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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2664_Библиотеки_им_академика_М_И_Перельмана
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USMLE Step 2 CK
Figure 2-1. Pituitary Gland
● Internal Medicine
Optic
chiasm
Releases inhibiting
hormones
Anterior lobe
Anterior
pituitary cells
GH, prolactin, TSH,
ACTH, LH, FSH
Third ventricle
Stalk
Portal
blood
system
Hypothalamus
Supra-optic
paraventricular
Posterior lobe (ADH oxytocin storage)
Nucleus
As a sample summary, the hypothalamus secretes releasing factors for each respective pituitary stimulatory hormone. Each pituitary hormone stimulates release of the active hormone
from the final target gland. The active hormones then inhibit release of releasing factors and
stimulatory hormones from the hypothalamus and pituitary gland, respectively. This is feedback inhibition, and it leads to a steady state of both respective hormones involved in the axis.
Clinically, disease states involving overproduction of target hormones lead to suppressed levels of pituitary hormones, while those involving underproduction of target hormones lead to
increased levels. We use this physiology to screen and diagnose these diseases.
10
Hypothalamus
Figure 2-2. Summary of Action
Chapter 2
● Endocrinology
–
–
Thyroid
T
, T
4
Releasing
factors
Pituitary
Stimulating
hormones
Target Glands
Adrenal
3
Cortisol
Gonads
(ovarian,
testes)
Estrogen, testosterone
GH
–
–
Liver
IGF-1
DISEASES OF THE ANTERIOR PITUITARY
Syndromes causing excess production of hormones usually arise from benign tumors only of
a single cell type.
Microadenomas are defined as tumors <1 cm in diameter. Macroadenomas are tumors >1 cm
in diameter. Larger tumors can occasionally compress the optic chiasm and can cause visual
deficits. Microadenomas are more common than macroadenomas.
Table 2-1. Pituitary Adenomas by Function
Prolactin 50–60%
Growth hormone (GH) 15–20%
ACTH 10–15%
Gonadotroph 10–15%
Hyperprolactinemia
A 32-year-old woman comes to your office because she has noticed milk-like
discharge from her breasts the past 4 weeks. She also states that she has not
menstruated in 2 months. The examination reveals galactorrhea but is otherwise
normal.
11
USMLE Step 2 CK
l Internal Medicine
Note
Cabergoline is used more
often than bromocriptine
because of a better sideeffect profile. It should be
considered the preferred
medical treatment for
galactorrhea.
Definition. Excess prolactin secretion is a common clinical problem in women and causes
the syndrome of galactorrhea-amenorrhea. The amenorrhea appears to be caused by inhibition of hypothalamic release of gonadotropin-releasing hormone (GnRH) with a decrease in
luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Prolactin inhibits the LH surge that causes ovulation. The LH/FSH-producing cells are not destroyed, just
suppressed. Although hyperprolactinemia is also seen in men, gynecomastia and especially
galactorrhea are very rare. The most common presenting symptom in men is erectile dysfunction and decreased libido.
Etiology. Hyperprolactinemia can be seen in natural physiologic states such as pregnancy,
early nursing, hypoglycemia, seizure, exercise, stress, sleep, cirrhosis, nipple stimulation, and
chronic renal failure (due to PRL clearance).
Autonomous production of prolactin occurs with pituitary adenomas; these so-called prolactinomas are the most common functioning pituitary adenomas, accounting for 60% of all
pituitary tumors. They are usually microadenomas when they occur in women and macroadenomas in men, usually presenting with visual field deficits, etc. Macroadenomas can obstruct
the pituitary stalk, increasing prolactin release by blocking dopamine transport from hypothalamus (stalk effect). Other examples are tumors, such as craniopharyngioma, meningioma,
and dysgerminoma; empty sella; and trauma.
