Transcript Lymphoma and Kidney Disease

ADDISON’S DISEASE
Nasimeh Rakhshani CC3
ADRENAL INSUFFICIENCY
Addison’s Disease
ADDISON’S DISEASE

First described by Thomas Addison
in 1855

His description referred to primary
adrenal insufficiency

At that time, the most common
etiology was tuberculosis infiltration

TB infiltration continues to be the
leading cause worldwide
ADRENAL INSUFFICIENCY (AI)


Impairment in synthesis and/or release of
adrenocortical hormones
Classified as:
Primary AI  results from disease intrinsic to the
adrenal cortex
 Secondary AI  results from impaired release or
effect of adrenocorticotropic hormone (ACTH) from
the pituitary gland
 Tertiary AI  results from the impaired release or
effect of corticotropin releasing hormone (CRH) from
the hypothalamus

THE HPA AXIS
(-)
Hypothalamus
CRH
(-)
ACTH
Adrenal Gland
Glucocorticoids
CLINICAL MANIFESTATIONS



In general, symptoms of AI include fatigue and
GI complaints (nausea and vomiting)
Clinical suspicion is important because the
presentation of AI may be insidious and subtle
Resultantly, clinical diagnosis is frequently
delayed or missed early  if unrecognized, may
present in a life-threatening crisis with acute
cardiovascular collapse (adrenal crisis)
CLINICAL MANIFESTATIONS

Signs and symptoms of primary adrenal
insufficiency vary depending on which hormones
are deficient and the severity of the defects
CLINICAL MANIFESTATIONS CONT’D
Glucocorticoid
Deficiency
Mineralocorticoid
Deficiency
Adrenal Androgen
Deficiency
Fasting
hypoglycemia
Hypotension
Decreased axillary
hair (females)
Increased insulin
sensitivity
Dizziness
Decreased pubic hair
(females)
Muscle weakness
Salt craving
Loss of libido
(females)
Morning headache
Weight loss
If prepubescent:
assymptomatic
↑ production of
POMC  ↑ melanin
Anorexia
↑pigmentation:
palmer creases,
gingival border,axilla
Electrolyte anomalies
(hypoNa, hyperK,
metabolic acidosis)
CLINICAL MANIFESTATIONS

Adrenal Crisis

Hypotension or shock


Particularly if disproportionate to apparent underlying
illness
Serum electrolyte and metabolic abnormalities:
Hyponatremia
 Hyperkalemia
 Metabolic Acidosis
 Hypoglycemia

Vomiting and diarrhea, sometimes with severe
abdominal pain
 Unexplained fever, weight loss and anorexia

CLINICAL MANIFESTATIONS

Adrenal Crisis: When to be suspicious???

In neonates, presents within 1st few days-weeks of
life with vomiting, diarrhea, ↓BP, ↓Na, ↑K and ↓BG
CAH (21-hydroxylase deficiency) most common cause
 In females with CAH is suggested by ambiguous genitalia


In infants and older children with previously
diagnosed AI
Weight loss, serum electrolyte abnormalities +/hyperpigmentation
 Often a history of an antecedent precipitating stress (eg,
surgery or infection)


Bilateral adrenal hemorrhage or infarction
Children with hypotension and shock that fail to respond to
vigorous fluid resuscitation and inotropic medications
 Especially if have severe hyponatremia and hyperkalemia

ETIOLOGY

Steroidogenesis disorders: Defects within the biosynthetic
pathways of glucocorticoids +/- mineralocorticoids  lead to
impaired synthesis of cortisol and/or aldosterone





There are also drugs that inhibit cortisol synthesis
(aminoglutethimide, ketoconazole, and etomidate)
Adrenal damage: Injury from factors extrinsic to the
adrenal gland may impair adrenal function
Abnormal adrenal development: A lack of normal
adrenocortical cell differentiation may result in adrenal
hypoplasia
Adrenal unresponsiveness to ACTH: Defects in adrenal
responsiveness to ACTH results in cortisol deficiency
Peroxisomal disorders: Accumulation of abnormal very long
chain fatty acids within peroxisomes which may lead to
adrenal impairment
ETIOLOGY
Steroidogenesis
disdorders
Adrenal
damage
Abnormal
adrenal
develop’t
Unresponsive Peroxisomal
to ACTH
defects
CAH
Adrenal
hemorrage
X-linked
AHC
Familial GC
deficiency
X-linked
ALD/AMN
Defect in
aldosterone
production
Infection
(TB, HIV,
fungal)
Adrenal
hypoplasia
SF-1 defect
- Allgrove
syndrome
(triple A syn)
Neonatal ALD
Defects in
Autoimmune
cholesterol
(polyglandular
biochemistry AIS)
Refsum
disease
-Wolman dz
Zellweger
syndrome
ETIOLOGY CONTINUED

Perry et al (2005):



