No time to comment, but this is what happens to mice on a high fat diet, IF YOU FORGET TO ADD THE SUCROSE. I have the full text (thank you Luca via THINCS), high fat diet was about 42% of calories from LARD. Oleic acid plus PALMITIC acid (gasp and shiver, oh cardiologist). And cornstarch, no sucrose. Prof Yudkin: Yu wuz right, agin.
BTW fed and fasting plasma insulin levels and obesity were worse in the high fat mice, but at 35% of calories from corn starch that's not surprising. There was no suggestion of the massive hyperinsulinaemia seen in sucrose feeding, but levels were definitely up.
Peter
Thursday, December 17, 2009
Wednesday, December 16, 2009
Mid Winter break!
OK, the blog has been a bit quiet postwise and replywise! We move house again of Friday and the lead up to it has not been particularly easy, but we're good to go now.
As we move we will leave everything in boxes and head south (to where it is snowing, from Glasgow, where the sun is shining!) for the holiday period, about two weeks. I don't think a lot of posting will go on but we should have net access in the new house by the time we get back.
I wish everyone a great time over Christmas, New Year and the Solstice.
Best Wishes
Peter
As we move we will leave everything in boxes and head south (to where it is snowing, from Glasgow, where the sun is shining!) for the holiday period, about two weeks. I don't think a lot of posting will go on but we should have net access in the new house by the time we get back.
I wish everyone a great time over Christmas, New Year and the Solstice.
Best Wishes
Peter
Wednesday, December 09, 2009
Who pays the piper part 2
Edit 2: Have the text, many thanks all, Anna got in first. Ta!
Thanks to Chris for this one.
Could I ask for the full text please, anyone with access, to see what these jokers are up to again?
Please bear in mind that Hunter is the group leader of Black, the guy who makes people prediabetic and forgets to notice or mention it, but still puts it in the results table! Is that dumb or... Discussed here.
Hunter is owned by The Sugar Bureau, if you hadn't guessed.
BTW, my aortic stiffness, a measure of cardiovascular "age" comes out consistently at 32 years of age. Not too bad for a 53 year old on a diet pushing 40% of calories from saturated fat...
Peter
EDIT: I'll try to get to recent comments from the last post tomorrow, been a bit frantic today! But productive.
Thanks to Chris for this one.
Could I ask for the full text please, anyone with access, to see what these jokers are up to again?
Please bear in mind that Hunter is the group leader of Black, the guy who makes people prediabetic and forgets to notice or mention it, but still puts it in the results table! Is that dumb or... Discussed here.
Hunter is owned by The Sugar Bureau, if you hadn't guessed.
BTW, my aortic stiffness, a measure of cardiovascular "age" comes out consistently at 32 years of age. Not too bad for a 53 year old on a diet pushing 40% of calories from saturated fat...
Peter
EDIT: I'll try to get to recent comments from the last post tomorrow, been a bit frantic today! But productive.
Monday, December 07, 2009
Vitamin D and UV fluctuations (2)
EDIT: I feel I should just add that a number of factors came together for these last two posts. Vieth's article from Ted crystalised it. I'd been thinking about JK and vitamin D for some time and Ken supplied, years ago, several interesting papers and ideas on D3 and skin colour. I think he's talking sense.
I discussed in my last post how Dr Vieth has a model of tissue 1,25(OH)2D synthesis and degradation in which the level of active substance is pretty well independent of blood vitamin D level, provided the level is either rising or stable. I think it is also worth pointing out that he is talking, hypothetically, about tissue 1,25(OH)2D, not plasma level... As we know, almost nothing is known about tissue 1,25(OH)2D control.
By Vieth's hypothesis tissue 1,25(OH)2D is OK so long as there is at least SOME vitamin D present in plasma and the level dose not vary too much. Obviously there is a level below which you can have as much of the enzyme for converting vitamin D to the active form as you like, if there is no vitamin D in your blood you can't make any 1,25(OH)2D in your tissues, or in your kidneys for export to your blood to control calcium levels. At the lower extremes we have rickets and osteomalacia. These are clear cut, unarguable markers of vitamin D deficiency, in the absence of confounding factors (there are a few).
For reasons which will become clearer I am far more interested in what is happening at the lower levels of vitamin D availability, rather than any toxicity from high dosages.
There was a problem of clinical rickets and osteomalacia in children and women of Asian and Middle Eastern origin in Glasgow from the 1960s onwards. The problem centres around gross deficiency of vitamin D, with 25(OH)D in the plasma sitting around 20nmol/l. Some of these people develop full blown rickets or frank osteomalacia, some don't. Dunnigan appears to have spent most of his career on this problem. A simple vitamin D deficiency does not seem to be adequate for rickets, though it is required.
Here's what Dunnigan has to say on the subject:
"The discovery of late rickets and osteomalacia in the Glasgow Muslim community in 1961 (Dunnigan et al. 1962) was followed by a study of 7 d weighed dietary intakes in rachitic and normal Muslim schoolchildren and in a control group of white schoolchildren (Dunnigan & Smith, 1965). Surprisingly, the dietary vitamin D intakes of rachitic Asian children, normal Asian children and Glasgow white children were similar. The higher fibre and phytate intakes of the Asian children were not considered aetiologically significant. Studies of daylight outdoor exposure showed no significant differences between the summer and non-summer exposures of rachitic and normal Muslim schoolchildren or between Muslim and white schoolchildren (Dunnigan, 1977). These patterns of daylight outdoor exposure did not conform to the Muslim ‘purdah’ stereotype, although sunbathing was unknown in the Asian community. It was also evident that many Glasgow white schoolchildren went out relatively little, even in fine weather, in a form of ‘cultural purdah’. Similar patterns of apparently adequate daylight outdoor exposure were noted in Asian women with privational osteomalacia wearing Western dress in London (Compston, 1979). These observations did not support the hypothesis that Asian rickets and osteomalacia resulted from deficient exposure to UVR or from deficient dietary vitamin D intake relative to white women and children in whom privational rickets and osteomalacia were unknown outside infancy and old age."
