Week 25 Thyroid and parathyroid Flashcards
Anatomy of the thyroid gland
2 lobes and isthmus.
Highly vascular.
Follicular cells/Thyrocytes
Epithelial cells that produce thyroid hormone.
Thyroid follicles
Functional unit of the thyroid.
Parafollicular cells (C cells)
Neuroendocrine cells that produce calcitonin.
Stroma
CT capsule containing blood vessels and lymphatics.
Colloid
Contains thyroglobulin, the precursor for thyroid hormones.
What are the 2 main hormones produced by the thryroid?
T4 - Tyroxine, 93% of thyroid hormones.
T3 - Triiodothyronin, the remaining 7% of thyroid hormones.
Structure of T4
2 tyrosine molecules + 4 iodine atoms.
Structure of T3
2 tyrosine molecules + 3 iodine atoms.
Discuss the relationship between T4 and T3
Almost all T4 is converted into T3 in the target tissues.
T3 is 4x’s more potent than T4, present in smaller quantities for a much shorter duration.
Steps of thyroid hormone synthesis
- Thyroglobin synthesis
- Iodide trapping
- Iodide oxidation
- Iodination of thyroglobulin (organification)
- Coupling of iodotyrosines
- Endocytosis of thyroglobin
- Cleavage of thyroid hormones from thyroglobin
- Secretion of thyroid hormones into the bloodstream
Where does tyrosine come from?
Can be converted from phenylalanine.
PKU lacks the enzyme that converts Phe into Tyr so those individuals need to get it from diet.
Functions of thyroglobin
Precursor of thyroid hormones.
Storage of inactive thyroid hormones.
Recommended dietary intake of iodide
150ug
Where is iodide absorbed
Into blood circulation in the small intestine and skin.
How much absorbed iodide is excreted through the kidneys?
80%
20% used for hormone synthesis.
Iodide trapping
The process of concentrating iodide in the cell.
What is the difference in iodide concentration in the follicular cells vs blood?
30-250 x’s higher in follicular cells.
How is iodide transported?
Iodide pump (Sodium-Iodide Symporter, NIS)
2Na+ and 1 I- pumped in.
Active secondary tranport.
Na/K pump helps balance by actively pumping Na out of cell. Helps keep intracellular Na level low so that NIS can use the gradient to import both Na+ and I-.
What do mutations of the NIS lead to?
Thyroid hormone deficiency.
I- vs I2
I-, IODIDE, reduced form absorbed by the body.
I2, IODINE, oxidized form used in synthesis of thyroid hormones.
Discuss the oxidation of Iodide to Iodine
Iodide transported out the apical surface of the cell via Pendrin.
Once in the colloid, Thyroid Peroxidase (TPO) oxidizes I- -> I2
I2 remains in colloid.
Discuss iodination (organification) of thyroglobin
Facilitated by TPO
Produces 2 intermediates:
MIT (first) or DIT (2MITs together)
Depends on how much iodine is present.
TPO + MIT + DIT + Thyroglobin = T3
TPO + DIT + DIT + Thyroglobin = T4
Still in colloid.
Discuss cleavage and secretion of polymers of thyroid hormones
Colloid complexes (thyroglobin + MIT/DIT/T3/T4) are brought back into the cell via pinocytosis.
Lysosomes merge with colloid droplets and proteases free the hormones.
T hormones transport back out basolateral surface of cell via diffusion and MCT8 transporters.
Thyroglobin
Glycoprotein that allows for long term storage of hormones.
Glycoproteins have carbohydrate chains which give structural support and stabilize protein. Also ‘hides’ from proteases.
What is the clinical implication of the thyroid being able to store large amounts of hormones?
Ability to withstand long periods without iodide ingestion or thyroid dysfunction, delay in clinical presentation of desease.
What happens to thyroid hormones when they enter blood circulation?
Immediately bind to plasma proteins and then are released to tissues slowly.
1/2 of the T4 in the blood is released every 6 days, 1/2 of T3 in 1 day.
What is the main plasma protein that thyroid hormones bind to?
Tyroxine-binding globulin
others are:
tyroxine-binding prealbumin, albumin.
Where are thyroid hormone binding proteins produced?
