Pituitary adenoma

Causes, presentation, and evaluation of sellar masses

Sellar masses typically present: ●With neurologic symptoms: visual impairment or headache
●Incidental finding on MRI ● hormonal abnormalities
Microadenomas= lesions < 1 cm. Macroadenomas= lesions >1 cm.
●Gonadotroph adenomas = clinically nonfunctioning sellar masses.
●Thyrotroph adenomas= clinically nonfunctioning or may cause hyperthyroidism
●Corticotroph adenomas = Cushing's disease.
●Lactotroph adenomas= hyperprolactinemia, which leads to hypogonadism in women & men.
●Somatotroph adenomas= acromegaly due to increased growth hormone secretion.
●Lactotroph/somatotroph adenoma= secrete and cause clinical syndromes of both hormones.
Pituitary hyperplasia- may be misdiagnosed as pituitary adenomas:
●Lactotroph hyperplasia during pregnancy
●Thyrotroph and gonadotroph hyperplasia due to long-standing primary hypothyroidism and
primary hypogonadism, respectively.
●Somatotroph hyperplasia due to ectopic secretion of GHRH.
Other benign tumors — craniopharyngiomas, meningiomas, and pituicytomas.
Craniopharyngioma — benign tumors that arise from remnants of Rathke's pouch. The major
presenting symptoms: growth retardation in children and abnormal vision in adults. Pituitary
hormonal deficiencies, including diabetes insipidus, are common.
Malignant tumors — germ cell tumors, sarcomas, chordomas, and lymphomas.
Metastatic disease — most commonly breast cancer in women and lung cancer in men.
Symptoms: diabetes insipidus, anterior pituitary dysfunction, visual field defects, retroorbital
pain, and ophthalmoplegia.
CLINICAL MANIFESTATIONS
Impaired vision is the most common symptom: bitemporal hemianopsia.
●Headaches, presumably caused by expansion of the sella.
●Diplopia= oculomotor nerve compression resulting from lateral extension of the adenoma.
●Pituitary apoplexy: causing excruciating headache and diplopia.
Hormone deficiencies- most common are gonadotropins, resulting in hypogonadism.
Radiologic procedures: MRI the single best imaging procedure for most sellar masses
Hormonal evaluation: Hypothalamic-pituitary hormonal function should be evaluated.
Hormonal hypersecretion —
● Lactotroph adenoma: prolactin >200 ng/mL
●Acromegaly: best single test for diagnosis is IGF-1. GH levels are measured after OGTT.
●Corticotroph adenoma: high 24-hour urine cortisol + high ACTH.
●Gonadotroph adenoma: characteristic patterns of basal and TRH-stimulated concentrations
of gonadotropins and their subunits; these patterns differ in men and women.
●Thyrotroph adenoma: diffuse goiter + high FT4 and T3 + innapropriately normal/ high TSH.
●Physiologic enlargement: pregnancy, primary hypothyroidism and primary hypogonadism.
●Hypophysitis, occurs most commonly in postpartum women.
●The extent of the evaluation in a pt with an incidentally discovered intrasellar MRI pituitary
incidentaloma depends upon its size. If it is larger than 10 mm, we recommend the hormonal
evaluation. If it is smaller than 10 mm and the pt has no clinical findings of pituitary
dysfunction, we recommend measuring only prolactin. ●Hormonal hyposecretion may be
caused by any hypothalamic or pituitary lesion and therefore usually has no value in the
differential diagnosis of a sellar mass. One exception to this statement is that the spontaneous
development of central diabetes insipidus indicates that the lesion affects the hypothalamus or
the stalk and is therefore not a pituitary lesion.

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Gonadotroph and other clinically nonfunctioning pituitary adenomas
Most pituitary adenomas present with signs and symptoms of hormone hypersecretion
(hyperprolactinemia, acromegaly, hypercortisolism). However, 30% of pituitary adenomas are
clinically nonfunctioning or “silent”; 80% of these are gonadotroph adenomas, making them
the most common type of pituitary macroadenoma. Clinically nonfunctioning adenomas
present with neurologic symptoms due to mass effects, while others may be asymptomatic
and be first detected on an imaging study. By the time pts present, high percentage has
biochemical evidence of hypopituitarism due to compression of pituitary cells by the
macroadenoma.
Gonadotroph adenomas are poorly differentiated and produce hormones inefficiently.
Gonadotroph adenomas, can occur as part MEN1 (+ parathyroid, +pancreatic islet cells).
Hormone deficiencies — symptoms of pituitary hormone deficiencies are nonspecific (fatigue
and lethargy). The most common hormone deficiency is impaired secretion of gonadotropins.
Gonadotroph adenomas: Although gonadotroph adenomas are considered “nonfunctioning”,
most do produce intact gonadotropins or their subunits. However, these adenomas are
inefficient producers and do not raise gonadotropin concentrations. They are “silent” .
However, about 35% of gonadotroph adenomas secrete enough LH or FSH to raise serum
gonadotropin levels, but clinical syndromes due to hypersecretion of intact gonadotropins are
rare. However, several syndromes have been recognized:
Macroadenomas compress pituitary stalk and obstruct normal inhibitory hypothalamic
influence on prolactins, resulting in modestly elevated prolactin (usually <100 ng/mL but
sometimes as high as 200 ng/mL).
Diagnosis of a gonadotroph adenoma with a reasonable degree of certainty:
●Prolactin <100 ng/mL.
●No symptoms of acromegaly and IGF-1 not elevated.
●No symptoms of Cushing's syndrome and 24-hour urine cortisol not elevated.
●In men, elevated FSH. High FSH+ LH and low testosterone indicate primary hypogonadism.
●In premenopausal women, irregular menses, elevated FSH and estradiol (E2), low LH, and
on pelvic ultrasound, massive polycystic ovaries and thickened endometrium.
●In postmenopausal women, elevated FSH and low LH. Elevation of both FSH and LH likely
indicate only normal postmenopausal gonadotropin secretion.
DIFFERENTIAL DIAGNOSIS — craniopharyngioma, meningioma, malignant tumors.
SUMMARY
● 30% of pituitary adenomas are “silent;” 80-90 % of these are gonadotroph adenomas.
●Clinically nonfunctioning adenomas (including gonadotroph adenomas) usually come to
clinical attention when they become large enough to cause neurologic symptoms: bitemporal
hemianopsia, headaches, diplopia, cerebrospinal fluid rhinorrhea, and pituitary apoplexy.
●Some are detected as an incidental finding when an MRI is done for other reasons.
● 60% of pts at time of diagnosis have hypopituitarism due to compression by
macroadenoma, but the hormonal deficiencies are usually not detected until the pt undergoes
biochemical testing.
●Gonadotroph adenomas are difficult to recognize because they secrete inefficiently, and the
resulting products often do not cause a clinical syndrome. Only 35 % secrete enough intact
FSH or alpha subunit to raise their serum levels. Uncommonly, however, gonadotroph
adenomas hypersecrete FSH in premenopausal women and cause ovarian hyperstimulation.
●Evaluation of the pt who presents with neurologic symptoms suggestive of a clinically
nonfunctioning sellar mass should include:
•Pituitary MRI
•Visual field testing

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•Biochemical testing for hormone hypersecretion (prolactin, IGF-1, 24-hour urine cortisol)
•Testing for hypopituitarism – 8 AM cortisol, thyroxine (T4) (plus TSH if the T4 is high),
testosterone in men and estradiol (E2) in women of premenopausal age, FSH, LH.
●The diagnosis of a gonadotroph adenoma is likely if there is a large sellar mass, no evidence
of acromegaly or Cushing, prolactin <100 ng/mL, and gonadotropins are characteristic.
•In men, characteristic patterns: elevated FSH or, rarely, elevated LH and testosterone.
•In premenopausal women of age: elevated FSH, and E2.
•In postmenopausal women: elevated FSH + low LH.

Radiation therapy of pituitary adenomas

●X-rays from a linear accelerator, CyberKnife, gamma knife, or protons. Radiation can be
delivered in a single large dose or multiple fractions.
●Radiation therapy of any kind controls adenoma volume in 90 to 100 % of pts. Radiation
therapy may also reduce hormonal hypersecretion, but the effect is slow.
●Radiation therapy causes hypopituitarism in up to 30 % of pts after 10 years.
●Radiation therapy of pituitary adenomas only after surgical and/or medical options have
been exhausted.

Acromegaly

Diagnosis of acromegaly
Acromegaly: hypersecretion of GH: stimulates hepatic secretion of IGF-1, which causes
clinical manifestations of acromegaly. GH excess: enlargement of the jaw (macrognathia),
hands, and feet, which result in increasing shoe and ring size. Enlargement of nose and frontal
bones. Change is so slow that few pts seek care. Other features are: cardiovascular disease,
sleep apnea, DM2, arthropathy, and symptoms of pituitary tumor (headache, visual loss). 75%
somatotroph adenomas are macroadenomas at the time of diagnosis.
DIAGNOSIS —
1.serum IGF-1
2.GH after OGTT. In normal subjects, GH falls to <1 ng/mL 2 h after OGTT. In contrast,
post-OGTT > 2 ng/mL in acromegaly. Inadequate suppression of GH confirms acromegaly.
Both GH and IGF-1 are increased in acromegaly. The increase in serum IGF-1 is often
disproportionately greater than that in GH. Unlike GH, IGF-1 does not vary according to food
intake, exercise, or sleep, but instead reflects GH secretion during 24-48h.
Lower IGF-1: hypothyroidism, malnutrition, poorly controlled DM1, liver failure, renal
failure, oral estrogen use. In these situations, it is possible that the diagnosis of acromegaly
could be missed, unless an OGTT is performed.
GH may be high in uncontrolled diabetes, liver disease, malnutrition.
3. pituitary MRI. If the MRI is normal, abdominal and chest imaging should be performed.
Clinical manifestations
●Somatic effects: growth of tissues: skin, connective tissue, cartilage, bone, viscera.
●Metabolic effects: nitrogen retention, insulin antagonism, and lipolysis.
Somatotroph macroadenoma, due to its size, can cause decreased secretion of other
pituitary hormones, mostly gonadotropins. Osteoporosis is caused by gonadal
insufficiency. Many women with acromegaly have menstrual dysfunction, estrogen
deficiency, with or without galactorrhea. Men may have erectile dysfunction, loss of libido,
decreased facial hair growth.
Hyperprolactinemia occurs in 30% acromegaly. It is due to cosecretion of prolactin and
GH by a somatomammotroph adenoma.

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Joint symptoms and back pain is common.
Visceral enlargement — thyroid, heart, liver, lungs, and kidneys.
Thyroid enlargement but function is usually normal. A few pts have central hypothyroidism
caused by their pituitary tumor.
Cardiovascular disease — HTA, LVH, cardiomyopathy (diastolic dysfunction, arrhythmias).
Metabolic — due to high GH and IGF-1: hyperinsulinism, insulin resistance, overt diabetes
10-15%, impaired glucose tolerance in 50%. Hypertriglyceridemia or hypercalciuria.
Acromegaly may be associated with tumors (colon, esophagus, melanoma, thyroid cancers
and uterine leiomyomata). Hyperphosphatemia (70%) due to direct stimulation of renal
phosphate reabsorption by IGF-1.
Treatment of acromegaly GOAL: to lower IGF-1 concentration, and GH to<1.0 ng/mL .
●Macroadenoma: transsphenoidal surgery.
●Long-acting somatostatin: octreotide (Sandostatin LAR 20-40 mg i.m. 1x month) or
lanreotide (Somatuline Depot).
●If somatostatin analog (+/- cabergoline) is not effective, add pegvisomant (HR antagonist)
●If adenoma size increases despite medical therapy (somatostatin analog plus pegvisomant),
we suggest radiotherapy or repeat surgery.
MRI should be repeated yearly for the first several years after initial treatment. Visual field
assessment is indicated for pts whose adenomas threaten their optic chiasm.
We suggest that colonoscopy be performed at baseline and then every three to four years
thereafter in pts over age 50, especially when GH levels are not strictly controlled.
Comprehensive cardiovascular evaluation should be performed: HTA and HF treated.

Diabetes insipidus

Diagnosis of polyuria and diabetes insipidus

Polyuria: urine>3 L/day: (dilute urine <250 mosmol/l): 1. primary polydipsia; 2. CDI; 3. NDI.
Central DI — (neurohypophyseal) is caused by deficient ADH. Idiopathic, trauma, surgery,
hypoxic encephalopathy.
Nephrogenic DI — Normal ADH with renal resistance to its water-retaining effect. This
problem, in mild form, is relatively common in elderly or with renal disease due to reduction
in maximum concentrating ability.
Nephrogenic DI is almost always due to chronic lithium use and hyperCa.
The onset is abrupt in central DI and gradual in nephrogenic DI or primary polydipsia.
●HypoNa + low urine osmolality (<1/2 plasma osmolality): water overload= primary
polydipsia.
●High-normal Na (> 142, due to water loss), urine osmolality < plasma osmolality = DI
●Normal Na + urine osmolality > 600 mosmol/kg, excludes a diagnosis of DI.
In adults with DI and no cognitive impairment, true hypernatremia (Na > 150 mmol/L) should
not occur because the initial loss of water stimulates thirst to match the urinary losses. An
exception occurs when DI is due to a central lesion that also impairs thirst, causing
hypodipsia. Adipsic DI is associated with: venous thrombosis, hyperNa, thermoregulatory
dysfunction, seizures, and significant mortality. In addition, withholding water (surgical
procedures) in DI can result in severe dehydration. Hospitalized pts should be hydrated iv.
The cause of polyuria is suggested from the history (age , rate of onset, eliciting the possible
presence of the different causes of DI), and by Na concentration.
Examine the response (urine volume and osmolality) to water restriction, administration
of exogenous ADH (desmopressin) when plasma osmolality reaches 295-300 mosmol/kg
or Na >145 mmol/L. Obtain blood at baseline and after water restriction.

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DO NOT perform water restriction test when NDI is suspected (long-term lithium): testing
for a lack of response to desmopressin can be performed without prior water restriction.
The response to water restriction and desmopressin helps establish the diagnosis:
●Small increase in urine osmolality after water restriction (≥300 mosmol/kg), + rise in
urine osmolality 100% after desmopressin in complete CDI and 15-50 % in partial CDI.
●Submaximal rise in urine osmolality in response to water restriction (but < 300 mosmol/kg),
with desmopressin producing little or no elevation in urine osmolality in complete NDI.
●Primary polydipsia will be associated with a rise in urine osmolality >500 mosmol/kg, and
no response to desmopressin since endogenous release is intact.
OSMOTIC DIURESIS — The above discussion has emphasized water diuresis. However, in
some polyuria of acute onset, the increase in urine output is due to a osmotic diuresis.
●Glucosuria (uncontrolled diabetes) is the major cause of osmotic diuresis. Also, CDI treated
with large volumes of dextrose can develop hyperglycemia, glycosuria, and polyuria that is
ADH resistant.
●Urea diuresis- Polyuria due to a urea diuresis (urea acts as osmotic agent) may develop in:
•Resolution from azotemia.
•Tissue catabolism: protein catabolism results in production of urea.
•Administration of high amounts of protein orally or iv, which will be catabolized to urea.
Urine osmolality in a solute diuresis is usually above 300 mosmol/kg, in contrast to the dilute
urine in a water diuresis.

Clinical manifestations and causes of central diabetes insipidus

CDI is caused by decreased ADH (vasopressin), resulting in polyuria.
Causes of CDI: idiopathic (50%, autoimmune), tumors, infiltrative, neurosurgery, trauma.
Despite the high frequency of polyuria after neurosurgery, most cases are not due to CDI.
More common causes are excretion of excess fluid and/or an osmotic diuresis: mannitol or
glucocorticoids given in an attempt to reduce cerebral edema.
Cancer -Primary or secondary (lung cancer, lymphoma) can involve the hypothalamic-
pituitary region and lead to CDI. Sometimes polyuria is the first symptom.
Hypoxic encephalopathy —Severe ischemia can lead to diminished ADH release.
Infiltrative disorders — Langerhans cell histiocytosis (histiocytosis X).
Post-supraventricular tachycardia — Water diuresis and natriuresis may be seen, due to
decreased secretion of ADH and increased release of atrial natriuretic peptide. These humoral
changes are due to increases in left atrial and systemic pressure, activating volume receptors.
Anorexia nervosa — ADH release is often subnormal or erratic in anorexia nervosa.
Treatment of central diabetes insipidus
1. low-solute (Na and protein) diet; 2. desmopressin: ADH analog; 3. other drugs.
1. Desmopressin
•Intranasal 5 -20 mcg 1x1 or 2x1.
•Tablet 0.1-0.2 mg 3x1
•Subcutaneous 1 mcg 2x1.
2.Chlorpropamide 100-250 mg/day — oral hypoglycemic agent, most commonly used
antidiuretic after desmopressin; it stimulates renal response to ADH. Lowers diuresis by 50%.
3.Thiazide diuretics: hydrochlorothiazide 25 mg 1x1 -2x1 (first-line therapy in NDI and
is also effective in CDI).
4.NSAIDs — increase urinary concentrating by inhibiting prostaglandins, which are ADH
antagonists. Pretreatment with NSAID increases antidiuretic effect of ADH. Not all NSAIDs
are equally effective in a given pt. As an example, some pts have a good response to
indomethacin but derive little if any benefit from ibuprofen.
Thiazide diuretics and NSAID are the only effective therapy for NDI.

