Disorders of the parathyroid gland and regulation of the

calcium metabolismcalcium metabolismDr. 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 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• 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 • 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.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• 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)• 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 hyperCa1.Increased bone resorption

• Primary hyperparathyroidism

• Tumors

• Hyperthyroidism• 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)• Increases the 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 absorptionRegulation 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• 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)HyperparathyroidismHyperparathyroidismMEN-I (Wermer sy) + pancreas endocrin tu+ hypophysis

adenomaMEN-II ( Sipple sy) + phaeochromocytoma+ medullary cc of

thyroidMEN-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 Disease may run a benign course for years prior detection.

1.Symptoms of hypercalcaemia

2.Osteitis fibrosa cystica

1.Symptoms of hypercalcaemiaCentral nervous system

Impaired mental function, loss of memory, depression, somnolence, coma

NeuromuscularWeakness, arthralgias, severe pruritus (metast. calcification of skin), restless leg sy (no comfortable position)

CardiovascularHypertension, bradycardia, shortening of QT

RenalPolyuria, nephrocalcinosis, recurrent Ca nephrolithiasis

GastrointestinalAnorexia, vomiting, constipation, peptic ulcer, pancreatitis

RheumatologicGout, 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),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 elevatednephrogeneous cAMP , calcitriol elevated( SAP level is increased in whom there is significant osteitis cystica-representing 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 rangereference 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)forarm)

With hyperplasia subtotal (3 ½) parathyreoidectomy is carried out• Postoperative complications:

hypoCa (hyperP)-hypoparathyroidismHungry 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 bone disease• No mental dysfunctionWithold excessive Ca intake, maintain

adequate hydration and phosphate intake, withhold thiazide diuretics and follow the patient

Causes of hyperCa2.Increased absorption of Ca from gut

Increased Ca intakeMilk-alkali syRenal failure (with the treatment of hypoCa)Renal failure (with the treatment of hypoCa)

D hypervitaminosisexcessive ingestionexcessive activation (granulomatous diseases, lymphomas)

Causes of hyperCa3.Miscellaneous causes

• Drugs (Lithium, thiazide diuretics, theophyllin intoxication)

• Phaeochromocytoma - PTH increases• Adrenal insufficiency(Addison)• 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 highprimary hyperpara/ or parathormon like hormon production

of malignancy (very rare)

2.PTH normal or slight increaseDetermine 24hour urin Ca(BFHyCa)Determine 24hour urin Ca(BFHyCa)

3.PTH lowEvaluate for malignancyEvaluate for drugs, TSHEvaluate 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+ Furosemide80-160mg/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 • 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 • 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 • 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), orHyperparathyroidism (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 • Cardiac: QT prolongation- syncope, death due to arrhythmias such as polymorphic ventricular tachycardia

• Respiratory: laryngospasm- stridor-significant 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 minutespressure 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 -b.Deficient PTH action (hormone resistance -pseudohypoparathyroidism)

2.Target organ dysfunction

1.Primary hypoparathyroidisma.Deficient PTH secretion

PostsurgicalMg deficiency - impaired secretion of PTHInherited forms of hypoparathyroidism

Familial - sex linked recessive ( males, first year of life, notassociated with other abnormalities)

- autosomal recessive (before the age 30, autoimmune origin, - autosomal recessive (before the age 30, autoimmune origin,

other abnormalities: mucocutan candidiasis, Addison, hypothyroidism, pernicious anaemia)

Congenital - di George sy- no parathyroid gland, no thymus-immundeficiency leads to early death

Sporadic, idiopathic hypoparathyroidismOther 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 hypoparathyroidismb.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 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 defectiveKidney receptor bad - hypoCa, hyperPbone receptor good - osteitis fibrosa cystica

Pseudohypoparathyreoidism type I.

Differencial dg in primary hypoparathyroidismSigns, symptoms Pseudo Fam./idiopat. Postsurg

Increased neuromusc.excitability + + +

Cataracts + + +

Basal gangl.calcification + + +

Prolonged QT + + +

Papilledema + + +

Dental defect + + +Dental defect + + +

Alopecia - + -

Vitiligo - + -

Moniliasis - + -

Hypothyroidism + + +

Hypoadrenalism - + -

Primary hypogonadism + + -

Osteodystrophy, brachydactily,sc. calcifications

+ - -

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 hypoCa2.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 alkalosisDecreased mobilisation from bone• HypoMg• Fluorid intox.• Bisphosphonate side effectReduced Ca absorption• Vitamin D deficiency, malabsorption diseasesMiscellanous : sepsis, severe burns, chemotherapy (cisplatin, leucovorin,5FU)

Treatment of hypoCa

• Treat Mg deficiency• Mild, asymptomatic (>0,8mm/l)-Ca intake

1gr/die1gr/die• Acute, symptomatic -1-2gr Cagluconate

iv/in 20 minutes• After parathyroidectomy-1-3grCa and 0,25-

0,5ug kalcitriol/die,+ dihidrotachysterol, +Thiazid diuretics

• Free calcium is tightly regulated (±5%)– Too low = neuronal hyper-excitability

– Too high = neuronal depression

Plasma Calcium Regulation

– 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 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– 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 • 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

• Vitamin D3 synthesis occurs in keratinocytes in the skin.

• 7-dehydrocholesterol is photoconverted to previtamin D3, then spontaneously converts to

Synthesis of Vitamin D

previtamin D3, then spontaneously converts to vitamin D3.

• 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, 1,25-

Synthesis of Vitamin D

modification to the active metabolite, 1,25-dihydroxy-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.

• 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.

Synthesis of Vitamin D

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• 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

• Attenuates absorptive ability of osteoclasts

• Inhibits formation of new osteoclasts– Osteoclast decrease causes osteoblast decrease

Effects of Calcitonin

– Effect to decrease calcium is transitory

– Causes reduced bone turnover

• Has weak effect in kidney and intestines