What appears to make a difference in his book is meat:
"Where UVR is limited by latitude and urbanization, the prevalence of privational rickets and osteomalacia is determined by dietary factors. Limited UVR is necessary but insufficient to induce ‘cases’ of privational rickets or osteomalacia unless the diet deviates from the Western omnivore pattern. This diet is characterized by high intakes of meat, fish and eggs, and low intakes of high-extraction cereals. The Western omnivore diet provides complete protection from privational rickets and osteomalacia from infancy to old age at the low levels of dietary vitamin D intake which characterize the largely unfortified British diet and at the levels of casual exposure to UVR experienced in the high latitudes of the UK. An omnivore Western diet will not prevent hypovitaminosis D at very low or zero UVR exposure levels; by inducing mild secondary hyperparathyroidism this may contribute to the risk of type two osteoporosis in old age. As the dietary pattern moves from omnivore to vegetarian, rachitic and osteomalacic risk rise synergistically with falling exposure to UVR (Fig. 1). UVR exposure levels associated with Asian rickets and osteomalacia in the UK are similar to the casual daylight exposure levels of a substantial proportion of the urban white population. Dietary risk factors for privational rickets and osteomalacia are independent of the low vitamin D content of most foods and appear to result from interactions between constituents of animal foods (predominantly meat and meat products) and the intermediary metabolism of endogenously-synthesized vitamin D."
Dunnigan feels the evidence from Glasgow suggests that an animal based diet largely protects against bone based effects of gross 1,25(OH)2D deficiency in the plasma. Supplementary vitamin D does also work, but was only transiently taken up by the Asian community.
"The provision of free vitamin D supplements in 1979 in an effort to reduce the prevalence of Asian rickets in the city is not responsible for this trend (Dunnigan et al. 1985). Supplement uptake declined rapidly within a few years of the onset of the campaign and vitamin D supplements are now rarely consumed by Asian schoolchildren and women (Henderson et at. 1989)."
Omnivory was taken up with westernisation of the diet. Along with the disappearance of rickets there was noted the arrival of appendicitis, an excellent confirmation of the switch in diet pattern.
From all of this I would deduce that, under marginal levels of UVB in Glasgow, the primary determinant of gross clinical expression of deficiency of vitamin D is vegetarianism. There is a protective effect of meat consumption. McDonalds will do. So might reindeeer meat in the Magdalenian Basin 18,000 years ago.
Which brings me to human migration out of the tropics and in to temperate areas. We came out of Africa and across central Russia about 60,000 years ago. During/since that time we northerners have lost our bulk melanin pigment layer, except for a faint induced tinge after summer sun exposure, which presumably acts to blunt excessive vitamin D production. If we can lose our sunscreen, yet still put up a temporary sunshade of a tan, do we really need 10,000iu per day year round?
Vieth argues for generous supplementation. I cannot see any argument against maintaining modest yet minimally variable levels, based on his own hypothesis. Modest UVB exposure with a meat based diet might well be adequate.
I would then tend to leave the vitamin D paradox as a suggestion that the role of vitamin D in cancer might need re evaluating. I am quite well convinced from the Glasgow experience that catastrophic vitamin D deficiency can be largely be ameliorated by eating meat. Can "suboptimal" vitamin D deficiency relating to cancer and CVD also be optimised by eating meat? Supplementing just 100iu/d sorts out rickets but the same effect can be achieved with the occasional burger.
Most of us who have ended up on low carbohydrate eating did not think it up for ourselves. There are shoulders on which we still try to scramble. For me it was Atkins, Yudkin, Lutz, Groves and especially Kwasniewski. No one was or is advocating 10,000iu/d of vitamin D. They were/are all advocating a diet based on meat and animal fat. These pioneers did not have the EBCT tracking which is available to many of us nowadays, but their clinical experience, with all of the caveats that that needs, is that LC, animal fat based diets reverse CVD.
I can see that aiming for a middle to upper lab range is a reasonable hedging of bets. I'm not sure it is needed unless you come from a history of vegetarianism or persist in the consumption of whole meal flour, especially if coupled with near complete UV avoidance. Never forget that much of the data on vitamin D supplementation comes from a population crushed under the Food Pyramid or its derivatives, an eating plan which almost seems to have been designed to maximise disease. Vitamin D might well help under these situations, but what of those of us who eat Food?
It seems like humans can get away with vegetarianism in the tropics. Move north and you need to eat meat.
Peter
I discussed in my last post how Dr Vieth has a model of tissue 1,25(OH)2D synthesis and degradation in which the level of active substance is pretty well independent of blood vitamin D level, provided the level is either rising or stable. I think it is also worth pointing out that he is talking, hypothetically, about tissue 1,25(OH)2D, not plasma level... As we know, almost nothing is known about tissue 1,25(OH)2D control.
