GOda Ellban

1. Diagnosis andDiagnosis and
Management ofManagement of
Parathyroid DiseaseParathyroid Disease
BYBY
PROF/ GOUDA ELLABBANPROF/ GOUDA ELLABBAN
FOM/SCUFOM/SCU
ellabbang@yahoo.comellabbang@yahoo.com

2. ObjectivesObjectives
 Review calcium homeostasisReview calcium homeostasis
 Understand parathyroid anatomy andUnderstand parathyroid anatomy and
histopathologyhistopathology
 Review embryo-anatomic relationships inReview embryo-anatomic relationships in
the central neckthe central neck
 Recognize the clinical features, diagnosisRecognize the clinical features, diagnosis
and surgical/medical management ofand surgical/medical management of
hyperparathyroidismhyperparathyroidism
 Understand the molecular basis ofUnderstand the molecular basis of
localization studieslocalization studies

3. CALCIUM HOMEOSTASIS ANDCALCIUM HOMEOSTASIS AND
PARATHYROID HORMONEPARATHYROID HORMONE
SECRETION AND REGULATIONSECRETION AND REGULATION
 Parathyroid hormone (PTH) containsParathyroid hormone (PTH) contains
84 amino acids84 amino acids
 Degradation into amino(N) andDegradation into amino(N) and
carboxyl(C)-terminal fragments.carboxyl(C)-terminal fragments.
 The N-terminal fragment biologicallyThe N-terminal fragment biologically
active and rapidly clearedactive and rapidly cleared
 C-terminal fragment is biologically inertC-terminal fragment is biologically inert
and cleared by the kidneyand cleared by the kidney

4. Continued….Continued….
 PTH release governed by serum ionizedPTH release governed by serum ionized
calcium levels.calcium levels.
 PTH secreted in response to decrease inPTH secreted in response to decrease in
serum-ionized calcium and inhibited by anserum-ionized calcium and inhibited by an
increase serum-ionized calcium.increase serum-ionized calcium.
 Target end organs: kidneys, skeletalTarget end organs: kidneys, skeletal
system, and intestine.system, and intestine.
 PTH binding to receptor sites results inPTH binding to receptor sites results in
cAMP 2cAMP 2ndnd
messenger system activation.messenger system activation.
 Half-life PTH few minutes.Half-life PTH few minutes.

5. Continued….Continued….

6. Etiology and PathogenesisEtiology and Pathogenesis
of Hyperparathyroidismof Hyperparathyroidism
 Parathyroid adenomas (PA) consideredParathyroid adenomas (PA) considered
monoclonal or oligoclonal neoplasms.monoclonal or oligoclonal neoplasms.
 Propagation through clonal expansion ofPropagation through clonal expansion of
cells with altered sensitivity to calcium.cells with altered sensitivity to calcium.
 PRAD1 implicated in only some PA.PRAD1 implicated in only some PA.
 Another mechanism involves alternation inAnother mechanism involves alternation in
tumor suppressor gene expression.tumor suppressor gene expression.

7. Continued….Continued….

8. Continued….Continued….

9. Parathyroid Anatomy andParathyroid Anatomy and
Histopathology: TheHistopathology: The
Normal Parathyroid GlandNormal Parathyroid Gland
 Supernumerary fifth parathyroid foundSupernumerary fifth parathyroid found
between 0.7%-5.8% patientsbetween 0.7%-5.8% patients
 55thth
glands found in the mediastinumglands found in the mediastinum
(thymus or related to the aortic arch),(thymus or related to the aortic arch),
thyrothymic tractthyrothymic tract

10. Parathyroid GlandParathyroid Gland
LocationLocation
 80% of superior parathyroid glands found at80% of superior parathyroid glands found at
the cricothyroid junction ~1 cm cranial tothe cricothyroid junction ~1 cm cranial to
juxtaposition of RLN & ITA.juxtaposition of RLN & ITA.
 Inferior parathyroid glands (IPG) variable inInferior parathyroid glands (IPG) variable in
location.location.
 61% of (IPG) near the lower pole of the61% of (IPG) near the lower pole of the
thyroid gland and 26% in thyrothymicthyroid gland and 26% in thyrothymic
ligament.ligament.
 Incidence of intrathyroidal parathyroidIncidence of intrathyroidal parathyroid
glands ~0.5% to 3%.glands ~0.5% to 3%.

