PTH related disorders

Course in Endocrinology, Year 4, HUJI, 31/10/2013

Simona Glasberg, MD

Neuroendocrine Tumors Unit,Endocrinology & Metabolism Service,

Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Introduction -The parathyroid glands small endocrine glands in the neck that produce parathyroid hormone (PTH). humans usually have four parathyroid glands, located in variable manner on the posterior surface of the

thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest (mediastinum) or even the thymus. control the amount of Ca in the blood and within the bones.

Parathyroid hormone- physiology

The primary function of PTH is to maintain the extracellular fluid (ECF) calcium concentration within a narrow normal range.

PTH acts directlydirectly on bone (Ca resorbtion) and kidney (Ca re-absorption) indirectlyindirectly on the intestine throughits effects on synthesis of 1,25(OH)-D

in turn, PTH production is closely regulated by the concentration of serum ionized calcium and vitamin D.

increase increase serum serum

CaCa

Calcium (through the Ca-SR) and vitamin D (through its nuclear receptor)- reduce PTH release and synthesis.

Hyperparathyroidism (HPT) excess production of PTH is a common cause of hypercalcemia is usually the result of autonomously functioning adenomas, or hyperplasia.

Hypocalcaemia, as might be induced by calcium-deficient diets, is counteracted by an increased secretion of PTH

(1) increased rate of dissolution of bone mineral increased flow of calcium from bone into blood

(2) reduced renal clearance of calcium, returning more of the calcium filtered at the glomerulus into ECF

(3) increased efficiency of calcium absorption in the intestine by stimulated production of 1,25(OH)2D

Immediate control

Steady state

PTH actions on kidneys

Inhibition of phosphate absorbtion (proximal tubule)

Augmentation of calcium reabsorbtion (distal tubule)

Stimulation of the renal 25- (OH) D3 1-alpha-hydroxylase.

As much as 12 mmol (500 mg) calcium is transferred between the ECF and bone each day

PTH acts as a homeostatic hormone to preserve calcium concentration in blood at the cost of bone demineralization.

PTH actions on bone

PTH-mediated changes in bone calcium release can be seen within minutes.

The chronic effects of PTH are to: increase the number of bone cells, both osteoblasts

and osteoclasts, and to increase the remodeling of bone

Continuous exposure to elevated PTH (as in hyperparathyroidism) leads to increased osteoclast- mediated bone resorption.

However, the intermittent administration of PTH, elevating hormone levels for 1–2 hours each day, leads to a net stimulation of bone formation rather than bone breakdown.

Striking increases, especially in trabecular bone in the spine and hip, have been reported with the use of PTH in combination with estrogen.

PTH(1-34) (teriparatide, Forteo Eli Lilly) as monotherapy caused a highly significant reduction in fracture incidence in a worldwide placebo-controlled trial.

PTH actions on bone, cont.

OsteoblastsOsteoblasts (or stromal cell precursors), which have PTH/PTHrP receptors, are crucial to this bone-forming effect of PTH.

OsteoclastsOsteoclasts, which mediate bone breakdown, lack such receptors. PTH-mediated stimulation of osteoclasts is indirect, acting in part, through cytokines released from osteoblasts to activate osteoclasts

In experimental studies of bone resorption in vitro, osteoblasts must be present for PTH to activate osteoclasts to resorb bone

PTH actions on bone - how it works?

PTH - Structure

PTH is an 84-amino-acid single-chain peptide. The amino-terminal portion, PTH(1–34), is critical for the biologic actions of the molecule.

PTH - Biosynthesis, Secretion, and Metabolism

Hypocalcemia Minutes secretion of preformed hormone.

Sustained hypocalcemia Hours PTH mRNA expression Days cellular replication increase gland mass.

PTH - Secretion

PTH secretion increases steeply to a maximum value of about five times the basal ratefive times the basal rate as calcium concentration falls from normal to the range of 1.9–2 mmol/L (7.5–8 mg/dL) (measured as total calcium).

Severe intracellular magnesium deficiency impairs PTH secretion.