By Vieth's hypothesis tissue 1,25(OH)2D is OK so long as there is at least SOME vitamin D present in plasma and the level dose not vary too much. Obviously there is a level below which you can have as much of the enzyme for converting vitamin D to the active form as you like, if there is no vitamin D in your blood you can't make any 1,25(OH)2D in your tissues, or in your kidneys for export to your blood to control calcium levels. At the lower extremes we have rickets and osteomalacia. These are clear cut, unarguable markers of vitamin D deficiency, in the absence of confounding factors (there are a few).
For reasons which will become clearer I am far more interested in what is happening at the lower levels of vitamin D availability, rather than any toxicity from high dosages.
There was a problem of clinical rickets and osteomalacia in children and women of Asian and Middle Eastern origin in Glasgow from the 1960s onwards. The problem centres around gross deficiency of vitamin D, with 25(OH)D in the plasma sitting around 20nmol/l. Some of these people develop full blown rickets or frank osteomalacia, some don't. Dunnigan appears to have spent most of his career on this problem. A simple vitamin D deficiency does not seem to be adequate for rickets, though it is required.
Here's what Dunnigan has to say on the subject:
"The discovery of late rickets and osteomalacia in the Glasgow Muslim community in 1961 (Dunnigan et al. 1962) was followed by a study of 7 d weighed dietary intakes in rachitic and normal Muslim schoolchildren and in a control group of white schoolchildren (Dunnigan & Smith, 1965). Surprisingly, the dietary vitamin D intakes of rachitic Asian children, normal Asian children and Glasgow white children were similar. The higher fibre and phytate intakes of the Asian children were not considered aetiologically significant. Studies of daylight outdoor exposure showed no significant differences between the summer and non-summer exposures of rachitic and normal Muslim schoolchildren or between Muslim and white schoolchildren (Dunnigan, 1977). These patterns of daylight outdoor exposure did not conform to the Muslim ‘purdah’ stereotype, although sunbathing was unknown in the Asian community. It was also evident that many Glasgow white schoolchildren went out relatively little, even in fine weather, in a form of ‘cultural purdah’. Similar patterns of apparently adequate daylight outdoor exposure were noted in Asian women with privational osteomalacia wearing Western dress in London (Compston, 1979). These observations did not support the hypothesis that Asian rickets and osteomalacia resulted from deficient exposure to UVR or from deficient dietary vitamin D intake relative to white women and children in whom privational rickets and osteomalacia were unknown outside infancy and old age."
What appears to make a difference in his book is meat:
"Where UVR is limited by latitude and urbanization, the prevalence of privational rickets and osteomalacia is determined by dietary factors. Limited UVR is necessary but insufficient to induce ‘cases’ of privational rickets or osteomalacia unless the diet deviates from the Western omnivore pattern. This diet is characterized by high intakes of meat, fish and eggs, and low intakes of high-extraction cereals. The Western omnivore diet provides complete protection from privational rickets and osteomalacia from infancy to old age at the low levels of dietary vitamin D intake which characterize the largely unfortified British diet and at the levels of casual exposure to UVR experienced in the high latitudes of the UK. An omnivore Western diet will not prevent hypovitaminosis D at very low or zero UVR exposure levels; by inducing mild secondary hyperparathyroidism this may contribute to the risk of type two osteoporosis in old age. As the dietary pattern moves from omnivore to vegetarian, rachitic and osteomalacic risk rise synergistically with falling exposure to UVR (Fig. 1). UVR exposure levels associated with Asian rickets and osteomalacia in the UK are similar to the casual daylight exposure levels of a substantial proportion of the urban white population. Dietary risk factors for privational rickets and osteomalacia are independent of the low vitamin D content of most foods and appear to result from interactions between constituents of animal foods (predominantly meat and meat products) and the intermediary metabolism of endogenously-synthesized vitamin D."
Dunnigan feels the evidence from Glasgow suggests that an animal based diet largely protects against bone based effects of gross 1,25(OH)2D deficiency in the plasma. Supplementary vitamin D does also work, but was only transiently taken up by the Asian community.
"The provision of free vitamin D supplements in 1979 in an effort to reduce the prevalence of Asian rickets in the city is not responsible for this trend (Dunnigan et al. 1985). Supplement uptake declined rapidly within a few years of the onset of the campaign and vitamin D supplements are now rarely consumed by Asian schoolchildren and women (Henderson et at. 1989)."
Omnivory was taken up with westernisation of the diet. Along with the disappearance of rickets there was noted the arrival of appendicitis, an excellent confirmation of the switch in diet pattern.
From all of this I would deduce that, under marginal levels of UVB in Glasgow, the primary determinant of gross clinical expression of deficiency of vitamin D is vegetarianism. There is a protective effect of meat consumption. McDonalds will do. So might reindeeer meat in the Magdalenian Basin 18,000 years ago.
Which brings me to human migration out of the tropics and in to temperate areas. We came out of Africa and across central Russia about 60,000 years ago. During/since that time we northerners have lost our bulk melanin pigment layer, except for a faint induced tinge after summer sun exposure, which presumably acts to blunt excessive vitamin D production. If we can lose our sunscreen, yet still put up a temporary sunshade of a tan, do we really need 10,000iu per day year round?
Vieth argues for generous supplementation. I cannot see any argument against maintaining modest yet minimally variable levels, based on his own hypothesis. Modest UVB exposure with a meat based diet might well be adequate.
I would then tend to leave the vitamin D paradox as a suggestion that the role of vitamin D in cancer might need re evaluating. I am quite well convinced from the Glasgow experience that catastrophic vitamin D deficiency can be largely be ameliorated by eating meat. Can "suboptimal" vitamin D deficiency relating to cancer and CVD also be optimised by eating meat? Supplementing just 100iu/d sorts out rickets but the same effect can be achieved with the occasional burger.
