Adrenal insufficiency

Clinic

• Adrenal glands do not produce adequate amounts of steroid hormones including Cortisol, Aldosterone and Androgens which leads to:
  • Abdominal pain
  • Vomiting
  • Muscle weakness
  • Fatigue
  • Low blood pressure
  • Depression
  • Mood and personality changes

• In severe cases organ failure and shock is occurred.

Three major types

Primary adrenal insufficiency:

• Autoimmune adrenalitis: 80-90%
• Congenital adrenal hyperplasia or Adrenoleukodystrophy
• Adrenal dysgenesis
• Destruction:
  • Addison's disease
  • Infection: MTB, CMV, Histoplasmosis
  • Drugs: e.g. anticonvulsants, etomidate, metyrapone, rifampicin
  • Vascular: e.g. hemorrhage from sepsis, adrenal vein thrombosis, hypercoagulable states such as heparin-induced thrombocytopenia and antiphospholipid syndrome
  • Neoplasia
  • Deposition disease: e.g. Hemochromatosis, Amyloidosis, Sarcoidosis
• Idiopathic

Secondary adrenal insufficiency

• It is caused by impairment of the pituitary gland, resulting in a lack of ACTH production and subsequent decreased adrenal stimulation.
• Principal causes include:
  • Pituitary adenoma or craniopharyngioma
  • Surgery or radiation
  • Exogenous corticosteroid use
  • Sheehan's syndrome / Pituitary apoplexy
  • Autoimmune polyendocrinopathies: Addison’s disease is frequently a component of autoimmune polyendocrinopathies while secondary adrenal insufficiency associated with autoimmune disorders is believed to be a rare event.
    • Autoimmune hypophysitis

• Other diseases included
  • Insulin-dependent diabetes mellitus
  • Pernicious anaemia
  • Vitiligo
  • Premature ovarian failure
  • Autoimmune thrombocytopaenia

Tertiary adrenal insufficiency

• It is caused by impairment of the hypothalamus, resulting in a lack of CRH production, causing downstream reduction in ACTH production and subsequently decreasing adrenal stimulation. Principal causes include: Sudden withdrawal from long-term exogenous steroid use and Brain tumors
• When the hypothalamus doesn't make enough CRH, the pituitary gland doesn't make enough ACTH. In turn, the adrenal glands don't make enough cortisol. CRH tells the pituitary to make ACTH, which in turn tells the adrenals to make cortisol

• Tertiary adrenal insufficiency is due to problems with the HPA axis from the hypothalamus.
• This can be due to malignancy, infection, trauma, or autoimmune disease. The functionality of the hypothalamus may be altered and affect its ability to release hormones that stimulate the pituitary and adrenal glands.
• Signs and symptoms of tertiary adrenal insufficiency may be characterized by fatigue, low blood pressure, syncope, craving salty foods, hypoglycemia, nausea, emesis, diarrhea, muscle pain, irritability, and hyperpigmentation of skin and tissue. The signs and symptoms are very similar to primary and secondary conditions because there is minimal cortisol being produced. CRH is not being produced in high enough quantities to elicit a response from the pituitary gland to make ACTH, which would then release cortisol from the adrenal cortex. Detection of an issue can be found by performing assays to stimulate CRH production. If, after administration of synthetic or exogenous CRH, the ACTH and cortisol levels increase, this helps confirm a tertiary cause of adrenal insufficiency.

Hypoadrenalism
Pathology	Hormone Levels in the Body	Responsible Organ
Primary (Addison's)	↓↓Cortisol, ↑↑ACTH, ↑↑CRH	Adrenal Gland
Secondary	↓↓Cortisol, ↓↓ACTH, ↑↑CRH	Pituitary Gland
Tertiary	↓↓Cortisol, ↓↓ACTH, ↓↓CRH	Hypothalamus

HPA

Miasms

	Entities	Miasms
Primary adrenal insufficiency (Autoimmune adrenalitis)	Adrenal insufficeincy	CMV MTB
Secondary adrenal insufficiency (Autoimmune polyendocrinopathies)	Secondary hypothyroidism Secondary Adrenal insufficiency Secondary Ovary failure	MTB

Signs / Symptoms

Common	Uncommon
Hypoglycemia Hyperpigmentation: Skin tanning: Patchy or all over the body Dehydration Weight loss Disorientation	Weakness / Tiredness Dizziness, Low blood pressure / Orthostatic hypotension Cardiovascular Collapse Myalgia Nausea / Vomiting / Diarrhea Goitre Vitiligo Eosinophilia Hyponatremia is a sign of secondary insufficiency

Note

• Most of these Sign / Symptoms are post node. therefore there are not useful in finding the appropriate miasm. The only way is to find other entities which accompany Adrenalitis
• Hypotention, Dizziness, Myalgia and many of these symptoms are dynamic symptom of this big entity, Adrenalitis
• In nervous system pathology, pathways are involved therefore Sign and symptoms of entities are originated from dysfunction of pathways whether they are completely disconnected / Hypo-active (MS, ALS) or hyperactivated (UMN, Neuralgia). In finding similar miasms for Neural entities, we may find some viruses which destruct pathways or nuclei. HPA axis is an special pathway since it contains neural pathways of Hypothalamus, pituetry and hormonal signaling from Pituatry to adrenal and vice versa. Are we have a viral miasm which could involve both neural pathway and hormonal signaling? Or we could use viral miasms of Autoimmune adrenalitis in this special situation?

