Fruit and Diabetes - some evidence

May 18, 2017, 3:54 pm

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It's a commonly discussed paradox of sorts - how can fruit have a negative association with diabetes in epidemiology when it's full of sugar?

Two recent papers from China go some way towards clearing this up in my opinion. One is a prospective study of Type 2 Diabetes risk, in which a difference is seen between different classes of fruit; apples are good, tropical fruits - pineapples, mangos, and bananas are not, but the effect is staggered by gender.[1]
Results: In 494,741 person-years of follow-up, 5207 participants developed T2DM. After adjustment for lifestyle and dietary risk factors, high total fruit consumption was not consistently associated with lower T2DM risk [men: HR of 1.33 (95% CI: 1.04, 1.71) for 3 or more servings/d compared with less than 1 serving/wk (P-trend = 0.17); women: HR of 0.88 (95% CI: 0.71, 1.11) (P-trend = 0.008); P-interaction = 0.003]. The direct association in men was observed for higher–glycemic index (GI) fruit [HR: 1.51 (95% CI: 1.22, 1.86) for 1 or more serving/d compared with rarely consumed; P-trend = 0.001] but not for lower or moderate GI fruit. In women, the consumption of temperate fruit, but not of subtropical or tropical fruit, was associated with lower T2DM risk [HR: 0.79 (95% CI: 0.67, 0.92) for 1 or more serving/d compared with rarely; P-trend = 0.006].

Conclusions: The consumption of temperate fruit, such as apples, was associated with a lower risk of T2DM in women, whereas the consumption of higher-GI fruit, such as bananas, was associated with higher risk in men. The impact of fruit consumption on the risk of diabetes may differ by the type of fruit, which may reflect differences in the glycemic impact or phytochemical content.

A second Chinese paper looked at fruit consumption in the second trimester and risk of gestational diabetes.[2] (This was posted by gestational diabetes expert Lily Nichols @LilyNicholsRDN on her blog)
As epidemiology goes, this paper has signs of class - look at table 1, where they have actually gone to the trouble to check that their respondents are representative of the whole population canvassed by giving the baseline characteristics of the people who didn't want too be in the study, who are well-matched with the people they included. This is textbook stuff, but I can't remember the last time I saw it done. Fruit intake was fairly high - 740g a day in the upper quartile.

An increase in total fruit consumption during the second trimester was associated with an elevated likelihood of GDM (highest vs. lowest quartile: crude OR, 3.20; 95% CI, 1.83 to 5.60). After adjustment for age, education, occupation, income level, pre-pregnancy BMI, gestational weight gain, family history of diabetes, smoking status and alcohol use in Model 1, a significantly higher likelihood of GDM was still observed in the third and fourth quartiles for total fruit consumption (OR 2.81; 95% CI 1.47 to 5.36; OR 3.47; 95% CI 1.78 to 6.36, respectively). After adjustment for potential confounding factors in Model 1 plus the consumption of grain, vegetables, meat and fish, the ORs for the lowest to the highest quartiles of fruit consumption were 1.00 (reference), 1.08 (95% CI 0.50 to 2.34), 3.03 (95% CI 1.54 to 5.94) and 4.82 (95% CI 2.38 to 9.76), respectively.

These are some huge ORs - what about type of fruit?

Comparison of fruit subtypes revealed that a greater consumption of pome fruit was associated with a lower likelihood of GDM (crude OR 0.59; 95% CI 0.37 to 0.96). The OR of GDM in the highest tertile of pome consumption was almost half that in the lowest tertile. However, the association attenuated to null after adjusting for potential confounding factors in Models 1, 2 and 3. Compared with the lowest tertile, the second tertile for consumption of gourd fruit was inversely associated with the likelihood of GDM, but this inverse association was neither observed in the highest tertile nor in the overall trend (P trend = 0.346). The adjusted ORs in Model 3 across the lowest to highest tertiles of fruit consumption were 1.00 (referent), 0.27 (95% CI 0.11 to 0.66) and 0.94 (95% CI 0.45 to 1.95), respectively. In contrast, compared with the corresponding lowest tertiles, the highest tertiles for consumption of citrus and tropical fruit were each related to a higher likelihood of GDM (adjusted OR in Model 3, 2.26; 95% CI 1.29 to 3.99; adjusted OR in Model 3, 3.73; 95% CI 1.74 to 8.01, respectively). Berry consumption was initially positively associated with GDM, but this association was attenuated to null in Model 3 (highest vs. lowest tertile in Model 3: OR, 1.69; 95% CI 0.80 to 3.56).

Ignore the berry association, it's obvious from the CIs that people didn't eat enough berries to give much of a result. But pomes are apples and pears, and again they look good. Why?

They also assessed the results by GI:

The increased consumption of fruit with moderate to high GI values was significantly associated with a higher likelihood of GDM. Compared with the lowest quartile, the highest quartile for consumption of fruits with moderate to high GI was associated with a higher likelihood of GDM (crude OR 3.04; 95% CI 1.80 to 5.06; adjusted OR in Model 3, 2.94; 95% CI 1.47 to 5.88).

High GI fruits were pineapple, mango, citrus. The authors hypothesised about effects of polyphenols, but this didn't really go anywhere.
Here's what I think; apples and pears are the only fruits you can't juice with your bare hands. When you eat an orange, you're swallowing juice and pulp separately. When you eat an apple, you're still swallowing them together, mostly. And this, I think, is what makes the difference. It takes longer for the sugar to appear in your blood, so people with an already impaired phase 1 insulin response are less affected by it, and the slower digestion produces a more satiating and less insulinogenic gut hormone response.
Of course it's possible that people with a sweet tooth ate the sweeter fruit and that a sweet tooth indicates some sort of internal starvation predictive of diabetes, but even so, eating the sweeter, juiceable fruit is not going to help.

The amount of fruit associated with a lower risk of diabetes in meta-analysis, as with pome fruit here ("one or more serving/day") is relatively low and would fit in many low carb diets (the same is true of wholegrains and legumes - the studies that say that these foods are associated with protection don't say that very high intakes are needed at all). Not that this effect, whatever it is, would be important or needed in a low carb diet, but it is available unless your preferred carb intake is under 50g. If people do include sweet or starchy carbs in their diet, the types of carbs are important.
Very important.

Also see Gannon and Nuttall's study comparing a 40% carb diet high in intrinsic sugars (fruit, milk, root veges) with a 60% carb diet high in starch.[3]

[1] Alperet DJ, Butler LM, Koh W-P et al. Influence of temperate, subtropical, and tropical fruit consumption on risk of type 2 diabetes in an Asian population. Am J Clin Nutr. 2017: ajcn147090
http://ajcn.nutrition.org.sci-hub.bz/content/early/2017/02/07/ajcn.116.147090.short?rss=1&related-urls=yes&legid=ajcn;ajcn.116.147090v1

[2] Huang W-Q, Lu Y, Xu M, Huang J, Su Y-X, Zhang C-X. Excessive fruit consumption during the second trimester is associated with increased likelihood of gestational diabetes mellitus: a prospective study. Scientific Reports. 2017;7:43620. doi:10.1038/srep43620.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341573/

[3] Gannon MC, Nuttall FQ, Westphal SA, Fang S, Ercan-Fang N. Acute metabolic response to high-carbohydrate, high-starch meals compared with moderate-carbohydrate, low-starch meals in subjects with type 2 diabetes. Diabetes Care. 1998 Oct;21(10):1619-26.
https://www.ncbi.nlm.nih.gov/pubmed/9773720

↧

Gilbert's Syndrome - a user's guide

June 3, 2017, 2:48 pm

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Last week I received some liver test results from my last follow-up visit to Auckland Clinical Services after clearing HCV genotype 3 in the Phase 3 Epclusa trial mentioned here.

ALT and AST were gratifying low at 12 and 15 U/L respectively, albumin healthy at 45 g/L, but total bilirubin was high at 23 umol/L despite direct bilirubin being low at 3 umol/L. The normal reference range for total bilirubin is 3-21 umol/L.
I've seen this before in LFT results and been told that it's consistent with Gilbert's syndrome, and I know that my brother has been told that he has Gilbert's syndrome. I vaguely remembered something about Gilbert's syndrome being a protective factor for heart disease. This meant nothing to me when I had no way of assessing this sort of health claim, but I thought it was worth looking into. And what I found was surprising - not only is the Gilbert's association real, but bilirubin level across the whole range may be something worth including in risk calculations.

