Positive Health Online

Case Presentation

Who/When     Milaim: 1 Year ago

Age:    Unknown

What: Disseminated Tuberculosis (TB)

Management& Outcome: Antibiotic Therapy: Cured TB But Milaim never regained strength

Problem 1:     Developed dark skin pigmentation

Problem 2:     Past weeks: Symptoms of Hypoglycaemia - 3 hours after meal

Problem 3:     Hypoglycaemic symptoms disappear > drinking orange juice

Problem 4:     Plasma fatty acid levels not elevated when hypoglycaemic  

What happened to Milaim?

Adrenals and other Infected Organs

• Tuberculosis: Contagious bacterial infection via inhaled droplets  containing Mycobacterium tuberculosis.
• Disseminated disease develops in infected people whose immune systems do not successfully heal the primary infection.
• Worldwide TB was most common cause of chronic adrenal insufficiency.
• TB causes granular tumours which infiltrate adrenal glands,  infect tissue, destroying glands.
• Loss of adrenal cortical function occurs, termed Primary Adrenal Insufficiency known also as Addison’s Disease.

What is Addison’s Disease

• Described in 1855 by Dr Addison as primary adrenal insufficiency.
• Original primary cause was TB: termed Primary Adrenal Insufficiency. Now known as Addison’s Disease or tuberculosis of adrenal glands.
• USA 75% due to idiopathic atrophy of adrenal cortex probably caused by autoimmune processes termed: Autoimmune adrenalitis. Occurs as isolated condition or Polyglandular Syndrome type 1 or 2.
• Type 1: Rare autosomal recessive condition (AIRE gene) with female predominance in children and adolescents, causing also hypo(para)thyroidism, candidiasis, diabetes I, ovarian failure, malabsorption, pernicious anaemia, hepatitis, alopecia, vitiligo  common in Finnish population and Iranian Jews.
• Type 2:  ‘Schmidt syndrome’ more common than type 1. Woman aged 20 – 40yrs familial inheritance. Causes also Hashimotos and Graves disease, diabetes mellitus, ovarian failure are all common.
• Other causes: Metastatic carcinoma, Amyloidosis, adrenal haemorrhage, sarcoidosis, fungal infections, Tumour, congenital adrenal hypoplasia, familial glucocorticoid deficiency, drugs blocking corticosteroid synthesis, inflammatory necrosis.

The Adrenal Glands

• TB granular infiltrates destroys adrenal glands, resulting in Primary Adrenal Insufficiency / Addison’s Disease.
• Inner medulla, source of catecholamines adrenaline and noradrenaline. Rich innervation by preganglionic sympathetic fibres and extension of the sympathetic nervous system.
• Adrenal cortex converts cholesterol into glucocorticoids (cortisol), mineral corticoids (aldosterone), and androgens.
• Loss of adrenal cortical function causes aldosterone and cortisol deficiency.
• Lack of aldosterone: excess sodium /water excretion from kidneys whilst retaining potassium (hyperkalaemia). Ultimately hypo-tension.
• Glucocorticoids regulate body glucose levels.

Adrenal Gland (Dis)Function in this Case

Adrenal Gland (Dis)function

Glucocorticoid deficiency & Hypoglycaemia

• Adrenal cortex failed producing adequate amounts of glucocorticoid cortisol.
• In muscle, cortisol activates protein breakdown, releasing alanine and glutamine into blood – substrates for gluconeogenesis.
• Alanine taken up by liver for gluconeogenesis. Glutamine used for fuel by small intestine and gluconeogenic substrate for kidneys.
• Cortisol deficiency therefore inhibits gluconeogenesis  in liver and Kidney, causing severe insulin sensitivity, hypoglycaemia and diminished liver glycogen results.
• Cortisol deficiency inhibits lipolysis - transfer of fatty acids from adipose cells to the liver. Glycerol also substrate for gluconeogenesis. Hence  plasma fatty acid levels are not elevated during hypoglycaemia.

Addison’s disease & Hypoglycaemia

• Cortisol deficiency results also in increased pituitary ACTH production and blood β-lipoprotein.
• Causes melanocyte-stimulating activity and, together with ACTH produces typically skin/mucous membrane hyperpigmentation seen in primary Addison’s disease only (Milaim’s case).

Hyperpigmentation

Diagnostic Tests (Plasma):

↓ Cortisol <5µg/dL 

↑ ACTH >50pg/mL  (negative feedback loss)

↑ Eosinophils  - ↑ Serum K - ↑ Urea - ↑ Hct -          

↓ WBC - ↓ Serum Na  - ↓ Fasting blood glucose (<50mg/dL)  -              ↓ Plasma Bicarbonate

Imaging Tests: Calcification in adrenal areas – Renal TB – Pulmonary TB

Summary & Treatment

• Patients with adrenal insufficiency (cortisol deficiency) develop hypoglycaemia after fasting (ca. 3hrs > meal) because of decreased gluconeogenesis resulting in diminished liver glycogen.
• In contrast patients with hypoglycaemia due to over-secretion of insulin can have attacks at any time.
• Cortisol deficiency causes decreased lipolysis (↓ fatty acids).

Addison’s Disease Treatment

• Oral Hydrocortisone 3 x day (15mg-30mg in total – less at night due to insomnia risk).
• Oral Fludrocortisone once/day to replace Aldosterone.
• Treatment delay may be fatal in hypoglycaemic patients!

Hypoglycemia Treatment

• Diet: Complex CHO & shorten intervals of food intake.
• Sucrose water - Glucose solution / tablets.
• Oral dextrose - IV dextrose in severe cases only.
• Candy other CHO foods
• Orange or other juice

References

Conlon JM. Evolution of the insulin molecule. Insights into the structure, activity and phylogenetic relationships. Peptides 2001;22:1183–93.

Cox M, Sterns RH, Singer I. The defense against hyperkalemia – the roles of insulin and aldosterone. New Engl J Med 1978;299:525–32.

Guyton AC, Hall JC. In: Textbook of Medical Physiology, Xth ed. 2000; p. 336–9, [chapter 29].

Irvine WJ, Barnes EW. Adrenocortical insufficiency. Clin Endocrinol Metab 1972; 1: 549–94.

Kong M-F, Jeff coate WJ. Eighty-six cases of Addison’s disease. Clin Endocrinol 1994; 41: 757–61.

Wang W. Regulation of renal potassium transport by dietary potassium intake. Annu Rev Physiol 2004;66:547–69.