11. EmbryologyEmbryology

12. MorphologicMorphologic
Characteristics ofCharacteristics of
Parathyroid GlandsParathyroid Glands
 Shape-oval, bean, or teardropShape-oval, bean, or teardrop
appearance or flat shape whenappearance or flat shape when
juxtaposed to thyroid gland.juxtaposed to thyroid gland.
 Color-yellowish brown to reddishColor-yellowish brown to reddish
brown in normal parathyroid glandsbrown in normal parathyroid glands
and lighter gray tone in pathologicaland lighter gray tone in pathological
states.states.

13. Vascular Anatomy of theVascular Anatomy of the
Parathyroid GlandsParathyroid Glands
 Normal parathyroid glands most commonlyNormal parathyroid glands most commonly
are supplied by a single dominant arteryare supplied by a single dominant artery
(80%).(80%).
 The length of the dominant artery supplyingThe length of the dominant artery supplying
glands vary from 1 to 40 mm.glands vary from 1 to 40 mm.
 ITA is dominant blood supply to bothITA is dominant blood supply to both
superior & inferior parathyroid glands mostsuperior & inferior parathyroid glands most
of the time.of the time.

14. Histopathology of theHistopathology of the
Parathyroid GlandsParathyroid Glands
 Parathyroid gland composed of chief cells,Parathyroid gland composed of chief cells,
oxyphilic cells and intermediate cellsoxyphilic cells and intermediate cells
 Solitary parathyroid adenoma ~80%-85% ofSolitary parathyroid adenoma ~80%-85% of
patients with primary hyperparathyroidismpatients with primary hyperparathyroidism
 Variations in parathyroid adenoma includesVariations in parathyroid adenoma includes
other subtypes (oncocytic adenoma,other subtypes (oncocytic adenoma,
lipoadenoma, large clear cell adenoma,lipoadenoma, large clear cell adenoma,
water-clear cell adenoma, and atypicalwater-clear cell adenoma, and atypical
adenoma).adenoma).

15. Continued….Continued….
 Primary parathyroid hyperplasia-proliferationPrimary parathyroid hyperplasia-proliferation
of parenchymal cells with increase in weightof parenchymal cells with increase in weight
in multiple glands with absence of stimulusin multiple glands with absence of stimulus
for parathyroid hormone secretion.for parathyroid hormone secretion.
 Two types of parathyroid hyperplasia areTwo types of parathyroid hyperplasia are
seen: the common chief cell hyperplasiaseen: the common chief cell hyperplasia
and the rare water cell or clear celland the rare water cell or clear cell
hyperplasia.hyperplasia.

16. Continued….Continued….
 Parathyroid carcinoma (PC) ~0.1% to 5.0% casesParathyroid carcinoma (PC) ~0.1% to 5.0% cases
of primary hyperparathyroidism.of primary hyperparathyroidism.
 PC tend to be large tumors, (30% to 50% palpablePC tend to be large tumors, (30% to 50% palpable
presentation).presentation).
 May measure up to 6 cm in diameter, mean ~3 cm.May measure up to 6 cm in diameter, mean ~3 cm.
 Lesion adheres to surrounding tissues including softLesion adheres to surrounding tissues including soft
tissues of the neck (thyroid gland, strap muscles,tissues of the neck (thyroid gland, strap muscles,
trachea & recurrent laryngeal nerve).trachea & recurrent laryngeal nerve).
 Regional metastasis rare.Regional metastasis rare.
 Pulmonary metastasis most common distantPulmonary metastasis most common distant
metastasis site.metastasis site.

