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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
l Internal Medicine
of the CNS, leading to dizziness, headache, clouding vision, blunted mental activity, loss of fine
motor skills, confusion, abnormal behavior, convulsions, and loss of consciousness. There is no
uniform correlation between a given level of blood sugar and symptoms. Major symptoms in
normal persons may not be seen until blood sugar is 20 mg/dL.
Classification. Postprandial hypoglycemia (reactive) can be secondary to alimentary hyperinsulinism (after gastrectomy, gastrojejunostomy, pyloroplasty, or vagotomy), idiopathic, and
galactosemia.
Fasting hypoglycemia can result from conditions in which there is an underproduction of glucose, such as hormone deficiencies (panhypopituitarism, adrenal insufficiency), enzyme defects,
substrate deficiency (severe malnutrition, late pregnancy), acquired liver disease, or drugs (alcohol, propanolol, salicylates). Fasting hypoglycemia can also occur in conditions related to overutilization of glucose such as hyperinsulinism. Hyperinsulinism can occur secondary to insulinoma,
exogenous insulin, sulfonylureas, drugs (quinine), endotoxic shock, and immune disease with
insulin receptor antibodies. Overutilization of glucose can also occur in states in which there are
appropriate insulin levels, such as extrapancreatic tumors and rare enzyme deficiencies.
Insulinoma (pancreatic B-cell tumor) can cause hypoglycemia. Ninety percent of these tumors
are single and benign. Clinical findings include symptoms of subacute or chronic hypoglycemia such as blurred vision, headache, feelings of detachment, slurred speech, and weakness.
Symptoms occur in the early morning or late afternoon or after fasting or exercise.
Diagnosis. This is made by finding a serum insulin level ≥8 mg/mL in the presence of blood
glucose <40 mg/dL (i.e., inappropriately high serum insulin level when glucose is low), noted
either spontaneously or during a prolonged fast (72 hours). CT scan, U/S, and arteriography
may also be useful in detecting the tumor(s). Management of insulinoma is by surgery, diet,
and medical therapy.
Factitious hyperinsulinism is caused by self-administration of insulin or ingestion of Equal or
oral sulfonylureas. It is common and exceeds the incidence of insulinomas. Most often, these
patients are associated with the health professions or have access to these drugs by a diabetic
member of the family. A triad of hypoglycemia, high immunoreactivity, insulin, and suppressed
plasma C peptide is pathognomonic of exogenous insulin administration.
Ethanol-induced hypoglycemia can also occur with prolonged starvation, when glycogen
reserves become depleted in 18–24 hours and hepatic glucose output depends completely on
gluconeogenesis. Ethanol at a concentration of 45 mg/dL can induce hypoglycemia by blocking
gluconeogenesis.
Table 2-6. Differential Diagnosis of Insulinoma and Factitious Hyperinsulinism
Test Insulinoma Exogenous Insulin Sulfonylureas
Plasma insulin High (usually
<200 µU/mL)
Proinsulin Increased Normal or low Normal
Very high (usually
>1,000 µU/mL)
High
40
C peptide (insulin
connective peptide) 1:1
Insulin antibodies Absent +/– Present Absent
Plasma or urine
sulfonylurea
Increased Normal or low Increased
Absent Absent Present
DISEASES OF THE ADRENAL GLAND
Figure 2-13. Adrenal Cortex Regions
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The adrenal gland is divided into 2 areas, the cortex and medulla. The cortex is divided into 3
areas, the outer zone (glomerulosa), which is the site of aldosterone synthesis; the central zone
(fasciculata), which is the site of cortisol synthesis; and the inner zone (reticularis), which
is the site of androgen biosynthesis. The disorders of hyperfunction of the gland are associated with the following specific hormones: increased cortisol is seen in Cushing syndrome;
increased aldosterone in hyperaldosteronism; and increased adrenal androgens with virilization in women.