Hyperprolactinemia can also occur with decreased inhibitory action of dopamine. This occurs
with the use of drugs that block dopamine synthesis (phenothiazines, metoclopramide) and
dopamine-depleting agents (α-methyldopa, reserpine). Tricyclic antidepressants, narcotics,
cocaine, SSRIs, and risperidone can also cause increased prolactin.
Note
A basal, fasting, morning
PRL level >100 to 200 mg/L
(normal <20 mg/L) in a
nonpregnant woman indicates
a need for an MRI of the
pituitary.
Stimuli that overcome the normal dopamine inhibition can also lead to hyperprolactinemia.
An example of this is primary hypothyroidism (resulting in an increase in thyrotropin-releasing hormone [TRH]) and subsequently an increase in prolactin release.
Always check TSH in patients with elevated prolactin.
Clinical. Hyperprolactinemia presents with galactorrhea, menstrual abnormalities amenorrhea/oligomenorrhea, osteopenia and osteoporosis in long-standing cases, infertility, and gynecomastia in women; men present with hypogonadism, erectile dysfunction, decreased libido,
gynecomastia, and infertility. Men typically do not develop galactorrhea. Women are detected
earlier because of menstrual symptoms. Hence, microadenomas are more common in women.
Diagnosis. Always exclude states such as pregnancy, lactation, hypothyroidism and medications before starting the work-up of hyperprolactinemia. Prolactinomas may co-secrete
growth hormone (GH).
Prolactin levels >100 ng/mL suggest probable pituitary adenoma. Prolactin level should be
commensurate with tumor size, with prolactin levels of 100 ng/mL correlating with tumor
approximately 1 cm, of 200 ng/mL correlating with tumor approximately 2 cm, etc.
Management. For prolactinomas, initially treat with cabergoline or bromocriptine (a dopamine agonist), both of which reduce prolactin levels in almost all hyperprolactinemic patients.
Dopamine normally inhibits prolactin release. Surgery is reserved only for adenomas not
responsive to cabergoline or bromocriptine, or if the tumor is associated with significant compressive neurologic effects. Surgery is more effective for microadenomas than macroadenomas.
Only 30% of macroadenomas can be successfully resected (long-term recurrence >50% in macroadenoma). About 90% of patients treated with cabergoline have a drop in prolactin to <10%
of pretreatment levels. Radiation therapy is used if drug therapy and surgery are ineffective in
reducing tumor size and prolactin levels.
12
Acromegaly
Definition. Acromegaly is a syndrome of excessive secretion of growth hormone. In children
this is called gigantism. Acromegaly is an insidious, chronic debilitating disease associated
with bony and soft tissue overgrowth, and increased mortality.
Wikimedia, Philippe Chanson and Sylvie Salenave
Figure 2-3. Acromegaly Facial Features
Etiology. Acromegaly is caused by pituitary adenomas, usually a macroadenoma in 75% of
the cases that produce growth hormone. Rarely ectopic tumors can produce GH or growth
hormone releasing hormone (GHRH) and cause this syndrome. Less than 1% are malignant.
Growth hormone is produced by 20% of pituitary tumors.
Chapter 2
l Endocrinology
Clinical Findings. Growth hormone excess occurs most frequently between the third and fifth
decades of life.
• Various skeletal and soft tissue changes occur.
• Enlargement of the hands and feet, coarsening of facial features, and thickened skin
folds occur. Shoe, hat, glove, and ring sizes increase.
• The nose and mandible (prognathism and separation of teeth) enlarge, sometimes
causing underbite.
• The voice becomes deeper.
• There is increased sweating.
• Obstructive sleep apnea can also develop.
• Internal organs are enlarged, including heart, lung, spleen, liver, and kidneys.
• Interstitial edema, osteoarthritis, and entrapment neuropathy (carpal tunnel syndrome)
are seen.
• Menstrual problems are common because prolactin is co-secreted by the GH-producing
tumor.
• About 10-20% of patients develop cardiac anomalies such as hypertension, arrhythmias, hypertrophic cardiomyopathy, and accelerated atherosclerosis.