In the first paper I found, the incidence of IHD was 2% in the Gilbert's sample, 12% in the case-matched general population.[1] The Gilbert's population had higher HDL but "According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD." The elevated antioxidant status in the Gilbert's cases would help to explain the higher (and probably more functional) HDL anyway.

Franchini et al have supplied an excellent review of the Gilbert's CVD link; their paper is a model of clarity in writing and layout.[2] Bilirubin is a breakdown product of heme, supposed by some authors to be the lethal ingredient in the toxic food red meat. However I could find no evidence that heme intake relates to meat intake, and have heard of vegans with Gilbert's syndrome. Indeed the Paleo Ketogenic Diet researchers have used an all-meat diet to manage an extreme case of Gilbert's syndrome (there is such a thing as excessive bilirubin, but this is not usually what is meant by Gilbert's Syndrome in adults).[3]

One of the most heartening findings is that not only Gilbert's syndrome but also higher bilirubin within the normal range is associated with independence in the elderly.[4]
"The OR of functional dependence for each standard deviation increment in the serum total bilirubin level was 0.56 (P = 0.002). After additional adjustment, the inverse association remained essentially unchanged. In quartile-based analysis, participants with higher quartiles of serum total bilirubin tended to have lower ORs of functional dependence. The trends of lower likelihood of functional dependence across increasing quartiles of the serum total bilirubin level were statistically significant (P= less than 0.05 for all trends)."
Bilirubin tends to increase with age and is not associated with reduced mortality over the age of 70 (but who cares if you're functionally independent). However, it's likely that survivor bias also applies. Bilirubin might even explain the changing LDL-associated risk in the elderly - because those with lower bilirubin were more likely to have had heart attacks when younger, and bilirubin rises with age, a healthy older population may have a higher % of people with Gilbert's syndrome or higher bilirubin and be protected from oxidised LDL and thrombosis, the two main benefits of higher bilirubin.
That Gilbert's syndrome also protects against platelet hyperactivity and thrombosis supports the various CVD hypotheses of Malcolm Kendrick and Gregory D. Sloop.[5]
Elevated levels of bilirubin are associated with reduced risk of cardiovascular disease especially in Gilbert's syndrome.
- Platelet hyper-activity due to oxidative stress increases the risk of thrombosis, and therefore myocardial infarction.
- Bilirubin may inhibit platelet activity by interacting with collagen and ADP receptors, or by improving resistance to oxidative stress.
- Inhibiting platelet activity may represent one mechanism to explain protection against cardiovascular disease leading to mortality in mildly hyperbilirubinemic individuals.

Bilirubin is a lipid soluble antioxidant which is easily recycled via biliveridin reductase.
"Bilirubin protects polyunsaturated fatty acids from lipid peroxidation, thus preventing damage by reactive oxygen species to cell membranes and proteins."[6]
Gilbert's syndrome is associated with a lean phenotype. Is this because of its inhibitory effect on omega-6 peroxidation? It is also associated with a reduced risk of NAFLD and type 2 diabetes.

However, Gilbert's syndrome has a dark side; the reduction in glucuronidation that results in elevated bilirubin can also alter estrogen metabolism and has been associated with an increased risk of hormone-sensitive breast cancer.[7]
"Patients with Gilbert syndrome have an impaired function of the enzyme UGT1A1, responsible for the degradation of 4-OH-estrogens. These elements are produced by the degradation of estrogens and are well-known carcinogens. In theory, patients with Gilbert syndrome accumulate 4-OH-estrogens and, therefore, might have a higher risk for breast cancer, especially when exposed to higher levels of estrogens."
In fact, because CVD is more of a risk for men, and women can expect longer lives in any case, the benefits of Gilbert's syndrome are probably not spread equally between the sexes. Avoidance of alcohol, which is estrogenic and associated with breast cancer risk, might be more important in women with Gilbert's.
A further risk with Gilbert's syndrome is that impaired function of the enzyme UGT1A1 means that some drugs, including acetaminophen (paracetamol) will be more active and there is theoretically a lower safety margin.[8] However the antioxidant activity of bilirubin may render this point moot with regard to acetaminophen, if not other drugs.

In any case bilirubin, especially if it can be assessed from more than one blood draw, and is not likely to be affected by drugs or liver disease, seems like something that should be used in risk assessment. There is, for example, probably not much point in prescribing a statin to someone with high bilirubin, not that there is any point in prescribing statins to healthy people anyway.

Can bilirubin be hacked? Phycobilin from algae such as spirulina, and phytochrome from green leafy vegetables, are analogous chemicals with similar properties, but will be less effective if they are not recycled by biliveridin reductase.

References

[1] Vítek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V, Novotný L, Kotal P. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis. 2002 Feb;160(2):449-56.

[2] Franchini M, Targher G, Lippi G. Chapter 3 – Serum Bilirubin Levels and Cardiovascular Disease Risk: A Janus Bifrons? Advances in Clinical Chemistry. 2010. 50; 47–63.
https://www.dropbox.com/s/nzhg9llideyg91d/franchini2010.pdf?dl=0

[3] Tóth C, Clemens Z. Gilbert’s Syndrome Successfully Treated with the Paleolithic Ketogenic Diet. American Journal of Medical Case Reports 2015; 3(4): 117-120.
http://pubs.sciepub.com/ajmcr/3/4/9/

[4] Kao TW, Chou CH, Wang CC et al. Associations between serum total bilirubin levels and functional dependence in the elderly. Intern Med J, 2012; 42: 1199–1207. doi:10.1111/j.1445-5994.2011.02620.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1445-5994.2011.02620.x/abstract
[5] Kundur AR, Singh I, Bulmer AC. Bilirubin, platelet activation and heart disease: A missing link to cardiovascular protection in Gilbert's syndrome? Atherosclerosis. 2015; 239(1): 73–84.
http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.042

[6] Läer S, Apel M, Bernhardt J, Kapitulnik J, Kahl R. Interactions between bilirubin and reactive oxygen species in liver microsomes and in human neutrophil granulocytes. Redox Rep. 1997; 3(2):119-24. doi: 10.1080/13510002.1997.11747098.
[7] Astolfi RH, Bugano DD, Francisco AA et al.Is Gilbert syndrome a new risk factor for breast cancer? Medical Hypotheses. 2011; 77(2): 162-164.
(See also https://www.dropbox.com/s/cfoadvmigzozymw/Breast%20Cancer%20AA.pdf?dl=0 )

[8] de Morais SM, Uetrecht JP, Wells PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology. 1992; 102(2):577-86.

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Low fat dairy recommendations for children completely lack an evidence base, to put it mildly

July 31, 2017, 2:46 pm

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"There is no finer investment for any community than putting milk into babies."

— Sir Winston Churchill (1874-1965) Radio broadcast (March 21, 1943)

After reading about the Toddler Paradox on the Care Factor Critical blog, I wondered what evidence was cited in New Zealand to support recommendations for low fat milk, lean meat, and so on in the diets of children. These recommendations were revised in 2015, so should be based on up-to-date science. And, if not, they should at least be based on science, right? Totality of the evidence and all that - if there's evidence that bears directly on the question, it should be cited?

Not in the background document for these recommendations - none of it is cited. Perhaps because none of it supports the recommendations? Surely not. Perhaps because the scientists signing off on the document were too busy to check? Who knows.

Here is the background document:

Ministry of Health. 2012. Food and Nutrition Guidelines for Healthy Children and Young People (Aged 2–18 years): A background paper – Revised February 2015. Wellington: Ministry of Health.
https://www.health.govt.nz/system/files/documents/publications/food-nutrition-guidelines-healthy-children-young-people-background-paper-feb15-v2.pdf

It contains the following statement, reinforced - with great specificity - in all menu examples –

Reduced- and low-fat milk is suitable for children aged two years and over, as long as growth is occurring normally. Therefore, it is recommended that children transition from standard homogenised (dark blue) milk to low-fat (green or yellow) milk from two years of age.

1) The Boyd Orr Cohort is selectively cited

There are few if any relevant citations in the document - the Boyd Orr cohort is interesting because it follows the long-term health of children raised in an era - the 1930's - when many fatty animal foods were considered health foods. Sources of saturated fat in these diets were dairy and meat, and tallow used for deep frying in in fish and chip shops, which were the only fast food outlets. There are two relevant Boyd Orr papers, but only one, from 1998, was cited.

