Download Disorders of the parathyroid gland

Disorders of the parathyroid
gland and regulation of the
calcium metabolism
Dr. Zoltán Böröcz
13.03.2017
Anatomy
Anatomy
• Arterial supply usually from
inferior thyroid artery
• 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
• Oxyphil cells - have the
potential to produce additional
autocrine/paracrine factors, such
as Parathyroid hormone-related
protein (PTHrP) and calcitriol.
PTH Physiology
• Synthesized in chief cells as large precursor –
pre-proparathyroid hormone
• Cleaved intracellularly into proparathyroid
hormone then to final 84 AA PTH
• PTH then metabolized by liver into hormonally
active N-term and inactive C-term
Parathyroid Hormone
Sch.I. 55 year-old man
• He was admitted to the hospital (1979) because
of 2 weeks history of somnolence, altered mental
function,weakness, weight loss, appetite loss.
• Past history: 1962.Ulcus duodeni- drug
treatment, 1976 TIA and polyneuropathy.
Hypertension since a few years.
Physical and laboratory examinations
• Pale, no palpable lymph nodes, no abdominal mass,
no cardiac or pulmonary abnormalities
• Blood pressure 190/110 mmHg P: 80/min
• Somnolence and dementia were observed.
• Se Na: 142 mM/l, K: 3,9 glucose: 5,4 CN: 10 mM/l,
Ht: 0,35, Hb: 123, wbc: 7000 , ESR: 6 mm/h, urine
sediment normal.
ECG
Hypercalcaemia
Se Ca > 2,65mM/L
Rule out
• Lab error (repeat the measurement)
• Severe dehydration
• Hyperalbuminaemia
• Hyperparaproteinaemia
Se Ca regulation
Causes of HyperCa
90% of cases tumor, or
hyperparathyroidism is the cause!
1.Increased bone resorption
2.Increased absorption of Ca from gut
3.Miscellaneous
Causes of hyperCa
1.Increased bone resorption
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Primary hyperparathyroidism
Tumors
Hyperthyroidism
Paget disease
Immobilization
Vitamin A excess (PTH secretion increase)
Normal physiology of
parathyroid glands
Four in number, found in close association with the thyroid
gland
Secretion of PTH:defends against hypoCa
• Stimulates osteolysis by osteoclasts in bone
• Increases the renal tubular reabsorption of Ca+ (Mg)
• Decreases the renal tubular reabsorption of phosphate,
bicarbonate
• Increases the calcitriol sythesis from 25OH-D in the
kidney-increases the intestinal Ca absorption
Regulation of PTH secretion occurs through negative feed
back loop ( Ca sensing receptors of parathyroid cells
trigger PTH secretion)
Cause, pathophysiology of
primary hyperparathyroidism
• 80% solitary, 3% multiple adenoma
• 15% hyperplasia
• 2% adenocarcinoma
Parathyreoid cells lose sensitivity to hyperCa
Epidemiology
• Common endocrine disease: affects 1 in 500 women, 1 in
2000 men/year, over 40 years
• Sporadic
• Familiarity ( multiple endocrine neoplasia MEN)
Role of 11, 10 chromosoma ( tumor suppressor gene failed)
Hyperparathyroidism
MEN-I (Wermer sy) + pancreas endocrin tu+ hypophysis
adenoma
MEN-II ( Sipple sy) + phaeochromocytoma+ medullary cc of
thyroid
MEN-III
+ MEN II+ Marfan phenotype+ mucosal
neurinomas
Symptoms of primary
hyperparathyroidism
Most patients are asymptomatic or with
minimal symptoms.
Disease may run a benign course for years
prior detection.
