ADRENOCORTICAL INSUFFICIENCY

1
ADRENOCORTICAL INSUFFICIENCY
2
THE ADRENALCORTEXBASIS CONCEPTS
3
ADRENOCORTICAL HISTOLOGY

• The adrenal cortex is composed of three
  concentric zones with distinct steroid
  biosynthetic capacities.
• Zona glomerulosa biosynthesis of
  mineralocorticoids
• Zona fasciculata biosynthesis of
  glucocorticoids
• Zona reticularis biosynthesis of adrenal
  androgens.

4
STEROID BIOSYNTHESIS

• Steroidogenesis results from specific sequential
  enzymatic conversions of cholesterol substrate
  into steroid hormones, which exert a wide variety
  of biological activities.

5
STEROID BIOSYNTHESIS

• A series of steroidogenic enzymes are
  compartmentalized either in the mitochondria or
  in the endoplastic reticulum.
• Several of these enzymes belong to the
  superfamily of mixed function oxidase enzymes
  known as
• cytochrome P450.

6
STEROID BIOSYNTHESIS

• Approximately 80 of adrenal cholesterol sources
  are provided by circulating low density
  lipoprotein (LDL).
• The adrenal cells can also synthesize cholesterol
  de novo from acetyl coenzyme A.

7
STEROID BIOSYNTHESIS

• The first rate-limiting step in steroidogenesis
  involves the removal of six carbons from the
  lateral chain of cholesterol by integral inner
  mitochondrial membrane P450 side chain cleavage
  (CYP11A1) enzyme to generate pregnenolone.

8
Nomenclature for steroidogenic enzymes now
utilized
Trivial name Past Current
Cholesterol side-chain cleavage enzyme desmolase P450scc CYP11A1
3ß-Hydroxysteroid dehydrogenase 3ß-HSD 3ß-HSD
17a-Hydroxylase/17,20-lyase P450c17 CYP17
21-Hydroxylase P450c21 CYP21A2
11ß-Hydroxylase P450c11 CYP11B1
Aldosterone synthase corticosterone 18-methylcorticosterone oxidase/lyase P450C11AS CYP11B2
9
Main steroid biosynthetic pathways
(mineralocorticoids and glucocorticoids).
CYP17
cholesterol
17,20-lyase
17a-hydroxylase
CYP11A1
17aOH-pregnenolone
pregnenolone
3ß-HSD II
17a OH-progesterone
progesterone
CYP21A2
11-deoxycorticosterone (DOC)
11-deoxycortisol (S)
CYP11B2
ZONA GLOMERULOSA
CYP11B1
11ß-hydroxylase
ZONA FASTICULATA
corticosterone (B)
18-hydroxylase
18OH-corticosterone
CORTISOL (F)
18-methyloxidase
ALDOSTERONE
10
Main steroid biosynthetic pathways (adernal
androgens).
cholesterol
CYP17
17ß-HSD
17a- hydroxylase
17,20-lyase
CYP11A1
Dehydro-epiandrosterone (DHEA)
17aOH- pregnenolone
Androstendiol
pregnenolone
3ß-HSD II
17a OH- progesterone
progesterone
?4-androstendione
testosterone
CYP19
estrone
estradiol
ZONA RETICULARIS
11
REGULATION OF GLUCOCORTICOID SECRETION

• The secretion of cortisol is regulated by several
  levels of signals and interactions between the
  brain, the hypothalamus, the pituitary, and the
  adrenal glands.

12
Regulation of the hypothalamic-pituitary-adrenal
axis.
Cicardian rhythms Feeding cycles
stress
HIGHER BRAIN CENTERS

Neurotransmitters neuropeptides

HYPOTHALAMUS
cytocines
-
-
CRH-AVP
PITUITARY GLAND
ACTH
ADRENAL CORTEX
CBG
Cortisol-CBG
-
-


Free-cortisol
-
-
cytokines
Inflammatry agents
PERIPHERIAL TISSUES
13
CORTICOTROPIN-RELEASING HORMONE(CRH)

• ?
• 41-aminoacid peptide synthesized by neurons in
  the paraventricular hypothalamic nucleus
• Action
• ?
• mRNA levels of pro-opiomelanocortin (POMC),
• the polypeptide precursor of ACTH

14
ADRENOCORTICOTROPIC HORMONE ACTH

• ?
• 39-aminoacid peptide capable of stimulating
  secretion of glucocorticoids, androgenic
  steroids, and to a lesser extent of
  mineralocorticoids from the adrenal cortex.
• In human ACTH stimulates melanin synthesis in
  skin melanocytes.