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Nephrogenic diabetes insipidus
NDI: resistance to ADH. In mild form, is common in elderly, acute or chronic kidney disease
(reduction in maximum concentrating ability). Max. urine osmolality (800 -1200
mosmol/kg) can fall to 350- 600 mosmol/kg.
NDI underlying cause: lithium toxicity, hyperCa, hypoK.
HyperCa: renal concentrating defect if Ca>2.75 mmol/l. It is reversible with correction.
HypoK (K<3 mmol/L) can impair urinary concentrating ability.
Less frequent cause of NDI: •Renal diseases •Pregnancy (vasopressinase from the placenta).
Treatment
1.Low Na-low protein diet.
2.Thiazide diuretic (hydrochlorothiazide 25 mg 1x1 to max 2x1 )
3.Amiloride 5-10 mg especially in lithium-induced DI.
4.Indomethacin 3 x 50 mg .

Hyperthyroidism/thyroiditis

Hyperthyroidism in adult
Graves' disease, the most common cause of hyperthyroidism, causes unique problems that are
not related to high thyroid hormones: Graves' ophthalmopathy and infiltrative dermopathy
(localized or pretibial myxedema).
SKIN — warm. Pretibial skin orange-peel papules.●Sweating, heat intolerance ●Onycholysis
(loosening and softening of the nails) ●Hyperpigmentation, mediated by increased ACTH
secretion ●Pruritus in Graves' hyperthyroidism ●Vitiligo and alopecia areata (in association
with autoimmune disorders) ●Thin hair.
EYES — Stare and lid lag occur in all hyperthyroidism. Lid lag is evaluated by having the
pt follow the examiner's finger as it is moved up and down.
Only Graves' disease have ophthalmopathy which results in proptosis (exophthalmos):
inflammation of extraocular muscles and orbital fat and connective tissue, impairment of eye-
muscle function, and periorbital and conjunctival edema. Corneal ulceration occur as a result
of proptosis and lid retraction, and severe proptosis causes optic neuropathy and blindness.
CARDIOVASCULAR —increase in cardiac output, increased peripheral oxygen needs and
increased cardiac contractility= systolic HTA. Peripheral vascular resistance is decreased.
High- or normal-output congestive HF can occur in severe hyperthyroidism. AF occurs in 10-
20%. In 60% rhythm converts spontaneously to sinus rhythm when hyperthyroidism is
treated. Anticoagulate hyperthyroid pts with AF.
METABOLIC / ENDOCRINE
Lipids — low cholesterol and HDL.
Hyperglycemia — Hyperthyroidism leads to increased insulin and antagonism to peripheral
action of insulin. The latter effect predominates, leading to impaired glucose tolerance.
In hyperthyroidism, cortisol binding globulin (CBG) is low, resulting in lower cortisol.
RESPIRATORY — Dyspnea and dyspnea on exertion.
GASTROINTESTINAL- Weight loss, hypermetabolism, hyperdefecation and malabsorption.
Celiac disease is more prevalent in Graves' disease. Younger pts have hyperphagia. Anorexia
is prominent in elderly pts. Abnormalities in liver function tests, high ALP.
HEMATOLOGIC — normochromic, normocytic anemia. Ferritin may be high.
Graves' hyperthyroidism is associated with autoimmune thrombocytopenia and pernicious
anemia. Hyperthyroidism may also be prothrombotic.
GENITOURINARY — Urinary frequency and nocturia are common in hyperthyroidism.

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In women, SHBG is high, which results in high estradiol, high LH, a reduced mid-cycle
surge in LH secretion, oligomenorrhea, and anovulatory infertility. Amenorrhea can
occur in women with severe hyperthyroidism.
In men, high SHBG results in high testosterone, but serum free testosterone is normal/ low.
Extragonadal conversion of testosterone to estradiol is increased, so that estradiol is
high. These changes cause gynecomastia, reduced libido, and erectile dysfunction.
Spermatogenesis decreased or abnormal.
BONE — Thyroid hormone stimulates bone resorption, resulting in increased porosity of and
reduced volume of bone. ALP and osteocalcin are high, indicative of increased bone
turnover. The increase in bone resorption may lead to an increase in serum calcium,
inhibiting parathyroid hormone secretion and the conversion of calcidiol (25-hydroxyvit
D) to calcitriol (1,25-dihydroxyvit D). These changes result in impaired calcium absorption
and increase in urinary calcium. The net effect is osteoporosis and an increased fracture
risk in chronic hyperthyroidism.
NEUROPSYCHIATRIC- behavioral and personality changes: agitation, depression.

Diagnosis of hyperthyroidism
Other conditions that should suggest hyperthyroidism: osteoporosis, hyperCa, HF, AF, and a
deterioration in glycemic control in previously diagnosed diabetes.
Older pts- cardiopulmonary symptoms: tachycardia (AF), dyspnea and edema.
●Thyroid enlargement from minimal to massive in Graves' disease or toxic multinodular
goiter. A nonpalpable thyroid is common in older Graves' disease.
● Painless (silent or lymphocytic) thyroiditis: minimal thyroid enlargement. The absence of
any thyroid enlargement should also suggest exogenous hyperthyroidism or struma ovarii.
●A single palpable nodule: autonomously functioning thyroid adenoma.
●Painful thyroid: in subacute (granulomatous) thyroiditis.
Laboratory tests
Primary hyperthyroidism: low TSH (most values <0.05 mU/l) + high FT4 and T3.
Other — low cholesterol, low LDL, and low HDL which increase after treatment.
Normochromic, normocytic anemia. ALP and osteocalcin are high: increased bone turnover.
T3-toxicosis — Graves' disease or nodular goiter have greater increases in T3 due to a
disproportionate increase in T3 secretion and increased extrathyroidal conversion of T4
to T3.
T4-toxicosis — Low TSH, high FT4, and normal T3 may be found in pts with
hyperthyroidism who have a concurrent nonthyroidal illness that decreases conversion of
T4 to T3. With recovery from the nonthyroidal illness, T3 concentrations rise.
Amiodarone inhibits conversion of T4 to T3.
DIFFERENTIAL DIAGNOSIS
●Nonthyroidal illness – Euthyroid nonthyroidal illness, especially those receiving high-dose
glucocorticoids or dopamine, have low TSH + low-normal FT4 + very low T3. In hospitalized
subnormal TSH and normal FT4 and T3. Reevaluate the pt in 4-8 weeks.
●The "physiologic" lowering of serum TSH in pregnancy.
Once the diagnosis of hyperthyroidism is established, the cause should be determined:
●Measurement of anti-TSHR,
●Determination of the radioactive iodine uptake
●Measurement of thyroidal blood flow on ultrasonography
If TSHR antibodies are positive, it confirms Graves’ disease. If negative, we proceed with
radioactive iodine uptake and scan to distinguish toxic multinodular goiter (multiple areas of
focal increased and suppressed uptake) and toxic adenoma (focal increased uptake) from
Graves’ disease (diffuse increased uptake). In pregnancy: thyroid ultrasound. .

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Thyroid tests — Sometimes the pattern of thyroid function test suggests a specific diagnosis:
● Low TSH + high T3 + normal FT4= Graves' disease or autonomous thyroid adenoma.
Radioactive iodine scan can differentiate between Graves’ disease or autonomy.
●Low TSH + high FT4 + normal T3 = hyperthyroidism with concurrent nonthyroidal
illness, amiodarone induced thyroid dysfunction, or exogenous T4 ingestion.
●Normal or high TSH + high FT4 and T3 = TSH-producing pituitary tumor.
●Hyperthyroidism with a high (normal) radioactive iodine uptake= de novo synthesis of
hormone.
●Hyperthyroidism with a low (nearly absent) radioactive iodine uptake = inflammation and
destruction of thyroid tissue with release of hormone into circulation or an extrathyroidal
source of thyroid hormone (factitious thyrotoxicosis, struma ovarii, where the functioning
thyroid tissue is in the pelvis).
Thyrotropin receptor (TSHR) antibodies —Graves’ disease is caused by autoantibodies.
SUMMARY
●Primary hyperthyroidism: low TSH. Overt hyperthyroidism: high FT4 and T3. In some pts,
however, only T3 or T4 is elevated.
●Once the diagnosis of hyperthyroidism has been established, the cause of the
hyperthyroidism should be determined. Diagnostic testing includes: TSH receptor antibodies,
radioactive iodine uptake, measurement of thyroidal blood flow on ultrasonography.
●Radioactive iodine is contraindicated during pregnancy and breastfeeding. For pregnant
hyperthyroid women, we measure anti-TSHR and thyroidal blood flow on ultrasonography.

Etiology of hyperthyroidism
Hyperthyroidism is more common in women than men (5:1).
Graves' disease — an autoimmune disorder resulting from TSHR antibodies.
"Hashitoxicosis" — autoimmune thyroid disease: initially hyperthyroidism and a high
radioactive iodine uptake caused by TSHR antibodies similar to Graves' disease. This is
followed by hypothyroidism due to infiltration with lymphocytes and autoimmune-mediated
destruction of thyroid tissue similar to chronic lymphocytic thyroiditis (Hashimoto's). The
initial therapeutic considerations are similar to Graves' disease. However, hypothyroidism
may develop.
Toxic adenoma and toxic multinodular goiter — Toxic adenoma and toxic multinodular
goiter are the result of hyperplasia of follicular cells independent of regulation by TSH.
Iodine-induced hyperthyroidism — iodine-induced hyperthyroidism can develop after an
iodine load: contrast agents used for angiography/CT or iodine-rich drugs (amiodarone).
Hydatidiform mole or choriocarcinoma or testicular germ cell tu (in men) via direct
stimulation of the TSH receptor.
TSH-mediated hyperthyroidism — Octreotide and longer-acting somatostatin analogue
lanreotide suppress TSH production.
Thyroiditis — inflammation of thyroid tissue with transient hyperthyroidism due to release
of hormones from the colloid. This initial presentation is followed by a hypothyroid phase and
then recovery of thyroid function. Thyroiditis therapy: BB for symptomatic control and
NSAID for antiinflammatory effects or in severe cases, prednisone.
Subacute granulomatous thyroiditis (de Quervain's thyroiditis), is a viral or post-viral
syndrome characterized by fever, malaise, and an exquisitely painful and tender goiter. In
comparison, painless thyroiditis (silent thyroiditis or subacute lymphocytic thyroiditis) is
part of the spectrum of autoimmune thyroid disease.
Other causes of thyroiditis: ●Amiodarone ●Radiation ●Drugs: interferon alfa, lithium.

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Exogenous and ectopic hyperthyroidism ● levothyroxine overdose (treat with BB, ipodate,
in severe cases, plasmapheresis or dialysis) ●Struma ovarii. ●metastases in bones from
metastatic follicular thyroid cancer cause hyperthyroidism.

Subclinical hyperthyroidism
Causes of subclinical hyperthyroidism are the same as the causes of overt hyperthyroidism.
The most common cause of subclinical hyperthyroidism: treatment with T4 (exogenous)
and autonomous thyroid adenomas and multinodular goiters (endogenous).
CLINICAL FINDINGS — Skeleton and cardiovascular system are the major target tissues.
Low bone density, and an increase in fracture: greatest in cortical bone (wrist). Increased risk
of AF, increase in left ventricular mass and higher risk of coronary heart disease.
Low TSH + normal FT4, T3. Measurement should be repeated 1-3 m. to confirm diagnosis.
Pregnancy — Transient subclinical hyperthyroidism in the first trimester of pregnancy
is considered a normal physiologic finding. Furthermore, in pregnant women with overt
hyperthyroidism, the goal of therapy is to maintain minimal mild hyperthyroidism.
MANAGEMENT
High risk for complications: older pts
●If TSH is <0.1 mU/L, we treat.
●If TSH is 0.1 -0.5 mU/L, we treat if there is cardiovascular disease or low bone density.
Observation if bone density is normal, measure TSH, FT4, and T3 every 6 months.
Low risk for complications: young pts, premenopausal women
●If TSH <0.1 mU/L, we treat.
●If TSH is 0.1-0.5 mU/L, observation is appropriate. Measure TSH, FT4, and T3 in 6 months.
Treatment options —
BB are useful to control symptoms of adrenergic overactivity (palpitations, tremor).
Graves’ disease or nodular thyroid disease + autonomy: thionamides, radioactive iodine, or
surgery.
Most thyroiditis require no treatment since thyroid dysfunction is transient.

Cardiovascular effects of hyperthyroidism

●Increases in heart rate, contractility, cardiac output, and myocardial oxygen consumption
●Reductions in systemic vascular resistance = Systolic HTA
●Angina-like chest pain, with ECG changes suggesting myocardial ischemia, especially in
women; result of coronary vasospasm and responds to treatment with oral CCB.
● increased LV mass and LVH, risk of AF, HF, pulmonary HTA. and angina.
SUBCLINICAL HYPERTHYROIDISM — more subtle cardiac findings.
TREATMENT — BB: propranolol 120-160 mg/day or atenolol 50 mg/day.
In overt HF: standard therapy of diuretics + digitalis should be given in elderly pt
Anticoagulation is recommended for prevention of ICV in thyrotoxic AF.

Hyperthyroidism during pregnancy

To meet increased metabolic needs during a normal pregnancy, there are changes in thyroid
physiology that are reflected in altered thyroid function tests:
●TBG excess results in high T4, but not high FT4.
●High hCG during early pregnancy and even higher in hyperemesis gravidarum or multiple
pregnancies may result in transient subclinical or rarely overt hyperthyroidism. There is
considerable homology between hCG and TSH. hCG has thyroid-stimulating activity.
Thyroid tests should be interpreted using trimester-specific reference ranges for pregnancy.
DIAGNOSIS — suppressed (<0.1 mU/L) or undetectable (<0.01 mU/L) TSH + high
FT4/FT3 (or T4/ T3) that exceeds normal range for pregnancy.

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— Graves' (1% of all pregnancies) and hCG-mediated hyperthyroidism (3% of pregnancies)
Presence of goiter or ophthalmopathy favors the diagnosis of Graves’ disease. Goiter is not a
classical clinical feature of hCG-mediated hyperthyroidism.
Anti-TSHR confirms Graves' disease. Radionuclide imaging is contraindicated in pregnant
women. Thyroid ultrasound with Doppler flow may be useful to distinguish Graves’ disease
(high blood flow) from painless or postpartum thyroiditis (low blood flow).
SUMMARY
●Many of the nonspecific symptoms associated with pregnancy are similar to those associated
with hyperthyroidism, including tachycardia, heat intolerance, and increased perspiration.
Specific findings such as goiter and ophthalmopathy suggest Graves' hyperthyroidism.
●Hyperthyroidism in pregnancy should be based on suppressed (<0.1 mU/L) or undetectable
(<0.01) TSH+ high FT4 and/or FT3 or that exceed normal range for pregnancy.
Treatment
● BB: atenolol 25-50 mg 1x1 or propranolol 20 mg 3-4 x 1 for pregnant women with
moderate to severe hyperthyroidism and hyperadrenergic symptoms. BB should be weaned as
soon as the hyperthyroidism is controlled by antithyroid drugs (ATDs).
●Propylthiouracil (PTU) in the first trimester and switch to methimazole (MMI) at the start
of the second trimester. PTU 50 mg 2x1 or less and MMI 5-10 mg 1x1; higher doses can
result in fetal goiter and hypothyroidism.
●We suggest not administering pharmacologic doses of iodine for long-term use because
chronic use can cause fetal goiter. ●Radioactive iodine therapy is absolutely contraindicated.

