PARATHYROID DISEASE

Dr. Pandji
Mulyono,SpPD,KEMD,FINASIM

 The

parathyroids are
4 small glands - 3 x 6
mm with a total
weight of about 0.4
g.
They
are
located
behind the thyroid
gland, one at each
end of the upper and
lower poles, usually
in the capsule that
covers the lobes of
the thyroid

ANATOMY
Arterial supply usually
from inferior thyroid art
Superior glands usually
imbedded in fat on
posterior surface of
middle or upper portion
of thyroid lobe
Lower glands near the
lower pole of thyroid
gland
In 1-5% pts, inferior
gland in deep
mediastinum

HISTOLOGY

50/50 parenchymal cells, stromal fat

Chief cells secrete PTH

Waterclear cells

Oxyphil cells

PTH FUNCTION

SYNTHESIS, REGULATORY MECHANISM AND

SECRETION OF PTH
Pre pro-PTH (115 amino acids) pro-PTH (90 amino acids) PTH
The biosynthesis and secretion of PTH is regulated by the plasma
Ca2+ concentration:
Acute Ca2+ plasma concentration PTH mRNA rate of PTH
synthesis and secretion.
PTH exists in storage vesicles, however most of the pro-PTH (80-90
%) synthesized is quickly degraded before it enters the storage
vesicle, especially when Ca2+ in the parathyroid cells are high.
PTH is secreted when Ca 2+ in the parathyroid cells is low.
Cathepsin B (a proteolytic enzyme) cleaves PTH into 2 fragments:
PTH 1-36 and PTH 37-84.

PTH 37-84 is not further degraded, however PTH 1-36 is rapidly and
progressively cleaved into dipeptides and tripeptides.
Most of the proteolysis of PTH occurs within the gland, but once
PTH is secreted, is degraded in other tissue especially the liver by
similar mechanism
Ca2+ plasma concentration blocks production of PTH

BIOLOGIC EFFECT OF PTH ON

CALCIUM AND PHOSPHATE
METABOLISM
Mechanism of action of PTH
PTH binds to the cell surface receptor in the
target cells stimulates the synthesis of
cAMP.
The action of PTH on bone and kidney
are mediated through its G-protein linked
receptor coupled to cAMP formation and
increased protein phosphorylation.
The intestinal action of PTH is indirect,
mediated through the enhanced renal
synthesis of active vitamin D

 Biologic

effect of PTH on calcium &

phosphate concentration
PTH increases plasma Ca2+ concentration by:
stimulating Ca2+ resorption from the bone
and the kidney
increasing dietary absorption of Ca 2+ from
the intestine
PTH stimulates bone resorption, renal Ca
reabsorption, and intestinal Ca absorption
increased blood calcium level.
PTH increases phosphate absorption from
the bone, and in the intestine, but markedly
increases phosphate excretion by the
kidneys
leading
to
decreased
blood

 Function

of bone mineral; bone

cells and bone remodeling
Function of bone mineral: to strengthen a
tough organic matrix of the bone.
The
crystalline salts (major: hydroxyapatite)
deposited in the organic matrix of bone are
composed
principally
of
calcium
and
phosphate.
Bone
cells consist of osteoblast and
osteoclast.
Bone is continually being
deposited by osteoblast, and absorbed where
osteoclasts are active.

Bone

remodeling functions to adjust

bone
strength
and
shape
in

FACTORS THAT CONTRIBUTE TO

THE CALCIUM METABOLISM

Calcitonin: tends to decrease plasma

calcium concentration and in general has
effects opposite to those of PTH.

intestinal absorption: increased if blood

calcium level is decreased, regulated by PTH
and vitamin D.
Vitamin D: promote intestinal calcium
absorption, decreases renal calcium
excretion and bone absorption leading to
increased blood calcium level.

PTH plays a major role in regulating the

activation of vitamine D:
High PTH stimulates the production of 1,25
dihydroxycholecalciferol (the active form of vit. D
= calcitriol) by the kidney, which in turn enhance
the transfer of intestinal Ca2+ to the blood.
Low PTH induces formation of inactive 24,25
dihydroxycholecalciferol {24,25(OH)2D}.