15
ADRENOCORTICOTROPIC HORMONE ACTH

• The acute effect of ACTH
• ?
• activation exisiting CYP11A1 to convert
  cholesterol to pregnenolone

• The chronic effects of ACTH
• ?
• increase in gene trascription of most of the
  steroidogenic enzymes
• (CYP11A1, CYP17, CYP21A2, CYP11B1)

16

• IN THE CHRONIC ABSENCE OF ACTH , THE ADRENAL
  CORTEX BECOMES ATROPHIC.

17
Glucocorticoid negative feedback.

• Glucocorticoids inhibit the release and synthesis
  of ACTH primarily by decreasing POMC gene
  transcription in pituitary corticotroph cells.
• Glucocorticoids inhibit the production and
  secretion of CRH and vasopressin in hypothalamic
  paraventricular nuclei.

18
ADRENOCORTICALINSUFFICIENCY

• Impairment of the adrenal production of
  glucocorticoids (cortisol) and mineralocorticoids
  (aldosterone) leads to a life-threatening
  situation that is often misinterpreted and
  neglected.

19
ADRENOCORTICAL INSUFFICIENCY

• PRIMARY
• (Addisons disease)
• damage of the adrenal glands

• SECONDARY
• inadequate ACTH and/or CRH secretion

20
BOTH PRIMARY AND SECONDARY ADRENAL INSUFFICIENCY
ARE RARE DISEASES.

• The prevalence of acquired primary insufficiency
  is estimated at 39 to 60 cases per 1 million
  people, with most the cases being diagnosed in
  the third to fifth decade of life.

21

• Iatrogenic adrenal insufficiency, secundary to
  exogenous glucocorticoid therapy, includes large
  number of patients and implies similar risks of
  acute adrenal crisis.

22

• Congenital adrenal hyperplasia (CAH) is a family
  of inborn errors of steroidogenesis, primarily
  characterized by a specific enzyme deficiency
  that impairs cortisol production by the adrenal
  cortex.
• Complete and near-complete blocks of the
  21-hydroxylase enzyme (classical form of CAH)
  occurs in 1 in 15 000 live births worlwide.

23
ADRENOCORTICAL INSUFFICIENCY

• For most cases of adrenal insufficiency,
  impairment of hormonal production can take place
  over the course of many years, and the clinical
  picture is insidiously dominated by the features
  of the disorder.

24
CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY

• Autoimmune adrenalitis (80)
• Infectoius adrenalitis
• tuberculosis (20)
• histioplasmosis, paracoccidioidomycosis,
  blastomycosis, coccidioidomycosis, cryptococcosis
• Invasive destruction
• metastases
• lymphoma
• amyloidosis, sarcoidosis

25
CAUSES OF PRIMARY ADRENOCORTICAL INSUFFICIENCY

• AIDS (infectious or invasive destruction)
• Adrenal hemorrhage
• Iatrogenic (mitotane, ketoconazole,
  aminoglutethimide, metyrapone, etomidate,
  surgery)
• Congenital and familiar
• Adrenoleukodystrophy
• Adrenal hypoplasia
• Familial glucocorticoid deficiency

26
AUTOIMMUNE ADRENALITIS

• The most common cause of Addisons disease.
• Humoral and cellular immunity are both involved.
• Antibodies to the adrenal cortex are detected in
  up to 70 of idiopathic insufficiences
• they inhibit adrenal steroidogenesis in vitro,
  and some of them are directed against enzymes of
  steroidogenesis.

27
AUTOIMMUNE ADRENALITIS

• Lymphocytic infiltration of the adrenals
• ?
• gradual destruction of cortical cells and their
  replacement by fibrotic tissue.

