Disorders of Multiple Endocrine Glands Flashcards
MEN I - Wermer’s Syndrome Affects what
The 3 Ps
Pituitary
Parathyroid
Pancreas
What is multiple endocrine neoplasm and what is its inheritance pattern
- neoplastic syndromes involving multiple endocrine glands
- tumours of neuroectodermal origin
- autosomal dominant inheritance with variable penetrance
What investigation has long-term benefit in MEN II
genetic screening for RET proto-oncogene on chromosome 10 has long-term benefit in MEN II
■ early cure and prevention of medullary thyroid cancer
MEN Classification types
MEN I (chromosome 11) - Wermer’s Syndrome
MEN II (chromosome 10)
- IIa Sipple’s Syndrome
- Familial Medullary Thyroid Ca (a variant of IIa)
- IIb
Wermer’s Syndrome tissues involved
Pituitary (15-42%)
Anterior pituitary adenoma
Parathyroid (≥95%)
Primary hyperparathyroidism from hyperplasia
Entero-pancreatic endocrine (30-80%) Pancreatic islet cell tumours Gastrinoma Insulinomas Vasoactive intestinal peptide (VIP)-omas Glucagonoma Carcinoid syndrome
Wermer’s Syndrome clinical manifestations
Headache visual field defects, often nonsecreting but may secrete GH (acromegaly) and PRL (galactorrhea, erectile dysfunction, decreased libido, amenorrhea)
Nephrolithiasis, bone abnormalities, MSK complaints, symptoms of hypercalcemia
Epigastric pain (peptic ulcers and esophagitis) Hypoglycemia Secretory diarrhea
Rash, anorexia, anemia, diarrhea glossitis
Flushing, diarrhea, bronchospasm
IIa Sipple’s Syndrome tissues involved
Thyroid (>90%)
Medullary thyroid cancer (MTC)
Adrenal medulla (40-50%) Pheochromocytoma (40-50%)
Parathyroid (10-20%) 1o parathyroid hyperplasia
Skin Cutaneous lichen amyloidosis
IIa Sipple’s Syndrome clinical manifestations
Physical signs are variable and often subtle
Neck mass or thyroid nodule; non-tender, anterior lymph nodes
HTN, palpitations, headache, sweating
Symptoms of hypercalcemia
Scaly skin rash
Familial Medullary Thyroid Ca (a variant of IIa) tissues involved
Thyroid MTC (≥95%)
Familial Medullary Thyroid Ca (a variant of IIa) clinical manifestations
MTC without other clinical manifestations of MEN IIa or IIb
MEN IIb tissues involved
Thyroid
MTC
Adrenal medulla
Pheochromocytoma (≥50%)
Neurons
Mucosal neuroma, intestinal ganglioneuromas (100%)
MSK (100%)
Men IIb clinical manifestations
MTC: most common component, more aggressive and earlier onset than MEN IIa HTN, palpitations, headache, sweating
Chronic constipation; megacolon
Marfanoid habitus (no aortic abnormalities)
MEN I investigations
■ laboratory
◆ may consider genetic screening for MEN-1 mutation in index patients – if a mutation is identified, screen family members who are at risk
◆ gastrinoma: elevated serum gastrin level (>200 ng/mL) after IV injection of secretin
◆ insulinoma: reduced fasting blood glucose (hypoglycemia) with elevated insulin and C-peptide levels
◆ glucagonoma: elevated blood glucose and glucagon levels
◆ pituitary tumours: assess GH, IGF-1, and prolactin levels (for over-production), TSH, free T4, 8 AM cortisol, LH, FSH, bioavailable testosterone or estradiol (for underproduction due to mass effect of tumour)
◆ hyperparathyroidism: serum Ca2 and albumin, PTH levels; bone density scan (DEXA)
■ imaging
◆ MRI for pituitary tumours, gastrinoma, insulinoma
MEN II investigations
■ laboratory
◆ genetic screening for RET mutations in all index patients – if a mutation is identified, screen family members who are at risk
◆ calcitonin levels (MTC); urine catecholamines and metanephrines (pheochromocytoma); serum Ca2+, albumin, and PTH levels (hyperparathyroidism)
◆ pentagastrin ± calcium stimulation test if calcitonin level is within reference range
◆ FNA for thyroid nodules-cytology
■ imaging
◆ CT or MRI of adrenal glands, metaiodobenzylguanidine (MIBG) scan for pheochromocytoma