Liver
Which thyroid hormone has a greater effect and why?
T3 because it has lower binding affinity to proteins, easier to get when we need it.
Discuss dionization of thyroid hormones
3 types of deiodinases:
Type 1 - liver, kidneys, thyroid. T3 -> T4, increasing circulating T3 levels.
Type 2 - brain, brown adipose, skm. T4 -> T3, increasing T3 levels in tissues.
Type 3 - brain, skin, placenta, pancreas. T4 -> rT3, inactivation of hormone.
Types of thyroid hormone receptors
TRa:
TRa1, TRa2, TRa3.
TRa1 binds to T3.
TRa2 & TRa3 are negative regulators of TRa1.
TRb:
TRb1, TRb2.
Both can bind to T3.
Also tissue specific expression of the receptors.
Where are thyroid hormone receptors located?
Nucleus.
Function of T3 binding to nuclear receptor
T3 binds to receptor and activates transcription process creating mRNA.
New proteins affect growth, CNS development, CV, metabolism, other systems.
Metabolic functions of thyroid hormones
Increase mito genesis
Increase Na/K atpase
Increase O2 consumption
Increase glucose absorption
Increase gluconeogenesis
Increase glycogenolysis
Increase lipolysis
Increase pr- synthesis
Increase BMR
Cardiovascular effects of thyroid hormones
Increase CO
Increase HR
Increase tissue blood flow
Increase contractility
Increase respiration
Effects of thyroid hormone on growth and development
Normal growth and brain development.
Discuss regulation of thyroid hormone synthesis
TSH from anterior pituitary stimulates thyroid hormone synthesis by:
Increasing NIS activity
Increased iodination of tyrosine
Increasing proteolysis of thyroglobin
Increasing the size and # of follicular cells.
What influences the release of TSH from anterior pituitary?
Hypothalamus releases Thyrotropin Releasing hormone (TRH) which regulates TSH.
Cold temps increase TRH
Prolonged fasting decreases TRH
Discuss the negative feedback in thyroid hormone regulation
Elevated levels of T3/T4 inhibit:
Hypothalamus from releasing TRH
Anterior pituitary from releaseing TSH
Discuss the Wolff-Chaikoff effect
Excess iodide inhibits TPO activity and NIS expression resulting in decreased thyroid hormone synthesis.
10-20x more iodide than RDA triggers this effect.
TSH sensitivity
Even small changes in thyroid hormones can lead to significant changes in TSH.
Small changes in TSH only result in small changes in hormones.
Is T3 or T2 the predominant inhibitor of TSH?
T3 - more potent
What is the clinical significance of TSH sensitivity?
Changes in TSH can be earlier than thyroid hormones.
Thyroid hormones are still available. No significant presentation, so the TSH levels in blood work can be an early indicator of dysfunction.
Is T3 or T4 better for hormone replacement therapy?
T4 because it is the more stable form
Thyrotoxicosis
Thyroid hormone excess of all causes.
Varies symptoms.
Symptoms severity does not correlate well with biochemical severity.
Adrenergic and/or catabolic symptoms w/heat intolerance.
Primary thyroid dysfunction
Thyroid is over or under releasing thyroid hormone.
Hypothalamus and pituitary are responding appropriately.
3 most common disease conditions causing primary hyperthyroidism
Grave’s disease
Autonomous (hot) nodules
Thyroiditis (several subtypes)
Hyperthyroidism
Speeding up: adrenergic type symptoms.
Heating up: energy wasting
Thinning: catabolic
What is diagnosis of primary hyperthyroidism based?
Pathophysiology.
Approprate feedback suppression of TSH is the most sensitive indicator.
Overt hyperthyroidism
Free T4/T3 are above the population normal range.
TSH will be low.
Subclinical hyperthyroidism
FT4 may be above the setpoint for the individual but within the population normal range.
TSH is suppressed.
May or may not be symptomatic.
What is the most sensitive indication of primary hyperthyroidism?
TSH suppression
Steps in diagnosis of thyrotoxicosis
- check TSH
- if TSH low -> measure fT4 & fT3
- confirm one or both are high.
- Classify as subclinical or overt.
- Discover the underlying cause
Thyroiditis
No increase in thyroid synthesis, leak of preformed hormone.