Most of us who have ended up on low carbohydrate eating did not think it up for ourselves. There are shoulders on which we still try to scramble. For me it was Atkins, Yudkin, Lutz, Groves and especially Kwasniewski. No one was or is advocating 10,000iu/d of vitamin D. They were/are all advocating a diet based on meat and animal fat. These pioneers did not have the EBCT tracking which is available to many of us nowadays, but their clinical experience, with all of the caveats that that needs, is that LC, animal fat based diets reverse CVD.
I can see that aiming for a middle to upper lab range is a reasonable hedging of bets. I'm not sure it is needed unless you come from a history of vegetarianism or persist in the consumption of whole meal flour, especially if coupled with near complete UV avoidance. Never forget that much of the data on vitamin D supplementation comes from a population crushed under the Food Pyramid or its derivatives, an eating plan which almost seems to have been designed to maximise disease. Vitamin D might well help under these situations, but what of those of us who eat Food?
It seems like humans can get away with vegetarianism in the tropics. Move north and you need to eat meat.
Peter
Friday, December 04, 2009
Vitamin D and UV fluctuations
Before I begin I'm going to put a few simplifications in place. I'm going to talk about 25(OH)D as Vitamin D because this is the substance in the blood produced from vitamin D3 in rough approximation to intake and/or available body stores. I will leave 1,25(OH)2D, the tissue active form, as exactly that.
Let's begin.
Ted Hutchinson posted a link to Dr Reinhold Vieth's discussion of vitamin D. Dr Vieth is extremely knowledgeable about vitamin D and is looking for an hypothesis to explain the prostate/pancreatic cancer paradox.
Figure 1 sets out the paradox, which is observational in nature.
Under year round UV exposure conditions (low latitudes, broken line, "High UV") there is no association between 25(OH)D and either prostate or pancreatic cancer. At high latitudes (Solid line, "Low UV") there is a positive association between blood levels of 25(OH)D and these cancers. The average year round levels of 25(OH)D actually tend to be higher in northern latitudes, higher than those where there is year-round solar UVB.
Vieth explains that we know almost nothing about the enzymes controlling tissue 1,25(OH)2D levels and much of his discussion is extrapolated from renal enzyme activity.
Formation of 1,25(OH)2D is under the direct control of blood Vitamin D, the more Vitamin D, the more 1,25(OH)2D is formed. An increase in Vitamin D will immediately produce an increase in 1,25(OH)2D as the enzyme is just there and waiting for substrate. Eventually the production of the enzyme down regulates but by then there is plenty of 1,25(OH)2D. The degradation of 1,25(OH)2D is also under the control of blood Vitamin D. There is a lag in response of this enzyme so as blood Vitamin D rises there will eventually be increased breakdown of 1,25(OH)2D and all will be hunky dory with optimal tissue levels.
So there is no problem dealing with rising or steady state Vitamin D levels.
The bug bear is during periods of falling blood Vitamin D levels. Falling substrate produces falling production of 1,25(OH)2D but the degradation enzyme is still active and takes time to shut down in response to low blood Vitamin D levels.
The result is graph A in Figure 5.
I'll put the whole figure up with legend after the individual graphs. In northern latitudes (in my hemisphere!) there is sub optimal 1,25(OH)2D from just after the summer solstice until the UVB comes back in March. The fall is relatively slow and the rise is rapid due to the enzyme kinetic reasons detailed above. Grey hatching suggests sub optimal or pro-neoplasic levels of 1,25(OH)2D in tissues.
Vieth points out in graph C that the situation can be largely ameliorated by constantly supplementing the mean level of northern people from graph A's 40nmol/l to fluctuations around the mean level of 130nmol/l:
There are several implications from this hypothesis.
Short term studies at constant dose rates will mimic the up-swing of Spring in the northern hemisphere. They should produce optimal tissue 1,25(OH)2D concentrations. The supplementation would need to be sustained and long term benefits need long term supplementation.
Anything which produces a falling Vitamin D level will put you in to the unpleasant grey zone. Large intermittent doses are the worst case scenario and are illustrated in graph D.
Stopping your supplements or reducing your dose rate will also put you in to the grey zone.
The very simple message is, if you are going to supplement, supplement consistently and don't take more than a week off at any given time.
But life is never quite that simple. It's time to look at graph B.
Graph B is the pattern of those southerners who get a bit of all year round sun but never go over the top or under the bar for sun exposure and Vitamin D levels. The grey zones in graph B look as small as those in "supplemented" graph C to me. Ultimately it is variations in vitamin D levels which produce the grey zones.
Because the synthetic and degradation enzymes for 1,25(OH)2D adapt to blood Vitamin D levels, provided there is a basic minimum of Vitamin D, tissue levels should be OK.
I'll take a break here and come back to the implications, especially for us Glaswegians, of diet in addition to sunlight and supplementation.
Enjoy
Peter
Oh, here are the four graphs and legend all together:
Let's begin.
Ted Hutchinson posted a link to Dr Reinhold Vieth's discussion of vitamin D. Dr Vieth is extremely knowledgeable about vitamin D and is looking for an hypothesis to explain the prostate/pancreatic cancer paradox.
Figure 1 sets out the paradox, which is observational in nature.
Under year round UV exposure conditions (low latitudes, broken line, "High UV") there is no association between 25(OH)D and either prostate or pancreatic cancer. At high latitudes (Solid line, "Low UV") there is a positive association between blood levels of 25(OH)D and these cancers. The average year round levels of 25(OH)D actually tend to be higher in northern latitudes, higher than those where there is year-round solar UVB.