Treatment of Graves' hyperthyroidism

Symptom control — BB atenolol 25-50 mg 1x1: advantages of single daily dosing and beta-
1 selectivity; however, all BB effectively diminish hyperthyroid symptoms.
Decrease of thyroid hormone synthesis
For significant symptoms of hyperthyroidism, start thionamide+BB. Once pt is euthyroid, we
suggest radioactive iodine as our first choice for definitive therapy of hyperthyroidism, in the
absence of moderate to severe ophthalmopathy. For mild symptoms, there is no need to
pretreat with a thionamide, and radioactive iodine can be given soon after the diagnosis.
Surgery is option for moderate- severe active ophthalmopathy who desire definitive therapy.
Thionamides
Methimazole (MMI) is almost exclusively used (rapid efficacy, few side effects).
Starting dose: small goiters+mild hyperthyroidism (FT4 1-1.5x upper limit) 10 mg 1x1;
larger goiters and severe hyperthyroidism (FT4 >2 x upper limit) start 20-30 mg 1x1.
Propylthiouracil (PTU) is used in 1st trimester of pregnancy because of potential teratogenic
effects of MMI and in pts with minor reactions to MMI and refuse radioactive iodine or
surgery.
We do not use thionamides if neutrophil count <500 mm3 or 5x elevated liver transaminases.
Radioactive iodine ablation — For nonpregnant pts with Graves’ disease, radioactive iodine
is first choice for definitive therapy of hyperthyroidism, in the absence of moderate or severe
orbitopathy.
Radioactive iodine therapy can cause development or worsening of Graves' ophthalmopathy.
Radioactive iodine induces extensive tissue damage, resulting in ablation of thyroid in 6-18
weeks. 20% pts fail the first radioactive iodine treatment and require a second dose.
Surgery — For a pt with severe hyperthyroidism and a large goiter, we suggest surgery.
Other medications — have been used in the management of hyperthyroidism, including:
●Glucocorticoids inhibit peripheral T4 to T3 conversion and, in Graves' hyperthyroidism,
reduce thyroid secretion. They have been used in severe hyperthyroidism and thyroid storm.

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●Cholestyramine (sekvestrant žućne kiseline) 4 g x4 + methimazole, lowers T4 and T3
more rapidly than MMI alone and is adjunctive therapy in pts who require rapid therapy.
●Carnitine is a naturally occurring peripheral antagonist of thyroid hormone action.
Skeletal health — Hyperthyroidism is associated with reduced bone density, osteoporosis.
Calcium 1200- 1500 mg daily through diet or supplements. Bisposphonates as needed.
MONITORING AFTER TREATMENT- 4-6 week until stabilized on maintenance therapy.

Amiodarone and thyroid dysfunction

Thyroid dysfunction (both hypo- and hyperthyroidism) is a common complication of
amiodarone therapy due to direct effects of the drug on the thyroid, and high iodine content:
● autoimmune thyroid disease are at highest risk for amiodarone-induced hypothyroidism
●Destructive thyroiditis occurs in pts with no underlying thyroid disease.
● amiodarone-induced hypothyroidism is more common than hyperthyroidism.
●We suggest continuing amiodarone therapy in pts who develop amiodarone-induced
hypothyroidism.
●Euthyroidism should be restored by replacement with thyroid hormone doses larger than
normal.
●Amiodarone should only be discontinued if it fails to control the underlying arrhythmia. If
amiodarone is discontinued in a pt without pre-existing autoimmune thyroid disease, the
hypothyroidism often resolves.
Hyperthyroidism — There are two types of amiodarone-induced thyrotoxicosis (AIT).
Type 1: increased synthesis of thyroid hormone.Type 2: excess release of T4 and T3 due to a
destructive thyroiditis. ●In pts who develop AIT in whom the amiodarone was prescribed for
life-threatening ventricular arrhythmias (and is effective), we suggest continuing the
amiodarone and simultaneously treating the hyperthyroidism.
●If the amiodarone was not prescribed for life-threatening ventricular arrhythmias (or is
ineffective), we suggest discontinuing the drug. For type 2 AIT: glucocorticoid prednisone
(40-60 mg/day) as our first-line drug (whether amiodarone is continued or discontinued).

Iodine in the treatment of hyperthyroidism

●Iodine solutions acutely block the release of T4 and T3 from the gland within hours and
inhibit iodine organification in the thyroid gland. In Graves’ disease, the iodine-induced
blockade of organification persists and can result in amelioration of hyperthyroidism. The
overall inhibitory effect of iodine is maximal after 10 days of treatment.
●Indications: preoperative preparation for Graves’ disease (iodine has the additional benefit
of decreasing thyroid gland vascularity), thyroid storm, or after radioactive iodine in Graves'
disease.

Ultrasonography in thyroid disease

●Cancer: hypoechogenic, microcalcifications, increased vascularity, indistinct margins .
Although ultrasound cannot diagnose cancer, it selects nodules for FNA biopsy.
●Ultrasonography plays an important role in the assessment of lymph nodes.

Thyroid storm
CLINICAL FEATURES — exaggeration of the usual symptoms of hyperthyroidism:
Tachycardia> 140 bpm and congestive HF. Hypotension, cardiac arrhythmia, cardiovascular
collapse. Hyperpyrexia 40-42°C, agitation, delirium, psychosis, stupor, or coma. Nausea,
vomiting, diarrhea, abdominal pain, hepatic failure with jaundice. Goiter, ophthalmopathy
(Graves’ disease), lid lag, hand tremor, warm and moist skin.

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Laboratory findings — low TSH and high FT4 and/or T3. Mild hyperglycemia
(catecholamine-induced inhibition of insulin), mild hypercalcemia (hemoconcentration and
enhanced bone resorption), abnormal liver function tests, leukocytosis, or leukopenia.
TREATMENT
●BB (propranolol 60-80 mg 4-6x1). In contraindications: CCB (diltiazem).
●Propylthiouracil (PTU) 200 mg 6x1 or methimazole 20 mg 4-6 x 1.
●One hour after the first dose of thionamide: iodine (Lugol's solution, 10 drops 3x1). Iodine
should be delayed for 1 hour after to prevent being used as substrate for hormone synthesis.
●Glucocorticoids (hydrocortisone 100 mg i.v. 3x1) to reduce T4-to-T3 conversion, promote
vasomotor stability, and possibly treat an associated relative adrenal insufficiency.
Sekvestrant žučne kiseline cholestyramine (4 g 4x1) to reduce enterohepatic circulation of
thyroid hormone. In addition, supportive therapy and recognition and treatment of any
precipitating factors (infection). Some pts require substantial fluid, while others require
diuretic because of congestive HF. Digoxin and BB requirements may be quite high because
of increased drug metabolism. Infection needs to be identified and treated, and hyperpyrexia
should be aggressively corrected. Acetaminophen instead of aspirin, since the latter can
increase FT4 and FT3 by interfering with their protein binding.
We continue treatment for up to 5-7 days. Surgery should not be delayed for more than 8
to 10 days because of a phenomenon called escape from the Wolff-Chaikoff effect. Large
doses of exogenous iodine inhibit the organification of iodine in the thyroid gland (the Wolff-
Chaikoff effect). This effect is transient: iodide transport system adapts to higher
concentrations of iodine, allowing thyroid hormone synthesis to proceed, with potential
exacerbation of thyrotoxicosis.
Other therapies — Plasmapheresis when traditional therapy has not been successful.
After clinical improvement, iodine therapy can be discontinued and glucocorticoids tapered
and discontinued. BB can be withdrawn only after thyroid function tests return to normal.
PTU should be switched to methimazole (better safety profile and better compliance).
In Graves’ disease, definitive therapy with radioactive iodine or thyroidectomy is important.
Radioactive iodine therapy is first choice for definitive therapy; surgery.

Thyroid disease in pregnancy

In pregnancy estrogen increases TBG production. This leads to increase in total T4 and T3.
hCG has weak thyroid-stimulating activity. hCG peaks at 10-12 weeks. During this peak, T4
and T3 increase. FT4 and FT3 increase slightly, and TSH is appropriately reduced. However,
in 10-20% women, TSH is transiently low or undetectable. This transient subclinical
hyperthyroidism should be considered a normal physiologic finding. Later in pregnancy,
hCG declines, FT4 and T3 decline and TSH rises.
Trimester-specific reference ranges for TSH (mU/L):
●First trimester 0.1 to 2.5
●Second trimester 0.2 to 3.0
●Third trimester 0.3 to 3.0
Iodine requirements are higher in pregnancy due to increase in T4 required to maintain
maternal euthyroidism.
WHO recommends 250 mcg of iodine daily during pregnancy and lactation.
HYPERTHYROIDISM COMPLICATING PREGNANCY -rare in pregnancy (0.1-0.4%).
Hyperthyroidism during pregnancy: suppressed (<0.1 mU/L) or undetectable (<0.01) TSH +
elevated thyroid hormone levels that exceed the normal range for pregnancy. TSH in healthy
pregnant women during the first trimester may be as low as 0.03 to 0.1 mU/L..
Treatment — hCG-mediated hyperthyroidism is transient and does not require
treatment. The goal of treatment for pregnant women with overt hyperthyroidism due to

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Graves’ or nodular thyroid disease is to reduce and maintain the mother's serum FT4
concentration in the high normal range using the lowest drug dose.
HYPOTHYROIDISM DURING PREGNANCY —most common is Hashimoto’s thyroiditis.
Diagnosis — high TSH, (1 trimester > 2.5 mU/L; 2. and 3. trimester> 3 mU/L), + low FT4.
Subclinical hypothyroidism: high trimester-specific serum TSH + normal FT4.
Women with central hypothyroidism from pituitary or hypothalamic disease have low TSH.
Universal screening for thyroid function in pregnant women or those planning to be pregnant.
Treatment : Women with preexisting hypothyroidism who become pregnant need more
T4 (+ 50 % T4 during pregnancy), and the increase occurs in fifth week of gestation.
Presence of thyroid autoantibodies in euthyroid women is associated with an increased risk of
spontaneous miscarriage and preterm birth. 20% euthyroid women with TPO antibodies
develop subclinical hypothyroidism. Euthyroid women with positive TPO antibodies
undergoing in vitro fertilization (IVF) also have higher miscarriage rates.
Levothyroxine 50 mcg 1x1 in TPO positive euthyroid women who had miscarriage, until
additional data become available. TSH should be measured every 4 weeks during the first half
of pregnancy and at least once during the last trimester to monitor for the development of
hypothyroidism. Star levothyroxine if TSH is above reference range (2.5 mU/L for 1, and
3.0 mU/L for 2, 3 trimesters). A pregnant woman found to have a thyroid nodule should be
evaluated in the same way as if she were not pregnant. Thyroid function tests TSH and FT4
and ultrasound. FNAB is safe in pregnancy.
Postpartum thyroiditis — 15%. Higher rates (25%) in women with DM1 and positive anti-
TPO who had normal thyroid function during pregnancy. Postpartum thyroiditis is
characterized by transient hyperthyroidism or hyperthyroidism followed by transient or rarely
permanent hypothyroidism. Postpartum exacerbation of Hashimoto's thyroiditis is
characterized by postpartum progression of autoimmune destruction.
Graves' disease — Women may develop Graves' disease postpartum or experience an
exacerbation.

Treatment of toxic adenoma and toxic multinodular goiter

Toxic adenoma and toxic multinodular goiter are second in prevalence after Graves' disease.
Once hyperthyroidism has been established, the cause of the hyperthyroidism should be
distinguished by 24-hour radioactive iodine uptake and scan (thyroid scintigraphy).
●A classic presentation for toxic adenoma: hyperthyroid pt + palpable thyroid nodule that
corresponds to area of increased radioactive iodine on scintigraphy; and suppression of
radioactive iodine uptake in surrounding and contralateral tissue.
●In addition to hyperthyroid symptoms and goiter, some pts with toxic multinodular goiter
have obstructive symptoms (cough, dysphagia). On scintigraphy: more focal areas of
increased radioactive iodine uptake. Nonfunctioning ("cold") nodules are also present in some
pts.
Thyroid ultrasound — Thyroid ultrasound should be performed in all hyperthyroid pts with
a thyroid nodule or nodular goiter. Nodules that are nonfunctioning on thyroid scintigraphy
should be evaluated in the same manner as a nonfunctioning solitary thyroid nodule, with fine
needle aspiration determined by nodule size and presence of suspicious US characteristics.
INDICATIONS FOR TREATMENT — All pts with overt hyperthyroidism (low TSH + high
FT4 and/or T3) due to toxic adenoma or MNG require treatment.
BB atenolol 25-50 mg 1x1.
Surgery and radioactive iodine: most effective treatments.
MMI 10-30 mg 1x1. PTU should be avoided except during pregnancy because of toxicity.
●For significant symptoms of hyperthyroidism and in elderly with underlying cardiac disease,
we suggest MMI to achieve euthyroidism prior to radioactive iodine therapy or surgery. We

13
discontinue MMI 3 days prior to radioactive iodine, 1 day before surgery. Preoperative
iodine should not be used in the routine preoperative preparation of toxic adenoma and
MNG owing to the increased risk of exacerbating hyperthyroidism.
●After radioactive iodine, pts require monitoring for hypothyroidism or recurrent hyper-
thyroidism. TSH, FT4, T3 should be measured 6-8 weeks after treatment and then 4-8 weeks.
●For pts who had near-total or total thyroidectomy, thyroxine should be initiated at 1.6
mcg/kg. Elderly pts and those with coronary disease: 50-75 mcg. TSH control in 6-8 weeks
and dose increased by 12 to 25 mcg/day if TSH is above normal .
●For persistent (6 months after initial treatment) or recurrent hyperthyroidism after
radioactive iodine or surgery, we suggest retreatment with radioactive iodine. We prefer to
avoid a second surgery in inadequate initial surgery due to an increased risk of surgical
complications (hypoparathyroidism, recurrent laryngeal nerve damage).

Drug interactions with thyroid hormones

●Drugs that inhibit TSH secretion: glucocorticoids, dobutamine, dopamine, octreotide.
●Iodine (iodide containing drugs), lithium, interferon-α, IL-2 cause hyper or hypothyroidism.
●Drugs that interfere with absorption of T4: bile acid resins, proton pump inhibitors, calcium
carbonate, and ferrous sulfate. Separate administration of these drugs and T4 by several hours.
●Phenobarbital, rifampin, phenytoin, and carbamazepine increase metabolism of T4 and T3.
As a result, T4-treated hypothyroid pts need a higher dose when treated with these drugs.

Lipid abnormalities in thyroid disease

●Hypothyroid pts have increased cholesterol and LDL, triglycerides, intermediate-density
lipoproteins, apo A-1 and apo B. Thyroxine therapy may reduce cholesterol and LDL.
●Similar findings are in subclinical hypothyroidism when TSH>10 mIU/L.
Hypercholesterolemia (and hypertriglyceridemia) should be screened for hypothyroidism
(and other secondary causes of hyperlipidemia) before specific lipid-lowering drug therapy.
●Hyperthyroidism is associated with low cholesterol, LDL, and HDL.

Thyroiditis
THYROIDITIS WITH THYROID PAIN: subacute, infectious, traumatic, radiation.
Acute /infectious thyroiditis —Bacterial infections (abscess) caused by Staphylococcus and
Streptococcus. Chronic occur in immunocompromised pts: mycobacterial, fungal.
Sudden onset of unilateral neck pain, fever. Thyrotoxicosis may be present. Painful thyroid
should be evaluated immediately with ultrasonography, FNAB, drainage and antibiotic iv.
Subacute thyroiditis — In the hyperthyroid phase, subacute thyroiditis (de Quervain's
thyroiditis, subacute granulomatous thyroiditis) is characterized by neck pain, a tender goiter,
and elevated T4 and/or T3. The classic pattern is hyperthyroidism, hypothyroidism, recovery.
Hyperthyroidism lasts only until the stores of T4 and T3 are depleted, 2-6 weeks.
Hypothyroidism is transient. It is caused by a viral upper respiratory infection (Coxsackie).
Radiation thyroiditis — thyroid pain 5-10 days after radiation-induced injury, necrosis of
thyroid cells, transient exacerbation of hyperthyroidism.
Palpation- or trauma-induced thyroiditis — Vigorous palpation, manipulation of the gland
during thyroid biopsy or neck surgery, especially parathyroid surgery, or even trauma.
THYROIDITIS WITHOUT PAIN AND TENDERNESS
Painless thyroiditis — lymphocytic thyroiditis: transient hyperthyroidism, hypothyroidism,
and then recovery. Painless thyroiditis accounts for 1-5 % cases of hyperthyroidism. It is
considered a variant form of chronic autoimmune Hashimoto's thyroiditis, suggesting that it is
part of thyroid autoimmune disease. It can be caused by interferon-α, interleukin-2, or lithium.