In bone, PTH and calcitriol act synergistically to

promote bone resorption.
In the kidney, PTH and calcitriol inhibit calcium
excretion by stimulating calcium reabsorption in
the distal renal tubules

Gain, maintenance and loss of bone

Bone is deposited in proportion to the compressional load
that the bone must carry. For instance, the bones of
athletes become considerably heavier than those of nonathletes.
Normally, except in growing bones, the rates of bone
deposition and absorption are equal to each other so that
the total mass of bone remains constant.
Bone is also being continually absorbed in the presence of
osteoclasts which are normally active on less than 1 per
cent of the bone surfaces of an adult.
Bone remodeling: the action of two types of bone cells :

Osteoblasts: synthesize collagen fibrils that form the

bulk of bones organic matrix where hydroxyapatite
{Ca5(PO4)3OH} is laid down it is inhibited by PTH

Osteoclasts
: participate in bone resorption it is
stimulated by PTH

THE VARIOUS PARATHYROID

DISORDERS, THE CAUSES OF
HYPOPARATHYROISISM
A.Hypoparathyroidism
Surgical
Idiopathic
Neonatal
Familial
Deposition of metals (Fe, Cu and Al)
Postradiation
Infiltrative
Functional (in hypomagnesemia

b. Resistance to PTH action

Pseudohypoparathyroidism
c. Primary hyperparathyroidism
Sporadic
Associated with MEN 1 or MEN 2A
Familial
After renal transplantation
d. Variant forms of hyperparathyroidism
Familial benign hypocalciuric hypercalcemia
Lithium therapy
Tertiaty hyperparathyroidism in chronic renal
failure

ETIOLOGY OF HYPO- AND

HYPERPATHYROIDISM

Hypoparathyroidism is most commonly seen

following thyroidectomy, when it is usually
transient
but
may
be
permanent
Hypoparathyroidism may also be seen in DiGeorges syndrome, along with congenital
cardiac and facial anomalies
Parathyroid deficiency may also be the result of
damage from heavy metals such as copper
(Wilsons disease) or iron (hemochromatosis,
transfusion
hemosiderosis),
granulomas,
sporadic autoimmunity, Riedels thyroiditis,
tumors, or infection.

CAUSES OF HYPOCALCEMIA
1. Hypoparathyroidism
2. Resistance to PTH action
Pseudohypoparathyroidism
Renal insufficiency
Medications that block osteodastic bone resorption
Plicamycin
Calcitonin
Bisphosphonates
3. Failure to produce 1,25(OH)aD normally
Vitamin D deficiency
Hereditaty vitamin D -dependent rickets, type 1
(renal 25- OH-vitamin D 1 -hydroxylase
deficiency)
4. Resistance to 1 ,25(OH)2D action
Hereditary vitamin 0-dependent rickets, type 2
(defectiveVDR

5. Acute complexation or deposition of

calcium
Acute

hyperphosphatemia
Crush injury With myonecrosis
Rapid tumor lysis
Parenteral phosphate administration
Excessive enteral phosphate
Oral (phosphate-containing antacids)
Phosphate-containing enemas

6. Acute pancreatitis
7. rated blood transfusion
8. Rapid, excessive skeletal mineralization
Hungry

bones syndrome
Osteoblastic metastasis

AD 1. HYPOPARATHYROIDISM
Hypoparathyroidism

may be:

surgical,
autoimmune,
familial, or idiopathic.
The signs and symptoms are those of
chronic hypocalcemia

 Biochemically,

the hallmarks of
hypoparathyroidism are;
hypocalcemia,
hyperphosphatemia (because the
phosphaturic effect of PTH is lost),
and an inappropriately low or
undetectable PTH level

CLINICAL FEATURES

Most of the symptoms and signs of

hypocalcemia occur because

of increase neuromuscular
excitability (tetany, paresthesias,
seizures, organic brain syndrome)
or because of deposition of
calcium in soft tissues (cataract,
calcification of basal ganglia).

SYMTOM AND SIGN OF

HYPOCALCEMIA
SYMTOM

vometing
diarhea
nervousness
weakness
paresthesia
muscle stiffnes and muscle cramps
headaches
abdominal pain

SIGN
Tetany/sceizure/muscle

spasm
Peripheral neurogic finding
- CHVOSTKS SIGN
- TROUSSEAUS SIGN
Irritability,confussion,hallucination,dem
entia
hair loss
cataract
papil edema

A. NEUROMUSCULAR MANIFESTATION
Clinically,

the hallmark of severe

hypocalcemia is tetany the classic
muscular component of tetany is
carpopedal spasm.
These involuntary muscle contractions
are painful.
Although the hands are most typically
involved, tetany can involve other
muscle groups, including lifethreatening spasm of laryngeal musdes

Lesser degrees of neuromuscular excitability (eg, serum

calcium 79 mg/clL) produce latent tetany, which can be
elicited

by

testing

for

Chvosteks

and

Trousseaus signs
Chvosteks

sign is elicited by rapping the

facial nerve about 2 cm anterior to the
earlobe, just below the zygoma. The
response is a contraction of facial muscles
ranging from twitching of the angle of the
mouth to hemifacial contractions. The
specificity of the test is low; about 25% of
normal individuals have a mild Chvostek
sign.