1.Symptoms of hypercalcaemia
2.Osteitis fibrosa cystica
1.Symptoms of hypercalcaemia
Central nervous system
Impaired mental function, loss of memory, depression,
somnolence, coma
Neuromuscular
Weakness, arthralgias, severe pruritus (metast. calcification of
skin), restless leg sy (no comfortable position)
Cardiovascular
Hypertension, bradycardia, shortening of QT
Renal
Polyuria, nephrocalcinosis, recurrent Ca nephrolithiasis
Gastrointestinal
Anorexia, vomiting, constipation, peptic ulcer, pancreatitis
Rheumatologic
Gout, pseudogout (intraarticular Ca-pyrophosphate crystals),
chondrocalcinosis
Clinical features of
hyperparathyroidism
ECG in hyperCa
Ca stones in hyperCa
Keratopathy in HyperCa
2.Osteitis fibrosa cystica
• Bone pain
• Radiographic manifestations:
subperiostal bone resorption (index finger),
bone cysts-brown tu
generalized osteopenia
Subperiostal osteopenia
Subperiostal resorption and
acroosteolysis
Brown tu of humerus
Diagnosis
• Laboratory: Se Ca elevated ( >2,6mM/L) ,
Se phosphorus decreased ( <0,81mM/L),
PTH level elevated ( N: 10-65 pg/ml)
nephrogeneous cAMP , calcitriol elevated
( SAP level is increased in whom there is significant osteitis cysticarepresenting increased reparative osteoblast activity)
• Bone radiography
• (Sestamibi scanning Sestamibi is a small protein
which is labeled with the radio-pharmaceutical
technetium-99.)
• US,CT,MRI
Identification of a parathyroid tu.
Sestamibi scan-parathyroid gland
in the mediastinum
Treatment/1. Surgical
Indications:
• Overt clinical manifestations of disease
• Age younger than 50years
• Se Ca > 2,6mM/L(1mg/dl) above the upper limit of
reference range
• Urinary Ca excretion greater than 400mg/die
• Low, or declining bone mineral density
• Poor or uncertain follow up
• Coexistent disease that may confound or contribute to
disease progression
• Patient request surgery
Treatment/1.Surgical
Removal of abnormal gland or glands
( Selection of surgeon! Identify all four glands! Approximately
20% of abnormal glands are in the mediastinum!
Autotransplantation of one of the glands to the muscles of the
forarm)
With hyperplasia subtotal (3 ½) parathyreoidectomy is carried out
• Postoperative complications:
hypoCa (hyperP)-hypoparathyroidism
Hungry bone sy: significant hypoCa without hyperP
(demineralized bone avidity for EC calcium)
Treatment/2.Observation
• Se Ca< 3mM/l
• No kidney stone
• No bone disease
• No mental dysfunction
Withold excessive Ca intake, maintain
adequate hydration and phosphate intake,
withhold thiazide diuretics and follow the
patient
Causes of hyperCa
2.Increased absorption of Ca from gut
Increased Ca intake
Milk-alkali sy
Renal failure (with the treatment of hypoCa)
D hypervitaminosis
excessive ingestion
excessive activation (granulomatous diseases,
lymphomas)
Causes of hyperCa
3.Miscellaneous causes
• Drugs (Lithium, thiazide diuretics, theophyllin
intoxication)
• Phaeochromocytoma - PTH increases
• Adrenal insufficiency(Addison)
• Rhabdomyolysis - acute renal insufficiency
• Benign familial hypocalciuric hypercalcaemia
Renal hypersensitivity to the hypocalciuric effect of
parathyreoid gland
Autosomal dominant trait, young male, 24 hour Ca
excretion < 150mg, moderate hyperCa, symptomless
Diagnostic steps in hyperCa
1.PTH high
primary hyperpara/ or parathormon like hormon
of malignancy (very rare)
production
2.PTH normal or slight increase
Determine 24hour urin Ca (BFHyCa)
3.PTH low
Evaluate for malignancy
Evaluate for drugs, TSH
Evaluate for granulomatous diseases (1-25(OH)2D3 level high)
Evaluate for Addison,Acromegaly,Phaeochr.,Paget
Treatment of hyperCa
• Fluid intake increase-3-4 L phys. NaCl infusion/day+ Furosemide
80-160mg/die SeMg! K!
• Steroid - 40-100mg prednisolon/die (best in certain lymphomas, and
granulomatous diseases)
• Inhibition of bone resorption and osteoclast activity - Calcitonin sc or
im. 4-8 IU/kg 4x/die for 2 days ,- Bisphosphonates( for malignancy):
pamidronate 30mg infusion/die for 3 days or zoledronate 4mg
effective for- 4-6 weeks(kidney!)
• Gallium nitrate (inhibition of PTHsecretion and osteoclast activity)
effective in 70% of malignant cases for 10-14 days
• Cinacalcet (calcimimetic drug, affects on Ca-senzing receptor) p.os
30-180mg/die for inoperable parathyroid diseases
Case report:diagnostic steps
• Se Ca 4,3mM/l ,Se P 0,8mM/L (moderate hypoP),
SAP normal, Se ELFO negative for paraprotein
• Chest X- ray: no malignancy, tbc, sarcoidosis
• Abdominal US:negative for tu or nephrocalcinosis
• Bone lesions: no specificity for hyperpara. or bone
metast.
