Diseases of the Parathyroid Gland

7/25/2019 Diseases of the Parathyroid Gland

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PRIMARY HYPERPARATHYROIDISM:

ETIOLOGY:

SOLITARY ADENOMAS: ~80%: a single abnormal gland is the cause (benign neoplasm,

adenoma or a parathyroid carcinoma)

~15%: all glands are hyperfunctioning (chief cell parathyroid

hyperplasia) Others: double adenomas

MULTIPLE ENDOCRINE NEOPLASIA (MEN): MEN 1 (Wermerssyndrome): hyperparathyroidism, pituitary and

pancreatic tumors, gastric hypersecretion and PUD (Zollinger-Ellisonsyndrome)

MEN 2A: pheochromocytoma, medullary carcinoma of the thyroid,hyperparathyroidism

MEN 2B: multiple neuromas without hyperparathyroidism


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PRIMARY HYPERPARATHYROIDISM:PATHOLOGY:

ADENOMAS: Most often located in the inferior parathyroid glands

Usually 0.5 to 5 grams in size but may be as large as 10-20 grams (normalglands weigh 25 mg on average)

Chief cells are predominant in both hyperplasia and adenoma

PARATHYROID CARCINOMA may be: (1) non-aggressive-long-term survival without recurrence is common if at

initial surgery the entire gland is removed without rupture of the capsule

(2) aggressivewith distant metastases ( lung, liver, bone)

Hyperparathyroidism from a parathyroid carcinoma may be indistinguishablefrom other forms of primary hyperparathyroidism; a potential clue to thediagnosis is provided by the degree of calcium elevation (> 3.5 to 3.7mmol/Lor 14-15 mg/dL)

GENETIC CONSIDERATIONS:

As in many other types of neoplasia, 2 fundamental types of geneticdefects have been identified in parathyroid gland tumors:

(1) overactivity of protooncogenes (2) loss of function of tumor-suppressor genes


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PRIMARY HYPERPARATHYROIDISM:SIGNS and SYMPTOMS:

~80% of patients with hyperparathyroidism are asymptomatic

MANIFESTATIONS: 1. KIDNEYS:

Due either to deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis

(60-70%)

Renal stones are usually composed of either calcium oxalate or calcium phosphate

Repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary

tract obstruction, infection and loss of renal function

Nephrocalcinosis may also cause decreased renal function and phosphate retention

2. BONE:

OSTEITIS FIBROSA CYSTICA- the distinctive bone manifestation

The pathognomonic histologic features are an increase in the giant multinucleated

osteoclasts in scalloped areas on the surface of the bone (HOWSHIPS LACUNAE) and thereplacement of the normal cellular and marrow elements by fibrous tissue

X-ray changes include resorption of the phalangeal tufts and replacement of the usually

sharp cortical outline of the bone in the digits by an irregular outline (SUBPERIOSTEAL

RESORPTION)

Cortical bone density is reduced while cancellous bone density, especially in the spine, is

relatively preserved


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3. CNS- neuropsychiatric manifestations

4. NEUROMUSCULAR MANIFESTATIONS: Proximal muscle weakness, easy fatigability, muscle atrophy

The distinguishing feature from a primary neuromuscular disorder isthe complete regression of neuromuscular disease after surgicalcorrection of the hyperparathyroidism

5. GASTROINTESTINAL MANIFESTATIONS Subtle or may present as vague abdominal complaints or as disorders

of the stomach and pancreas Duodenal ulcer in MEN 1 may be the result of associated pancreatic

tumors that secrete excessive quantities of gastrin (Zollinger-Ellisonsyndrome)


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PRIMARY HYPERPARATHYROIDISM:DIAGNOSIS:

Made by detecting an elevated immunoreactive PTH level in a patient withasymptomatic hypercalcemia

Serum phosphate is usually low, but may be normal especially if renal failure hasdeveloped

TREATMENT:

MEDICAL SURVEILLANCE vs. SURGICAL TREATMENT

SURGERYis mandatory if (+)severe hypercalcemia (3.7 to 4.5 mmol/L or 15-18mg/dL)

ASYMPTOMATIC HYPERPARATHYROIDISM:

Defined as documented (presumptive) hyperparathyroidism without signs or symptomsattributable to the disease

SURGERYis recommended by the National Institutes of Health (NIH) for the following: (1) patients 50 y/o

(2) if patient wishes to avoid surgery

(3)the guidelines recommending surgery were not present***


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PRIMARY HYPERPARATHYROIDISM:MEDICAL MANAGEMENT GUIDELINES for

ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISMwho do not undergo parathyroid surgery: (1)Serum calcium measurement should be monitored

biannually

(2) Serum creatinine monitoring should be done annually

(3) Bone density measurement (lumbar spine, hip,forearm) should be undertaken annually

