PARATHYROİD

DISEASE
Prof.Dr.Yusuf Bükey
Anatomy
Anatomy
Anatomy / Embryology
 Parathyroid Anatomy and Histopathology:
The Normal Parathyroid Gland

 Supernumerary fifth parathyroid found between

0.7%-5.8% patients
 5th glands found in the mediastinum (thymus or
related to the aortic arch), thyrothymic tract
 PATHOLOGY
 HYPERPARATHYROIDISM


1 : 1,000 prevalence

 F:M 2:1

 Usually mild / asymptomatic

 Histopathology of the Parathyroid Glands

 Parathyroid gland composed of chief cells, oxyphilic cells

and intermediate cells
 Solitary parathyroid adenoma ~80%-85% of patients with
primary hyperparathyroidism
 Variations in parathyroid adenoma includes other
subtypes (oncocytic adenoma, lipoadenoma, large clear
cell adenoma, water-clear cell adenoma, and atypical
adenoma).
Ob P1- parathyroid glands and the physiology of calcium hemostasis.

 Synthesize and secret parathyroid hormone,

which along with vitamin D maintains calcium
hemostasis.

Calcium PTH

Bone resorption, Renal resorption

urine phosphorus
 Parathyroids
Ca++
-
PTH
-

GI tract
1,25D

Ca++ Bone
a b s or b
Kidney ↑ Ca r e

1,25D
 Calcium Metabolism
 Intestine Bone kidney (2.1-2.6 mmol/l)
 97% of reservoir in bone, chronic regulation.
 Kidney involved in minute to minute flux.Filters
8000mg daily.
 Net intestinal absorption is 200mg daily..
 If long term calcium losses exceed net calcium
absorption the deficit is resorbed from bone
leading to demineralisation.
 Calcium Metabolism - PTH
 Parathyroid Hormone (PTH), 84 AA
structure. Secreted from parathyroid gland
in response to hypocalcemia.
 Amino terminal (1-34 AA) contains the
biological activity.
 PTH acts on receptors in target tissues
leading to stimulation of adenylaye
cyclase activity.
 Calcium Metabolism- Vitamin D
 Vitamin D formed in skin(D3 or cholecalciferol) by uv
light. Major source of vitamin D (90%). Also present in
diet. This is the inert form
 Hydroxylated in the liver to 25-OH-VitD.
 Renal hydroxylation to 1,25 dihydroxy vitamin D (very
active metabolite). Renal also produces 24,25 dihydroxy
vit D. (inactive)
 Calcium deficiency leads to 1,25 Dit D production
 1,25 vit D acts on small intestine to increase calcium
absorption.
 Also acts on bone to cause resorption.
 Effects of PTH
 Increases calcium reabsorption by the
kidney.
 Decreases phosphate reabsorption by the
kidney.
 Increases osteoclastic bone resorption.
Three forms of calcium in serum
 Ionised (physiological form).
 Protein-bound (50%), mainly to albumin
 Complexed to citrate and phosphate(1-
2%).
 Causes of Hypercalcaemia
 COMMON (97%) of  LESS COMMON
all cases  Familial benign
 Primary hypercalcaemia
Hyperparathyroidism (FBH)
 Malignancy  Sarcoidosis
 Thyrotoxicosis
 Vitamin D poisoning
 Acute renal failure
 Causes of Hypercalcemia-RARE

 Immobilisation
 VIPomas
 Tuberculosis
 Milk-alkali syndrome
 Addison’s Disease
 Lithium
 Thiazide diuretics
 Parenteral feeding
 List the causes, symptoms, and signs of hypercalcemia.

