Adrenocortical hypofunction.
Mineralocorticoid excess states.
Timea Baló MD.
12.03.2013.
Semmelweis University
Adrenocortical hypofunction
1. Primary inability of the adrenal to
elaborate sufficient quantities of hormone
2. Secondary failure due to inadequate
ACTH formation or release
Classification of adrenal insufficiency I.
Primary adrenal insufficiency
Anatomic destruction of gland (chronic or acute)
„ Idiopathic atrophy” (autoimmun, adrenoleukodystrophy)
Surgical removal
Infection (tuberculous, fungal, viral-especially in AIDS)
Haemorrhage
Invasion: metastatic
Metabolic failure in hormone production
Congenital adrenal hyperplasia
Enzyme inhibitors (metyrapone, ketokonazole, aminogluethimid)
Cytotoxic agents (mitothan)
ACTH blocking antibodies
Mutation in ACTH receptor gene
Adrenal hypoplasia congenita
Adrenoleukodystrophy
X-linked inherited disorder
Disease of the very-long chain fatty acid metabolism
Progressive neurological symptoms from demyelinisation
Classification of adrenal insufficiency II.
Secondary adrenal insufficiency
Hypopituitarism due to hypothalamic pituitary
disease
Suppression of hypothalamic pituitary axis
By exogenous steroid
By endogenous steroid from tumor
Adrenocortical hypofunction
Addison’s disease
„ general languor and
debility, feebleness of the
heart’s action, irritability of
the stomach, and a peculiar
change of the color of the
skin”
Thomas Addison (1793-1860)
Adrenocortical deficiency
and pernicious anaemia
(1849): ‘Anaemia—
disease of the
suprarenal capsules in
which the disease is not
distinctly separated from
a new form of anaemia’
In Addison's day
tuberculosis was found
at autopsy in 70-90% of
cases.
Etiology and pathogenesis
Incidence: acquired forms-rare, secondary: relatively common
Etiology: progressive destruction of the adrenals > 90%
Chronic granulomatosus diseases (tbc, histoplasmosis, cryptococcosis, coccidioidomycosis)
Idiopathic atrophy-autoimmun mechanism
Rarely: adrenoleukodystrophy, haemorrhage, tumor metastases, HIV, CMV, amyloidosis, sarcoidosis, familiar adrenal insufficiency
Pathogenesis - autoimmun mechanism?
Circulating adrenal antibodies
Specific adrenal antigens include 21 –hydroxylase (CYP21A2) – significance is unknown
ACTH receptor blocking antibodies
Antibodies against the thyroid, parathyroid, gonadal tissue
Increased incidence of chronic lymphocytic thyroiditis, premature ovarian failure, type 1 diabetes mellitus, hypo/hyperthyroidism
Type II polyglandular syndrome
Polyglandular autoimmun syndrome
type 2.
Pernicious anaemia
Vitiligo
Alopecia
Coeliakia
myasthenia gravis
Result of a mutant gene on chromosome 6 and is associated with the HLA alleles B8 and DR3.
Type I. polyglandular autoimmun
syndrome
Parthyroid and adrenal insufficiency
Chronic mucocutaneous candidiasis
Pernicious anaemia
Chronic active hepatitis
Alopecia
Primary hypothyreoidism
Premature gonadal failure
No HLA association
Inherited
AR
APECED gene
mutations
Presents during
childhood
Primary adrenal insufficiency
Loss of all three types of adrenal steroids
90% of glands must be destroyed to manifest clinically
- high functional reserve
Clinical signs and symptoms I.
Insidious onset of fatigability, weakness
anorexia, nausea and vomiting
Cutaneous and mucosal pigmentation
Hypotension
Occasionally hypoglycaemia
99%
90%
98% - 82%
87%
Clinical signs and symptoms II.
Abdominal pain
Salt craving
Diarrhoea
Constipation
Syncope
Vitiligo
34%
22%
20%
19%
16%
9%
Depending on the duration and degree of adrenal hypofunction , the
manifestations vary from mild chronic fatigue to fulminating shock associated
with acute destruction of the glands
= Waterhouse - Fridrichsen syndrome
Waterhouse- Friedrichsen syndrome
• bleeding into the gland
• Severe infection with
meningococcus bacteria
• It can be caused by
procoagulants
• Other causes: low
platelet count, primary
anti - phospholipid
syndrome, renal vein
thrombosis, steroid use
Clinical signs and symptoms III.