14
Painless thyroiditis should be considered as the cause of hyperthyroidism in any woman (who
is not postpartum) or man who has had symptoms for <2 months and has a small diffuse
goiter or no thyroid enlargement. The key clinical findings are: mild hyperthyroidism of short
duration, little or no thyroid enlargement, and no ophthalmopathy or pretibial myxedema.
Postpartum thyroiditis — similar to painless thyroiditis, it occurs after 10% pregnancies. In
clinically hyperthyroid women, it must be distinguished from postpartum exacerbations of
Graves' disease. Postpartum thyroiditis: if anti-TSH or anti-TPO are elevated, risk of
permanent thyroid disease is greater.
●The majority of women with postpartum thyroiditis need no treatment during either the
hyperthyroid or the hypothyroid phases of their illness.
●Women with symptoms of hyperthyroidism: 40-120 mg propranolol or 25-50 mg atenolol
until T3 and FT4 are normal. For women who are breastfeeding, propranolol is preferred
because it is not concentrated in breast milk as much as other BBs.
●Women with symptomatic hypothyroidism: L-thyroxine 50-100 mcg/day. asymptomatic
women: treat when TSH > 10 mU/L.
Since postpartum thyroid dysfunction is often transient, many experts favor weaning T4 after
6-12 months. Dose can be halved and TSH, FT4 reevaluated in 6-8 weeks. 30% women never
recover from the initial hypothyroid phase, and a rising TSH level during levothyroxine
weaning is indicative of persistent hypothyroidism, requiring long-term T4. For women who
have fully recovered from postpartum thyroiditis, we measure TSH annually.
Drug-induced thyroiditis — interferon-alfa, amiodarone, or lithium.
Fibrous thyroiditis — Riedel's or invasive thyroiditis: extensive fibrosis and infiltration of
the thyroid gland that extends into adjacent tissues. Most pts are euthyroid, antiTPO is high.
Diagnosis is established by biopsy. Pts should be evaluated for systemic fibrosis in other
areas. Prednisone for local symptoms.

Subacute thyroiditis treatment

Ibuprofen 1200 to 3200 mg in divided doses.
If there is no improvement in 2-3 days, discontinue NSAID and start prednisone 40 mg 1x1.
Prednisone should result in pain relief in 1-2 days; if not: diagnosis should be questioned.
In severe pain, prednisone is a reasonable first-line therapy.
Once the pain is relieved, find the lowest possible dose that provides pain relief by reducing
dose by 5- 10 mg every 5-7 days. BB (40-120 mg propranolol, or 25-50 mg atenolol 1x1
for a few weeks). Thionamides should not be used because hyperthyroidism is not
caused by excess thyroid hormone synthesis.

Hypothyroidism

Hypothyroidism in nonpregnant adults

Primary: (95% of pts with hypothyroidism) low FT4 + high TSH.
Secondary (central): low T4 + TSH low, normal, or slightly high (5-10 mU/L) due to
secretion of biologically inactive TSH. In hypothyroidism caused by hypothalamic/pituitary
disease, TSH does not increase appropriately as T4 falls. As a result, symptoms and FT4 must
be used to make the diagnosis.
CLINICAL FEATURES — fatigue, cold intolerance, weight gain, constipation, dry skin,
myalgia, and menstrual irregularities. Goiter (iodine deficiency or Hashimoto’s), bradycardia,
dyastolic HTA, and delayed relaxation of deep tendon reflexes. In chronic autoimmune
thyroiditis, anti-TPO are elevated. Hypercholesterolemia, macrocytic anemia, HypoNa.

15
DIFFERENTIAL DIAGNOSIS: resistance to TSH or thyroid hormone, recovery from
nonthyroidal illness. High TSH also occurs in primary adrenal insufficiency.
Chronic autoimmune hypothyroidism (Hashimoto’s thyroiditis). Two major forms are:
goitrous and atrophic, with lymphocytic infiltration and high anti-TPO and Tg.
Thyroid function should be measured in the following:
●Substantial hyperlipidemia or a change in lipid pattern
●HypoNa, resulting from high ADH (another manifestation of hypothyroidism).
●High muscle enzyme concentrations.
●Macrocytic anemia.
●Pericardial or pleural effusions.
●Previous thyroid injury (radioactive iodine therapy, thyroid or neck surgery, radiation
therapy).
●Pituitary or hypothalamic disorders.
●History of autoimmune diseases.
●Drugs that decrease TSH: dopamine, glucocorticoids, octreotide.
Drugs that increase TSH secretion: dopamine antagonists.

Clinical manifestations of hypothyroidism

●Slowing of metabolic processes and accumulation of glycosaminoglycans in the interstitium
of many tissues; depression, decreased hearing, diastolic HTA, pleural / pericardial effusions.
Neurologic manifestations: cognitive impairment, dementia, peripheral neuropathy (Carpal
tunnel syndrome), myopathy. Most of complications are responsive to therapy.
●Manifestations of central hypothyroidism are similar to primary hypothyroidism. Associated
endocrine deficiencies (hypogonadism, adrenal insufficiency) may mask hypothyroidism.
●Clearance of drugs (antiepileptic, anticoagulant, hypnotic, opioid) is decreased in hypothyroism.

Subclinical hypothyroidism
●Normal FT4 + high TSH. For pregnant women, use trimester-specific TSH reference ranges.
●Many pts with subclinical hypothyroidism eventually develop overt hypothyroidism.
●Subclinical hypothyroidism is associated with increased risk of cardiovascular disease
(coronary heart disease, HF), particularly when TSH>10 mU/L.
●Treat subclinical hypothyroidism at TSH ≥10 mU/L. For younger pts with TSH 4.5-10
mU/L + symptoms of hypothyroidism, or who have anti-TPO we also treat.
●Older pts (>70 yrs) and TSH 4.5-8 mU/L, we suggest not treating.
●We treat women with subclinical hypothyroidism (TSH >2.5) who are pregnant, wish to
become pregnant, or have ovulatory dysfunction and infertility.
●For older pts with underlying CVD, the initial dose of T4 is 25-50 mcg/day. For younger,
initiate treatment at slightly below full replacement doses (1.6 mcg/kg/day). The goal is to
reduce the pt's TSH into the lower half of normal reference range.

Cardiovascular effects of hypothyroidism

 Bradycardia
 HTA resulting from the increase in vascular resistance (dyastolic HTA)
 Cardiac dysfunction with poor contractility, dilatation or pericardial effusion
 Edema, often nonpitting
 Pericardial effusions in 25% of pts and may be quite large
Rhythm disturbances - hypothyroid pts may have VES. Treatment with amiodarone can
produce hypothyroidism and further predispose the ischemic heart to ventricular arrhythmias.
In HTA+ hypothyroidism: renin is low. ECG: low voltage, nonspecific ST - Q wave changes.

16
Coronary artery disease — angina pectoris pts have less symptoms if they become
hypothyroid, because they are less active and peripheral oxygen demands decrease. Anginal
pain+ hypercholesterolemia, diastolic HTA, elevated homocysteine: accelerated CAD.
Periorbital edema and edema of hands and feet due to interstitial accumulation of
glycosaminoglycans (hyaluronic acid), with extravascular water retention at the same
time that plasma volume is decreased. Ascites, pleural, and scrotal effusions.
Lipids- high cholesterol and LDL, VLDL and hypertriglyceridemia.
High homocysteine, high CK. 15% of hypothyroid pts have raised CK-MB, which can be
confusing in chest pain. This problem is resolved by troponin (normal in hypothyroidism).
TREATMENT — In older pts or those with a history of angina, begin therapy with a low
dose of T4, 25 mcg daily, because of the possibility of inducing arrhythmia or angina. T4 has
slow onset of action, so that the dose should not be increased for 4-6 weeks.
Clearance of anticoagulant drugs is decreased in hypothyroidism. In pts being treated with
warfarin, the dose required to maintain a INR increases during hypothyroidism, and this
increase is reversed with restoration of a normal TSH.

Treatment of hypothyroidism
Treatment of choice is synthetic thyroxine (T4). T4 is a prohormone with very little intrinsic
activity. It is deiodinated in peripheral tissues to form T3= active thyroid hormone. This
deiodination process accounts for 80 % of the total daily production of T3 in normal subjects;
as a result, T3 is in normal range in hypothyroid pts receiving adequate T4 therapy.
Dose and monitoring — T4 should be taken on an empty stomach, 1 hour before breakfast.
Initial dose 1.6 mcg/kg/day in young, healthy pts, lower in older pts (25-50 mcg).
After 6 weeks if TSH is above reference range, T4 dose can be increased by 12-25 mcg/day.
The process of increasing the dose of T4 every 3-6 weeks (depending upon the pt's
symptoms) should continue, until high TSH in return to the reference range.
Situations in which a different dose may be needed: ● pregnancy ● if the pt gains weight,
gastrointestinal disorders, if excretion is increased (nephrotic syndrome).
FT4 measurements can help determine appropriate dose when TSH is very high. For example,
if steady-state conditions exist and TSH is 30-80 mU/L, and FT4 is half the mean value, the
dose may need to be doubled, while a pt with a similar TSH and a FT4 that is in the lower
third of the normal range may only require a 25- 50% dose increase.
●Small decreases in dose, 12-25 mcg/day, are needed as pts age, lose weight, or during
androgen therapy.
The dose of T4 need not be altered in pts who are clinically euthyroid if their TSH is only
slightly above (or below) the normal range. In older pts, upper limit of TSH is 7.5 mU/L
Overreplacement — it causes subclinical hyperthyroidism or even overt hyperthyroidism.
The main risk of subclinical hyperthyroidism is AF, accelerated bone loss. It is important to
educate pts about adverse effects of overtreatment with T4.
For most pts with hypothyroidism, we do not suggest treatment with T3; rapid gastrointestinal
absorption, relatively short half-life in the circulation (about one day). In addition, T4 remains
low in pts treated with T3; it may be confusing and lead to inappropriate changes in dose.
Temporary treatment with T3 is appropriate in thyroid cancer who are to undergo
radioactive iodine imaging. To shorten the period of hypothyroidism, the pt's T4 therapy is
discontinued and T3 is substituted for 3-4 weeks until the T4 is cleared.
Pregnancy — 85% of women with preexisting hypothyroidism need a higher dose of T4
during pregnancy to maintain normal TSH secretion, from 5th week of gestation.
Estrogen therapy — In women receiving T4 therapy, estrogens increase serum thyroxine-
binding globulin concentrations, and may increase the need for T4.

17
Surgical pts — hypothyroid pts have a higher frequency of perioperative and postoperative
ileus, hypotension, HypoNa, and central nervous system dysfunction. They also have less
fever during serious infections and increased sensitivity to anesthesia and opiate pain
medications. It is prudent to postpone elective surgery until the euthyroid state is restored.
Pts receiving chronic T4 therapy who undergo surgery and are unable to eat for several days
need not be given T4 parenterally. If oral intake cannot be resumed in 5-7 days, only then T4
should be given intravenously. The dose should be 70 to 80 % of oral dose.
Thyroid cancer — Pts who have had a thyroidectomy for thyroid cancer, need to take T4 not
only for treatment of hypothyroidism, but also to prevent recurrence of cancer.
Selenium reduces anti-TPO, improves ultrasound structure of thyroid gland, and reduces
the occurrence of post-partum thyroiditis in pregnant women with anti-TPO.
SUMMARY AND RECOMMENDATIONS
●Treatment of choice for hypothyroidism is synthetic thyroxine (T4). We suggest NOT using
combination T4- T3. T4-T3 therapy may improve symptoms in the rare subgroup of a
polymorphism in the type 2 deiodinase, which converts T4 to T3.
●We suggest that pts remain on the same formulation of T4. If a switch from one
manufacturer to another is made, we measure TSH 6 weeks after changing preparations.
●The initial dose can be the full anticipated dose (1.6 mcg/kg/day) in young, healthy pts, and
lower dose (25-50 mcg) in older pts. T4 should be taken 1 hour before breakfast.
●After initiation of T4 therapy, the pt should be reevaluated and TSH measured in 6 weeks,
and the dose adjusted accordingly. Symptoms may begin to resolve after 2-3 weeks, but
steady-state TSH concentrations are not achieved for at least 6 weeks.
●The goals of therapy: amelioration of symptoms and normalization of TSH (0.5-5.0 mU/L).
●For pts who have hypothyroid symptoms, and TSH in the upper limits of reference range,
we suggest increasing dose of T4 with the aim of lowering TSH into the lower half of the
normal range. However, it is important to note that there is an age-related shift towards higher
TSH in older pts, with an upper limit of normal of about 7.5 mU/L in 80 year olds.

Central hypothyroidism
Pituitary tumors can cause hypothyroidism by compression of pituitary thyrotrophs. Other
causes of central hypothyroidism: Sheehan syndrome, brain injury, SAH, infiltrative disease.
Pts with central hypothyroidism frequently have other pituitary hormone deficiencies.
Central hypothyroidism is sometimes milder than primary. Goiter is not present.
In central hypothyroidism, FT4 is low or low-normal, but TSH may be low, normal, or even
slightly elevated (up to about 10 mU/L): TSH that has reduced biologic activity.
TRH stimulation test — iv TRH (200 mcg) with measurement of TSH at baseline and 20-60
min after TRH. The normal increase in TSH at 20 minutes is 5- 30 mU/L, with a decrease at
60 minutes. Classically, one would expect no serum TSH response to TRH in pituitary
disease. But, the response to TRH is highly variable, limiting the utility of this test.
In pituitary tumors, there is deficiency or excess of other pituitary hormones, such as
hypogonadism or hyperprolactinemia.
Central hypothyroidism should be suspected in the following circumstances:
●There is known hypothalamic or pituitary disease
●A mass lesion is present in the pituitary
●Symptoms and signs of hypothyroidism are associated with other hormonal deficiencies
Central versus primary hypothyroidism – A pt with a low T4/ FT4 and a slightly high TSH
(5-10 mU/L) could have either primary or central hypothyroidism. A higher TSH value would
be expected if the pt had primary hypothyroidism, but in central hypothyroidism elevations of
biologically inactive TSH, definitive diagnosis requires further evaluation. In this setting, we
measure anti-TPO, gonadotropins, estradiol or testosterone. Absence of anti-TPO

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antibodies and abnormalities in other pituitary hormones favors central hypothyroidism.
Hyperprolactinemia may be present in both central and primary hypothyroidism.
EVALUATION — MRI + assesment of pituitary-adrenal function, by ACTH stimulation
test, before thyroxin therapy is begun in all central hypothyroidism. Evaluation of other
hypothalamic-pituitary hormonal function (gonadotropins, testosterone, estradiol, prolactin,
IGF-I) is necessary in a sellar mass on MRI.
Start with T4 dose of 1.6 mcg/kg. Dose should be adjusted according to symptoms and FT4
values, aiming to maintain FT4 in the upper half of normal range. TSH cannot be used to
monitor therapy, as it is suppressed to <0.1 mU/L in nearly all pts taking doses of T4 that
raise their FT4 to normal. Surgery may lead to an improvement in anterior pituitary function.

