Download Methodical pointing for students on the topic “Chronic adrenal

SE"Dnipropetrovsk Medical Academy of the Ministry of Health of Ukraine"
Approved by
At the meeting of the Department
of Endocrinology
Protocol # 1
01/09/2015
INTERNAL MEDICINE: Module 1
Content module 1 "Foundations of diagnosis, treatment and prevention of
major endocrine diseases"
Methodological development for students IV year course
for the Practical Class on:
«Diseases of Hypothalamus and Pituitary, disturbances of body height.
Diseases of sexual glands. Concluding session: Differential test.».
Specialities: 7.12010001 "Medicine"
Dnipropetrovsk – 2015
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Methodical pointing for students on the topic «Diseases of Hypothalamus and
Pituitary, disturbances of body height. Diseases of sexual glands. Concluding session:
Differential test»
Amount of hours: 7.
Place of: educational room, hospital units.
I. Purpose: to study methods of diagnosis and treatment of patients with Cushing's
disease, hypopituitarism, diabetes insipidus, acromegaly, hyperprolactinemia, obesity,
growth and sexual disorders.
II. Professional orientation of students.
The hypothalamus and pituitary gland form a unit that exerts control over the
function of several endocrine glands—thyroid, adrenals, and gonads—as well as a wide
range of physiologic activities. This unit constitutes a paradigm of neuroendocrinology—
brain-endocrine interactions. The actions and interactions of the endocrine and nervous
systems, whereby the nervous system regulates the endocrine system and endocrine
activity modulates the activity of the central nervous system, constitute the major
regulatory mechanisms for virtually all physiologic activities. Somatic displays of a
pituitary pathology are various, has a catastrophic character in case of acute development
needs to precise and resolute actions for saving patient`s life.
III. Base level of knowledges and abilities.
A student must know:
1. Structure, location of the hypothalamus and pituitary glands, sexual glands, function of
hormones, their methods of investigation.
2. Mechanism of interaction between hypothalamic-pituitary hormones and hormones of
other endocrine glands.
3. Pathogenesis of hypothalamic-pituitary disorders.
4. Carbohydrate, lipid and protein metabolism in case of hypothalamic-pituitary disorders.
5. The influence of different endocrine disorders upon one another.
6. Genetic peculiarities of pituitary and gonads pathology.
A student must be able:
1. Recognize the clinical symptoms of hypothalamus and pituitary disease.
2. Identify basic pathological syndromes.
3. To examine heart, lungs, abdomen, peripheral vessels, endocrine glands in patients.
3. Interpret laboratory data, results of determination of tropic hormones.
4. Implement differential diagnosis.
5. Make plan for laboratory and instrumental investigations, treatment plan.
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IV. PREAPEARING program of students:
1. Etiology and pathogenesis of the following diseases: Cushing's disease, hypopituitarism,
diabetes insipidus, acromegaly, hyperprolactinemia, obesity, growth and sexual disorders.
2. Classification of the following diseases: Cushing's disease, hypopituitarism, diabetes
insipidus, acromegaly, hyperprolactinemia, obesity, growth and sexual disorders.
3. Clinical features of diseases: Cushing's disease, hypopituitarism, diabetes insipidus,
acromegaly, hyperprolactinemia, obesity, growth and sexual disorders.
4. Diagnosis, differential diagnosis of diseases: Cushing's disease, hypopituitarism,
diabetes insipidus, acromegaly, hyperprolactinemia, obesity, growth and sexual disorders.
5. Treatment algorithm of Cushing's disease, hypopituitarism, diabetes insipidus,
acromegaly, hyperprolactinemia, obesity, growth and sexual disorders.
6. Principles of hormonal replacement therapy of diabetes insipidus.
7. Surgical treatment of Cushing's disease, acromegaly, bariatric obesity surgary.
V. Short maintenance of theme
Hypopituitarism
Pituitary adenomas are the most common cause of hypopituitarism, but other
causes include parasellar diseases, pituitary surgery, radiation therapy,
inflammatory and granulomatous diseases, and head injury. The sequential loss of
pituitary hormones secondary to a mass effect is in the following order: growth
hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH),
thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and
prolactin. Isolated deficiencies of various anterior pituitary hormones can occur. In
general, pituitary microadenomas are rarely associated with hypopituitarism.