17. Continued….Continued….
 PC tends to be an indolent tumor.PC tends to be an indolent tumor.
 Multiple recurrences after resectionMultiple recurrences after resection
common and may occur over a 15- tocommon and may occur over a 15- to
20-year period.20-year period.
 Death results from from effects ofDeath results from from effects of
excessive PTH secretion andexcessive PTH secretion and
uncontrolled hypercalcemia ratheruncontrolled hypercalcemia rather
than growth of the tumor mass.than growth of the tumor mass.

18. Clinical features PrimaryClinical features Primary
Hyperparathyroidism (PH)Hyperparathyroidism (PH)
 Incidence 27 cases annually perIncidence 27 cases annually per
100,000100,000
 Prevalence PH general populationPrevalence PH general population
0.1%-0.3%0.1%-0.3%
 Prevalence women >60 years morePrevalence women >60 years more
than 1%than 1%

19. CALCIUM HOMEOSTASIS ANDCALCIUM HOMEOSTASIS AND
PARATHYROID HORMONEPARATHYROID HORMONE
SECRETION AND REGULATIONSECRETION AND REGULATION

20. Continued….Continued….
 Osteitis fibrosis cysticaOsteitis fibrosis cystica
 NephrolithiasisNephrolithiasis
 Hypercalcemic crisisHypercalcemic crisis
 Osteitis fibrosis occurs ~1% of patientsOsteitis fibrosis occurs ~1% of patients
 Renal stones ~10%-20% of patients have renalRenal stones ~10%-20% of patients have renal
stones.stones.
 Nonspecific symptoms: malaise, fatigue,Nonspecific symptoms: malaise, fatigue,
depression, sleep disturbance, weight loss,depression, sleep disturbance, weight loss,
abdominal pains, constipation, vagueabdominal pains, constipation, vague
musculoskeletal pains in the extremities, andmusculoskeletal pains in the extremities, and
muscular weaknessmuscular weakness

21. Continued….Continued….
 Kidney/Urinary Tract:Kidney/Urinary Tract: 4% with nephrolithiasis4% with nephrolithiasis
and nephrocalcinosis (stone composition, calciumand nephrocalcinosis (stone composition, calcium
oxylate or calcium phosphate). Sx of urolithiasis:oxylate or calcium phosphate). Sx of urolithiasis:
renal colic, hematuria, pyuria.renal colic, hematuria, pyuria.
 Skeletal System:Skeletal System:
1.1. Osteitis fibrosis cystica (rare)Osteitis fibrosis cystica (rare)
2.2. Subperiosteal erosion of the distal phalangesSubperiosteal erosion of the distal phalanges
3.3. Bone wasting and softeningBone wasting and softening
4.4. Chondrocalcinosis as a result of bone demineralizationChondrocalcinosis as a result of bone demineralization
5.5. Bone painBone pain
6.6. Pathologic fracturePathologic fracture
7.7. Cystic bone changesCystic bone changes
8.8. Bone loss: cortical bone sites sparing trabecular boneBone loss: cortical bone sites sparing trabecular bone

22. Continued….Continued….
 NeuromuscularNeuromuscular ::
1.1. Muscle weakness, (proximal extremity muscle groupsMuscle weakness, (proximal extremity muscle groups
with fatigue and malaise)with fatigue and malaise)
2.2. Neuromuscular syndrome improves in 80%-90% ofNeuromuscular syndrome improves in 80%-90% of
patients.patients.
 Neurologic:Neurologic:
1.1. Depression, nervousness, and cognitive dysfunctionDepression, nervousness, and cognitive dysfunction
2.2. Deafness, dysphagia, and dysosmiaDeafness, dysphagia, and dysosmia
3.3. Many psychiatric symptoms improve afterMany psychiatric symptoms improve after
parathyroidectomy. Fifty percent of patients withparathyroidectomy. Fifty percent of patients with
depression or anxiety, or both will improve after surgery.depression or anxiety, or both will improve after surgery.

