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Adrenal insufficiency

Adrenocortical insufficiency or hypofunction may be

  1. Primary adrenal Disease
  2. Secondary hypoadrenalism (decreased stimulation of ACTH due to deficiency of ACTH).

Table - Classification of Adrenal Insufficiency  

  1. Primary Adrenal Insuffiency
    1. Anatomic destruction of gland (chronic or acute)
      1. "Idiopathic" atrophy (autoimmune)
      2. Surgical removal
      3. Infection (tuberculous, fungal, viral—especially in AIDS patients)
      4. Hemorrhage
      5. Invasion: metastatic (The most common site of primary in a patient presenting with secondries to adrenals is Melanoma.), Lung, Breast, lymphoma, RCC
    2. Metabolic failure in hormone production
      1. Congenital adrenal hyperplasia
      2. Enzyme inhibitors (metyrapone, ketoconazole, aminoglutethimide)
      3. Cytotoxic agents (mitotane)
      4. Adrenal hypoplasia congenital
  2. Secondary Adrenal Insufficiency
    1. Hypopituitarism due to hypothalamic-pituitary disease
    2. Suppression of hypothalamic-pituitary axis
      1. By exogenous steroid
      2. By endogenous steroid from tumor
  1. Primary adrenocortical insufficiency

Physiology of Addison disease (Primary adrenocortical insufficiency)

 

 

Extra Edge:
  1. The increased MSH in Addison's causes melanocytes to disperse melanin in the epidermis thus increasing pigmentation.
  2. Hyper pigmentation due to increase ACTH which is a precursor of MSH. But Vitiligo may be associated.
  3. GI: nausea or vomiting, abdominal pain, diarrhea or constipation. Note: Both diarrhea or constipation can occur (Ref. Hari. 18th ed., table 336-7, Page 2263)

 

Table - Signs and Symptoms of Adrenal Insufficiency (AI)

  1. Signs and Symptoms Caused by Glucocorticoid Deficiency 
    1. Fatigue, lack of energy           
    2. Weight loss, anorexia
    3. Myalgia, joint pain                 
    4. Fever
    5. Anemia, lymphocytosis, eosinophilia
    6. Slightly increased TSH (due to loss of feedback inhibition of TSH release)
    7. Hypoglycemia (more frequent in children)
    8. Low blood pressure, postural hypotension
    9. Hyponatremia
  2. Signs and Symptoms Caused by Mineralocorticoid Deficiency (Primary AI Only) 
    1. Abdominal pain, nausea, vomiting
    2. Dizziness, postural hypotension
    3. Salt craving
    4. Low blood pressure, postural hypotension
    5. Increased serum creatinine (due to volume depletion)
    6. Hyponatremia
    7. Hyperkalemia
  3. Signs and Symptoms Caused by Adrenal Androgen Deficiency 
    1. Lack of energy
    2. Dry and itchy skin (in women)
    3. Loss of libido (in women)
    4. Loss of axillary and pubic hair (in women)
  4. Other Signs and Symptoms 
    1. Hyperpigmentation (primary AI only) [due to excess of pro-opiomelanocortin (POMC)–derived peptides]
    2. Alabaster-colored pale skin (secondary AI only) (due to deficiency of POMC-derived peptides)

 

Note: Due to low BP & hypoglycemia, the commonest symptom of Addison’s disease is Asthenia

 

Clinical Feature of addisonian crises
  1. Intractable vomiting
  2. Acute pain abdomen
  3. Hypotension
  4. COMA and death

 

This increased pigmentation is diffuse but may be accentuated in the

  1. Palmer crease
  2. Sites of friction & pressure areas - Knuckles, elbows, knees, nail beds
  3. Scars
  4. Oral mucosa, gums & conjunctival
  5. Areolae of nipples 
Important Points:
  1. Increase in ACTH occurs only in primary Addison’s disease.
  2. It is not seen in secondary Addison disease as it is caused due to decrease in ACTH.
  3. Therefore, pigmentation can not occur in secondary Addison's disease.

 

Extra Edge:
  1. Primary Addison’s disease both aldosterone and glucocorticoid are deficient,
  2. In secondary Addison’s disease only glucocorticoid deficiency is seen. 

 

Tests of adrenal insufficiency

  1. âNa+ & K+
  2. Glucose
  3. Ca2+â, (MCQ)                                                
  4. Eosinophilia, (MCQ) 

Extra Edge (Ref. Hari. 18th ed., Pg- 2956)

  1. Hyponatremia is a characteristic feature in primary adrenal insufficiency. Hyperkalemia is also a feature. 
  2. Hyponatremia is primarily caused by mineralocorticoid deficiency but can also occur in secondary adrenal insufficiency due to diminished inhibition of ADH by cortisol, resulting in mild SIADH.
  3. Glucocorticoid deficiency also results in slightly increased TSH concentrations that normalize within days to weeks after initiation of glucocorticoid replacement.  

Note: The commonest symptom of Addison’s disease is Asthenia due to low BP & hypoglycemia. 