[1] Gunnell DJ, Frankel SJ, Nanchahal K, et al. 1998. Childhood obesity and adult cardiovascular mortality: a 57-year follow-up study based on the Boyd Orr cohort. American Journal of Clinical Nutrition 67: 1111–18. LINK

Is cited to support the claim that childhood obesity increases the risk of cardiovascular disease and early mortality.

“Compared with those with BMIs between the 25th and 49th centiles, the hazard ratio (95% CI) for all-cause mortality in those above the 75th BMI centile for their age and sex was 1.5 (1.1, 2.2) and for ischemic heart disease it was 2.0 (1.0, 3.9)”

However the 2005 Boyd Orr cohort paper relating to saturated fat intake and cardiovascular and all-cause mortality was not cited.

[2] Ness AR, Maynard M, Frankel S, et al. Diet in childhood and adult cardiovascular and all cause mortality: the Boyd Orr cohort. Heart. 2005;91(7):894-898. doi:10.1136/hrt.2004.043489.

In this paper fat and saturated fat were not associated with the outcomes attributed to obesity in the earlier paper, and were non-significantly protective, making it unlikely that higher fat and saturated intake in this cohort either contributed to childhood obesity or had any adverse effect on the outcomes strongly associated with childhood obesity, i.e. all-cause mortality and cardiovascular disease.

“The age, energy, and sex adjusted rate ratio between the highest and lowest quartiles of total fat intake was 0.89 (95% CI 0.46 to 1.72, p for trend 0.80). The fully adjusted rate ratio between the highest and lowest quartiles of total fat intake was 0.87 (95% CI 0.38 to 2.00, p for trend 0.80). The age, energy, and sex adjusted rate ratio between the highest and lowest quartiles of saturated fat intake was 0.70 (95% CI 0.38 to 1.29, p for trend 0.30). The fully adjusted rate ratio between the highest and lowest quartiles of saturated fat intake was 0.62 (95% CI 0.28 to 1.37, p for trend 0.30).”

The 2005 Boyd Orr cohort paper bears directly on recommendations made often in the 2015 document and is from a body of research which was found evidential enough to be included as the 1998 paper; it should have also been included.

2) observational studies on low fat vs whole milk and dairy in children

No papers were cited in the document that directly support (or otherwise directly relate to) the recommendation to drink “Low fat calcium enriched milk” in place of whole milk.

There are, as well as relevant papers that were available at the time of writing the document, also more recent papers showing that whole milk consumption is associated with leaner BMI in children.

[3] Vanderhout SM, Birken CS, Parkin PC, Lebovic G, Chen Y, O’Connor DL, Maguire JL; TARGet Kids! Collaboration. Relation between milkfat percentage, vitamin D, and BMI z score in early childhood. Am J Clin Nutr 2016;104:1657–64. LINK

“Among the 2745 included children there was a positive association between milk-fat percentage and 25(OH)D (P = 0.006) and a negative association between milk-fat percentage and zBMI (P less than 0.0001). Participants who drank whole milk had a 5.4-nmol/L (95% CI: 4.32, 6.54) higher median 25(OH)D concentration and a 0.72 lower (95% CI: 0.68, 0.76) zBMI score than children who drank 1% milk. Milk volume consumed modified the effect of milk-fat percentage on 25(OH)D (P = 0.003) but not on zBMI (P = 0.77).”

The following paper is important for ruling out a role of reverse causation in the others.

[4] Prentice P, Ong KK, Schoemaker MH, et al. Breast milk nutrient content and infancy growth. Acta Paediatrica (Oslo, Norway : 1992). 2016;105(6):641-647. doi:10.1111/apa.13362.

“Higher HM TCC was associated with lower 12‐months body mass index (BMI)/adiposity, and lower 3–12 months gains in weight/BMI. HM %fat was inversely related to 3–12 months gains in weight, BMI and adiposity, whereas %carbohydrate was positively related to these measures. HM %protein was positively related to 12‐months BMI.”

[5] Rolland-Cachera MF, Maillot M, Deheeger M, Souberbielle JC, Peneau S, Hercberg S. Association of nutrition in early life with body fat and serum leptin at adult age. Int J Obes (Lond) 2013;37:1116–22. LINK

“In adjusted linear regression models, an increase by 100 kcal in energy intake at 2 years was associated with higher subscapular skinfold thickness (β=6.4% SF, 95% confidence interval 2.53–10.30, P=0.002) and higher FFM (0.50 kg, 0.06–0.95, P=0.03) at 20 years. An increase by 1% energy from fat at 2 years was associated with lower subscapular skinfold thickness (−2.3% SF, −4.41 to −0.18, P=0.03), lower FM (−0.31 kg, −0.60 to −0.01, P=0.04) and lower serum leptin concentration (−0.21 μg l−1, −0.39 to −0.03, P=0.02) at 20 years."

[6] Alexy U, Sichert-Hellert W, Kersting M, Schultze-Pawlitschko V. Pattern of long-term fat intake and BMI during childhood and adolescence—results of the DONALD study. Int J Obesity Relat Metab Dis. 2004;28: 1203–9. LINK

“The mean BMI during the study period differed significantly, with the highest BMI in the low fat intake cluster.”

Consistent with a review of the evidence in adults

[7] Kratz M, Baars T, Guyenet S. The relationship between high-fat dairy consumption and obesity, cardiovascular, and metabolic disease. Eur J Nutr. 2013;52:1–24. LINK

“The observational evidence does not support the hypothesis that dairy fat or high-fat dairy foods contribute to obesity or cardiometabolic risk, and suggests that high-fat dairy consumption within typical dietary patterns is inversely associated with obesity risk.”

One Brazilian study which could be interpreted as supporting the recommendation - though it is at best ambiguous - found that higher full-fat dairy consumption was associated with higher triglycerides in obese and overweight children eating fewer servings of full-fat diary than recommended in that country. However no comparison with low-fat dairy was available. Saturated fat and full-fat dairy were not associated with higher LDL cholesterol (non-significant correlation of full-fat dairy with lower LDL, multivariate linear regression coefficient −0.38 (−0.77;0.01) p=0.06)

[8] Rinaldi AEM, de Oliveira EP, Moreto F, Gabriel GFCP, Corrente JE, Burini RC. Dietary intake and blood lipid profile in overweight and obese schoolchildren. BMC Research Notes. 2012;5:598. doi:10.1186/1756-0500-5-598.

3) trial evidence.

Few trials have tested the effect of increasing fat and saturated fat from dairy in the diets of children, due to current recommendations to do the opposite. However the available example shows that this does not result in harm in the context of a nutritionally adequate diet.

[8] van der Gaag EJ, Wieffer R, van der Kraats J. Advising Consumption of Green Vegetables, Beef, and Full-Fat Dairy Products Has No Adverse Effects on the Lipid Profiles in Children. Nutrients 2017, 9(5), 518; doi:10.3390/nu9050518.

"In children, little is known about lipid profiles and the influence of dietary habits. In the past, we developed a dietary advice for optimizing the immune system, which comprised green vegetables, beef, whole milk, and full-fat butter. However, there are concerns about a possible negative influence of the full-fat dairy products of the diet on the lipid profile. We investigated the effect of the developed dietary advice on the lipid profile and BMI (body mass index)/BMI-z-score of children. In this retrospective cohort study, we included children aged 1–16 years, of whom a lipid profile was determined in the period between June 2011 and November 2013 in our hospital. Children who adhered to the dietary advice were assigned to the exposed group and the remaining children were assigned to the unexposed group. After following the dietary advice for at least three months, there was a statistically significant reduction in the cholesterol/HDL (high-density lipoproteins) ratio (p < 0.001) and non-HDL-cholesterol (p = 0.044) and a statistically significant increase in the HDL-cholesterol (p = 0.009) in the exposed group, while there was no difference in the BMI and BMI z-scores. The dietary advice has no adverse effect on the lipid profile, BMI, and BMI z-scores in children, but has a significant beneficial effect on the cholesterol/HDL ratio, non-HDL-cholesterol, and the HDL-cholesterol."

The diet advice in this trial also resulted in a decrease in respiratory infections, possibly an outcome of interest with regard to the New Zealand population and the incidence of rheumatic fever.

