HyperparathyroidismHyperparathyroidism

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.

Parathyroid glands-Surgical anatomyParathyroid glands-Surgical anatomyEndocrine glands. Usually2 on each side i.e 4 in No(84%, Endocrine glands. Usually2 on each side i.e 4 in No(84%,

>4 in 13%, <4 in3%..>4 in 13%, <4 in3%..2 sup .glands: parathyroid IV, derived from 42 sup .glands: parathyroid IV, derived from 4thth pharyngeal pharyngeal

pouch.constant in position ,behind RLNpouch.constant in position ,behind RLN

2inf PG.variable in position, derived from 32inf PG.variable in position, derived from 3rdrd pharyngeal pouch, hence called parathyroid pharyngeal pouch, hence called parathyroid III. Usually lie ant. toRLN.III. Usually lie ant. toRLN.

Each gland: 5 to 7 mm(6X2X2 mm).Wt 40-Each gland: 5 to 7 mm(6X2X2 mm).Wt 40-50mg.yellowish-Brown firm gland which 50mg.yellowish-Brown firm gland which sinks in water unlike fat (Float)sinks in water unlike fat (Float)

Blood supply:Mostly from inf thyroid art.-Blood supply:Mostly from inf thyroid art.-entering a hilumlike structure,a featurethat entering a hilumlike structure,a featurethat differentiates it from fatdifferentiates it from fat

Venous drainage- ipsilat.to Sup,middle,inf TVVenous drainage- ipsilat.to Sup,middle,inf TV

HypercalcemiaHypercalcemiaI.HyperparatyhyroidismI.Hyperparatyhyroidism

-Primary hyperparathyroidism-Primary hyperparathyroidismTertiary HPTTertiary HPT

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

III. Endocrine diseases:III. Endocrine diseases:Hyperthyroidism.Addisonian crisis.pheochromocytomaHyperthyroidism.Addisonian crisis.pheochromocytoma

IV- Granulomatous diseases:Sarcoidosis.T.B.IV- Granulomatous diseases:Sarcoidosis.T.B.IV. Iatrogenic:IV. Iatrogenic:

Excessive intake of Vit D or calciumExcessive intake of Vit D or calcium-Rx with lithium-Rx with lithium-Thiazide diuretics-Thiazide diuretics

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

VI-Familial hypocalcuric hypercalcemiaVI-Familial hypocalcuric hypercalcemia-Milk-alkali syndrome-Milk-alkali syndrome

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

Primary HyperparathyroidismPrimary HyperparathyroidismPHPTPHPT

Incidence :0.1-0.3%. 1 case per 1000 men and 2-3 Incidence :0.1-0.3%. 1 case per 1000 men and 2-3 cases per 1000 women.25/100000 populationcases per 1000 women.25/100000 population– Incidence increases above age 40Incidence increases above age 40– Most patients with sporadic PHPTare Most patients with sporadic PHPTare

postmenopausal women with an average age of postmenopausal women with an average age of 55 years55 years

Etiology: a solitary parathyroid adenoma(83%)Etiology: a solitary parathyroid adenoma(83%) Multiple adenomas (6%)Multiple adenomas (6%) Hyperplasia 10%Hyperplasia 10% Carcinoma 1% Carcinoma 1%

Primary HPT: Clinical FeaturesPrimary HPT: Clinical Features Symptomatic:Symptomatic: Classical pentad of Classical pentad of

symptoms(Kid.stones,symptoms(Kid.stones, painful bones,abdominal painful bones,abdominal

groans,psychic moans,& fatigue groans,psychic moans,& fatigue overtones)overtones)– Osteitis fibrosa cysticaOsteitis fibrosa cystica– NephrolithiasisNephrolithiasis– Pathologic fracturesPathologic fractures– Neuromuscular diseaseNeuromuscular disease– Life-threatening hypercalcemiaLife-threatening hypercalcemia– DU.pancreatitisDU.pancreatitis