Diabetes insipidus is almost never seen in patients with pituitary adenomas at
presentation.
Somatotropin (Growth Hormone) Deficiency
The symptoms of GH deficiency in adults are subtle, consisting of decreased
muscle strength and exercise tolerance and reduced sense of well-being (e.g.,
diminished libido, social isolation). Patients with GH deficiency have increased
body fat and decreased lean body mass, and they might have decreased bone
mineral density.
Random measurements of GH and gender- and age-adjusted insulin-like growth
factor-1 (IGF-1) levels are not reliable to diagnose GH deficiency because GH
secretion is pulsatile, and up to 65% of patients with GH deficiency have a normal
IGF-1 level. Therefore, GH deficiency is best evaluated by dynamic testing,
including the insulin tolerance test or GH-releasing hormone (RH)/arginine test.3
Gonadotropin Deficiency
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In reproductive-aged women, gonadotropin deficiency causes infertility and
oligomenorrhea or amenorrhea. It is often associated with lack of libido, hot
flushes, and dyspareunia. In men, hypogonadism is diagnosed less often, because
decreased libido and impotence may be considered functions of aging.
Hypogonadism is often diagnosed retrospectively in men and postmenopausal
women when patients present with mass effect. Osteopenia is a consequence of
long-standing hypogonadism and responds to hormone replacement therapy.
Gonadotropin deficiency is diagnosed in the presence of low or normal LH and
FSH levels in postmenopausal women, in reproductive-aged women with
amenorrhea, or in men with low testosterone levels (<200 ng/dL). Measurement of
gonadotropin and estradiol levels in reproductive-aged women with irregular
menstruation is usually not informative. The presence of normal menstruation is
the best indicator of the integrity of the gonadotropin axis in women of
reproductive age.
Testosterone may be replaced by intramuscular injection, transdermal patch, or a
gel. Oral testosterone is not recommended because of the potential risk for liver
toxicity. The serum prostate-specific antigen (PSA) level, hematocrit, and lipid
profile should be monitored in men during testosterone replacement therapy.
Estrogen replacement is necessary in hypogonadal women of reproductive age to
prevent osteoporosis and to treat hot flushes, decreased libido, and vaginal dryness.
Corticotropin Deficiency
Patients with ACTH deficiency maintain their mineralocorticoid secretion because
aldosterone is regulated primarily by the renin-angiotensin system and serum
potassium concentration. Symptoms usually include chronic malaise, fatigue,
anorexia, low-grade fever, and hypoglycemia. Patients might present with
hyponatremia, which is secondary to inappropriate ADH secretion.
An ACTH stimulation test and early morning (8 am) plasma cortisol level
measurement are reasonable initial tests for evaluating the corticotropin axis. An
early morning cortisol level lower than 3 μg/dL confirms adrenal insufficiency,
and a level higher than 15 μg/dL makes the diagnosis highly unlikely. Cortisol
levels in the range of 3 to 15 μg/dL are indeterminate and should be further
evaluated by the cosyntropin stimulation test (CST), which can be performed at
any time during the day. The standard-dose CST uses an IV or intramuscular
injection of 250 μg cosyntropin, and plasma cortisol levels determined before and
30 minutes after the injection. A normal response is a plasma cortisol concentration
higher than 18 μg/dL at 30 minutes. Patients with mild partial or recent-onset
pituitary ACTH or hypothalamic corticotropin-releasing hormone (CRH)
deficiency (e.g., within 2 to 4 weeks after pituitary surgery) may have a normal
response to 250 μg CST because the adrenal glands have not undergone sufficient
atrophy and still respond to very high concentrations of ACTH stimulation.
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The suggested replacement regimen is 15 to 20 mg hydrocortisone/day, usually
given in two or three divided doses, with the highest dose given in the morning.