 Trousseaus

sign is elicited by inflating a

20 mm Hg
above systolic pressure for 3 minutes. A
blood pressure cuff to about

positive response is carpal spasm.

Trousseaus sign is more specific than
Chvosteks, but 14% of normals have
positive Trousseau signs
Other

central nervous system effects of

hypocalcemia include pseudtumor cerebri,
papilledema, confusion, lassitude, and
organic brain syndrome.

B. OTHER MANIFESTATION OF HYPOCALCEMIA

1.

Cardiac
effectsRepolarization
is
delayed, with prolongation of the QT
interval. Excitation-contraction coupling
may be impaired, and refractory congestive
heart failure is sometimes observed,
particularly in patients with underlying
cardiac disease.
Ophthalmologic effectsSubcapsular
cataract
is
common
in
chronic
hypocalcemia, and its severity is correlated
with the duration and level of hypocalcemia

2.

3. Dermatologic effectsThe skin

is often dry and flaky and the
nails brittle. A dermatitis known
as impetigo herpetiformis or
pustular psoriasis is peculiar to
hypocalcemia.

B. LABORATORY FINDINGS
Serum

calcium
is
low,
serum
phosphate high, urinary calcium low,
and alkaline phosphatase normal.
Parathyroid hormone levels are low.
Serum
magnesium
should
be
determined since hypomagnesemia
frequently accompanies hypocalcemia
and may exacerbate symptoms and
decrease parathyroid function.

C. IMAGING
Radiographs or CT scans of the skull
may
show
basal
ganglia
calcifications; the bones may be
denser than normal. Cutaneous
calcification may occur.
D. OTHER EXAMINATIONS
Slit-lamp examination may show
early posterior lenticular cataract
formation.
The
ECG
shows
prolonged QT intervals and T wave

THE PRINCIPLES OF
MANAGEMENT OF HYPO- AND
HYPERCALCEMIA

TREATMENT OF HYPOCALCEMIA
a. Acute Hypocalcemia
Patients with tetany should receive intravenous
calcium as calcium chloride (272 mg calcium per
10 mL), calcium gluconate (90 mg calcium per
10 mL), or calcium gluceptate (90 mg calcium
per 10 mL). Approximately 200 mg of elemental
calcium can be given over several minutes.
The patient must be observed for stridor and the
airway secured if necessary. Oral calcium and a rapidly
acting preparation of vitamin D should be started.
If necessary, calcium can be infused in doses of 400
1000 mg/24 h until oral therapy has taken effect.
Intravenous calcium is irritating to the veins. Caution
must be exercised in patients taking digitalis, since
they are predisposed to toxicity by infusion of calcium.

B. Chronic Hypocalcemia
The objective of chronic therapy is to keep the patient free of
symptoms and to maintain a serum calcium of approximately
8.59.2 mgIdL. With lower serum calcium levels, the patient
may not only experience symptoms but may be predisposed
over time to cataracts. With serum calcium concentrations in
the upper normal range, there may be marked hypercalciuria,
which occurs because the hypocalciuric effect of PTH has
been lost. This may predispose to nephrolithiasis,
nephrocalcinosis, and chronic renal insufficiency. In addition,
the patient with a borderline elevated calcium is at increased
risk of overshooting the therapeutic goal, with symptomatic
hypercalcemia.
The mainstays of treatment are calcium and vitamin D. Oral
calcium can be given in a dose of 1.53 g of elemental
calcium per day. These large doses of calcium reduce the
necessary dose of vitamin D and allow for rapid normalization
of calcium if vitamin D intoxication subsequently occurs.
Numerous preparations of Calcium are available.

A short-acting preparation of vittamin D (calcitriol) and

the very long-acting preparations such as vitamin D2
(ergocalciferol) are available. By far the most
inexpensive regimens are those that use ergocalciferol.
In addition to economy, they have the advantage of
rather easy maintenance in most patients. The
disadvantage
is
that
ergocalciferol
can
slowly
accumulate and produce delayed and prolonged vitamin
D intoxication. Caution must be exercised in the
introduction of other drugs that influence calcium
metabolism.
For example, thiazide diuretics have a hypocalciuric
effect. By reducing urinary calcium excretion in treated
patients, whose other adaptive mechanisms, PTH and
1,25(OH)2D3, are n000perative and who are thus
absolutely dependent on renal excretion of calcium to
maintain the serum calcium level, thiazides may produce
severe hypercalcemia. In a similar way, intercurrent
illnesses that compromise renal function may produce

