1.Addis Ababa UniversityCollege of Health SciencesDepartment of medical PhysiologyPresentation on AdrenocorticalHypofunction
By GIRMAY F.
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2. Topic out line
Objectives
Introduction
Adrenal insufficiency

PrimaryAdrenalinsufficiency

3. Secondary AdrenalinsufficiencyAddison'sCrisis
Treatment modalities
Isolated Hypoadrenalism
Adrenal Insufficiency
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4. learning Objectives
At the end of these presentation learners expected to:-
Know the pathophysiology of adrenal insufficiency.
Identify the cause of adrenal insufficiency.
List the clinical manifestation of adrenal insufficiency
Explain Addison's crisis
Know pathophysiology of isolatedhypoadrenalism
Know the treatment modalities
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5. Endocrine Abnormalities
Endocrine abnormality expressed by hypersecretion or hyposecretion ofhormone.
Primary disorder-result from the gland it self.
Secondary disorder-the problem result from other organ ortarget tissue.
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6. Cause Of Endocrine Abnormalities
Metabolic factors.
Physical damage
Congenital problems.
Genetic abnormalities.
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7. Adrenal Insufficiency
Definition
Adrenal insufficiencyis a condition in which the adrenal gland is not able to function well enough to produce the amount ofall corticosteroid hormones which the body needs.
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8. Contd
According the site of problem

primary adrenal insufficiency.

9. Secondary adrenal insufficiency. 10. Primary Adrenal insufficiency- The gland it self is damaged.
- Secondary adrenal insufficiency-The gland
healthybut lacks hormonal stimulation
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11. Primary Adrenal insufficiency
Addison's disease

itoccurs when 90% of the adrenal gland is destroyed.

12. is a relatively uncommon disorder that occurs in people of all ages and both sexes. 13. characterized by decreased mineralocorticoid, glucocorticoid, and androgen secretion.Adrenal Insufficiency
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14. contd
Cause
1. idiopathic Autoimmune Adrenalitis

The most common type.

15. Atrophy of adrenal cortex due to autoimmune diseases, the adrenal medulla is intact. 16. Accounts 70% of the Addison s disease. 17. 15% of patients withAddison's disease have an associated autoimmune disease , gravesdisease being the most commonAdrenal Insufficiency
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18. Contd
Idiopathic autoimmune Addison disease may occur in isolation or in association with other autoimmune phenomena such as:
- Schmidt syndrome: The association of Addison disease and Hashimoto thyroiditis.
-polyglandular autoimmune syndrome type 1:
The association of Addison disease with hypoparathyroidism and mucocutaneouscandidiasis.

It may have an autosomal recessive mode of inheritance. It has no human leukocyte antigen (HLA) associations.

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- polyglandular autoimmune syndrome type2:
The association of Addison disease with type 1 diabetes mellitus and Hashimoto thyroiditis or Graves disease.
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20. Primary adrenal insufficiency contd
2.Infections

Tuberculosis-most common

21. AIDS 22. Fungal infections( histoplasmosis, Cryptococcus) 23. CMV infectionAdrenal Insufficiency
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24. Contd
Hematogenous spread of the M.tuberculosis from else where in the body to the adrenal gland cause-initial enlarged with extensive epitheloidgranulomasthenfollowed by degeneration of the adrenal gland.
Both cortex and adrenal medulla is affected.
Fibrosisfollowsthe adrenal become smaller with calcification of 50% evident.
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25. Contd
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26. Contd
3. Miscellaneous-Rare causes Addison's disease

Bilateral cancer metastasis-lung ,breastca.

Amyloidosis, hemosiderosis (rare)
ketoconazole use, macrophage-released cytokines are risk factors
Intra adrenal bleeding
Bilateral adrenoloctomy
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27. Contd
Intra adrenal bleeding- cause necrosis of the adrenal may occur in severely sick patient, with underlying infection, trauma, orcoagulopathy.
- cause of severe septicemia, particularly in children in whom a common cause is infection with Neisseria Meningitidis.
when caused by meningococci,the association with adrenal insufficiency is know as the Waterhouse Friederichsensyndrome.
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28. WATERHOUSE-FRIDERICHSENSYNDROME

Acute, bilateral hemorrhagic infarction of the adrenals.

