Endocrinology Flashcards
Calcium Physiology: Pearl 1 & 2
In a parathyroid-mediated
process, serum calcium and
phosphate go in the opposite
direction
e.g.
Hyperparathyroidism: ↑Ca ↓PO4
Hypoparathyroidism: ↓Ca ↑PO4
In a vitamin D mediated process,
serum calcium and phosphate go
in the same direction
e.g.
Osteomalacia: ↓Ca, ↓PO4
Vitamin D Excess: ↑Ca, ↑PO4
(ex. 1,25-hydroxyvitamin D excess from
granulomatous disease)
Calcium Physiology: Pearl 3 & 4
When the calcium, phosphate
and PTH are all high, think kidney
(reduced ability to excrete
phosphate)
e.g.
Tertiary Hyperparathyroidism (in
long-standing renal failure):
↑Ca, ↑PO4
Magnesium deficiency reduces
PTH secretion and causes PTH
resistance. Therefore think of
hypomagnesemia in someone
with apparent
hypoparathyroidism (or
inappropriately normal PTH).
Treatment of Primary Hyperparathyroidism (PHPT)
Symptomatic PHPT = Surgery!
Asymptomatic PHPT= “Stay The Fudge Away U Stupid Calcium”
If patient NOT a candidate for surgery (e.g. per ENT, or too frail for surgery) -> Medical Mgmt*:
* Calcium intake should be consistent with nutritional guidelines (1000-1200 mg/d)
* Correct vitamin D deficiency/insufficiency: target serum 25OH vit D to >75 nmol/L
* Bisphosphonates and denosumab are effective at increasing BMD
* Cinacalcet ($) is effective in reducing serum Ca and should be considered for symptomatic PHPT if surgery is not an option. May combine w BP or denosumab in selected pts (to reduce Ca AND increase BMD).
Indications for Surgery for Primary Hyperparathyroidism (PHPT)
AT DIAGNOSIS:
Serum total calcium > 0.25 mmol/L above upper limit
T-score <= -2.5 at L-spine, total hip, femoral neck or distal 1/3 radius
Fractures (Vertebral only; by X-ray, CT, MRI or VFA)
Age < 50
Urine calcium >6.25 mmol/d (>250mg/d) in women or >7.5 mmol/d in
men (>300mg/d) NEW cutoffs in 2022
Stones or nephrocalcinosis by x-ray, ultrasound, or CT
Creatinine clearance < 60 mL/min (stage 3 CKD)
Indications for Surgery for Primary Hyperparathyroidism (PHPT) at follow up?
NEW AT SUBSEQUENT FOLLOW-UP:
* Serum calcium consistently >0.25 mmol/L above upper limit
* A fracture
* A kidney stone
* Significant reduction in BMD to T-score <= -2.5
* Significant reduction in CrCl (defined as decline of >3ml/min annually
to <60 ml/min)
What are symptoms of PHPT?
In primary hyperparathyroidism, one or more of the parathyroid glands is overactive. As a result, the gland makes too much parathyroid hormone (PTH).
Too much PTH causes calcium levels in your blood to rise too high.
Symptoms include
muscle weakness
fatigue
depression
aches and pains in bones and joints
People with more severe disease may have
loss of appetite
nausea
vomiting
constipation
confusion
increased thirst and urination
What are the causes of Primary Hyperparathyroidism (PHPT)?
benign, or noncancerous, tumor called an adenoma has formed in one of the parathyroid glands.2 The tumor causes the gland to become overactive. In most other cases, extra PTH comes from two or more adenomas or from hyperplasia, a condition in which all four parathyroid glands are enlarged. People with rare inherited conditions that affect the parathyroid glands, such as multiple endocrine neoplasia type 1 or familial hypocalciuric hypercalcemia are more likely to have more than one gland affected.
Rarely, primary hyperparathyroidism is caused by cancer of a parathyroid gland.
PHPT Monitoring if No Surgery
Serum Ca, 25OH vitamin D annually
Skeletal monitoring:
* 3-site DXA scan every 1-2 years [hip, lumbar spine, distal 1/3 radius]
* Vertebral XR or vertebral fracture assessment (VFA) if clinically
indicated (to look for fracture)
Renal monitoring:
* CrCl (preferred over eGFR) annually
* Abdominal imaging (XR, CT, or US) if clinically indicated (r/o stones)
What must you rule out before going to surgery for primary hyperparathyroidism?