HYPERPARATHYROIDISM
Primary

Hyperparathyroidism
Normal feedback of Ca disturbed,
causing increased production of PTH
Secondary Hyperparathyroidism
Defect in mineral homeostasis leading
to a compensatory increase in
parathyroid gland function
Tertiary Hyperparathyroidism
After prolonged compensatory
stimulation, hyperplastic gland
develops autonomous function

PRIMARY HYPERPARATHYROIDISM
Epidemiology
25/100,000
50,000 new cases yearly
F > M
Incidence increases w/ age
Most in > 50 years old

ETIOLOGY
Unknown

cause
Single gland adenomatous disease
Multiglandular disease exogenous
stimulus
Overexpression of PRAD1 oncogene
controlls cell cycle
Ionizing radiation exposure

CLINICAL PRESENTATION
Nephrolithiasis
Bone Disease
Peptic Ulcer Disease
Psychiatric disorders
Muscle weakness
Constipation
Polyuria
Pancreatitis
Myalgia
Arthralgia

30
2
12
15
70
32
28
1
54
54

HYPERCALCEMIA
I.Parathyroid-related
-Primary hyperparathyroidism
-Lithium therapy
-Familial hypocalciuric hypercalcemia
II. Malignancy-related
-Solid tumor with metastases (breast)
-Solid tumor with humoral mediation of hypercalcemia (lung, kidney)
-Hematologic malignancies (multiple myeloma, lymphoma, leukemia)
III. Vitamin D-related
-Vitamin D intoxication
- 1,25(OH)2D; sarcoidosis and other granulomatous diseases
-Idiopathic hypercalcemia of infancy
IV. Associated with high bone turnover
-Hyperthyroidism
**Primary
-Immobilization
-Thiazides
hyperparathyroidis
-Vitamin A intoxication
m and cancer
V. Associated with renal failure
-Severe secondary hyperparathyroidism
account for 90% of
-Aluminum intoxication
cases of
-Milk-alkali syndrome

hypercalcemia

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

SECONDARY
HYPERPARATHYROIDISM
Decreased GFR leads to reduced inorganic phosphate
excretion and consequent phosphate retention
Retained phosphate has a direct stimulatory effect on
PTH synthesis and on cellular mass of the parathyroid
glands
Retained phosphate also causes excessive production
and secretion of PTH through lowering of ionized
Ca2+ and by suppression of calcitriol production
Reduced calcitriol production results both from
decreased synthesis due to reduced kidney mass and
from hyperphosphatemia.

Low calcitriol levels, in turn, lead to hyperparathyroidism via

both direct and indirect mechanisms. Calcitriol is known to
have a direct suppressive effect on PTH transcription and
therefore reduced calcitriol in CRD causes elevated levels of
PTH
Reduced calcitriol leads to impaired Ca2+ absorption from the
GI tract, thereby leading to hypocalcemia, which then
increases PTH secretion and production.

Secondary HPT

Clinical presentation
Usually asymptomatic
Diagnosis
Elevated PTH in the setting of low or normal serum
calcium is diagnostic
If phosphorous is elevated, cause is renal
If phosphorous is low, other causes of vit D deficiency
should be sought
Prevention
Vit D replacement
Phosphorus binders [Sevelamer]
Treatment
Medical
Calcimimetic agents
Surgical
Considered in cases of refractory
severe hypercalcemia, severe
bone disease, severe pruritis,
calciphylaxis, severe myopathy

TERTIARY
HYPERPARATHYROIDISM
Tertiary hyperparathyroidism develops
in patients with long-standing
secondary hyperparathyroidism,
which stimulates the growth of an
autonomous adenoma. A clue to the
diagnosis of tertiary
hyperparathyroidism is intractable
hypercalcemia and/or an inability to
control osteomalacia despite vitamin
D therapy.
Surgical Referral
- calcium- phosphate product > 70

LAB ABNORMALITIES
Primary

HPT

Increased

serum calcium
Phosphorus in low normal range
Urinary calcium elevated
Secondary

HPT (renal etiology)

Low

or normal serum calcium

High phosphorus
Tertiary
High

HPT (renal etiology)

calcium and phosphorus

BONE DISEASE
Osteitis

fibrosa cystica
In early descripts of disease, many had
severe bone disease (50-90%), but
now 5-15%
Subperiosteal resorption
pathognomonic of
hyperparathyroidism

Familial Syndromes

MEN

I
MEN IIA
Familial Hypocalciuric
Hypercalcemia
Hyperparathyroidism-jaw tumor
syndrome
Fibro-osseous jaw tumors
Renal cysts
Solid renal tumors