MEDICAL TREATMENT OPTIONS: (1) RALOXIFENE (Evista)

the 1stof the SERMS has bone protective effects in osteoporotic subjectsand increased bone density at the same time lowering the incidence ofbreast cancer compared to estrogens

(2) CALCIMIMETIC DRUGS selectively stimulate the calcium sensor and suppress PTH secretion ,

decreasing calcium levels to normal and lower PTH levels by at least 50%for > 1year of continuous use


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PRIMARY HYPERPARATHYROIDISM:GUIDELINES for PARATHYROID SURGERY in ASYMPTOMATIC PRIMARY

HYPERPARATHYROIDISM:

(1) Serum calcium >0.3mmol/L (1.0 mg/dL) above upper limit of normal

(2) 24-h urinary calcium >400 mg

(3) Creatinine clearance reduced by 30%

(4) Bone mineral density T-score < 2.5 at any site

(5) Age 1 glandis abnormal

Another approach involves a combination of preoperative sestamibi imaging, cervicalblock anesthesia, minimal surgical incision and intraoperative PTH measurement whichhas allowed successful outpatient surgical management with a clear-cut cost benefitcompared to general anesthesia and more extensive neck surgery

When parathyroid carcinoma is encountered, the tissue should be widely excised; care

must be taken to avoid rupture of the capsule to prevent local seeding of tumor cells


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In multiple gland hyperplasia, 2 schemes have beenproposed for surgical management: (1) total removal of 3 glands with partial excision of the 4th

gland; care is taken to leave a good blood supply for theremaining gland

(2) total parathyroidectomy with immediate transplantation of aportion of a removed, minced parathyroid gland into themuscles of the forearm, with the view that surgical excision iseasier from the ectopic site in the arm if there is recurrenthyperfunction

When a 2ndparathyroid exploration is indicated, minimallyinvasive techniques such as UTZ, CT scan and isotopescanning may be combined with venous sampling and/orselective digital arteriography, with intraoperative PTH

monitoring to guide the surgery


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PRIMARY HYPERPARATHYROIDISM:HYPOCALCEMIA after PARATHYROID SURGERY:

A decline in serum calcium occurs within 24hrs after successful surgery

Blood calcium falls to low-normal values for 3-5days until the remainingparathyroid tissue resumes hormone secretion

Once hypocalcemia signifies successful surgery, patients can be put on a high-calcium intake or be given oral calcium supplements

If serum calcium falls to


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MAGNESIUM DEFICIENCY after PARATHYROID SURGERY:

Magnesium deficiency may also complicate the postoperative course

Magnesium deficiency impairs PTH secretion, so hypomagnesemia shouldbe corrected whenever detected

Because the depressant effect of magnesium on central and peripheralnerve functions does not occur at levels


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LITHIUM THERAPY:

Lithium, used in the management of bipolar depression and otherpsychiatric disorders, causes hypercalcemia in ~10% of treatedpatients

The hypercalcemia is dependent on continued lithium treatment,

remitting and recurring when lithium is stopped and restarted

Long-standing stimulation of parathyroid cell replication by lithiummay predispose to the development of adenomas

Parathyroid surgery should not be recommended unlesshypercalcemia and elevated PTH level persist after lithium isdiscontinued


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FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH):

Also called Familial Benign Hypercalcemia

Inherited as an autosomal dominant trait

Involves excessive secretion of PTH, but does not involve a primary growth disorder of the

parathyroids

PATHOPHYSIOLOGY:

The primary defect is abnormal sensing of the blood calcium by the parathyroid gland

and renal tubule, causing inappropriate PTH secretion and excessive renalreabsorption of calcium

Many different mutations in the calcium-sensing receptor have been identified- these

mutations lower the capacity of the sensor to bind calcium, and the mutant receptors

function as though blood calcium levels were low

Excessive PTH secretion occurs from an otherwise normal gland Few clinical signs or symptoms are present, and other endocrine abnormalities are not

present

Parathyroid surgery or medical treatment seem needed to lower the calcium

The exception to the rule against parathyroid surgery is NEONATAL SEVERE

HYPERCALCEMIA


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JANSENS DISEASE:

A rare autosomal dominant syndrome and variant of hyperparathyroidism

Caused by excessive biologic activity of the PTH receptor in targettissues

Does not involve a primary growth disorder of the parathyroid glands

Manifestations:

The disorder leads to short-limbed dwarfism due to abnormalregulation of the bone growth plate

In adult life, there are numerous abnormalities in bone, includingmultiple cystic resorptive areas resembling those seen inhyperparathyroidism