Thus it appears that the Ministry of Health document was prepared without a proper literature search, and that no-one involved in the 2015 version was familiar with the extensive literature regarding a specific recommendation that was being made.

I'm aware that there are controversies in nutrition science, but this does not appear to be one. The evidence is all on one side, and yet it is being ignored by people who think they know better.

With what results we see.

↧

Fibre and the risk of Type 2 Diabetes - the InterAct meta-analysis

December 5, 2017, 8:07 pm

≫ Next: My first podcast interview, over at Break Nutrition

≪ Previous: Low fat dairy recommendations for children completely lack an evidence base, to put it mildly

Recently the Australian government publicised claims generated by Nutrition Australia, in an opinion paper funded by Kellogg's, that Australians increasing their cereal fibre intake could reduce the cost of CVD and diabetes to the Australian economy:

“This research demonstrates that if Australian adults use grain fibre to increase their intake of dietary fibre to target intake levels for chronic disease risk reduction (28g for women, 38g for men):

• The potential healthcare expenditure savings would be approximately $1 billion for CVD and over $285 million for T2D in 2015–16. The savings for CVD would represent approximately 0.6% of total Australian health expenditure and savings for T2D would be around 0.2% of health expenditure.

• The potential productivity cost savings were estimated to be approximately $600 million for CVD and $1.4 billion for T2D. The savings for CVD represent approximately 0.04% of gross domestic product (GDP) and for T2D, approximately 0.08% of GDP.

The total combined economic savings could potentially reach $3.3 billion.”

Zoe Harcombe looks into the evidence base here and finds it lacking; however as her article requires a subscription and she asked me to look at the evidence to try to make sense of some convoluted manipulations, I'm going to discuss some extra aspects of the main type 2 diabetes study used, the EPIC-InterAct study and its meta-analysis.[1]

This paper presents the results from a large multicentre epidemiological study from the EPIC cohorts, followed by what is supposed to be a meta-analysis of prospective epidemiological studies (more on that later).The EPIC-InterAct data is the "news" here, and it doesn't support the hypothesis that cereal fibre prevents type 2 diabetes when adjusted for age and sex, or for "lifestyle, diet and BMI" but does in the purely lifestyle and diet adjusted models.
However, if we look at the forest plot, we can see that the associations are all over the place, and there are many countries without a protective association, including France with a non-significant HR of 1.72. Another outlier is the UK with an HR of 0.74 (NS).

What are the differences in these populations? The French cohorts, for some reason, are all 100% female, which isn't the case for any other country. And the largest of the two UK cohorts is EPIC-Oxford.[2]
"The majority of participants recruited by the EPIC Oxford (UK) centre consisted of vegetarian and “health conscious” volunteers from England, Wales, Scotland, and Northern Ireland"
So these health conscious volunteers are probably being compared with people with lower fibre intakes in the less health-conscious UK cohort.
Sweden always interests me because one of their two cohorts is the Malmo Diet and Cancer Study, which uses a 7-day food diary for all subjects, and in Sweden the HR is a more reasonable 0.96. So less confounding by conscientiousness and more accurate diet recall tends to minimize the cereal fibre and type 2 diabetes association. If cereal fibre prevented type 2 diabetes in any important way, it should show up in most of these populations, not just a few.

The InterAct authors then follow up this rather inconsistent evidence by including it in a meta-analysis of all other prospective cohort studies on the question. This is an example of advocacy epidemiology - our study didn't convincingly support our belief, so we'll incorporate it into the totality of less relevant evidence that does. Presumably an intention of InterAct is to inform European dietary recommendations, for which the European evidence is most relevant, and for which it seems to say that the effect of cereal fibre on type 2 diabetes risk depends a great deal on what country you're a citizen of, so cannot be guaranteed either way.

Lo and behold the larger meta produces the strongly supportive associations that informed the Australian Kellogg's paper.
But hang on.
At least one of the studies included, the Finnish Diabetes Prevention Study, isn't a prospective cohort study at all - it's a mixed intervention of diet and exercise advice vs no intervention.
This simply should not have been included. It's a small study so shouldn't have biased the result too much if at all, but it doesn't inspire confidence that the selection of studies for inclusion was as rigorous as it should have been. (It's discussed and excluded from an analysis in a supplementary paper, so this isn't an error).
There are 3 Australian studies, two small ones with protective associations and a large one, Hodge 2004, with none.[3] However Hodge 2004 finds that white bread is associated with type 2 diabetes, and that lower GI carbs, including sugar, aren't. White bread in Australia is so bad that even sugar looks good by comparison. Does it follow that putting a few grams of bran in white bread will improve it? Why not just say "avoid white bread"? Anyway, if fibre isn't associated with type 2 diabetes in a fairly large sample of Australians, who as Zoe Harcombe pointed out tend to have fairly high fibre intakes anyway by OECD standards, why do Aussies need to take their lead from the USA?
Because most of the weighty studies in favour of fibre for type 2 diabetes prevention in the meta-analysis come from the USA. There are two important facts about the USA - low fibre intakes are lower than they are anywhere else (so basically a high intake of deep fried food, white breads, and soda in these groups), and conscientiousness is an identifiable confounding factor in many populations. For example, the Nurses' Health Study and Health Professionals' Follow-up Study; here we have the populations not only given the most advice about fibre being healthy, but also given the job of passing it on to the other US populations. In other words, grain fibre - like red meat - is one of the signifiers separating conscientious Americans from other Americans (it's harder to eat fruit and vege without their fibre, and vege in the US includes fried potatoes). It's almost a class distinction.

Look at this subgroup analysis of the "dose response" (ESM Table 3) - it's ALL about the USA. Zoe and I couldn't get our heads around how this "dose-response" was calculated from such diverse studies that all had differing groupings and cut-offs, but even taken at face value, why would an Australian government claim it showed any health savings for Australians?
If we compare diabetes prevalence between countries with mean fibre intakes, the USA with its abnormally low fibre intake for a high-cereal society fits, but other countries don't.

"The mean±SD fibre intake in the subcohort was 22.9± 6.2 g/day (ranging from 19.9 g/day in Sweden to 25.2 g/day in Denmark; data not shown)."

Germany (7.40%) and Denmark (7.20%) have higher diabetes prevalence rates than Sweden (4.70%). USA's mean total fibre intake is 16.1 g/day and diabetes prevalence is 10.80%.
Germany and Denmark were the other populations in EPIC-InterAct where fibre had some protective association with type 2 diabetes. I'm not sure about T2D, but the amount of wholegrain associated with a modest degree of ischaemic CVD protection in Malmo was only 2.5 servings a day, and there was a protective association between fibre (mostly cereal) and saturated fat (a high SFA, high fibre diet was the most protective combination).[4,5]
We are probably seeing - in all these studies - a protective effect of eating high quality food with a minimal human interference factor (dairy and ryebread in Scandinavia) and belonging to the social class that is more likely to do this. With regard to iCVD bran may be a "failsafe" source of silicon, needed for vascular resilience and repair (you can get silicon from other foods and water, but bran in a staple food would guarantee it was present in the diet), but it is hard to see how this applies to T2DM. If a microbiotal mechanism was strongly involved, presumably other types of fibre would be more protective than they are. I come back to what whole grains are not. They are not white bread, and what is white bread? It used to be made with alloxan, a chemical used to produce experimental diabetes in animals. Today it contains

INGREDIENTS: White Bread (Enriched Wheat Flour (Flour, Malted Barley Flour, Niacin, Iron(Ferrous Sulfate, Reduced Iron), Thiamine Mononitrate, Riboflavin, Folic Acid), Water, Yeast, Salt, Soybean Oil, Sugar, Malt, Dough Conditioners(Ascorbic Acid, Calcium Sulfate, Sodium Stearoyl Lactylate),Calcium Propionate(To Retard Mold Growth))

ALLERGENS: Wheat, Soybeans, Gluten

This Harvard-supplied list is incomplete - NZ white bread contains soy protein; Tip Top's omega 3 loaf supplies;

Wheat Flour, Water, Soy Fibre, Baker's Yeast, Wheat Gluten, Vinegar, Iodised Salt, Vegetable Gum (412), Soy Flour, Canola Oil, Tuna Oil (0.05%) (Contains Fish, Soy), Milk Protein (Sodium Caseinate), Emulsifiers (481, 471, 472e), Vitamins (Thiamin, Folate, Vitamin E, Niacin, Vitamin B6), Minerals (Iron, Zinc).