STIGMATA OF MEN I

Lipomas

Collagenomas
Angiofibromas

RENAL COMPLICATIONS
Generally

the most severe clinical

manifestations
Many have frequency, polyuria, polydipsia
Usually present w/ nephrolithiasis (2030%)
Calcium phosphate or Calcium oxalate
Nephrocalcinosis (in 5-10%) calcification
w/in parenchyma of kidneys
Severe

renal damage

Hypertension

impairment

secondary to renal

GASTROINTESTINAL
MANIFESTATIONS
Peptic

Ulcer disease
Pancreatitis
Cholelithiasis 25-35%

EMOTIONAL DISTURBANCES
Hypercalcemia

of any cause
assoc w/ neurologic or psychiatric
disturbances
Depression, anxiety, psychosis,
coma
Severe disturbances not usually
correctable by parathyroidectomy

ARTICULAR AND SOFT TISSUE

Chondrocalcinosis

and

Pseudogout 3-7%
Deposits of Calcium
pyrophosphate in articular
cartilages and menisci
Vascular and Cardiac
calcifications

NEUROMUSCULAR
COMPLICATIONS
Muscular

weakness, fatigue
More commonly in proximal
muscles
Sensory abnormalities also
possible

LABORATORY DIAGNOSIS
Elevated

Serum Ca and PTH

Must

measure Ionized Ca (subtle cases of

hyperPTH will have normal Serum Ca)

50%

will have hypophosphatemia

Elevated Alkaline Phosphatase in 1040%
Hyperchloremic metabolic acidosis
Low Mg in 5-10%
High Urinary Ca in almost all cases

HYPERPARATHYROID CRISIS
Most

pts w/ hyperparathyroidism
chronically ill w/ renal and skeletal
abnormalities
Rarely can become acutely ill
Rapidly developing weakness, N/V,
weight loss, fatigue, drowsiness,
confusion, Azotemia
Uncontrolled PTH production, hyperCa,
polyuria, dehydration, reduced renal
function, worsening hyperCa

HYPERPARATHYROID CRISIS
Definitive

therapy - resection
Must reverse hyperCa first
Diuresis

- Saline hydration then Lasix

to excrete Ca
Calcitonin - rapid affect, inhibits
bone resorption
Steroids - take up to a week
Mithramycin - rapidly inhibiting bone
resorption

TREATMENT
Only

Curative treatment Parathyroidectomy

Who should have surgery?
Many found incidentally, assx

SURGICAL CANDIDACY
Symptomatic

primary HPT
NIH Consensus Development Panel 2002
Revised Guidelines [if any of the following
are met]
Serum

calcium greater than 1mg/dL above the

upper limit of the reference range
24 hour urine calcium greater than 400 mg
Creatinine clearance reduced by more than
30% compared with age-matched subjects
Bone density at the lumbar spine, hip, or
distal radius more than 2.5 SD below peak
bone mass
Age under 50
Patients for whom medical surveillance is not
creatinine clearance (mL/min) =
desirable or possible

((urine creatinine in mg/dL) *

(urine volume in mL)) / ((plasma
creatinine in mg/dL) * (time

OTHER CONSIDERATIONS IN
SURGICAL REFERRAL
Neuropsychological abnormalities
Several studies document improvement in
HRQL after parathroidectomy
Studies on neurobehavioral abnormalities
have reported less consistent results with
parathyroidectomy
Cardiovascular abnormalities
Symptomatic patients suffer from increased
cardiovascular mortality before and after
treatment
Asymptomatic primary HPT is associated
with LVH; some studies suggest this is
reversible with parathyroidectomy
Primary HPT patients have increased
calcifications of mitral and aortic valve
Perimenopausal women
Asymptomatic primary HPT associated with

MEDICAL MANAGEMENT
Asymptomatic

patients may elect

to be closely followed and
managed medically
A

recent study of pts with

asymptomatic primary HPT showed
that the majority of pts followed for
ten years did not demonstrate an
increase in serum calcium or PTH
levels25% of patients had
progressive disease including
worsening hypercalcemia,
hypercalciuria and reduction in bone
massyounger patients more likely
to have progression of disease

Patients

opting not to have

MEDICAL MANAGEMENT
PRIMARY HPT
Estrogen

Dose

SERMs

required is high

Reduction

in serum calcium and

markers of bone turnover after 4 weeks

Bisphosphonates

Studies

have shown increase in lumbar

spine and femoral neck mineral density

Calcium/Vitamin

D
Calcimimetic agents (Cinacalcet)
Under

investigation for primary HPT