Hypercalcemia and hypophosphatemia with undetectable or low PTH

levels are typically seen


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MALIGNANCY-RELATED

HYPERCALCEMIA:CLINICAL SYNDROMES and MECHANISMS of HYPERCALCEMIA:

Previously, hypercalcemia associated with malignancy was thought to be due to localinvasion and destruction of bone by tumor cells

Many cases are now known to result from the elaboration by the malignant cells ofhumoral mediators of hypercalcemia

Parathyroid hormone related protein (PTHrP) is the responsible humoral agent

MECHANISMS OPERATIVE in CANCER HYPERCALCEMIA:

(1) many solid tumors associated with hypercalcemia (squamous cell and renal tumors)produce and secrete PTHrP that causes increased bone resorption and mediate thehypercalcemia through systemic actions on the skeleton Alternatively, direct bone marrow invasion occurs with hematologic malignancies (leukemia, lymphoma,

multiple myeloma)

Lymphokines and cytokines produced by cells involved in the marrow response to the tumors promotebone resorption through local destruction

(2) HUMORAL HYPERCALCEMIA of MALIGNANCY solid tumors (cancers of the lung and kidney) in which bone metastases are absent, minimal or not

detectable clinically, secrete PTHrP, which activates PTH1R, resulting in a pathophysiology resemblinghyperparathyroidism (hypercalcemia, hypophosphatemia);

elimination or regression of the primary tumor leads to disappearance of the hypercalcemia


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MALIGNANCY-RELATED HYPERCALCEMIA:DIAGNOSIS:

Clinical suspicion that malignancy is the cause of the hypercalcemia is heightened whenthere are other paraneoplastic signs or symptoms (weight loss, fatigue, muscle weakness,

unexplained skin rash) or when symptoms specific for a particular tumor are present

Squamous cell tumors are most frequently associated with hypercalcemia (lung, kidney,

head and neck, and urogenital tract)

Radiologic examinations should focus on squamous cell tumor locations when clinical

evidence is unclear

Bone scans are useful for detection of osteolytic metastases

Bone marrow biopsies are helpful in patients with anemia or abnormal PBS

TREATMENT:

Directed to control of tumor

Reduction of tumor mass usually corrects hypercalcemia


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VITAMIN D-RELATED HYPERCALCEMIA:

Can be due to excessive ingestion or abnormal metabolism of thevitamin

Vitamin D metabolism is carefully regulated, particularly the activityof renal 1--hydroxylase, the enzyme responsible for the production

of 1,25(OH)2D

The regulation of 1--hydroxylase and the normal feedbacksuppression by 1,25(OH)2D seem to work less well and operatepoorly in sites other than the renal tubule

These phenomena explain the occurrence of hypercalcemiasecondary to excessive 1,25(OH)2D3 production in infants withWilliams syndrome and in adults with sarcoidosis or lymphoma


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VITAMIN D INTOXICATION:

Chronic ingestion of 50-100x the normal physiologic requirement of vitamin D

(amounts>50,000 to 100,000 U/day)is required to produce significant hypercalcemia in

normal individuals

Vitamin D excess increases intestinal calcium absorption, and if severe, also increases

bone resorption

Hypercalcemia in vitamin D intoxication is due to an excessive biologic action of the

vitamin, the consequence of increased levels of 25(OH)2D rather than merely increasedlevels of the active metabolite 1,25(OH)2D

DIAGNOSIS:

substantiated by documenting elevated levels of 25(OH)D > 100ng/mL

TREATMENT: Hypercalcemia is controlled by restriction of dietary calcium intake and appropriate

attention to hydration

Vitamin D stores in fat may be substantial, and vitamin D intoxication may persist for

weeks after vitamin D ingestion is terminated

Glucocorticoids (Hydrocortisone) in doses of 100mg/day return serum calcium levelsto normal over several days


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SARCOIDOSIS and Other

GRANULOMATOUS DISEASES: In patients with sarcoidosis and other granulomatous diseases (TB,

fungal infections), excess 1,25(OH)2D is synthesized in macrophagesor other cells in the granulomas

The usual regulation of active metabolite production by calcium or

PTH does not operate in the above conditions- hypercalcemia doesnot lead to reduction in the blood levels of 1,25(OH)2D, and itsclearance from the blood may be decreased as well

TREATMENT:

Avoiding excessive sunlight exposure and limiting vitamin D andcalcium intake

Glucocorticoids (Hydrocortisone


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IDIOPATHIC HYPERCALCEMIA of INFANCY:

Also referred to as WILLIAMS SYNDROME

An autosomal dominant disorder due to abnormal sensitivity to Vitamin D

Characterized by multiple congenital development defects:

supravalvular AS, MR

an elfin facies hypercalcemia

Levels of 1,25(OH)2D are elevated ranging from 46 to 120 nmol/L (150-500pg/mL)