Rapid (minutes) changes in PTH availability depends on the proteolytic destruction of preformed hormone (posttranslational regulation of posttranslational regulation of hormone productionhormone production)

High calcium increases Low calcium inhibit

PTH - availability

CaCa PTHPTH

the proteolytic the proteolytic destruction of PTH destruction of PTH

storesstores . .

Ca++ sensing receptor (CaSR)

a G protein-coupled receptor (GPCR). serves for the ECF calcium control of PTH secretion.

its stimulation by high Ca levels suppresses PTH secretion.

is present in PT glands and the calcitonin-secreting cells of the thyroid (C cells), as well as in other sites such as brain and kidney.

Heterozygous point mutations associated with loss-of-function cause the syndrome of FHH, in which the blood calcium abnormality resembles that observed in hyperparathyroidism but with hypocalciuria.

Heterozygous gain-of-function mutations cause a form of hypocalcemia resembling hypoparathyroidism.

CaSR - mutations

PTH - Metabolism Most of the proteolysis of hormone occurs in the

liver and kidney.

PTHrP (Parathyroid hormone-related protein)

Same receptor as PTHImportant in fetal life

PTHrP

Most cell types produce PTHrP, including brain, pancreas, heart, lung, mammary tissue, placenta, endothelial cells, and smooth muscle.

PTHrP is responsible for most instances of hypercalcemia of malignancy - a syndrome that resembles HPT but without elevated PTH levels.

In fetal animals, PTHrP directs transplacental calcium transfer, and high concentrations of PTHrP are produced in mammary tissue and secreted into milk, but the biologic significance of the very high concentrations of this hormone in breast milk is unknown.

in adults PTHrP appears to have little influence on calcium

homeostasis in disease states (e.g., large tumors, especially of the

squamous cell type as well as renal cell carcinomas), there is massive overproduction of PTHrP and hypercalcemia.

Calcitonin

Antagonist to PTHLimited physiologic significance in humans (no

need for replacement) Tumor marker – MTCAdjunctive treatment in severe hypercalcemia and

in Paget's disease of bone Calcitonin from salmon, which is used

therapeutically, is 10–100 times more potent than mammalian forms in lowering serum calcium

I. Parathyroid-related II. Malignancy-related

Hypercalcemia

Primary Hyperparathyroidism

1. Adenoma(s)

2. Hyperplasia (MEN)

3. Carcinoma

Lithium therapy Familial hypocalciuric

hypercalcemia (FHH)

Solid tumor with bone metastases (breast)

Solid tumor with humoral mediation of hypercalcemia (lung, kidney)

Hematologic malignancies (multiple myeloma, lymphoma, leukemia)

III. Vitamin D - related IV. High bone turnover

Hypercalcemia

Vitamin D intoxication

1,25(OH)2D: sarcoidosis and other granulomatous diseases

Idiopathic hypercalcemia of infancy

Hyperthyroidism

Immobilization

Thiazides

Vitamin A intoxication

False positive Hypercalcemia

hemoconcentration during blood collection elevation in serum proteins such as albumin

No need for fasting

Hypercalcemia - Clinical features

Asymptomatic usually due to PHPT. Malignancy-associated hypercalcemia the disease is usually not occult

The interval between detection of hypercalcemia and death, especially without vigorous treatment, is often <6 months.

Hypercalcemia - Signs & symptoms

FatigueDepressionMental confusionAnorexia, nausea, vomiting

Constipation

Reversible renal tubular defects

Increased urinationA short QT interval in the ECG

Cardiac arrhythmias

More common at calcium levels >2.9–3 mmol/L (11.5–12 mg/dL)

>3.2 mmol/L (13 mg/dL), calcification in kidneys, skin, vessels, lungs, heart, and stomach occurs and renal insufficiency may develop, particularly if blood phosphate levels are normal or elevated due to impaired renal function.

Severe hypercalcemia, usually defined as 3.7–4.5 mmol/L (15–18 mg/dL), can be a medical emergency; coma and cardiac arrest can occur.

Hypercalcemia - Signs & symptoms

Primary Hyperparathyroidism

(PHPT)

PHPT - Natural history & incidence

High PTH, Hypercalcemia, hypo-phosphatemia.

