I appreciate you taking the time to reply. Firstly, no argument on NSAIDs, their effect on gastric mucosa is well known. Paracetamol as a COX inhibitor has to

I appreciate you taking the time to reply. Firstly, no argument on NSAIDs, their effect on gastric mucosa is well known. Paracetamol as a COX inhibitor has to have some effect here but certainly not as significant as the NSAIDs. Secondly, and because it is really important to recognise, paracetamol overdose (honestly I think I could say pretty effectively that it is essentially always intentional with a very small number of accidentals in children, those with dementia or other severe issues where there is an issue with self care) is the leading cause of hospitalisation and death amongst overdose attempts, i have personally seen dozens, and so despite everything I am about to say I recognise Paracetamol as a dangerous drug that is widely available in the community. I think you may be misunderstanding some of the mechanisms and concepts around paracetamol induced liver failure and toxicity. The general qty of Paracetamol which is considered dangerous in an otherwise healthy person is around 8-10g daily, and 150-200mg/kg for children [0]. In adults, the maximum dose (at least in Australia) is 4g, so there is a massive therapeutic index/therapeutic index reserve (if that is a pharmacokinetic term, i'm pretty sure it is not) between the recommended and level you start to see damage. The damage is mediated by a secondary metabolite, of which about 10% of paracetamol goes through for secondary conjugation with glutathione which occurs really rapidly. The issue in everyone is when that secondary conjugation gets overwhelmed. You get hepatocellular necrosis which isn't something that can happen at a low level (ie it is a totally different pathology to alcoholic or cirrhotic liver disease or NASH (non-alcoholic steatohepatitis) The impression I get from your descriptions are that the damage occurs at low levels over a long time and we don't see it in the elderly because they are old when they start and then they die. There isn't anything in the pathological literature or findings that imply that this is the case, and I hope you can see from my description of the pathophysiology why that is. The occurrence of damage to the liver from paracetamol (or more specifically NAPQI) toxicity is a binary outcome. It either doesn't happen, pretty much all the time; or it happens - because the secondary pathway has been totally overwhelmed by an immense quantity of paracetamol (more than 8-10g in a regular adult) and so the NAPQI goes to work immediately killing hepatocytes en masse. Which has clinical signs and effects pretty immediately. Whilst it is true that even short-ish regular dosing leads to a mild transamininitis, which can be implied to be having an effect on the liver, it is also true that thousands of other combinations of things, including certain diets, physical activity and the like also result in this. > your liver reserve and regenerative functions are so large This is highly variable both person-to-person, but also lifestyle-to-lifestyle. Again, anecdotal, but I have heard of both ends of the spectrum -- from a heavy alcoholic having the liver function of a 12 year old kid, to someone living 'clean' that had severe cirrhosis. I'd reject this assertion. People who 'live clean' and don't have any genetic conditions that affect the liver or have contracted any illnesses that affect the liver don't develop cirrhosis. You have to belt the absolute bejesus out of your liver in order to kill it. It performs about 500 jobs, can regenerate from being half its size, and all the while keep you running - a liver takes a lot of killing. And I don't think the idea that long term regular paracetamol has any groundwork in the literature, in the minds of gastroenterologists or pathologists, or even in actual fact - and I won't until there is actual evidence of harm in these people who you say are accumulating damage at a slow rate over a number of years - because across the millions of people who are on a regime like this, it hasn't appeared to date, and they are the population who are most regularly visiting their doctor. [0] https://emedicine.medscape.com/article/820200-overview?form=fpf https://emedicine.medscape.com/article/820200-overview?form=...