Region Hormones Controlled by
+
Capsule
Zona Aldosterone Angiotensin II, [K
Glomerulosa
Zona
Fasciculata Cortisol
and ACTH
]
Chapter 2
l Endocrinology
Zona Androgens
Reticularis
(LH has no effect on the production
of adrenal androgens)
Medulla Epinephrine Autonomic Nervous
System
Hyperfunctioning of the Gland
Cushing syndrome
Definition. A group of clinical abnormalities caused by prolonged exposure to increased
amounts of cortisol or related corticosteroids.
Etiology. Exogenous, iatrogenic causes are the most common overall causes of Cushing syndrome and can be secondary to prolonged use of glucocorticoids.
The etiology of Cushing syndrome includes adrenal hyperplasia. This can be secondary to
pituitary ACTH production, which occurs in pituitary-hypothalamic dysfunction, and pituitary ACTH-producing adenomas (microadenoma, e.g., Cushing disease). ACTH-producing
pituitary adenomas cause about 60–80% of Cushing cases. Adrenal hyperplasia can also be
secondary to ACTH or corticotropin-releasing hormone (CRH), produced by nonendocrine
tumors (bronchogenic carcinoma, carcinoma of the thymus, pancreatic carcinoma, and
bronchial adenoma). Adrenal neoplasia, such as adenoma or carcinoma, and adrenal nodular hyperplasia account for about 30% of Cushing cases. Excessive cortisol production by
an autonomous adrenal results in a low ACTH level. About 15% of Cushing cases are from
ACTH from a source that cannot be located.
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USMLE Step 2 CK
l Internal Medicine
Clinical Findings. The clinical findings of Cushing syndrome include deposition of adipose
tissue in characteristic sites such as upper fat, moon facies; interscapular buffalo hump; and
mesenteric bed, truncal obesity. Other clinical findings include hypertension, muscle weakness,
and fatigability related to mobilization of peripheral supportive tissue; osteoporosis caused
by increased bone catabolism; cutaneous striae; and easy bruisability. Women may have acne,
hirsutism, and oligomenorrhea or amenorrhea resulting from the increased adrenal androgen
secretion. Emotional changes range from irritability or emotional lability to severe depression
or confusion; even psychosis can occur as well. Glucose intolerance is common in Cushing disease, with 20% of patients having diabetes.
Cushing and glucocorticoid use are also associated with hypokalemia and leukocytosis.
Hypokalemia occurs because of the mineralocorticoid effect of the steroids.
Clinically significant hypokalemia is uncommon.
Other manifestations are delayed wound healing, renal calculi from increased calcium levels,
and glaucoma. Polyuria is from hyperglycemia. There is increased susceptibility to infections
because neutrophils exhibit diminished function because of high glucocorticoid levels.
Diagnosis. The diagnostic tests used to establish the syndrome of cortisol excess are the 1-mg
overnight dexamethasone suppression test and the 24-hour urine-free cortisol. The tests
used to establish a precise etiology of the cortisol excess are the ACTH level, high-dose dexamethasone suppression test, CT and MRI scanning, and occasionally sampling of the petrosal
venous sinus, which drains out of the pituitary.
The 1-mg overnight dexamethasone suppression test is used to rule out the diagnosis of Cushing
syndrome or glucocorticoid excess. If you give a milligram of dexamethasone at 11 p.m., the
cortisol level at 8 a.m. should come to normal if there is the normal ability to suppress ACTH
production over several hours. The problem with this test is that there can be falsely abnormal or
positive tests. Any drug that increases the metabolic breakdown of dexamethasone will prevent its
ability to suppress cortisol levels. Examples of drugs increasing the metabolism of dexamethasone
are phenytoin, carbamazepine, and rifampin. Stress increases glucocorticoid levels. The 1-mg
overnight dexamethasone suppression test can be falsely positive in stressful conditions such as
starvation, anorexia, bulimia, alcohol withdrawal, or depression.