What are the TSH receptor causes of hyperthyroidism?
Grave’s = TSH receptor antibody
TSH oma
HCG gestational
3 main causes of hyperthyroidism
Grave’s
Toxic “hot” autonomous nodules
Thyroiditis
Discuss Graves’ disease
Anatomy:
Diffusely hyperplastic and hyperfunctioning thyroid.
Thyroid often enlarged and hypervascular.
Diffuse soft goitre, sometimes with Bruit.
Histology:
Epithelium hyperplastic, elongated cells, larger nuclei may have papillary projections.
Small oddly shaped follicles.
Increased Iodide uptake -> production/secretion T3/4.
Iodine imaging shows marked increase diffusely.
AUTOIMMUNE: TSH receptor stimulating antibody.
Extra-thyroidal manifestations of Graves’ disease
Thyroid eye disease:
Orbital soft tissues -
Inflammation
Swelling
Entrapment/restriction of eye mvmt (diploplia)
Compression of CN2
Pretibial myxedema - deposition of infl material in soft tissue.
Thyroid acropachy (severe clubbing w/inf arthritis of the wrist)
Treatment of hyperthyroidism
Symptomatic: rest, stress relief
Beta blocker for adrenergic symptoms (CI’d in asthma)
Treatment for Graves
Anti-thyroid meds (temporary tx - hoping for regression)
Radioactive iodine.
Thyroidectomy.
MOI of anti-thyroid drug tx
Inhibit TPO.
Dampens immune response to the thyroid.
See drop in levels 2-3 weeks.
Methimazole - drug of choice, teratogenic.
6-Propyl-3-Thyouracil (PTU) - safer(?) in pregnancy, still teratogenic risk.
Hot nodules
Focal nodule of hyperplastic/hyperfunctioning thyroid.
Only the nodule shows increased iodide uptake/production of T3/4.
Rest of the gland is low uptake.
Diagnosis ONLY by functional imaging; I-123 thryoid scan will differentiate between diffuse increased uptake of I- (Grave’s) vs nodule.
Physical exam:
Nodules in one or both sides, not always palpable.
Anatomy: benign nodules.
Pathophys: Nodules secrete thryoid hormone. TSH is low. Benign lesions.
Histology: Tall hyperplastic epithelium, disorderly micro/macro follicles.
Tx: Medical management for hyperthyroidism, radioactive I-, hemithyroidectomy.
Treatment for hot nodules
Radioiodine treatment dose
Second line; hemi-thyroidectomy
Thyroiditis
Acute inflammatory condition causes leak of hormones.
Reduced I- uptake, but Increased output of T4/3.
Iodine imaging -> Low iodine uptake diffusely.
Physical exam: May be firm, tender, enlarged.
Anatomy: firm rubbery gland
Histo: early, neut destruction of follicles with colloid depletion.
late, granulomas and some fibrosis.
Thyroiditis tx:
NSAID for pain
Prednisone for subacute or more rapid resolution.
Discuss the prevalence of hypothyroidism
5% population lifetime risk.
15% of women over 50 have subclinical hypothyroidism.
Women:Men 5:1
Symptoms of overt hypothyroidism
Slowing
Cooling
Thickening
Diagnostic pathway for hypothyroidism
- Check TSH
- High TSH -> measure fT3/4
- Confirm one or both are low
- Classify as ‘subclinical’ or ‘overt’
- Discover underlaying cause
- Discuss thyroxine supplementation
Causes of hypothyroidism
Primary Congenital: thyroid not formed or ectopic, thyroid not functional.
Primary Acquired:
Autoimmune - transient (thyroiditis), permanent (Hashimoto’s)
Removal/destruction of thyroid
Iodine deficiency
Drug induced
Central hypothyroidism: thyroid not receiving stimulation
Hashimoto’s Thyroiditis
Chronic Lymphocytic thyroiditis
Permanent hypothyroidism.
Physical exam: Variable goitre
Function: Variably reduced production of T3/4.
Imaging: Diffusely echogenic on US. Iodine imaging not useful.
Histology: Infiltration with chronic inflammatory cells.
Underlaying cause: AI, lymphocytic inflammation and gradual destruction.