• Bone marrow biopsy:no myeloma, no tumor
• No history of drug
History
• Treatment with NaCl infusion, Furosemide,
steroid, were ineffective
• Suggested dg was hyperparathyroidism
• Surgical removal of parathyroid glands –no
response – further continous hyperCa
• Patient died
• Autopsy showed a small bronchus cc
(parathormon like hormon production?)
Think of hypercalcemia, if the
patient
• Is somnolent, confused, or unconscious
• Has osteoporosis
• Has recurrent calcium kidney stones, or
nephrocalcinosis
• Has recurrent pancreatitis of unknown
origin
• Has short QT on ECG
If the patient has high Ca level,
know,that
In 90% of cases
Hyperparathyroidism (PTH high), or
Tumor
(PTH low)
IS THE CAUSE!
Hypocalcemia
Symptoms of hypoCa
• Neurologic: neuromuscular irritability.
paraesthesias, muscle cramping, tetany or
seizures
• Cardiac: QT prolongation- syncope, death
due to arrhythmias such as polymorphic
ventricular tachycardia
• Respiratory: laryngospasm- stridorsignificant airway obstruction
Physical examination
• Trousseau sign:
is a cardpopedal spasm that occurs after a blood pressure
cuff around the arm is inflated to the systolic blood
pressure for several minutes
• Chvostek sign:
twitching of facial muscles with tapping on the facial nerve
in front of the ear. It is present in 25% of healthy adults.
Carpopedal spasm
ECG
Se Ca regulation
Causes of hypoCa
1.Primary hypoparathyroidism
a.Deficient PTH secretion
b.Deficient PTH action (hormone resistance pseudohypoparathyroidism)
2.Target organ dysfunction
1.Primary hypoparathyroidism
a.Deficient PTH secretion
Postsurgical
Mg deficiency - impaired secretion of PTH
Inherited forms of hypoparathyroidism
Familial - sex linked recessive ( males, first year of life, not
associated with other abnormalities)
- autosomal recessive (before the age 30, autoimmune origin,
other abnormalities: mucocutan candidiasis, Addison,
hypothyroidism, pernicious anaemia)
Congenital - di George sy- no parathyroid gland, no thymusimmundeficiency leads to early death
Sporadic, idiopathic hypoparathyroidism
Other causes: metastases, cc chemotherapy, iron storage-, copper
storage diseases
Di-George sy
(low set ears,microstomia,hypertelorism,congen. heart
disease)
Familial autosomal recessive
(multiple endocrine deficiencies)
(keratitis ,photophobia,Addison,hypogonadism)
HypoCa-keratitis
1.Primary hypoparathyroidism
b.deficient PTH action (pseudohypoparathyroidism)
PTH high, parathyroid hyperplasia
(secondary hyperparathyroidism)
Type I.- 50% deficiency in Gs protein that couples PTH
receptor to enzym forming cAMP
(hypothyroidism,hypogonadism, short stature, round face,
shortened third and fourth metacarpals, sc, calcifications,
subnormal intelligence) PTH infusion - no cAMP increase
Type II.- Gs is normal, PTH receptor defective
Kidney receptor bad - hypoCa, hyperP
bone receptor good - osteitis fibrosa cystica
Pseudohypoparathyreoidism type I.
Differencial dg in primary hypoparathyroidism
Signs, symptoms
Pseudo Fam./idiopat. Postsurg
Increased neuromusc.excitability
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Cataracts
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Basal gangl.calcification
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Prolonged QT
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Papilledema
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Dental defect
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Alopecia
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Vitiligo
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Moniliasis
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Hypothyroidism
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Hypoadrenalism
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Primary hypogonadism
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Osteodystrophy, brachydactily,sc.
calcifications
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Diagnosis of primary hypoparathyroidism and
pseudohypoparathyroidism
• HypoCa, hyperP, normal creatinin, PTH low=
Primary hypoparathyroidism
• HypoCa, hyperP, normal creatinin, PTH high=
Pseudohypoparathyroidism
Se Ca regulation
Causes of hypoCa
2.Target organ dysfunction (sec.hyperparathyroidism)
Increased Ca loss, or Ca deposition into bone
• hyperP- renal failure,increased intake,rapid cell lysis
• Acute pancreatitis (precipitation of Ca salts of fatty acids)
• Osteoblastic metastases
• „Hungry bone”(after parathyroidectomy)
• Only ionized Ca decrease-complex formation (citrate,lactat,foscarat)
-acute respiratory alkalosis
Decreased mobilisation from bone
• HypoMg
• Fluorid intox.