Familial hypocalciuric hypercalcemia (FHH) is an inherited disorder that causes abnormally high levels of calcium in the blood (hypercalcemia) and low to moderate levels of calcium in urine (hypocalciuric).
MUST DO A URINE CALCIUM before sending someone
for surgery
- Urine calcium:creatinine ratio < 0.01 (less than 1%!) - think
FHH; PHPT generally have UCa:Cr ratio >0.02
What is Secondary Hyperparathyroidsim ?
Secondary Hyperparathyroidism
– Appropriate increase in PTH release in the face of hypocalcemia or vitamin D
deficiency (most common)
– PTH is appropriately working to absorb all the urine calcium/salvage calcium level
Common in CKD
Random Tips re secondary hyperparathyroidism
TIP #1 : Postop Gastic Surgery (ex. gastric bypass/bilroth/whipples surgery where a
portion of stomach is removed)
* You CANNOT use Calcium Carbonate as a supplement (there is no acidity to absorb
this!) = use Calcium Citrate
– TIP #2: Pt w Renal disease (CKD)
* treat with Vitamin D (Calitrol), phosphate restriction, non-calcium phosphate binders
* Cinacalcet (with target PTH levels depending on CKD stage; often in consultation with
Nephrology)
What is Tertiary Hyperparathyroidism?
– Longstanding hypocalcemia (an appropriate stimulus for PTH release) parathyroid glands can become autonomous
– Usually in the setting of end-stage renal disease or post-transplant
Cinacalcet MOA
Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
What are some phosphate binders?
Aluminum-free, calcium-free phosphorus binders, such as Renagel (sevelamer) and Renvela (sevelamer carbonate), mix with phosphorus in the intestinal tract, but do not contain aluminum or calcium, so they don’t cause problems with excess aluminum or calcium load.
Indications for Surgery in Tertiary Hyperparathyroidism
Refractory hyperPTH despite vit D analogues/
calcimimetics (No absolute #/PTH cutoff, KDIGO defines as PTH
still rising, symptomatic)
* Hypercalcemia severe / symptomatic
* Calciphylaxis
* Progressive bone disease
What releases PTH?
low ca, low vit d and high phosphate
Hypoparathyroidism diagnosis and management
Hypocalcemia in the presence of undetectable, low or
inappropriately normal PTH
* measured on two occasions >2 weeks apart
* Supported by high phosphorus and low (1,25)OH2 vitamin D
* Permanent postsurgical hypoPTH is defined as persisting >12
months after surgery
Management:
* 1st line = Conventional therapy w/ oral calcium & active vitamin D
(calcitriol or alfacalcidol)
* PTH therapy can be considered if conventional therapy insufficient
Hypoparathyroid Differential
Acquired
– Hypomagnesemia - PTH resistance
– Hypermagnesemia - reduce PTH synthesis/secretion
– Post-surgical (common complication post-total thyroidectomy) or post- radiation
– Infiltrative disease (sarcoid, amyloid, cancer metastasis)
– Autoimmune polyglandular syndrome type 1 (APS-1)
Congenital
– Pseudohypoparathyroidism (genetic mutation in GNAS gene)
– DiGeorge Syndrome / 22q11.2 deletion syndrome : parathyroid agenesis
– Note: Hypocalcemia outside of hypoparathyroidism can also occur in
Extravascular sequestration – Hyperphosphatemia, Pancreatitis,
Osteoblastic metastases
Medical Treatment of Hyperthyroidism?
Thyroid receptor antibodies (Graves’)
Treatment Options for Graves: thionamides, surgery (total thyroidectomy), or RAI
ablation; latter two renders the patient hypothyroid - need levothyroxine
replacement lifelong
Medical Management:
* Use MMZ instead of PTU because less hepatotoxic EXCEPT in the following
situations: (SE of both = liver tox and agranulocytosis)
-First trimester of pregnancy (risk of aplasia cutis & cleft palate)
-Thyroid storm
-Minor MMZ reactions (if severe, then shouldn’t use anti-thyroid drugs at all)
– PTU should be discontinued if transaminases reach >3x ULN if found incidentally or if clinically
measured
Other treatment for (not meds) hyperthyroidism?
RAI
– Single dose of ablative radioactive iodine.