Metabolic changes include impaired glucose tolerance (80%) and diabetes (13–20%).
Hypertension is seen in one third of patients. Headaches and visual field loss can also occur.
Articular cartilage proliferates and causes severe joint disease.
Note
Diagnosis. Patients with acromegaly have symptoms for an average of 9 years before the diagnosis is made. The best initial test is IGF-1 level. A significantly elevated IGF level compared to
the average IGF-1 for age-matched equivalents is a positive screen for acromegaly.
The most common cause
of death in acromegaly is
cardiovascular mortality.
13
USMLE Step 2 CK
l Internal Medicine
Confirmatory testing involves the measurement of GH after 100 g of glucose is given orally;
this test is positive if GH remains high (>5 ng/mL) and suggests acromegaly. Normally a glucose load should completely suppress levels of GH.
Measurement of insulin-like growth factor (IGF) or somatomedin correlates with disease activity.
Radiologic studies such as CT scanning and MRI are used to localize the tumor but should
be done only after GH excess is documented biochemically. MRI is superior to CT scan.
MRI will show a tumor in 90% of people with acromegaly.
Management. The objectives are to decrease GH levels to normal, stabilize or decrease tumor
size, and preserve normal pituitary function. Transsphenoidal surgery provides a rapid
response. Hypopituitarism can result in 10–20%. Primary treatment is surgery.
Somatostatin analogues are the drugs of choice. Octreotide and lanreotide reduce GH values in around 70% of patients and cause partial tumor regression in 20–50% of patients.
Octreotide is the best medical therapy for acromegaly. The main side effect of concern with
somatostatin analogues is cholestasis, leading to cholecystitis.
Dopamine agonists such as bromocriptine and cabergoline are used if surgery is not curative.
10% of patients respond to these drugs.
Pegvisomant is a growth hormone analogue that antagonizes endogenic GH by blocking
peripheral GH binding to its receptor in the liver. Important to note, pegvisomant is a second-line agent.
Radiotherapy, used only if surgery and drug therapy do not work, results in slow resolution of
disease and hypopituitarism in 20% of patients.
Complications. Complications of acromegaly can arise from pressure of the tumor on the
surrounding structures or invasion of the tumor into the brain or sinuses. Other complications include cardiac failure (most common cause of death in acromegaly), diabetes mellitus,
cord compression, and visual field defects.
Hypopituitarism
Definition. Hypopituitarism is partial or complete loss of anterior function that may result
from any lesion that destroys the pituitary or hypothalamus or that interferes with the delivery of releasing and inhibiting factors to the anterior hypothalamus. GH and gonadotropins
(FSH, LH) are typically lost early.
Etiology. Large pituitary tumors, or cysts, as well as hypothalamic tumors (craniopharyngiomas, meningiomas, gliomas) can lead to hypopituitarism. Pituitary adenomas are the most
common cause of panhypopituitarism. The mass compresses the gland, causing pressure,
trauma, and necrosis.
Pituitary apoplexy is a syndrome associated with acute hemorrhagic infarction of a preexisting pituitary adenoma, and manifests as severe headache, nausea or vomiting, and depression
of consciousness. It is a medical and neurosurgical emergency.
14
Inflammatory diseases can lead to hypopituitarism: granulomatous diseases (sarcoidosis,
tuberculosis [TB], syphilis), eosinophilic granuloma, and autoimmune lymphocytic hypophysitis (usually associated with other autoimmune diseases such as Hashimoto thyroiditis and
gastric atrophy). Trauma, radiation, surgery, infections, and hypoxia may also damage both
the pituitary and hypothalamus.
Vascular diseases such as Sheehan postpartum necrosis (initial sign being the inability to lactate) and infiltrative diseases including hemochromatosis and amyloidosis may induce this
state as well.
Stroke can also damage these cells. Stroke can cause central diabetes insipidus due to damage
of hypothalamus and/or posterior pituitary.