?Asymptomatic:Hypercalmic?Asymptomatic:Hypercalmic– Fatigue, muscle weakness & Fatigue, muscle weakness &

acheache– DepressionDepression– Polydipsia.PolyuriaPolydipsia.Polyuria– Anorexia,dyspepsia wt Anorexia,dyspepsia wt

loss.Constipationloss.Constipation– SOB.HT SOB.HT

Biochemical features of prim HPTBiochemical features of prim HPT

Serum tests Alteration

Calcium Increased

Intact PTH Increased(>0.5mg/L)

Phosphate

P Chloride

CL:PO4 (>33)

Alkaline phosphatase

Uric acid

N or (in the presence of bone disease)

N or

Acid-base status

Ca-:creatinine clearance ratio

Urine Test:24h urinary Ca

Mild hyperchloremic metabolic acidosis

>0.02(vs<0.01 in BFHH)

N or (>250mg/24h)

InvestigationsInvestigations

Intact PTH and chemistry panelIntact PTH and chemistry panel– PTH elevated (normally 0.15-1ng/ml)despite elevated serum calcium.PTH elevated (normally 0.15-1ng/ml)despite elevated serum calcium.

(fasting + no cuff on arm on sampling)(fasting + no cuff on arm on sampling)– Serum phosphate decreases. Alkaline phosphatase elevatedSerum phosphate decreases. Alkaline phosphatase elevated– 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 clearance ratio Values below 100mg/24 hours or a calcium creatinine clearance ratio

of <0.01 are suggestive of FHHof <0.01 are suggestive of FHH XR-Skull; salt pepper appearance.;Subperiosteal erosion of radial XR-Skull; salt pepper appearance.;Subperiosteal erosion of radial

side of middle phalanx.Osteitis fibrosa cystica.side of middle phalanx.Osteitis fibrosa cystica. 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 on….Ionized calcium versus serum calcium—the debate rages 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)])

Surgical CandidacySurgical Candidacy Symptomatic primary HPTSymptomatic primary HPT

– Serum calcium greater than 1mg/dL above the upper Serum calcium greater than 1mg/dL above the upper limit of the reference range(>11mg%)limit of the reference range(>11mg%)

– 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– Marked reduced Bone density Marked reduced Bone density – Age under 50Age under 50– -Urinary calculi-Urinary calculi– Neuromascular presentationNeuromascular presentation

general Considerations in Mx general Considerations in Mx

PRICIPLES OF Mx;PRICIPLES OF Mx;I-Clinically_I-Clinically_ 1-Do symptoms due to hypercalcemia Or no?t.Duration?.1-Do symptoms due to hypercalcemia Or no?t.Duration?. 2- symptoms related to malignant disease or not2- symptoms related to malignant disease or not Recent cough,wheeze,or hemoptysis—consider Bronchogenic Ca.Recent cough,wheeze,or hemoptysis—consider Bronchogenic Ca. Hematuria may suggest:hypernephroma, bladder Ca. or Renal stonesHematuria may suggest:hypernephroma, bladder Ca. or Renal stones 3-Conditions associated with HPT?.-Renal colic, PU,Pancreatitis,,HT,Gout.3-Conditions associated with HPT?.-Renal colic, PU,Pancreatitis,,HT,Gout. 4-Possible excess use of milk products,antacids,baking soda,or vitamins4-Possible excess use of milk products,antacids,baking soda,or vitamins II-Biochemically-LabII-Biochemically-LabHigh S. Calcium+S.Phosphate-----Suggest HPTHigh S. Calcium+S.Phosphate-----Suggest HPTHigh S. Calcium + Normal S. phosphate( in50% of HPT,& may also in patients High S. Calcium + Normal S. phosphate( in50% of HPT,& may also in patients

with Vit D intoxication,sarcoidosis,malig dis without metastasis& with Vit D intoxication,sarcoidosis,malig dis without metastasis& hyperthyroidismhyperthyroidism

