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

Thank You for Your attention!

Thank You for Your attention!