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Why hypokalemia in Cushing's

Cushing's disease causes hypertension, hypokalemia, and alkalosis.

Am sure you are aware that ACTH has no control on zona glomerulosa and so no control on mineralocorticoids.

So Why?
Physiology did not answer this question with a solid evidence yet!
Some theories;

  • Cushing's causes increased corticosterone and deoxy corticosterone seen in the aldosterone pathway and they have mineralocorticoid activity. That was suggested because they found that aldosterone receptor anatogonist did not ameliorate the hypertension seen in Cushing's.
  • ACTH inhibits 11 Beta hydroxlase so in Cushing's this inhibition is lost (due to low ACTH), however, this theory was abandoned because hypokalemia was observed in Cushing's disease also (ectopic ACTH).

However, the most plausible and agreed upon explanation is that cortisol itself has some mineralocorticoid effects (that's why we see hypernatremia and hypokalemia in steroid therapy). Use this logic in answering your USMLE questions.
 

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cushing disease is synonymous with hypercortisolism. it is secondary hypercotisolism which means the problems starts from the pituitary gland (not the adrenal gland). in excess of ACTH from the pituitary, the cortisol level in z.fasciculata increases as well.

your question is if its hypokalemic and why?

u see, when the ACTH rises, it affects the z.fasciculata right? in this zone, before cortisol is made, a weak mineralocorticoid (11-deoxycorticosterone) is made in excess (due to the very high ACTH). so this high levels of weak mineralocorticoid works just as well as high levels of aldosterone. which will cause Na+ retention along with H2O (hypertension), secretion of H+ (which will cause alkalosis) and secretion of K+ (hypokalemia).

so all in all, cushind disease causes hypertension, hypokalemia and met. alkalosis.

the 2 MUST remember adrenal related syndromes/diseases for the USMLE step 1 are cushing disease and addison disease (primary dificiency of cortisol). also u should remember that when they say primary adrenal, its from the adrenal, and secondary means the pituitary related.

good luck!! pls understand cushing disease and addison disease well!!:):):)
 

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also, real sorry sabio, but the theories you found are rather confusing. pls look at the adrenal hormone metabolism carefully. there is a beautiful easy to understand explanation for any of the diseases. this adrenal hormone pathways can be found online too. (pathways of adrenal steroid synthesis)

good luck sabio!!
 

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also, real sorry sabio, but the theories you found are rather confusing. pls look at the adrenal hormone metabolism carefully. there is a beautiful easy to understand explanation for any of the diseases. this adrenal hormone pathways can be found online too. (pathways of adrenal steroid synthesis)

good luck sabio!!
Hi Seetal,

Thank you very much for the nice explanation.

Our friend lemontea did not specify whether he's asking about Pituitary or Ectopic ACTH causes of Cushing (where we have elevated ACTH) OR Adrenal or Iatrogenic Cushing (where we have depressed ACTH). I was thinking that he must be confused because in both the situations you have hypokalemia (checked all references).

So what you said, explains how high ACTH causes the effects but you did not tell us how a low ACTH (Cushing Syndrome) will cause low potassium!

Also there's another mistake in your answer, you said that 11-deoxycorticosterone is in the cortisol (fasciculata) pathway while it's not. 11-deoxycorticosterone is present in the aldosterone (granulosa) pathway and it should NOT be stimulated by ACTH. In the fasciculata pathway we have 11-Deoxycortisol which has no mineralocorticoid activity whatsoever.

The cause of hypokalemia and alkalosis is not yet understood. Because in Cushing syndrome they consistently have found normal renin and normal aldosterone blood levels. Therefore, they are thinking that it must be the cortisol itself is the cause of hypokalemia.

Check the following references;
http://www.ncbi.nlm.nih.gov/pubmed/12381548 (read the last 4 lines where they said there's no relation between ACTH level and hypokalemia and ....etc)
Also this article
http://xnet.kp.org/permanentejournal/winter09/hypertension.html

And several other articles on the web
 

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to sabio's reply

Dear Sabio,

well thanks for the linked references. good references.

however, i wasnt wrong about the 11-deoxycorticosterone having its effects in the z.fasciculata. yes it should be read primarily as in z.glomerulosa, but let me ask u, how do u get 11-deoxycortisol in the z.fascilulata? from progesterone in z.glomerulosa rite? its all interlinked. like when u have 11-beta OH deficiency how several pathways are affected. anyways, if u have the kaplan notes u can look up cushing syndrome. these are the characteristics listed for hypercortisolism (cushing syndrome):

1. protein depletion as a result of excessive protein catabolism
2. inhibition of inflammatory response n poor wound healing
3. hyperglycemia leads to hyperinsulinemia and insulin resistance
4. hyperlipidemia
5. bone dissolution and osteoporosis
6. thinning of skin with purple striae around abdomen
7. increased adrenal androgens (from zona reticularis!!)
8. MINERALOCORTICOID effects of the high levels of glucocorticoid leading to salt and water retention, hence potassium depletion and HYPOKALEMIC alkalosis.
9. redistribution of body fat

well, this is what i got from the KAPLAN notes and guyton physiology. i guess as info provided by sabio, if we wanna update ourselves then we should read his articles. but then for our exam, dont we need to clearly understand for now, that our references points towards an explanation of the hypokalemia and increase in mineralocorticoids indirectly in cushing disease? or should we stick to thinking that what happens in each zone does not affect the others? how? how? how?:confused:
 

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dear sabio,

pls if u find the time, explain then to me why the kaplan notes say that mineralocorticoid and adrenal activity increases? it has to be linked rite? like when there is def in eitehr 21-beta OH or 11-beta OH? its all linked rite??:eek::(
 

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dear sabio,

pls if u find the time, explain then to me why the kaplan notes say that mineralocorticoid and adrenal activity increases? it has to be linked rite? like when there is def in eitehr 21-beta OH or 11-beta OH? its all linked rite??:eek::(
Yah, you are right. They are all interlinked
 
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