• Bisphosphonate side effect
Reduced Ca absorption
• Vitamin D deficiency, malabsorption diseases
Miscellanous : sepsis, severe burns, chemotherapy (cisplatin, leucovorin,5FU)
Treatment of hypoCa
• Treat Mg deficiency
• Mild, asymptomatic (>0,8mm/l)-Ca intake
1gr/die
• Acute, symptomatic -1-2gr Cagluconate
iv/in 20 minutes
• After parathyroidectomy-1-3grCa and 0,250,5ug kalcitriol/die,+ dihidrotachysterol,
+Thiazid diuretics
Plasma Calcium Regulation
• Free calcium is tightly regulated (±5%)
– Too low = neuronal hyper-excitability
– Too high = neuronal depression
• Control points for calcium
– Absorption – Via intestines
– Excretion – Via urine
– Temporary storage – Via bones
Se Ca regulation
Active Control of Calcium
• Vitamin D3
– Diet and sun
• Parathyroid hormone
– Parathyroid gland
• Calcitonin
– Thyroid gland
• Skeletal loading
– Osteoblasts and osteoclasts
Vitamin D3 and Calcium Control
• Vitamin D3 (Cholecalciferol,
cholesterol derivate)
– Converted to precursor in liver
• Initially stored
• Converted to 25-Hydroxycholecalciferol
• Feedback control limits concentration
– Converted to active form in kidney
• 1,25-Dihydroxycholecalciferol
• Under the feedback control of parathyroid
hormone (PTH)
Synthesis of Vitamin D
• Humans acquire vitamin D from two sources.
• Vitamin D is produced in the skin by ultraviolet
radiation and ingested in the diet.
• Vitamin D is not a classic hormone because it is
not produce and secreted by an endocrine “gland.”
Nor is it a true “vitamin” since it can be
synthesized de novo.
• Vitamin D is a true hormone that acts on distant
target cells to evoke responses after binding to
high affinity receptors
Synthesis of Vitamin D
• Vitamin D3 synthesis occurs in keratinocytes in
the skin.
• 7-dehydrocholesterol is photoconverted to
previtamin D3, then spontaneously converts to
vitamin D3.
Synthesis of Vitamin D
• PTH stimulates vitamin D synthesis. In the winter
or if exposure to sunlight is limited (indoor jobs!),
then dietary vitamin D is essential.
• Vitamin D itself is inactive, it requires
modification to the active metabolite, 1,25dihydroxy-D3.
• The first hydroxylation reaction takes place in the
liver yielding 25-hydroxy D3.
• Then 25-hydroxy D3 is transported to the kidney
where the second hydroxylation reaction takes
place.
Synthesis of Vitamin D
• The mitochondrial P450 enzyme 1α-hydroxylase
converts it to 1,25-dihydroxy-D3, the most potent
metabolite of Vitamin D.
• The 1α-hydroxylase enzyme is the point of
regulation of D3 synthesis.
• Feedback regulation by 1,25-dihydroxy D inhibits
this enzyme.
• PTH stimulates 1α-hydroxylase and increases
1,25-dihydroxy D3.
• Phosphate inhibits 1α-hydroxylase and decreased
levels of PO4 stimulate 1α-hydroxylase activity
Effects of Active Form of Vit D3
• Promotes intestinal absorption of calcium
• Causes synthesis of calcium-binding protein and
related facilitated transport
• Takes a couple of days to fully develop response
• Has slight effect to increase calcium re-absorption
in kidneys
• Works with PTH to cause calcium absorption
from bone
Calcitonin
• Secreted by the thyroid gland
• Effects are much less than those of PTH
Effects of Calcitonin
• Attenuates absorptive ability of osteoclasts
• Inhibits formation of new osteoclasts
– Osteoclast decrease causes osteoblast decrease
– Effect to decrease calcium is transitory
– Causes reduced bone turnover
• Has weak effect in kidney and intestines