Woah - the fibre isn't even grain fibre, and there are 3 emulsifiers. Emulsifiers are experimentally linked to obesity and diabetes.

So it's hard to rule out that whole grains just tend to replace a cause of type 2 diabetes in some societies.

So, if you're an American eating a lot of starch from fibre-free foods, replacing these with whole grain foods (which for one thing won't be cooked in oil) should decrease your risk of type 2 diabetes. Replacing them with anything closer to nature will likely have the same effect.
If you're a European, Brexit will be bad news, because you won't be able to move to the one place where fibre is really protective, but you can still go to Sweden and enjoy the best of both worlds.
If you're an Australian, ask yourself, do I eat like the average American who isn't health conscious? If the answer is yes, then sprinkling a bit of bran on your food won't save you. But if you avoid bread or cereals altogether, are you at extra risk of type 2 diabetes? That's what we really want to know, and what none of the epidemiology can tell us at all, unless it's the risk marker epidemiology, which as far as I know says low TG/HDL, high LDL, low HbA1c = lowest T2DM risk.

References

[1] The InterAct Consortium. Dietary fibre and incidence of type 2 diabetes in eight European countries: the EPIC-InterAct Study and a meta-analysis of prospective studies. Diabetologia. 2015;58(7):1394-1408. doi:10.1007/s00125-015-3585-9.ghbhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472947/

[2] The InterAct Consortium, Langenberg C, Sharp S, et al. The InterAct Project: An Examination of the Interaction of Genetic and Lifestyle Factors on the Incidence of Type 2 Diabetes in the EPIC Study. Diabetologia. 2011;54(9):2272-2282. doi:10.1007/s00125-011-2182-9.

[3] Hodge AM, English DR, O'Dea K, Giles GG. Glycemic index and dietary fiber and the risk of type 2 diabetes. Diabetes Care. 2004;27:2701–2706. doi: 10.2337/diacare.27.11.2701

[4] Wallström P, Sonestedt E, Hlebowicz J, et al. Dietary Fiber and Saturated Fat Intake Associations with Cardiovascular Disease Differ by Sex in the Malmö Diet and Cancer Cohort: A Prospective Study. Obukhov AG, ed. PLoS ONE. 2012;7(2):e31637. doi:10.1371/journal.pone.0031637.

[5] Sonestedt E, Hellstrand S, Schulz C-A, et al. The Association between Carbohydrate-Rich Foods and Risk of Cardiovascular Disease Is Not Modified by Genetic Susceptibility to Dyslipidemia as Determined by 80 Validated Variants. Müller M, ed. PLoS ONE. 2015;10(4):e0126104. doi:10.1371/journal.pone.0126104.

↧

My first podcast interview, over at Break Nutrition

January 30, 2018, 1:19 pm

≫ Next: Uncoupling - Saturated fatty acids and glucose are preferred muscle fuels, but unsaturated fats act as buffers

≪ Previous: Fibre and the risk of Type 2 Diabetes - the InterAct meta-analysis

Raphi Sirt of Break Nutrition interviewed me last week for a podcast. This was a far-ranging interview that took me to some unexpected places - but was a chance to expand on the big-picture stuff and the unanswered questions around the situational hypercholesterolaemia that marks the lean mass hyper-responder phenotype and the lessons about insulin resistance hidden in statin trials.

http://breaknutrition.com/episode-37-george-henderson-takes-us-tour-public-health-research/

"But who really knows what this all means?"

For (much) more background on the LMHR question, please also visit Dave Feldman's blog. If you don't know his work, and you're interested in lipids (whether yours or other peoples') I promise your mind will be blown by the Inversion Pattern amongst other matters.

http://cholesterolcode.com/are-you-a-lean-mass-hyper-responder/

http://cholesterolcode.com/impact-of-endurance-running-on-cholesterol/

Also look into the other Break Nutrition podcasts - I know Tucker Goodrich and Gabor Erdosi recorded a very interesting discussion recently, and I'm going to see what else there is.

↧

Uncoupling - Saturated fatty acids and glucose are preferred muscle fuels, but unsaturated fats act as buffers

April 3, 2018, 4:04 pm

≫ Next: Never attribute to pathology what can be adequately explained by adaptive physiology

≪ Previous: My first podcast interview, over at Break Nutrition

An intriguing new study looked at 2 different types of enteral feeding in 60 critically ill patients for 7 days. The fat-based formula was 37%E glucose, so this was not a test of a low carb diet, and predictably the differences in glucose and insulin AUC, though trending in the right direction, were not significant.[1]

The significant finding was higher resting energy expenditure (REE) in the higher-fat group.

In my opinion this was not an effect of higher fat feeding but an effect of a high intake of a particular type of fat – no-one in the real world would ever eat 45% of energy as fat from rapeseed and sunflower oil exclusively (if nothing else, natural protein foods would supply other fats not found in the protein isolate used here).

“Fat-based EN formulas contain 45% fat, 37% carbohydrates, 18% protein, and 2.3 g of fiber per 100 ml, whereas glucose-based EN formulas are comprised of 30% fat, 55% carbohydrates, 15% protein, and contain 1.5 g of fiber per 100 ml. Both formulas have a caloric density of 1 kcal/ml and contain rape seed oil and sunflower oil. Initial assessment of resting energy expenditure (REE) was performed for each patient using the technique of indirect calorimetry. Target energy was 25% above the measured REE [13]. Both study groups received early EN that was initiated with the target dosage and continuously administered at a constant rate for 7 days via a nasogastric tube.”

The diet was very high in monounsaturated and polyunsaturated fat, and very low in saturated fat.

Unsaturated fats are well-known to activate uncoupling proteins in the mitochondria of muscle and adipose cells (in brown adipose tissue, there is good evidence that saturated fats can drive uncoupling; brown adipose is a highly functional cell type that exists for this sort of thing rather than storage, so I’m going to ignore it for now).[2,3]

I’m really interested in fuel use by muscle. The big, novel question in physiology today bar none is the lean mass hyper-responder lipid profile discovered by Dave Feldman (@DaveKeto). Because this relates to muscle mass/fat mass (and activity) ratio, and because different fatty acids in people eating normal diets have differential effects on lipid profiles, it’s necessary to know how muscles use fats before we investigate whether this can influence a lipid profile.

Effect of fatty acids on D-[U-14C]glucose oxidation in 1h incubated rat soleus (A) and extensor digitorium longus (EDL) (B) muscles. Muscles were incubated for 1 h in the absence or presence of 10 mU/mL insulin and/or 100 μM of different fatty acids.

Here’s a study on two types of muscle cell isolated from rats which shows a different effect of saturated vs unsaturated fats in extensor digitorium muscle (the soleus muscle, A, is less clear but I'm going with B for now; however the faster oxidising (medium chain) SFAs in A behave like palmitate in B).[4] To summarise the findings, unsaturated fats activate uncoupling; that is, a proportion of the potential energy released by their beta-oxidation is wasted, instead of generating ATP (the more double bonds, the more uncoupling). And this wastage – which will produce extra heat - allows the cell to burn extra glucose at the same time to make up the shortfall in ATP.

This is what is meant by unsaturated fats improving insulin sensitivity. Glucose and saturated fatty acids are the two preferred fuels of muscle cells, but they exist in competition. At times of energy excess, they would be at loggerheads if both were available together without other “softer” fuels. The effect of unsaturated (uncoupling) fats is to buffer the potentially harmful effect of this competition, by occupying the beta-oxidation mechanism (carnitine etc) yet leaving some ADP free for both glucose and SFA catabolism to convert to ATP. When glucose is restricted, the saturated fat level of the blood falls, despite a higher intake, because the competing effect of glucose and its insulin-driven uptake is removed. At this extreme, the buffering effect of unsaturated fat is unnecessary. At fat intakes below 37%, on the other hand, a differential effect on insulin sensitivity can more easily be detected, because glucose is the primary fuel, and insulin is driving SFA synthesis and retention.

(Thus the low fat diet, especially with refined carbs at current availability, was the very thing that painted us into the corner where there might be some reason to worry about the types of fat we use! Who the hell wants to be in that shithole.)