Patients should be instructed to carry a medical alert, double their replacement
dosage for 2 to 3 days in case of an acute disease, and should be covered by stress
doses of hydrocortisone if undergoing surgery.
Thyrotropin Deficiency
The symptoms of thyrotropin (TSH) deficiency are similar to those in patients with
primary hypothyroidism, including malaise, fatigue, leg cramps, dry skin, and cold
intolerance.
The diagnosis cannot be established only through measurement of TSH because
these patients might have a normal TSH level. For this reason, if secondary
hypothyroidism is clinically suspected, TSH and free thyroxine (T 4) should be
measured together. Usually, patients have a low or normal TSH level along with a
low free T4 level.
Therapy for TSH deficiency is similar to that for primary hypothyroidism. The
levothyroxine replacement dose should be adjusted according to the patient’s
clinical status and free T4 and free triiodothyronine (T3) levels, but not TSH. In
general, one should try to keep the free T4 level in the upper normal range while
the free T3 level stays in the normal range. It is important to evaluate the
corticotropin axis before initiating levothyroxine replacement, because therapy in
those with underlying undiagnosed ACTH deficiency can result in an
adrenocortical crisis secondary to an increase in metabolic demand.
Excess Pituitary Hormone Secretion
Prolactinomas
Figure 3: Click to Enlarge
Prolactinomas are pituitary adenomas that secret prolactin in varying degrees and
account for about 30% of all pituitary adenomas. They are seen in all age groups
but are more common in women, with a peak incidence during the childbearing
years.
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Clinical features of prolactinomas may be related to excess prolactin and
associated secondary hypogonadism or mass effect. Women of reproductive age
mainly present with oligomenorrhea, amenorrhea, galactorrhea, or infertility. Men
and postmenopausal women usually come to medical attention because of mass
effect, such as headaches and visual field defects. All patients with
macroprolactinomas and most patients with microprolactinomas require treatment.
Some indications for treatment of patients with microprolactinomas include
bothersome galactorrhea, oligomenorrhea or amenorrhea, infertility, and sexual
dysfunction.
Hyperprolactinemia can be physiologic or pathologic (Box 1). Pregnancy should
always be ruled out. Biochemical analysis to evaluate renal and hepatic function
and the TSH determination should be carried out. The drug history is an important
part of the initial evaluation, because some medications are associated with
hyperprolactinemia and their discontinuation for at least 3 days, if possible, will
prevent any further and often expensive workup (Fig. 3). The majority of patients
with a serum prolactin level above 100 μg/L have prolactinoma. A serum prolactin
level lower than 100 μg/L in the presence of a large pituitary adenoma suggests
stalk compression.
Box 1 Differential Diagnosis of Hyperprolactinemia
Physiologic considerations
Pregnancy, postpartum, suckling, stress, intercourse, exercise
Pituitary disorders
Prolactinomas, mixed pituitary tumors, pituitary tumors or disorders with stalk
effect
Hypothalamic, stalk disorder
Aneurysm, inflammatory or granulomatous disease, tumors such as
craniopharyngioma and meningioma, metastasis, trauma, radiotherapy
Drugs
Neuroleptics, metoclopramide, verapamil, methyldopa, reserpine, opiates, cocaine
Tricyclic antidepressants, monoamine oxidase inhibitors, some selective serotonin
reuptake inhibitors (SSRIs)
Estrogen, antiandrogens
Systemic Diseases
Hypothyroidism
Chronic renal failure
Cirrhosis
Neurogenic factors
Chest wall disorders
Spinal nerve or cord lesion
Seizures
Ectopic factors
Hypernephroma
Gonadoblastoma
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Ovarian teratomas
Idiopathic
Mostly secondary to a small microprolactinoma not identified by magnetic
resonance imaging
Dopamine agonists are the therapy of choice for most patients, and they are
effective in decreasing adenoma size and restoring normal prolactin level in most
patients. Dopamine agonists usually restore visual field defects to an extent similar
to surgery. Therefore, visual field defects associated with prolactinomas are not a
neurosurgical emergency. Cabergoline and bromocriptine are potent inhibitors of
PRL secretion and often cause tumor shrinkage. Dopamine agonists should be
initiated slowly, because side effects often occur at the beginning of treatment. The
most common side effects include nausea, headache, dizziness, nasal congestion,
and constipation. Bromocriptine is the drug of choice in women planning
pregnancy because there is considerable worldwide experience with the drug.