Hypothyroidism during pregnancy

Symptoms may be overlooked or attributed to the pregnancy itself. Because of the changes in
thyroid physiology during pregnancy, upper limit of TSH: 2.5 mU/L in 1; 3 mU/L in 2 and 3.
Pregnancy complications -Preeclampsia and gestational HTA ●Preterm delivery, even before
32 weeks ●Perinatal morbidity and mortality ●Neurocognitive impairment
Subclinical hypothyroidism (high TSH, normal FT4) is more common than overt
hypothyroidism, occurring in 2.5% of screened women.
TREATMENT —All pregnant women with newly diagnosed overt hypothyroidism (TSH
above trimester-specific range + low FT4) should be treated with T4. We suggest treatment of
pregnant women with subclinical hypothyroidism (TSH above trimester-specific range +
normal FT4), regardless of TPO- antibody status. We do not suggest the treatment of pregnant
women with isolated hypothyroxinemia (low FT4, normal TSH). Treat overt
hypothyroidism with 1.6 mcg/kg. If TSH <10 mU/L started with 1 mcg/kg daily. TSH
control in 4 weeks. Maintain TSH (0.1 to 2.5 mU/L, 0.2 to 3 mU/L, and 0.3 to 3 mU/L). If
TSH remains above this, T4 is increased 12 -25 mcg/day. Measure TSH every 4 weeks
during the first half of pregnancy; dose adjustments are often required. TSH can be
monitored less (once each trimester) in the latter half of pregnancy, if the dose is unchanged.
Preexisting hypothyroidism — Hypothyroid women who are newly pregnant should increase
levothyroxine dose by 30%. We accomplish this by increasing dose from once daily dosing
to a total of 9 doses per week (double the daily dose 2 days each week). Dose requirements
increase by as much as 50 % during pregnancy, as early 5th week of gestation.
Women with high TPO antibodies are at high risk for developing subclinical hypothyroidism
in the first trimester and thyroiditis in the postpartum period. The decision to treat euthyroid
women with TPO antibodies with T4 or to monitor for the development of hypothyroidism
during pregnancy is controversial.

Myxedema coma
Hypothermia, hypoventilation, hypotension, bradycardia, HypoNa, hypoglycemia.
Abnormal deposits of mucin in skin and other tissues (myxedema). Precipitating infection or
other acute illness: pt may not have a febrile response. Hypothermia - due to the decrease in
metabolism. Untreated, pts will progress to coma. HypoNa: excess ADH or impaired renal
function. Low Na is reversible after treatment of the hypothyroidism. Hypoglycemia may be
caused by hypothyroidism alone or, more often, by concurrent adrenal insufficiency due to
autoimmune adrenal disease, decreased gluconeogenesis, starvation.
Severe hypothyroidism: bradycardia, low cardiac output, and sometimes hypotension. Overt
congestive HF is rare in the absence of preexisting cardiac disease (lower tissue demands for
oxygenation and cardiac output). Pericardial effusion (diminished heart sounds, low ECG
voltage, large heart on x-ray). All cardiac abnormalities are reversible with thyroid therapy.

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Before therapy with thyroid hormone and a glucocorticoid is given, blood should be drawn for
measurements of TSH, FT4, ACTH, cortisol. Ideally, cortisol should be measured before and
after ACTH administration because of the possibility of associated adrenal insufficiency .
Treatment should be instituted in myxedema coma without waiting for laboratory tests.
Thyroid hormone — give both hormones because activity of T3 is greated & rapid, than T4.
T4 loading dose 200-400 mcg followed by a daily dose of 1.6 mcg/kg initially iv and,
when feasible, orally. T3 is given simultaneously 5 -20 mcg, followed by 2.5 -10 mcg 3x1.
T3 is continued until there is clinical improvement and the pt is stable.
Glucocorticoids (hydrocortisone iv 100 mg 3x1). Until the possibility of coexisting adrenal
insufficiency is excluded, the pt must be treated with glucocorticoids in stress doses.
Supportive measures — iv fluids ectrolytes and glucose, correction of hypothermia, and
treatment of any underlying infection.
Passive rewarming with a blanket. Active rewarming causes vasodilatation and worsening
hypotension. As with any critically ill, comatose pt, empiric administration of antibiotics
should be considered until appropriate cultures are proven negative.

Thyroid cancer

Differentiated thyroid cancer

Incidence of thyroid cancer has increased faster than any other malignancy in recent years.
Papillary and follicular= differentiated cancers.
Surgery is the primary mode of therapy for differentiated thyroid cancer. Radioactive iodine
(131-iodine) is the most effective adjuvant treatment for papillary thyroid cancer.
After thyroidectomy, levothyroxine therapy for all pts to prevent hypothyroidism and to
minimize potential TSH stimulation of tumor growth.
Follicular thyroid cancer
●A cold thyroid nodule. FNA biopsy alone cannot distinguish between follicular adenomas
and cancers. It requires pathologic evaluation of the thyroid after surgery.
●Important prognostic features: stage, age, and characteristics (tumor size, vascular invasion,
capsular extension, histologic grade, and distant metastases).
●Total or near-total thyroidectomy and I-131 for ablation of any remaining functioning tissue.
●After surgery and radioactive iodine ablation, we recommend thyroid hormone replacement.
Papillary thyroid cancer
RISK FACTORS: radiation exposure, familial polyposis, MEN2.
Clinical signs: rapid growth, fixation to surrounding tissues, hoarseness, lymphadenopathy.
Mortality is 6 %. Higher risk: older age (≥45 years), size of tumor, invasion or metastases.
Medullary thyroid cancer
This is a neuroendocrine tumor of parafollicular or C cells of the thyroid gland (4% of thyroid
carcinomas). Production of calcitonin is main feature.
Sporadic MTC: (80%). Solitary thyroid nodule (95%). 50% pts have detectable cervical
lymph nodes and 5% have distant metastatic disease (liver, lung, bones).
Calcitonin can cause diarrhea or facial flushing. In addition, occasional tumors secrete
ACTH= ectopic Cushing's syndrome, CEA, which, like calcitonin, is used as a tumor marker.
Thyroid function tests are normal. Ultrasound: hypoechoic, microcalcifications.
●MEN2A: MTC + pheochromocytoma + primary parathyroid hyperplasia.
●MEN2B :MTC + pheochromocytoma +marfanoid habitus + intestinal ganglioneuromatosis.
Anaplastic thyroid cancer
Anaplastic thyroid cancers are undifferentiated tumors, extremely aggressive, with mortality
100 %. Early recognition of the disease is essential to allow prompt initiation of therapy.

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●Lungs are the most common site of metastases, up to 90%
●15 % have bone metastases. ●5% have brain metastases.
The primary symptom is a rapidly enlarging neck mass. Neck pain and tenderness, and
compression (invasion) of the upper aerodigestive tract: dyspnea, dysphagia, hoarseness,
cough (hemoptysis 25%). Anorexia, weight loss, fatigue, fever. Bilateral asymmetric thyroid
enlargement. 50% of pts have enlarged cervical lymph nodes. Skin over the tumor is
erythematous or ulcerated, metastases in the skin of the chest and abdomen. Focal neurologic
symptoms suggesting brain metastases may also be present. Most pts have normal thyroid
hormones and TSH, except for tumor-related thyroiditis and hyperthyroidism from rapid
tumor growth and tissue destruction. Diagnosis is established by cytologic examination of
cells obtained by fine needle aspiration biopsy or of tissue obtained by surgical biopsy.
Laboratory: TSH, T4, calcium, phosphorus due to compromise of the parathyroid.
Complete resection+radiotherapy and chemotherapy. Survival from diagnosis is 3-7 months.

Hypoparathyroidism

Hypoparathyroidism
Parathyroid glands are destroyed (autoimmune, surgical), or PTH production is
decreased. When PTH secretion is insufficient, hypoCa develops: symptoms (mild) to life-
threatening seizures, refractory HF, or laryngospasm (severe).
Acute postsurgical hypoparathyroidism: acute hypoCa: tetany. Mild: paresthesias of
hands and feet, muscle cramps. Severe: carpopedal spasm, laryngospasm, seizures. Latent
tetany: Trousseau's and Chvostek's signs. Prolonged QT, hypotension, HF and arrhythmia.
Chronic manifestations- basal ganglia calcifications (lead to parkinsonism), cataracts, dental
abnormalities. Skeletal: increased bone mineral density. Skin is dry, puffy, and coarse.
Coarse, brittle, and sparse hair with patchy alopecia, and brittle nails.
Laboratory: low PTH, hypoCa, hyperP, normal 25-hydroxyvit D, normal/low 1,25-
dihydroxyvit D (because of the reduced capacity of PTH to stimulate renal production of
1,25-D) normal Mg and creatinine. Urinary Ca is high in hypoparathyroidism.
In contrast to high urinary calcium, reduced urine phosphorus = high serum phosphorus.
Hypoparathyroidism should be suspected in low Ca+ autoimmune disease, head and neck
surgery, neck scar. PTH can be interpreted correctly only with serum calcium.
DIFFERENTIAL DIAGNOSIS: kidney disease, vit D deficiency (diagnosed by low 25-
hydroxyvit D), and pancreatitis all cause hypoCa, but PTH is high.
HypoMg (Mg <0.8 mmol/L) causes hypoCa by inducing PTH resistance or deficiency.
Hypocalcemia should resolve after restoration of normal serum Mg.
Once hypoparathyroidism is diagnosed, measure 24-hour urine Ca and 25-hydroxyvit D.
MANAGEMENT
Acute hypoparathyroidism: tetany, seizures, or markedly prolonged QT intervals:
1.10 mL 10% calcium gluconate in 50 mL of 5% dextrose over 10 -20 minutes
2. infusion of calcium gluconate.
3. Calcitrol tbl 0.5 mcg 2x1 and Ca tbl 1-4 g daily as soon as possible.
When calcium >1.9 mmol/L and the pt is asymptomatic, iv calcium is gradually weaned.
Chronic hypoparathyroidism
Calcium 1-2 g daily, in divided doses.
Calcitriol 0.25 mcg 2x1, with weekly dose increments to achieve a low-normal calcium.
Nutritional vit D deficiency: 50,000 IU vit D2 or D3 1 x week for 6-8 weeks, and then 800-
1000 IU of vit D3 daily. Vit D requirements vary considerably from pt to pt and the correct
dose is determined by trial and error. Monitoring of urinary and serum calcium and serum
phosphate is required weekly, until a stable calcium (low-normal range) is reached. The

21
addition of recombinant PTH 1-84 is an option for chronic hypoparathyroidism in pts who
cannot maintain stable serum and urinary calcium levels with calcium and vit D.
In hypoMg: 10% sol. Mg-sulfate 2g i.v. over 10 - 20 minutes, followed by 1gr in 100 mL
i.v./hour. Persistent hypomagnesemia, /ongoing gastrointestinal or renal losses/ requires
supplementation with oral Mg 300 to 400 mg daily divided into three doses.
Chronic kidney disease —oral Ca + vit D is required in some of these pts.
Chronic liver disease — Calcidiol (25-hydroxyvit D) is most useful in liver disease.

Etiology of hypoCa
HypoCa + low PTH (hypoparathyroidism) — surgery or autoimmune hypoparathyroidism
(polyglandular autoimmune syndrome type I: + chronic mucocutaneous candidiasis and
adrenal insufficiency). This syndrome presents in children with candidiasis, followed by
hypoparathyroidism, and then adrenal insufficiency during adolescence.
HypoCa + high PTH (secondary hyperparathyroidism):
1.Vit D deficiency or resistance — poor intake or malabsorption, reduced exposure to UV,
decreased conversion of vit D to calcidiol (25-hydroxyvit D) in liver, decreased conversion of
calcidiol to calcitriol (1,25-dihydroxyvit D) in kidney.
2.Chronic kidney disease — decrease in renal production of 1,25-dihydroxyvitamin D.
3.Hyperphosphatemia —calcium is deposited mostly in bone and extraskeletal tissue.
4. Acute pancreatitis — precipitation of calcium soaps in the abdominal cavity.
5. Sepsis, severe illness- hypoMg and action of inflammatory cytokines on parathyroid gl.
6.Acute respiratory alkalosis increases Ca binding to albumin and reduces serum ionized Ca.
7. Bisphosphonates — HypoCa may result from treatment of Paget disease or osteoporosis
with bisphosphonates, which act to reduce osteoclastic bone resorption. HypoCa is likely with
high doses of potent bisphosphonates (zoledronic acid).

Hyperparathyroidism

Primary hyperparathyroidism
Primary hyperparathyroidism: high PTH + hyperCa. Adenoma or malignancy are the most
common causes of hypercalcemia (>90%). Drugs: thiazide diuretics and lithium.
Management of primary hyperparathyroidism
Symptomatic primary hyperparathyroidism: parathyroid surgery. Asymptomatic individuals:
monitor calcium and creatinine annually and bone density (hip, spine, and forearm) every 1-2
years. If disease progression occurs, we would proceed to surgery, as described above.
●For pts who are unfit for surgery: Cinacalcet 30 mg 1x1.
●For pts unfit for surgery and whose primary indication is low bone mass: bisphosphonates.
●For concomitant vit D deficiency (25-hydroxyvit D ≤50 nmol/L), we suggest vit D.
Secondary hyperparathyroidism — high PTH + hypoCa. Secondary hyperparathyroidism
occurs in response to hypoCa. PTH concentrations rise, and calcium is mobilized by:
increasing intestinal absorption (via increase in calcitriol) and by increasing bone resorption.
Secondary hyperparathyroidism is caused by: renal failure and impaired calcitriol (1,25
dihydroxyvit D) production, inadequate calcium intake, vit D deficiency, gastrointestinal
malabsorption. Assessment of renal function (creatinine), 25-hydroxyvit D, and urinary
calcium excretion differentiates normocalcemic primary and secondary hyperparathyroidism.
Measurement of bone mineral density is essential part of management of the disease. Degree
of bone loss is reflective of the severity of hyperparathyroidism.
Renal imaging — nephrocalcinosis or calcium kidney stones.

Treatment of hyperCa

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Calcium <3 mmol/L does not require immediate treatment. Avoid factors that can aggravate
hypercalcemia: thiazide diuretics, lithium, dehydration.
Severe (Ca >3.5: 0.9% NaCl 200-300 mL/h to maintain urine output 100-150 mL/hour.
In renal insufficiency/HF, careful monitoring and loop diuretics required to prevent overload.
●For immediate short-term management: calcitonin (in addition to saline hydration).
●For long-term control of hypercalcemia due to excessive bone resorption: bisphosphonate,
zoledronic acid iv. Denosumab is option for hyperCa refractory to zoledronic acid.
●Dialysis is generally reserved for those with severe hypercalcemia.

MEN 2
●MEN2A: MTC, pheochromocytoma, parathyroid hyperplasia.
●MEN2B: MTC, pheochromocytoma, intestinal ganglioneuromas, Mar-fanoid habitus.
●We recommend total thyroidectomy for medullary thyroid cancer. MTC should be evaluated
for possible pheochromocytoma before thyroidectomy; if it is found, should be removed first.

Diabetes

DM1
●Polyuria occurs when glucose >10 mmol/L. Glycosuria causes osmotic diuresis (polyuria)
and hypovolemia. Polyuria may present as nocturia, bedwetting.
●Polydipsia – thirst and increased serum osmolality from hyperglycemia and hypovolemia.
●Weight loss – hypovolemia and increased catabolism. Insulin deficiency in diabetic children
impairs glucose utilization in skeletal muscle and increases fat and muscle breakdown.
Initially, appetite is increased, but over time, children are more thirsty than hungry, and
ketosis leads to nausea and anorexia, contributing to weight loss.
Duration of symptoms before presentation is 10 days. The classic symptoms of polyuria and
polydipsia are present in >90% of pts only after obtaining a careful history (nocturia and
bedwetting, increased frequency and/or unusually wet diapers, and persistent thirst).
Perineal candidiasis is a relatively common in young girls. Visual disturbances are common.
Children with longstanding hyperglycemia may present with cataracts.
Diabetic ketoacidosis — (hyperglycemia and ketoacidosis) is the second most common form
of presentation for DM1. In addition to polyuria, polydipsia, and weight loss, ketoacidosis,
fruity-smelling breath and neurologic drowsiness and lethargy. DKA can be misinterpreted as
an acute vomiting illness because classic pediatric symptoms of dehydration (decreased
urination) are masked by the polyuria that is associated with glycosuria.
Silent presentation — dehydration, abdominal pain, or fatigue, the clinician should include
diabetes in the differential diagnosis and measure glucose and glucosuria.
Diabetes is diagnosed upon 1 of the 4 signs of abnormal glucose metabolism:
●Fasting glucose ≥7 mmol/L on more than one occasion. Fasting= no caloric intake for 8h.
●Random glucose ≥ 11.1 mmol/L in a pt with classic symptoms of hyperglycemia
●Glucose ≥11.1 mmol/L 2h after OGTT. Most children and adolescents are symptomatic
and have glucose ≥11.1 mmol/L; thus, OGTT is seldom necessary to diagnose DM1.
●HbA1c ≥6.5 %
Glycosuria is suggestive of diabetes, but not diagnostic.
DM1 vs DM2 — DM1 is characterized primarily by insulin deficiency, whereas DM2 is
characterized primarily by insulin resistance with relative insulin deficiency. As the incidence
of DM2 increases in children, it is increasingly important to distinguish type 1 from type 2.
●DM2 are usually obese and DM1 have weight loss, although up to 25 % are overweight.
● DM2 after the onset of puberty, DM1 at earlier age (DM1<10 years; DM2 > 10 years).