 Stones
 Nephrolithiasis
 Bones
 Painful resorption of bone
 Moans and Psychatric overtones

Fatigue, depression, confusion
 Abdominal groans
 Peptic ulcer and pancreatitis
 Symptoms
 Tiredness and lethargy
 Proximal muscle weakness
 Polyuria,
nocturia and thirst
 Nausea Vomiting and constipation
 Depression, psychosis and impaired
consciousness.
SIGNS AND SYMPTOMS
OF HYPERCALCEMIA
CNS
Lethargy, drowsiness
Depression
Psychosis
Stupor, coma
Neuromuscular
Weakness
Proximal muscle weakness
Hypotonia
SIGNS AND SYMPTOMS OF
HYPERCALCEMIA

 Cardiovascular
 HTN

Arrhythmia
 Short QT

 Renal

Polyuria and polydipsia
volume depletion
 Renal stones

Nephrocalcinosis
SIGNS AND SYMPTOMS OF
HYPERCALCEMIA

 Musculoskeletal

Myalgias and arthralgias
 Metastatic calcifications

− Ca-PO4 product > 70

 Bone
 Osteitis fibrosis cystica

 Osteoporosis

 Fracture
SIGNS AND SYMPTOMS
OF HYPERCALCEMIA

GI tract
Constipation
Anorexia, N/V
Dyspepsia, PUD
Pancreatitis
 Know the difference between 1°, 2°, 4°
hyperparathyroidism.

 Primary Hyperparathyroidism
PTH calcium (normal renal function)
83% parathyroid adenoma, 15% parathyroid

hyperplasia, carcinoma is rare 1-2%

 Secondary Hyperparathyroidism
poor renal function calcium, PO4 PTH
normal Ca
 Tertiary Hyperparathyroidism
Hyperplastic parathyroids from chronic
stimulation continue post renal transplant
 Primary HPT
 500 cases/million
 More common in females
 Incidence increases with
age
 Autonomous production of PTH
 Benign Adenoma
 Asymptomatic pick-up.
 Hyperparathyroidism in other syndromes
(RARE)
 MEN Type 1 (Parathyroid adenoma, Pituitary
adenoma, and pancreatic islet cell tumours).
 MEN Type 2 (Parathyroid adenoma, medullary
thyroid carcinoma and phaeochromocytoma)
 Discuss ddx of a paitent with hypercalcemia.
 Hyperparathyroidism
 Malignancy

Hematologic
 PTHrP producer
 Hyperthyroidsm
 Multiple myeloma
 Sarcoidosis
 Milk-alkili syndrome
 Vit D or A intoxication
 Paget’s disease
 Immobilization
 Thiazide diuretics
 Addisonian Crisis
 Familial hypocalcuric
hypocalcemia
 Neonatal severe
hyperparathyroidism.
 HYPERCALCEMIA
DIFFERENTIAL DIAGNOSIS

 Primary hyperparathyroidism
 Hypercalcemia of malignancy
 Familial hypocalcuric hypercalcemia
 Granulomatous disease
 Endocrinopathies
 Drugs
 Immobilization
 DISEASES ASSOCIATED WITH
HYPERCALCEMIA

Primary Hyperparathyroidism 111 (54%)

Malignant Disease 72 (35%)

Unknown 12 ( 6%)

Other Causes 12 ( 6%)

TOTAL 207 (100%)

ETIOLOGY OF HYPERCALCEMIA

 Primary hyperparathyroidism

Most common etiology in outpatients
 1 in 500 to 1 in 1000

Most common in 6th decade

Women > men, 3:2 ratio

Many patients found on routine
screening with minimal symptoms
 ETIOLOGY OF HYPERCALCEMIA

 Primary
hyperparathyroidism

80% due to solitary
adenoma

4 gland hyperplasia
− Association with
MEN I and MEN II A
 5% are carcinoma
ETIOLOGY OF HYPERCALCEMIA

 Primary
hyperparathyroidism
 Labs - ↑ Ca ++, ↓ PO
4

↑ PTH
↑ urinary calcium
excretion
 ETIOLOGY OF HYPERCALCEMIA
 Hypercalcemia of malignancy
 Humoral hypercalcemia of malignancy

