes))in mg/dL) * (time period in minutes))

Other Considerations in Surgical Other Considerations in Surgical ReferralReferral

Neuropsychological abnormalitiesNeuropsychological abnormalities– Several studies document improvement in HRQL after Several studies document improvement in HRQL after

parathroidectomyparathroidectomy– Studies on neurobehavioral abnormalities have reported less Studies on neurobehavioral abnormalities have reported less

consistent results with parathyroidectomyconsistent results with parathyroidectomy Cardiovascular abnormalitiesCardiovascular abnormalities

– Symptomatic patients suffer from increased cardiovascular Symptomatic patients suffer from increased cardiovascular mortality before and after treatmentmortality before and after treatment

– Asymptomatic primary HPT is associated with LVH; some Asymptomatic primary HPT is associated with LVH; some studies suggest this is reversible with parathyroidectomystudies suggest this is reversible with parathyroidectomy

– Primary HPT patients have increased calcifications of mitral Primary HPT patients have increased calcifications of mitral and aortic valveand aortic valve

Perimenopausal womenPerimenopausal women– Asymptomatic primary HPT associated with increased bone Asymptomatic primary HPT associated with increased bone

turnover, reduced bone mineral density and higher risk for turnover, reduced bone mineral density and higher risk for fracturesfractures

Pre-Operative ImagingPre-Operative Imaging High-resolution ultrasoundHigh-resolution ultrasound

– Sensitivity 65-85% for adenoma; 30-90% for enlarged glandSensitivity 65-85% for adenoma; 30-90% for enlarged gland– Results suboptimal in pts with multinodular thyroid disease, Results suboptimal in pts with multinodular thyroid disease,

pts with short thick neck, ectopic glands (15-20%)pts with short thick neck, ectopic glands (15-20%)– May be useful in detecting sestamibi scan negative May be useful in detecting sestamibi scan negative

adenomasadenomas CT with contrast/thin sectionCT with contrast/thin section

– Sensitivity of 46-87%Sensitivity of 46-87%– Good for ectopic glands in the chestGood for ectopic glands in the chest

MRIMRI– Sensitivity of 65-80%Sensitivity of 65-80%– Good for ectopic glandsGood for ectopic glands

SestamibiSestamibi– 85-95% accurate in localizing adenoma in primary HPT85-95% accurate in localizing adenoma in primary HPT

Sestamibi-SPECTSestamibi-SPECT– Sensitivity 60% for enlarged gland and 98% for solitary Sensitivity 60% for enlarged gland and 98% for solitary

adenomasadenomas

Scintigraphy Images

Traditional Sestamibi

Sestamibi-SPECT

Medical ManagementMedical Management Asymptomatic patients may elect to be Asymptomatic patients may elect to be

closely followed and managed medicallyclosely followed and managed medically– A recent study of pts with asymptomatic A recent study of pts with asymptomatic

primary HPT showed that the majority of pts primary HPT showed that the majority of pts followed for ten years did not demonstrate an followed for ten years did not demonstrate an increase in serum calcium or PTH levels—25% increase in serum calcium or PTH levels—25% of patients had progressive disease including of patients had progressive disease including worsening hypercalcemia, hypercalciuria and worsening hypercalcemia, hypercalciuria and reduction in bone mass—younger patients reduction in bone mass—younger patients more likely to have progression of disease more likely to have progression of disease

Patients opting not to have surgery should Patients opting not to have surgery should have a serum calcium level drawn every 6 have a serum calcium level drawn every 6 months and should have annual bone months and should have annual bone densiometry at all three sitesdensiometry at all three sites

Medical Management Primary HPTMedical Management Primary HPT

EstrogenEstrogen– Dose required is highDose required is high

SERMsSERMs– Reduction in serum calcium and markers of Reduction in serum calcium and markers of

bone turnover after 4 weeksbone turnover after 4 weeks BisphosphonatesBisphosphonates

– Studies have shown increase in lumbar spine Studies have shown increase in lumbar spine and femoral neck mineral densityand femoral neck mineral density

Calcium/Vitamin DCalcium/Vitamin D Calcimimetic agents (Cinacalcet)Calcimimetic agents (Cinacalcet)

– Under investigation for primary HPTUnder investigation for primary HPT

Familial SyndromesFamilial Syndromes MEN IMEN I MEN IIAMEN IIA Familial Hypocalciuric Familial Hypocalciuric

HypercalcemiaHypercalcemia Hyperparathyroidism-jaw tumor Hyperparathyroidism-jaw tumor

syndromesyndrome– Fibro-osseous jaw tumorsFibro-osseous jaw tumors– Renal cystsRenal cysts– Solid renal tumors Solid renal tumors

Familial isolated Familial isolated hyperparathyroidismhyperparathyroidism

MEN IMEN I MEN IMEN I

– 1 in 30,000 persons1 in 30,000 persons– Features:Features:

Hyperparathyroidism (95%)Hyperparathyroidism (95%)– Most common and earliest endocrine manifestationMost common and earliest endocrine manifestation