Vieth explains that we know almost nothing about the enzymes controlling tissue 1,25(OH)2D levels and much of his discussion is extrapolated from renal enzyme activity.
Formation of 1,25(OH)2D is under the direct control of blood Vitamin D, the more Vitamin D, the more 1,25(OH)2D is formed. An increase in Vitamin D will immediately produce an increase in 1,25(OH)2D as the enzyme is just there and waiting for substrate. Eventually the production of the enzyme down regulates but by then there is plenty of 1,25(OH)2D. The degradation of 1,25(OH)2D is also under the control of blood Vitamin D. There is a lag in response of this enzyme so as blood Vitamin D rises there will eventually be increased breakdown of 1,25(OH)2D and all will be hunky dory with optimal tissue levels.
So there is no problem dealing with rising or steady state Vitamin D levels.
The bug bear is during periods of falling blood Vitamin D levels. Falling substrate produces falling production of 1,25(OH)2D but the degradation enzyme is still active and takes time to shut down in response to low blood Vitamin D levels.
The result is graph A in Figure 5.
I'll put the whole figure up with legend after the individual graphs. In northern latitudes (in my hemisphere!) there is sub optimal 1,25(OH)2D from just after the summer solstice until the UVB comes back in March. The fall is relatively slow and the rise is rapid due to the enzyme kinetic reasons detailed above. Grey hatching suggests sub optimal or pro-neoplasic levels of 1,25(OH)2D in tissues.
Vieth points out in graph C that the situation can be largely ameliorated by constantly supplementing the mean level of northern people from graph A's 40nmol/l to fluctuations around the mean level of 130nmol/l:
There are several implications from this hypothesis.
Short term studies at constant dose rates will mimic the up-swing of Spring in the northern hemisphere. They should produce optimal tissue 1,25(OH)2D concentrations. The supplementation would need to be sustained and long term benefits need long term supplementation.
Anything which produces a falling Vitamin D level will put you in to the unpleasant grey zone. Large intermittent doses are the worst case scenario and are illustrated in graph D.
Stopping your supplements or reducing your dose rate will also put you in to the grey zone.
The very simple message is, if you are going to supplement, supplement consistently and don't take more than a week off at any given time.
But life is never quite that simple. It's time to look at graph B.
Graph B is the pattern of those southerners who get a bit of all year round sun but never go over the top or under the bar for sun exposure and Vitamin D levels. The grey zones in graph B look as small as those in "supplemented" graph C to me. Ultimately it is variations in vitamin D levels which produce the grey zones.
Because the synthetic and degradation enzymes for 1,25(OH)2D adapt to blood Vitamin D levels, provided there is a basic minimum of Vitamin D, tissue levels should be OK.
I'll take a break here and come back to the implications, especially for us Glaswegians, of diet in addition to sunlight and supplementation.
Enjoy
Peter
Oh, here are the four graphs and legend all together:
Wednesday, December 02, 2009
Liver; can you over do it?
Yes, but you have to be very unlucky!
Olga posted these links on the liver and bacon post out of personal experience but as they won't get seen there, here they are again.
Vit A toxicity 1
Vit A toxicity 2
Vit A toxicity 3
To reiterate, you have to be very, very, very unlucky to become ill from eating reasonable amounts of liver, but it does appear to be possible... For the rest of the world, outside of this small number people with specific vitamin A intolerance, enjoy liver. Bacon and onions are a great accompaniment!
Just for everyone's information.
Peter
Olga posted these links on the liver and bacon post out of personal experience but as they won't get seen there, here they are again.
Vit A toxicity 1
Vit A toxicity 2
Vit A toxicity 3
To reiterate, you have to be very, very, very unlucky to become ill from eating reasonable amounts of liver, but it does appear to be possible... For the rest of the world, outside of this small number people with specific vitamin A intolerance, enjoy liver. Bacon and onions are a great accompaniment!
Just for everyone's information.
Peter
Cirrhosis and fructose
This is the paper for continued speculation about alcoholic and non alcoholic fatty liver disease. Rats again, to begin with!
I was looking at the endotoxin levels (from Table 3) in the blood of rats on various feeding protocols. The correct level of endotoxin in your blood is zero. Endotoxin (gram negative bacterial wall components) belongs in your gut, not in your bloodstream (if endotoxin is in your blood stream one function of LDL cholesterol to mop it up. Hmmm, rosuvastatin triggers diabetes, possibly termed hepatic failure to respond to insulin correctly! Is there a link here?). It's a reasonable marker of increased intestinal permeability and a serious toxin in its own right. Ethanol increases endotoxin blood level markedly in combination with fish oil but only moderately if combined with saturated fat. So, apart from ethanol, fish oil has some influence on the increased intestinal permeability induced by alcohol. That's not too surprising if you read this paper about the effects of DHA in its own right. Now I have no idea of what 100 microM DHA means in terms of drinking a slug of fish oil or how real this cell culture system is in terms of the human gut but I can see that people going the grass fed meat route have less to be concerned about that those of us using fish oil as a supplement. And I'm sure that Christian will love the taurine link! I would suspect that the best time to take DHA might be in association with your main meal of the day if you are looking to "mimic" grass fed meat...
