With total calcium levels between 8.4 – 10.2 mg/dl

Hypercalcemia

MILD: levels between 10.3 –

11.2 mg/dl

Within 1mg/dl above the upper limits of normal

MODERATE: levels between 11.2 –

13.5 mg/dl

Between greater than 1 mg/dl above the upper

limits of normal but below 2 to 2.5 mg/dl above

the upper limits of normal

SEVERE: levels greater than 13.5

mg dl

Forms of plasma calcium: ionized (50%), bound to proteins

(40%), complexed to various anions (10%)

� The ionized fraction is the physiologically critical one and is closely regulated.

� Clinically, significant hypercalcemia involves an elevation of ionized as opposed to total

plasma calcium.

� Ionized calcium levels are corrected for proteins (hypoproteinemia, dehydration, myeloma)

and acid-base status (alteration of calcium binding to albumin in acidosis)

Effect of the albumin concentration and pH on total, protein-

bound, ionized, and nonionized calcium concentrations.

Ionized calcium is the physiologically important fraction

Conditions Causing Hypercalcemia

• Common:– Hyperparathyroidism

– Malignancy• Humoral (PTHrP)

• Local osteolytic

• Vitamin D / Lymphoma

• Uncommon:– Sarcoid & other granulomatous disorders

– Familial hypocalciuric hypercalcemia

– Endocrinopathies• Hyperthyroidism

• Adrenal insufficiency

– Medications (lithium, thiazides, etc.)

– Immobilization

Differential diagnosis of

hypercalcemia

PTH vs. non-PTH

mediated

PTHrP

PTH

PTH and PTHrP Genes

I II III IV V VI VII VIII IX

I II III

Aminoterminal sequences

of PTH and PTHrP

A V S E H Q L L H D K G K S I Q D L R R R F F L H H L I A E I

S V S E I Q L M H N L G K H L N S M E R V E W L R K K L Q D V

PTHrP

PTH

Utility of Parathyroid Hormone Measurement

Pathogenesis

• Increased bone resorption

• Increased calcium absorption

• Decreased kidney excretion

• Decreased bone formation

Primary Hyperparathyroidism

Incidence in the USA:

100.000 new cases occur each year

Incidence increases with age

Men over the age of 60 is 1:1000 per year

Women over the age of 60 is 2:1000 per year

PARATHYROIDECTOMY IN U.S.A.*

Age-adjusted (to 2000 U.S. whites) incidence (per 100,000

person/years) of definite primary hyperparathyroidism among

Rochester women (solid line) and men (dashed line), 1965-2001

JBMR 21:171, 2006

The Parathyroid Axis

Extracellular ionized calcium

Renal tubule

Calcium sensing receptor

Parathyroid cell

Endocrine mechanism

PTH

PTHrP

PTHrP

PTH receptor

Cartilage and PTHrP target cells in many

other tissues

Blood and other extracellular fluid

Autocrine-paracrine mechanism

Duodenal lumen

Bone

Calcium sensing receptor

PTH receptor

1,25(OH)2D

Le Fosfatonine: Nuovi Regolatori

dell’Omeostasi del Fosfato

• Fibroblast Growth Factor 23 [FGF-23]

• Secreted Frizzled Related Protein-4 [sFRP-4]

• Matrix Extracellular Phosphoglycoprotein [MEPE]

• Fibroblast Growth Factor 7 [FGF-7]

Regulation of Plasma FGF-23 by Calcium in pHPT

Time-course of changes in

plasma FGF-23 levels in pHPT after PTXSimple regression analysis of plasma FGF-23

and corrected calcium levels in post-PTX subject

Adapted from: Eur. J. Endocrinol. 154:93, 2006

Gli stati paratiroidei

“Quanto all’esistenza di un iperparatiroidismo, noi non abbiamo, fino ad oggi, alcun dato anatomo-clinico o sperimentale per ammetterlo né per escluderlo; si può creare un quadro clinico corrispondente, ma puramente ipotetico; e noi volentieri rinunciamo a questi voli della fantasia”

Endocrinologia, N. Pende, 1924

High secretory rates for parathyroid hormone

SyndromeSecretion suppressible by

hypercalcemia

Primary Hyperparathyroidism

Parathyroid Adenoma

Parathyroid Hyperplasia

Ectopic Hyperparathyroidism (non-

parathyroid tumors)