Gastrinoma (45%)Gastrinoma (45%) Pituitary tumor (25%)Pituitary tumor (25%) Facial angiofibroma (85%)Facial angiofibroma (85%) Collagenoma (70%)Collagenoma (70%)

HPT in MEN IHPT in MEN I– Early onsetEarly onset– Multiple glands affectedMultiple glands affected– Post-op hypoparathyroidism more common (more Post-op hypoparathyroidism more common (more

extensive surgery)extensive surgery)– Successful subtotal parathyroidectomy followed by Successful subtotal parathyroidectomy followed by

recurrent HPT in 10 years in 50% of casesrecurrent HPT in 10 years in 50% of cases

STIGMATA OF MEN I

Lipomas

Collagenomas

Angiofibromas

MEN IIA (Sipple’s Syndrome)MEN IIA (Sipple’s Syndrome)

Features:Features:– MTC(95%)MTC(95%)– Pheochromocytoma(50%)Pheochromocytoma(50%)– HPT(20%)HPT(20%)

RET mutation (98%)RET mutation (98%) 1 in 30,000-50,000 people 1 in 30,000-50,000 people Usually single adenoma but may Usually single adenoma but may

have multi-gland hyperplasiahave multi-gland hyperplasia

Familial Hypocalciuric Familial Hypocalciuric HypercalcemiaHypercalcemia

This benign condition can be easily mistaken for mild This benign condition can be easily mistaken for mild hyperparathyroidism. It is an autosomal dominant hyperparathyroidism. It is an autosomal dominant inherited disorder characterized by hypocalciuria inherited disorder characterized by hypocalciuria (usually < 50 mg/24 h), variable hypermagnesemia, (usually < 50 mg/24 h), variable hypermagnesemia, and normal or minimally elevated levels of PTH. and normal or minimally elevated levels of PTH. These patients do not normalize their hypercalcemia These patients do not normalize their hypercalcemia after subtotal parathyroid removal and should not be after subtotal parathyroid removal and should not be subjected to surgery. The condition has an excellent subjected to surgery. The condition has an excellent prognosis and is easily diagnosed with family history prognosis and is easily diagnosed with family history and urinary calcium clearance determination. and urinary calcium clearance determination.

Secondary HyperparathyroidismSecondary Hyperparathyroidism Decreased GFR leads to reduced inorganic phosphate Decreased GFR leads to reduced inorganic phosphate

excretion and consequent phosphate retention excretion and consequent phosphate retention Retained phosphate has a direct stimulatory effect on PTH Retained phosphate has a direct stimulatory effect on PTH

synthesis and on cellular mass of the parathyroid glandssynthesis and on cellular mass of the parathyroid glands Retained phosphate also causes excessive production and Retained phosphate also causes excessive production and

secretion of PTH through lowering of ionized Ca2+ and by secretion of PTH through lowering of ionized Ca2+ and by suppression of calcitriol productionsuppression of calcitriol production

Reduced calcitriol production results both from decreased Reduced calcitriol production results both from decreased synthesis due to reduced kidney mass and from synthesis due to reduced kidney mass and from hyperphosphatemia. hyperphosphatemia. – Low calcitriol levels, in turn, lead to hyperparathyroidism via Low calcitriol levels, in turn, lead to hyperparathyroidism via

both direct and indirect mechanisms. Calcitriol is known to both direct and indirect mechanisms. Calcitriol is known to have a direct suppressive effect on PTH transcription and have a direct suppressive effect on PTH transcription and therefore reduced calcitriol in CRD causes elevated levels of therefore reduced calcitriol in CRD causes elevated levels of PTHPTH

– Reduced calcitriol leads to impaired Ca2+ absorption from the Reduced calcitriol leads to impaired Ca2+ absorption from the GI tract, thereby leading to hypocalcemia, which then GI tract, thereby leading to hypocalcemia, which then increases PTH secretion and production. increases PTH secretion and production.

Secondary HPTSecondary HPT Clinical presentationClinical presentation

– Usually asymptomaticUsually asymptomatic DiagnosisDiagnosis

– Elevated PTH in the setting of low or normal serum calcium is Elevated PTH in the setting of low or normal serum calcium is diagnosticdiagnostic

– If phosphorous is elevated, cause is renalIf phosphorous is elevated, cause is renal– If phosphorous is low, other causes of vit D deficiency should If phosphorous is low, other causes of vit D deficiency should

be soughtbe sought PreventionPrevention

– Vit D replacementVit D replacement– Phosphorus binders [Sevelamer]Phosphorus binders [Sevelamer]

TreatmentTreatment– MedicalMedical

Calcimimetic agentsCalcimimetic agents– SurgicalSurgical

Considered in cases of refractoryConsidered in cases of refractory severe hypercalcemia, severe severe hypercalcemia, severe bone disease, severe pruritis, bone disease, severe pruritis, calciphylaxis, severe myopathycalciphylaxis, severe myopathy

Tertiary HyperparathyroidismTertiary HyperparathyroidismTertiary hyperparathyroidism develops in patients with Tertiary hyperparathyroidism develops in patients with

long-standing secondary hyperparathyroidism, which long-standing secondary hyperparathyroidism, which stimulates the growth of an autonomous adenoma. A stimulates the growth of an autonomous adenoma. A clue to the diagnosis of tertiary hyperparathyroidism is clue to the diagnosis of tertiary hyperparathyroidism is intractable hypercalcemia and/or an inability to control intractable hypercalcemia and/or an inability to control osteomalacia despite vitamin D therapy.osteomalacia despite vitamin D therapy.

