Transcript Adrenal failure

THE ADRENALS
ADRENAL CORTEX: is formed in the weeks V-VI:
Cells are derived from the cells derived from genital crest which will form
sterodegenetic cell from adrenal glands and gonads. They develop under
the control of genes SF- 1, DAX
ADRENAL MEDULLA: is of neuroectodermic origin
Fetal adrenal glands are formed of 3 zones:
“definitive” under the capsulla (it produces mineralocorticoids )
of transition ( glucocorticoids)
fetal zone has the most important area during fetal life and produces
androgens - DHEA-S which are transformed within e placenta into
estrogens
zona glomerulosa and fasciculata are completely formed at 3 years, and
zona reticularis at 15 years
Zona reticularis
Zona fasciculata
Zona glomerulosa
STERODOGENESIS IN THE ADRENAL CORTEX
•
Pattern of steroidogenesis
within the adrenal cortex
Glucocorticoid synthesis is produced into zona fasciculata
Cholesterol is converted into pregnenolone due to an enzyme that
produces the clivage of lateral chain of cholesterol and StAR –
steroidogenetic acute regulatory protein
1.Pregnenolone is transformed into 17 hydroxi-pregnenolone due to
enzyme 17 hydroxilase (C17)
2. 17 hydroxi-pregnenolone in transformed into 17
hyroxiprogesterone due to 3β hydroxysteroid dehydrogenase
3. 17 hyroxiprogesterone is transformed into 11 deoxy-cortisole by
21 hydroxilase
4.11 deoxy-cortisole is converted into cortisole by 11 β hydroxilase
Mineralocorticoid biosynthesis
1. Cholesterol is converted into pregnenolone due to an enzyme that
produces the clivage of lateral chain of cholesterol and StAR –
steroidogenetic acute regulatory protein
2. Pregnenolone is transformed into progesterone due to enzyme 3β
hydroxysteroid dehydrogenase
3. Progesterone is converted into deoxycorticosterone under the action
of 21 hydroxilase
4. Deoxycorticosterone is convertes into corticosterone due to 11 β
hydroxilase
5. Corticosterone is transformed into 18 hydroxi-corticosterone due to
18 hyroxilase (corticosterone methyl oxidase I)
6. 18 hydroxi-corticosterone is converted into aldosterone due to 18
hydrogenase (corticosterone methil oxidase II)
Steroid
Production rate
Carrier protein
Cortisole
8-25 mg/24 h
Corticosteroidbinding
3-10 %
Globulin (CBG)
Transcortin – 90 %
albumin
20-140 (F)
40-180 (M)
Aldosterone
DOC
0.15 mg/24 ore
0,6 mg /14 ore
Transcortin:
40 % aldo
20 % aldo and %24 % DOC
DOC
Albumin:
40 %aldo nd %DOC
0,15 - 0,17
0,15 – 0,17
DHEA
DHEA-S
Testosterone
0,7 mg /14 ore (F) SHBG
6-8 mg /24 ore
TeBG
0,23 mg/24 ore (F) Sex
hormone
binding globulin
Progesterone
Estradiol
(conversion
% free fraction
–
Transcortin
SHBG
Plasma circulation of adrenal steroids
Plasma concentration
ng/ml
5,34 ± 1,57
1130 (F), 1260 (M)
0,48 ± 0,14 (F)
5,59 ± 1,51 (B)
11,8 ± 7 (F)
0,18 ± 0,1 (M
Adrenal steroids metabolism
LIVER
CORTISOL E
CO RTISOLE
Kidney
CO RTISOLE
3 HDH
DIHY DROCO RTIZO LE
T ETRAHY DROCO RTIZO L
E
CO RTIZO NE
11 HDH
DIHY DROCO RTIZO NE
T ETRAHY DROCO RTIZO N
CO RTOLE
Free
ur inary
cor tisole
CO RTOLO NE
GLICURONID
TRANSFERASE
GLIC URO NOC O NJUGATI
URINE
17 OH -C S
Steroid receptor
1
2
NH2
COOH
Transactivational domain – regulates DNA tr nscr iption
DNA -binding domain – activates the transcr iption
DNA -binding domanin which is resposable for nuclear localisation of
ster oid receptor and dymer asation
Steroid receptors
Receptor
ligand
Other ligands for
the same
receptor
Receptor
antagonist
Main actions