Patients may present with multiple signs and symptoms, including recurrent nephrolithiasis, peptic ulcers, mental changes, and, less frequently, extensive bone resorption.

The diagnosis is frequently made in patients who have no symptoms and minimal, if any, signs of the disease other than hypercalcemia and elevated levels of PTH. The manifestations may be subtle, and the disease may have a benign course for many years or a lifetime.

PHPT - Incidence

The incidence is 1 in 800 people. This rate is much higher in women over 50: 1 in 250.

The disease has a peak incidence between the third and fifth decades but occurs in young children and in the elderly.

At young ages, hyperparathyroidism is often caused by a familial hyperparathyroidism syndromes.

has been reported in patients with a history of irradiation to the head and neck (eg, for the treatment of childhood malignancy, for the treatment of benign conditions, or after nuclear power plant accidents).

PHPT - Etiology

Most often - isolated adenomas

Hyperplasia - in hereditary syndromes such as MEN syndromes.

Carcinoma < 1%

Solitary AdenomasA single abnormal gland is the cause of PHPT in ~85%

Double adenomas are reported.

Hereditary Syndromes and Multiple Parathyroid Tumors

In ~15% of patients, all glands are hyperfunctioning (parathyroid hyperplasia) - usually hereditary and associated with other endocrine abnormalities. MEN 1 (Wermer's syndrome): hyperparathyroidism ,tumors of the

pituitary and pancreas. MEN 2A: pheochromocytoma, MTC, PHPT MEN 2B usually lacks hyperparathyroidism; has additional

associated features such as multiple neuromas. The hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs in

families with parathyroid tumors (sometimes carcinomas) in association with benign jaw tumors - often termed non-syndromic familial isolated hyperparathyroidism (FIHP).

Adenomas - Pathology

Most often located in the inferior parathyroid glands

6 -10% ectopic: thymus, thyroid, pericardium, or behind the esophagus.

Usually 0.5–5 g in size but may be as large as 10–20 g (normal glands weigh 25 mg on average).

Chief cells are predominant in both hyperplasia and adenoma.

Parathyroid carcinoma

Often not aggressive. Long-term survival without recurrence is common if at initial surgery the entire gland is removed without rupture of the capsule.

Recurrent parathyroid carcinoma is usually slow-growing with local spread in the neck, and surgical correction of recurrent disease may be feasible.

The diagnosis of carcinoma is often made in retrospect. HPT from a parathyroid carcinoma is usually more severe clinically.

Genetic Defects Associated with Hyperparathyroidism

Mutations in the Menin tumor suppressor gene (MEN1) . Over 1300 mutations have been reported to date. The MEN1 phenotype is inherited via an autosomal-dominant pattern and is associated

with neoplasms of the pituitary gland, the parathyroid gland, and the pancreas.

Crystal Structure of Human Menin

Retinoblastoma (Rb) gene a tumor-suppressor gene located on chr 13q14, initially

associated with retinoblastoma, but implicated in other neoplasias, including parathyroid carcinoma

HRPT2 gene sporadic parathyroid carcinomas frequently have HRPT2

mutations. some patients with apparently sporadic parathyroid

carcinoma carry germ-line mutations in HRPT2 and may have the HPT-JT syndrome or a phenotypic variant.

RET encodes a tyrosine kinase type receptor; specific inherited germ-line mutations lead to a

constitutive activation of the receptor- MEN 2

Genetic Defects Associated with Hyperparathyroidism, cont.

PHPT - Signs and symptoms

In series in which patients are followed without operation, as many as 80% are classified as without symptoms.

Kidney involvement, due either to deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis, was present in 60–70% of patients prior to 1970.

With earlier detection, renal complications occur in <20% of patients in many large series. Renal stones are usually composed of either calcium oxalate or calcium phosphate.

In occasional patients, 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.

PHPT - Bone involvement

The distinctive bone manifestation is osteitis fibrosa cystica, which occurred in 10–25% of patients in series reported 50 years ago.

Histologically, the pathognomonic features are: an increase in the giant multinucleated osteoclasts in scalloped areas

on the surface of the bone (Howship's lacunae) replacement 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).

In recent years, osteitis fibrosa cystica is very rare, due to the earlier detection of the disease.

