Adrenal insufficiency pathophysiology

Adrenal insufficiency Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Xyz from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X-ray
Echocardiography and Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Interventions
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Adrenal insufficiency pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Adrenal insufficiency pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Adrenal insufficiency pathophysiology
CDC on Adrenal insufficiency pathophysiology
Adrenal insufficiency pathophysiology in the news
Blogs on Adrenal insufficiency pathophysiology
Directions to Hospitals Treating Psoriasis
Risk calculators and risk factors for Adrenal insufficiency pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayeesha Kattubadi, M.B.B.S[2]

Overview

It is thought that adrenal insufficiency is the result of multiple etiologies like autoimmune adrenalitis, X-linked adrenoleukodystrophy, chronic glucocorticoid use, adrenal hemoorage etc. The pathophysiology depends on each etiological subtype.

Pathophysiology

Physiology

Adrenal insufficiency arises due to the deficiency of adrenocortical hormones.The normal physiology of adrenocortical hormone production can be understood as follows: The adrenal cortex is divided into three zones from outside to inside as - Zona glomerulosa, zona fasciculata and zona reticularis which are responsible for the production of streroidogenic hormones like mineralocorticoid, glucocorticoid and androgens respectively.

Pathogenesis

The pathophysiology of adrenal insufficiency depends on the etiological subtype.

Autoimmune adrenalitis: Both humoral and cell-mediated immune mechanisms attack enzymes involved in adrenocortical hormone synthesis. Autoantibodies against 21-hydroxylase, an enzyme required in the biosynthesis of adrenocortical hormones can be found. The patients remain asymptomatic until 90% of the cortex is destroyed. It can present as isolated autoimmune adrenalitis in 30-40% of cases or as an autoimmune polyglandular syndrome in 60-70% of cases. The autoimmune polyglandular syndrome in subclassified as autoimmune polyglandular syndrome type 1(APS type 1) and autoimmune polyglandular syndrome type 2 (APS type 2)

X-linked Adrenoleukodystrophy(X-ALD): X-ALD occurs due to mutations in the peroxisomal ATP-binding cassette (ABC) transporter encoded by the ABCD1 gene. Disruption of this transport protein leads to the accumulation of Very Long Chain Fatty Acids (VLCFA). Male patients usually present in childhood or adolescence, whereas heterozygous females present between 40-50 years. The lifetime prevalence of adrenal insufficiency is 80% in males, with the highest risk being in the first decade. Adrenal Insufficiency is extremely rare in females.

Chronic glucocorticoid use: Chronic use of glucocorticoids can cause secondary or tertiary adrenal insufficiency and is the most common cause of adrenal insufficiency. Exogenous glucocorticoid use causes feedback inhibition of the HPA axis leading to reduced synthesis of CRH and ACTH by the hypothalamus and pituitary. As a consequence of reduced ACTH, the adrenal cortex slowly loses the ability to synthesize cortisol. The mineralocorticoid synthetic function of the adrenal cortex is retained as it depends on RAAS. HPA axis is usually suppressed when glucocorticoids were used for >2weeks. In some cases, the HPA axis may remain suppressed for as long as 6-12 months after glucocorticoid withdrawal. HPA axis can be suppressed with oral, inhaled, topical, injectable, intraarticular, intradermal, paraspinal, or rectal glucocorticoid preparations.

Genetics

Autoimmune adrenalitis: Genes involved in the pathogenesis of autoimmune adrenalitis include HLA DR3/DQ2 and DR4/DQ8.

• The autoimmune polyglandular syndrome type 1 is transmitted in an autosomal recessive pattern. Gene involved in the pathogenesis is the autoimmune regulator gene (AIRE).
• The autoimmune polyglandular syndrome type 2 shows a polygenic inheritance. A strong association has been shown with HLA DR3 of MHC.

X-linked adrenoleukodystrophy: Genes involved in the pathogenesis of X-ALD include the ABCD1 gene which causes an alteration in peroxisomal ATP-binding cassette (ABC) transporter.

Associated Conditions

Autoimmune adrenalitis:

• Autoimmune polyglandular syndrome type 1 is also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). It is associated with chronic mucocutaneous candidiasis, hyperparathyroidism, total alopecia.

• Autoimmune polyglandular syndrome type 2 is associated with autoimmune thyroiditis, vitiligo, premature ovarian failure, type 1 diabetes mellitus, pernicious anemia.

X-linked Adrenoleukodystrophy: Apart from presenting as adrenal insufficiency it is also associated with cerebral inflammatory demyelination, myelopathy.

Gross Pathology

On gross pathology, the adrenal gland is atrophied in autoimmune adrenalitis. Autopsy findings show a decrease in the size and weight of the gland. In addition there may be hyperpigmentation of the gland.

Microscopic Pathology

On microscopic histopathological analysis, infiltration of the adrenal cortex with chronic inflammatory cells like lymphocytes is a characteristic finding in autoimmune adrenalitis. The adrenal cortex can be atrophied with the preservation of the medulla.