Cabergoline is more potent, may be taken only twice a week, and is better tolerated
by most patients. Few reports associate high-dose cabergoline with valvular heart
disease in patients with Parkinson’s disease, but risk seems to be insignificant with
the doses used for treatment of prolactinoma.5-6 Surgery is reserved for patients
who are intolerant of or refractory to medical therapy. Radiation therapy may be
considered for patients who poorly tolerate dopamine agonists and cannot be cured
by surgery.
Acromegaly
Figure 4: Click to Enlarge
Acromegaly is a rare disease caused by a GH-secreting pituitary adenoma in more
than 99% of patients. At diagnosis, about 75% of patients have macroadenomas.
The mean age at diagnosis is about 45 years. Clinical features of acromegaly may
be related to excess GH or IGF-1 or to associated mass effect including
hypopituitarism, because most patients present with pituitary macroadenomas (Box
2 and Fig. 4). Excess growth hormone before the fusion of the epiphyseal growth
plates results in gigantism. Acromegalic patients probably carry an increased risk
of malignancy such as premalignant adenomatous colon polyps and colon cancer,
although published data vary greatly in their findings.
Box 2 Clinical Features of Patients with Acromegaly
Acral enlargement
Arthralgias, neuropathic joints
Carpal tunnel syndrome
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Coarsening of facial features
Excessive sweating
Goiter
Hypertension, congestive heart failure, arrhythmias
Impaired glucose tolerance, diabetes mellitus
Macroglossia
Malocclusion and tooth gaps
Pituitary mass effect, including headache and visual field defect
Pituitary insufficiency
Sensory and motor peripheral neuropathies
Snoring, sleep apnea
Symptoms associated with hyperprolactinemia
Thick and coarse skin, skin tags
Figure 5: Click to Enlarge
Figure 6: Click to Enlarge
Figure 7: Click to Enlarge
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Because of the pulsatile nature of GH secretion, random GH levels can overlap in
acromegalic patients and normal persons. IGF-1 has a longer plasma half-life than
GH and is the best single test for the diagnosing acromegaly (Fig. 5). Acromegaly
is associated with increased morbidity and mortality if untreated. The goal of
therapy for most patients is to achieve a normal sex- and age-adjusted IGF-1 and
GH less than 2 ng/mL.
Surgery is the treatment of choice for most patients presenting with acromegaly
even if a cure cannot be achieved. Even a subtotal resection of the tumor will
improve the efficacy of subsequent adjuvant therapy. Medical treatment of
acromegaly has gained significance since the limitations of radiation and surgical
therapy have become evident. Somatostatin analogues inhibit GH secretion mainly
by binding to somatostatin receptors and result in normalization of IGF-1 in up to
65% of patients. The most common side effects are gastrointestinal, including
diarrhea, abdominal pain, and nausea. Gallbladder sludge and cholelithiasis have
been reported in up to 25% of patients on long-term therapy with somatostatin
analogues, but most patients were asymptomatic. Dopamine agonists have variable
efficacy in patients with acromegaly but may be an attractive first-line therapy,
especially in those with cosecretion of prolactin and GH. Pegvisomant has higher
affinity to GH receptors than native GH but inhibits its dimerization, which is
necessary for the action of GH. It is administered once daily and is usually
reserved for patients not responding to other medical therapies. It is very effective,
normalizing IGF-1 in up to 95% of patients. The tumor size and liver function need
to be monitored during therapy. During therapy with pegvisomant, IGF-1 is used to
monitor therapy. Radiotherapy is reserved for patients who cannot be cured by
surgery and do not respond to or tolerate medical therapy.