Clinical Findings. The following hormones will appear in the order in which they are lost in
hypopituitarism.
• Gonadotropin deficiency (LH and FSH) can occur in women and lead to amenorrhea,
genital atrophy, infertility, decreased libido, and loss of axillary and pubic hair.
• In men, decreased LH and FSH results in impotence, testicular atrophy, infertility,
decreased libido, and loss of axillary and pubic hair.
• GH deficiency occurs next and is not clinically detectable in adults, though it may
manifest as fine wrinkles and increased sensitivity to insulin (hypoglycemia). GH deficiency gives an asymptomatic increase in lipid levels and a decrease in muscle, bone,
and heart mass. It also may accelerate atherosclerosis, and it increases visceral obesity.
• GH deficiency in children results in growth failure and short stature.
• Thyrotropin (TSH) deficiency results in hypothyroidism with fatigue, weakness,
hyperlipidemia, cold intolerance, and puffy skin without goiter.
• Adrenocorticotropin (ACTH) deficiency occurs last and results in secondary adrenal
insufficiency caused by pituitary disease.
• There is decreased cortisol, which results in fatigue, decreased appetite, weight loss,
decreased skin and nipple pigment, and decreased response to stress (as well as fever,
hypotension, and hyponatremia).
Chapter 2
l Endocrinology
Electrolyte changes like hyperkalemia and salt loss are minimal in secondary adrenal insufficiency because aldosterone production is mainly dependent on the renin-angiotensin system.
ACTH deficiency does not result in the salt wasting, hyperkalemia, and death that are associated with aldosterone deficiency.
Diagnosis. The first step in diagnosing pituitary insufficiency is to measure GH, TSH, LH, and
IGF-1. The most reliable stimulus for GH secretion is insulin-induced hypoglycemia. After
injecting 0.1 µ/kg of regular insulin, blood glucose declines to <40 mg/dL; in normal conditions
that will stimulate GH levels to >10 mg/L and exclude GH deficiency. Random GH and IGF levels are not sensitive enough to diagnose GH deficiency. This is why a provocative test is used.
Arginine infusion can also stimulate growth hormone release. Measure GH levels after infusing arginine. This is less dangerous because it does not lead to hypoglycemia.
To diagnose ACTH deficiency, basal cortisol levels may be preserved (the problem could be only
in response to stress). Insulin tolerance test is diagnostic and involves giving 0.05–0.1 U/kg
of regular insulin and measuring serum cortisol; plasma cortisol should increase to >19 mg/dL.
Metyrapone tests for decreased ACTH production. Metyrapone blocks cortisol production, which
should increase ACTH levels. A failure of ACTH levels to rise after giving metyrapone would indicate pituitary insufficiency. Cosyntropin (ACTH) stimulation may give abnormally low cortisol
output if pituitary insufficiency has led to adrenal atrophy.
To diagnose gonadotropin deficiency in women, measure LH, FSH, and estrogen. In males,
gonadotropin deficiency can be detected by measuring LH, FSH, and testosterone. To diagnose
TSH deficiency, measure serum thyroxine (T4) and free triiodothyronine (T3), which are low,
with a normal to low TSH.
15
USMLE Step 2 CK
● Internal Medicine
Management. Management of hypopituitarism involves treating the underlying causes.
Multiple hormones must be replaced, but the most important is cortisol replacement.
Empty Sella Syndrome (ESS)
ESS is in the differential diagnosis of enlarged sella caused by pituitary tumors. In ESS, the
sella has no bony erosion. It is caused by herniation of the suprasellar subarachnoid space
through an incomplete diaphragm sella. No pituitary gland is visible on CT or MRI. The
syndrome can be primary (idiopathic) and is also associated with head trauma and radiation
therapy. Most patients with these syndromes are obese, multiparous women with headaches;
30% will have hypertension; endocrine symptoms are absent. Therapy is reassurance.