Serum marker: Anti thyroid peroxidase AB (anti-TPO) is not causal but high titres are predictive
Treatment of subclinical hypothyroidism
If confirmed by repeat test (persistent) and 1+ of:
symptoms
TSH >10mu/L
TSH above normal w/high titre anti-TPO and/or goitre
Planning or is pregnant
Treatment for persistent hypothroidism
Hormone replacement with levothyroxine (synthetic T4) 1mcg/lb.
Start at >75% full dose.
Should have improvement 2-3 weeks.
Recheck TSH in 2-3 months, then annually.
Target TSH to lower 1/2 of normal range.
Expect slow increase in requirement.
What are the requirements for ordering lab tests for thyroid?
Test TSH and then fT4 if abnormal.
What are the requirements for ordering lab tests if you are suspicious of pituitary dysfunction?
Order both TSH & fT4 BUT
You MUST indicate suspicion of pituitary dysfunction or the lab will cancel the fT4.
What meds can cause thyroid dysfunction?
Hyperthyroidism:
Biologicals
Iodine containing meds - Amiodarone
Hypothyroidism:
Lithium
Iodine and iodine containing meds.
Biologicals
Biotin can give false TSH and fT4 levels.
Discuss maternal-fetal thyroidology changes in pregnancy
Rise in estrogen - high thyroid binding globulin, High total T4
hCG - is a TSH analog, stimulates TSH receptor, increases thyroid hormone secretion beyond what is necessary to compensate for increased binding.
Small increase is thyroid size.
Increased iodine requirement in pregnancy & breastfeeding.
Physiology of hyperthyroidism of first trimester
hCG is TSH analog.
Thyroid hormone production may ‘overshoot’.
TSH suppression and fT4 elevation.
Fetus is dependent on maternal thyroid hormone until 16 weeks.
What is the most common cause of preventable mental impairment?
Iodine deficiency
What occurs if iodine deficient during pregnancy?
Mother, fetus, and later infant are hypothyroid.
How much more iodine is required in pregnancy?
50-75%
What ensures adequate iodine in breast milk?
Na-Iodine symporter - non TSH dependent.
How long does the infant brain need thyroid hormone and Iodine?
Birth to age 3.
Treatment for pregnancy
If TSH >4 or TSH >2.5 & anti-TPO then supplement with thyroxine.
Target low normal TSH <2.5
If already on rx, bump dose 25% at dx of pregnancy.
Follow TSH levels q 4 weekly x first 20 weeks.
Why to rx:
Safeguard fetal brain.
Avoid excess risk of spontaneous abortion, abruption, preterm.
What type of imaging is used to investigate endocrine system?
Nuclear imaging + conventional imaging modalities.
What is the clinical importance in endocrine imaging?
Accurate characterization of thyroid and parathyroid abnormalities is key for right tx.
What is CT used for in endocrine?
Mostly just for the parathyroid gland.
Nuclear medicine
Medical specialty where radioactive substance is used to diagnose and treat disease.
Radiotracers injected/ingested and imaged to see how body processes them.
Looks at functional information.
Role of nuclear imaging in thyroid/parathyroid
Thyroid: assess iodine trapping and organification.
Parathyroid: assesses mitochondrial activity.
Indications for thyroid imaging
Palpable nodule
Screening for high risk patients.
Suspicious cervical lymphadenopathy.
Follow up of prev dx.
What is the gold standard for thyroid FNA?
Ultrasound guided FNA
Hot nodule vs cold nodule
Hot = functional nodule
Cold = non-functioning nodule
Indications for radioactive iodine therapy
Graves disease
Hot nodule
(benign conditions)
Discuss the Masters & Johnson Sexual Response Cycle
- Desire
- Arousal
- Orgasm
- Refractory period
Says it has to happen in that order.
Discuss the Basson Incentive Based Sexual Response Cycle
Circle, doesnt require spontaneous urge/desire, outcomes influence future incentives/motivation.
How does a woman’s experience of sexual arousal differ from mens?
Men experience physical and mental at same time.
Women have incruency between physical and mental.
Discuss MOI for viagra
NO released into cavernous sm mm.
NO converts GTP into cGMP and then its sexy time.
There is a cock blocker called PDE5 that degrades cGMP.
