Thread by @DPipilasMD

Why do people with cholestasis itch? The short answer is we don’t fully know. The long answer is much more interesting. Last weekend before Cards Fellowship writing my first tweetorial. Here we go! (photo by Gustave Doré)

Pruritis is a symptom associated with many cholestatic liver diseases and can be so severe it wakes patients from sleep. Some patients even scratch using knives and forks to cause pain and relieve the itching. ncbi.nlm.nih.gov/pubmed/22541702

Something the liver makes causes itch. Dr. Bergasa summarizes three observations supporting this hypothesis: cessation of itch is associated with liver failure, patients don't itch post-transplant, and fixing obstruction is associated with rapid relief. ncbi.nlm.nih.gov/books/NBK20092…

So what is building up and causing the itching in cholestasis?

In 1967, bile salts were isolated using cotton swabs from the backs of four patients with cholestasis. Authors theorized that bile acids were the culprit, but weren’t entirely convinced.
nature.com/articles/21309…

Years later, evidence against bile acids mounted. Pruritis disappears in ESLD when bile salts are highest, not all patients with cholestasis and elevated bile salts report pruritis and pruritis fluctuates independently from concentration of bile acids. ncbi.nlm.nih.gov/pubmed?term=90…

What about histamine? Histamine levels are elevated in patients with chronic cholestasis and antihistamines provide relief. However, patients don’t show erythema or edema and it's widely accepted that histamine is not the driver of cholestatic pruritis. ncbi.nlm.nih.gov/pubmed/2108078

Studies have demonstrated increased concentrations of endogenous opioids (EOs) in rats and humans with cholestasis. EOs also accumulate in the livers of patients with HCV and PBC. ncbi.nlm.nih.gov/pubmed?term=25…, ncbi.nlm.nih.gov/pubmed/8938629, ncbi.nlm.nih.gov/pubmed/12028403, ncbi.nlm.nih.gov/pubmed/18753988

Based on this observation, in 1988, Thornton and Losowsky gave 11 patients with cholestasis the opioid antagonist nalmefene. They suffered an intense opioid withdrawal-like reaction but their pruritis disappeared. ncbi.nlm.nih.gov/pubmed/3147046

The theory is that peripheral opioids cross into the CNS and cause centrally-mediated itching. Rats that underwent bile duct resection had downregulation of central opioid receptors, suggesting chronic opioid exposure. ncbi.nlm.nih.gov/pubmed/1324272

Based on this information, what drug would you use to try to treat cholestatic pruritis?

Opioid antagonists have been shown to be highly effective in several trials, but can cause a short, self-limited opioid withdrawal syndrome. One study showed significant improvement in daytime and nighttime itching with oral naltrexone. ncbi.nlm.nih.gov/pubmed?term=93…

Thanks for reading my first tweetorial! Of note, other mechanisms have been implicated (lipid signaling molecules) and there are several other treatment strategies that I didn't cover. How many patients with cholestatic pruritis have you treated with opioid antagonists?