Endotoxin in the blood appears to be one of the best agents to convert a fatty liver to an inflamed fatty liver. The switch from fish oil to saturated fat lowers endotoxin somewhat (about halves it) but markedly reduces the products of the genes controlled by NF-kappaB. I was particularly looking at Table 4 where mRNA for COX-2, the inducible pro inflammatory cyclo-oxygenase enzyme, is reduced to zero and that for TNFalpha is markedly reduced. The mRNA for the housekeeping enzyme COX-1 is unaffected, as you would expect. It's also worth noting that fish oil/dextrose produces a zero level of mRNA for COX-2, rehabilitation fish oil somewhat in the absence of ethanol (or fructose?).
Staying on endotoxin but switching to humans and fructose, we are all well aware that fructose is "associated" with fatty liver and that this association is probably causal.
What I find far more interesting is that fructose is "associated" with increased plasma endotoxin in humans. I haven't found the intervention study to confirm a causal role of fructose on endotoxin uptake but, with the known effects of fructose on clinical NAFLD in humans, I think it will turn out to be the case. Fructose does seem to be the perfect replacement for alcohol if you want a tea-total cirrhotic liver. And be labelled a secret drinker by your hepatologist!
To summarise, both alcohol and fructose cause fatty liver. Both alcohol and fructose allow endotoxin from the gut to the bloodstream. PUFA (certainly omega 3, probably omega 6) enhance intestinal permeability effects. Endotoxin and the lipid peroxides from PUFA activate NF-kappaB. There is a cascade of inflammation in the liver as a consequence of this.
I think it is also worth noting (from table 3 again) that non haem iron is elevated in the livers of those rats with maximum endotoxin absorption. This is another aspect of the common hepatopathy of iron overload which needs thinking about.
Peter
I was looking at the endotoxin levels (from Table 3) in the blood of rats on various feeding protocols. The correct level of endotoxin in your blood is zero. Endotoxin (gram negative bacterial wall components) belongs in your gut, not in your bloodstream (if endotoxin is in your blood stream one function of LDL cholesterol to mop it up. Hmmm, rosuvastatin triggers diabetes, possibly termed hepatic failure to respond to insulin correctly! Is there a link here?). It's a reasonable marker of increased intestinal permeability and a serious toxin in its own right. Ethanol increases endotoxin blood level markedly in combination with fish oil but only moderately if combined with saturated fat. So, apart from ethanol, fish oil has some influence on the increased intestinal permeability induced by alcohol. That's not too surprising if you read this paper about the effects of DHA in its own right. Now I have no idea of what 100 microM DHA means in terms of drinking a slug of fish oil or how real this cell culture system is in terms of the human gut but I can see that people going the grass fed meat route have less to be concerned about that those of us using fish oil as a supplement. And I'm sure that Christian will love the taurine link! I would suspect that the best time to take DHA might be in association with your main meal of the day if you are looking to "mimic" grass fed meat...
Endotoxin in the blood appears to be one of the best agents to convert a fatty liver to an inflamed fatty liver. The switch from fish oil to saturated fat lowers endotoxin somewhat (about halves it) but markedly reduces the products of the genes controlled by NF-kappaB. I was particularly looking at Table 4 where mRNA for COX-2, the inducible pro inflammatory cyclo-oxygenase enzyme, is reduced to zero and that for TNFalpha is markedly reduced. The mRNA for the housekeeping enzyme COX-1 is unaffected, as you would expect. It's also worth noting that fish oil/dextrose produces a zero level of mRNA for COX-2, rehabilitation fish oil somewhat in the absence of ethanol (or fructose?).
Staying on endotoxin but switching to humans and fructose, we are all well aware that fructose is "associated" with fatty liver and that this association is probably causal.
What I find far more interesting is that fructose is "associated" with increased plasma endotoxin in humans. I haven't found the intervention study to confirm a causal role of fructose on endotoxin uptake but, with the known effects of fructose on clinical NAFLD in humans, I think it will turn out to be the case. Fructose does seem to be the perfect replacement for alcohol if you want a tea-total cirrhotic liver. And be labelled a secret drinker by your hepatologist!
To summarise, both alcohol and fructose cause fatty liver. Both alcohol and fructose allow endotoxin from the gut to the bloodstream. PUFA (certainly omega 3, probably omega 6) enhance intestinal permeability effects. Endotoxin and the lipid peroxides from PUFA activate NF-kappaB. There is a cascade of inflammation in the liver as a consequence of this.
I think it is also worth noting (from table 3 again) that non haem iron is elevated in the livers of those rats with maximum endotoxin absorption. This is another aspect of the common hepatopathy of iron overload which needs thinking about.
Peter
Tuesday, December 01, 2009
Cirrhosis and fish oil
The first paper in this post is just the abstract as Wiley Interscience are not particularly generous with access. There are lots of details about the diet (though not quite everything you would really want) in the second paper by the same group which is full text.
These people are using ethanol/fish oil as their model for alcoholic cirrhosis. Now I have been very rude about these models and I should be a little more consistent but, what the... While fish oil/ethanol is a bit strange as a diet the findings are exactly the same as for the corn oil/ethanol combo, nutrients which might warm the cockles of any modern cardiologist's heart.
Here is the first really impossible feat performed by the rats on booze. They can reverse both fatty liver and fibrosis of the liver. Stopping the alcohol intake does not do this UNLESS the fish oil is stopped and replaced with, you guessed, saturated fat. You can choose palm oil or coconut oil, either will do. Dextrose instead of alcohol won't hack it.
Let's pretend humans and rats are the same. Let's pretend fructose and alcohol are the same. Let's pretend fish oil and corn oil are the same. Good game. Probably true.