23. Continued….Continued….
 CardiovascularCardiovascular
1.1. Hypertension (50% of patients)Hypertension (50% of patients)
2.2. Parathyroidectomy results in a reduction in BP inParathyroidectomy results in a reduction in BP in
minority of patients.minority of patients.
 Hypercalcemic syndromeHypercalcemic syndrome
1.1. polydipsia and polyuria, anorexia, vomiting, constipation,polydipsia and polyuria, anorexia, vomiting, constipation,
muscle weakness and fatigue, mental status changes.muscle weakness and fatigue, mental status changes.
2.2. Metastatic calcifications at the corneal/scleral junction,Metastatic calcifications at the corneal/scleral junction,
so-called band keratopathyso-called band keratopathy
3.3. Shortened Q-T interval on electrocardiogram, ectopicShortened Q-T interval on electrocardiogram, ectopic
calcium deposits, and pruritus.calcium deposits, and pruritus.

24. Continued….Continued….
 Band KeratopathyBand Keratopathy

25. Continued….Continued….
 Diagnosis:Diagnosis:
1.1. Elevated serum CaElevated serum Ca
2.2. Elevated PTH (suppressed in PTH-rp inducedElevated PTH (suppressed in PTH-rp induced
hypercalcemia)hypercalcemia)
3.3. Other:Other:
 AlbuminAlbumin
 PhosphorousPhosphorous
 BUN/CrBUN/Cr
 24-hour urine Ca (r/o FHH)24-hour urine Ca (r/o FHH)
 Bone Mineral DensityBone Mineral Density

26. Localization StudiesLocalization Studies
 Noninvasive preoperative methods Noninvasive preoperative methods
1.1. Ultrasonography Ultrasonography
2.2. Radioiodine or technetium thyroid scan Radioiodine or technetium thyroid scan
3.3. Thallium-technetium scintigraphy Thallium-technetium scintigraphy
4.4. Technetium-99m sestamibi scintigraphy Technetium-99m sestamibi scintigraphy
5.5. Computed tomography scan Computed tomography scan
6.6. Magnetic resonance imagingMagnetic resonance imaging
 Invasive preoperative methods Invasive preoperative methods
1.1. Fine-needle aspiration Fine-needle aspiration
2.2. Selective arteriography or digital subtraction angiography Selective arteriography or digital subtraction angiography
3.3. Selective venous sampling for parathyroid hormone assay Selective venous sampling for parathyroid hormone assay
4.4. Arterial injection of selenium-ethionineArterial injection of selenium-ethionine
 Intraoperative MethodsIntraoperative Methods
1.1. Intraoperative ultrasonography Intraoperative ultrasonography
2.2. Toluidine blue or methylene blue Toluidine blue or methylene blue
3.3. Urinary adenosine monophosphate Urinary adenosine monophosphate
4.4. Quick parathyroid hormone intraoperativeQuick parathyroid hormone intraoperative

27. Sestamibi-Technetium 99mSestamibi-Technetium 99m
ScintographyScintography
 Sestamibi taken up mitochondria of parathyroid cells greaterSestamibi taken up mitochondria of parathyroid cells greater
than surrounding parenchyma.than surrounding parenchyma.
 Inject 20 to 25 millicuries of technetium-99m sestamibi.Inject 20 to 25 millicuries of technetium-99m sestamibi.
Images obtained at 10-15 minutes then 2-3 hours after theImages obtained at 10-15 minutes then 2-3 hours after the
injection.injection.
 Late phase preferable for detecting parathyroid adenomas, asLate phase preferable for detecting parathyroid adenomas, as
thyroid nodules clear uptake faster than do parathyroidthyroid nodules clear uptake faster than do parathyroid
neoplasms.neoplasms.
 Sensitivity (solitary adenoma) ~100%, Specificity ~90%.Sensitivity (solitary adenoma) ~100%, Specificity ~90%.
 False-positive:False-positive:
1.1. Solid thyroid nodules (adenomas)Solid thyroid nodules (adenomas)
2.2. Hurthle cell carcinomaHurthle cell carcinoma
3.3. Malignant thyroid lymph node metastasesMalignant thyroid lymph node metastases
4.4. No false-positive with cystic lesions of the thyroid glandNo false-positive with cystic lesions of the thyroid gland

28. Continued….Continued….
 False-negativesFalse-negatives
1.1. Smaller parathyroid adenoma size.Smaller parathyroid adenoma size.
2.2. Suboptimal dosing of technetium-99mSuboptimal dosing of technetium-99m
sestamibi.sestamibi.

