Thread by @ebtapper

1/

WHY does #cirrhosis cause palmar erythema?
HOW is estrogen involved?
WHO is ready for a #tweetorial?

Let's talk hormones, the liver, the impact of imbalanced testosterone/estrogen, & the history of spironolactone
#livertwitter #medtwitter #MedEd

2/

Palmar erythema is:
1⃣Common (3 in 4 with #cirrhosis)
2⃣variably distributed on palm surface
3⃣caused by dilated capillaries

In 1942, Perrera showed the dilated vessels were not present on autopsy. A circulating factor must cause it.

What could it be?

3/

Enter William Bean.
He knew that:
1⃣Palmar erythema happens in🤰
2⃣A 1940 paper showed that estrogen causes capillary dilation (in🐇🐇)

So, of course, he...
injected estrogen into men w/#cirrhosis & controls without.
Those w/#cirrhosis developed palmar erythema.

4/
What does #cirrhosis have to do with estrogen?

1⃣The liver metabolizes estrogen. Jacked up livers⬆️estrogen
2⃣Testosterone can become estrogen
3⃣ #cirrhosis ⬆️conversion of testosterone 2 an estrogen
4⃣The specific metabolite (16a-hydroexyestrone) is like turbo estrogen

5/

Does estrogen/testosterone balance matter in #cirrhosis?

Yes. Yes it does!

Impacts:
1⃣physical changes - palmar erythema, spider angiomas, gynecomastia, sarcopenia, menstrual changes
2⃣Infertility, ED, decreased libido

Read: aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.10…

6/

What can be done about this imbalance of estrogen over testosterone?

You can:
1⃣Give clomiphene, a partial estrogen agonist, which⬆️testosterone levels
2⃣Inject a ton of testosterone

☹️But, in both cases, these interventions⬆️free estrogen levels

What's the deal?

7/

Q: Why is free testosterone so low in #cirrhosis?
A: ⬆️conversion to estrogen but also ⬆️Sex Hormone Binding Globulin

Fig1⃣
SHGB🫂testosterone, albumin🫂estrogen
⬆️SHGB=⬇️free testosterone,⬆️estrogen

Fig2⃣
SHGB ⬆️⬆️in cirrhosis
Cirrhosis⬇️Albumin, which⬆️estrogen

8/

SHBG and the Testosterone/Estrogen imbalance

1⃣⬆️testosterone conversion 2 estrogen
2⃣⬇️Albumin=⬆️free estrogen
3⃣⬆️estrogen=⬆️SHBG
4⃣⬆️SHBG=⬇️free testosterone

This is why SHBG correlates with palmar erythema, spider angiomas, & gynecomastia

9/

Estrogen imbalance in #cirrhosis is a problem that reflects the underlying disease.

So we would never make it worse... right?

Wrong!

Gather round for a story

10/

In 1955, a patient with Addisons was given progesterone and it was accidentally discovered that it caused increased sodium excretion by the kidney

Is … progesterone… a diuretic!?

11/

Additional experiments revealed that progesterone increases sodium excretion by blocking the action of aldosterone

12/

Based on these findings, many investigators created a family of synthetic 'progesterones' with stronger mineralocorticoid receptor antagonism.

The name for this family?
The spironolactones!

13/

Spironolactone, of course, revolutionized the treatment of hypertension related to hyper-aldosteronism and ascites - a hyperaldo state!
(Throw back to:

https://twitter.com/ebtapper/status/1338951653479882754?s=20

)

But spironolactone is not selective for the mineralocorticoid receptor!

14/

Spironolactone is "anti-androgenic"

It:
1⃣⬆️metabolic clearance (to estrogen)
2⃣⬇️testosterone production
3⃣displaces testosterone from its nuclear receptor

This has effects like gynecomastia & hair loss which are wanted or unwanted based on the clinical context

15/

SUMMARY

1⃣Palmar erythema is caused by estrogen's effects on capillaries
2⃣ #cirrhosis is associated with ⬆️estrogen/⬇️testosterone due to ⬆️T-to-E conversion, ⬆️SHBG levels,&⬇️albumin
3⃣Spironolactone, a progesterone analog, exacerbates this hormonal imbalance

End/

I hope you enjoyed this #tweetorial on palmar erythema as a window into the endocrinology of #cirrhosis

Thank you for reading. Thank you to the patients who inspire me to learn more. And thanks to @BloomPringle for her feedback.