An abnormality on the 1-mg overnight test should be confirmed with a 24-hour urine-free
cortisol. The 24-hour urine-free cortisol is more accurate and is the gold standard for confirming or excluding Cushing’s syndrome.
A third screening test for Cushing is the midnight salivary cortisol. In normal patients, cortisol
is at its lowest at midnight. In Cushing patients, cortisol is abnormally elevated at midnight.
The precise etiology of the Cushing syndrome is established by using ACTH levels, sometimes
in combination with high-dose dexamethasone suppression testing. ACTH levels are elevated
with either a pituitary source of ACTH such as an adenoma or with an ectopic source. Highdose dexamethasone suppression testing can distinguish the difference. The output of a pituitary adenoma will suppress with high-dose dexamethasone. The output of an ectopic source
will not suppress with high-dose dexamethasone.
If the ACTH level is low, then the etiology is most likely from an adrenal tumor such as
an adenoma, cancer, or from adrenal hyperplasia. When the adrenal gland is the source of
increased cortisol production, there is feedback inhibition on the pituitary and the ACTH
level is suppressed.
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When there is a low ACTH level, the precise etiology is confirmed with a CT scan of the adrenals.
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When there is a high ACTH level, the precise etiology is confirmed with an MRI of the pituitary looking for an adenoma or a CT scan of the chest looking for an ectopic focus. If neither
of these show a lesion or the MRI of the brain is equivocal, then inferior petrosal sinus sampling should be done to see if there is increased ACTH coming out of the brain.
Single random cortisol levels are not reliable.
• High plasma ACTH levels = pituitary or ectopic source
• Low plasma ACTH levels = adrenal tumors or hyperplasia
Management. Depends on the etiology, and can be surgical or medical. Unresectable adrenal
tumors are treated with ketoconazole or metyrapone.
Chapter 2
l Endocrinology
43
USMLE Step 2 CK
Figure 2-14. Evaluating a Patient with Presumed Cushing Syndrome
l Internal Medicine
Clinical suspicion
Osteoporosis
Central adiposity
Diabetes mellitus
Hirsutism amenorrhea
Overnight dexamethasone
suppression test
Abnormal
(can be seen in obese,
alcoholic or depressed
individuals [false ])
24-hour urine-free
cortisol
Abnormal
test
Cushing syndrome
Dexamethasone suppression
test (high dose)
+
Normal
test
Normal
No
Cushing
No
Cushing
Suppression to
<50% control
Pituitary adenoma
(Cushing disease)
MRI pituitary
Adrenal lesions:
hyperplasia,
adenoma, neoplasia
CT/MRI adrenals
No response
• ACTH-producing tumor
• Adrenal neoplasia
ACTH level
HighLow
Adrenal hyperplasia due
to ACTH-producing tumor (lung)
CT chest
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Hyperaldosteronism
Figure 2-15. Mechanism of Hyperaldosteronism
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Hyperaldosteronism is a syndrome associated with hypersecretion of the major adrenal mineralocorticoid, aldosterone. The normal function of aldosterone is to reabsorb sodium and
excrete potassium and acid (H+). Hyperaldosteronism can be divided into the following:
• Primary aldosteronism, in which the stimulus for the excessive aldosterone production is within the adrenal gland
• Secondary aldosteronism, in which the stimulus is extraadrenal
The most common cause of primary hyperaldosteronism is a unilateral adrenal adenoma
(70%). Bilateral hyperplasia accounts for 25–30%. Excessive black licorice ingestion can
mimic this effect. Licorice has aldosterone-like qualities.
Chapter 2
l Endocrinology
Primary Aldosteronism
↑
Intravascular
volume
↑
Na+ retention
↑
Aldosterone
production
Initiating event
Clinical. Primary hyperaldosteronism is characterized by hypertension and low potassium
levels. Most of the other symptoms, such as muscle weakness, polyuria, and polydipsia, are
from the hypokalemia. Metabolic alkalosis occurs because aldosterone increases hydrogen ion
(H+) excretion. Aldosterone causes alkalosis. Edema is uncommon with primary hyperaldosteronism because of sodium release into the urine.