The mechanism of the abnormal sensitivity to vitamin D and of theincreased circulating levels of 1,25(OH)2D is still unclear

Studies suggest that mutations involving the elastin locus and perhaps othergenes on chromosome 7 may play a role in the pathogenesis


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HYPERCALCEMIA Associated with

HIGH BONE TURNOVER:1. HYPERTHYROIDISM:

~20% of hyperthyroid patients have high-normal or mildly elevated

serum calcium concentrations associated with hypercalciuria

The hypercalcemia is due to increased bone turnover, with boneresorption exceeding bone formation

Severe calcium elevations are not typical, and the presence of such

suggests a concomitant disease such as hyperparathyroidism

Hypercalcemia is managed by treatment of the hyperthyroidism

2. IMMOBILIZATION:

The mechanism appears to involve a disproportion between bone

formation and bone resorption


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HYPERCALCEMIA Associated with HIGH BONE TURNOVER:

3. THIAZIDES:

Administration of thiazides can cause hypercalcemia in patients with high rates of

bone turnover, such as patients with hypoparathroidism treated with high doses ofvitamin D

Chronic thiazide administration leads to reduction in urinary calcium; thehypocalciuric effect appears to reflect the enhancement of proximal tubularresorption of sodium and calcium in response to sodium depletion

The abnormal effects of thiazide on calcium metabolism disappear within days ofcessation of the drug:

4. VITAMIN A INTOXICATION:

Calcium levels can be elevated into the 3 to 3.5mmol/L (12-14mg/dL) range afterthe ingestion of 50,00100,000 units of vitamin A daily (10-20x the minimumdaily requirement)

Excess vitamin A intake is presumed to increase bone resorption

DIAGNOSIS:

established by history and by measurement of vitamin A levels in serum

skeletal x-rays reveal periosteal calcifications

TREATMENT:

withdrawal of the vitamin Hydrocortisone 100mg/d


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HYPERCALCEMIA Associated with RENAL FAILURE:

1. SEVERE SECONDARY HYPERPARATHYROIDISM:

Secondary hyperparathyroidism occurs when partial resistance to the metabolic actionsof PTH leads to excessive production of the hormone

Parathyroid gland hyperplasia occurs because resistance to the normal level of PTH leadsto hypocalcemia, which, in turn, is a stimulus to parathyroid gland enlargement

SYMPTOMS:

Bone pain, ectopic calcification, pruritus

RENAL OSTEODYSTROPHY- bone disease seen in patients with secondaryhyperparathyroidism and renal failure

OSTEOMALACIA -due to vitamin D and calcium deficiency

OSTEITIS FIBROSA CYSTICA -due to excessive PTH action on bone may also occur

TREATMENT: Reduction of excessive blood phosphate by restriction of dietary phosphate

The use of nonabsorbable antacids (CALCIUM CARBONATE ) is preferred overaluminum-containing antacids to prevent aluminum toxicity

CALCITRIOL(0.25 to 2.0ug/day)

TERTIARY HYPERPARATHYROIDISM- a state of severe hyperparathyroidism in patientswith renal failure that requires surgery


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HYPERCALCEMIA Associated with RENAL FAILURE:

2. ALUMINUM INTOXICATION: May occur in patients on chronic dialysis

MANIFESTATIONS: Acute dementia, unresponsive and severe osteomalacia, bone pain, multiple nonhealing

fractures (ribs, pelvis), proximal myopathy

Hypercalcemia develops when these patients are treated with vitamin D or calcitriolbecause of impaired skeletal responsiveness

PREVENTION: avoidance of aluminum excess in the dialysis regimen

TREATMENT: mobilizing aluminum through the use of the chelating agent

(DEFEROXAMINE)

3. MILK-ALKALI SYNDROME: Due to excessive ingestion of calcium and absorbable antacids (milk, use of

calcium carbonate in osteoporosis)

CLINICAL PRESENTATIONS: Hypercalcemia, alkalosis, renal failure

The cycle of mild hypercalcemia-> bicarbonate retention-> alkalosis-> renal calciumretention-> severe hypercalcemia perpetuates and aggravates hypercalcemia andalkalosis as long as calcium and absorbable alkali are ingested

BURNETTS SYNDROME- the chronic form of the disease associated with irreversiblerenal damage

The acute syndromes reverse if the excess calcium and absorbable alkali arestopped


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ALGORITHM for the EVALUATION of

PATIENTS with HYPERCALCEMIA:


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TREATMENT:1. HYDRATION, INCREASED SALT INTAKE and MILD and FORCED DIURESIS:

Many hypercalcemic patients are dehydrated because of vomiting, inanition,and/or hypercalcemia-induced defects in urinary concentrating ability

The resulting drop in GFR is accompanied by an additional decrease in renaltubular sodium and calcium clearance