– Contraindications: Pregnancy, breastfeeding, moderate-severe
orbitopathy, thyroid cancer
– Adverse effects: Worsened Orbitopathy, Thyroiditis
– Delay pregnancy for 6 months after tx
– If giving RAI with orbitopathy, should give steroids
– Should be off methimazole for at least 2-3 days before radioactive iodine ablation
- Surgery
- Patient should be euthyroid prior to surgery
Graves Orbitopathy (GO) Treatment
Depends on activity and severity of disease which is determined by
assessment tools
Active: + signs of inflammation (redness, swelling, pain)
* Severity: Mild, Moderate-Severe, Sight-threatening (very-severe)
- For all patients with GO of any activity or severity:
- Quit smoking
- Refer to specialized GO eye center
- Topical non-preserved artificial tears
- Restore euthyroidism
MILD: Selenium supplementation x 6 months (fasting
intake)
MOD-SEVERE: IV Steroids + mycophenolate is the
EUGOGO first-line treatment for those
with ACTIVE GO if no contraindications (ie
CHF, severe hyperglycemia).
* Alternative first-line regimen is IV steroids
alone at higher doses
* Surgery only offered for stable INACTIVE
GO (must be inactive >6 months)
What are the symptoms of Thyroid Storm?
Think of this with a very sick patient with thyrotoxicosis (tachycardia, confusion,hyperthermia)
The degree of T4 excess is not necessarily more than with other forms of hyperthyroidism
COMPONENTS:
* Fever
* Neurological symptoms
* GI symptoms/hepatic dysfunction
* Tachycardia
* A. fib
* Heart failure
* Precipitants (infection, surgery, trauma, iodine load, pregnancy; most common is medication non-
What is Thyroid Storm Treatment?
ABCs – get ICU involved early!
* Supportive care
* Beta-blockers (careful with hemodynamic status!!) * E.g. Propranolol 60-80mg PO q4-6h, if unsure, start at lower Propranolol
dose 20-40mg po q4-6hr [the intention is to reduce adrenergic drive]
- PTU (usually 200 mg PO q4h) THEN
- Iodine* Lugol’s iodine 10 drops q8h
- Should be given 1 hour after the loading dose of PTU
- Glucocorticoids (often AI co-exists, also helps to reduce fT4à
fT3 conversion)
What is the treatment of Subclinical Hypothyroidism?
TSH above upper limit of normal with normal Free T4
- Treat when:
TSH > 10 mIU/L - 1.6mcg x weight (kg) = typical starting dose; titrate every 4-6 weeks
** if cardiac disease (CAD) or frail elderly, can start at lowest possible dose
(e.g. 25mcg po daily or 50mcg po daily to avoid risk of inducing AFib)
Tx: synthroid, eltroxin
Others: cytomel - if issue with T4-> T3 conversion
Dessicated thyroid
Consider treatment when:
-Symptomatic
-Goiter
-Pregnancy/pregnancy-planning
-Positive anti-TPO antibodies
Aside:
No apparent benefits to treating older persons with
subclinical hypothyroidism
Choosing Wisely: routinely, we do not test for anti-TPO (also
called anti-microsomal ab), but in subclinical, can test to
push your treatment decision.
Test for anti-TPO if child bearing age (can lose child)
Clinical Pearl Regarding Imaging hyper/hypo thyroidsm
only image thyroid if thyroid nodule felt or seen on carotid imaging
What is the presentation of Myxedema Coma?
Severe hypothyroidism leading to:
– Altered LOC / lethargy
– Hypothermia
– Hypotension
– Bradycardia
– Hyponatremia
– Hypoventilation
Life-threatening SLOWING of
function in multiple organs!
Diagnosis is clinical – but
often see very
low/undetectable FT4, high
TSH
What is the treatment of Myxedema Coma?
IV levothyroxine load 200-400mcg x1 followed by
1.6mcg/kg/d (this is the PO dose, multiple by 75% if given IV)
– Lower dose should be considered if cardiac history or elderly
– PO levothyroxine ~75% as potent as IV form
- IV glucocorticoids (HC 100mg IV Q8H) until AI ruled out
- IV liothyronine (T3) load 5-20mcg x1 followed by 2.5-10mcg Q8H
- Supportive measures (ICU monitoring, mechanical
ventilation, fluids, warming)
Subclinical Hypothyroidism in Pregnancy tx?
see chart in notes
-Pregnant women with TSH >2.5 mU/L should be evaluated for TPOAb
-Once on treatment, target TSH ≤ 2.5 throughout the pregnancy
-In Canada, we do not routinely screen TSH in asymptomatic pregnant women
Treatment of Pre-existing Hypothyroidism in Pregnancy?