No

No

No

Secondary Hyperparathyroidism

Osteomalacia

Chronic Renal Disease

Yes

Yes

Pseudohypoparathyroidism Yes

Primary Hyperparathyroidism

•

• Benign, solitary adenoma (80%)

• Hyperplasia of all four parathyroidglands (15-20%)

• Carcinoma (<1%)

Definition:

persistent hypercalcemia toghether with an

elevated serum PTH concentration

Genes Involved in the Pathogenesis

of Primary Hyperparathyroidism

CaSR PRAD1MEN1 HRPT2 RET

Calcium

RecognitionGland

Growth

Serum

PTH

Hereditary and Sporadic Primary Hyperparathyroidism

• Hereditary causes represent only a minority of all primary hyperparathyroid states

• Heredity facilitates identification of a gene that predisposes to a rare syndrome

• Genes that predispose to rare syndromes often contribute to non-hereditary tumors

• Gene mutations may be germline, somatic, or a combination of both

Sporadic

Hereditary

6%

Possible co-activators towards the

parathyroid tissue tumorigenesis

Endogenous (cancer modifier) Exogenous

Hypocalcemia

Defects of vitamin D receptoror of 25OHD1αααα-hydroxylaseCaSR gene polymorphisms

Lithium

Calciolytic drugs

Neck radiation

Diet low in calcium

Diet low in vitamin D

Diet high in phosphate

A tissue specific co-activator can or must sinergize with the mutant gene

to cause a tumor

This can invoke a co-activator role for selected medications

Plasma 25-OH D is Associated with

Parathyroid Adenoma Secretion in pHPT

• Cross-sectional study

• 171 consecutive Caucasian patients with surgically proven

parathyroid adenoma

• Preoperative plasma PTH correlated inversely to plasma levels

of 25-OH D

Vitamin D deficiency increases PTH secretion activity

Adapted from: Eur. J. Endocrinol. 155:237, 2006

pHPT: Laboratory Findings

Serum calcium (total or ionized) concentrations

Serum PTH level

Serum 1,25 (OH)2D concentration

Serum phosphorus concentration

Urinary calcium excretion

Tubular reabsorption of phosphorus

Urinary excretion of ncAMP

pHPT: Clinical Presentation(s)

HYPERPARATHYROIDISM - TYPES

• Asymptomatic

• Insidious onset - Nephrolithiasis

• More rapid course – marked ⇑⇑⇑⇑ Ca,bone pain, fracture, weight loss,debility

CAUSES “ stones, bones, abdominal

groans, and psychic overtones”

pHPT

Target Organs in pHPT

CLASSICAL NON-CLASSICAL

Bone

Kidney

Cardiovascular System

Neuropsychological Involvement

Gastrointestinal System

Renal Calcinosis

Parathyroidectomy Reduced the Risk

of Bone Fractures in pHPT

Arch. Surg. 141:885, 2006

10-year fracture-free survival of 1569 patients with pHPT [73% vs 59%, (p<.001)]

pHPT: Lessons from Bone Histomorphometry

• pHPT is not as harmful to bone mass and structure as previously

reported

• Cancellous bone mass and cancellous bone architecture remain

uncharged despite a 50% increase in bone turnover

• At the cortical envelope, increased bone resorption causes

cortical thinning and porosity. Thus pHPT causes cortical

bone loss

• In severe cases of pHPT the negative effects on cortical bone

may override the positive impact on cancellous bone and lead

to increased risk of fracture

Adapted from: JBMR 17:N95, 2002

Manifestazioni non Scheletriche

dell’Iperparatiroidismo Primitivo

Maria Luisa Brandi

Università degli Studi di Firenze

Centro Regionale

T.E.E.

Parathyroid Hormone Receptors

PTH1R – mediates several PTH actions through many

distinct second messengers (indistinquishable efficacy

of PTH and PTHrP)

PTH2R – mediates the actions of tubular infundibular

peptide of 39 amino acids and is efficiently activated

by PTH in humans

PTH3R – cloned from zebrafish, not present in

mammalians, responds to PTHrP more efficiently than

to human PTH

PTH-Rs: TISSUE DISTRIBUTION

Bone Cells (osteoblasts, marrow stromal, cartilage cells)

Endothelial Cells

Smooth Muscle Cells

Kidney Tubular Cells

Mammary Cells

Keratinocytes

Insulinoma Cells

Central Nervous System Cells

Mammalian Supraoptic Nucleus (VP release?)