Cortical bone density is reduced while trabecular (cancellous) bone density, especially in the spine, is relatively preserved (distal radius…)

PHPT - Neurologic manifestations

Neuropsychiatric Neuromuscular- proximal muscle weakness, easy fatigability, and atrophy of muscles, complete regression of neuromuscular disease after surgical correction of the hyperparathyroidism

PHPT – GIT manifestations

Sometimes subtle and include vague abdominal complaints and disorders of the stomach and pancreas

MEN 1 - duodenal ulcer may be the result of associated pancreatic tumors that secrete excessive quantities of gastrin (ZES)

Pancreatitis has been reported in association with hyperparathyroidism, but the incidence and the mechanism are not established.

Asymptomatic PHPT (APHPT)

Biochemically confirmed hyperparathyroidism (elevated or inappropriately normal PTH levels despite hypercalcemia) with the absence of signs and symptoms typically associated with more severe hyperparathyroidism such as features of renal or bone disease.

APHPT - Issues of concern

Potential for cardiovascular deteriorationThe presence of subtle neuropsychiatric symptomsLonger-term status of skeletal integrity in patients

not treated surgically. The current consensus is that medical monitoring

rather than surgical correction of hyperparathyroidism may be justified in certain patients.

The evidence of eventual (>8 years) deterioration in BMD after a decade of relative stability.

Guidelines for Surgery in APHPT

ParameterGuideline

Serum calcium (above normal)<1 mg/Dl

24-h urinary CaNo indication

Creatinine clearance<60 mL/min

Bone densityT score <–2.5 at Any of 3 sites

Age <50

Guidelines for Monitoring in APHPT

ParameterGuideline

Serum calciumAnnually

24-h urinary calciumNot recommended

Creatinine clearanceNot recommended

Serum creatinine 

Annually

Bone densityAnnually (3 sites)

APHPT - Diagnosis

Elevated PTH level Asymptomatic hypercalcemia Phosphate is usually low but may be normal, especially if renal failure has developed

Treatment: PHPT

Surgical excision of the abnormal parathyroid tissue is the definitive therapy for this disease.

The conventional parathyroidectomy procedure was neck exploration with general anesthesia; this procedure is being replaced in many centers, whenever feasible, by an outpatient procedure with local anesthesia, termed minimally invasive parathyroidectomy.

Parathyroid exploration is challenging and should be undertaken by an experienced surgeon

USPreoperative 99mTc sestamibi scans with single-

photon emission CT (SPECT) are used to predict the location of an abnormal gland

Intraoperative sampling of PTH before and at 5-minute intervals after removal of a suspected adenoma to confirm a rapid fall (>50%) to normal levels of PTH.

Multiple-gland hyperplasia

Two schemes have been proposed for surgical management. One is to totally remove three glands with partial excision of the

fourth gland; care is taken to leave a good blood supply for the remaining gland.

Other surgeons advocate total parathyroidectomy with immediate transplantation of a portion of a removed parathyroid gland into the muscles of the forearm, with the view that surgical excision is easier from the ectopic site in the arm if there is recurrent hyperfunction.

In a minority of cases, if no abnormal parathyroid glands are found in the neck, the issue of further exploration must be decided. There are documented cases of five or six parathyroid glands and of unusual/ectopic locations for adenomas such as in the mediastinum.

When a second parathyroid exploration is indicated, the minimally invasive techniques for preoperative localization such as ultrasound, CT scan, and isotope scanning are combined with venous sampling and/or selective digital arteriography in one of the centers specializing in these procedures.

Intraoperative monitoring of PTH levels by rapid PTH immunoassays may be useful in guiding the surgery

long-term cures have been achieved with selective embolization or injection of large amounts of contrast material into the end-arterial circulation feeding the parathyroid tumor.

Post-op A decline in serum calcium occurs within 24 hours after

successful surgery. Usually blood calcium falls to low-normal values for 3–5 days until

the remaining parathyroid tissue resumes full hormone secretion.

Acute postoperative hypocalcemia is likely only if severe bone mineral deficits are present injury to all the normal parathyroid glands occurs during surgery.