Arachnoid
dura
Pia
CSF
Normal
Arachnoid
CSF
Arachnoid
dura
Diaphragma
sella
Anterior
lobe
Figure 2-4. Empty Sella Syndrome
Empty Sella
Pia
DISEASES OF THE POSTERIOR PITUITARY LOBE
Vasopressin or ADH and oxytocin are synthesized in neurons of the supraoptic and paraventricular nuclei in the hypothalamus, then transported to the posterior pituitary lobe to
be released into the circulatory system. The syndrome associated with an excess secretion of
ADH is called SIADH (syndrome of inappropriate secretion of ADH), and the syndrome
associated with a deficiency of ADH is called diabetes insipidus (DI).
Basilar
cisterns
CSF
16
Central and Nephrogenic Diabetes Insipidus
Definition. Central diabetes insipidus (CDI) is a disorder of the neurohypophyseal system
caused by a partial or total deficiency of vasopressin (ADH), which results in excessive, dilute
urine and increased thirst associated with hypernatremia. Nephrogenic DI is caused by renal
resistance to the action of vasopressin.
Etiology. DI frequently starts in childhood or early adult life and is more common in men
than women. DI caused by ADH insufficiency is called central diabetes insipidus and DI
caused by renal unresponsiveness to ADH is nephrogenic diabetes insipidus.
The causes of central DI include neoplastic or infiltrative lesions of the hypothalamus or
pituitary (60% also have partial or complete loss of anterior pituitary function); in the
hypothalamus these lesions can be secondary to adenomas, craniopharyngiomas, etc.; in the
pituitary gland, adenomas, leukemias, or sarcoid histocytosis can lead to DI. Other causes
of central DI include pituitary or hypothalamic surgery, radiotherapy, severe head injuries,
anoxia, hypertension, and meningitis. Idiopathic DI starts in childhood. Encephalitis, TB,
and syphilis may affect the pituitary as well.
Nephrogenic DI can be idiopathic or it can be secondary to hypercalcemia, hypokalemia, sickle cell disease, amyloidosis, myeloma, pyelonephritis, sarcoidosis, or Sjögren syndrome. Drugs
(lithium, demeclocycline, colchicine) are among the most common causes of nephrogenic DI.
Clinical Findings. Clinical findings of DI include polyuria, excessive thirst, polydipsia
(16–20 L/d), hypernatremia with high serum osmolarity and coexisting low urine osmolarity and urine specific gravity <1.010. Nocturia is expected. Hypertonicity is not usually
present if the patient has an intact thirst mechanism and can increase water intake to keep
up with urinary loss.
Chapter 2
l Endocrinology
Normal
1400
1200
1000
800
osm
U
600
400
200
0
P
osm
Figure 2-5. P
Diagnosis. The water deprivation test compares U
versus U
osm
during Dehydration in Normal Subjects
osm
after dehydration versus U
osm
osm
after
vasopressin. In a normal person, the response to fluid restriction is to increase urine osmolality and decrease urine volume. In DI, the urine volume remains high despite volume depletion. ADH levels will be low in central DI and high in nephrogenic DI. If they fall to the right
of the shaded area, the patient has DI (see Figure 2-5).
17
USMLE Step 2 CK
● Internal Medicine
Giving
ADH
NDI
Urine volume
Central DI
Normal
Serum osmolarity
Figure 2-6. Water Restriction Test
Differential Diagnosis. The differential diagnosis of DI includes primary disorders of water
intake (psychogenic polydipsia, drug-induced polydipsia from chlorpromazine, anticholinergic drugs, or thioridazine) and hypothalamic diseases.
Management. The management for central DI includes hormone replacement with vasopressin subcutaneously or desmopressin subcutaneously, orally, or intranasally. Some drugs can be
used that stimulate the secretion of ADH or increase release (chlorpropamide, clofibrate, or
carbamazepine).