↓
Renin
–
Secondary Aldosteronism
Initiating event
↓
Intravascular
volume
↑
Na+ retention
↑
Aldosterone
production
↑
Renin
Table 2-7. Clinical and Laboratory Findings in Primary and Secondary Aldosteronism
Primary Aldosteronism Secondary Aldosteronism
Diastolic hypertension + –
Muscle weakness + +/–
Polyuria, polydipsia + +/–
Edema – +/–
Hypokalemia + +
Hypernatremia + –
Metabolic alkalosis + +
45
USMLE Step 2 CK
l Internal Medicine
Diagnosis. The preliminary screen for hyperaldosteronism is a plasma aldosterone concentration (PAC) and plasma renin activity (PRA). A positive screen is a PAC/PRA ratio >20:1 and a
PAC >15. To confirm hyperaldosteronism, an NaCl challenge is required. This can be via normal saline, NaCl tabs, or fludrocortisone. After an NaCl challenge, PAC should be suppressed
as in a normal individual. If PAC is still elevated, this confirms the diagnosis.
Management. Adrenal adenomas are removed surgically. Bilateral hyperplasia is treated with
spironolactone, which blocks aldosterone.
Bartter Syndrome. The exception of secondary hyperaldosteronism without edema or hypertension is Bartter syndrome. Bartter syndrome is caused by a defect in the loop of Henle in
which it loses NaCl. This is due to a defect in the Na-K-2Cl cotransporter. This is like having a
furosemide-secreting tumor.
In Bartter syndrome there is juxtaglomerular hyperplasia, normal to low blood pressure, no
edema, severe hypokalemic alkalosis, defect in renal conservation of sodium or chloride, and
renal loss of sodium, which stimulates renin secretion and aldosterone production.
Syndromes of adrenal androgen excess
Syndromes of adrenal androgen excess result from excess production of dehydroepiandrosterone (DHEA), and androstenedione, which are converted to testosterone in extraglandular
tissues. The elevated testosterone accounts for most androgenic effects.
Note
The ‘biphasic’ presentation
is rare. When you think
about 11 deficiency,
think mineralocorticoid
excess (hypertension and
hypokalemia) with low cortisol
production (remember you
need C-11 for the final step in
converting to cortisol).
Clinical Signs and Symptoms. Hirsutism, oligomenorrhea, acne, and virilization. Etiology
includes congenital adrenal hyperplasia, adrenal adenomas (rare), and adrenal carcinomas.
Congenital adrenal hyperplasia (CAH)
Definition. Congenital adrenal hyperplasia is a syndrome associated with increased adrenal
androgen production because of enzymatic defects.
Etiology. CAH is the most common adrenal disorder of infancy and childhood. CAH arises
from autosomal recessive mutations, which produce deficiencies of enzymes necessary for the
synthesis of cortisol.
Common Enzymatic Defects Associated with CAH. Enzymatic defects include C-21 hydroxylase deficiency in 95% of all cases. C-21 hydroxylase deficiency is associated with reduction
in aldosterone secretion in one-third of patients. Adrenal virilization occurs with or without
an associated salt-losing tendency, owing to aldosterone deficiency, which leads to hyponatremia, hyperkalemia, dehydration, and hypotension.
Patients are female at birth with ambiguous external genitalia (female pseudohermaphrodism), enlarged clitoris, and partial or complete fusion of the labia. Postnatally CAH is associated with virilization. Patients may be male at birth with macrogenitosomia; postnatally this is
associated with precocious puberty.
