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All Roads Lead To Anhydroretinol: The Sneaky Vitamin A metabolite that causes Vitamin A Toxicity
Quote from tim on April 9, 2024, 7:14 pmI've been commenting on it being a bad idea to take any supplement containing manganese for years. I read something about it being involved in the development of Creutzfeldt-Jakob disease and noticed that based on RDAs that it like copper tends to be over supplied in the diet.
Masterjohn's article contains important information that I wasn't aware of.
It may be necessary for some to follow a low manganese diet however I disagree with him that everyone with a genetic predisposition to iron overload necessarily needs to start doing that.
I suspect that while HH can make one very susceptible to iron and manganese toxicity that it's not guaranteed. It may be that toxicity normally occurs once some kind of liver dysfunction occurs.
The environment and the human genome are closely entangled and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, the selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for diseases. Hereditary hemochromatosis (HH) is a potentially lethal disease leading to iron accumulation mostly due to mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype. However, both penetrance of the C282Y variant and the clinical manifestation of the disease are extremely variable, suggesting that other genetic, epigenetic and environmental factors play a role in the development of HH, as well as, and in its progression to end-stage liver diseases.
Liver dysfunction can cause iron overload in those without HH.
Several lines of evidence indicate that ferritin levels and body iron stores should be considered as hallmarks of metabolic syndrome (MetS) whose key pathogenic feature is represented by insulin resistance (IR) [54,55,56]. Patients affected by nonalcoholic fatty liver disease (NAFLD), which is considered the hepatic manifestation of MetS [57], are frequently characterized by mild hepatic iron accumulation [58]. The pathological condition that encompasses fatty liver, increased ferritin levels and enhanced body iron depots in the presence of IR, is referred to as dysmetabolic iron overload syndrome (DIOS). DIOS is observed in 15%–30% of patients with MetS and it is considered the most common iron overload disorder [59].
Hyperinsulinemia may cause iron overload.
Insulin signaling and iron homeostasis are closely entangled, as revealed by a broad number of clinical and preclinical studies [68,69]. Insulin is able to stimulate ferritin synthesis and facilitates iron uptake. In turn, increased iron concentrations lead to peripheral hyperinsulinemia [70]. The likely mechanism through which the iron excess impairs hepatocyte insulin sensitivity is due to its direct interfering with the insulin receptor and intracellular insulin signaling cascade [71]. Moreover, pancreatic β-cells are extremely sensitive to iron-related ROS, thus precipitating T2D and its comorbidities onset [60].
Hypervitaminosis A may do too.
Vitamin A is a fat-soluble antioxidant molecule and it is also involved in iron homeostasis. It has been demonstrated that Vitamin A positively affects intestinal iron absorption. Indeed, its supplementation has been shown to prevent the inhibitory effect of phytates and polyphenols on iron absorption by sequestering iron in soluble complexes thus improving non-heme iron absorption from phytates-rich foods such as rice, wheat and corn [121].
Iron and manganese dysregulation may occur via epigenetic effects.
However, the field of diet-epigenome interaction in HH and its comorbidities remains largely unexplored.
VDR receptor resistance (caused by mold, heavy metals, electrosmog, Hypervitaminosis A, liver dysfunction) may play a major role in manganese overload.
Notably, genes implicated in zinc, manganese and iron homeostasis were largely increased by vitamin D3 treatment. An ∼10-fold increase in ceruloplasmin and ∼4-fold increase in haptoglobin gene expression suggested a possible association between vitamin D and iron homeostasis. SLC30A10, the gene encoding the zinc and manganese transporter ZnT10, was the chiefly affected transporter, with ∼15-fold increase in expression. SLC30A10 is critical for zinc and manganese homeostasis and mutations in this gene, resulting in impaired ZnT10 function or expression, cause manganese intoxication, with Parkinson-like symptoms.
In conclusion, we have shown that vitamin D3 transactivates the SLC30A10 gene in a VDR-dependent manner, resulting in increased ZnT10 protein expression. Because SLC30A10 is highly expressed in the small intestine, it is possible that the control of zinc and manganese systemic levels is regulated by vitamin D3 in the intestine.
Through optimising overall health I think it may be possible for those with genetic susceptibility to iron and manganese overload to remain healthy without dietary restrictions.
If someone can maintain healthy iron levels without the use of phlebotomy that may be a good indicator for healthy manganese levels too.