Surgical ReferralSurgical Referral- calcium- phosphate product > 70- calcium- phosphate product > 70- severe bone disease and pain- severe bone disease and pain -intractable pruritus-intractable pruritus- extensive soft tissue calcification with tumoral calcinosis - extensive soft tissue calcification with tumoral calcinosis -calciphylaxis-calciphylaxis

Lab AbnormalitiesLab Abnormalities

Primary HPTPrimary HPT– Increased serum calciumIncreased serum calcium– Phosphorus in low normal rangePhosphorus in low normal range– Urinary calcium elevatedUrinary calcium elevated

Secondary HPT (renal etiology)Secondary HPT (renal etiology)– Low or normal serum calciumLow or normal serum calcium– High phosphorusHigh phosphorus

Tertiary HPT (renal etiology)Tertiary HPT (renal etiology)– High calcium and phosphorusHigh calcium and phosphorus

Quiz #1Quiz #1

A 45 year old woman is referred to you for A 45 year old woman is referred to you for evaluation of elevated calcium and PTH evaluation of elevated calcium and PTH found on routine lab work. The PCP found on routine lab work. The PCP ordered a 24 hour urine collection and the ordered a 24 hour urine collection and the urinary calcium is less than 50 mg for 24 urinary calcium is less than 50 mg for 24 hrs. Next step?hrs. Next step?A. Order the mibi/schedule the surgeryA. Order the mibi/schedule the surgeryB. Consider estrogen replacement in this B. Consider estrogen replacement in this

perimenopausal womanperimenopausal womanC. Take a careful family historyC. Take a careful family historyD. Look for stigmata of MEN ID. Look for stigmata of MEN I

Quiz #2Quiz #2

You receive a hospital consult for You receive a hospital consult for “parathyroidectomy”. You look at the pts “parathyroidectomy”. You look at the pts labs and note elevated PTH, calcium and labs and note elevated PTH, calcium and phosphorus. phosphorus. A. Have primary team order a mibi before you A. Have primary team order a mibi before you

see the patientsee the patientB. Suspect MEN IIA and have the primary team B. Suspect MEN IIA and have the primary team

order ret-proto oncogene screeningorder ret-proto oncogene screeningC. Evaluate the pt in the dialysis unit with careful C. Evaluate the pt in the dialysis unit with careful

questioning as to symptoms of pruritis, skin questioning as to symptoms of pruritis, skin calcifications or necrosiscalcifications or necrosis

Quiz #3Quiz #3

Primary HPT:Primary HPT:A.A. Is more common in post-menopausal Is more common in post-menopausal

womenwomen

B.B. Is most likely due to a parathyroid Is most likely due to a parathyroid adenomaadenoma

C.C. Usually is discovered when the pt is Usually is discovered when the pt is “asymptomatic”“asymptomatic”

D.D. All of the aboveAll of the above

Quiz #4Quiz #4

Surgical candidacy for primary HPT Surgical candidacy for primary HPT includes:includes:

A.A. 24 hour urine calcium greater than 400 24 hour urine calcium greater than 400 mgmg

B.B. Age under 50Age under 50

C.C. Creatinine clearance decreased 30% Creatinine clearance decreased 30% when compared to age matched normswhen compared to age matched norms

D.D. All of the aboveAll of the above

Quiz #5Quiz #5

You are in endocrine multidisciplinary You are in endocrine multidisciplinary clinic presenting a patient. You are clinic presenting a patient. You are asked “What is the calcium-asked “What is the calcium-creatinine clearance ratio?”creatinine clearance ratio?”– You reply “ask an endorinologist”You reply “ask an endorinologist”– You ask “the calcium creatinine what?”You ask “the calcium creatinine what?”– You say “Let me just answer this page, You say “Let me just answer this page,

I’ll be right back” and you consult Dr. I’ll be right back” and you consult Dr. Quinn’s online textbookQuinn’s online textbook

Quiz #6Quiz #6 You have a patient with “asymptomatic” You have a patient with “asymptomatic”

primary HPT. You discuss surgery with primary HPT. You discuss surgery with her but she is very reluctant. You tell her her but she is very reluctant. You tell her that patients with primary HPT can be that patients with primary HPT can be followed medically and…followed medically and…

A.A. Her chance of dying from complications of Her chance of dying from complications of primary HPT in the next year are 50%primary HPT in the next year are 50%

B.B. She will need monthly serum calcium and 24 She will need monthly serum calcium and 24 hour urine collections to monitor her diseasehour urine collections to monitor her disease

C.C. Most patients with asymptomatic primary Most patients with asymptomatic primary HPT do not demonstrate progression of their HPT do not demonstrate progression of their disease over a ten year perioddisease over a ten year period