For nephrogenic DI, HCTZ or amiloride may be used, which enhances the reabsorption of
fluid from the proximal tubule. Chlorthalidone is effective as well. Abnormalities of calcium
and potassium should be corrected as well.
Syndromes Associated with Vasopressin (ADH) Excess
Syndromes associated with ADH excess involve a mechanism of defense against hypovolemia
or hypotension. This includes adrenal insufficiency, excessive fluid loss, fluid deprivation, and
probably positive-pressure respiration.
Excessive release of ADH from the neurohypophysis is associated with drugs or diseases
(SIADH).
Syndrome of Inappropriate Secretion of ADH (SIADH)
Etiology. The etiology of SIADH includes malignancies such as small cell carcinomas, carcinoma
of the pancreas, and ectopic ADH secretion. Nonmalignant pulmonary diseases such as TB,
pneumonia, and lung abscess can also lead to SIADH. CNS disorders including head injury,
cerebral vascular accident, and encephalitis are other etiologies. Drugs such as chlorpropamide,
clofibrate, vincristine, vinblastine, cyclophosphamide, and carbamazepine can induce SIADH.
18
Clinical Findings. In general, increased ADH causes water retention and extracellular fluid
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volume expansion without edema or hypertension, owing to natriuresis. The water retention
and sodium loss both cause hyponatremia, which is a key feature in SIADH. Hyponatremia
and concentrated urine (U
>300 mOsm) are seen, as well as no signs of edema or dehydra-
osm
tion. When hyponatremia is severe (sodium <120 mOsm), or acute in onset, symptoms of
cerebral edema become prominent (irritability, confusion, seizures, and coma).
Diagnosis. Laboratory findings in diagnosis of SIADH include hyponatremia <130 mEq/L,
and P
<270 mOsm/kg. Other findings are urine sodium concentration >20 mEq/L (inap-
osm
propriate natriuresis), maintained hypervolemia, suppression of renin–angiotensin system,
and no equal concentration of atrial natriuretic peptide. Low blood urea nitrate (BUN), low
creatinine, low serum uric acid, and low albumin will also be seen.
Management. Management of SIADH involves treating underlying causes when possible. Fluid
restriction to 800–1,000 mL/d should be obtained to increase serum sodium. Demeclocycline
can be used in chronic situations when fluid restrictions are difficult to maintain.
Demeclocycline inhibits ADH action at the collecting duct (V2). Conivaptan and tolvaptan are
V2 receptor blockers indicated for moderate to severe SIADH. For very symptomatic patients
(severe confusion, convulsions, or coma), hypertonic saline (3%) 200–300 mL intravenously in
3–4 h should be used. The rate of correction should be between 0.5–1 mmol/L/h of serum Na.
Chapter 2
l Endocrinology
DISEASES OF THE THYROID GLAND
Generalities. The normal function of the thyroid gland is directed toward the secretion of
l-thyroxine (T
processes.
Diseases of the thyroid could be quantitative or qualitative alterations in hormone secretion,
enlargement of thyroid (goiter), or both. Insufficient hormone secretion results in hypothyroidism; excess secretion results in hyperthyroidism. Focal enlargement of the thyroid can be
associated with tumors (benign or malignant). Generalized enlargement can be associated with
increased, normal, or decreased function of the gland depending on the underlying cause.
Laboratory Tests in Thyroid Disease. The most sensitive test in thyroid diseases is the TSH.
If the TSH is normal, then the patient is euthyroid.
Total T4 and T3 do not always reflect actual thyroid function. For example, increased TBG lev-
els are seen in pregnancy and the use of oral contraceptives. This will increase total T4 but free
or active T
of androgens. This will decrease total T4 but free or active T4 level is normal with the patient
being euthyroid.
) and l-3,5,5′-triiodothyronine (T3), which influence a diversity of metabolic
4
level is normal. Decreased TBG levels are seen in nephrotic syndrome and the use
4
Clinical Pearl
Always check free T4 to assess
thyroid function.
19
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