– Mediated by PTH-RP
– Most often seen in solid tumors
 Lung CA - squamous cell,

adenocarcinoma, large cell

 Breast CA

 Squamous cell CA of head and neck or

female repro tract

 Renal cell CA

– Not associated with bone mets

– Labs - ↑ Ca ++, ↓ PTH, ↑ PTHrP
 ETIOLOGY OF HYPERCALCEMIA
 Hypercalcemia of malignancy

Local osteolytic bone metastasis
• Hematologic malignancies -
multiple myeloma
• May be seen with breast CA
• Local release of osteoclast
activating cytokines
• Labs - ↑ Ca ++, ↓ PTH and
PTH-rP
ETIOLOGY OF HYPERCALCEMIA
 Familial hypocalcuric hypercalcemia
 Autosomal dominant syndrome of

asymptomatic hypercalcemia
 Must be ruled out before sending

patient to surgery for primary HPTH

 Due to defect in calcium receptor

 Diagnose by measuring

calcium/creatinine clearance (CaU/CrU

X CrS/CaS)
– HPTH > 0.03
– FHH < 0.01
 ETIOLOGY OF HYPERCALCEMIA
 Granulomatous disease
 Increased formation of 1,25D within granulomas

– Sarcoidosis
– TB
– Eosinophilic granuloma
– Histo, cocci, candida
– Lymphoma
 Hypercalcuria preceeds hypercalcemia


Labs - ↑ Ca ++, ↑ 1,25D, normal 25D
↓ PTH, ↑ ↑ urinary calcium excretion
ETIOLOGY OF HYPERCALCEMIA
 Endocrinopathies
 Hyperthyroidism

– Direct effect to increase bone resorption

 Adrenal insufficiency -

– Volume contraction vs no glucocorticoids

to oppose 1,25D action in gut
 Pheochromocytoma

– Volume contraction
– Changes in PTH set point
– Associated with MEN 2A
ETIOLOGY OF HYPERCALCEMIA
 Drugs
 Vitamin D or A intoxication


Thiazides - decrease urinary Ca excretion
by potentiation of PTH action in kidney
 Lithium - increased set point for inhibition

of PTH secretion
 Milk-alkali syndrome

– Associated with use of large doses of

calcium carbonate
ETIOLOGY OF HYPERCALCEMIA

 Immobilization
– Weight bearing is required for normal
bone remodelling
– Prolonged bedrest results in increased
osteoclastic resorption and decreased
bone formation
– Usually not seen with normal renal
function. Renal insufficiency or volume
depletion precedes development of
hypercalcemia
– Labs - ↑ Ca ++, ↓ PTH, normal 25-
hydroxy and 1,25 dihydroxyvitamin D
 Hypercalcemia

intact PTH

Elevated Suppressed Known malignancy

25(OH)vitamin D and 1,25(OH)

2
vitamin D
Fractional excretion calcium

Normal to low 25-vit D High 25-vit D Normal 25-vit D

Low High High 1,25-vit D and 1,25-vit D
and 1,25-vit D
< 0.01 > 0.03

Granulomatous
disease Malignancy
Familial hypocalcuric Primary Vitamin D Endocrine causes
or lymphoma intoxication Drugs
hypercalcemia hyperparathyroidism Immobilization
 Localization Studies
 Noninvasive preoperative methods
1. Ultrasonography
2. Radioiodine or technetium thyroid scan
3. Thallium-technetium scintigraphy
4. Technetium-99m sestamibi scintigraphy
5. Computed tomography scan
6. Magnetic resonance imaging
 Invasive preoperative methods
1. Fine-needle aspiration
2. Selective arteriography or digital subtraction angiography
3. Selective venous sampling for parathyroid hormone assay
4. Arterial injection of selenium-ethionine
 Intraoperative Methods
1. Intraoperative ultrasonography
2. Toluidine blue or methylene blue
3. Urinary adenosine monophosphate
4. Quick parathyroid hormone intraoperative
 Sestamibi-Technetium 99m
Scintography
 Sestamibi taken up mitochondria of parathyroid cells greater than
surrounding parenchyma.
 Inject 20 to 25 millicuries of technetium-99m sestamibi. Images
obtained at 10-15 minutes then 2-3 hours after the injection.
 Late phase preferable for detecting parathyroid adenomas, as
thyroid nodules clear uptake faster than do parathyroid neoplasms.
 Sensitivity (solitary adenoma) ~100%, Specificity ~90%.
 False-positive:
1. Solid thyroid nodules (adenomas)
2. Hurthle cell carcinoma
3. Malignant thyroid lymph node metastases
4. No false-positive with cystic lesions of the thyroid gland
 Continued….