S.Chloride: S. Phosphate ratio >33 suggestsHPTS.Chloride: S. Phosphate ratio >33 suggestsHPTMeasure S. Parathyroid hormone- low or normal in all causes of hypercalcemia Measure S. Parathyroid hormone- low or normal in all causes of hypercalcemia

other than Prim HPT or Benign familial hypocalcuric other than Prim HPT or Benign familial hypocalcuric hypercalcemia(BFhH).Chronic hypercalcemia+mildly elevated PTH level+ low hypercalcemia(BFhH).Chronic hypercalcemia+mildly elevated PTH level+ low urinary Calcium+family Hy of hypercalcemia esp.in childrenurinary Calcium+family Hy of hypercalcemia esp.in children

III-Localization-Usually required in persistent or recurrent HPTIII-Localization-Usually required in persistent or recurrent HPTUS-localize the tumors in 75%. &SESTAMBI scan in 85%..These studies localize in US-localize the tumors in 75%. &SESTAMBI scan in 85%..These studies localize in

35% of Hyperplasia35% of HyperplasiaExperienced surgeon can find tumors in 95 % without these tests in 1Experienced surgeon can find tumors in 95 % without these tests in 1 stst op. op.

IV-post-opIV-post-op Bone hunger-Bone hunger- In 24-48h-hypocalcemia’In 24-48h-hypocalcemia’ Mild oral Calcium+ active vit D3(one alpha-leo Vit D3-0.5μg Mild oral Calcium+ active vit D3(one alpha-leo Vit D3-0.5μg

bidbid Severe – I.V Calcium gluconate(10ml) slowly over 10mint or Severe – I.V Calcium gluconate(10ml) slowly over 10mint or

infusioninfusion

Pre-Operative Imaging-Pre-Operative Imaging-LocalizationLocalization

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-SPECT(single photone emission CT)Sestamibi-SPECT(single photone emission CT)– 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 (SippleMEN IIA (Sipple’’s Syndrome)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

Hypercalcemic crisisHypercalcemic crisisHypercalcemia (Ca. very high >12mg% +Hypercalcemia (Ca. very high >12mg% +

Acute:Acute: GIT symptoms; nausea, vomiting, abd. Pain,dehydration GIT symptoms; nausea, vomiting, abd. Pain,dehydration

NM;fatigue, M weaknessNM;fatigue, M weaknessCNS- confusion , decreased level of consciousnessCNS- confusion , decreased level of consciousness

2-Foeced diuresis (N/S + Lasix2-Foeced diuresis (N/S + Lasix 3- Mithramycin-25µg/kg/day IV for 3-4 days- inhibits 3- Mithramycin-25µg/kg/day IV for 3-4 days- inhibits

osteoclast .rapid onset in 12 hosteoclast .rapid onset in 12 h 4- Calcitonin 4 IU/kg SC/IM. Inhibits osteoclast onset of 4- Calcitonin 4 IU/kg SC/IM. Inhibits osteoclast onset of

action in hours , but short –livedaction in hours , but short –lived 5-Biphosphonates(pamidronate)- 60-90 mg IV over 4-24h. 5-Biphosphonates(pamidronate)- 60-90 mg IV over 4-24h.

Inhibits osteoclast rapid onset (2-3 days)Inhibits osteoclast rapid onset (2-3 days) 6-Gallium nitrate- 200mg/ m sq.BSA/d IV for 5 days. 6-Gallium nitrate- 200mg/ m sq.BSA/d IV for 5 days.

increases urinary calcium.Delayed onset of action(5-7days)increases urinary calcium.Delayed onset of action(5-7days) 7-Sterois Hydrocortisone 100mg IV /8h. Delayed onset (7-10 7-Sterois Hydrocortisone 100mg IV /8h. Delayed onset (7-10

days) .useful for hematologic malig., sarcoidosis, vit D days) .useful for hematologic malig., sarcoidosis, vit D intoxication. hyperthyroidism intoxication. hyperthyroidism