Area or sterod
production
Glucocorticoid
corisolel
Corticosterone
Prednisone
DXM
RU 486
Intermediary
metabolism and
stress response
Yona fasciculata
and reticularis
Mineralocorticoid
Aldosterone
cortisole
DOC
Spironolactone
Na+ , K +
Zona
glomerulosa
Androgen
Dihydrotestoster
one
testosterone
Spironolactone
cyproterone
Sexual and
reprodcutive
action in man
Testisl
adrenal
Estrogens
Estradiol
Tamoxifen
SERM
Sexual and
reproductive
function in
women
Ovary, follicle,
placenta
Progesterone
progesterone
RU486
Sexual and
reproductive
function in
women
Ovary – yelow
body and
placenta
Vitamin D
1,25 di hidroxi
colecalciferole
Calcium
metabolism
kidney
Estrone
Estriole
GLUCOCORTICOD - ACTIONS
Tissue and controlled
metabolism
Liver glucose
metabolism
Periferal glucose
metabolism
Actions and implications
Increased neogluco geensis and l iv er response to othe stimulators
(catheco lamines and glu cagon )
Increased substrate fo r neoglu cogenesis f rom amino acids rezultin g
from protein catab olism and free fatty acids liberatio n
Decreased glucose uptake by tissues w ith secondary insulin
resistance
Fat metabolism
Increased ly polisis an free fatty acid liberation
Ly pogenesis due to increase d apetite and high insuli n lev els
Increased fat deposits in some areas of the body : face, thorax,
abdomen, upper part of the bo dy
Protein metabolism
Increased protein metabol ism
Inhibition of amino acid s uptake by tissues
Glucocorticoid actions
Tissue and metabolic
control
Growth
Actions and implication
S timulate grow th in phy siological con centratio ns
G lucocortico id excess prod uces catabo lic effct s, decreses G h, IGF 1, and inhibits g row th
G lucorticoid t reatment duri ng chil dhood may produce definitiv e
grow th deficiency
Erithropoesis
stimulation
Leucocytes
S timulation of neuthrophi ls liberat ion from bone marrow
Decreased circulat ing ly mphocy tes, macrophage migration and
inflamation
Incresed suscept ibility to infections i n endogenous o r exoge nous
glucoco rtico id exce ss
Immune system
Inhibition of all facto r inv olved in immune response: macro phage
migration, pros taglandin l iberation, ant igen presentat ion by
macrophages, antibo dy production, interle ukine 1,2, liberation,, in
gamma interferon,CSF , TNF, histamine, serotonine and bradikin ine
liberation.
GLUCOCORTICOID ACTIONS
CONTROLLED TISSUE
AND METABOLISM
ACTIONS AND IMPLICATIONS
CARDIOVASCULAR
SYSTEM
G lucocortico id excess may produce hy pertension
KIDNEY
Increased blood ci rculat ion in the kidney and glomerular filt ration
A ntagonism w ith v asopressin
CENTRAL NERVOUS
SYSTEM AND
BEHAVIOR
G lucocortico id deficie ncy produces phy sical and psy chological
tiredness
G lucocortico id excess prod uces eupho ria follow ed by depression
ENDOCRINE GLA NDS
F eed-back control in the sy stem C RH/ACTH
Thy roid: inhibit s TSH response to TRH and conv ersion of T4 in
T3
G onads: inhibits l LH and F H response to LH -Rh
decrease G H
A drenal medulla: stimulates N E and E by activ ating thy rosinhy droxilaze
OTHER ACTIONS
Increased gastri c acid secretion w ith peptic ul cer du ring hig h dose
glucoco rtico id treatment
Increased intra ey e pressure
Adrenal failure
Adrenal insufficiency is a disorder first described by Thomas
Addison in 1855, which is characterized by impaired
adrenocortical function and decreased production of
glucocorticoids, mineralocorticoids and/or adrenal
androgens.