29. Continued….Continued….
 Four gland hyperplasiaFour gland hyperplasia

30. Continued….Continued….
 Double adenomaDouble adenoma

31. Medical ManagementMedical Management
 Intravascular volume expansion + loopIntravascular volume expansion + loop
diuretics (avoid thiazide diuretics)diuretics (avoid thiazide diuretics)
 BisphosphonatesBisphosphonates
 CalcitoninCalcitonin
 PlicamycinPlicamycin
 Estrogens therapyEstrogens therapy
 Oral phosphate saltsOral phosphate salts
 Calcimimetic agents (investigational drug R-Calcimimetic agents (investigational drug R-
568)568)

32. Case 1Case 1
 65 y.o. male with history of a left65 y.o. male with history of a left
thyroid mass underwent, FNA atypicalthyroid mass underwent, FNA atypical
follicular lesion. Patient underwent L.follicular lesion. Patient underwent L.
thyroid lobectomy with final diagnosisthyroid lobectomy with final diagnosis
of follicular adenoma. Patient hadof follicular adenoma. Patient had
been noted in past to havebeen noted in past to have
asymptomatic hypercalcemia. PTHasymptomatic hypercalcemia. PTH
126, 24-hour urine calcium 380mg,126, 24-hour urine calcium 380mg,
Ionized Ca 1.4Ionized Ca 1.4

33. Continued….Continued….
 Tc-99mTc-99m
SestamibiSestamibi
suggestedsuggested
parathyroidparathyroid
adenoma in Radenoma in R
inferior pole ofinferior pole of
thyroid gland.thyroid gland.

34. Continued….Continued….
 Patient taken to OR for MIRP using aPatient taken to OR for MIRP using a
Neoprobe.Neoprobe.

35. Continued….Continued….
 664 mg right superior parathyroid664 mg right superior parathyroid
gland identifiedgland identified
 PTH decreased from 126 to 15PTH decreased from 126 to 15

36. Surgical ManagementSurgical Management
 Clinical indicators for surgery*Clinical indicators for surgery*
1.1. Serum calcium is >1.0 mg/dL above the upper limitSerum calcium is >1.0 mg/dL above the upper limit
of normal.of normal.
2.2. Creatinine clearance is reduced >30% for age inCreatinine clearance is reduced >30% for age in
the absence of another cause.the absence of another cause.
3.3. Twenty-four hour urinary calcium is >400 mg/dL.Twenty-four hour urinary calcium is >400 mg/dL.
4.4. Patients are younger than 50 years of age.Patients are younger than 50 years of age.
5.5. Bone mineral density measurement at the lumbarBone mineral density measurement at the lumbar
spine, hip, or distal radius is reduced >2.5 standardspine, hip, or distal radius is reduced >2.5 standard
deviations (by T score).deviations (by T score).
6.6. Patients request surgery, or patients are unsuitablePatients request surgery, or patients are unsuitable
for long-term surveillance.for long-term surveillance.
*Consensus conference held by the National Institutes of Health in 2002

37. Continued….Continued….
 AdenomaAdenoma
1.1. Directed unilateral cervicalDirected unilateral cervical
exploration.exploration.
2.2. Curative in >95% of patientsCurative in >95% of patients
3.3. Preoperative localization withPreoperative localization with
technetium-99m sestamibi + IOPTHtechnetium-99m sestamibi + IOPTH

38. Continued….Continued….
 MEN 1MEN 1
1.1. Subtotal vs. total with autotransplantation.Subtotal vs. total with autotransplantation.
 Men 2a-Men 2a-
1.1. 100% cure rate with no recurrences100% cure rate with no recurrences
whether total parathyroidectomy,whether total parathyroidectomy,
subtotal parathyroidectomy, or excisionsubtotal parathyroidectomy, or excision
of enlarged glands performed.of enlarged glands performed.
2.2. R/O pheochromocytoma prior to OR tripR/O pheochromocytoma prior to OR trip
(hypertensive crisis).(hypertensive crisis).