C-11 hydroxylase deficiency can also occur. The mineralocorticoid manifestations in C-11
deficiency can be ‘biphasic.’ In early infancy, despite having excessive mineralocorticoid hormones, patients sometimes present with relative ‘salt wasting’ (aldosterone deficiency). This
is because some infants have inefficient salt conservation as well as immature aldosterone
production. During this phase, infants can present with hypotension and hyperkalemia (very
similar to 21 hydroxylase deficiency). Later in life (childhood and adulthood), there is better
46
ability to hold onto salt, so the patient develops the typical C-11 deficiency syndrome: hyper-
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tension and hypokalemia.
C-17 hydroxylase deficiency can occur as well, and is characterized by hypogonadism, hypokalemia, and hypertension resulting from increased production of 11-deoxycorticosterone.
Diagnosis. CAH should be considered in all infants exhibiting failure to thrive, especially
those with episodes of acute adrenal insufficiency, salt wasting, or hypertension. The most
useful measurements are of serum testosterone, androstenedione, dehydroepiandrosterone,
17-hydroxyprogesterone, urinary 17-ketosteroid, and pregnanetriol.
Management. Treatment is glucocorticoid (hydrocortisone) replacement.
Hypofunctioning of the Gland
Adrenal insufficiency
Definition. Adrenal insufficiency can be divided into primary adrenocorticoid insufficiency
(Addison disease) and secondary failure in the elaboration of ACTH. Primary adrenocortical
insufficiency is a slow, usually progressive disease due to adrenocorticoid hypofunction.
Chapter 2
l Endocrinology
Etiology. The etiology of Addison disease can be secondary to anatomic destruction of
the gland (chronic and acute). Idiopathic atrophy is the most common cause of anatomic
destruction, and autoimmune mechanisms are probably responsible. Autoimmune destruction accounts for 80% of cases. Anatomic destruction can also be secondary to surgical
removal, infection (TB, fungal, cytomegalovirus), hemorrhagic, trauma, and metastatic invasion. Metabolic failure in hormone production can also lead to Addison disease and can be
secondary to CAH, enzyme inhibitors, and cytotoxic agents (mitotane).
Clinical Findings. The clinical findings in Addison disease include weakness, paresthesias,
cramping, intolerance to stress, and personality changes such as irritability and restlessness. Chronic disease is characterized by a small heart, weight loss, and sparse axillary hair.
Hyperpigmentation of the skin can occur and appears as diffuse brown, tan, or bronze darkening of both exposed and unexposed body parts. Arterial hypotension is seen and is often
orthostatic owing to lack of effect of cortisol on vascular tone. Abnormalities of GI function
are found, and symptoms vary from mild anorexia with weight loss to nausea, vomiting, diarrhea, and abdominal pain. Acute Addisonian crisis is characterized by fever and hypotension.
A low sodium with a high potassium level and mild acidosis are also present.
Diagnosis. The diagnosis of Addison disease is made through rapid ACTH administration
and measurement of cortisol. Laboratory findings include white blood cell count with moderate neutropenia, lymphocytosis, and eosinophilia; elevated serum potassium and urea nitrogen; low sodium; low blood glucose; and morning low plasma cortisol.
The definitive diagnosis is the cosyntropin or ACTH stimulation test. A cortisol level is
obtained before and after administering ACTH. A normal person should show a brisk rise in
cortisol level after ACTH administration.
Differences between primary and secondary adrenal insufficiency:
•
Hyperpigmentation (occurs only with primary insufficiency)
• Electrolyte abnormalities
• Hypotension
47
USMLE Step 2 CK
l Internal Medicine
Signs and Symptoms
• Weakness
• Hypotension
• Weight loss
• Hyperpigmentation
Screening Test
Plasma cortisol 30–60 minutes after 250 µg cosyntropin IM or IV
Subnormal response
Primary
High ACTH
Subnormal aldosterone increment
Primary adrenal insufficiency
Figure 2-16. Diagnosis of Adrenal Insufficiency
Normal aldosterone increment
Secondary adrenal insufficiency
Secondary
Low ACTH
Management. The management of Addison disease involves glucocorticoid, mineralocorticoid, and sodium chloride replacement, in addition to patient education.