Adrenal insufficiency can be caused by diseases affecting
the adrenal cortex (primary),
the pituitary gland and the secretion of adrenocorticotropic
hormone (ACTH) (secondary)
or the hypothalamus and the secretion of corticotropicreleasing hormone (CRH) (tertiary).
Adrenal insuficiency
TERTIARY - CRH
SECONDARY - ACTH
H
h
CHRONIC
ACUTE
PRIMARY :G-ALD-ANDRO
CSR
Primary – due to adrenal failure
Secondary – due to ACTH deficiency
Tertiary – due to CRH deficiency
Prevalence:
• 39-60 new cases in 1 million /year
• 60-70 % of cases are diagnosed between 30 – 50 de years
•Sex ratio : F/M = 1,25 /1 in tuberculosis si 2,6 - 3/1 in autoimmune adrenal failure
Primary
insufficiency
adrenal
Idiopathic
(autoimmune)
Tuberculosis
other (Miller si Tyrel,
Felig 1996)
Autoimmune
Tuberculosis
Other
Causes of adrenal
failure between
1928-1938
17
79
4
67 – 70
15
15
Causes of adrnal
failure between %
1962-1972
78
21
1
Causes of Primary Adrenal
Insufficiency
• The etiology of primary adrenal
insufficiency has changed over time. Prior
to 1920, the most common cause of
primary adrenal insufficiency was
tuberculosis, while since 1950, the
majority of cases have been ascribed to
autoimmune adrenalitis, either in isolation
or in the context of complex polyglandular
syndromes
Causes of Primary Adrenal
Insufficiency
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Autoimmune adrenalitis : This condition is the result of an autoimmune process that destroys
the adrenal cortex. Both humoral and cell-mediated immune mechanisms directed at the adrenal
cortex are involved. The adrenals appear small and atrophic and the surrounding capsule is
thickened. Antibodies that react with several steroidogenic enzymes, as well as all three zones of
the adrenal cortex are detected in 60-75% of patients with autoimmune primary adrenal
insufficiency, but only rarely in patients with other causes of adrenal insufficiency or normal
subjects
Causes of Primary Adrenal
Insufficiency
. Considerable progress has been made in identifying genetic factors that
predispose to the development of autoimmune adrenal insufficiency . In addition
to the well-known association of the HLA genotype DR3/4-DQB1*0302 with type
1 diabetes mellitus and adrenal insufficiency, a strong susceptibility for the latter
was also found for the DR3-DQ2/DRB1*0404-DQ8 genotype, which predicted
early onset of primary adrenal insufficiency
Approximately 50% of patients with autoimmune adrenal insufficiency have one
or more other autoimmune endocrine disorders, whereas patients with the more
common autoimmune endocrine disorders, such as type 1 diabetes mellitus,
chronic autoimmune thyroiditis, or Graves' disease, rarely develop adrenal
insufficiency. The combination of autoimmune adrenal insufficiency with other
autoimmune endocrine disorders is referred to as the polyglandular autoimmune
syndromes type I and II
Causes of Primary Adrenal
Insufficiency
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Primary Adrenal Insufficiency Autoimmune (polyglandular failure)
Tuberculosis
Sarcoidosis, amyloidosis, hemochromatosis
Hemorrhage (meningococcemia, anticoagulants, trauma)
Fungal infections
Metastatic neoplasia/infiltration
Congenital adrenal hyperplasia
Congenital adrenal hypoplasia hypoplasia drenalis congenita
Congenital unresponsiveness to ACTH (glucocorticoid deficiency, ACTH resistance)
Adrenoleukodystrophy/Adrenomieloneuropathy
Aquired immynodeficiency syndrome
Bilateral adrenalectomy
Steroid synthesis inhibitors (e.g., metyrapone, ketoconazole, aminoglutethimide)
Adrenolytic agents (o,p’DDD, suramin)
Glucocorticoid antagonists (RU 486)
Causes of secondary and tertiary
Adrenal Insufficiency
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Secondary and Tertiary Adrenal Insufficiency
Following discontinuation of exogenous glucocorticoids or ACTH
Following the cure of Cushing’s syndrome
Pituitary and hypothalamic lesions
Tumors
Inflammation
Infections
Autoimmune lesions
Granulomatios infilitration
Trauma
Congenital aplasia, hypoplasia, dysplasia, ectopy
Pituitary-hypothalamic surgery
Pituitary-hypothalamic radiation
Pituitary-hypothalamic hemorrhage (apoplexy)
Acquired isolated ACTH deficiency
Familial corticosteroid-binding-globulin deficiency
Causes of Primary Adrenal
Insufficiency
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Infectious adrenalitis : Many infectious agents may attack the adrenal
gland and result in adrenal insufficiency, including tuberculosis (tuberculous
adrenalitis), disseminated fungal infections and HIV-associated infections,
such as adrenalitis due to cytomegalovirus and mycobacterium avium
complex .