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●Insulin resistance –DM2: acanthosis nigricans (sign of insulin resistance), HTA,
dyslipidemia, and PCOS (girls). These findings are less likely in children with DM1.
● DM2: high fasting insulin and C-peptide.
Levels are inappropriately low or normal relative to the concomitant glucose in DM1. At
presentation, insulin and C-peptide levels may be suppressed by severe hyperglycemia and
illness. It is usually best to assess these levels after the newly diagnosed pt has recovered from
acute illness.
Insulin deficiency in DM1 results from autoimmune destruction of pancreatic beta cells and is
referred to as type 1A diabetes (85%). clinical features of DM1 but without detectable
autoantibodies are type 1B diabetes (15%).
Other causes of diabetes
●Diseases of exocrine system: Cystic fibrosis, hereditary hemochromatosis, chr. pancreatitis.
●Endocrine abnormalities– Cushing sy, growth-hormone, glucagon, catecholamine.
●Drug-induced – glucocorticoids, cyclosporine, tacrolimus, atypical antipsychotic agents.
●Monogenic diabetes (maturity onset diabetes of the young, MODY) –non-insulin
dependent diabetes presenting at a young age, lack of autoantibodies. MODY should be
suspected in a pt presenting with mild diabetes <25 years, lack of islet autoantibodies,
and lack of acanthosis nigricans. Th: sulphonylureas.
● DM1 is suggested by the presence of autoantibodies against islet cells, and by low or
inappropriately normal fasting C-peptide and insulin levels with hyperglycemia.

DM2 in children and adolescents

CLINICAL PRESENTATION — ●Asymptomatic – 40 %
●Symptomatic (polydipsia and polyuria) without ketonuria or acidosis – 60 %
●Diabetic ketoacidosis (DKA) – 5 to 10 %
PREDIABETES
●Impaired fasting glucose (IFG) –6 - 7 mmol/L., GUK after 2h OGTT < 7.0 mmol/l.
●Impaired glucose tolerance (IGT) – FG<7.0 mmol/l ,7.0 - 11 mmol/L 2h after OGTT.,
●HbA1C 5.7-6.4 %
Prediabetes pts should be engaged in intensive lifestyle interventions: weight reduction.
Treatment with metformin improves markers of insulin sensitivity and slightly reduces BMI.

Classification of diabetes and genetic diabetic syndromes

DM1- autoimune destruction of pancreatic beta cells (type 1A). No evidence of autoimmunity
and no other cause for beta cell destruction (idiopathic, type 1B).
Latent autoimmune diabetes in adults (LADA) — 7% of adults >25 have autoantibodies
directed against pancreatic beta cell antigens. It may account for a very small fraction of DM.
DM2 — most common type in adults, variable degrees of insulin deficiency and resistance.
Maturity onset diabetes of the young (MODY)- non-insulin dependent diabetes
diagnosed at a young age (<25 years) and lack of autoantibodies.
Endocrine abnormalities: ●Cushing's or exogenous glucocorticoids ●Acromegaly
●Catecholamines in pheochromocytoma ●Glucagontumors (glucagonomas) ●Somatostatin-
secreting tumors (somatostatinomas): triad diabetes, cholelithiasis, diarrhea with steatorrhea
●Hyperthyroidism, which can interfere with glucose metabolism.
GESTATIONAL DIABETES — occurs when a woman's pancreatic function is not sufficient
to overcome both the insulin resistance created by the anti-insulin hormones secreted by the
placenta during pregnancy (estrogen, prolactin, human chorionic somatomammotropin,
cortisol, and progesterone) and the increased fuel consumption necessary to provide for the
growing mother and fetus. It occurs in 2% pregnancies, usually in 2, 3 trimester.

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HF in diabetes
DM increases risk of HF regardless of CAD and HTA and causes “diabetic cardiomyopathy”.
Diabetic CMP is manifested by systolic and/or diastolic dysfunction.
Greater diastolic dysfunction is observed in those with worse glycemic control and in HTA.
●Thiazolidinediones cause fluid retention. Contraindicated in NYHA class III or IV HF.
●Metformin is contraindicated in HF because of the risk of lactic acidosis.
THERAPY: Diabetic HF same as nondiabetics: BB +ACEI
Musculoskeletal complications in diabetes
●Carpal tunnel syndrome - 20% ●Dupuytren's contractures- ●Tenosynovitis
●Diabetic sclerodactyly ●Adhesive capsulitis (frozen shoulder) and calcific periartritis.

Diabetic nephropathy
Microalbuminuria: urin albumin 30-300 mg/day or 30-300 mg/g creatinine in urine sample
Macroalbuminuria: urin albumin >300 mg/day or >300 mg/g creatinine in urine sample.
●Diabetic nephropathy occurs in both type 1 and DM2 .
●Three major changes: mesangial expansion; glomerular basement membrane thickening; and
glomerular sclerosis.

Diabetic polyneuropathy
•Loss of vibratory sensation and altered proprioception, pain, touch, and temperature.
●Diabetic neuropathy can lead to formation of foot ulcers and muscle and joint disease.
●Diabetic neuropathy should be suspected in DM1 >5 yrs duration and all DM2. Because of
severe complications (amputation) for infected nonhealing ulcers, early detection is important.

TREATMENT OF DM2 IN THE OLDER PT

All oral hypoglycemic drugs and insulin are safe in older pts. "Start low and go slow".
Start with metformin. In contraindications or intolerance: short-acting sulfonylurea
(glipizide) . In a pt with CKD: repaglinide as initial therapy.
Sulfonylurea — Hypoglycemia is the most common side effect of long-acting sulfonylurea
(glibenklamide and glimepiride). We prefer to use a short-acting sulfonylurea (glipizide).
Meglitinides — they act similarly to sulfonylureas. They have a similar risk for weight gain
as sulfonylureas but less risk of hypoglycemia. Repaglinide is principally metabolized by
the liver (use in pts with CKD).
Thiazolidinediones (glitazoni- rosiglitazone and pioglitazone) improve insulin resistance.
They increase insulin secretion in response to glucose. Contraindicated in NYHA III- IV.
Pioglitazone is preferred (increased risk for cardiovascular events with rosiglitazone).
Metformin — with caution in older diabetic pts because of the risk of lactic acidosis (MI,
stroke, HF, pneumonia). GFR >30 mL/min is a safe level. Any older pt should be cautioned to
stop taking the drug immediately if they become ill for any reason.
DPP-IV inhibitors — DPP4 deactivates GLP-1 and GIP; therefore, its inhibition affects
glucose regulation through multiple effects. DPP-IV inhibitors are moderately effective as
monotherapy or when used in combination with metformin, sulfonylureas, or
thiazolidinediones. They are relatively weak agents and lower HBA1C by 0.6 %.
DPP-IV inhibitors have no risk of hypoglycemia and are weight-neutral. However, they are
relatively expensive. The dose of DPP-IV inhibitors should be adjusted in renal insufficiency.
GLP-1 therapies — Incretin effect: oral glucose has a greater stimulatory effect on insulin
secretion than iv glucose. Exenatide, liraglutide, and albiglutide for use as monotherapy or
in combination with oral agents. Exenatide 2x1 daily or 1x1 weekly with a long-acting
formulation, liraglutide 1x1 daily, and albiglutide 1x1 weekly by SC injection. There is no

25
risk of hypoglycemia; associated with significant reduction in weight. Adverse events are
nausea, vomiting, and diarrhea in 40%. Exenatide should not be used in CrCl< 30 mL/min.
Insulin — Pts may wrongly assume that their symptoms of fatigue are due to "old age" rather
than hypoglycemia. However, in many older pts, quality of life improves substantially when
they take 1-2 doses of intermediate- or long-acting insulin. Insulin metabolism is altered in
renal failure, so less insulin is needed when GFR <50 mL/min.
Monitoring of blood glucose — HbA1C 2x yearly in stable glycemic control, and 4x yearly
in pts whose therapy has changed or not meeting glycemic goals.
MICROVASCULAR COMPLICATIONS —Retinopathy —screen also for cataracts and
glaucoma, which are more common in older diabetic compared with nondiabetic subjects.
Nephropathy — all must be screened for increased urinary albumin excretion annually.
Feet examined at every visit; an assessment of the pt's ability to see and reach his feet.
CARDIOVASCULAR RISK REDUCTION — Risk reduction should be focused upon the
following areas: ●Smoking ● HTA ● dyslipidemia ●Aspirin ●Exercise
RECOMMENDATIONS
● HbA1C <7.0 % in fit older pts who have a life expectancy of over 10 years, Goal ≤8.0 % in
frail older adults with multiple comorbidities whose life expectancy is less than 10 years.
Risk of hypoglycemia is substantially increased in older adults.
1. metformin or short-acting sulfonylurea (glipizide)
2. repaglinide is a reasonable alternative, particularly in CKD at risk for hypoglycemia.
3. DPP-IV-inhibitors -monotherapy when HBA1C is relatively close to the goal level.

Incretin mimetics
1. DPP-4 inhibitors
2. GLP-1 receptor agonists
Increase insulin secretion, slow gastric emptying, reduce postprandial glucagon and reduce
food intake. Do not cause hypoglycemia. GLP-1 is incretin and is naturally occurring gut
hormone that is released after a meal and stimulates insulin synthesis and secretion.
Sitagliptin (Januvia) 100 mg 1x1: monotherapy, a second agent in those who do not respond
to a single agent /sulfonylurea, metformin, thiazolidinedione/ and as a third agent when dual
therapy with metformin+ sulfonylurea does not provide adequate glycemic control. Reduction
to 50 mg for GFR 30-50 mL/min and 25 mg for <30 mL/min.
Linagliptin 5 mg 1x1. No dose adjustment is necessary in renal or hepatic impairment.
Saxagliptin 2.5-5 mg 1x1; Alogliptin 25 m 1x1
ADVERSE EFFECTS —headache, nasopharyngitis, and upper respiratory tract infection.
Acute pancreatitis has been reported in association with DPP-4 inhibitors.

Treatment of HTA in DM
● ACEI/ARB is preferred as initial therapy in HTA + DM + macroalbuminuria. Also start
ACEI/ARB in HTA diabetics without proteinuria. Combination therapy is required in most
pts: amlodipine + ACEI/ARB.
BB: carvedilol, nebivolol because of potential benefits on glycemic control. Loop diuretic in
renal disease or HF. Goal BP< 130/80 mmHg (may slow progression of nephropathy).
Try to lower systolic pressure < 130-135 mmHg if it can be achieved without side effects.
Diabetes in pregnancy
Pregnancy is accompanied by insulin resistance, placental secretion of diabetogenic hormones
(growth hormone, corticotropin-releasing hormone, placental lactogen, and progesterone).
Diabetes develops during pregnancy when pancreatic function is insufficient to overcome the
insulin resistance associated with the pregnant state. Consequences: increased risks of
preeclampsia, macrosomia, and cesarean delivery, and their associated morbidities.

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Prevalence 7% increases in maternal age and weight. Offspring are at risk of obesity, met sy.
Risk of gestational diabetes: ●impaired glucose tolerance or gestational diabetes in a previous
pregnancy ●Family history ●Prepregnancy weight ≥110 % of ideal body weight or BMI >30
kg/m2 ●age >25 ●Previous baby >4.1 kg ●Previous unexplained perinatal loss ●Medical
condition associated with diabetes: MetSy, PCOS, use of glucocorticoids, HTA.
SCREENING AND DIAGOSTIC TESTING
75-g 2-h OGTT — is diagnostic of gestational diabetes when one glucose value is elevated.
APPROACH : at initial prenatal visit check HBA1C; diagnosis of DM is made if HBA1C
≥6.5 %. Fasting glucose >7.0 mmol/L is diagnostic of DM. To identify pregnant women with
impaired glucose tolerance, perform OGTT when HBA1C is 5.7- 6.4 % at the first prenatal
visit. Because HBA1C<6.5 % cannot be taken as strong evidence against diagnosis of DM.
Exclusion of diabetes in women with HBA1Cs associated with increased risk for diabetes (5.7
- 6.4 %) is best achieved with OGTT. 25% of women with HBA1C 5.7-6.4 % in early
pregnancy develop gestational diabetes when screened and tested later in pregnancy.
For women who have not been previously diagnosed with DM, 24 -28 perform OGTT.
SUMMARY AND RECOMMENDATIONS —
Diagnosis of diabetes at 24-28 weeks of gestation: gestational diabetes.
Diagnosis at the first prenatal visit (in early pregnancy): overt diabetes.
Overt diabetes: HBA1C ≥6.5%. Fasting glucose≥7.0. If HBA1C is 5.7- 6.4%, perform OGTT.
Gestational diabetes glucose targets:
●Fasting blood glucose ≤ 5.3 mmol/L
●One-hour postprandial glucose ≤ 7.8 mmol/L
●Two-hour postprandial glucose ≤6.7 mmol/L.
HBA1C values tend to be lower in pregnant compared to nonpregnant women because the
average blood glucose is 20 % lower in pregnant women and, in the first half of pregnancy,
there is a rise in red cell mass and increase in red blood cell turnover.
Monitoring for ketonuria -DKA is associated with DM1 and also in DM2 under conditions
of stress, serious infection, trauma. Women with diabetes should test urine for ketones if
glucose >11.1 mmol/L, in illness or stress, or if there are symptoms of ketoacidosis such as
nausea, vomiting, and abdominal pain. Pregnant women develop elevated β-hydroxybutyrate
more rapidly. Advise pregnant women, with or without GDM, to avoid prolonged fasting.
Insulin — initiate insulin when glucose is high despite nutritional therapy. Dose of insulin is
0.7-2 IU/kg (present pregnant weight).
Titration of insulin dose to glucose levels is based upon frequent self-monitoring. 4-6 glucose
measurements each day are needed to optimize therapy (fasting + 1-2 hours postprandial +
pre-lunch and pre-dinner) and ensure a smooth increase of insulin as insulin requirements
increase with pregnancy progression. Twin gestations complicated by GDM may require an
approximate doubling of the insulin requirement throughout pregnancy.
If low glucose is noted more than once at the same time of day, insulin doses are decreased.
Only lispro and aspart have been investigated in pregnancy and have acceptable safety
profiles, minimal transfer across placenta and no evidence of teratogenesis.
Oral anti-hyperglycemic agents — When either metformin or glyburide is prescribed, pts
should be made aware that information regarding the long-term effects of transplacental
passage are not known, and thus caution is warranted.
Metformin — Second and third trimester metformin treatment of GDM appears to be safe
in the short term, but 50% women using metformin will need supplemental insulin.
Metformin crosses the placenta. It is not known whether fetal exposure metformin is
beneficial or harmful, and thus caution is warranted in its use in pregnancy. Because offspring
of diabetic mothers may not manifest obesity until 5-7 years, longer-term studies are needed.

27
Until such studies demonstrate long-term safety, pts who are prescribed metformin should be
informed of the uncertainties about the effects of transplacental passage.
Other — Use of thiazolidinediones, glitinides (repaglinide and nateglinide), and GLP-1 during
pregnancy is considered experimental. There are no controlled data available in pregnancy.
MATERNAL PROGNOSIS — GDM is predictive of an increased risk of developing DM2,
DM1, MetSy and CAD. All women with GDM should have OGTT 6-12 weeks after delivery.
●Women with an abnormal OGTT are then classified as having prediabetes or overt diabetes.
SUMMARY AND RECOMMENDATIONS
●Medical nutritional therapy is the initial approach.
•Calories are divided over 3 meals and 3 snacks: 40% carbohydrate, 20 % protein, 40 % fat.
•Self blood glucose monitoring should evaluate the effectiveness of nutritional therapy.
●Start insulin in women who do not achieve glycemic control with nutrition and exercise.
•Start insulin if FG ≥5.3 mmol/L, 1h PPglucose 7.2-7.8 mmol/L, or 2h glucose >6.7 mmol
•Goal: FG <5.3 mmol/L , 1h PP <7.2-7.8 mmol/L and 2h PP <6.7 mmol/L.
●Insulin (aspart/ lispro) 0.7.-2 IU/kg. Glyburide or metformin is a reasonable alternative for
women who refuse to take, or are unable to comply with insulin therapy. The long-term
effects of transplacental passage of oral anti-hyperglycemic agents are not known.