 Tc-99m
Sestamibi
suggested
parathyroid
adenoma in R
inferior pole of
thyroid gland.
 Primary HPT - Diagnosis
 Persistent Hypercalcaemia.
 Low serum phosphate.
 High normal or elevated PTH
concentration.
 24h urinary Calcium excretion
 Sestemebi scan
 Indications for surgery
 Nephrolithiasis, bone disease, and
neuromuscular symptoms respond well to
surgery.
 Primary hyperparathyroidism due to adenoma is
cured surgically by excision of the adenoma. All
four glands must be identified though!
 Primary hyperparathyriodism due to parathyroid
hyperplasia is treated with subtotal
parathyroidectomy (3 1/2) or total
parathyroidectomy with autotranspantation into
the arm.
 Surgical indications for
asymptomatic hyperparathyroidism
 On initial evaluation  Following asymptomatic
 Markedly elevated CA pt
 Pt becomes symptomatic

Hx of life threatening  Ca 1-1.6 mg/100 ml above
hypercalcemia (??) normal

Reduced Cr CL.  Nephrolithiasis
 Nephrolithiasis  Decline in bone mass
 Markedly elevated
 Neuro or psych problems
24hr U Ca
 Pt desire to fix.
 Substantially reduced
bone mass
 HYPERCALCEMIA
TREATMENT

 Acute treatment for any etiology


Volume repletion with NS to increase
Ca++ filtration
 Can add lasix (promotes calcium

excretion) when volume replete

 More long term therapy is dependent on
the etiology
 TREATMENT OF HYPERCALCEMIA
GENERAL PRINCIPLES

 Virtually all patients with severe and

symptomatic hypercalcemia will be volume
depleted. Volume replacement should be started
first.
 Acute therapy of hypercalcemia is usually
effective. Long term therapy is more
problematic.
TREATMENTS FOR HYPERCALCEMIA

GENERAL SPECIFIC
Vol. Expansion (saline) I.V. Pamidronate
Diuresis (Lasix) I.V. Zoledronate
Mobilization Calcitonin
Restrict PO Calcium Gallium nitrate
Dialysis Plicamycin
Glucocorticoids
Phosphate
Indomethacin
Antitumor Therapy
 Surgical Management
 Clinical indicators for surgery*
2. Serum calcium is >1.0 mg/dL above the upper limit of
normal.
3. Creatinine clearance is reduced >30% for age in the
absence of another cause.
4. Twenty-four hour urinary calcium is >400 mg/dL.
5. Patients are younger than 50 years of age.
6. Bone mineral density measurement at the lumbar spine,
hip, or distal radius is reduced >2.5 standard deviations
(by T score).
7. Patients request surgery, or patients are unsuitable for
long-term surveillance.