Thanks for your reply, great to have intelligent discussion! Fascinating quotes! I think you are on to something that it is liver dysfunction that can lead to the problems associated with iron overload. Yeah I will never take a multivitamin with manganese in it, glad I never fell for the multivitamin junk anyway. We get plenty when we eat plant foods, I probably got more than enough when I was consuming lots of maple syrup and grape juice, at least 2 mg a day. Now I still get about that consuming beans as they are a rich source as well. But you may be right that manganese is less of an issue if you get liver functioning well, get enough vitamin D, and lower insulin. Metabolic syndrome is a killer.
My husband was heading in that direction. He was an overeater with chronic stress. He is trying out the carnivore diet as he can eat just plain meat and be happy. All that iron makes me nervous, but if the liver is the root cause then lowering his visceral fat might be a cure? It seems that way for a lot of people, I just worry about when he decides to start eating carbs again. I agree with you that glucose is our fuel source, but what about someone who is not using it properly? Just packs on fat? High triglycerides, highish blood pressure, obstructive sleep apnea, low T. And I think his insulin was too high, he was hungry all the time, always had cravings. He mostly tried to control his cravings we didn't allow junk in our life, but he didn't lose any weight just trying to control his hunger. We just set up a home gym as he loves to lift weights, so hopefully that will help with insulin sensitivity and maybe he will be able to add back carbs without excessive hunger.
Do you think part of why aspirin works is it causes some micro bleeding in the intestine? He was using that for many yrs. He finally got off it, but now I'm like maybe he should be on it to promote a little bleeding! But then Chris Masterjohn says with blood donations you have to be careful not to become toxic in manganese. He's done those too. I duno I think it's the liver. He has some liver spots showing up on his face. It's probably fatty. There's just no way around needing to lose fat.
Quote from tim on April 10, 2024, 2:59 amWe actually want more iron coming in than manganese and many on plant based diets have far too much manganese. Could explain why pant based eaters look so wrinkled.
Once manganese homeostasis regulation is disrupted then yeah eating a lot of whole plant foods may be problematic and eating an animal based diet may be best.
An animal based diet can cause liver stress though and may not facilitate the restoration of liver health.
If homeostasis is lost it signals liver dysfunction and health may not be present on any diet until normal organ function is restored.
The goal should always be to restore homeostasis not unnecessarily accept the need to eat restrictively on a permanent basis.
Have you ever read any of Jan Kwasniewski's books? He treated many patients at his sanatorium with a low carb, adequate protein, very high fat diet including many egg yolks (which provide a lot of choline to handle all the fat). It's possible this diet could be helpful for people with Type 1 diabetes as well as manganese and iron overload.
No I had not heard of Jan. Yeah I think the high fat diet can help a lot of people with insulin problems. So you would recommend egg yolks on a carnivore diet? My husband isn't doing a ton of fat yet, he eats 85 or 90% ground beef, though it seems he's been having some craving for dairy as he started putting cheese on his patty.. No eggs because he gets the sulfur farts. But maybe he should add in at least one egg yolk a day.
You're welcome. Yeah I think the science really indicates that it's extra important for those with certain SNPs to optimise their health as much as possible. SNPs mean reduced physiological function not absent physiological function. Physiological function that is often reduced by non genetic causes simultaneously.
Is your husband genetically susceptible to iron overload?
High fat diets tend to decrease insulin sensitivity whereas low fat high carb diets tend to increase insulin sensitivity. It's the opposite of what the low carb proponents say.
It's possible though that if certain micronutrients like choline and magnesium are sufficient on a high fat diet that decreased insulin sensitivity can be minimised.
Kwasniewski's diet is not a carnivore diet. It doesn't include much protein. He recommended a small amount of carbohydrate from potato or bread. I'm not recommending it just mentioning it because it would restrict both iron and manganese intake for people with hemochromatosis. He recommended multiple egg yolks per day and very fatty pork sausage.
He said that if one found a high fat diet unappealing one should consume a low fat high starch diet. In other words he thought it best to be in fat metabolism or glucose metabolism and not in glucose metabolism while consuming much fat. I'm not saying I agree with that, I see insulin resistance as being caused by liver dysfunction not by mixed carb fat diets. When fat intake goes up choline intake must too though otherwise NAFLD and insulin resistance can occur.
Egg yolks are very high in cholesterol and choline. Red meat is high in carnitine, cholesterol and choline. Increased choline and carnitine intake can increase TMA levels and a percentage of cholesterol oxidizes during cooking. Both TMA and oxysterols appear to be atherogenic. It's not known how significant this is though. The evidence points again to gut, kidney and liver health being the most important factor in terms of whether TMA and oxysterols are much of a problem or not.
There are two ways to reduce choline requirements. One is to reduce alcohol, sugar and fat intake and eat more grains, legumes and potatoes. The other is to increase trimethylglycine (betaine) intake. Unfortunately trimethylglycine can also convert into TMA though. Animal studies show that it can replace a large portion of choline requirements. The best source is quinoa followed by amaranth, wholegrain wheat, beet root and spinach.