Placenta

Lymphocytes

Adipocytes

Liver (Kuppfer cells and hepatocytes)

Extraskeletal Complications of PHPT

Classical

Non Classical

Classical Extraskeletal

Complications

KIDNEY

BONE

Non Typical Targets of

Parathyroid Hormone

Central Nervous System

Cardiovascular System

Muscles

Gastrointestinal System

“Other” Symptoms of Hyperparathyroidism

Loss of energy. Don’t feel like doing too much. Tired all time.

Can’t concentrate

Depression

Don’t sleep like you used to. Wake up in the middle of the night. Trouble getting to sleep

Spouse claims you are more irritable and harder to get along with (cranky, bitchy)

Forget simple things that you used to remember very easily

Gastric acid reflux; heart burn

Decrease in sex drive

Thinning hair

High blood pressure (sometimes mild, sometimes quite severe, up and down a lot)

Recurrent headaches

Heart palpitations (arrhythmias, typically atrial)

Most people with hyperparathyroidism will have 2-4 of these symptoms.

Some will have lots of them. A few people will say they don’t have

any…but after an operation they will often say otherwise

Psychiatric and Cognitive Disturbances

in Primary HyperparathyroidismMild personality changes

Nervousness

Severe depression

Obsessive compulsive behavior

Paranoia

Each stage can continue for several months to several years

Symptoms markedly improve after parathyroidectomy

Severity of psychiatric symptoms is correlated with the

increase in serum calcium

Severe psychiatric symptoms occur frequently in older patients

Depression is not improved by classical anti-depressant

NEUROLOGIC SIGNS AND SYMPTOMS

Classical PHPT was associated with type 2 cell atrophy

a. Both type 1 and type 2 fibers are affected, but

type 2 more severely

b. Easy fatigability, symmetric proximal muscle

weakness

c. No changes in nerve conduction velocity

d. Both clinical and EMG features were reversible

after PTX

In the milder less symptomatic form of PHPT this disorder is

rarely seen, but paresthesias and muscle cramps are reported

CARDIOVASCULAR DISEASE

Hypercalcemia High PTH levels

Vascular and miocardial calcifications

Arrhythmia

Hypertension

Left ventricular hypertrophy

Increased Mortality

Controversial Data between USA and Europe

Vasodilatatory effects

Inotropic and chronotropic

effects on the heart

HYPERTENSION

Therefore, recommendations for or against surgery

should not be based on the presence of hypertension

More prevalent in mild, asymptomatic patients with PHPT than

in matched controls (inconsistently invoked renin activity and

serum Mg)

Inconsistent reports on hypertension improving after successful PTX

No cause and effect relationship between PHPT and hypertension

CARDIAC ABNORMALITIES

Coronary artery disease is disputed

The shortened QT interval associated with hypercalcemia

creates the potential for cardiac arrhythmia in PHPT

Left ventricular hypertrophy was reported to regress after

PTX, particularly in patients without coexisting hypertension

Increased cardiac sympathetic drive was suggested in mild PHPT

VASCULAR ABNORMALITIES

Vascular function could be associated with PHPT in the absence

of overt CVD

Endothelial dysfunction was evaluated but results are discordant

Macrovascular changes were shown through the measurement

of vascular stiffness, that was increased in PHPT

No data are available on the longitudinal

course of such alterations

METABOLIC ABNORMALITIES IN PHPT

Impairment of glucose tolerance

Diabetes

Altered lipid profile (↓↓↓↓HDL-C; ↑↑↑↑LDL-C)

High serum levels of uric acid

Increased serum levels of leptin

Decreased serum levels of adiponectin

Increased serum levels of N-terminal pro-ββββ-type natriuretic peptide

pHPT: Glucose Tolerance, Diabetes and Body Weight

• High frequency of both impaired glucose tolerance (GT) and undiagnosed

type 2 diabetes (DM)