Pathophysiology

Diagram detailing the hypothalamus-pituitary-adrenal axis in the normal state, primary adrenal insufficiency, secondary adrenal insufficiency, and tertiary adrenal insufficiency. When functioning normally, the adrenal glands secrete glucocorticoids (primarily, cortisol) in the zona fasciculata and mineralocorticoids (primarily, aldosterone) in the zona glomerulosa to regulate metabolism, blood pressure, and electrolyte balance. Adrenal hormone production is controlled by the hypothalamic-pituitary-adrenal axis, in which the hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to produce cortisol. High levels of cortisol inhibit the production of both CRH and ACTH, forming a negative feedback loop. The types of adrenal insufficiency thus refer to the level of the axis in which the dysfunction originates: primary, secondary, and tertiary for adrenal glands, pituitary gland, and hypothalamus, respectively.

In adrenal insufficiency, there is a deficiency in cortisol production which may be accompanied by a deficiency in aldosterone production (primarily in primary adrenal insufficiency). Depending on the cause and type of adrenal insufficiency, the mechanism of the disease differs. Generally, the symptoms manifest through the systemic effects of cortisol and aldosterone. In secondary and tertiary adrenal insufficiency, there is no effect on the production of aldosterone within the zona glomerulosa as this process is regulated by the renin–angiotensin–aldosterone system (RAAS).

Adrenal insufficiency can also affect the zona reticularis and disrupt production of androgens, which are precursors to testosterone and estrogen. This leads to a deficiency of sex hormones and can contribute to symptoms of depression and menstrual irregularities.

Cortisol deficiency[edit]

Cortisol increases blood sugar by inducing gluconeogenesis in the liver, lipolysis in adipose tissue, and proteolysis in muscle while increasing glucagon secretion and decreasing insulin secretion in the pancreas. Deficiency results in hypoglycemia, with associated nausea, vomiting, fatigue, and weakness. Over time, the breakdown of fat and muscle can cause weight loss (in severe cases, anorexia) and muscle aches.^{[citation needed]}

Cortisol potentiates the effectiveness of angiotensin II and catecholamines such as norepinephrine in vasoconstriction. Thus, a deficiency can contribute to hypotension, though this effect is most pronounced in mineralocorticoid deficiency.

In primary adrenal insufficiency, the lack of negative feedback from cortisol leads to increased production of CRH and ACTH. ACTH is derived from pro-opiomelanocortin (POMC), which is cleaved into ACTH as well as α-MSH, which regulates production of melanin in the skin.^{[citation needed]} The overproduction of α-MSH leads to the characteristic hyperpigmentation of Addison's disease.

Aldosterone deficiency[edit]

Although the production of aldosterone occurs within the adrenal cortex, it is not induced by adrenocorticotropic (ACTH); instead, it is regulated by the renin–angiotensin-aldosterone system (RAAS). Renin production in the juxtaglomerular cells of the kidney is induced by decreased arterial blood pressure, decreased sodium content in the distal convoluted tubule, and increased sympathetic tone. Renin initiates the downstream sequence of cleavage of angiotensinogen to angiotensin I to angiotensin II, in which angiotensin II stimulates aldosterone production in the zona glomerulosa. Thus, dysfunction of the pituitary gland or the hypothalamus does not affect the production of aldosterone. However, in primary adrenal insufficiency, damage to the adrenal cortex (e.g. autoimmune adrenalitis a.k.a. Addison's disease) can lead to destruction of the zona glomerulosa and therefore a loss of aldosterone production.

Aldosterone acts on mineralocorticoid receptors on epithelial cells lining the distal convoluted tubule, activating epithelial sodium channels (ENaC) and the Na⁺/K⁺-ATPase pump. This results in the absorption of sodium (with resulting retention of fluid) and the excretion of potassium. Deficiency of aldosterone leads to urinary loss of sodium and effective circulating volume, as well as retention of potassium. This can cause hypotension (in severe cases, shock), dizziness (from orthostatic hypotension), dehydration, and salt craving.

Differently from mineralocorticoid deficiency, glucocorticoid deficiency does not cause a negative sodium balance (in fact a positive sodium balance may occur).

Causes[edit]

Causes of acute adrenal insufficiency are mainly sudden withdrawal of long-term corticosteroid therapy, Waterhouse–Friderichsen syndrome, and stress in people with underlying chronic adrenal insufficiency. The latter is termed critical illness–related corticosteroid insufficiency.^{[citation needed]}

For chronic adrenal insufficiency, the major contributors are autoimmune adrenalitis (Addison's Disease), tuberculosis, AIDS, and metastatic disease. Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections, hemochromatosis, and sarcoidosis.

Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol. These are adrenal destruction (disease processes leading to glandular damage), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol), or adrenal dysgenesis (the gland has not formed adequately during development).