Let's think about human fatty liver progressing to hepatic fibrosis and inflammation, triggered by fructose and corn oil. I think this is common. Going to a low carb diet to treat fatty liver will clearly fail if all you do is stop the fructose. Something else is needed, something difficult to do in the current nutritional climate. You have also got stop the consumption of corn oil. You have got to eat saturated fat.
Now that is not so easy in a saturophobic climate. How many people with fructose induced hepatopathy, who have been told that the cause is "unknown" are willing to adopt a diet which is based on that ultra demonic, evolutionarily catastrophic monster: PALMITIC ACID? OMG it might increase your LDL. Better die of cirrhosis than increase your LDL!
Anyhoo, back to the fishoil 'n' booze nourished rats:
This paper tells us much more about reversing fish oil/alcohol induced liver damage in rats. The core finding is that you don't even need to stop the alcohol. Just get rid of the fish oil, provided you replace it with saturated fat. So theoretically you could continue to consume fructose while limiting your corn oil consumption, if it is correct that hepatic injury is core to metabolic syndrome...
From my point of view, if we are going to eat real foods which contain some PUFA and some fructose, simply limiting both to easily achievable limits seems a whole load better than the total elimination of one to allow extra consumption of the other...
As always, I have the greatest respect for Kwasniewski and I suspect the concept of liver disease being irreversible is completely specific to the context of the saturophobic modern nurtitional dogma. Waiting until your liver is a minute scrap of scarred fibrous tissue with a mass of non-functional hyperplastic nodules and is at end stage cirrhosis is a bit too late. Having a "mysterious" elevation in ALT is a good time to reach for the beef dripping.
NAFLD and NASH are candidates for reversal.
I'll kick around a few ideas about PUFA, endotoxin and cirrhosis in the next post.
Oh, and fish oil: I think some DHA is a good idea, it has lots of uses in cell membranes. Drinking it by the tablespoon is not something I would recommend! Getting 30% of your calories as fish oil is OUT. Do not do this.
Peter
These people are using ethanol/fish oil as their model for alcoholic cirrhosis. Now I have been very rude about these models and I should be a little more consistent but, what the... While fish oil/ethanol is a bit strange as a diet the findings are exactly the same as for the corn oil/ethanol combo, nutrients which might warm the cockles of any modern cardiologist's heart.
Here is the first really impossible feat performed by the rats on booze. They can reverse both fatty liver and fibrosis of the liver. Stopping the alcohol intake does not do this UNLESS the fish oil is stopped and replaced with, you guessed, saturated fat. You can choose palm oil or coconut oil, either will do. Dextrose instead of alcohol won't hack it.
Let's pretend humans and rats are the same. Let's pretend fructose and alcohol are the same. Let's pretend fish oil and corn oil are the same. Good game. Probably true.
Let's think about human fatty liver progressing to hepatic fibrosis and inflammation, triggered by fructose and corn oil. I think this is common. Going to a low carb diet to treat fatty liver will clearly fail if all you do is stop the fructose. Something else is needed, something difficult to do in the current nutritional climate. You have also got stop the consumption of corn oil. You have got to eat saturated fat.
Now that is not so easy in a saturophobic climate. How many people with fructose induced hepatopathy, who have been told that the cause is "unknown" are willing to adopt a diet which is based on that ultra demonic, evolutionarily catastrophic monster: PALMITIC ACID? OMG it might increase your LDL. Better die of cirrhosis than increase your LDL!
Anyhoo, back to the fishoil 'n' booze nourished rats:
This paper tells us much more about reversing fish oil/alcohol induced liver damage in rats. The core finding is that you don't even need to stop the alcohol. Just get rid of the fish oil, provided you replace it with saturated fat. So theoretically you could continue to consume fructose while limiting your corn oil consumption, if it is correct that hepatic injury is core to metabolic syndrome...
From my point of view, if we are going to eat real foods which contain some PUFA and some fructose, simply limiting both to easily achievable limits seems a whole load better than the total elimination of one to allow extra consumption of the other...
As always, I have the greatest respect for Kwasniewski and I suspect the concept of liver disease being irreversible is completely specific to the context of the saturophobic modern nurtitional dogma. Waiting until your liver is a minute scrap of scarred fibrous tissue with a mass of non-functional hyperplastic nodules and is at end stage cirrhosis is a bit too late. Having a "mysterious" elevation in ALT is a good time to reach for the beef dripping.
NAFLD and NASH are candidates for reversal.
I'll kick around a few ideas about PUFA, endotoxin and cirrhosis in the next post.
Oh, and fish oil: I think some DHA is a good idea, it has lots of uses in cell membranes. Drinking it by the tablespoon is not something I would recommend! Getting 30% of your calories as fish oil is OUT. Do not do this.
Peter
Cirrhosis and corn oil
I think it is becoming clear that the collection of problems known as metabolic syndrome appear to centre around liver pathology. I accidentally ended up in these posts via iron overload and MODY1 of all things. Anyway, here's an introduction to the strange world of alcohol research in lab rats.
First I've got to apologise for these next few posts. They are mostly based around rats, fed by surgically implanted gastric canulae, with bizarre diets formulated to be fed as a liquid by constant rate infusion 23 out of 24h a day. Don't ask me why the rats got an hour off! I have to admit that I personally think lab rats are more like humans than many other observers do, but that may be because I've had so many of them as pets over the years. These rats do a number of things which are supposed to be impossible and a number which are just interesting.