Restoring a normal ECF volume corrects these abnormalities and increasesurine calcium excretion by 2.5-7.5 mmol/d (100-300mg/d)

Increasing urinary sodium excretion to 400-500 mmol/d increases urinary

calcium excretion even further than simple rehydration

After rehydration, saline can be administered or furosemide or ethacrynicacid can be given to depress the tubular reabsorptive mechanism for calcium

Precautions should be taken to prevent potassium and magnesium depletion;renal calculi are also a potential complication


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TREATMENT:

2. BIPHOSPHONATES: Analogues of pyrophosphate

High affinity for bone especially in areas of increased bone turnover

Powerful inhibitors of bone resorption

1stgeneration: Etidronate

2ndgeneration: Pamidronate 3rdgeneration: Zolendronate

3. CALCITONIN: Calcitonin acts through receptors on osteoclasts to block bone

resorption and to increase urinary calcium excretion by inhibition ofrenal tubular calcium reabsorption

Usual doses are 2-8U/kg BW IV, SC or IM q 6-12hrs


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TREATMENT:4. OTHER THERAPIES: PLICAMYCIN:

inhibits bone resorption but has been replaced by biphosphonates because of its toxicity

Given IV, either as a bolus or by slow infusion at a dose of 25ug/kg BW

GALLIUM NITRATE:

Exerts a hypocalcemic action by inhibiting bone resorption and altering the structure of bone crystals

GLUCOCORTICOIDS:

Increase urinary calcium excretion and decrease intestinal calcium absorption Malignancies in which hypercalcemia responds to glucocorticoids: multiple myeloma, leukemia,

Hodgkins disease, carcinoma of the breast

Glucocorticoids are also effective in treating hypercalcemia due to vitamin D intoxication andsarcoidosis

Prednisone 40-100mg daily in 4 divided doses

DIALYSIS: Treatment of choice for severe hypercalcemia complicated by renal failure

PHOSPHATE THERAPY:

Correcting hypophosphatemia lowers the serum calcium concentration

The usual oral dose is 1 to 1.5g phosphorus per day

IV phosphate is used only in severe hypercalcemia with cardiac or renal failure at a dose of >1500 mgover 6-8hrs leads to a decrease of serum calcium to 1.2-2.5mmol/L (5-10mg/dL)


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TREATMENT:SUMMARY:

The choice of treatment depends on the underlying disease, the

severity of the hypercalcemia, the serum inorganic phosphate level,and the renal, hepatic and bone marrow function

MILD HYPERCALCEMIA (3.7mmol/L or 15mg/dL): Calcitoningiven for its rapid blockade of bone resorption

IV biphosphonates- pamidronate or zolendronate

For the 1st24-48hrs, aggressive sodium-calcium diuresis with IV salineand large doses of furosemide or ethacrynic acid following initial

hydration while monitoring cardiac and renal function Dialysis

MODERATE HYPERCALCEMIA (3-3.7mmol/L or 12-15mg/dL):vigorous hydration plus the most appropriate selection for the

patient of the combinations used with severe hypercalcemia


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HYPOCALCEMIA:

SIGNS and SYMPTOMS: Paresthesia around the mouth, fingers and toes

Tetany: (+) Trousseau & Chvostek signs

Seizures

Dementia

Cataracts

Calcification of the basal ganglia

Epidermal changes (dry skin, coarse hair, brittle nails)

ECG abnormalities (prolonged QT intervals & QRS and ST changes which mimicMI)

FACTITIOUS HYPOCALCEMIA: Decrease in total Ca, but not ionized Ca

Majority is due to hypoalbuminemia caused by chronic Illness, psoriasis,malnutrition, volume expansion


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HYPOCALCEMIA:ETIOLOGIES:

1. ABSENCE of PTH or PARATHYTOID GLANDS A. Congenital

B. Postsurgical hypoparathyroidism

C. Infiltrative disorders (e.g., hemochromatosis)

D. Hypoparathyroidism secondary to radioactive iodine thyroid ablation

E. Autoimmune hypoparathyroidism (isolated or as part of Polyglandular Autoimmune Syndrome Type1)

2. IMPAIRED SECRETION of PTH

A. Hypomagnesemia B. Respiratory alkalosis

C. Activating mutations of the Ca sensor

3. TARGET ORGAN RESISTANCE to PTH A. Hypomagnesemia

B. Pseudohypoparathyroidism (Type I and II)

4. VITAMIN D RELATED A. Vitamin D deficiency

B. Accelerated vit D loss C. Impaired 25-hydroxylation

D. Impaired 1-alpha-hydroxylation (e.g., renal failure)

E. Target-organ resistance

5. OTHERS A. Chelation with drugs

B. Pancreatitis

C. Septic shock

D. Hungry bone disease

HYPOCALCEMIA


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HYPOCALCEMIA: ACUTE HYPOCALCEMIA:

Patients have rapid decrease in serum Ca (


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FUNCTIONAL CLASSIFICATION of HYPOCALCEMIA:I. PTH ABSENT:

A. Hereditary hypoparathyroidism

B. Acquired hypoparathyroidism

C. Hypomagnesemia

II. PTH INEFFECTIVE:

A. Chronic renal failure

B. Active vitamin D lacking: 1. Decreased dietary intake or sunlight

2. Defective metabolism Anticonvulsant therapy

Vitamin D-dependent rickets type I

C. Active vitamin D ineffective 1. Intestinal malabsorption

2. Vitamin D-dependent rickets type II

D. Pseudohypoparathyroidism

III. PTH OVERWHELMED:

A. Severe, acute hyperphosphatemia 1. Tumor lysis

2. Acute renal failure

3. Rhabdomyolysis

B. Osteitis fibrosa after parathyroidectomy


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PTH ABSENT:

1. HEREDITARY HYPOPARATHYROIDISM: Onset is gradual and associated with other developmental defects

of the thymus or failure of other endocrine organs (adrenal, thyroid,ovary)

Manifest within the 1stdecade but may appear later

MANIFESTATIONS: Basal ganglia calcification and extrapyramidal syndromes are more

common and earlier in onset than in acquired hypoparathyroidism

Papilledema and raised ICP may occur in both hereditary and acquiredhypoparathyroidism, as do chronic changes in the fingernails and hairand lenticular cataracts

Skin manifestations: alopecia, candidiasis


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PTH ABSENT:IDIOPATHIC HYPOPARATHYROIDISM :Hereditary hypoparathyroidism occuring as an isolated entity

without other endocrine or dermatologic manifestations

DiGEORGE SYNDROME (Velocardiofacial Syndrome):

A rare form of hypoparathyroidism associated with defective development of both the thymus andthe parathyroid glands

Congenital cardiovascular, facial and other developmental defects are present, and most patientsdie in early childhood with severe infections, hypocalcemia and seizures, or cardiovascularcomplications

Most cases are sporadic, but an autosomal dominant form has been described

POLYGLANDULAR AUTOIMMUNE TYPE 1 DEFICIENCY:

Hypoparathyroidism occurs in association with a complex hereditary autoimmune syndromeinvolving failure of the adrenals, the ovaries, the immune system, and the parathyroids inassociation with recurrent mucocutaneous candidiasis, alopecia, vitiligo and pernicious anemia

AUTOSOMAL DOMINANT HYPOCALCEMIA:

Due to gain-of-function mutations in the calcium-sensing receptor The activated receptor suppresses PTH secretion leading to hypocalcemia: receptor activation in

the kidney results in excessive calcium excretion

HYPOPARATHYROIDISM associated with MITOCHONDRIAL DYSFUNTION and MYOPATHY:

1. KEARNS-SAYRE SYNDROME (KSS)associated with ophthalmoplegia and pigmentaryretinopathy

2. MELAS SYNDROMEMitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes


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PTH ABSENT:2. ACQUIRED HYPOPARATHYROIDISM:

Usually the result of inadvertent surgical removal of all the parathyroid glands

The most frequent cause in the past was surgery for hyperthyroidism; hypoparathyroidismnow usually occurs after surgery for hyperparathyroidism

Rare causes:

Radiation-induced damage subsequent to radioiodine therapy of hyperthyroidism

Glandular damage in patients with hemochromatosis or hemosiderosis after repeatedblood transfusions

TRANSIENT HYPOPARATHYROIDISMoccurs following surgery for hyperparathyroidismafter normal parathyroid function returns to normal due to hyperplasia or recovery ofremaining tissue

TREATMENT: Treatment of acquired and hereditary hypoparathyroidism involves :

(1) Replacement with Vitamin D (40,000 to 120,000 U/day)

(2) 1,25(OH)2D (calcitriol) at 0.5 to 1.0 ug

(3) High oral calcium intake

(4) Thiazides- diuretics lower urine calcium by as much as 100mg/day in

hypoparathyroid patients on Vitamin D, provided they are maintained on a low sodiumdiet


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PTH ABSENT:

3. HYPOMAGNESEMIA: Severe hypomagnesemia (


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PTH INEFFECTIVE:

PTH is ineffective when:

(1) the hormone receptor-guanyl nucleotide-bindingprotein complex is defective (PHP) resulting in failure of

PTH to increase intracellular cAMP

(2) PTH action to promote calcium absorption from thediet is impaired due to Vitamin D deficiency or becausevitamin D is ineffective (receptor or synthesis defects)

