Congenital adrenal hyperplasia- an example of gene error in enzyme expression: the defect in one enzyme, ‘backlashes’ in the other.

 The human body is like a test tube. Thousands of reactions, catalysed by enzymes go on simultaneously. The system of reactions are intricately interconnected, in as much, that the slowing or absence of enzyme activity in one pathway leads to a compensatory increase in the interconnected pathways. The system is analogous to a traffic blockade in a thoroughfare, that leads to spontaneous diversion of the traffic to the adjacent interconnected roads. The biochemical ‘conglomerate’ runs mechanisms that propels the human body to struggle and survive. Stressors are plenty and the body responds adequately and timely. The adrenal gland is the seat of the response to stress. Adrenaline from adrenal medulla fills the body with energy and ‘strength’ in the hour of acute stress. Simultaneously, at all times, be it the ‘acute stress’ or otherwise, the adrenal cortex continuously ‘infuses’ the  corticosteroids into the circulation to maintain the state of ‘vigil’ required for ‘existence’. The adrenal cortex synthesises three important hormones- the Glucocorticoids, mineralocorticoids and androgens. The parent ‘raw material’ of the three hormones is same, and is nothing but cholesterol. In Congenital Adrenal Hyperplasia (CAH), the enzymes synthesising aldosterone and cortisol are partially or completely repressed. Low serum cortisol exerts a feedback stimulation on the pituitary to produce large quantities of ACTH. The result of ACTH action on adrenal cortex is adrenal hyperplasia. However, the adrenal overgrowth is not able to produce aldosterone or cortisol. Instead, the enzymatic machinery is diverted towards production of large amounts of androgens. Depending upon the degree of enzyme repression, a female child may present with ambiguous genitalia at birth or virilization features with growth; a male child may develop precocious puberty; and both male and female child may present at birth with extreme salt wasting, vomiting, dehydration, hyponatremia and failure to thrive. While extreme salt wasting and dehydration is an emergency, necessitating fluid and electrolyte replacement, long term management of the condition involves replacements ment of  cortisol or aldosterone or both depending upon the deficiencies. Surgical management of ambiguous genitalia is not a life saving measure but options for corrective surgical procedures should be kept open for the proper psychological and social rehabilitation of the patient.

The ‘other side’ of paracetamol : overdosage

 One of the most commonly used antipyretic and analgesic is paracetamol. Considered to be very safe with the least nephrotoxic potential, it is widely prescribed in all age groups. Like most lipid soluble drugs, paracetamol is metabolised in the liver. The major metabolites are sulphate and glucoronide conjugates of the drug which are highly water soluble and rapidly eliminated from the body. A minor metabolite is N acetyl p aminobenzoquinone Imine (NAPQI) formed by CYP2E1. With increase in dose, the major pathways are saturated, and the formation of  the metabolite NAPQI increases. NAPQI has hepatotoxic potential. The endogenous scavengers ( read glutathione) detoxify the toxin but in overdosage of paracetamol, the scavengers are overwhelmed and hepatotoxicity occurs. The antidote recommended for treatment of paracetamol induced liver injury is N acetyl cysteine. N acetyl cysteine is an antioxidant and is a precursor of  glutathione and therefore replenishes tissue glutathione stores. Replenished glutathione detoxify NAPQI and prevent hepatic injury.

Steroids: the ‘manna dew’ or the ‘devil’s bait’

 Steroids are hormones which are indispensable for physiological functions. In naturally occurring conditions of deficiency of these hormones, the treatment of choice is replacement in required doses. 

Steroids have also anti-inflammatory actions at supra-physiological doses. The bulk of indications of steroids are attributed to their anti-inflammatory action. Steroids do not alter the causative factor but provides symptomatic relief by suppressing inflammation.

So, while the hormone replacement therapy is used for adreno-cortical insufficiency and congenital adrenal hyperplasia, the list of indications of the anti-inflammatory use of steroids is ‘endless’.

Adverse effects with replacement therapy are rare because they are simply the replacement of the physiological requirements with the right dose. Side effects which are dose dependent may occur during dose adjustment or lack of proper monitoring.

On the other hand, anti-inflammatory doses which are supra physiological are very commonly associated with adverse effects. The incidence of adverse effects increases with the dose and duration of therapy. While hyperglycaemia, fluid retention, delayed wound healing, secondary infections can occur immediately after steroid initiation, fat redistribution, osteoporosis, myopathy, peptic ulcer and cataract can occur in the long run.

An inevitable consequence of long term steroid therapy is suppression of the hypothalamus-pituitary adrenal axis. It is generally innocuous during ongoing steroid therapy, but if abruptly stopped, will land the patient in acute adrenal crisis. The condition is life threatening. So any steroid therapy which is continued for more than two weeks is gradually tapered with decrease in the daily dose every week allowing time for the HPA axis to regain its normal functioning.

In the end, we can say that steroids are life saving drugs  (Manna’s dew) providing relief and solace to the suffering millions but if used improperly can turn the Manna’s dew into the ‘devil’s bait’.