28
AUTOIMMUNE ADRENALITIS

• In 50 of the cases
• ?
• association to other autoimmune endocrine or
  nonendocrine disorders
• ?
• polyglandular autoimmune syndromes

29
POLYGLADULAR AUTOIMMUNE SYNDROME

• Type I
• Often familial, inhereted in an autosomal
  recessive pattern
• First manifestation hypoparathyroidism and/or
  mucocutaneous candidiasis occurring during
  childhood
• Addisons disease develops in 60 of the cases
  during adolescence.

• Type II
• The more frequent
• Familial in half of the cases
• Occurs mostly between 20 and 40 years of age
• It often develops in a sequence
• Insulin type 1
• Graves disease
• Addisons disease
• Hypoparathyroidism and candidiasis are absent

30
INFECTIOUS ADRENALITIS

• Adrenal tuberculosis is the second-most common
  cause of Addisons disease in most countries
  (20).
• The adrenal gland are completely destroyed,
  including the medulla.
• ?
• caseous necrosis
• ?
• fibrosis

31
INFECTIOUS ADRENALITIS

• Disseminated fungal infections can destroy the
  adrenal glands
• ?
• histoplasmosis
• paracoccidioidomycosis
• South American blastomycosis
• Syphilis has also become a rare cause.

32
INVASIVE DESTRUCTION OF ADRENALS

• Metastatic involvement of the adrenals
• ?
• lung cancer
• breast cancer
• stomach cancer
• colon cancer
• melanoma
• Hodgkin and non-Hodgkin lymphoma
• Amyloidosis and sarcoidosis are rare invasive
  causes.

33
ACQUIRED IMMUNE DEFICIENCY SYNDROME

• Patients with AIDS may have adrenal insufficiency
  through multiple mechanism
• Infection by cytomegalovirus, tuberculosis,
  mycobacterium avium-intracellulare,
  toxoplasmosis, cryptococcosis
• Invasion by Kaposis sarcoma and lymphoma
• Drugs (ketoconazole, rifampin, phenytoin)
• Symptoms and signs of Addisons disease may be
  mistaken and imputed to AIDS itself.

34
IATROGENIC ADRENAL DEFICIENCY

• Iatrogenic adrenal deficiency is a predicted
  situation in medically treated Cushingsyndrome.
• mitotane ? blocks the synthesis of
  corticosteroids and induces necrosis of the
  adrenal cortex
• aminoglutethimide, metyrapone, ketoconazole ?
  reversibly inhibit several steps of
  steroidogenesis.
• Barbiturans, rifampin, phenytoin increases
  cortisol metabolism
• ?
• they may precipitate acute crisis in cases
  undiagnosed adrenal insufficiency.

35
ADRENAL HEMORRHAGE

• Adrenal hemorrage is a cause of rapid and total
  destruction of adrenal glands, leading to acute
  adrenal insufficiency.
• In adults ? patients on anticoagulant therapy
  usually after 50 years of age
• In patients with severe, often life-threatening
  illnesses (infection with sepsis, burns, major
  surgery, complicated pregnancy, trauma, severe
  cardiovascular disease, acute renal disease).
• In children ? meningococcal or pseudomonas
  septicemia
• In neonates ? after complicated delivery.

36
CONGENITAL AND FAMILIAL ETIOLOGIES

• Adrenoleukodystrophy
• defective oxidation of very long chain fatty
  acids (VLCFA) in peroxisomes
• ?
• accumulation of VLCFA in central and peripheral
  nervous tissue, adrenals, gonads, and other
  organs.