Cushing’s Disease
Cushing’s syndrome (CS) comprises symptoms and signs associated with
prolonged exposure to inappropriately high levels of plasma free glucocorticoids
(Box 3). Exogenous glucocorticoid intake is the most common cause of CS. The
endogenous causes are divided into ACTH-dependent and ACTH-independent CS
(Box 4). In contrast to pale striae that occur postpartum or with weight gain, the
striae in CS are usually red-purple, more than 1 cm wide, and located on the
abdomen, upper thighs, breasts, and arms (Fig. 6). Increased skin pigmentation is
rare and only occurs in the ectopic ACTH syndrome. Supraclavicular and
dorsocervical fat pads (buffalo hump) and moon face are nonspecific and are seen
in many patients of obesity clinics. Women complain of menstrual irregularity
(84%) and hirsutism (especially vellous hypertrichosis of the face), and men and
women exhibit loss of libido (≤100%). Psychiatric abnormalities occur in 50% of
patients, with agitated depression and lethargy being the most common
manifestations. A high clinical suspicion, attention to suggestive clinical features
(see Box 3), and an appropriate screening test are the keys to early diagnosis of CS
(Fig. 7). Because of the challenging nature of diagnosing CS, it is important to
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follow a stepwise evaluation, know the limitations of each test, and avoid
shortcuts.
Box 3 Clinical Features Suggesting Cushing’s Syndrome
Central obesity
Unexplained osteoporosis
Proximal myopathy
Wide purplish striae (>1 cm)
Facial plethora
Spontaneous bruising
Hypokalemia
Serial photographs
Box 4 Causes of Endogenous Cushing’s Syndrome
ACTH-Dependent Cushing’s Syndrome
Cushing’s disease (67%)
Ectopic ACTH secretion (12%)
Ectopic CRH secretion (<1%)
ACTH-Independent Cushing’s Syndrome
Adrenal adenoma (10%)
Adrenal carcinoma (8%)
Micro- and macronodular adrenal hyperplasia (1%)
ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.
Pseudo-Cushing’s disease refers to features of CS along with some evidence of
hypercortisolism that resolve after resolution of the underlying cause, such as
chronic alcoholism, psychiatric disorders (e.g., major depression, anxiety disorder,
obsessive-compulsive disorder), anorexia nervosa, morbid obesity, and poorly
controlled diabetes. Cyclic CS is characterized by periods of excess alternating
with intervals of normal or decreased cortisol production, which occurs in some
patients with CS.
Surgical removal of the ACTH-secreting pituitary tumor is the treatment of
choice.10 Availability of an experienced neurosurgeon is crucial, and the long-term
remission rate is about 60 to 80% following surgery. A low (<3 μg/dL) or
undetectable postoperative cortisol level off glucocorticoids is considered to be a
good marker for long-term cure. For those not cured by the surgery, other options
include reoperation and radiotherapy. Bilateral adrenalectomy is reserved for those
who continue to be hypercortisolemic. Medical therapy for Cushing’s syndrome
has limited value because of the associated toxicity and gradual decrease in
efficacy. Among the available agents, ketoconazole is the most commonly used.
During therapy, liver function tests need to be closely monitored.
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Diabetes Insipidus
Diabetes insipidus (DI) is characterized by the chronic excretion of abnormally
large volumes (>50 mL/kg) of dilute urine. The true prevalence of DI is unknown,
but it is usually underdiagnosed because the symptoms and signs are benign and
many patients ignore them or are unaware of them. There are four major types of
DI: central (neurogenic) DI, nephrogenic DI, primary polydipsia, and gestational
DI. Central DI is secondary to inadequate ADH secretion that is insufficient to
concentrate the urine.
Diabetes insipidus by itself is usually well tolerated and results in few symptoms,
including polydipsia and polyuria. Nocturia of a large urine volume is often the
primary reason for which patients seek medical attention. In most patients, DI is
not associated with any abnormality on the physical examination or routine
laboratory evaluation, except a low urine osmolality. Overt disturbances in fluid
and electrolytes are uncommon unless other factors interfere with the normal
compensatory mechanism of polydipsia, such as loss of consciousness.