 

Diagnosis (Ref. Hari. 18th ed.,  pg -  2959 Fig 342.15)

  1. ACTH stimulation test (Most confirmatory Test)
     
    The diagnosis of adrenal insufficiency should be made only with ACTH stimulation testing to assess adrenal reserve capacity for steroid production. In brief, the best screening test is the cortisol response 60 min after 250 μg of cosyntropin given IM or IV. Cortisol levels should be 18 μg/dL.
  2. If the response is abnormal, then primary and secondary adrenal insufficiency can be distinguished by measuring aldosterone levels from the same blood samples. In secondary, but not primary, adrenal insufficiency, the aldosterone increment will be normal [150 pmol/L (5 ng/dL)].
  3. 21-Hydroxylase adrenal autoantibodies: +ve in autoimmune disease in >80%.
  4. In Addison disease - Increased Plasma renin and reduced plasma aldosterone level
     
    In secondary adrenal insufficiency both plasma renin and plasma aldosterone level are raised.
  5. Addison’s disease is associated with serum cortisol <3 mcg/dl 

Extra Edge: Low plasma cortisol (<3 mcg/dl) at 8:00 AM is diagnostic especially if accompanied by simultaneous elevation of plasma ACTH level (usually >200 pg/ml)

  

Treatment of Addison disease

  1. Replace steroids: 15-25mg hydrocortisone daily, in 2-3 divided doses.
  2. Mineralocorticoid replacement is needed if postural hypotension: fludrocortisone from 50-200 mg daily.  

Recent advances (Ref. Hari. 18th ed.,  pg -  1678)
 
Eflornithine is used in the treatment of facial hirsutism (excessive facial hair growth) as well as in African trypanosomiasis (sleeping sickness).


Waterhouse-Friderichsen Syndrome

 

This uncommon but catastrophic syndrome is characterized by the following:
  1. An overwhelming bacterial infection, which is classically associated with Neisseria meningitidis septicemia but occasionally is caused by other highly virulent organisms, such as Pseudomonas species, pneumococci, Haemophilus influenzae, or staphylococci
  2. Rapidly progressive hypotension leading to shock
  3. Disseminated intravascular coagulation with widespread purpura, particularly of the skin
  4. Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage
  5.  Whatever the basis, the adrenals are converted to sacs of clotted blood virtually obscuring all underlying detail.

Congenital Adrenal Hyperplasia (CAH)


 

Figure - Consequences of C-21 hydroxylase deficiency. 21-Hydroxylase deficiency impairs the synthesis of both cortisol and aldosterone. The resultant sex of rearinsulting ultimately in adrenal hyperplasia and increased synthesis of testosterone. The sites of action of 11-, 17-, and 21-hydroxylase are shown by the numbers in circles. 

 

TABLE  -- Diagnosis and Treatment of Congenital Adrenal Hyperplasia

 

DISORDER

SIGNS AND SYMPTOMS

LABORATORY FINDINGS

THERAPEUTIC MEASURES

21-Hydroxylase deficiency, classical form

 

 

 

 

 

Glucocorticoid deficiency

 

Mineralocorticoid deficiency (salt-wasting crisis)

 

Female pseudohermaphroditism

Postnatal virilization in males and females

Cortisol, ACTH

↑↑ Baseline and ACTH-stimulated 17-hydroxy-progesterone

Hyponatremia, hyperkalemia

Plasma renin

Serum androgens

 

Glucocorticoid (hydrocortisone) replacement

 

Mineralocorticoid (fludrocortisone) replacement; sodium chloride supplementation

 

Vaginoplasty and clitoral recession

Suppression with glucocorticoids

11β-Hydroxylase deficiency

 

 

 

 

Glucocorticoid deficiency

 

Female pseudohermaphroditism

Postnatal virilization in males and females

Hypertension

Cortisol, ACTH

↑↑ Baseline and ACTH-stimulated 11-deoxycortisol and deoxycorticosterone

Serum androgens

Plasma renin, hypokalemia

Glucocorticoid (hydrocortisone) administration

 

Vaginoplasty and clitoral recession

Suppression with glucocorticoids

Suppression with glucocorticoids

3β-Hydroxysteroid dehydrogenase deficiency, classical

From

 

 

 

 

Glucocorticoid deficiency

 

Mineralocorticoid deficiency (salt-wasting crisis)

 

Male and female pseudohermaphroditism

Precocious adrenarche, disordered puberty

Cortisol, ACTH

↑↑ Baseline and ACTH-stimulated δ5 steroids (pregnenolone, 17-OH pregnenolone, DHEA)

Hyponatremia, hyperkalemia

Plasma renin

DHEA, androstenedione, testosterone, and estradiol

 

Glucocorticoid (hydrocortisone) replacement

 

Mineralocorticoid (fludrocortisone) replacement; sodium chloride supplementation

 

Surgical correction of genitals and sex hormone replacement as necessary consonant with sex of rearing
Suppression with glucocorticoids

17α-Hydroxylase/17, 20-lyase deficiency

 

 

 

 

Cortisol deficiency (corticosterone is an adequate glucocorticoid)

 

Male pseudohermaphroditism

Sexual infantilism

Hypertension

Cortisol, ACTH

DOC, corticosterone response to ACTH Low 17α-hydroxylated steroids; poor

Serum androgens; poor response to hCG

Plasma renin; hypokalemia

Glucocorticoid (hydrocortisone) administration

 

Orchidopexy or removal of intra-abdominal testes; sex hormone replacement consonant with sex of rearing Sex hormone replacement consonant with sex of rearing





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