◆ octreoscan and/or radionuclide scanning for determining the extent of metastasis
Treatment MEN I
■ medical
◆ proton pump inhibitor (PPI) for acid hypersecretion in gastrinoma
◆ cabergoline or other dopamine agonists to suppress prolactin secretion
◆ somatostatin for symptomatic carcinoid tumours
■ surgery for hyperparathyroidism, insulinoma, glucagonoma, pituitary tumours (if medical treatment fails for the latter)
◆ trans-sphenoidal approach with prn external radiation
Treatment Men II
■ surgery for MEN IIa with pre-operative medical therapy
◆ prostaglandin inhibitors to alleviate diarrhea associated with thyroid cancer
◆ α blocker for at least 10-21 d for pheochromocytoma pre-operatively
◆ hydration, calcitonin, IV bisphosphonates for hypercalcemia
Normal calcium levels
- normal total serum Ca2+: 2.2-2.6 mmol/L
- ionic/free Ca2+ levels: 1.15-1.31 mmol/L
- serum Ca2+ is about 40% protein bound (mostly albumin), 50% ionized, and 10% complexed with PO43- and citrate
What regulates calcium
regulated mainly by two factors: parathyroid hormone (PTH) and vitamn D
What organs does calcium act on
actions mainly on three organs: GI tract, bone, and kidney
PTH: source, regulation of calcium and net effect
From parathyroid glands
Regulation - Stimulated by low serum Ca2+ and high serum PO43-;
inhibited by chronic low serum Mg2+, high serum Ca2+, and calcitriol
Net effect
Inc Ca
Inc Calcitriol
Dec PO4
Calcitriol (1,25 - (OH)2D3) source, regulation of calcium and net effect
Source:
Dietary intake Synthesized from cholesterol: UV on skin makes cholecalciferol (vitD3) liver makes calcidiol (25-(OH)D3) kidneys make calcitriol
Regulation: Renal calcitriol production is stimulated by low serum PO43- and PTH; inhibited by high serum PO43- and calcitriol in negative feedback
Net effect
Inc Ca
Inc PO4
Calcitonin source, regulation of calcium and net effect
Source: thyroid cells
Regulation: Stimulated by pentagastrin (GI hormone) and high se um Ca2+; inhibited by low serum Ca2+
Net effect
Dec Ca (in pharmacologic doses)
Dec PO4
Mg effect
Cofactor for PTH secretion
PO4 effect
Dec Ca
Primary hyperparathyroidism definition and etiologies and treatment
Increased PTH secretion commonly due to parathyroid adenoma lithium therapy; less often parathyroid carcinoma or parathyroid h perplasia
Most commonly related to a solitary adenoma or less commonly multiple gland hyperplasia. Surgical excision acts as definitive treatment and is recommended for patients who are symptomatic. For mild asymptomatic disease medical surveillance may be appropriate with annual serum calcium, creatinine, and bone mineral density (BMD) For asymptomatic patients surgery is recommended for those who meet ≥1 of the following criteria: • Serum calcium concentration more than 0.25 mmol/L (1.0 mg/dL) above the upper limit of normal • Creatinine clearance <60 mL/min • BMD T-score
Secondary hyperparathyroidism definition and etiologies
Partial resistance to PTH action leads to parathyroid gland hyperplasia and increased PTH secretion, often in patients with renal failure and osteomalacia (due to low or low normal serum calcium levels)
Tertiary hyperparathyroidism definition and etiologies
Irreversible clonal outgrowth of parathyroid glands, usually in long-standing inadequately treated chronic renal failure on dialysis
Most common cause of hypercalcemia in healthy outpatients
Primary hyperparathyroidism
Pseudohypercalcemia
Increased protein binding leading to an elevation in serum total Ca2+ without a rise in the ionized/free form, e.g. hyperalbuminemia from severe dehydration
Parathyroid hormone regulation
TN E37
Hyperccalcemia definition
• total corrected serum Ca2+ >2.6 mmol/L OR ionized Ca2+ >1.35 mmol/L
Approach to hypercalcemia
- Is the patient hypercalcemic (correct for albumin)
- Is the PTH high/normal or low?