Viagra is your wing man and degrades PDE5.
Only works if there is some NO being produced from mental sexual arousal. Need the mental!!
Flibanseran
Drug to help with female arousal.
Didnt do much and was $$$$$ and no etOH allowed.
Bremenlanotide
SC injection 45 min prior to sex.
Increased sexual desire but did not increase the # of sexually satisfying events.
Also $$$$$ and lots of nausea.
Dyspareunia
Persistent or recurrent pain with attempted or complete vaginal entry and/or penile vaginal intercourse.
Provoked vestibulodynia
Chronic nerve pain condition affecting the vestibule of the vagina.
Causes dyspareunia in up to 15% of pre-menopausal
Vaginismus
Difficulty allowing vaginal entry of a penis, finger, or any object despite the person’s desire to do so.
Genito/Pelvic pain/Penetration disorder
New classification in DSM-5 that groups dyspareunia and vaginismus together.
Pathologies associated with follicular cells
Benign adenomas
Well-differentiated thyroid cancers: papillary/follicular
Anaplastic thyroid cancer
Pathologies associated with c cells
Medullary thyroid carcinoma
Discuss benign thyroid changes and nodules
Nodules:
95% benign
Colloid nodules/adenomas
Cycts
Focal thyroiditis
Goitre/diffuse enlargement:
#1 cause iodine deficiency
Other causes; Hashimoto’s, Grave’s, multinodular disease.
Discuss thyroid ademomas
True benign neoplasm from follicular cells.
Homogenous, solitary, encapsulated.
Functioning (<1% risk of malig) vs Non-functioning (20% risk of malig)
Women >30 years.
Dx with US unless:
50% volume change or 20% growth in 2 dimensions.
Discuss thyroid cysts
Not a specific dx. Adenomas and nodules have varying amts of cyst fluid.
15-25% of all nodules are cystic.
Pathophys: Intranodular ischemia ->tissue necrosis ->liquefacation. Can grow rapidly.
Investigations: FNA; thick “chocolate” fluid. Aspiration can help with compressive symptoms as well.
3 classes of thyroid cancers
Well differentiated Thyroid Cancers 90%
Medullary thyroid Carcinoma 5-9%
Anaplastic Thyroid Carcinoma 1-2%
Well Differentiated Thyroid Cancers
90%
Papillary thyroid cancer (most common)
Follicular thyroid cancer
Excellent prognosis
Medullary Thyroid Carcinoma
5-9%
Presents early in life.
Multiple Endocrine Neoplasia (MEN) 2A and 2B
Familial Medullary Thyroid Carcinoma (FMTC)
Anaplastic Thyroid Carcinoma
1-2%
Very aggressive
Rapid progression
“Woody” very firm gland.
Poor prognosis.
Thyroid Cancer Incidence
Fastest growing cancer in women:
23.4/100,000
Highest in women 50-54 years
M: 7.2/100,000
Mortality rates stable 0.5/100,000 for M&W
Pretest probability for thyroid nodules:
Age/sex
Fam hx
Ethnicity
Growth
Symptoms
Radiation exposure
Age/Sex:
Male
<20 years
Men >40, W>50
Fam hx: 1st degree
Ethnicity: Filipino
Growth: Rapid growth, diff between aggressive CA vs hemorrhage into cyst
Symptoms:
Dysphagia, difficulty breathing
Voice change = RLN invasion
Hyper S&S = Rare to have CA in hyper
Thyroiditis = throat/neck pain
Radiation: previous exposure
Physical exam of thyroids concerning findings
Hard fixed lesion
Large mass >2.5 cm
Pain (cancer often painless)
Lymphadenopathy
Hoarse breathy voice/stridor (vocal cord paralysis)
Lab investigations for thyroid
FIRST: TSH
+/- fT4/3 if TSH low
Neoplasia/familial CA:
PTH = hyperparathyroidism
Calcitonin = medullary thryoid, MEN 2A/B, hyperparathyroidism, pheochromocytoma
Imaging for thyroid
US is the first test to order:
characterize nodules via TIRADS system
Facilitates FNA biopsy
Radioisotope w I-123 if low TSH
CT neck/chest if CA dx made:
Assess for local invastion, mets to lymph vs mets to lungs.