39. Continued….Continued….
 Non-MEN familialNon-MEN familial
hyperparathyroidism (NMFH).hyperparathyroidism (NMFH).
1.1. Subtotal or total (autotransplant) withSubtotal or total (autotransplant) with
bilateral cervical thymectomy.bilateral cervical thymectomy.
 Familial neonatalFamilial neonatal
hyperparathyroidism.hyperparathyroidism.
1.1. Total (autotransplant) + bilateralTotal (autotransplant) + bilateral
transcervical thymectomytranscervical thymectomy

40. Continued….Continued….
 Renal failure-inducedRenal failure-induced
hyperparathyroidism.hyperparathyroidism.
1.1. Subtotal vs. total parathyroidectomy (autotransplant)Subtotal vs. total parathyroidectomy (autotransplant)
with or without cryopreservation.with or without cryopreservation.
 Parathyroid CarcinomaParathyroid Carcinoma
1.1. en bloc resection of the tumor and areas of potentialen bloc resection of the tumor and areas of potential
local invasion and/or regional metastasis (ipsilaterallocal invasion and/or regional metastasis (ipsilateral
central neck contents including the thyroid lobe andcentral neck contents including the thyroid lobe and
tracheoesophageal soft tissues, lymphatics, andtracheoesophageal soft tissues, lymphatics, and
resection of soft tissues within the superior anteriorresection of soft tissues within the superior anterior
mediastinum)mediastinum)
2.2. RLN, esophageal wall, or strap muscles may requireRLN, esophageal wall, or strap muscles may require
sacrifice if the tumor adheres to them.sacrifice if the tumor adheres to them.
3.3. Not enough data to recommend for or againstNot enough data to recommend for or against
chemotherapy or RT.chemotherapy or RT.

41. Continued….Continued….
 MIRPMIRP
1.1. Preoperative administration of technetium 99m sestamibiPreoperative administration of technetium 99m sestamibi
before operation + intraoperative hand-held gamma probe.before operation + intraoperative hand-held gamma probe.
2.2. Advantages:Advantages:
1.1. Improved patient comfort postoperatively.Improved patient comfort postoperatively.
2.2. Performance of ambulatory procedures.Performance of ambulatory procedures.
3.3. Reduced cost.Reduced cost.
4.4. Avoidance of general anesthetic.Avoidance of general anesthetic.
3.3. Disadvantages:Disadvantages:
1.1. Potential for conversion to bilateral dissection in event of failedPotential for conversion to bilateral dissection in event of failed
exploration.exploration.
2.2. Patient anxiety when conversion needed (general anesthesia).Patient anxiety when conversion needed (general anesthesia).

42. ConclusionConclusion
 No substitute for strong foundationNo substitute for strong foundation
surgical embryology, anatomy, andsurgical embryology, anatomy, and
technique for approaching parathyroidtechnique for approaching parathyroid
disease.disease.

43. BibliographyBibliography
 Cummings Otolaryngology Head andCummings Otolaryngology Head and
Neck Surgery. 2005.Neck Surgery. 2005.
 Rosen F., Pou A.,Rosen F., Pou A., ParathyroidParathyroid
Disease. March 2002Disease. March 2002. UTMB site. UTMB site
 http://www.mrcophth.com/corneacommonchttp://www.mrcophth.com/corneacommonc
(Image-Band Keratopathy)(Image-Band Keratopathy)