• The spectrum of GT to DM in pHPT improves after parathyroidectomy

• Hypophosphatemia can worsen the GT and insulin resistance

� Fat mass is an important predictor of PTH levels in postmenopausal women

� pHPT is associated with increased body weight

Adapted from: Diab. Med. 2002; JCEM 2005; Diab./ Metab. Res. Rev. 2006; Eur. J. Clin. Nutr. 2006; Bone 2006

All togheter these facts contribute to the high CV mortality and morbidity in pHPT

Association Between pHPT and Increased Body Weight

JCEM 90:1525, 2005

GASTROINTESTINAL MANIFESTATIONS

Hypercalcemia is associated with high gastrin levels and increased gastric acid secretion

Epigastric pain and dyspepsia

Peptic ulcer is not more represented

Frequent gastric fundus athrophy

PEPTIC ULCER

PANCREATITIS

Frequently reported only in pregnant patients with PHPT

No causal relationship between the two disorders has been documented

Acute pancreatitis may cause hypocalcemia, masking hypercalcemia in PHPT

CONSTIPATION

Obstinate

It can lead to intestinal obstruction

PHPT and CANCER

Thyroid carcinoma

Mammary carcinoma

Osteosarcoma

The current philosophy that APHPT

patients do not need surgical care

will have to be revaluated

NON CLASSICAL COMPLICATIONS OF PHPT

NIH Consensus Development Conference 1991

“The relationship of psychologic symptoms to HPT is uncertain.

All investigators have suggested that neuromuscular symptoms

are frequent and often reversed by successful PTX; other less

specific somatic symptoms are rarely improved by operation”

NIH Consensus Development Conference 2002

“Guidelines for surgery of PHT:

neuropsychological, cardiovascular and gastrointestinal

abnormalities should not to be considered an indication for PTX”

Asymptomatic Primary Hyperparathyroidism

• NIH consensus development conference in 1991 – JBMR 6:1, 1991

•Workshop on Asymptomatic Primary Hyperparathyroidism: a Prespective for the 21st

Century – JBMR 17:N1-N162, 2002

• Diagnosis of Primary Hyperparathyroidism: Controversies, Practical Issues and the Need

for Australian Guidelines – Int. Med. J. 33:598, 2003

• Asymptomatic Primary Hyperparathyroidism: Standards and Guidelines for Diagnosis

and Management in Canada – End. Pract. 9:400, 2003

• The NIH Criteria for Parathyroidectomy in Asymptomatic Primary Hyperparathyroidism:

Are they too Limited? – Ann. Surg. 239:528, 2004

• Asymptomatic Primary Hyperparathyroidism: a Surgical Perspective – Surg. Clin. N. Am.

84:803, 2004

• Asymptomatic Primary Hyperparathyroidism: a Medical Perspective – Surg. Clin. N. Am.

84:787, 2004

• The American Association of Clinical Endocrinologists and the American Association

of Endocrine Surgeons Position Statement on the Diagnosis and Management of

Primary Hyperparathyroidism – End. Pract. 11:49, 2005

pHPT: Monitoring

The 2002 NIH guidelines recommend that patients with pHPT

without parathyroid surgery be monitored as follows:

• Serum calcium concentration every 6 months

• Serum creatinine concentration annually

• Bone density of the spine, hip, and forearm annually

Current NIH Guidelines for Surgical

Intervention in Primary Hyperparathyroidism

• Age younger than 50 years

• Serum calcium concentration of 1 mg/dl above normal

• 24-hours urinary calcium excretion of more than 400 mg

• Creatinine clearance reduced by more than 30% compared with controls

• Bone mineral density reduced by more than 2.5 standard deviation below

the bone density of age, gender, and race-matched norms

• Patients for whom medical surveillances either not desirable or possible

About 20% of patients with hyperparathyroid disease

meet these objective indications

Adapted from: JCEM 84:2275, 1999 JCEM 87:5353, 2002;

pHPT: Medical Therapy

• Lifestyle recommendations

Diet with a normal calcium intake

Supplementation with vitamin D (if needed)

Exercise

Avoid dehydration

• Medications

HRT

Raloxifene

Oral Bisphosphonates

Cinacalcet

JCEM 90:135, 2005

Cinacalcet Maintains Long-term Normocalcemia in pHPT