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

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20 years of data, 103 patients <18 y/o  Primary AI
73% congenital adrenal hyperplasia (CAH)
13% autoimmune adrenal insufficiency
5% Peroxisomal disorders
3% Wolman disease (lysosomal acid lipase deficiency)
1% Adrenal hypoplasia congenita
1% Triple A syndrome (Unresponsiveness to ACTH)
6% No diagnosis identified
DIAGNOSIS
3
Step Process:

Confirm adrenal insufficiency 
demonstrating inappropriately low cortisol
secretion

Determine whether the cortisol deficiency is
primary or central AI

Determine the cause of the underlying
disorder
DIAGNOSTIC TESTS

Static Tests
Cortisol, ACTH, Adrenal Androgens
 Mineralocorticoid status

Serum electrolytes
 Plasma renin activity (PRA), direct [renin]


Dynamic Tests

Short ACTH stimulation test:


Serum cortisol levels are measured before and 60 minutes
after the rapid IV infusion of synthetic ACTH (cosyntropin)
Tests of ACTH secretory ability
Insulin-induced hypoglycemia
 Glucagon
 Metyrapone test


CRH stimulation test: helps determine if 2o or 3o AI
1. CONFIRMING AI
 Initial
step: measurement of serum ACTH
and cortisol in the morning (8 a.m.) and in
the fasting state

If serum cortisol is low and serum ACTH is
high  likely primary AI and diagnosis can be
confirmed with an ACTH stimulation test


If low cortisol and normal lytes the rapid ACTH
stimulation test often performed simultaneously
If serum ACTH is also low, serum cortisol is
indeterminate or pituitary disease is
suspected  likely central AI  tests of ACTH
secretory ability
1. CONFIRMING AI CONT’D
 In
patients suspected of adrenal crisis:
Immediate treatment crucial and must not
postpone until diagnosis confirmed
 Draw required samples and initiate therapy
(saline and GC replacement)



Cortisol, ACTH, electrolytes, PRA, renin, etc.
May perform a short ACTH stimulation test
following treatment in these patients if:
Treatment has been given for < a few days (no
adrenal suppression secondary to treatment)
 Dexamethasone used to treat (not detected in
cortisol assay unlike hydrocortisone and
cortisone)

2. ESTABLISH THE LEVEL OF DEFECT

Diagnosis of Primary AI:↓ am cortisol and ↑ am
ACTH levels + ↓ or absent cortisol in response to
ACTH stimulation test


Often evidence of mineralocorticoid deficiency 
hyponatremia, hyperkalemia, ↑ PRA and/or ↑ [renin]
Diagnosis of Central AI: ↓ Basal and ACTH
stimulated cortisol secretion and ↓ Basal ACTH
 tests of ACTH secretory ability +/- CRF
stimulation test
Practically, not always necessary to determine if AI
is 2o or 3o treatment is often the same
 Plasma levels of renin and aldosterone are usually
unaffected in central AI

3. EVALUATION OF CAUSE

Primary AI
Evaluate for CAH (most common cause of 1o AI ) 
adrenal androgens
 Measure adrenal antibodies  if +ive screen for
autoimmune polyglandular syndromes



If antibodies negative screen for other causes of 1o AI


Measuring antibodies to other endocrine glands (thyroid,
parathyroid, and islet cell antibodies)
Imaging (CT) identifying adrenal hemorrhage,
calcifications, or infiltrative disease
Central AI

Evaluate for secretion of other pituitary hormones
DIAGNOSTIC APPROACH
TREATMENT OF ADRENAL INSUFFICIENCY
 Principles:

Maintenance Therapy (Replacement)

Stressed Conditions
TREATMENT CONT’D

Maintenance Therapy

Glucocorticoid Therapy
Calculated according to body surface area
 Often hydrocortisone is preferred because of its short
duration of action and low potency  ease in titration to
optimal dose (5-16 mg/m2/d divided into 3 doses)
 During follow-up must ensure adequate somatic growth
(weight, BA, height and weight velocities) and screen for
symptoms of insufficiency
 Must also screen for symptoms of GC excess


Mineralocorticoid Therapy
Fludrocortisone (Florinef)  0.05-0.2 mg/d do not vary by
age or surface area because aldosterone secretion rate is
nearly constant throughout the lifespan
 Monitor for signs of inadequate replacement: dehydration,
poor weight gain, salt-craving, and hyponatremia with
hyperkalemia

TREATMENT CONT’D

Stress Conditions
Primary goal is to avoid serious consequences of an
adrenal crisis  always wear identification
 Illness:

Minor stress (e.g. sore throat, rhinorrhea, T < 38ºC)  may
not require ∆ dose
 Moderate stress (e.g. severe URTI)  double the GC
replacement dose
 Major stress (e.g. T > 38ºC and/or vomiting), three to four
times the GC replacement dose
 If child unable to keep down oral dose administer IM GC


Surgery:
During general anesthesia, +/- surgery, the GC
requirements increases greatly
 Protocols vary depending on nature of surgery, length of
surgery, age of patient etc
 Stress dosing is generally continued until the patient can
tolerate oral intake, is afebrile, and is hemodynamically
stable

THANK YOU!!!
Questions???