Before we go to alcohol, lets just look at saturated fat and weight gain. These diets are isolacoric to the nth degree. There is no need to correct for caloric intake. They all got the same, 23/7. So we are not talking appetite here, just calories in vs calories out. All diets were 45% fat with protein and carbs also held constant. The table doesn't specifiy but you can be certain that the carbohydrate will be glucose or a glucose precursor. If you are looking at alcoholic cirrhosis you're not going to feed fructose!
Table 1 gives you the diet composition. That 45% of calories from fat was either pure corn oil or had increasing amounts replaced by a mix of beef and MCT fats. The highest saturated fat group had 30% of calories from saturated fat and 15% from corn oil.
Table 3 gives you the weight gain. Just look at the control groups: "Eat" corn oil as your sole source of fat and you gain 5.5g/d. Replace some of that corn oil with 10% of calories from saturated fat and there is a similar weight gain but go to 20% of calories as saturated fat and weight gain drops to 4.9g/d and go to 30% of calories from saturated fat and weight gain is 3.8g/d.
Under isocaloric conditions, simply switching from something quite like butter or coconut oil to "heart healthy" sunflower oil will make you FAT. Of course if you are used to eating butter and someone cooked your eggs in yellow boot polish you might lose weight because you would spit the "food" out on the floor anyway!
The rats got no choice. Corn oil fattens relative to a beef/coconut fat mixture.
Now it's worth looking at the effect of alcohol on liver pathology. This is best shown in Figure 2.
Without alcohol the lipid composition of the diet has no effect on liver pathology (small black bars). Replace carbohydrate with ethanol and the lipid source of the diet determines you liver pathology. Corn oil is catastrophic. By the time you are eating 30% of your calories as saturated fat and only 15% as corn oil your liver is almost OK. I leave it to anyone's eye to follow the trend and think about a diet which has 45% of it's calories as saturated fat and none as corn oil.
To me the message is clear. In the presence of ethanol the determinant of your liver pathology is the amount of corn oil you "drink". Fish oil does the same, the next few posts all use fish oil.
If anyone thinks that fructose is different to alcohol in it's effect on the liver, you're wrong!
I think the Food Standards Agency in the UK must have some sort of shares in liver transplantation programs or hardware.
Oh, another aspect of this study; at a given level of corn oil the weight gain was always less in the alcohol group than in the control group. Alcohol calories were being substituted for carbohydrate calories. Alcohol is not insulogenic, carbohydrate is. I'd expect alcohol to be associated with less weight gain as blood insulin levels would be lower. Come back Gary Taubes. You wus right agin! Dr Jebb, it's not a closed system.
Peter
First I've got to apologise for these next few posts. They are mostly based around rats, fed by surgically implanted gastric canulae, with bizarre diets formulated to be fed as a liquid by constant rate infusion 23 out of 24h a day. Don't ask me why the rats got an hour off! I have to admit that I personally think lab rats are more like humans than many other observers do, but that may be because I've had so many of them as pets over the years. These rats do a number of things which are supposed to be impossible and a number which are just interesting.
Before we go to alcohol, lets just look at saturated fat and weight gain. These diets are isolacoric to the nth degree. There is no need to correct for caloric intake. They all got the same, 23/7. So we are not talking appetite here, just calories in vs calories out. All diets were 45% fat with protein and carbs also held constant. The table doesn't specifiy but you can be certain that the carbohydrate will be glucose or a glucose precursor. If you are looking at alcoholic cirrhosis you're not going to feed fructose!
Table 1 gives you the diet composition. That 45% of calories from fat was either pure corn oil or had increasing amounts replaced by a mix of beef and MCT fats. The highest saturated fat group had 30% of calories from saturated fat and 15% from corn oil.
Table 3 gives you the weight gain. Just look at the control groups: "Eat" corn oil as your sole source of fat and you gain 5.5g/d. Replace some of that corn oil with 10% of calories from saturated fat and there is a similar weight gain but go to 20% of calories as saturated fat and weight gain drops to 4.9g/d and go to 30% of calories from saturated fat and weight gain is 3.8g/d.
Under isocaloric conditions, simply switching from something quite like butter or coconut oil to "heart healthy" sunflower oil will make you FAT. Of course if you are used to eating butter and someone cooked your eggs in yellow boot polish you might lose weight because you would spit the "food" out on the floor anyway!
The rats got no choice. Corn oil fattens relative to a beef/coconut fat mixture.
Now it's worth looking at the effect of alcohol on liver pathology. This is best shown in Figure 2.
Without alcohol the lipid composition of the diet has no effect on liver pathology (small black bars). Replace carbohydrate with ethanol and the lipid source of the diet determines you liver pathology. Corn oil is catastrophic. By the time you are eating 30% of your calories as saturated fat and only 15% as corn oil your liver is almost OK. I leave it to anyone's eye to follow the trend and think about a diet which has 45% of it's calories as saturated fat and none as corn oil.
To me the message is clear. In the presence of ethanol the determinant of your liver pathology is the amount of corn oil you "drink". Fish oil does the same, the next few posts all use fish oil.
If anyone thinks that fructose is different to alcohol in it's effect on the liver, you're wrong!
I think the Food Standards Agency in the UK must have some sort of shares in liver transplantation programs or hardware.
Oh, another aspect of this study; at a given level of corn oil the weight gain was always less in the alcohol group than in the control group. Alcohol calories were being substituted for carbohydrate calories. Alcohol is not insulogenic, carbohydrate is. I'd expect alcohol to be associated with less weight gain as blood insulin levels would be lower. Come back Gary Taubes. You wus right agin! Dr Jebb, it's not a closed system.
Peter
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