Strictly speaking we don’t need to consume unsaturated fats (beyond tiny EFA amounts of PUFA) because we can make oleic acid MUFA from SFA by DNL elongation and desaturation, although there is genetic variation in the ability to do this. Realistically speaking, this separation of SFA from MUFA in the diet is never going to happen anyway. Humans eat fat of all types, not SFA, MUFA or PUFA.

Although linoleic acid was an uncoupling fat in muscle in vitro, muscle in vivo may not be using much of this fuel. LA has a high rate of conversion to other lipids (cholesterol and SFA) in liver, is used to make eicosanoids and is otherwise peroxidizable, and is still stored in adipose in amounts that seem excessive in proportion to dietary intakes. In practical terms, oleic acid (C18:1) is probably always the dominant uncoupling fatty acid in muscle, and the more unsaturated fats (which would uncouple more) are lousy fuels. This might(?) help to explain the prevalence of CPT1A mutations, which suppress fatty acid oxidation on high fat diets, in populations with a high take of fat from oily fish (Inuit, Faroe Islands, Northern Japan).[5]

There’s another pathway by which UFA protects against SFA-glucose competition in muscle – in humans, triglyceride synthesis always requires at least one UFA.[6] So you can’t store any excess of SFA that turns up in a cell without some UFA; this is also a form of buffering that clears the track for whichever of the preferred fuels is dominant. Without it, incoming glucose would drive SFA elongation into excess ceramide, and the cell would be stuffed.

So in our critically ill population, an enteral diet very high in unsaturated fats produced a higher REE through uncoupling, and improved insulin sensitivity non-significantly (the control diet was relatively high in UFA by normal standards anyway). I’m not sure what the split of muscle vs adipose and other tissue fuel use would have been for bed-rest REE (I'm only using that study for a kicking-off point here). I’m told that elevated REE isn’t desirable in the critically ill. Maybe one day a more sensible enteral formula including, say, beef fat will be tested.

If you are overeating on a higher carb diet, the various energetically futile aspects of UFAs could be protective of your metabolism (but the eicosanoids and peroxidation products of PUFAs, especially LA, could well catch up with you eventually if you rely on those rather than MUFA). If you are restricting carbs, working hard, undereating or IF, or otherwise burning fat, do you really want to generate a lot of heat for less available energy? I can’t see a high degree of uncoupling being of benefit in endurance activities where heat loss is maxed out. I can’t see it being anything but exhausting. Even the Inuit may(?) have evolved to side-step it to some extent.
\

references

[1] Wewalka M, Drolz A, Seeland B, et al. Different enteral nutrition formulas have no effect on glucose homeostasis but on diet-induced thermogenesis in critically ill medical patients: a randomized controlled trial. European Journal of Clinical Nutrition. 2018;72,496–503
doi:10.1038/s41430-018-0111-4

[2] Graier WF, Trenker M, Malli R. Mitochondrial Ca2+, the secret behind the function of uncoupling proteins 2 and 3? Cell calcium. 2008;44(1):36-50. doi:10.1016/j.ceca.2008.01.001.

[3] Romestaing C, Piquet M-A, Bedu E, et al. Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutrition & Metabolism. 2007;4:4. doi:10.1186/1743-7075-4-4. LINK

[4] Hirabaraa SM, Silveiraa LR, Alberic LC, et al. Acute effect of fatty acids on metabolism and mitochondrial coupling in skeletal muscle. Biochimica et Biophysica Acta (BBA) - Bioenergetics
Volume 1757, Issue 1, January 2006, Pages 57-66. LINK

[5] https://yk-health.org/images/3/36/Arctic-Variant-CPT-1.pdf

[6] Henique C, Mansouri A, Fumey G, et al. Increased Mitochondrial Fatty Acid Oxidation Is Sufficient to Protect Skeletal Muscle Cells from Palmitate-induced Apoptosis. J Biol Chem. 2010;
285, 36818-36827. LINK

↧

Never attribute to pathology what can be adequately explained by adaptive physiology

June 18, 2018, 8:07 pm

≫ Next: A Grand Unified Theory of Polyunsaturated Fatty Acid Misbehaviour in Inflammatory Disease

≪ Previous: Uncoupling - Saturated fatty acids and glucose are preferred muscle fuels, but unsaturated fats act as buffers

When this paper stumbled across my desk the other day my first thought was of course "Aha! Linoleic acid not so hot, this explains lack of benefit in RCTs as analysed by Steve Hamley".[1]

Unsaturated Fatty Acids Inhibit Cholesterol Efflux from Macrophages by Increasing Degradation of ATP-binding Cassette Transporter A1.[2]

http://www.jbc.org/content/277/7/5692.full

I still think, maybe it does - once there's a pathology in the house, which was often the case in those RCTs - but I can think of an alternative explanation, connecting this paper with my previous post.

It's not obvious why MUFA (oleic acid is the only MUFA ever worth considering, which is odd given the diversity of saturated fats and their effects) should be bad for reverse cholesterol transport. It's in everything that supplies SFA in, overall, comparable amounts, and is 60% of your adipose fat.
Unsaturated Fatty Acids Reduce Cellular ABCA1—Because
ABCA1 controls the rate of apoA-I-mediated lipid efflux, we
assayed the effects of fatty acids on the cell membrane content
of ABCA1. Incubating cells with unsaturated fatty acids caused
a significant decrease in membrane ABCA1 (Fig. 4A). In contrast,
saturated fatty acids had no or little effect on ABCA1
levels. As with lipid efflux, oleate and linoleate reduced ABCA1
membrane protein in a concentration-dependent manner (Fig.
4B). We compared the effects of stearate and linoleate on the
plasma membrane content of ABCA1 by treating cells for 6 h
with fatty acids, biotinylating cell-surface proteins, isolating
ABCA1 by immunoprecipitation, and assaying for biotinylated
(cell-surface) ABCA1 with a streptavidin probe. Results
showed that linoleate, but not stearate, reduced both the total
and plasma membrane content of ABCA1.

Nutritional studies have shown that different fatty acids

have diverse effects on lipoprotein metabolism. It is believed

that substituting dietary saturated fatty acids with cis-unsaturated

fatty acids protects against cardiovascular disease by

lowering plasma LDL levels (reference is Hu et al the way to Willett, 1997).
Our results suggest that,

although reducing atherogenic particles, these dietary manipulations

may suppress cholesterol efflux from macrophages.

This may partially explain why a meta-analysis of clinical

trials showed only a small cardiovascular risk benefit with

modified dietary fat intake.(Ref is Hooper et al, 2001)

The culture medium DMEM supplies 1000mg/L glucose, that's 100 mg/dL or 5.5 mmol/L.

But think - what is the use of this? Remember the last post - UFAs promote fat storage, SFAs do not.
If the macrophage is storing fat, it needs to retain some cholesterol; if it cannot store fat, because all the fat is SFA and mammalian cells cannot synthesise a TG from 3 SFAs, it might as well release cholesterol normally.
That's what I think is going on. Of course, if the macrophage is always storing fat and cholesterol because glucose and insulin are always high, that's part of the pathology (excess lipid droplet formation leading to creation of foam cells), and functionality will be impaired by UFAs in the manner described in this paper as regulation fails to keep pace with overactivation, but we also have to think of every cell in the body as not only performing a function but also as an obligate consumer of the body's different fuels. Even macrophages need something to eat, and even macrophages might want to put a little aside for later when there's a lot on the plate.
An additional question is whether macrophages synthesise cholesterol from LA, as hepatocytes do.

I like the way these authors understand CVD as a disease of cholesterol retention, rather than excess LDL per se. This is a view often kicked to the kerb by those who only have LDL-lowering meds to sell. TheEuropean Heart Journal, for example, seems to publish an editorial bashing HDL every other week. We get it, HDL is not a drug target, and not much of a genetic lottery either, but it is still a part of the system nature supplied to regulate the accumulation of cholesterol in cells, and worth making friends with.

[1] Hamley, S. The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials. Nutr J. 2017; 16: 30

[2] Wang, Y, Oram, JF. Unsaturated Fatty Acids Inhibit Cholesterol Efflux from Macrophages by Increasing Degradation of ATP-binding Cassette Transporter A1. February 15, 2002
The Journal of Biological Chemistry. 277, 5692-5697.