Need ~30-35% more LT4 as soon as pregnant
= take an extra LT4 pill on Saturdays and Sundays (two
extra pills/week = 9 pills/week) as soon as they are
pregnant
Need ~30-35% more LT4 as soon as pregnant
= take an extra LT4 pill on Saturdays and Sundays (two
extra pills/week = 9 pills/week) as soon as they are
pregnant
-Upon delivery, go back to pre-pregnancy dose
-Target TSH ≤ 2.5 throughout pregnancy
TX of Graves’ in Pregnancy ?
- Anti-thyroidal medications are teratogenic.
a) Use PTU in the first trimester (conversion ~1mg MMZ:20mg
PTU), MMZ after that (or discontinue all ATDs if possible!)
- Patients on MMZ <10mg/d or PTU <200mg/d may try
discontinuing
b) Use the lowest possible dose (aim for T4 at high-normal
range) - TSH-R Ab can cross the placenta.
a) Check Ab titer in second trimester. If very high (3x ULN),
need increased fetal monitoring for fetal Graves’. - Long-term treatment with β-blockers has been
associated with intrauterine growth restriction, fetal
bradycardia, and neonatal hypoglycemia. - Watch for post partum exacerbations
a) Could also be post partum thyroiditis
What is the presentation and treatment of Gestational Transient Thyrotoxicosis?
In normal pregnancy, Thyroid Binding Globulin and
total T4 increase by 7 wks GA and peak at 16 wks GA
* hCG stimulates the TSH receptor on the thyroid gland
causing ↑thyroid hormone & ↓TSH
* The hCG effect may be even more pronounced in:
-Hyperemesis gravidarum
-Molar pregnancy
-Multiple gestation
-Choriocarcinoma
Generally self-limited, improves by 14-18 weeks
* Treat hyperemesis if present
* Use B-blockers if really necessary for symptoms
* Do NOT give PTU or methimazole
Diagnosis of Osteoporosis
A) Fragility fracture
OR
B) Bone mineral density of 2.5 or more standard
deviations (SD) below the peak bone mass for young adults (T-score ≤ –2.5) on dual-energy x- ray absorptiometry (DEXA)
Risk Stratification and who to screen?
How do we risk stratify?
* History: identify signs of “automatic high risk”
* CAROC or FRAX tools
BMD
* 50–64 yr with a previous osteoporosis-related fracture or ≥ 2 clinical risk factors
* ≥ 65 yr with 1 clinical risk factor for fracture
* ≥ 70 yr
Spine x-ray / vertebral fracture assessment
* ≥ 65 yr with T-score ≤ –2.5 (femoral neck, total hip or lumbar spine)
* 10-yr major osteoporotic fracture risk between 15% and 19.9% (moderate)
* Clinical signs: vertebral tenderness, height loss (historical 6 cm, prospective
2cm), occiput to wall > 5 cm, rib-pelvis < 2 fingers
When do you treat osteoporosis ?
When to Treat: High Risk
* Hip, vertebra or ≥ 2 osteoporosis-related fractures
* 10-yr major osteoporotic fracture risk ≥ 20%
* ≥ 70 yo and have a T-score ≤ –2.5 (femoral neck, total hip or lumbar spine)
Before initiating pharmacotherapy, assess for secondary causes of osteoporosis:
ALP (Paget’s), PTH, Calcium/Alb/PO4 (parathyroid), Cr/eGFR (renal disease),
TSH (hyperthyroidism), 25OH vitamin D (deficiency, malabsorption), Meds/Alcohol
SPEP – vertebral #, anemia (MM), Eating disorders, Bariatric Surgery Hx, testosterone
(hypogonadism), CRP (IBD), tTG-IGA (Celiac) etc.
