BRANDI Ipercalcemie 20 Ott 2014web.mit.edu/asabatin/www/Med/SMC1/20141020-Brandi... · 100.000 new...
Transcript of BRANDI Ipercalcemie 20 Ott 2014web.mit.edu/asabatin/www/Med/SMC1/20141020-Brandi... · 100.000 new...
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