(3) CRF where the calcium-elevating action of PTH isimpaired

PTH INEFFECTIVE


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PTH INEFFECTIVE:1. MECHANISMS of HYPOCALCEMIA in CHRONIC RENAL FAILURE (CRF):

Phosphate retention and impaired production of 1,25(OH)2D are the principal factors that cause

calcium deficiency, secondary hyperparathyroidism and bone disease

Low levels of 1,25(OH)2D due to hyperphosphatemia and destruction of renal tissue are

critical in the development of hypocalcemia

Hyperphosphatemia in renal failure lowers blood calcium levels by the following mechanisms:

(1) Extraosseous deposition of calcium and phosphate

(2) Impairment of the bone-resorbing action of PTH

(3) Reduction in 1,25(OH)2D production by remaining renal tissue

The uremic state also causes impairment of intestinal absorption by mechanisms other than

defects in vitamin D metabolism

TREATMENT: Phosphate restriction in the diet

Avoidance of aluminum-containing phosphate-binding antacids to prevent aluminum intoxication

Oral calcium supplementation (1-2g/day) and Calcitriol (0.25-1.0 ug/day)

The aim of therapy is to restore normal calcium balance to prevent osteomalacia and secondary

hyperparathyroidism, and to prevent secondary from becoming autonomoushyperparathyroidism.


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PTH INEFFECTIVE:

2. VITAMIN D DEFICIENCY due to INADEQUATE DIET and/or SUNLIGHT: PTH hypersecretion compensates for the tendency for the blood calcium to

fall but also induces renal phosphate wasting and results in osteomalacia

3. DEFECTIVE VITAMIN D METABOLISM:

A. ANTICONVULSANT THERAPYinduces vitamin D deficiency by increasingthe conversion of Vitamin D to inactive compounds

B. VITAMIN D-DEPENDENT RICKETS TYPE I (Pseudo-vitamin D-resistantrickets)

Due to the resistance to the action of vitamin D as well as to vitamin D deficiency

Autosomal recessive caused by mutations in the gene encoding 25(OH)D-1-alpha-

hydroxylase Differs from true vitamin D-resistant rickets in that it is less severe and the

biochemical and radiographic abnormalities can be reversed with appropriatedoses of vitamin D or its active metabolite 1,25(OH)2D3

CLINICAL FEATURES:hypocalcemia, often with tetany and convulsions,hypophosphatemia, secondary hyperparathyroidism and osteomalacia associatedwith skeletal deformities and increased alkaline phosphatase


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PTH INEFFECTIVE:4. VITAMIN D INEFFECTIVE:

A. INTESTINAL MALABSORPTION: Mild hypocalcemia, secondary hyperparathyroidism, severe

hypophosphatemia, and a variety of nutritional deficiencies occur with GIdiseases

Hepatocellular dysfunction (portal or biliary cirrhosis of the liver) can lead toreduction in 25(OH)D levels

Malabsorption of vitamin D and its metabolites (1,25(OH)2D) may occur in avariety of bowel diseases, hereditary or acquired

Hypocalcemia can lead to steatorrhea due to deficient production ofpancreatic enzymes and bile salts

B. VITAMIN D-DEPENDENT RICKETS TYPE II: Results from end-organ resistance to the active matabolite 1,25(OH)2D

CLINICAL FEATURES: hypocalcemia, hypophosphatemia, secondaryhyperparathyroidism, rickets, and partial or total alopecia

All of the genetically characterized genotypes have mutations in the gene forthe vitamin D receptor


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PTH INEFFECTIVE:5. PSEDOHYPOPARATHYROIDISM (PHP):

A hereditary disorder characterized by symptoms and signs of hypoparathyroidism inassociation with distinctive skeletal and developmental defects

The hypoparathyroidism is due to a deficient end-organ response to PTH

Hyperplasia of the parathyroids, a response to hormone resistance, causes elevation of PTHlevels

CLASSIFICATION:

1. PHP-Ia

2. PHP-Ib

3. PHP-II 4. PPHP

TREATMENT:

Treatment is similar to that of hypoparathyroidism, except that the doses of vitamin Dand calcium are usually lower than those required in true hypoparathyroidism,presumably because the defect in PHP is only partial because of imprinting in specifictissues


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CLASSIFICATION of PHP and PPHP:


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PTH OVERWHELMED:

The loss of calcium from the ECF is so severe that PTHcannot compensate

Situations in which there is rapid efflux of calcium:

Acute pancreatitis

Severe acute hyperphosphatemia in association with renalfailure

Severe hypocalcemia can occur quickly; PTH rises inresponse to hypocalcemia but does not return bloodcalcium to normal


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PTH OVERWHELMED:A. SEVERE ACUTE HYPERPHOSPHATEMIA:

Severe hyperphosphatemia is associated with extensive tissue damage or celldestruction

The combination of increased release of phosphate from muscle and impaired ability toexcrete phophorus because of renal failure causes moderate to severehyperphosphatemia, the latter causing calcium loss from the blood and mild tomoderate hypocalcemia

Hypocalcemia is usually reversed with tissue repair and restoration of renal function asphosphorus and creatinine values return to normal

Other causes of hyperphosphatemia: hypothermia, massive hepatic failure, hematologicmalignancies

TREATMENT: Directed toward lowering of blood phosphate by the administration of phosphate-

binding antacids or dialysis

Although calcium replacement may be necessary if hypocalcemia is severe andsymptomatic, calcium administration during the hyperphosphatemic period tends toincrease extraosseous calcium deposition and aggravate tissue damage


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PTH OVERWHELMED:

B. OSTEITIS FIBROSIS after PARATHYROIDECTOMY:

Hypocalcemia can persist for days afterparathyroidectomy if calcium replacement isinadequate

Treatment:

parenteral calcium calcitriol and oral calcium supplementation is

sometimes needed for weeks to a month or two untilbone defects are filled


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DIFFERENTIAL DIAGNOSIS: CHRONIC HYPOCALCEMIA:

Can be ascribed to disorders associated with absent or ineffective PTH Characterized by LOW CALCIUM and LOW PHOSPHORUS

Important clinical criteria include: duration of the illness, sings or symptoms of associated disorders,presence of features that suggest a hereditary abnormality, nutritional history, history of excessive alcoholintake (magnesium deficiency)

HYPOPARATHYROIDISM and PHP:

Typically lifelong illnesses, usually appearing by adolescence Characterized by a LOW CALCIUM and HIGH PHOSPHORUS in the absence of renal failure or massive tissue

destruction

A recent onset of hypocalcemia that results in deficient or ineffective vitamin D in an adult: NUTRITIONAL DEFICIENCIES, RENAL FAILURE or INTESTINAL DISORDERS

POSTOPERATIVE HYPOPARATHYROIDISM- follows neck surgery

A history of SEIZURE DISORDER raises the issue of ANTICONVULSANT THERAPY

RICKETS and a variety of neuromuscular syndromes and deformities may indicate ineffectivevitamin D action, either due to defects in vitamin D metabolism or to vitamin D deficiency


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DIAGNOSIS: LABORATORY TESTS:

(1) Serum Ca (ionized Ca is the preferred measurement) (2) Albumin:

Hypoalbuminemia may result in false hypocalcemia if total serum calcium is measured

For each 1g/dL decrease in albumin below 4g/dL, subtract 0.8g/dL from the total serum Ca

(3) Phosphorus, PTH, Mg and if available, 25(OH)D and 1,25(OH)2D

PARATHYROID-RELATED DISORDERS: low serum Ca, high serum phosphate, low 1,25(OH)2D, low PTH

VITAMIN D-RELATED DISORDERS: hypocalcemia, hypophosphatemia, high PTH, low 1,25(OH)2D in vitamin D-

deficient patients

Failure to detect elevated PTH levels in the presence of hypocalcemia establishes the diagnosis ofHYPOPARATHYROIDISM; elevated levels suggest the presence of SECONDARY HYPERPARATHYROIDISM

Low or normal 25(OH)D indicates VITAMIN D DEFICIENCY due to lack of sunlight, inadequate vitamin D intake

or intestinal malabsorption

A low level of 1,25(OH)2D in the presence of elevated PTH suggests ineffective PTH action (CRF, severevitamin D deficiency, vitamin D-dependent rickets type I, PHP)


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TREATMENT: (1) VITAMIN D ANALOGS:

May be necessary in cases of vitamin D deficiency or resistance, dialysis patients, hypocalcemia fromsubtotal parathyroidectomy

Vitamin D 200 U (5ug/d) or Calcitriol 0.25 to 1.0 ug/drequired to prevent rickets in normal individuals

40,000 to 120,000 U (1-3mg) of vitamin D2 or D3required in hypoparathyroidism; calcitriol dosage isunchanged since the defect is in hydroxylation

(2) CALCIUM (PO or IV): Patients with hypoparathyroidism should also be given 2-3g elemental calcium by mouth daily

Patients who present with signs and symptoms of acute hypocalcemia need to be treated with rapidparenteral administration of calcium; chronic, asymptomatic hypocalcemia may be treated with Ca (PO)

(3) MAGNESIUM (PO or IV): Mg (IV) is administered if acute hypocalcemia is associated with hypomagnesemia, to be replaced as

soon as possible by Mg (PO) to replace body stores since Mg (IV) is excreted in the urine

Diseases of the Parathyroid Gland

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