Hemorrhagic infarction: Bilateral adrenal infarction caused by hemorrhage
or adrenal vein thrombosis may also lead to adrenal insufficiency . The
diagnosis is usually made in critically ill patients in whom a computed
tomography (CT) scan of the abdomen shows bilateral adrenal
enlargement. Several coagulopathies and the heparin-induced
thrombocytopenia syndrome have been associated with adrenal vein
thrombosis and hemorrhage, while the primary antiphospholipid syndrome
has been recognized as a major cause of adrenal hemorrhage . Adrenal
hemorrhage has been mostly associated with meningococcemia
(Waterhouse-Friderichsen syndrome) and Pseudomonas aeruginosa
infection).
Causes of Primary Adrenal
Insufficiency
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Adrenoleukodystrophy : This is an X-linked recessive disorder affecting 1
in 20.000 males . Adrenoleukodystrophy is characterized by spastic
paralysis and adrenal insufficiency, usually beginning in infancy or
childhood, and is caused by mutations in the ABCD1 gene, resulting in
defective beta oxidation of very long chain fatty acids (VLCFAs) within
peroxisomes. The abnormally high concentrations of VLCFAs in many
organs, including the adrenal cortex, result in the clinical manifestations of
this disorder.
Causes of Primary Adrenal
Insufficiency
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Drug-induced adrenal insufficiency : Drugs that may cause adrenal
insufficiency by inhibiting cortisol biosynthesis, particularly in individuals with
limited pituitary and/or adrenal reserve, include aminoglutethimide
(antiepileptic), etomidate (anesthetic-sedative) , ketoconazole (antimycotic)
and metyrapone. Drugs that accelerate the metabolism of cortisol and most
synthetic glucocorticoids by inducing hepatic mixed-function oxygenase
enzymes, such as phenytoin, barbiturates, and rifampicin can also cause
adrenal insufficiency in patients with limited pituitary or adrenal reserve, as
well as those who are on replacement therapy with glucocorticoids .
Furthermore, some of novel tyrosine kinase-targeting drugs (e.g. sunitinib)
have been shown in animal studies to cause adrenal dysfunction and
Adrenal hemorrhage in the context of a sepsis, anticoagulant
treatment
.
PATHOPHYSIOLOGY OF ADRENAL
INSUFFICIENCY
Pathophysiology of Primary Adrenal Insufficiency
• In primary adrenal insufficiency, all the above mentioned causes result in gradual
destruction of the adrenal cortex. However, the clinical manifestations of the condition
appear when the loss of the adrenocortical tissue of both glands is higher than 90% .
In the initial phase of chronic gradual destruction, the adrenal reserve is decreased
and although the basal steroid secretion is normal, the secretion in response to stress
is suboptimal. Consequently, any major or even minor stressor can precipitate an
acute adrenal crisis. With further loss of adrenocortical tissue, even basal steroid
secretion is decreased, leading to the clinical manifestations of the disease. Low
plasma cortisol concentrations result in the increase of production and secretion of
ACTH due to decreased negative feedback inhibition . The elevated plasma ACTH
concentrations are responsible for the well-recognised hyperpigmentation observed in
these patients.
Pathophysiology of Secondary Adrenal Insufficiency
• ACTH deficiency leads to decreased secretion of cortisol and adrenal androgens,
while mineralocorticoid production remains normal. In the early stages, basal ACTH
secretion is normal, while that of stress-induced is impaired . With further loss of
basal ACTH secretion, there is atrophy of zonae fasciculata and reticularis of the
adrenal cortex. Therefore, basal cortisol secretion is decreased but aldosterone
secretion by the zona glomerulosa is preserved.