Pregestational diabetes
We do not start oral agents during pregnancy. However, women with DM2, PCOS and
impaired glucose tolerance are conceiving while on oral anti-hyperglycemic agents. We
generally continue metformin, but discontinue other oral agents. We then initiate insulin
therapy as needed to achieve adequate metabolic control.
Ideally, insulin should be started prior to conception. Insulin requirements during first
trimester are similar to those prior to pregnancy. During the second half of pregnancy,
insulin requirements increase (3rd trimester 1.6 U/kg/day in DM2 and 1.2 U/kg/day in
DM1). Lispro and aspart have acceptable safety profiles, minimal transfer across placenta.
Dose — The average insulin requirement in pregnant women with DM1 is 0.7 units/kg in the
first trimester, 0.8 U/kg for weeks 13-28, 0.9 U/kg for weeks 29-34, and 1.0 U/kg for weeks
35 to term; however, the range of change in insulin requirements is broad. Large maternal
weight gain is associated with a greater increase in the insulin requirement. Massively obese
women may need initial doses of 1.5 to 2.0 U/kg in order to overcome their insulin resistance.
Meal related insulin lispro and aspart doses are calculated as 50 % of the insulin
requirement. For most pregnant women, this dose is approximately 0.15 times their pregnant
weight in kg. As an example, an 80 kilogram pregnant diabetic woman would take 12 units of
lispro or aspart before each meal. The other 50 % of her insulin dose should cover basal
needs. The dose is calculated as 0.45 times the pt's weight in kilograms. For example, our 80
kilogram women would take 18 units of NPH twice daily. The first dose is given before
breakfast and the second dose is given either before dinner with a rapid acting insulin or at
bedtime, whichever works best for avoiding nocturnal hypoglycemia. Although there are no
clinical trials to show the safety or efficacy of the long acting insulin analogues glargine and
detemir in pregnancy, some clinicians use these drugs. For our 80 kilogram woman, the dose
would be 36 units of glargine once a day or 18 units of detemir twice a day.
Glucose targets:
•Preprandial, bedtime, and overnight target glucose concentrations: 3.3- 5.5 mmol/L
•Peak postprandial target glucose: 5.6-7.2 mmol/L 1-2 hours after the beginning of the meal
●Measure HBA1C monthly, 2nd and 3rd trimester values are less reflective of true glycemic
control.
● HBA1C goal <6.5 %.
●Urinary ketones should be measured in glucose >10 mmol/L in DM1 pregnant woman.

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●Women with DM1 require insulin: lispro/aspart +NPH (Neutral Protamine Hagedorn)
●Moderate, low-risk exercise can be performed during pregnancy.

DKA
Symptoms of nausea, vomiting, thirst, polyuria, polydipsia, abdominal pain, change in mental
status. Laboratory findings: hyperglycemia (>13.9), acidemia (pH <7.30), elevated anion gap
(>12 mmol/L), ketonemia, low bicarbonate (<15 mmol/L), elevated base deficit (>4 mmol/L),
and renal dysfunction. DKA is well documented to occur at lower blood glucose during
pregnancy. Severe hyperglycemia can cause osmotic diuresis resulting in volume depletion,
produce life-threatening fetal hypoxemia and acidosis. Maternal mortality is < 1 %, but fetal
mortality 36%. Thus, DKA is a true obstetrical emergency.
DKA is managed similarly in pregnant and nonpregnant pts: iv insulin, fluids, electrolyte (K,
Mg), acidosis, precipitating causes (infection). Timing of delivery is individualized based on
multiple factors: gestational age, maternal condition (whether the mother is responding to
aggressive therapy or deteriorating), and fetal condition (whether the fetal heart rate pattern is
improving or deteriorating). Fetal heart rate abnormalities resulting from maternal acidosis
will often improve as DKA is treated and maternal condition improves.

Polyglandular autoimmune syndrome

Polyglandular autoimmune syndrome type I

●Adrenal insufficiency
●Primary hypogonadism
●Hypoparathyroidism
●Malabsorption, chronic mucocutaneous candidiasis

Polyglandular autoimmune syndrome type II

●Adrenal insufficiency
●Primary hypogonadism.
● Autoimmune thyroid disease or DM
●Hypoparathyroidism does not occur.

Addison’s disease

Primary adrenal insufficiency (Addison's disease)

Autoimmune 70%, TBC 10%, infectious diseases, cancer, adrenal hemorrhage or infarction.
Pts female (70%). Combination with other autoimmune endocrine disorders in polyglandular
autoimmune sy I, II. Other nonendocrine autoimmune disorders: vitiligo, myasthenia gravis,
thrombocytopenic purpura, Sjögren's, RA, antiphospholipid syndrome, occur occasionally.
DRUGS that inhibit cortisol biosynthesis: etomidate, ketoconazole and fluconazole.
Drugs that suppress CRH or ACTH: glucocorticoids, opioids.

Clinical manifestations of adrenal insufficiency

Onset is gradual and may go undetected until illness or stress precipitates adrenal crisis.
ADRENAL CRISIS — acute adrenal insufficiency may occur in the following:
 In a previously undiagnosed pt who has serious infection or other acute, major stress.
 In primary adrenal insufficiency when pt does not take more glucocorticoid during infection.
 Less frequently in secondary or tertiary adrenal insufficiency during acute stress
Adrenal crisis: shock, vomiting, abdominal pain, weakness, fever, confusion or coma.

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 Hypoglycemia is rare in acute primary adrenal insufficiency; it is common in secondary
adrenal insufficiency caused by ACTH deficiency.
 Chronic adrenal insufficiency: hyperpigmented pts (due to chronic ACTH hypersecretion).
 Acute onset: no time for hyperpigmentation.
Major hormonal factor precipitating adrenal crisis is mineralocorticoid deficiency, and
major clinical problem is hypotension. Thus, adrenal crisis can occur in pts who receive
glucocorticoid if their mineralocorticoid is low.
Although it is not primarily responsible, glucocorticoid deficiency can contribute to
hypotension by decreased vascular responsiveness to angiotensin II and norepinephrine.
Evidence of occult hemorrhage (sudden fall in Hgb and Hct), HyperK, HypoNa, and volume
contraction are other signs. Risk factors for adrenal hemorrhage: anticoagulant therapy or
coagulopathy, meningococcemia (Waterhouse-Friderichsen syndrome)
Pituitary apoplexy: adrenal crisis can occur; symptoms are due to low ACTH and cortisol .
Chronic primary adrenal insufficiency: symptoms of glucocorticoid, mineralocorticoid and,
in women, androgen deficiency. In contrast, secondary or tertiary adrenal insufficiency
usually have normal mineralocorticoid function. Its onset is quiet, gradual development of
symptoms. Most common features are: fatigue, anorexia, weight loss. Hypotension is due to
aldosteron deficiency. HTA is strong evidence against a diagnosis of adrenal insufficiency.
Glucocorticoids are necessary for epinephrine synthesis, and in adrenal insufficiency there is
decreased epinephrine and compensatory increase in norepinephrine.
HypoNa is caused by mineralocorticoid deficiency and increased ADH (because of cortisol
deficiency). HyperK + mild hyperchloremic acidosis (due to mineralocorticoid deficiency).
Hyperpigmentation is in primary adrenal insufficiency, most characteristic finding. It is due to
increased melanocyte stimulating hormone (MSH). It fades after glucocorticoid therapy.
Sexual dysfunction — Decreased axillary, pubic hair, loss of libido are common in women, in
whom androgen production primarily occurs in the adrenal glands. These changes are unusual
in men, in whom androgen production occurs in testes. Amenorrhea develops in 25% women.
Psychiatric manifestations; depression, irritability, negativism, agitation, hallucinations.
Vitiligo: bilateral areas of depigmented skin due to autoimmune destruction of melanocytes.
Secondary or tertiary adrenal insufficiency- similar to primary with few major exceptions:
 Hyperpigmentation is not present.
 HypoNa and hypervolemia may be present (increase in ADH due to cortisol deficiency).
 HyperK and hypotension is not present, reflecting the presence of aldosterone.
 Gastrointestinal symptoms are less common.
 Hypoglycemia is more common. Pts tolerate illness longer and present with symptoms of
chronic glucocorticoid deficiency, rather than mineralocorticoid deficiency.
 Signs of pituitary tumor, deficiency of other pituitary hormones, headache, visual defects.
SUMMARY .
Chronic adrenal insufficiency
Primary: hyperpigmentation, fatigue, weight loss, abdominal pain, electrolyte disbalance.
Secondary or tertiary: due to glucocorticoid deficiency. Major differences from primary:
 Hyperpigmentation is not present.
 Dehydration, hypotension and hyperK is not present (aldosterone is present).
 HypoNa and volume expansion may be present.
 Hypoglycemia is more common in secondary adrenal insufficiency.

Diagnosis of adrenal insufficiency

1. Low cortisol
2. Is ACTH high or low?
3. Is mineralocorticoid high or low?

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3. Seeking a treatable cause of the disorder (adrenal glands or pituitary adenoma)
Diagnosis of adrenal insufficiency: low cortisol. Caution in abnormalities of albumin
(cirrhosis, nephrotic syndrome, oral estrogens). Salivary or free cortisol are alternatives.
Low morning cortisol (<80 nmol/L) strongly suggests adrenal insufficiency.
Other cortisol measurements are of no value in establishing diagnosis of adrenal insufficiency.
Urinary cortisol — low in severe adrenal insufficiency, but may be low-normal in partial
adrenal insufficiency.
If both cortisol and ACTH are obtained at the time, the diagnosis and cause of adrenal
insufficiency could be established in most cases.
●Low cortisol+ high ACTH: primary adrenal insufficiency. Obtain aldosterone and renin.
●Low cortisol + low ACTH: secondary (pituitary disease) or tertiary (hypothalamic disease).
When evaluating the pt with possible adrenal insufficiency:
●measure 8 AM cortisol and ACTH, and a high-dose 250 mcg ACTH stimulation test.
●in acute ACTH deficiency (pituitary surgery): low-dose 1 mcg ACTH stimulation test.
Short ACTH stimulation test — should be performed in all pts in whom adrenal
insufficiency is being considered. It is best to perform the test in the morning. High and low
dose test are available. For both tests, a subnormal response confirms adrenal insufficiency,
but further studies establish the type and cause.
High-dose test (250 mcg) — A normal response is a rise in cortisol after 30/60 minutes
≥500-550 nmol/L. A normal response excludes primary adrenal insufficiency and most
secondary adrenal insufficiency.
Low-dose test (1 mcg) — normal cortisol response after 20/30 minutes: 400-620 nmol/L.
Choice of test — we suggest 1 mcg low-dose test if acute ACTH deficiency is suspected
(pituitary surgery). For all other pts, we suggest the high dose ACTH stimulation test.
ACTH stimulation test can be performed after glucocorticoid treatment provided that therapy
has not been given for more than a few days, after which it suppresses hypothalamic-pituitary-
adrenal axis and compromise the adrenal response.
●Primary adrenal insufficiency: Low cortisol, aldosterone, Na. High ACTH, renin, K.
●Secondary adrenal insufficiency: Low ACTH, cortisol. Normal renin, aldosterone, K.
Primary adrenal insufficiency
Abdominal CT can detect enlarged adrenal glands or adrenal calcification (infectious,
hemorrhagic, or metastatic cause); these findings eliminate autoimmune disease. Pts
presenting initially with TBC adrenal insufficiency always have active TBC elsewhere.
Diagnosis of autoimmune adrenal insufficiency is based upon the presence of associated
autoimmune disorders and exclusion of other causes.
●Electrolyte disturbances in primary adrenal insufficiency (hypoNa and hyperK) are due to
diminished secretion of cortisol and aldosterone.
●HypoNa is mediated by increased ADH which results in water retention and reduction in Na.
Both cortisol and aldosterone deficiency contribute to this problem. HypoNa is most often
seen with primary adrenal insufficiency.
●HyperK in adrenal insufficiency is entirely due to hypoaldosteronism.
●HypoNa in adrenal insufficiency is rapidly corrected by cortisol and volume repletion.
Although cortisol replacement with hydrocortisone also may increase K excretion,
mineralocorticoid replacement is required in primary adrenal insufficiency.
The dose of mineralocorticoid should be increased in elevated plasma renin activity.

Treatment of adrenal insufficiency

Primary adrenal insufficiency: cortisol and mineralocorticoid deficiency. In contrast,
secondary and tertiary adrenal insufficiency: cortisol deficiency.

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Adrenal crisis in primary adrenal insufficiency include hyperK and hypoNa. HypoNa occurs
due to mineralocorticoid deficiency and excess ADH that is caused by cortisol deficiency.
Combined mineralocorticoid and glucocorticoid deficiency lead to urinary Na loss, volume
depletion with increased urea.
Secondary adrenal insufficiency (isolated glucocorticoid deficiency) decreases vascular
tone, which leads to hypotension. Pure cortisol deficiency: dilutional HypoNa, normal K.
Adrenal crisis therapy:
●1-3L 0.9% NaCl in the first 12-24h
Hydrocortisone (100 mg IV bolus). This can rapidly decrease ADH and correct HypoNa.
●In contrast to glucocorticoid replacement, mineralocorticoid replacement is not necessary
acutely because it takes several days for its Na-retaining effects to appear, and adequate Na
replacement is achieved by IV saline alone. Hydrocortisone is preferred because of its
mineralocorticoid activity.
●After the initial bolus, hydrocortisone 50 mg IV 3x1 until stabilization of vital signs.
●Unless there is a major complicating illness, iv glucocorticoid therapy can be tapered over 1-
3 days and changed to an oral stress or maintenance dose.
Precipitating cause (infection) should be appropriately treated. Once the pt's condition is
stable, diagnosis can be confirmed with short ACTH stimulation test.
CHRONIC ADRENAL INSUFFICIENCY- Ideal glucocorticoid replacement therapy would
mimic the endogenous cortisol rhythm: Hydrocotison tbl 10+5+ 2.5 mg.
Longer-acting agents such as dexamethasone or prednisone provide a smoother physiological
effect and avoid the marked changes in serum glucocorticoid levels that occur with short-
acting drugs. The usual are dexamethasone 0.5 mg 1x1 and prednisone 5 mg 1x1.
We suggest using the lowest glucocorticoid dose that relieves symptoms of glucocorticoid
deficiency and avoids signs and symptoms of glucocorticoid excess.
Symptom assessment:
●The dose may be too low if symptoms of apparent glucocorticoid deficiency are present.
●The dose may be too high if excessive weight gain, facial plethora or other symptoms of
Cushing's syndrome are present. Osteoporosis likely with excessive glucocorticoid therapy.
Mineralocorticoid—for primary adrenal insufficiency: Fludrocortisone 0.05- 0.1 mg 1x1.
Secondary adrenal insufficiency: evaluation and replacement for other pituitary hormones .
During minor illnesses, pt can increase dose of glucocorticoid to 2-3x the usual daily dose for
3 days without consulting a clinician (3 x 3 rule). The increased dose will decrease fever and
malaise and will not compromise the immune response. If the illness becomes worse, doctor
determines if other treatment (antibiotics) is indicated. Authors suggest a total daily dose
equivalent to 100 to 150 mg hydrocortisone for major surgical procedures given in divided
doses for two to three days, then returning to the usual dose.
PREGNANCY — The usual glucocorticoid and mineralocorticoid replacement doses are
continued; an occasional woman requires slightly more glucocorticoid in the third trimester.
Pts should be followed closely throughout pregnancy for electrolyte abnormalities and signs
of volume depletion. Plasma renin activity is index of adequate fludrocortisone dose.