29. Occurs secondary to shock and DIC, in a septicemic infection. Endotoxic hemorrhaging.Tiny fibrin thrombi occlude the vessels going to the adrenal glands ------> infarction.
Neisseria Meningitidis is the most common agent causing the infection.
Also Pneumococci, Staph, Strep, Haemophilus, Diphtheria.Herpes Virus can cause it.
Complete and sudden collapse of cortical function
SYMPTOMS: like symptoms of shock ,infectionand DIC (petechia, thrombocytopenia, increased PT and PTT).
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30. Contd
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31. Contd
4. congenital and genetic abnormalities
A.congenital Adrenal Hypoplasia (CAH)

It is an X-linked disorder comprising congenital adrenal insufficiency and hypogonadotrophic hypogonadism.

32. caused by mutations in the NROB1 gene. 33. DAX-1 gene-a member of the nuclear receptor familythat is expressed in the adrenal cortex, gonads, and hypothalamus.Adrenal Insufficiency
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34. Contd

Mutations in another transcription factor steroidogenicfactor-1may also result in adrenal insufficiency due to lack of development of a functional adrenal cortex.

35. CAH may also occur in association with glycerolkinase deficiency and muscular dystrophy.
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36. Contd
B.Adrenoleukodystrophy
An inherited metabolic disorder resulting in accumulation of very-long-chain fatty acids (VLCFA) in tissues including the brain and adrenal cortex, resulting in:
Progressive demyelination of cerebral white matter
Adrenal insufficiency

Only males have the fully expressed condition and carrier females are usually normal.

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37. Pathogenesis
Accumulation ofVLCFA
VLCFA esterified to cholesterol, making cholesterol unavailable as a steroid/hormone precursor
Adrenocorticalcells with these inclusions have decreased mitochondrial and microsomalenzyme activity
Over time these cells atrophy, further deteriorating adrenocorticalfunction
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38. Contd
C.Familial glucocorticoid deficiency (FGD)

inherited unresponsiveness to ACTH.

39. Itis a rare autosomal recessive cause ofhypoadrenalism .

Usually presents in childhood.

40. The renin-angiotensin-aldosterone axis is intact. 41. children usually present either with neonatal hypoglycemia or later with increasing pigmentation, often with enhanced growth velocity. 42. Two types-type 1 variant-25% of the case.- type 2 variant .
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43. contd
D.Allgrove syndrome: congenital adrenocortical unresponsiveness to ACTH typically presents in childhood with failure to thrive, features of adrenocortical insufficiency andhypoglycemia.
- disease to chromosome 12q13 but the responsible gene is unknown.
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44. Secondary Adrenal insufficiency

Loss of hypothalamic-pituitary function and deficiency of ACTH.

45. Will usually have deficiencies of other gland regulated by hypothalamic-pituitary system. 46. Aldosterone secretion may continue intact.Adrenal Insufficiency
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47. Contd
Problems in hypothalamus or pituitary

plasma levels of ACTH low.

unable to stimulate the zona fasiculateand zona reticularies of adrenal cortex.

cortisol levels low.

Adrenal cortices do response to exogenous ACTH.

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48. Contd
Cause
Sudden cessation of exogenous glucocorticoid
therapy.
Abrupt withdrawal of corticosteroids is a very common cause of secondary acute adrenal insufficiency.

chronic exogenous glucocorticoid

Suppresses diurnal CRH/ACTH release

both time- and dose-related
reversible
recovery may take up to long time
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49. STEROID THERAPY
STEROID LEVELS
PITUITARY GLAND IS INHIBITED TO REALEASE ACTH
ENDOGENOUS CORTISOL
PRODUCTION &
RELEASE BY ADRENAL CORTEX
ADRENAL ATROPHY
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2.Pan- Hypopituitarism
reflect inadequate ACTH production from the anterior pituitary gland.
In many of these, other pituitary hormones are deficient in addition to ACTH, so that the patient presents with partial or complete hypopituitarism.
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51. Contd
3.Surgical cause
- Selective removal of ACTH-secreting pituitary adenoma
-pituitary surgery.
4.Postpartum pituitary infarction (Sheehan's syndrome)
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52. Signs & Symptoms
1. Hyper Pigmentation of skin & mucous membrane due to excess ACTH secretion because of cortisol deficiency.
- ACTH causes pigmentation by its melanocyte stimulating action. on the sun exposed areas of the skin, extensor surface,knuckles,elbows and knees.
2.Vitiligo is also common in auto Immune Addison's disease due to destruction of melanocyte.
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53. Hyperpigmentation
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54. Contd
2.Electroliyteand acid base balance abnormalities.

Hyponatremia.