Adrenal insufficiency signs and
symptoms
• Chronic Primary Adrenal Insufficiency:
Patients with chronic primary adrenal
insufficiency may have symptoms and signs of
glucocorticoid, mineralocorticoid, and androgen
deficiency. By contrast, patients with secondary
or tertiary adrenal insufficiency usually have
normal mineralocorticoid function. The onset of
chronic adrenal insufficiency is often insidious
and the diagnosis may be difficult in the early
stages of the disease.
Adrenal insuficiency signs and
symptoms
Clinical signs and symptoms occur when more than 90 % of
adrenals is non functional. Glucocorticoid defficiency
determines by feed-back an increased of pro-opio melanocortin
and ACTH and MSH respectively . with skin pigmentation.
Chronic adrenal insufficiency evolves in 4 stages:
• aldosterone deficiency with increased plasma rennin activity.
• subclinical cortisole deficiency with increased ACTH
• low response of cortisole to SCTH stimulation test
• Clinical signs and symptoms of the disease
• Cortisole deficiency: hypoglycemia, lethargy, reducer apetite,
anemia, depression.
• Aldosterone deficiency: hyponatremia, reduced plasma volume
, low blood pressure, reducered ability of kidney to respond to
vasopressin and excrete free water.
Adrenal insufficiency signs and
symptoms
• The most common clinical manifestations of chronic
primary adrenal insufficiency include:
• General malaise, fatigue, weakness,
• anorexia, weight loss,
• nausea, vomiting, abdominal pain or diarrhea, which
may alternate with constipation,
• hypotension,
• electrolyte abnormalities (hyponatremia, hyperkalemia,
metabolic acidosis),
• hyperpigmentation, autoimmune manifestations
(vitiligo),
• decreased axillary and pubic hair, and loss of libido and
amenorrhea in women
Adrenal insufficiency signs and
symptoms
• Skin and mucosal pigmentation occurs on areas
exposed to sun, exposed to pressure such as
knuckles, toes, elbows and knees. Pigmentation
of bucal mucosa and gums are preceded by
generalized skin pigmentation. Increased
pigmentation of palmar creases, nail beds,
nipples, areolae, perivaginal and perianal
mucosa is also found. Scars that have been
formed after the onset of the diseas are also
pigmented.
Adrenal CT: large pseudotumors of the adrenals due to
bilateral tuberculomas
Symptoms
Weakness, fatigue,
Anorexia
Gastro intestinal symptoms: nausea and
vomiting, abdominal pain
Salt craving
Postural hypotension
Muscle and joint pains
100 %
100 %
56-92 %
16-19 %
12 %
6-13 %
Signs
100%
92-94 %
88-94 %
10-20 %
8%
Weight loss
Skin pigmentation
Hypotension (TAS < 110 mm Hg)
Vitiligo
Hypoglicemie
Laboratory data
Hyponatremia
Hyperkaliemie
Hypercalcemie
Hyperazotemie
Anemia
Eozinophilia
88 %
64 %
6%
55 %
40 %
17 %
Adrenal Crisis
• Adrenal Crisis: Adrenal crisis or acute adrenal insufficiency may
complicate the course of chronic primary adrenal insufficiency, and
may be precipitated by a serious infection, acute stress, bilateral
adrenal infarction or hemorrhage. It is rare in patients with
secondary or tertiary adrenal insufficiency.
• The main clinical manifestation of adrenal crisis is shock, but
patients may also have nonspecific symptoms, such as anorexia,
nausea, vomiting, abdominal pain, weakness, fatigue, lethargy,
confusion or coma.
• Hypoglycemia is rare in acute adrenal insufficiency, but more
common in secondary adrenal insufficiency. Hypoglycemia is a
common manifestation in children and thin women with the disorder.
• Hyperpigmentation due to chronic ACTH hypersecretion and weight
loss are indicative of long-standing adrenal insufficiency, while
additional symptoms and signs relating to the primary cause of
adrenal insufficiency may also be present.