Adrenal Crisis. In an adrenal crisis, fever, vomiting, abdominal pain, altered mental status, and vascular collapse may occur. Get a cortisol level, then rapidly administer fluids and
hydrocortisone. This may occur in:
• Previously undiagnosed patient with adrenal insufficiency who has undergone surgery, serious infection, and/or major stress
• Bilateral adrenal infarction or hemorrhage
• Patient who is abruptly withdrawn from chronic glucocorticoid therapy
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Pheochromocytoma
Definition. A rare, usually benign, tumor that arises from the chromaffin cells of the sympathetic nervous system. The rule of 10% applies in pheochromocytoma with 10% being
extraadrenal, 10% malignant, 10% in children, and 10% bilateral or multiple (>right side).
Also, 10% are not associated with hypertension.
Epidemiology. Pheochromocytoma occurs in approximately 0.1% of the hypertensive pop-
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ulation. Familial pheochromocytoma occurs in 5% of cases, and is transmitted as an autosomal dominant trait alone or in combination with MEN type II or III, von Recklinghausen
neurofibromatosis, or von Hippel-Lindau retinal cerebellar hemangioblastomatosis.
Pathology. In adults, 80% of pheochromocytomas occur as a unilateral solitary lesion with
10% being bilateral and 10% extraadrenal. In children, 25% of the tumors are bilateral and
25% are extraadrenal. Solitary lesions favor the right side. Extraadrenal pheochromocytomas
are mostly located within the abdomen and near the celiac, superior mesenteric, and inferior
mesenteric ganglia.
Catecholamine Secretion. Secretion of dopamine occurs more in familial syndromes and is
not associated with hypertension. Epinephrine secretion causes tachycardia, sweating, flushing, and hypertension. Norepinephrine is secreted by all extraadrenal tumors.
Clinical Findings. Clinical findings of pheochromocytoma include paroxysms or crisis. This
accounts for the typical manifestations occurring in >50% of patients. The attack has a sudden onset, lasting from a few minutes to several hours or longer. Headache, profuse sweating,
palpitations, and apprehension are common in this setting. Pain in the chest or abdomen may
be associated with nausea and vomiting. Blood pressure is elevated with tachycardia in crisis.
Forty percent of patients have blood pressure elevation only during the attack, and 60% have
stable hypertension. Anxiety, tremor, and weight loss are also found.
Chapter 2
l Endocrinology
>33% of pheochromocytomas cause death prior to diagnosis; death is often due to cardiac
arrhythmia and stroke.
Other clinical features include orthostatic hypotension and glucose intolerance. The hyperglycemia is only found in about 33% of patients and is mild.
Diagnosis. Diagnosis is established by demonstrating increased amounts of catecholamines
or catecholamine metabolites in a 24-hour urine collection. Urinary-free catecholamines,
urinary metanephrines, vanillylmandelic acid, and plasma catecholamines are tests of choice.
Metanephrines are catecholamine metabolites. A 24-hour urinary VMA, metanephrines, and
free catecholamines are the best initial tests. Recently, plasma metanephrine levels have been
used in conjunction with urinary tests. Overall, metanephrines are the most sensitive and specific individual test. Smoking can increase plasma-free metanephrines. The patient must not
smoke at least 4 hours before the test.
Clonidine should suppress epinephrine levels. Failure of epinephrine levels to fall after clonidine administration is highly suggestive of pheochromocytoma. A clonidine-suppression test
is used when the above screening tests are equivocal.
When the catecholamine or metanephrine levels are abnormal, the tumor is confirmed with
CT or MRI scan. MIBG (metaiodobenzylguanidine) scanning is used to locate a pheochromocytoma not found on a CT scan. If the biochemical tests (catecholamines, metanephrines)
are positive and the CT scan does not show the location of the pheochromocytoma, then do
an MIBG scan.
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