Asthenia: early it may be sporadic
usually most evident in times of stress
later the patient is continously fatigued
Arterial hypotension:
with postural accentuation
blood pressure may be in the range of 80/50 Hgmm or less
Clinical signs and symptoms IV.
Sexual dysfunction
Muskuloskeletal symptoms (myalgia,
arthralgia)
Auricular cartilage calcification
(exclusively in men)
Psychiatric manifestations (memory loss,
organic brain symptom, depression,
psychosis)
Other: splenomegaly, lymphoid tissue
hyperplasia
Chronic adrenal insufficiency
Clinical presentation
Hyponatremia
Hyperkalemia
- Only occurs in primary
- Mild with associated azotaemia & metabolic acidosis
Laboratory
Basal steroid output may be normal/decreased After stress subnormal increase Adrenal stimulation with ACTH elicites
subnormal increase in cortisol levels, or no increase at all
Serum sodium, chloride and bicarbonate levels are reduced, Se potassium is elevated
Sodium loss depletes extracellular fluid volume and accentates hypotension
Hyperkalemia is due to aldosterone deficiency, impaired glomerular filtration, and acidosis
Mild to moderate hypercalcaemia occurs in 10-20% (unknown reason)
Normocytic anaemia, lymphocytosis, eosinophilia
Diagnosis
ACTH stimulation
250 ug Synacthen iv – cortisol response 60 min after.
Cortisol level should exceed 495 nmol/l (18 ug/dl)
If the response is abnormal, measure aldosteron levels ( in secondary aldosterone increasement will be normal>5 ng/dl)
Differential diagnosis
Because symptoms are common, and unspecific, early diagnosis is difficult
Racial pigmentation can be a problem
Hyperpigmentation is usually absent when adrenal destruction is rapid, as in bilateral adrenal haemorrhage
Hyperpigmentation can also occur with other diseases together
Treatment
Specific hormone replacement
Careful education about the disease
Replacement therapy should correct both glucocorticoid and mineralocorticoid deficits
Cortizol 20-30 mg/d (it should be taken with meals)
Two-third of the dose is taken in the morning, one third is taken late afternoon
Optimizing therapy only by clinical symptoms
Fludrocortizone 0.05-0.1 mg/d
Patient should be instructed to maintain an ample intake of sodium (3-4 g/d)
Control blood pressure and serum electolytes
Special therapeutic problems
Intercurrent illness – fever: double dose
Severe illness 75-150 mg/d (when oral administration is not possible, parenteral routes )
Fludrocortison dose should be increased and add salt to the normal diet during period of strenuous exercise with sweating, diarrhoea, extremely hot weather
Major surgery ( the day of surgery it will mimic the output of cortisol in normal individuals undergoing prolonged major stress)
Secondary adrenal insufficiency
HPA axis failure
- deficiency of glucocorticoids and adrenal androgens
- mineralocorticoids are unaffected
1 cause = chronic exogenous glucocorticoid
- suppresses diurnal CRH/ACTH release
- both time and dose related (short course, and daily dose of prednisolone 5 mg or less)
- reversible (recovery may take up to a year)
Secondary adrenal insufficiency
Less common causes:
- Postpartum necrosis (Sheehan syndrome)
- Adenoma haemorrhages
- Pituitary destuction from head trauma
- typically have associated focal neurological changes, visual deficits, diabetes insipidus or panhypopituitarism
Symptoms
same like in primary deficiency
Not hyperpigmented (ACTH and related peptides are low)
Plasma ACTH is decreased or absent (in primary elevated)
Near normal level of aldosterone secretion
Patients may have hyponatremia (dilutional or secondary to a subnormal increase in aldosterone secretion in response to severe sodium restriction)
Treatment
Glucocorticoid supplementation
doesn’t differ from that for the primary
disorder
Mineralocorticoid therapy is not
necessary as aldosterone secretion
is preserved
Adrenal crisis
serious infection or other acute major stress
Who doesn’t take more GC during an infection, or persistent vomiting
After bilateral adrenal infarction or haemorrhage
Patients with secondary adrenal insuff during acute stress
In patients who are abruptly withdrawn from doses of glucocorticoid that cause secondary adrenal insufficiency. (inhaled medication)
Adrenal crisis
Catastrophic HPA axis failure
- Head trauma
- Haemorrhage of pituitary adenoma
- Post-partum herniation (Sheehan’s syndrome)
- Usually neurological deficits, headaches, visual field cuts, diabetes insipidus
Adrenal crisis
Abrupt adrenal failure usually from gland haemorrhage or thrombosis
- Anticoagulation
- DIC
- Sepsis (Waterhouse – Friedrichson sy)
- Usually have abdominal and flank pain
- Can resemble ruptured AAA!