37
CONGENITAL AND FAMILIAL ETIOLOGIES

• Adrenal hypoplasia
• Adrenal failure shortly after birth
• ?
• impaired development of the adult adrenal cortex

38
CONGENITAL AND FAMILIAL ETIOLOGIES

• Familial glucocorticoid deficiency
• Rare autosomal recessive disorder
• ?
• unresponsiveness to ACTH
• (mutation of the ACTH receptor gene)

39
ADRENOCORTICAL INSUFFICIENCY-PATHOPHYSIOLOGY

• Glucocorticoids deficiency
• ?
• decreased sense of well-being
• hypoglycemia
• gastrointestinal disturbances
• water retention
• reduced vascular adrenergic tone
• The decreased negative feedback by cortisol
• ?
• increased synthesis and secretion of ACTH and
  other POMC-derived peptides

40
ADRENOCORTICAL INSUFFICIENCY-PATHOPHYSIOLOGY

• mineralocorticoid deficiency
• ?
• increased sodium renal loss ? hyponatremia
• increased renal retention of potassium and
  hydrogen ions ? hyperkaliemia and acidosis
• Adrenal androgen deficiency
• ?
• decrease in axillary and pubic hair and libido
  (in women)

41
ADRENOCORTICAL INSUFFICIENCY-PATHOPHYSIOLOGY

• In most cases the loss of adrenal function is
  progressive.
• Symptoms and signs appear when more than 90 of
  the glands are destroyed.
• Before that point, the increased ACTH and renin
  maximally stimulate remaining cortical tissue

no sufficient increase in response to stress
normal basal amounts of glucocorticoids and
mineralocorticoids
42

• During transient state of partial steroid
  deficiency or decreased adrenal reserve, an acute
  crisis may be precipitated by surgery, trauma or
  infection.

43
ADRENOCORTICAL INSUFFICIENCY-CLINICAL FINDINGS

• The clinical features of Addisons disease are
  often misleading and may go unnoticed for months.
• Most of the symptoms and signs taken separately
  are non-specific.

44
Clinical and laboratory features of chronic
primary adrenal insufficiency

• Weakness, malaise
• depression, lack of initiative, impairment of
  memory
• dizziness, postural hypotension, postural syncope
• myalgias, arthralgias
• anorexia, salt craving, weight loss
• hyperpigmentation
• hyponatremia, hyperkaliemia, azotemia
• eosinophilia, lymphocytosis, normochromic anemia
• hypoglycemia
• ammenorrhea with decreased axillary and pubic
  hair in women
• loss of libido in both sexes

45
ADRENOCORTICAL INSUFFICIENCY-CLINICAL FINDINGS

• Weakness, fatigue, malaise
• ?
• constant complaints.
• Weakness occurs for usual, routine tasks and
  improves with rest, and it is frequently
  associated with myalgias and arthalgias.

46
ADRENOCORTICAL INSUFFICIENCY-CLINICAL FINDINGS

• Postural dizziness or (less often) syncope,
• postural hypotension with tachycardia
• ?
• are observed.
• The existence of systolic hypertension is a
  strong indication to exclude the diagnosis of
  adrenal insufficiency (moreover, spontaneous
  improvement of pre-existing hypertension is
  reported).

47
ADRENOCORTICAL INSUFFICIENCY-CLINICAL FINDINGS

• Gastrointestinal symptoms
• ?
• are common.
• Anorexia (with weight loss) is almost constantly
  found among patients.
• Salt craving, an increased thirst for iced
  liquids
• ?
• are reported

48
ADRENOCORTICAL INSUFFICIENCY-CLINICAL FINDINGS

• Spontaneous hypoglycemia
• ?
• is common in infants and children
• (infrequent in adults)
• It may be precipitated by infection, fever, or
  alcohol ingestion.

49
ADRENOCORTICAL INSUFFICIENCY-CLINICAL FINDINGS

• hyperpigmentation
• ?
• is a highly specific sign of chronic primary
  adrenal insufficiency.
• Vitiligo may coexist with hyperpigmentation in10
  of patients with autoimmune Addisons disease.

50
ADRENOCORTICAL INSUFFICIENCY-DIAGNOSTIC
PROCEDURES

• The routine laboratory findings
• Hyponatremia
• Hyperkaliemia
• Mild acidosis
• Fasting blood glucose usually low to normal
• Mild elevation of urea and creatinine (secondary
  to dehydratation)
• Moderate eosinophilia, lymphocytosis,
  normochromic anemia
• Elevations of hepatic transaminases
• Mild hypercalcemia

51
ADRENOCORTICAL INSUFFICIENCY-DIAGNOSTIC
PROCEDURES

• The diagnosis is confirmed by the rapid ACTH
  stimulation test.
• This test can be done at any time of the day,
  since, in contrast to the circadian rhythm of
  basal cortisol, the stimulated cortisol
  concentration is independent of the time of day.