55. Hyperkalemia and metabolic acidosis 56. Hypercalcemia.Adrenal Insufficiency
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57. Contd
3.Dehydretion with loss of sodium
- As ECF becomes depleted.
- plasma volumefall.
- COP decreased.
4.Muscle weakness.
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58. Contd
5. Decreased cardiac output & decreased workload of the heart leading to decrease in size of the heart.
6. Hypoglycemia.
7. Inability to withstand any type of stress like physical, mental, even exposure to mild stress, trauma.
8.Decreased pubic and axillary hair in women.
9.Nausea,vomiting and diarrhea.
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59. Contd
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60. Contd
Primaryvs. secondaryadrenal hypo function
primary secondary
Site=adrenalsite=hypothalamus-pituitary
ACTH ACTH
pigmentationpigmentation
weight lossweight change vary
No change in GHand GH and gonadotropins
Gonadotropins.
Deficient in all corticosteroids other adrenal hormones normal or
slightly
No response to exogenous ACTHsluggish response to
exogenousACTH.
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61. Diagnosis
1.ACTH stimulation test
Blood and/or urine cortisol levels are measured.
Administration of synthetic ACTH.
Cortisol measurement in blood is repeated 30 to 60 minutes after an IV ACTH injection.
In healthy person rise in blood andurine cortisol levels
In adrenal insufficiency respond poorly or do not respond at all.
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62. Contd
2.insulin-induced hypoglycemia test
Blood measure of glucose and cortisol level.
An injection of fast acting insulin.
Blood glucose and cortisol levels are measured at 30,45 and 90 minutes after the insulin injection.

The normal response is -blood glucose level

-cortisol level.
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63. Addisons crisis
A life treating emergency of exacerbate adrenal insufficiency of undiagnosed patient duringfacing stress full conditions.
symptoms are intensified. Nausea, vomiting, and abdominal pain may become intractable.
In all patients in addisonians crisis, a precipitating cause should be identify.
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64. Addison's Crisis
Clinical Presentation
Life-threatening emergency
May be primary or secondary
HYPOTENSION
Typically resistant to catecholamine and IVF resuscitation
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65. contd
Abrupt adrenal failure usually from glandhemorrhage or thrombosis
Anticoagulation
DIC
Sepsis
Usually have abdominal and flank pain
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66. Contd
Catastrophic HPA axis failure
Head injury
Hemorrhage of pituitary adenoma
Post-partum herniation (Sheehan syndrome)
Usually neurological deficits, headaches, visual field cuts and diabetes insipidus.
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67. Treatment Modalities
Different treatment regimes.
Emergency treatments
maintenance therapy.
Replacement of glucocorticoids and mineralo corticoids.
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68. Treatment of Addison'scrisis
hydrocortisone 50-100 mg every 6-8 hours
intravenous fluids
dextrose
search for precipitating cause
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69. Treatment
Patients with symptomatic adrenal insufficiency, should be treated with hydrocortisone or cortisone therapy.
The usual initial dose is 25 mg of hydrocortisone (divided into doses of 15 and 10 mg)
37.5 mg of cortisone (divided into doses of 25 and 12.5 mg)
The daily dose may be decreased to 20 or 15 mg of hydrocortisone as long as the patient remains asymptomatic.
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70. Treatment chronic AI
hydrocortisone 12-15 mg in one or divided doses
titrate to lowest tolerated dose
consider mineralocorticoid ( fludrocortisone ) if primary AI. in a single daily dose of 50 to 200 g, as a substitute for aldosterone.
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71. Contd

The dose can be guided by measurements of blood pressure, serum potassium, and plasma renin activity, which should be in the upper-normal .

double or triple the dose of hydrocortisone temporarily whenever they have any febrile illness or injury.
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72. Hypoaldosteronism
Secondary hypoaldosteronism (hyporeninism hypoaldosteronism)
Inadequate stimulation of the zona gromulesa of the adrenal cortex despite intact adrenal cortex.
CAUSE
Hyporeninism, as an inherited biosynthetic defect.
postoperatively following removal of aldosterone- secreting adenomas.
during protracted heparin administration.
Renal insufficiency .
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73. pseudohypoaldosteronism
An inherited disease characterized by severe neonatal salt wasting, hyperkalemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormone action.
The disease can be due to a loss-of-function mutation in
the mineralocorticoid receptor .
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74. References
1.Williams text book of endocrinology,11th Edition
2.Ganongs review of medical physiology,23th Edition.
3. Harrisons principles of internal medicine.16thedition.
4.Guyton Text book of medical physiology,11th edition
5. Internet websites.
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75. Thank you!!!
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