Thread by @nephrotox

Thanks #medtwitter #meded #nephpearls for answering this question! As suggested by the wisdom of the crowd, the correct answer is cyanide poisoning due to "vitamin B17." (Shout-out to @J_Corky who guessed early on). See tweetorial for discussion!

https://twitter.com/nephrotox/status/1234420218077810688

@J_Corky Wait, they didn't cover that in training? Vitamin B17 is not a vitamin - it's marketed as one, though, and used as alternative therapy for cancer and "general health." Some alternative rx is innocuous - vitamin B17 is not.

@J_Corky Let's call vitamin B17 what it is - amygdalin. Amygdalin is a compound found in Prunus species seeds - peach pits, apricot seeds, bitter almonds. See that -CN (cyano) moiety at the bottom of the structure? That's right - it is hydrolyzed by gastric acid to cyanide. 2/

@J_Corky How does cyanide cause lactic acidosis? That requires a discussion of our friend the electron transport chain (or for you purists, the mitochondrial respiratory chain) and oxidative phosphorylation (oxphos). It's a "type B" lactic acidosis, but we can go deeper. 3/

@J_Corky Normally, the ETC uses the energy from oxiziding NADH and FADH2 to pump H+ into the intermembrane space. This sets up a pH gradient between the IM space and the mitochondrial matrix, which drives ATP synthesis as below: 4/

@J_Corky There are several ways for this process to be interrupted by poisoning, with the most common mechanisms being uncoupling and decoupling of oxidative phosphorylation.

@J_Corky Uncouplers (e.g, salicylates, sympathomimetic drugs like cocaine) open a separate pore - the permeability transition pore (mPTP) - which allows H+ to go back into the matrix without generating ATP. ETC actually increases activity as a result!
mPTP info: hindawi.com/journals/omcl/…

@J_Corky Remember ∆G and ∆H? Well, this process is energetically favorable and thus exothermic, resulting in heat production. This is how bears keep warm during hibernation and babies keep warm (carried out in brown fat, though all mitochondria have mPTP). Can cause hyperthermia. 7/

@J_Corky No ATP results in the patient having to carry out more anaerobic metabolism, making a smaller amount of ATP along with lactic acid. The widespread cellular dysfunction (no ATP = bad) can cause multiorgan failure, and lactic acidosis can be severe.
Uncoupling example: 8/

@J_Corky That's not what cyanide does. Cyanide is a decoupler - it binds to the ETC (cyt a3) and stops the ETC cold: 9/

@J_Corky This process also makes the PATIENT cold. Many severe cyanide poisonings result in mild-moderate hypothermia (from decreased movement of H+ / decreased metabolic rate). 10/

@J_Corky And the lactic acidosis, like uncoupling, results from increased anaerobic metabolism (and all that unused NADH reducing pyruvate ➡️ lactate). 11/

@J_Corky What's different between uncoupling and decoupling: decouplers (cyanide, azide, hydrogen sulfide) make patients MUCH sicker. Severe ATP depletion and severe acidosis often lead to shock and rapid death (minutes from exposure), especially with hydrogen sulfide. 12/

@J_Corky Because small amounts of cyanide are made as a byproduct of many biological processes, we have endogenous mechanisms of detoxification: rhodanese converts it to thiocyanate. 13/
link.springer.com/article/10.100…

@J_Corky You can eat a few apricot seeds (or bitter almonds) without peril, but not a lot - toxicity escalates rapidly when rhodanase is saturated and cyanide builds up. 14/

@J_Corky So, our patient ingested amygdalin, cyanide gets cleaved off and absorbed, rhodanese is saturated, and cyanide toxicity resulted. It took two doses in this case, and clearly wasn't profound toxicity - but we have seen much worse B17 poisoning cases. Natural ≠ safe. 15/

@J_Corky As for the other choices, methamphetamines can cause lactic acidosis through uncoupling (see tweetorial), but the patient would be sicker, hypertensive, agitated, and not resolve so quickly. 16/

@J_Corky Metformin is kind of like a decoupler (it depletes FADH2 through inhibiting mitochondrial glycerophosphate dehydrogenase) - toxicity not expected in therapeutic use without abnormal kidney function. Overdose may cause rapid rise, then fall, of lactate - but can be much worse. 17/

@J_Corky D-lactic acidosis does not raise serum lactate, and is usually due to production of D-lactate due to gut bacteria (usually bacterial overgrowth in short bowel); it causes acute encephalopathy and AG acidosis with normal serum (L-) lactate. Or propylene glycol ➡️D,L-lactate! 18/

@J_Corky (This is my first tweetorial that isn't just some long rambling rant / response to other posts, so comments / suggestions / corrections welcome!) 19/19