52
Diagnostic approach to primary and secondary
adrenal insufficiency
CONCOMITANT
Baseline plasma ACTH
IN EARLY MORNING
Rapid ACTH stimulation test
Abnormal ACTH stimulation test
Normal ACTH stimulation test
High plasma ACTH
ADRENAL INSUFFICIENCY
Metyrapone or insulin test
High plasma ACTH
Low or normal plasma ACTH
INCIPIENT PRIMARY ADRENAL INSUFFICIENCY(rare)
Abnormal
Normal
PRIMARY ADRENAL INSUFFICIENCY
SECUNDARY ADRENAL INSUFFICIENCY
NORMAL HYPOTHALAMIC PITUITARY ADRENAL AXIS
53
ADRENOCORTICAL INSUFFICIENCY-DIAGNOSTIC
PROCEDURES

• Aldosterone concentration is low, non-responsive
  to ACTH or to the upright position, and is
  associated with high renin activity.
• Adrenal androgens (dehydroepiandrosterone,
  dehydroepiandrosterone sulfate, and androsterone)
  are low.

54
ADRENOCORTICAL INSUFFICIENCY-DIAGNOSTIC
PROCEDURES

• Adrenal CT scan should be perfomed.
• If bilateral adrenal enlargement is observed,
  futher evaluation is indicated to determine the
  specific cause (tuberculosis, other granulomatous
  diseases, metastatic cancer, or hemorrhage).

55
ADRENOCORTICAL INSUFFICIENCY-DIAGNOSTIC
PROCEDURES

• Adrenal autoantibodies positive
• ?
• autoimmune adrenalitis
• ?
• (evaluation of presence of other autoimmune
  diseases)

56
ADRENOCORTICAL INSUFFICIENCY-TREATMENT

• Treatment for chronic primary adrenal
  insufficiency includes
• substitutions for both glucocorticoid and
  mineralocorticoid function.

57
ADRENOCORTICAL INSUFFICIENCY-TREATMENT

• The evaluation of glucocorticoid replacement is
  based on clinical judgement of a patients
  subjective feeling, and the aim of treatment
  should be to administrate the smallest dose to
  keeps the patients well-being at a normal level.
  
• Mineralocorticoid adequacy is obtained when blood
  pressure, sodium, potassium, and plasma renin
  levels are normal without orthostatic hypotension
  and tachycardia.

58
ADRENOCORTICAL INSUFFICIENCY-TREATMENT

• Glucocorticoid doses must be doubled or tripled
  at the onset of minor illnesses for 24 or 48
  hours.
• Moderately stressful situations
• hydrocortisone i.v. (100 mg or more).
• In cases of severe illness or trauma, patients
  should be treated as in acute adrenal
  insufficiency.

59
SECONDARY ADRENAL INSUFFICIENCY

• Causes of secondary adrenal insufficiency
• Long-term glucocorticoid administration
• Selective cure of Cushings syndrome
• Pituitary adenomas
• Metastatic tumors
• Lymphocytic hypophisitis
• Sarcoidosis, histiocytosis
• Sheehans syndrome
• Pituitary surgery, radiotherapy
• Isolated ACTH deficiency

60
SECONDARY ADRENAL INSUFFICIENCY

• Clinical findings
• The clinical presentation of secondary adrenal
  insufficiency is similar to those suffering from
  Addisons disease, with the excepition of absent
  hyperpigmentation.
• Dehydratation, and hyperkalemia are usually
  absent.

61
SECONDARY ADRENAL INSUFFICIENCY

• Diagnostic procedures
• Abnormal cortisol response to ACTH stimulation
  test (70)
• normal or subnormal plasma ACTH levels

62
SECONDARY ADRENAL INSUFFICIENCY

• Diagnostic procedures
• In 30 of cases ? normal cortisol response to
  ACTH stimulation test
• ?
• Metyrapone test or insulin-induced hypoglycemia
  test
• subnormal responce
• normal or low ACTH levels

63
SECONDARY ADRENAL INSUFFICIENCY

• Treatment
• Treatment for chronic secondary adrenal
  insufficiency is similar to that of primary
  deficiency, except that mineralocorticoids are
  seldom necessary.