Some foods such as garlic and olive oil reduce TMA production. People that consume a diet higher in plant foods appear to have less TMA producing flora. When researchers fed a steak to a vegan hardly any TMAO was produced.
TMA is metabolized into TMAO in the liver. TMAO appears to be correlated with heart disease. A Polish team has provided evidence to back up their hypothesis that TMA is the causative toxin, not TMAO as is more commonly believed.
I see a lower fat, lower sugar, lower animal product, high starch diet as the healthiest diet for most people. It's the most liver friendly way of eating.
When liver dysfunction occurs a lot of physiology is affected. That includes VDR receptor sensitivity and insulin receptor sensitivity. The solution to insulin resistance is not to avoid carbohydrates. It's to restore insulin sensitivity by improving liver function.
If aspirin causes gut permeability I don't think that's a good thing.
Exercise significantly improves insulin sensitivity.
I have to agree with @tim-2 that a lower fat, lower sugar, lower animal product and high starch diet is a healthy diet. The total grams of Fat, Proteins and Carbohydrates of Grant's diet is 532g. Although Grant eats beef, his proportion of Fat (47g) or 9%, Proteins (121g) or 23%, and Carbohydrates (364g) or 68% aligns with this scenario.
@fred Grant has calorie intake like 45kg 12yo girl . If I was consuming under 2000kcal let alone 1500 like Grant does. I would be walking(maybe not even walking) zombie... He is basically consuming the same amount of calories like guys in this study and look how they are looking. Like walking death. Because that will happen when you have healthy metabolism and you drop yur calories so much. I said id many times. Grants body adapted and his metabolism is very slow. The fact that he doesn't sweat says it all. There is no question that Grants diet is very low or deficient in all kinds of micronutrients especially when you are consuming so little calories. https://en.wikipedia.org/wiki/Minnesota_Starvation_Experiment
Most people would probably be healthier eating half of that protein intake in my opinion.
Glucose is protein sparing, if glycogen stores are kept topped up by eating plenty of starch protein intake can be kept low without affecting muscle mass.
Avoiding excess protein places less stress on the liver and kidneys due to reducing the need for the Urea Cycle.
@tim-2 yeah
potatoes, turnips, rutabagas, dark bread, and macaroni.
But if you were eating 1550kcal from noting but chicken breast you would starve even more than eating root vegetables and dark bread.. Simply it is not healthy amount of calories for adult male. If they were eating the same diet, but normal calorie intake like they had in control period around 3200kcal a day you would see much smaller changes in their health and body mass loss. If any.. Because as we know many people even Ray Peat said potatoes have perfect amino acid and micro nutrient profile. Dark bread also has decent amount of protein. So it is not so bad diet. But the body still needs enough calories to function properly. They even said that after starvation period they had all the protein, vitamins, minerals etc.. but their body was not recovering until they simply started increasing calories a lot..
Hi @ jiri,
It appears that Grant's calorie count is too low. However, if his weight is stable at over 160lbs, then his body is getting the calories necessary to maintain this. Micronutrients however would be a different story.
@fred yes his body had to lower metabolic rate obviously. There is plenty of even obese people who can't lose weight/burn fat on crazy low calories. Because their metabolism completely shut down. I did bodybuilding for 10+ years. I know how the body works in this regard. The goal and ideal should be eat as much calories as you can while not gaining fat and not lower calories to the point that you don't lose weight even on 1500kcal.. Females in fitness are notorious for completely crash their metabolism from chronically low calories.. They can eat even under 1000kcal and still not lose weight.. Matt Stone 180 degree health and his eat for heat had a lot of things right. The basic principles. He just pushed his ideas to far to the point where it was no longer helpful and obviously he had many things wrong like calories from cookies and ice cream are not the same as cookies from potatoes and steak, and that you don't have to overeat many thousands of calories to slowly speed up you metabolism. All it takes is 300-500kcal to slowly gain or lose weight. Also you do need to move your body and exercise. I don't know what he was thinking how can be person healthy without moving their body.. Anyway Grant is doing good in comparison with his younger self, but that doesn't meant that what he is doing is ideal for other people. Everyone is different, has completely different life style, has different goals etc.. If we are talking health, longevity and quality of life everything points to fasting, but not chronic calorie restriction. So having periods without food, but on average having adequate calorie intake so the body has no reason for slowing down metabolism, shutting down unnecessary processes in the body like hair growth, libido, drive, energy and motivation to live life to the fullest etc.. That's all I wanted to say..