↧

A Grand Unified Theory of Polyunsaturated Fatty Acid Misbehaviour in Inflammatory Disease

September 18, 2018, 7:42 pm

≫ Next: Egregious - the Richard M. Fleming Story

≪ Previous: Never attribute to pathology what can be adequately explained by adaptive physiology

One of the great mysteries of nutrition is the behaviour of polyunsaturated fatty acids (PUFAs). They often look good in the kind of sloppy epidemiology used to drive or latterly protect dietary guidelines*, are more ambiguous in RCTs, and can easily be shown to have deleterious effects in a number of specific medical and experimental conditions that might be expected to have a "canary in the coalmine" validity as warnings when it comes to the longer-term effects of consuming more, sometimes much more, that the essential nutrient requirement for these functional molecules (which is, at a rough consensus, around 3% of energy, with 1% coming from omega-3 PUFAs).

However, higher intakes are sometimes tolerated well; any fairly liberal ketogenic diet including pork or olive oil or nuts or avocado will almost certainly exceed 3%, and even though PUFA over 3% is almost a requirement for the induction of NAFLD, Browning et al reversed NAFLD quickly with a ketogenic diet supplying 15%E as PUFA.[1]

So what gives? What is the nature of the interaction between PUFAs and other dietary components or metabolic states that produces inflammation?

In an earlier blog post I identified the enzyme systems upregulated in NAFLD as those of the microsomal ethanol oxidase system (MEOS) and also showed that the evolutionary function of the MEOS is to degrade PUFA, rather than alcohol which is a latecomer to our diets.
But what activates the MEOS when alcohol does not? How, for example, does fructose send PUFAs down this pathway, and how does this promote inflammation?

I found a clue in this hepatitis C editorial by Jenny Heathcote on a study in which weight loss improved liver function.[1] This is some quite brilliant speculation.

Here is the description of fatty liver due to insulin resistance (HCV causes IR by a pharmacological action of its core protein):

In peripheral tissues, insulin normally downregulates the hormone sensitive lipase (HSL) enzyme responsible for hydrolysis of stored triglycerides from free fatty acids within adipocytes. In patients who are insulin resistant, this enzyme is no longer suppressed. In addition, counterregulatory hormones such as catecholamines, glucagon, and growth hormone are increased in response to increased circulating insulin levels. These counterregulatory hormones stimulate HSL to hydrolyse more triglycerides into free fatty acids, the end result being an increased flux of dietary and stored free fatty acids away from the adipose tissues and towards the liver. Unfortunately, Hickman et al did not measure free fatty acid levels before or after the weight reduction programme. Within the liver, insulin upregulates esterification of free fatty acids to triglycerides. Once the triglycerides are formed, insulin downregulates the secretory pathways, thus favouring increased storage of triglycerides in the cytosolic pool. Furthermore, free fatty acids can themselves upregulate the esterification pathway. The net result is a positive feedback cycle contributing to an ever increasing amount of free fatty acids and triglycerides in the liver. Thus portal hyperinsulinaemia leads to hepatic steatosis.

And here is the description of how hepatic steatosis influences PUFA disposal:

These studies have suggested that the presence of fat in patients with hepatitis C is associated with markers of progressive liver disease in that fat was associated with increased stellate cell activation, but the mechanism by which this takes place is uncertain. It is possible that this occurs secondary to saturation of beta oxidation pathways within mitochondria which then leads to free fatty acids becoming more available to intracellular microsomes where they undergo lipid peroxidation. There are three main products of microsomal lipid peroxidation: malondialdehyde, 4-hydroxynonenal, and hydrogen peroxide. Malondialdehyde has been shown to activate stellate cells to produce fibrin, and may be responsible at least in part for liver fibrosis in patients with non-alcoholic steatohepatitis.

Malondialdehyde (MDA) and 4-HNE are unsaturated products of PUFA, and H2O2 is also a step in the MEOS disposal of PUFA, requiring catalase for its reduction to H2O + O.

We can see how this relates to the "essential" role that PUFA plays in the development of alcoholic liver disease; not only can the liver become fatty from the conversion of alcohol to triglycerides, but also the disposal of excess ethanol through the MEOS has upregulated this enzyme system (hepatic CYP2E1 is upregulated 10-fold by ethanol); to add insult to injury, the liver's ability to dispose of excess fat via beta oxidation is impaired by the depletion of NAD+ during the conversion of ethanol to fat.
But another clue was supplied by Tucker Goodrich, the PUFA ninja, who found a rodent study showing that 4-HNE and 9-ONE could themselves be cleared if beta-oxidation pathways were upregulated enough, that is, by a ketogenic diet.[3]

Our results showed that livers from rats fed ketogenic diet or high fat mix diet had high ω-6 polyunsaturated fatty acid concentrations and markers of oxidative stress. However, high concentrations of HNE (1.6 ± 0.5 nmol/g) and ONE (0.9 ± 0.2 nmol/g) were only found in livers from rats fed the high fat mix diet. Livers from rats fed the ketogenic diet had low HNE (0.8 ± 0.1 nmol/g) and ONE (0.4 ± 0.07 nmol/g), similar to rats fed the standard diet. A possible explanation is that the predominant pathway of HNE catabolism (i.e. beta oxidation) is activated in the liver by the ketogenic diet. This is consistent with a 10 fold decrease in malonyl-CoA in livers from rats fed a ketogenic diet compared to a standard diet. The accelerated catabolism of HNE lowers HNE and HNE analog concentrations in livers from rats fed the ketogenic diet. On the other hand, rats fed the high fat mix diet had high rates of lipid synthesis and low rates of fatty acid oxidation, resulting in the slowing down of the catabolic disposal of HNE and HNE analogs. Thus, decreased HNE catabolism by a high fat mix diet induces high concentrations of HNE and HNE analogs. The results of the present work suggested a potential causal relationship to metabolic syndrome induced by western diets (i.e. high fat mix), as well as the effects of the ketogenic diet on the catabolism of lipid peroxidation products in liver.

So - any state in which beta-oxidation is inhibited, but fat is present, will see PUFA shunted into the microsome - essentially the MEOS - and a high production of damaging peroxides and aldehydes. This also happens when mice are fed a ketogenic diet, but the aldehydes can be disposed of by beta-oxidation.
Note that the high fat (non-keto) diet in the mouse study was the Surwit diet relatively low in PUFA and MUFA (coconut and soy oil), overloading beta-oxidation with a mixture of ~50% saturated fat and 22.5% sucrose. Don't try this at home, kids.

For reasons of time I haven't gone into every possible ramification such as the role of peroxisomal oxidation in PUFA disposal, the proper function of the MEOS (making and disposing of eicosanoids), the hormetic effect on antioxidant systems of low level HNE production, and the difference between liver and other fat-burning tissues (i.e. is this relevant to heart disease if the same thing happens in muscle, macrophages, or endothelial cells? Magic 8 ball says very probably).

However, here's a model that allows us to predict and explain the likely role of PUFA in inflammatory diseases at a metabolic level. Especially, for now, liver diseases.

* FFQ epidemiology studies are notoriously inaccurate at capturing intakes of calories (and protein, which often looks wonky in epidemiology). They really can't tell you in what context PUFA is being consumed, and in any case it's hard to see how deep frying oil in food can really be measured - do you even know what your chips (fries) are cooked in and in what part of the FFQ would you put this information?

[1] Browning JD, Baker JA, Rogers T et al. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr. 2011 May; 93(5): 1048–1052.

[2] Heathcote J. Weighty issues in hepatitis C. Gut. 2002;51(1):7-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1773268/

[3] Li Q, Tomcik K, Zhang S, Puchowicz MA, Zhang G-F. Dietary-regulation of catabolic disposal of 4-hydroxynonenal analogs in rat liver. Free radical biology & medicine. 2012;52(6):1043-1053. doi:10.1016/j.freeradbiomed.2011.12.022
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289253/

↧

Egregious - the Richard M. Fleming Story

September 30, 2018, 3:50 pm

≫ Next: Don't Drink (oil) and Fry (in the sun) - the link between polyunsaturated vegetable oil and skin cancer

≪ Previous: A Grand Unified Theory of Polyunsaturated Fatty Acid Misbehaviour in Inflammatory Disease

An RCT paper claiming to show harmful effects of a low-carb diet passed briefly over the internet on the weekend before being shot down in flames.
The title is:

Long‐term health effects of the three major diets under self‐management with advice, yields high adherence and equal weight loss, but very different long‐term cardiovascular health effects as measured by myocardial perfusion imaging and specific markers of inflammatory coronary artery disease.
The paper is published in Clinical Cardiology [edit: not Preventive Cardiology], and is free to access.
https://onlinelibrary.wiley.com/doi/abs/10.1002/clc.23047

Three of the authors work at Fleming's medical imaging company in California, one is a deceased psychologist from Iowa, another is a pediatric nutritionist from New York and one is a Kellogg's employee from Illinois.
How this group was able to run a 12-month diet trial in 120 subjects is something of a mystery.