64
ACUTE ADRENAL INSUFFICIENCY

• Acute adrenal insufficiency is a medical
  emergency that is too often misdiagnosed.
• It may occur in a patient with known and treated
  adrenal insufficiency, in the presence of a
  stressfull situation if
• the dose of glucocorticoid treatment has not been
  appropriately increased,
• or the patients cannot retain medication because
  of vomiting.

65
ACUTE ADRENAL INSUFFICIENCY

• Acute adrenal insufficiency develops rapidly
• (not days but hours).
• Symptoms and signs
• gastrointestinal symptoms
• fever
• Hypotension
• hyponatremia, hyperkaliemia, lymphocytosis, and
  eosinophilia

66
ACUTE ADRENAL INSUFFICIENCY

• Gastrointestinal symptoms
• anorexia
• nausea
• vomiting
• abdominal pain
• ?
• mimics an acute surgical abdomen

67
ACUTE ADRENAL INSUFFICIENCY

• Fever is commonly associated

Hypoadrenalism itself
infection
68
ACUTE ADRENAL INSUFFICIENCY

• Hypotension may develop into
• hypovolemic shock with apathy and confusion.

69
ACUTE ADRENAL INSUFFICIENCY

• In the previously undiagnosed patient, clinical
  features are highly misleading.
• The presence of hyperpigmentation (primary
  adrenal disease) suggests the diagnosis.

70
ACUTE ADRENAL INSUFFICIENCY

• In the cause of adrenal hemorrhage causing acute
  destruction of the glands, the presenting
  features are abdominal or flank pain, in addition
  to rapidly developing signs of acute adrenal
  insufficiency
• (hiperpigmentation is absent).

71
ACUTE ADRENAL INSUFFICIENCY

• The confirmation of the diagnosis should not
  delay the institution of therapy.

72
ACUTE ADRENAL INSUFFICIENCY

• In the majority of cases, it is sufficient to
  obtain a plasma sample
• ?
• for assay of cortisol (and ACTH)

73
ACUTE ADRENAL INSUFFICIENCY

• If the plasma cortisol level is below
• 20 ?g/dl (SI0.56 ?mol/l)
• in the face of hypovolemia or shock
• ?
• the diagnosis is confirmed.

74
ACUTE ADRENAL INSUFFICIENCY

• A rapid (30-minute) ACTH stimulation test may be
  obtained,
• without delaying the appropriate therapy
• ?
• by use of dexamethasone as a starting
  glucocorticoid

75
ACUTE ADRENAL INSUFFICIENCYTREATMENT

• In the face of a strong clinical suspicion for
  acute adrenal insufficiency, blood is drown for
  the measurement of electrolytes, glucose,
  cortisol and (if possible) ACTH, and treatment is
  instituted immediately, without waiting for the
  results.

76
ACUTE ADRENAL INSUFFICIENCYTREATMENT

• Vigorous intravenous rehydration
• saline 0.9
• or 5 glucose in 0.9 saline
• ?
• e.g., 2 liters in 3 hours
• continued at a lower rate for the next 24 to 48
  hours

77
ACUTE ADRENAL INSUFFICIENCYTREATMENT

• Hydrocortisone iv 100 mg is injected as soon as
  possible, and given every 6 hours iv or imm at
  the same dose for the first 24 hours.
• Mineralocorticoids are not necessary.

78
ACUTE ADRENAL INSUFFICIENCYTREATMENT

• Any precipitating illness should be explored and
  appropriately treated.

79
ACUTE ADRENAL INSUFFICIENCYTREATMENT

• In the absence of complications, treatment can be
  tapered within 3 to 5 days and oral
  mineralocorticoids
• (9?-fluorocortisol 0.1 mg/day)
• are started when the patient is able to take food
  and when hydrocortisone has been decreased to
  less than 60 mg per day.