Discuss TIRADS classification
Grades based on; composition, echogenicity, shape, margin, echogenic foci.
TR1: Benign, <5% risk for malig, No FNA
TR2: Not suspicious, <5% risk for malig, No FNA
TR3: Mildly suspicious, 5% risk for malig, FNA if >2.5cm, follow if >1.5 cm
TR4: Moderately suspicious, 5-20% risk for malig, FNA if >1.5 else follow
TR5: Highly suspicious, >20% risk for malig, FNA if >1cm else follow
Discuss FNA in thyroid conditions
High specificity and sensitivity **GOLD STANDARD for dx
Safe, few complications
15% poor samples, repeat biopsy required 3 months later
3 general possibilities found:
Indeterminate - Repeat FNA
Benign - Observation
Suspicious - diagnostic lobectomy
What is used to estimate risk of malig and guide management based on FNA results
Bethesda System for Reporting Thyroid Cytopathology.
I Nondiagnostic
II Benign
III AUS/FLUS
IV FN/SFN
V Suspicious for malignancy
VI Malignant
Non Invasive Follicular Thyroid Neoplasm with Papillary like Nuclear Features (NIFTP)
Borderline or premalignant lesion
Molecular testing for thyroid CA
BRAF B600E
RET/PTC1 rearrangement
TERT promoter
Associated with aggressive CA 66% of the time.
Preoperative tool to help guide decision making.
Managemnnt of nonfunctional thyroid nodules
Observation based on TIRADS
Radiofrequency ablation for solid benign or hyper nodules if surgery CI’d or not wanted.
Hemithyroidectomy for compressive symptoms, cosmesis or >4cm nodule.
Management of thyroid CA
Multidisciplinary w/ Surgery and Endocrinology.
Surgery: Thyroidectomy (subtotal vs total), Lymphectomy (neck dissection) for mets.
Radioactive Iodine: Adjuvan/post surgery for microscopic disease
Sporadic CA vs Hereditary CA
Sporadic: Initial molecular lesion among normal cells
Hereditary: Inherited driver mutation in all cells of the body.
2 hit theory
One copy of tumor suppressor gene is inherited.
Other copy gets knocked out at some point in the individuals lifetime.
Explains why family hx of CA leads to a higher risk factor of developing CA in lifetime (1 allele is already fucked up).
Discuss the importance of penetrance
High penetrance, rare cancers
Moderate penetrance
Low penetrance, common cancers
Can test for gene associated with High/Mod penetrance and predict risk.
Discuss autosomal dominance in hereditary CA
Individuals inherit the susceptibility for gene mutation, not the CA itself.
Reduced penetrance
May appear to skip generations
Discuss recessive inheritance in hereditary CA
Comes from De novo mutations
Usually younger age of onset.
How many generations of family hx needs to be taken?
3!!!
List cancer risk modifiers
Carcinogens
Response to DNA damage
Modifier genes
Hormonal, immune
Discuss genetic testing for hereditary CA assmt.
Tumor-based:
Mismatch repair deficiency
Triple negative breast cancer
Tumour mutation
Discuss indicators of a cancer predisposition
Family hx
Age of onset
Type of CA or multiple primary CA
Tumour location/pathology
Risk prediction models
Active tumour screening
Why is it important for acknowledging indicators of CA disposition?
Therapeutic implications are expanding
Impacts therapy decisions
Early-detection
Cascade carrier testing - risk reduction strategies for carriers.
List some diagnoses that are immediate flag for genetic assmt
Retinoblastoma
Adrenocortical or choroid plexus carcinoma
Pheocromocytoma or paraganglioma
Retinal/cerebellar hemagioblastoma
Optic pathway tumour, malig peripheral sheath tumour
Medullary thyroid cA
Acoustic/vestibular scwannomas
Why test for hereditary CA predisposition
Reduce morbidity and mortality from inherited forms of CA
Identify at-risk individuals for targeted risk reduction and early detection.
Predictive for future cancers.
Prognostic for disease course.
Predictive for treatment utility.
3 areas of transformation required for improved cancer care
Access
Assessment
Follow-up
How much of serum Ca is protein bound?