Once diabetes mellitus and hypercalcemia have been excluded, patients should
have their 24-hour urinary volume measured during ad libitum fluid intake. DI is
diagnosed in those with abnormally high urinary output (>50 mL/kg/day), low
urinary osmolality (<300 mOsm/kg), and an appropriate creatinine excretion (1418 mg/kg body weight) as an indicator of an accurate 24-hour urine collection.14
Measurement of spot urine osmolality is usually unreliable to exclude or diagnose
DI, because it may be decreased significantly in an otherwise healthy person who
drinks large amounts of water and can be increased to normal by fasting in a
patient with partial DI. Patients with DI who are conscious usually have sufficient
thirst to maintain a normal serum sodium level in spite of polyuria. Once the
diagnosis has been established, the next step is to differentiate the type of DI. A
water deprivation test may need to be performed by an experienced endocrinologist
to differentiate among types of partial DI.
The therapy of choice for central DI is the administration of the ADH analogue
desmopressin (DDAVP). It is available in a subcutaneous form or as an oral or
nasal spray. The spray or oral form of desmopressin is usually started at bedtime
and is gradually titrated for the desired antidiuretic effect.
VI. Materials for assessment in the last stage of the lesson (situational cases)
Case 1. A 53-year-old woman who was transferred to hospital with complaints of
increase of body weight, muscular weakness, increase of blood pressure up to
180/100 mmhg.
The patient's height and body weight were 162 cm and 94.5 kg. The patient
presented with moon face, central obesity, and pigmentation and atrophy of the
skin. No neurological deficits were observed, including in the visual field.
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Endocrinological studies performed during the patient's first admission showed
that the basal ACTH and cortisol levels were elevated to 110 pg/mL and 21.3
g/dL, and urinary free cortisol was also elevated to 267 g/d. In the 2-mg
dexamethasone suppression test, no inhibitory effect was observed, but an
inhibitory effect was observed with 8 mg of dexamethasone. The patient's MRI at
the time of admission showed a low-density mass in the left lobe of the pituitary
gland with slight pituitary stalk deviation to the right.
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What is the most credible diagnosis?
Chronic adrenal insuficiency
Hyperaldosteronism
*Cushing`s disease
Pheochromocytoma
Hyperthyroidism
Case 2. A 32-year-old woman presents with a history of acne, oily skin, and mild
hirsutism and was found by her dermatologist to have elevated testosterone levels.
The patient also complains of excessive sweating and some gradual enlargement of
her hands and feet, such that she recently had to resize a ring that she has worn for
years. Her menstrual cycles have become more irregular and she has developed
breastmilk production. Upon further questioning, she states that she has started to
snore and occasionally has a headache upon awakening. She reports no history of
diabetes, hypertension, joint pain, or change in vision.
The physical examination woman has prognathism. She is normotensive.
Visual fields are intact to confrontation. Significant soft tissue thickening and
diaphoresis of the hands and feet are noted. There is mild facial hirsutism; no
acanthosis nigricans or significant skin tags are noted. The remainder of the
examination is normal.
Laboratory evaluation in the fasting state reveals an IGF-1 (epidermal
growth factor) of 963 ng/mL (138-410) and a random GH (growth hormone) of
19.3 ng/mL (< 2.5). Prolactin and glucose levels are normal. Pituitary MRI scan
reveals a macroadenoma with cavernous sinus invasion; the optic chiasm is not
affected by the tumor.
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What is the most credible diagnosis?
*Acromegaly
Prolactinoma
Cushing`s disease
Pheochromocytoma
Empty sella turcica syndrome
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VII. Information sources:
1. Contemporary Aspects of Endocrinology / A. Diamanti – Kandarakis. – 2011. –
478p.
2. Eear Book of Endocrinology / M. Schott. – 2012. – 408 p.
3. Hot topics in Endocrine and Related Disease / M. Fedele. – 2013. – 274 p.
4. Williams Textbook of Endocrinology, 12th Edition / S. Melted, K. Polonsky, P. Reed
Larsen / 2012. – 1920 p.
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