Adrenal Crisis
• The major factor precipitating an adrenal crisis is
mineralocorticoid deficiency and the main clinical
problem is hypotension. Adrenal crisis can occur in
patients receiving appropriate doses of glucocorticoid if
their mineralocorticoid requirements are not met
whereas patients with secondary adrenal insufficiency
and normal aldosterone secretion rarely present in
adrenal crisis. However, glucocorticoid deficiency may
also contribute to hypotension by decreasing vascular
responsiveness to angiotensin II, norepinephrine and
other vasoconstrictive hormones, reducing the synthesis
of renin substrate, and increasing the production and
effects of prostacyclin and other vasodilatory hormones
Acute adrenal
insufficiency during
WaterhouseFrederikson)
Syndrome
= severe sepsis with
adrenal insufficiency
Secondary adrenal insufficiency
• Secondary or Tertiary Adrenal Insufficiency: The clinical features
of secondary or tertiary adrenal insufficiency are similar to those of
primary adrenal insufficiency. However, hyperpigmentation is not
present because ACTH secretion is not increased.
• Also, given that the production of mineralococorticoids by the zona
glomerulosa is mostly preserved, dehydration and hyperkalemia are
not present, and hypotension is less prominent.
• Hyponatremia and increased intravascular volume may be the
result of “inappropriate” increase in vasopressin secretion.
• Hypoglycemia is more common in secondary adrenal insufficiency
possibly due to concomitant growth hormone insufficiency and in
isolated ACTH deficiency.
• Clinical manifestations of a pituitary or hypothalamic tumor, such as
symptoms and signs of deficiency of other anterior pituitary
hormones, headache or visual field defects, may also be present
CHRONIC ADRENAL INSUFFICIENCY investigation
flowchart
CHINICAL SIGNS AND SYMPTOMS
Hypo Na, hyperK, eosinophilia, acidosis, hypoglicemia, EKG
Decreased plasma cortisole, urinary
cortisole, 17KS, 17OH-CS
2
1
ACTH test 1 or 250 μg
Cortisole not increased
Cotisole increases
Male >40 years
Female,
ACTH dosage:increased
Adrenal calcifications
Other autoimmune
disease
Megative metopirone test
Adrenal TB
Antibodies against 21
OH, 11 OH
Autoimmune
3
Imagery for hypothalamic or
pituiatry diseases
Treatment of adrenal
insuficiency
glucocorticods:
– hydrocortisone: 12-15 mg/m2 or 25 mg/day in 3 doses, or
– cortisone acetate oral. 20 mg at 8 a.m. and 10 mg at 5 p.m.
– prednisone p.o. 5 mg la 8 a.m. şi 2,5 mg at 5 p.m.
mineralocorticoids:
– 9a-fluoro-hidrocortisone (Astonin, Florinef) 0,05-0,2 mg/day
Patients must avoid any stressful situation and to increase the
dosage of glucocorticoids when this is anticipated, including
surgery. Patients must have an identification bracelet and to
have always with them a vial of hydrocortisone hemisuccinate
for immediate intervention if un unexpected stressful event
occurs or they have hypotension. They will consume salt
following their needs.
Treatment of adrenal crisis
1.Treat the precipiting factors
2. introduce an intravenous line and blood taking if the crisis occurs
in a patients with unknown disease to assess: na, K, BUN,
cortisole, ACTH
3. Plasma volume corection with normal saline with glucose 5 %,
3000 ml in 24 h, First 1000 ml will be given in the first 3 hours
4. Hidrocortizon hemisuccinat in a bolus of 100 mg. then 100 mg
every 6 hours in the first day. The dose is rediced to 50 mg every 6
hours in the second day and then after following the patient’s
evolution
5. 4-5 days after crisis the patient may be put on oral medication
6. mineralocoirticoids - 9 fluoro hidrocortizon 0,1mg-0,2 mg /zi, will
be associated when gluccorticoid therapy could be reduced to
50/75 mg/day
in case of unfavorable evolution 200-400 mg hydrocortisone
hemisuccinate dose will be maintained until the maintaining factor is
treated .