In general, there are few problems encountered in patients

with uncomplicated disease such as a single adenoma (the clear majority), who do not have symptomatic bone disease nor a large deficit in bone mineral, who are vitamin D and magnesium sufficient, and who have good renal and gastrointestinal function.

The extent of postoperative hypocalcemia varies with the surgical approach. If all glands are biopsied, hypocalcemia may be transiently symptomatic and more prolonged.

Hypocalcemia is more likely to be symptomatic after second parathyroid explorations, particularly when normal parathyroid tissue was removed at the initial operation and when the manipulation and/or biopsy of the remaining normal glands are more extensive in the search for the missing adenoma.

Hypocalcemia

Hypocalcemia

muscle twitching, a general sense of anxiety, and positive Chvostek's and Trousseau's signs coupled with serum calcium consistently <2 mmol/L (8 mg/dL).

parenteral calcium replacement should be instituted when hypocalcemia is symptomatic.

The rate and duration of IV therapy are determined by the severity of the symptoms and the response of the serum calcium to treatment.

Calcitriol…Hypomagnesemia should be corrected

PHPT - Medical Management

When surgery is not selected, or not medically feasible

It has been established that bisphosphonate increase bone mineral density significantly without changing serum calcium

Calcimimetics (Cinacalcet (Sensipar) mimics calcium at the PTH receptor) lower PTH secretion, lower calcium but do not affect bone mass density (BMD).

Other Parathyroid-Related Causes of

Hypercalcemia

Lithium

Lithium, used in the management of bipolar depression and other psychiatric disorders, causes hypercalcemia in ~10% of treated patients.

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 lithium may predispose to development of adenomas (as is documented in secondary hyperparathyroidism and renal failure).

Fortunately, there are usually alternative medications for the underlying psychiatric illness.

Parathyroid surgery should not be recommended unless hypercalcemia and elevated PTH levels persist after lithium is discontinued.

Familial hypocalciuric hypercalcemia (FHH)

Autosomal dominant trait. Affected individuals are discovered because of

asymptomatic hypercalcemia. Caused by an inactivating mutation in a single allele of

the calcium sensing receptor inappropriately normal or even increased secretion of

PTH

FHH - Pathophysiology The primary defect is abnormal sensing of the

blood calcium by the parathyroid gland and renal tubule, causing inappropriate secretion of PTH and excessive renal reabsorption of calcium.

Many different inactivating mutations in the calcium-sensing receptor have been identified in patients with FHH.

These mutations lower the capacity of the sensor to bind calcium, and the mutant receptors function as though blood calcium levels were low; excessive secretion of PTH occurs from an otherwise normal gland

Patients with FHH have >99% renal calcium reabsorption. The hypercalcemia in FHH is often detectable in the first decade of life

PTH may be elevated in FHH, but the values are usually normal or lower for the same degree of calcium elevation in patients with PHPT.

Parathyroid surgery performed in a few patients with FHH before the nature of the syndrome was understood led to permanent hypoparathyroidism; nevertheless, hypocalciuria persisted, establishing that hypocalciuria is not PTH-dependent (now known to be due to the abnormal calcium-sensing receptor in the kidney).

In those patients inadvertently operated upon, the parathyroids appeared normal or moderately hyperplastic.

Few clinical signs or symptoms are present in patients with FHH, and other endocrine abnormalities are not present.

Most patients are detected as a result of family screening after hypercalcemia is detected in a proband.

Parathyroid surgery is not appropriate

Rare cases of acquired hypocalciuric hypercalcemia are reported due to antibodies against the Ca-SR.

They appear to be a complication of an underlying autoimmune disorder and respond to therapies directed against the underlying disorder.

Jansen’s disease (Jansen's metaphyseal chondrodysplasia)

A rare AD syndrome: less than 20 reported cases worldwide

Activating mutations in the PTH/PTHrP receptor (PTH1R)

Short-limbed dwarfism due to abnormal regulation of chondrocyte maturation in the growth plates of the bone.

Numerous abnormalities multiple cystic resorptive areas in bone resembling those seen in

severe hyperparathyroidism. Hypercalcemia and hypophosphatemia with undetectable or low

PTH levels are typically seen..