5 ms·

Do you have any evidence for your claims? I ask because I just don't see what you are claiming in any of the conversations around the hospital, or indeed in the

Do you have any evidence for your claims? I ask because I just don't see what you are claiming in any of the conversations around the hospital, or indeed in the patient population that I am exposed to, many of whom have decades long exposure to 4g a day of paracetamol. The recommended dose of paracetamol/acetaminophen is built for the entire population. Which includes 80 year olds knocking back half a bottle of wine a day. Which is a staggeringly large percentage of 80 year olds who are actually on this cocktail day in, day out, and I am not aware of any evidence in the literature suggesting we try and cut back the enormous number of people aged 65 and above who are on this recommended max of 4g paracetamol a day, for decades. You're also giving significantly less credit to the liver than is due. Diabetes isn't hepatic dysfunction, and your liver reserve and regenerative functions are so large that unless you did permanent damage to your liver in a wildly mis-spent youth that would likely stretch over 10 years, it is very unlikely you came close to even touching the sides of your liver's capacity to totally blot that from your record (even if you show other physical and mental strains of this), unless you were using needles and managed to contract something that is going to stick around and has an affinity for the liver.

genocidicbunny 3y ago
> Do you have any evidence for your claims? Purely anecdotal, I admit, but it's also coming from conversations with doctors and nurses that I know. I also know a few people that seem to have developed gastric and hepatic issues due to long-term usage of NSAIDs, although that association is pretty strongly duck-typed. > The recommended dose of paracetamol/acetaminophen is built for the entire population. But with what sort of margin of error? The metabolic pathway for paracetamol produces some pretty toxic metabolites, that's pretty irrefutable, so like I said, you're relying on your liver metabolizing those further to non-toxic compounds quickly enough that they can't do significant damage before they've been expelled. > Which includes 80 year olds knocking back half a bottle of wine a day. Which isn't really saying much. Someone's grandfather that I know is pushing 90, smokes 2-3 packs of unfiltered Camels per day, and goes through half a case of beer every day. I'm not entirely joking when I say he might outlive me. There's also the matter that there's not a whole lot of younger people knocking back said cocktail on a daily basis, there's a bit of a bias towards the older population due to the base reasons for why you would even be chronically consuming paracetamol. So if the effects of chronic usage take years, or decades, to show, they're less likely to show up in the older populations. Also, general organ damage is not always easily differentiated from drug-induced damage in people who are already likely to have general organ damage due to age. There's not much mention in literature because the effects do take a while to show up, and generally if you're chronically consuming paracetamol, there's probably more problematic comorbidities to deal with anyways. It works well enough, for enough people, with few enough side effects, that it's generally not treated as a problem. > Diabetes isn't hepatic dysfunction You're right, that was a bit of a shortcut on my part. T2 is often related to other issues that also affect the liver, which is why I made that leap. > 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.
- robbiep 3y ago
  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=...

genocidicbunny 3y ago

> Do you have any evidence for your claims? Purely anecdotal, I admit, but it's also coming from conversations with doctors and nurses that I know. I also know a few people that seem to have developed gastric and hepatic issues due to long-term usage of NSAIDs, although that association is pretty strongly duck-typed. > The recommended dose of paracetamol/acetaminophen is built for the entire population. But with what sort of margin of error? The metabolic pathway for paracetamol produces some pretty toxic metabolites, that's pretty irrefutable, so like I said, you're relying on your liver metabolizing those further to non-toxic compounds quickly enough that they can't do significant damage before they've been expelled. > Which includes 80 year olds knocking back half a bottle of wine a day. Which isn't really saying much. Someone's grandfather that I know is pushing 90, smokes 2-3 packs of unfiltered Camels per day, and goes through half a case of beer every day. I'm not entirely joking when I say he might outlive me. There's also the matter that there's not a whole lot of younger people knocking back said cocktail on a daily basis, there's a bit of a bias towards the older population due to the base reasons for why you would even be chronically consuming paracetamol. So if the effects of chronic usage take years, or decades, to show, they're less likely to show up in the older populations. Also, general organ damage is not always easily differentiated from drug-induced damage in people who are already likely to have general organ damage due to age. There's not much mention in literature because the effects do take a while to show up, and generally if you're chronically consuming paracetamol, there's probably more problematic comorbidities to deal with anyways. It works well enough, for enough people, with few enough side effects, that it's generally not treated as a problem. > Diabetes isn't hepatic dysfunction You're right, that was a bit of a shortcut on my part. T2 is often related to other issues that also affect the liver, which is why I made that leap. > 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.

robbiep 3y ago
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=...