- If PTH is low, is phosphate high/normal or low? If phosphate is high/normal is the level of vitamin D metabolites high or low
How to calculate corrected calcium and what different calcium levels indicate
Corrected Ca2+ (mmol/L) = measured Ca2++ 0.02 (40 – albumin)
For every decrease in albumin by 10, increase in Ca2+ by 02
Benign (less likely malignant): Ca2+ <2.75 mmol/L)
Pathologic (more likely malignant): Ca2+ >3.25 mmol/L
Differential diagnosis of hypercalcemia
E38
Clinical features of hypercalcemia
Symptoms depend on the absolute Ca2+ value and the rate of its rise (may be asymptomatic)
CVS: HTN Arrhythmia Short QT Deposition of Ca2+ on valves, coronary arteries, myocardial fibres
GI:
Constipation Anorexia Nausea Vomiting (groans) PUD pancreatitis
Renal:
Polyuria (Nephrogenic DI) Polydipsia Nephrolithiasis (stones) Renal failure (irreversible) Dehydration
Rheumatological:
Gout
Pseudogout Chondrocalcinosis
MSK:
Weakness
Bone pain (bones)
Psychiatric:
>3 mmol/L
Increased alertness Anxiety Depression Cognitive dysfunction Organic brain syndromes
>4 mmol/L (16 mg/dL) Psychosis (moans)
Neurologic:
Hypotonia Hyporeflexia Myopathy Paresis
“Bones, stones, groans and psychiatric overtones”
Symptoms of hypercalcemic crisis
Usually >4 mmol/L
primary symptoms include oliguria/anuria and mental status changes including somnolence and eventually coma –> this is a medical emergency and should be treated immediately!
Hypercalcemia treatment
- treatment depends on the Ca2+ level and the symptoms
- treat the underlying cause of the hypercalcemia
- treat acute, symptomatic hypercalcemia aggressively
- mild asymptomatic hypercalcemia; monitor, avoid: thiazide, volume depletion, high Ca2+ diet, lithium, bed rest
What is the most common cause of hypercalcemia in hospital
Malignancy - associated hypercalcemia
Malignancy - associated hypercalcemia usual presentation and mechanisms
- Usually occurs in the later stages of disease
- Most commonly seen in lung, renal, breast, ovarian, and squamous tumours, as well as lymphoma and multiple myeloma
Mechanisms:
• Secretion of parathyroid hormone-related protein (PTHrP) which mimics PTH action by preventing renal calcium excretion and activating osteoclast-induced bone resorption
- Cytokines in multiple myeloma • Calcitriol production by lymphoma
- Osteolytic bone metastases direct effect
- Excess PTH in parathyroid cancer
Differential diagnosis of hypercalcemia
- Primary hyperparathyroidism
- Malignancy: hematologic, humoral, skeletal metastases (>90% from 1 or 2)
- Renal disease: tertiary hyperparathyroidism
- Drugs: calcium carbonate, milk alkali syndrome, thiazide, lithium, theophylline, vitamin A/D intoxication
- Familial hypocalciuric hypercalcemia
- Granulomatous disease: sarcoidosis, TB, Hodgkin’s lymphoma
- Thyroid disease: thyrotoxicosis
- Adrenal disease: adrenal insufficiency, pheochromocytoma
- Immobilization
Treatment of acute hypercalcemia/hypercalcemic crisis
Increase urinary Ca Excretion:
- Isotonic saline (4-5 L) over 24 h ± loop diuretic (e.g. furosemide) but only if hypervolemic (urine output >200mL/h)
- Calcitonin: 4 IU/kg IM/SC q12h 8 IU/kg IM/SC q6h Only works for 48 h Rapid onset within 4-6
Diminish bone resorption:
1. Bisphosphonates (treatment of choice)
Inhibits osteoclastic bone resorption and promotes renal excretion of calcium
Acts rapidly but often transient response (decreased by 0.3-0.5 mmol/L beginning within 4-6 h) max effect usually in 7 d
Combination of calcitonin and steroids may prolong reduction in calcium
Tachyphylaxis may occur
Indicated in malignancy-related hypercalcemia (IV pamidronate or zoledronic acid used)
2. Mithramycin (rarely used) – effective when patient cannot tolerate large fluid load
Dangerous – hematotoxic and hepatotoxic
Decrease GI Ca absorption
1. Corticosteroids in hypervitaminosis D and hematologic malignancies
Anti-tumour effects -> decreased calcitriol production by the activated mononuclear cells in lung and lymph node
Slow to act (5-10 d); need high dose
Dialysis
1. Tx of last resort
Indication - severe malignancy - associated hypercalcemia and renal insufficiency or heart failure
What deficiency can impair PTH secretion and action
Hypomagnesmia
Hypocalcemia definition
total corrected serum Ca2+ <2.2 mmol/L
Clinical features of hypocalcemia
Acute hypocalcemia:
Paresthesia (perioral, hands, and feet)
Laryngospasm (with stridor)
Hyperreflexia
Tetany
Chvostek’s sign (tap CN VII just anterior to the external auditory meatus elicits ipsilateral spasm of the orbicularis oculi or orbicularis oris muscles)
Trousseau’s sign (inflation of a blood pressure cuff above systolic pressure for 3 min elicits carpal spasm and paresthesia)
ECG changes
Delirium
Psychiatric Sx: emotional instability, anxiety, and depression
Chronic hypocalcemia:
CNS: lethargy, seizures, psychosis, basal ganglia calcification, Parkinson’s, dystonia, hemiballismus, papilledema, pseudotumour cerebri
CVS: prolonged QT interval g Torsades de pointes (ventricular tachycardia)
GI: steatorrhea
ENDO: impaired insulin release
SKIN: dry, scaling, alopecia, brittle and transversely fissured nails, candidiasis, abnormal dentition
OCULAR: cataracts
MSK: generalized muscle weakness and wasting
Differential diagnosis of tetany
- Hypocalcemia
- Metabolic alkalosis (with hyperventilation)
- Hypokalemia
- Hypomagnesemia
Approach to hypocalcemia?
- Is the patient hypocalcemic?
- Is the PTH high or low?
- If PTH is high, is phosphate low or normal?
- Is the Mg2+ level low?
Hypocalcemia treatment
- correct underlying disorder
- treat concurrent hypomagnesemia
• mild and symptomatic (ionized Ca2+ >0.8 mmol/L)
■ treat by increasing dietary Ca2+ by 1000 mg/d
■ calcitriol 0.25 µg/d (especially in renal failure)
acute or symptomatic hypocalcemia (ionized Ca2+ <0.7 mmol/L)
■ immediate treatment required
■ IV calcium gluconate 1-2 g over 10-20 min followed by slow infusion if necessary
■ goal is to raise Ca2+ to low normal range (2.0-2.1 mmol/L) to prevent symptoms but allow maximum stimulation of PTH secretion
- if PTH recovery not expected requires long-term therapy with calcitriol and calcium
- do not correct hypocalcemia if asymptomatic and suspected to be transient
What is a common complication following subtotal thyroidectomy
Transient hypoparathyroidism (resulting in hypocalcemia) common after subtotal thyroidectomy (permanent in <3% of surgeries)
Etiology and clinical approach to hypocalcemia
E40