*Consensus conference held by the National Institutes of Health in

2002
 Continued….
 Adenoma
2. Directed unilateral cervical exploration.
3. Curative in >95% of patients
4. Preoperative localization with
technetium-99m sestamibi + IOPTH
 Continued….
 MEN 1
1. Subtotal vs. total with autotransplantation.
 Men 2a-
1. 100% cure rate with no recurrences whether
total parathyroidectomy, subtotal
parathyroidectomy, or excision of enlarged
glands performed.
2. R/O pheochromocytoma prior to OR trip
(hypertensive crisis).
 Continued….
 Non-MEN familial hyperparathyroidism
(NMFH).
1. Subtotal or total (autotransplant) with
bilateral cervical thymectomy.
 Familial neonatal hyperparathyroidism.
1. Total (autotransplant) + bilateral
transcervical thymectomy
 Continued….
 Renal failure-induced hyperparathyroidism.
1. Subtotal vs. total parathyroidectomy (autotransplant) with or
without cryopreservation.
 Parathyroid Carcinoma
1. en bloc resection of the tumor and areas of potential local
invasion and/or regional metastasis (ipsilateral central neck
contents including the thyroid lobe and tracheoesophageal
soft tissues, lymphatics, and resection of soft tissues within
the superior anterior mediastinum)
2. RLN, esophageal wall, or strap muscles may require sacrifice
if the tumor adheres to them.
3. Not enough data to recommend for or against chemotherapy
or RT.
 Continued….
 MIRP
2. Preoperative administration of technetium 99m sestamibi before
operation + intraoperative hand-held gamma probe.
3. Advantages:
 Improved patient comfort postoperatively.
 Performance of ambulatory procedures.
 Reduced cost.
 Avoidance of general anesthetic.
4. Disadvantages:
1. Potential for conversion to bilateral dissection in event of failed
exploration.
2. Patient anxiety when conversion needed (general anesthesia).
 Familial Benign Hypercalcaemia
(FBH).
 Familial, AD. Family history important.
 Often come to light after failed
parathyroidectomy
 Benign. Asymptomatic.
 Low urinary calcium excretion.
 Primary HPT- treatment
 Parathyroidectomy.
 Serum calcium should be normal within
24h.
 Postoperative hypocalcaemia.
 Recurrent laryngeal nerve injury.
 TREATMENT

 Hypercalcemia of malignancy
 IV Pamidronate

– Inhibits osteoclastic bone resorption

– Takes 2-4 days to see full effect
– Must be given every 30-60 days to
prevent recurrence of hypercalcemia
 Calcitonin

– Inhibits osteoclast action

– See an effect within 24 hrs
– Effect wears off within 2-3 days due to
tachyphalaxis
 TREATMENT

 Increased 1-hydroxylation of vitamin D due to

granulomatous disease
 High dose steroids are effective in

sarcoidosis
 Questionable whether steroids are effective in

other granulomatous diseases

 Hypercalcaemia of malignancy

 Carcinomas of breast, lung, head and

neck,renal.
 Usually squamous carcinomas.
 PTHrP increased
 PTH normal
 Low serum albumin, high ESR, anemia.
 Myeloma, local bone resorption.
 Sarcoidosis
 Small numbers of patients with sarcoidosis
develop hypercalcaemia.
 May develop after prolonged sun
exposure.
 1,25 diOH Vit D high, prodiced by alveolar
macrophages. PTH is normal.
 Corrected by Steroids
 Thyrotoxicosis
 Severe thyrotoxicosis
 Increased calcium release from bone
(Thyroxine acts on bone)
 PTH is normal
 Takes 4-6 weeks to resolve with
antithyroid treatment
 Persistent hypercalcaemia usually means
concomitant HPT.
 Band Keratopathy
 HYPOCALCEMIA:
ETIOLOGIES
 HYPOPARATHYROID STATES:
 AUTOIMMUNE

 CONGENITAL

• DIGEORGE SYNDROME
 POSTSURGICAL

 SEVERE MAGNESIUM DEFICIENCY

 NECK IRRADIATION

 INFILTRATIVE

• HEMOCHROMATOSIS
• SARCOIDOSIS
• WILSON’S DISEASE

HUNGRY BONE SYNDROME
 HYPOCALCEMIA:
ETIOLOGIES
 NONHYPOPARATHYROID STATES
 VITAMIN D DEFICIENCY

• LACK OF SUNLIGHT EXPOSURE

• DIETARY LACK
• MALABSORPTION
• UPPER GI SURGERY
• LIVER DISEASE
• RENAL DISEASE
• ANTICONVULSANTS
• VITAMIN D DEPENDENT RICKETS (1α-HYDROXYLASE
DEFICIENCY)
 HYPOCALCEMIA:
ETIOLOGIES
 NONHYPOPARATHYROID STATES
 PARATHYROID HORMONE STATES