50%
Normal serum Ca levels
2.1-2.6 mmol/L
Normal levels of ionized Ca (i[Ca])
1.15-1.4 mmol/L
Acid-base effects of plasma protein binding of Ca and i[Ca]
Acidosis - decreased Ca binding to protein.
Alkalosis - increased Ca binding to protein.
Kidney impact on Ca
Kidney reabsorbs 98% of i[Ca] daily.
Key place for regulation of serum Ca
3 controllers of Ca flux
Calcium sensing receptor CsR
Parathyroid hormone PTH
Vitamin D
Mechanism of CsR
Increased s[Ca] leads to increased binding of CsR.
CsR puts the brakes on:
PTH secretion
Osteoclastic activity
Renal tubular Ca reabsorption
1 alpha hydroxylation of vit D.
&
Increases calcitonin secretion which directly:
Inhibits osteoclast function
Enhances renal calcium excretion
Parathyroid response to Ca binding of CsR
Decrease PTH
Kidney response to Ca binding of CsR
Decrease Ca & Mg reabsorption.
Fast regulation of Ca
PTH release in response to drop in i[Ca]
Slower regulation of Ca
Up regulation of PTH synthesis in response to low activated Vit. D.
What is the defense against hypocalcemia?
PTH - all actions to raise serum Ca.
Acts on kidney to Increase Ca reabsorption, Decrease phosphate reabsorption.
Main regulation step in Vit. D. synthesis
Kidney - 1 alpha hydroxylation activates the molecule to calcitriol
Function of Vit. D in relationship to Ca
Bodily and skeletal acquisition of Ca.
Primary hyperparathyroidism
Serum Ca levels elevated.
PTH inappropriately high.
Most often caused by a parathyroid adenoma.
Increases risk for renal stones, bone loss, fractures.
Features of hypercalcemia
Stones
Bones
Moans (abdominal pain/constipation)
Psyciatric overtones (depression)
Thrones (polyuria/constipation)
Ultimately coma and death.
Hypercalcemia crisis
Coma and acute renal failure.
Renal S&S:
polyuria, polydipsia, nephrogenic diabetes insipidus,
ARF:Water loss -> decreased GFR -> decreased Ca elimination -> rapid rise in Ca.
Neurologic S&S:
Fatigue, decrease concentation.
CONFUSION, STUPOR, COMA.
CV: short QT, bradycardia, HTN
GI: VOMITING, Anorexia, nausea
Diagnostic approach to hypercalcemia
Elevated serum CA
Repeat to check levels corrected for albumin/ i[Ca]
Confirm serum CA
Measure intact PTH
PTH:
Elevated - Primary hyperparathyroidism
Mid - upper normal - Primary hyperparathyroidism likely, consider FHH
Low - Non-PTH mediated hypercalcemia
Criteria for diagnosis of primary hyperparathyroidsim
PTH inappropriately high in context of HIGH CA - confirmed x 2
Urine CA at least high normal or high (stones)
Tx of primary hyperparathyroidism
Surgery.
Some cases can observe if surgery not appropriate (elderly, mild stable hypercalcemia, no symptoms)
Non PTH hypercalcemia DDx
Unregulated bone Ca release:
Cancers, Plasma cell myeloma, PTH-RP cancers, Paget’s ds.
Excess Vit D and/or Ca input:
vit D intoxication, milk alkali syndrome, granulomatous diseases
Other small print cause: Addison’s
Drug induced: Li, thiazide, Vit. A.
Common reasons for secondary hyperparathyroidsim
Vit D deficiency and deprivation of dietary Ca
Chronic renal insufficiency
In kidney disease: Phosphate rises -> Activation of Vit D impaired -> low sCa -> increase PTH -> bone loss
Features of hypocalcemia
Acute: Tetany
Chronic: Lethary/depression, dry skin, coarse hair, brittle nails, long QT
Late: heart failure, steatorrhea
Approach to hypocalcemia
Check PTH, P, Mg, GFR
Appropriately high PTH: CKD (high P, low GFR), Vit D/Ca deficiency (High P, normal GFR)
Inappropriately low/low normal PTH: Hypoparathyroidism (High P, normal GFR), Malnutrition (Low Mg, Low P, normal GFR).