Adrenal crisis
Life-threatening emergency
May be primary or secondary
HYPOTENSION – SHOCK!
- Typically resistant to catecholamine and iv. fluid replacement
Clinical and laboratory findings
suggesting adrenal crisis
Dehydration, hypotension,or shock out of proportion to severity of illness
Nausea and vomiting with a history of weight loss and anorexia
Abdominal pain, so-called „ acute abdomen”
Unexplained hypoglycaemia
Unexplained fever (indicates infection, which must be identified, and treated)
Hyponatremia, hyperkalemia, azotaemia, hypercalcaemia or eosinophilia
Hyperpigmentation or vitiligo
Other autoimmun endocrine deficiencies, such as hypothyroidism or gonadal failure
Summary
„ Unexplained hyponatremia and hyperkalemia in the setting of hypotension unresponsive for catecholamin and fluid administration….
…..should receive 100 mg hyrocortisone intravenously”
Frequency of various diagnoses in
hypertensive patients - 2007
Essential
Chronic kidney disease
Renovascular disease
Phaeocromocytoma
Aldosteronism
Cushing’s syndrome
Coarctation
Oral contraceptives
92-95%
3-6%
0.2-1%
0.1-0.2%
5-13%
0.1-0.2%
0.1-0.2%
0.2-1%
Mineralocorticoid excess states
Conn’s Syndrome
Hypersecretion of aldosterone
In primary hyperaldosteronism the cause for the excessive aldosterone production resides in the adrenal gland
In secondary aldosteronism the stimulus is extraadrenal
Prof. Jerome W. Conn (1907-1981)
dietary modification of glucose tolerance,
aldosterone and the regulation of salt excretion (the syndrome of hyperaldosteronism)
the renin-angiotensin system in hypertension
the nutritional regulation of insulin secretion.
Primary aldosteronism - causes
Unilateral adenoma (small, may occur
on either side)
Bilateral cortical nodular hyperplasia =
idiopathic hyperaldosteronism (the
cause is unknown)
Adrenal carcinoma - rarely
Primary aldosteronism
Twice as common in women as in men
Usually occurs between ages of 30 and 50
Is present in 1% of unselected
hypertensive patients
However the prevalence may be even 5%,
it’s depending upon the study population
In many patients with clinical and
biochemical features of primary
aldosteronism, a solitary adenoma is not
found at surgery
Signs and symptoms
Increases the renal distal tubular exchange of intratubular sodium for secreted hydrogen and potassium ions
Progressive depletion of potassium, development of hypokalemia
Diastolic hypertension, headaches
Hypertension is due to the increased sodium reabsorption and extracellular volume expansion
Signs and symptoms
Potassium depletion is responsible for muscle weakness and fatigue (effect of potassium depletion on the muscle cell membrane)
Polyuria: impairment of urinary concentrating ability
Can be associated with polydipsia
Some patients may have normal potassium levels
Signs and symptoms
EKG, X-ray: left ventricular enlargement
Left ventricular hypertrophy is disproportionate to
the level of blood pressure when compared to
individuals with essential hypertension
After removal of the adrenal APA regression in
hypertrophy can occur
EKG (low potassium): prominent U waves, cardiac
arrythmias, premature contractions
In the absence of associated congestive heart
failure, renal disease or preexsisting abnormalities
(thrombophlebitis) edema is absent
Complications
Structural damage to the cerebral
circulation, retinal vasculature and
kidney
Proteinuria may occur in 50% of
patients
Renal failure occurs in up to 15%
Probably excess aldosterone
production induces cardiovascular
damage independent of its effect on
blood pressure
Laboratory
Urine concentration inability ( overnight concentration test)
Urine pH is neutral to alkaline
Hypokalemia (< 3 mmol/l) may be severe, and reflects body potassium depletion > 300 mmol
Hypernatremia is infrequent
Metabolic alkalosis
If hypokalemia is severe serum magnesium levels are also reduced
When to screen aldosteronism?