Suggest Treatment: Moderate Risk
- 10-yr major osteoporotic fracture risk between
15% and 19.9% - < 70 yr and have a T-score ≤ –2.5 (femoral
neck, total hip or lumbar spine)
Other treatment decision factors to consider: - a fracture in the last 2 years (risk of subsequent fracture highest)
- ongoing risk factors
Osteoporosis Treatment
See Chart
- Oral Bisphosphonates (First line in consideration of cost and access)
- IV Zolendronic Acid (If GI effects on oral bisphosphonates)
- Denosumab (If intolerant to bisphosphonates) *
- Romosozumab or Teriparatide (If vertebral body height loss >40% OR > 1
vertebral fracture AND a T-score ≤ –2.5) - HRT (if female < 60, within 10 yr of menopause start, with goals to
treat menopause symptoms Ω) - Raloxifene (Over no treatment in postmenopausal females who cannot
tolerate any other therapies) - Off Label Bisphosphonate Dose/frequency reduction, Denosumab,
collaborative decision making with nephro & endo (If CKD, eGFR<30)
Length of treatment
Bisphosphonates: initial therapy for 3–6 yr, Reassess during drug
holiday with BMD/FRAX in 3 years (or sooner if clinical indication)
* Denosumab: long-term uninterrupted therapy (should not delay
Q6month dosing by more than 1 mo) may be re-assessed after 6–10 yr
* If stop at ≤ 4 doses, transition to bisphosphonate 6 mo after the last dose of
denosumab (reduces risk of rapid bone loss. Bisphosphonate therapy for 1 yr
and then reassessing).
* If stop at ≥ 5 doses (risk of rapid bone loss or vertebral fractures is high): refer
to OP expert
* Teriparatide (24 mos)/Romo (12 mos): one course then transitionto antiresorptive agent to maintain bone density gains
Bisphosphonate (BP) Drug Holiday
BP effects on bone persist for several years after discontinuation it
should be FIRST LINE for most patients with OP
* Atypical femur fracture (AFF) and Osteonecrosis of Jaw (ONJ) risks
rise sharply after 3-5 years, and can be reduced by taking a drug
holiday
* Drug holiday = temporarily stopping BP for up to 5 years
– Restart therapy within 5 years if significant BMD decline, interval fracture,
or other risk factors that increase risk
- Once on therapy, reassess fracture risk in 3-5 years
– If HIGH-RISK à continue therapy or switch to another agent
– If LOW-MODERATE à drug holiday; reassess fracture risk every 2-4 years - Restart therapy if significant bone loss or enters high risk
BMD Monitoring Frequency
* Not a candidate for pharmacological treatment:
– 5–10 yr: if risk of major osteoporotic fracture (MOF) is < 10%
– 5 yr if risk of MOF is 10%–15%
– 3 yr if the risk of MOF is > 15%
* Those on Therapy:
– 3 yr after starting Rx
* Those on Bisphosphonate Drug Holiday:
– 3 yrs after stopping
*BMD measurement may be repeated sooner/more frequently in people with new
fracture, secondary causes of osteoporosis, or new clinical risk factors associated with
rapid bone loss
When to Use Teriparatide (PTH)?
Severe osteoporosis (T-score <-2.5) with multiple
vertebral fractures look for contraindications to
bisphosphonates and denosumab when considering
* Fractures despite prolonged bisphosphonate use
* High fracture risk and low bone formation
* Osteoporosis and prolonged steroid use
* Osteonecrosis of the Jaw
* Atypical Femoral Fracture
Contraindications to Teriparatide
Renal insufficiency (not well-studied)
* Renal stones
* Primary hyperparathyroidism/hypercalcemia
* Extensive skeletal radiation
* Paget’s disease
Don’t use in:
* children or young adults
* women who are pregnant or nursing
* gout or hyperuricemia
Maximum duration = 24 months, longer use may ↑risk of osteosarcoma (animal
data)
Romosuzumab
Monoclonal anti-sclerostin antibody
– Sclerostin is produced by osteocytes and inhibits bone formation.
– Anti-sclerostin promotes bone formation and bone remodeling.
* SC injection given monthly for up to 12 months
– Can be used in eGFR <30 but risk of hypocalcemia
* Benefits:
– reduced vertebral, non-vertebral, *hip fractures
– very low risk of atypical femoral fractures or osteonecrosis of jaw
*not powered adequately but signal towards less hip #
* Side Effects:
– Most worrisome is increased risk of MACE events noted in ARCH trial
(Romosuzumab vs Alendronate, 2017)
– Most common side effect were injection site reactions or hypersensitivity reactions
– Very low risk of AFF and ONJ but still possible