• PSEUDOHYPOPARATHYROIDISM
• SEVERE MAGNESIUM DEFICIENCY
 VITAMIN D RESISTANCE

 DRUGS

• BISPHOSPHONATES
• CISPLATINUM
• KETACONAZOLE
• PENTAMIDINE
• FOSCARNET
 HYPOCALCEMIA:
ETIOLOGIES
 MISCELLANEOUS
 ACUTE PANCREATITIS

 MASSIVE TUMOR LYSIS


OSTEOBLASTIC METASTASES
 PHOSPHATE INFUSION

 MULTIPLE CITRATED BLOOD TRANSFUSIONS

 ACUTE RHABDOMYOLYSIS

 ACUTE SEVERE ILLNESS

 MANEFESTATIONS OF
HYPOCALCEMIA

 NEUROLOGIC
 PERIPHERAL IRRITABILITY (TETANY)
+CHVOSTEK’S AND TROUSSEAU’S SIGNS
 CENTRAL IRRITABILITY (SEIZURES)
 INTRACRANIAL CALCIFICATIONS (BASAL GANGLIA)
 PAPILLEDEMA
 MENTAL CHANGES
 CATARACTS
 ABNORMAL DENTITION
 CARDIOVASCULAR
 PROLONGED Q-T INTERVAL

CHF, DIGITALIS RESISTANCE
HYPOCALCEMIA:
SIGNS
 TREATMENT OF HYPOCALCEMIA
 ACUTE HYPOCALCEMIA
 ASX PATIENT WITH MILD HYPOCALCEMIA (7.5-8.5 MG/DL): WATCH;
MAY USE ORAL CALCIUM (500 TO 1000 MG PER DAY ELEMENTAL
CALCIUM)
 PATIENT WITH TETANY MUST TREAT WITH PARENTERAL CALCIUM
 PATIENT WITH SERUM CALCIUM < 7.5 OR WITH SX’S, TREAT WITH
PARENTERAL CALCIUM
 USE CALCIUM GLUCONATE (90 MG/ 100 ML)
• 1 TO 2 AMPULES IN 50 TO 100 ML OF 5% DEXTROSE (180 MG
ELEMENTAL CALCIUM) OVER 5 TO 10 MIN
• FOLLOW WITH 15 TO 20 MG/KG ELEMENTAL CALCIUM OVER 4
TO 6 HR
• WILL RAISE SERUM CALCIUM BY 2-3 MG/DL
• IF HYPOCALCEMIA IS LIKELY TO PERSIST, INITIATE ORAL
CALCIUM (1-2 GM PER DAY) WITH CALCITRIOL (O.5-1.0 µg/day)
 MONITOR SERUM MAGNESIUM AND REPLACE IF NECESSARY
 TREATMENT OF HYPOCALCEMIA

 CHRONIC HYPOCALCEMIA
 START SUPPLEMENTAL ORAL CALCIUM (1-2

GM PER DAY) AND A VITAMIN D

PREPARATION (ERGOCALCIFEROL 50,000
UNITS ONCE PER WEEK TO DAILY; OR
ROCALTROL 0.5-1.0 ΜICROGRAMS PER DAY)
 MAINTAIN SERUM CALCIUM IN THE LOW

NORMAL RANGE BECAUSE OF THE RISK OF

HYPERCALCIURIA AND NEPHROLITHIASIS
 Complications of parathyroid surgery.

 Hypocalcemia
 Persistent hypercalcemia
 Recurrent laryngeal nerve injury