Cushing’s disease

Causes and pathophysiology of Cushing's syndrome

Cushing's syndrome may be ACTH -dependent or -independent. The most common cause is
iatrogenic. The second common is Cushing’s disease (pituitary hypersecretion of ACTH).
ACTH-dependent — bilateral adrenocortical hyperplasia.
●Cushing's disease (pituitary hypersecretion of ACTH) – 70 %
●Ectopic secretion of ACTH by nonpituitary tumors – 15 %

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ACTH-independent — The causes of ACTH-independent Cushing's syndrome are:
●Iatrogenic or factitious Cushing's syndrome, which is by far the most common cause
●Adrenocortical adenomas and carcinomas –20 %
● Bilateral adrenal micronodular hyperplasia – < 1 %
●Bilateral adrenal macronodular hyperplasia - < 1 %.
Cushing's disease: pituitary adenoma (microadenoma 90%). Increased ACTH causes
bilateral adrenocortical hyperplasia and hypersecretion of cortisol. Consequently, the normal
circadian rhythm in cortisol secretion is lost. Morning ACTH and cortisol may be normal, but
late-evening concentrations are high. Increased cortisol is reflected by increased urinary
cortisol and 17-hydroxycorticosteroid (17-OHCS). Corticotroph adenoma cells function at
a higher than normal set point for cortisol feedback inhibition. This characteristic is clinically
important because it permits the use of dexamethasone suppression to distinguish pituitary
and ectopic ACTH secretion; the latter is more resistant to glucocorticoid negative feedback.
Ectopic ACTH — malignant ectopic sources: lung (small cell Ca), pancreas, thymus.
ACTH-INDEPENDENT CUSHING'S SYNDROME
Cushing's syndrome due to primary adrenocortical disease (tumor, micronodular or
macronodular hyperplasia), increased cortisol secretion suppresses CRH and ACTH. Normal
pituitary corticotroph cells atrophy, as do zona fasciculata and reticularis of adrenal gland.
As ACTH is suppressed, dehydroepiandrosterone (DHEA-S) is low. However, occasional
adrenal adenomas produce relatively large amounts of androgen.
Bilateral macronodular adrenal hyperplasia — This syndrome is associated with adrenal
glands that weigh 25-500 g and contain multiple nonpigmented benign adrenal nodules.
●Pseudo-Cushing’s is physiologic hypercortisolism in: severe obesity, depression, alcoholism.
Clinical manifestations of Cushing's syndrome
It occurs mainly in women 25-45 years. Symptoms of hypercortisolism: supraclavicular fat
pads, skin atrophy, wide purplish striae, and proximal muscle weakness. Symptoms vary by:
●presence or absence of androgen excess, as hypercortisolism doesnt cause hirsutism or acne.
●Adrenal carcinoma or ectopic ACTH cause tumor-related symptoms that overshadow the
effects of hypercortisolism (such as weight loss instead of weight gain).
●In adrenal adenomas, clinical manifestations of Cushing's syndrome tend to be less severe in
pts >50 yrs. Many incidentally-discovered adrenal adenomas have subclinical Cushing's
syndrome (mild hypercortisolism). Glucose intolerance and HTA are common.
Common feature of Cushing's syndrome is progressive central obesity , "moon" face, "buffalo
hump", fat pads in supraclavicular fossae: thick and shortened neck. Higher serum leptin than
in obese subjects with similar BMI. Dermatologic manifestations: skin atrophy, ecchymoses,
striae, fungal infections (tinea versicolor), hyperpigmentation (increased ACTH= principal
pigmentary hormone in humans. It acts via binding to melanocyte-stimulating hormone
receptors)- generalized, and in areas exposed to light (face, neck, and back of the hands).
Acanthosis nigricans also can be present.
Menstrual irregularities — correlated with increased cortisol and decreased estradiol, due to
suppression of gonadotropin-releasing hormone by hypercortisolemia.
Signs of androgen excess- Major source of androgens in women is adrenal gland (major
source of androgens in men is testes). Signs of androgen excess are most common in
women with adrenal carcinomas (large amounts of androgen precursors because they are
inefficient at converting cholesterol to cortisol). In comparison, signs of androgen excess are
mild in women with ACTH-dependent Cushing's syndrome and do not occur in women
with adrenal adenomas. Androgen excess in women: ●Hirsutism ●Acne ●Increased libido.
●Virilization, including temporal balding, deepening voice.
Proximal muscle wasting, weakness- catabolic effects of glucocorticoid on skeletal muscle.

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Bone loss — Osteoporosis is common. It is caused by decreased intestinal calcium absorption,
decreased bone formation, increased bone resorption, and decreased renal calcium
reabsorption. Pathologic fractures may occur. Osteonecrosis (aseptic necrosis) of the femoral
head: in chronic high-dose glucocorticoid therapy. Low back pain is very common and is
attributed to osteoporosis, muscle wasting. Increased bone resorption can lead to hyper-
calciuria and renal calculi. Bone mineral density improves after treatment of Cushing's sy.
Glucose intolerance is due to gluconeogenesis (cortisol) and insulin resistance (obesity). DM
occurs in 15%. Hyperglycemia becomes easier to control when hypercortisolism is reversed.
Cardiovascular disease — increased risk of MI, ICV, and thromboembolism. Common in
Cushing’s syndrome are: HTA, dyslipidemia, central obesity. Treatment of HTA in Cushing's
is same as primary HTA. Blocking mineralocorticoid with spironolactone is particularly
effective in very high cortisol, especially with hypoK.
Glucocorticoids inhibit immune function, contributing to an increased frequency of infections.

Diagnosis of Cushing's syndrome

Exclude exogenous glucocorticoid intake.
Adrenal incidentalomas and subclinical Cushing's: obesity, HTA, glucose intolerance or
diabetes, dyslipidemia, osteoporosis. Milder cases: normal 24-hour urinary cortisol with
slightly elevated midnight salivary cortisol, incompletely suppressed morning serum cortisol
following 1 mg dexamethasone suppression test and partially suppressed ACTH levels.
DOES THE PT HAVE CUSHING'S SYNDROME?
Diagnostic tests
24-hour urinary cortisol: a direct and reliable index of cortisol secretion, integrated measure
of serum free cortisol concentration (cortisol that is not bound to cortisol-binding globulin).
Urinary cortisol excretion > 3x upper limit of normal: hypercortisolism.
Dexamethasone suppression test- Dexamethasone should suppress ACTH in normal
pituitary gland, leading to suppression of cortisol and reductions in serum and urinary cortisol.
Overnight 1 mg test —1 mg of dexamethasone and measurement of serum cortisol at 8 AM
the next morning. Most normal individuals have 8 AM cortisol <55 nmol/L.
2-day 2 mg test- 0.5 mg dexamethasone every 6 h (8 doses), and measure cortisol 2 hrs after
the last dose. Same criteria for normal suppression (<50 nmol/l) are used for 2-day 2 mg test.
Late evening cortisol — Measurement of cortisol in the late evening is based upon the fact
that lowest point in serum cortisol is in late evening. We obtain cortisol on 3 evenings.
 At least 2 tests should be abnormal to establish the diagnosis of Cushing's syndrome.
 We suggest late night cortisol, urinary cortisol, and 1 mg dexamethasone suppression test.
 The urinary cortisol excretion should be clearly increased (3x> the upper limit).
 Diagnosis of Cushing's syndrome is confirmed when two tests are clearly abnormal.
 Pt should undergo additional evaluation if results are discordant or slightly abnormal.

Dexamethasone suppression tests

●The low-dose dexamethasone suppression tests (1 mg overnight and 2-day, 2 mg) are used
to assess non-suppressible cortisol production by adrenal incidentalomas and to differentiate
Cushing's syndrome of any cause from pts who do not have Cushing's syndrome.
●The high-dose 8 mg dexamethasone suppression tests help to distinguish Cushing's disease
(pituitary hypersecretion of ACTH) from ectopic ACTH syndrome from malignant tumors.

Vasopressin and desmopressin stimulation test

Vasopressin is synthesized in neurohypophysis; it is co-secreted with corticotropin-releasing
hormone (CRH). Vasopressin and its analog desmopressin assess this axis to:
●Test pituitary ACTH secretion

34
●Evaluate the cause or cure of ACTH-dependent Cushing's syndrome (desmopressin)
●Distinguish between Cushing’s syndrome and pseudo-Cushing’s (CRH vs. desmopressin)
Desmopressin test can be useful, in conjunction with high-dose dexamethasone suppression
test to suggest a pituitary source of excess ACTH, which will require petrosal venous sinus
catheterization for confirmation in the absence of a pituitary tumor > 6 mm on MRI.
CRH stimulation test: to distinguish primary and secondary adrenal insufficiency.

Treatment of Cushing's syndrome

Treat co-morbidities: HTA, osteoporosis, and diabetes, and prevent thrombosis and bone loss.
CUSHING'S DISEASE
1. Transsphenoidal surgery.
2. Medical therapy: cabergoline, when surgery is delayed, contraindicated, or unsuccessful.
3. Pituitary irradiation
4.Bilateral total adrenalectomy with lifelong daily glucocorticoid and mineralocorticoid
replacement therapy is the final definitive cure.
ECTOPIC ACTH
1.Surgical excision of the tumor, removing the source of ACTH.
2.Nonresectable tumors: adrenal enzyme inhibitors: ketoconazole, metopirone, etomidat.
3.Octreotide (somatostatin analogue) reduces ectopic ACTH secretion, but not tumor size.
PRIMARY ADRENAL DISEASES.
Adrenal adenomas — unilateral adrenalectomy. Postoperative glucocorticoid therapy is
needed because excess cortisol secretion has suppressed CRH and ACTH.
Prognosis: HTA and glucose intolerance improve but may not disappear. Osteoporosis of
Cushing's syndrome begins to improve 6 months after hypercortisolemia is cured, but may not
normalize: bisphosphonates, calcium, vit. D, gonadal steroid replacement is recommended.

Medical therapy of hypercortisolism (Cushing’s syndrome)

●The hypercortisolism in Cushing’s syndrome is primarily treated surgically.
●Ketoconazole is the first-line drug. Liver function (hepatotoxicity). If ketoconazole does
not control cortisol, we add metopirone.
●Mitotane is used for adrenal carcinoma.
●Drugs for reducing ACTH: dopamine agonist and somatostatin analogs.

Pheochromocytoma

Pheochromocytoma: adrenal pheochromocytomas, catecholamine-secreting paragangliomas.

Distinction is important because of associated neoplasms, risk for malignancy.
Classic triad of symptoms: headache, sweating, tachycardia.
●Sustained or paroxysmal HTA (90%).
●Headache, which may be mild or severe (90 %).
●Generalized sweating (60-70%). Other symptoms: palpitations, tremor, pallor, dyspnea.
Insulin resistance, impaired fasting glucose, DM2 are directly related to catecholamines.
Symptoms are caused by hypersecretion of: norepinephrine, epinephrine, dopamine.
Familial pheochromocytoma — in MEN2.
Malignant potential — About 10 % of all catecholamine-secreting tumors are malignant.
DIAGNOSTIC TESTS
1.Plasma fractionated metanephrines is first-line test when for high index of suspicion.
2.24-hour urinary fractionated metanephrines
Plasma catecholamines — poor accuracy, plasma catecholamines no longer has a role.
Vanillylmandelic acid — 24-hour urinary VMA excretion has poor diagnostic sensitivity.

35
Biochemical confirmation is followed by radiological evaluation (95% in abdomen & pelvis).
Differential diagnosis:
●Autonomic dysfunction: Guillain-Barré syndrome or post-spinal cord injury.
●A stress response after cardiac bypass surgery or during a panic reaction.
●Drugs: cocaine, amphetamines, epinephrine, phenylephrine, terbutaline.
Hyperthyroidism, menopausal symptoms, glucose intolerance, primary HTA, renovascular
disease, hypoglycemia.
Measure 24-h urinary fractionated metanephrines +catecholamines in adrenal incidentalomas.
Treatment
All pts should undergo surgery of pheochromocytoma following appropriate preparation.
Avoid agents that provoke pheochromocytoma: glucagon, histamine, metoclopramide.
Preoperative pharmacologic preparation: alpha-adrenergic and BB, CCBs, and metyrosine.
BP twice daily target <120/80 mmHg.
1. Selective alpha1-adrenergic blocker (prazosin, or doxazosin).
2. High Na diet — On 2-3 day of alpha-adrenergic blockade, start high Na (>5 gr daily)
because of catecholamine-induced volume contraction and alpha-adrenergic blockade. This
degree of volume expansion is contraindicated in congestive HF or renal insufficiency.
3. BB - After adequate alpha-adrenergic blockade, start BB 2-3 days preoperatively. BB
should never be started first because blockade of vasodilatory peripheral beta-adrenergic
receptors with unopposed alpha-adrenergic stimulation can lead to a further elevation in BP.
●First day: propranolol 10 mg 4x1.
●Second day: beta-adrenergic blockade is converted to single long-acting dose.
●The dose is then increased as necessary to control the tachycardia (goal HR is 60-80 bpm).
●In general, pt is ready for surgery 10-14 days after start of alpha-adrenergic blockade.
CCB- a second regimen involves CCB. Nicardipine 30 mg 2x1, to supplement combined
alpha-+ BB protocol when BP control is inadequate or to replace this protocol in side effects.
Metyrosine — inhibits catecholamine synthesis.
Adrenalectomy: safely performed for pheochromocytoma and paragangliomas in 90% cases.
Acute hypertensive crises— during surgical resection: i.v. Na nitroprusside, nircadipine.
●Cardiac arrhythmias: lidocaine 50 -100 mg iv or esmolol 50-200 mcg/kg/ min iv.
●For MEN2; which is a diffuse medullary disease: we suggest complete bilateral
adrenalectomy because of the risk of recurrent pheochromocytoma.

Paget’s disease of the bone

Clinical manifestations and diagnosis of Paget disease of bone

Paget disease of bone= osteitis deformans, is a focal disorder of bone metabolism that occurs
in the aging skeleton; accelerated rate of bone remodeling, resulting in overgrowth of bone at
selected sites and impaired integrity of affected bone. It is a disease of the osteoclast.
CLINICAL MANIFESTATIONS ●Arthritis ●Pain ●Bone deformity ●Fracture
●Radiculopathy due to nerve compression ●Chronic back pain ●Hearing loss ●Headache
Paget disease has a predilection for: skull, thoracolumbar spine, pelvis, long bones of the leg.
Metabolic complications: high-output HF and hypercalciuria with kidney stones.
Lab: high ALP, normal Ca and P. HyperCa and hypercalciuria occur with fracture.
Characteristic radiographic findings include:
●“Osteoporosis circumscripta”: osteolytic lesions in the skull in early disease
●Pseudofractures, which may be seen as small fissures on the convex surface of long bones.
●Pelvic involvement that results in protrusio acetabuli.

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DIAGNOSIS — primarily radiologic: characteristic deformity of bone. In elevated ALP, Ca
and 25-hydroxyvit D should be obtained to exclude other causes of this elevation.
DIFFERENTIAL DIAGNOSIS : ●Osteoarthritis ●Osteosarcoma and other primary bone
tumors ●Metastatic disease ●Osteomalacia ●Hyperparathyroidism
Treatment
Nitrogen-containing bisphosphonates (zoledronate, pamidronate, risedronate, alendronat)
Calcitonin is antiresorptive agent that is less potent and unlikely to result in remission.
However, it is safe and can be used in pts intolerant of bisphosphonates.
All bisphosphonates are poorly absorbed when taken orally. As a result, they must be taken
with water, 30 min before breakfast. Pts should sit during this period to prevent GERB.
●All pts: vit D 800 IU 1x1 and Ca 1200 mg /day in divided doses. Additional vit D
supplementation (50,000 IU weekly) should be given for 8 weeks prior to initiating therapy in
pts whose 25-hydroxyvit D level <50 nmol/L.
Oral therapy with risedronate or alendronate preferred in younger pts with limited disease.
SURGERY — corrective osteotomy for long bone deformity, fracture fixation, joint
arthroplasty, spinal decompression, and resection of bone tumors.

MEN1: Clinical manifestations and diagnosis

 Tumors of Parathyroid glands, Pituitary, and Pancreatic endocrine cells. Primary
hyperparathyroidism is the initial manifestation of MEN1 (hyperCa + high PTH).
 The most common type of pituitary adenoma in MEN1 is lactotroph adenoma, but
somatotroph, corticotroph, gonadotroph, and nonfunctioning adenomas can also occur.
Diagnosis and therapy of pituitary adenomas in MEN1 is similar to sporadic adenomas.
 Pancreatic islet cell tumors 30% cases of MEN1. The most common is Zollinger-Ellison
(gastrinoma) syndrome.

MEN1: Treatment
 The indications for parathyroidectomy: symptomatic hypercalcemia, nephrolithiasis, bone
disease (diminished bone density or fracture).
 Pituitary adenomas in MEN1 should be treated in the same way as sporadic adenomas.
 Zollinger-Ellison syndrome as part of the MEN1 syndrome: PPI to limit complications of
peptic ulcer disease.
 Surgery is indicated for MEN1 and insulinoma. Because MEN1 often have additional
pancreatic tumors that may include other insulinomas, local excision of any tumors in the
head of the pancreas plus a distal subtotal pancreatectomy is frequent.

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