Hypertension and spontaneous hypokalemia
Hypertension and adrenal tumor
Resistant hypertension (20% incidence)
Screening
Plasma aldosterone concentration (PAC) and plasma renin activity (PRA)
Drawn from ambulant seated patient
Morning blood draw
Potassium must be normalized (not hypokalemic) to avoid false suppression of aldosterone
Positive screening, further investigation
for PHA
Aldosterone-renin ratio (ARR) >
30
20-60? PRA is normalized to 0.5 if
< 0.5
AND:
Aldosterone level >15 ng/dl
Potential alterations in ARR with
medication
Do we need for stop medications before testing?
Beta blockers False + ARR (lower renin and therefore lower
aldosterone) Angiotensin receptor blockers (ACE-I) False – ARR (lower aldosterone, raises renin) Diuretics (thiazids and loop diur raises renin
and aldo, so ratio doesn’t change) Spironolactone must be stopped Calcium channel blockers Minimal effect (Gallay BJ et al; Am.J Kidney dis.37:699-705)
Aldosterone suppression tests
%ARR with lack of suppression – mean 60%, range 26-95% (Kaplan NM. J Hypertension 22:863-69, 2004)
Iv saline suppression 500 ml 0.9% Nacl/h for 4 hours Draw PAC at time 0’- 240 ‘for short test Suppression if PAC <8.5 ng/dl (>10 PA) Oral sodium chloride suppression 10 g Nacl daily for 4 days On day 4 collect 24 h urine aldosterone, sodium Suppression, if aldosterone <14 mcg and sodium
>200 mEq/24h Fludrocortisone suppression test High salt diet, and large doses of Florinef over 4
day hospitalization
Localization
Abdominal CT scan (thin cuts of adrenal gland), MRI, 131-I-Iodocholesterol
If the CT scan is negative percutaneous transfemoral bilateral adrenal vein catheterization with adrenal vein sampling ( 2-3fold increase in plasma aldosterone concentration on the involved side)
In cases of hyperaldosteronism secondary to cortical nodular hyperplasia no lateralization is found
Differential diagnosis
Patients with hypertension and hypokalemia may have either primary or secondary hyperaldosteronism
In secondary form hypertension occurs due to elevated plasma renin levels, in contrast patients with primary aldosteronism
Ectopic ACTH production should also be considered in patiebts with hypertension and severe hypokalemia
Other hypermineralocorticoid states
Nonaldosterone mineralocorticoid states will have suppressed renin activity, but low aldosterone levels
In a few instances, hypertensive patients with hypokalemic alkalosis have adenomas that secrete deoxycorticosterone
Hypermineralocorticoidism
Low plasma renin activity:
Glucocorticoid remediable aldosteronism (inherited, AD trait, treated with glucocorticoids)
High plasma renin activity:
Bartter sy
Gitelman syndrome
Increased mineralocorticoid action:
Liddle syndrome
Treatment of PHA
Surgical excision of the adenoma
Aldosterone antagonists (25-100 mg spironolactone/8 h), triamteren, amiloride, eplerenone
Chronic therapy in men is limited by side effects: gynecomastia, decreased libido, impotence
When idiopathic bilateral hyperplasia is suspected, surgery is only indicated when significant symptomatic hypokalemia cannot be controlled with medical therapy
Secondary aldosteronism
Increased production of aldosterone in response to activation of the renin angiotensin system
Hypertension+edema Pregnancy Hypertension: overproduction of
renin (primary:because of the decreased renal blood flow, or perfusion pressure)
Secondary : atherosclerosis of aa renales, fibromuscular dysplasia
Renin producing tumors
Aldosterone and cardiovascular
damage
LVH Albuminuria Stroke Aldosteron provokes the activation of
proinflammatory molecules with a histologic picture of perivascular macrophage infiltrate and inflammation, followed by cellular death fibrosis and ventricular hypertrophy
Importantly the level of sodium intake is a critical co factor
If salt intake is restricted, no damage occurs even if the aldosterone is markedly elevated
Many trial confirmed the role of aldosterone antagonists in haert failure