The conclusions:

One‐year body mass changes did not differ by diet (P .999). Effect sizes (R, R2) were statistically significant for all indices. Coronary blood flow, R (CI 95%) = .48 to .69, improved with low‐to‐moderate‐fat and declined with lowered carbohydrate diets. Inflammatory factor Interleukin‐6 (R = .51 to .71) increased with lowered carbohydrate and decreased with low‐to‐moderate‐fat diets.
Conclusions
One‐year lowered‐carbohydrate diet significantly increases cardiovascular risks, while a low‐to‐moderate‐fat diet significantly reduces cardiovascular risk factors. Vegan diets were intermediate.

First I'll consider all the good reasons to reject this study, but after that I'll do something we should always do, even for the worst study - take it at face value.

1) Lead author Dr Richard M. Fleming is a self-confessed and convicted felony fraudster who has admitted falsifying data in another RCT.

Fleming admitted to knowingly executing and attempting to execute a scheme to defraud Medicare and Medicaid healthcare benefit programs in connection with the delivery of and payment for healthcare benefits, items, and services, namely by submitting payment claims for tomographic myocardial perfusion imaging studies that he did not actually perform. Fleming also pled guilty to one count of felony mail fraud in violation of 18 U.S.C. 1341 and 2 for conduct relating to money paid him to conduct a clinical study of a soy chip food product for the purpose of evaluating health benefits. As Fleming admitted during his guilty plea, he received approximately $35,000 for conducting a clinical trial, but he fabricated data for certain subjects.

https://www.federalregister.gov/documents/2018/09/28/2018-21210/richard-m-fleming-denial-of-hearing-final-debarment-order

2) Fleming obtained Robert Atkins' medical records by deception and shared them with Neal Barnard of the vegan activist group PCRM in 2004, another unethical behaviour and one demonstrating that Fleming has a long-standing animus against Atkins and his diet.
https://theskepticalcardiologist.com/2016/12/18/what-does-the-death-of-robert-atkins-tell-us-about-the-atkins-diet/

Now, vegans can do research into this exact question with a high standard of rigour, see Chris Gardner's studies - one can certainly dispute the interpretation of some results, but not the results themselves. And I have reviewed a vegan diet study favourably here (dealing with another Fleming paper in passing) - good results are good results; I don't doubt these diets can have also cardiovascular benefits over the short-to-medium term, but question their long-term effects on mental health, reproductive health, dental health, joint health etc.

3) The trial protocol number on the paper links to a study that was completed in 2002. This explains how a convicted felony fraudster was able to conduct a study. The protocol was posted in 2006, 4 years after the study concluded, which seems unusual on the Clinical Trials website.

https://clinicaltrials.gov/ct2/show/NCT00324545

4) The study has 35 citations - 15 of these are to Fleming's own papers. This self-spamming, which helps boost an author's citation rate, is frowned upon by reputable journals. One of these references has the word "quantum" in the title. Other references are to news articles and book chapters. The low carbohydrate diet references are more than 15 years old. Ref 16 is curious as an anonymous reviewer is given credit for the wording of a paragraph of interpretation, surely a run-of-the-mill interaction with a reviewer.

5) The novel aspect of this paper may lie in the reference to that novel vegan touchstone, Neu5Gc. Pro-tip - if the vegan diet had a magic mechanism, you ought to know it already; some major low-carb mechanisms have been understood for generations. At this rate, if there is a magic mechanism for vegan health benefit, it will be discovered by a low-carb scientist.

We now know that these food choices and their impact are at least partially precipitated by the inflammatory effect of our diets based given our inability to convert Neu5Ac to Neu5Gc and our bodies immune response to the Neu5Gc present in animal protein.

At this point, let's take the study at face value. the vegan diet avoided animal protein and Neu5Gc, the low carb diet probably included twice as much protein as the other diets (based on reference 6), but the low fat diet included more animal protein and Neu5Gc than the vegan diet.

One‐year lowered‐carbohydrate diet significantly increases cardiovascular risks, while a low‐to‐moderate‐fat diet significantly reduces cardiovascular risk factors. Vegan diets were intermediate.

So Fleming's own study, taken at face value, doesn't support the Neu5Gc hypothesis. In fact, it's unusual for the vegan diet to be inferior to the low-fat diet in any vegan study, and it's unusual for the low carb diet to be inferior to the low-fat diet in any low-carb study.

6) adherence to diets over 12 months was 100%. Of course, this is unheard of and entirely implausible; if honestly reported, it seems to show considerable gullibility or self-deception in the study team.

That 100% of participants continued on their respective diet plans through a full year of dieting contrasts sharply with much of diet research experience with drop outs and with common experience with difficulties of dieting and remaining on diets. This success can be attributed to attention to well-established psychological principles of habit acquisition and extinction and of behaviour modification through Bandura [17] counseling.

Bandura's ethos seems sensible enough and appropriate for such a project, except perhaps when the people using it for counselling already believe that one approach is preferable to another.

7) the original report of the 2002 study (ref 6), if it is the same study, reports diet groups differently.

8) Implausible randomisation was the red flag that saw the PREDIMED study and many others retracted. Here randomisation of n=120 into 6 groups produced this result:

The 58 female and 62 male participants were randomly assigned to equal dietary groups by casting a die. There were no statistical demographic differences between group assignments. There were no statistically significant differences, or even trends, between diet groups at the initiation of the study. Since the groups were unequivocally randomized for all fifteen-baseline indices, statistical inference to the initial population, described by Table 1, is appropriate.

9) Fleming et al state "A four-month post-intervention analysis was obtained to determine post-intervention treatment, which has not previously been reported in the literature."

Post intervention status was in fact reported at 4 years by the Shai et al DIRECT study group.

10) the sponsor is listed as the Camelot Foundation. A search turned up this mention - Dr Fleming is the editor of a predatory journal, and the Camelot Foundation has little other existence online, it seems to be a 501(c)(3) legal tax-avoidance scheme within Fleming's own business.
https://www.omicsonline.org/editor-profile/richard-maximus-fleming/

11) Cardiovascular improvement by Fleming's medical imaging method correlates with improvement in the TG/HDL ratio. Taken at face value, although TG/HDL doesn't improve in Fleming's "low carb" arm, it does in most of the people reading this who have tried a low carb approach, so if Fleming's diagnostics are accurate this is not bad news. Interleukin 6 also improves during fasting but not a ketogenic diet in a 6-day study, but improves in a low carb diet vs a low fat diet in a 6 month study here (as there was at least one previous study in the literature that came to different conclusions from Fleming et al with regard to an outcome they highlighted, this should really have been cited).

Both LFD and LCD led to similar reductions in body weight, while beneficial effects on glycaemic control were observed in the LCD group only. After 6 months, the levels of IL-1Ra and IL-6 were significantly lower in the LCD group than in the LFD group, 978 (664–1385) versus 1216 (974–1822) pg/mL and 2.15 (1.65–4.27) versus 3.39 (2.25–4.79) pg/mL, both P < 0.05.

Taken at face value, Fleming's possibly fraudulent paper predicts cardiovascular benefit from a low carb diet if people get different results from the ones he claims to have produced, which is usually the case in other studies and in real life...

The question is, how did this paper pass peer review with all the red flags above? [edit]

Credit to @MacroFour and Ivor Cummins @FatEmperor for the links regarding Dr Fleming's colourful past.

↧

Don't Drink (oil) and Fry (in the sun) - the link between polyunsaturated vegetable oil and skin cancer

January 16, 2019, 3:45 pm

≫ Next: Two important new papers on climate change.

≪ Previous: Egregious - the Richard M. Fleming Story

It was good to see this well-researched burst of sunscreen scepticism doing the rounds this (southern) summer - Is Sunscreen the New Margarine? *
I was particularly struck by the unintentionally ironic title, because margarine's role in this story goes well beyond that of a handy analogy for a misguided public health initiative.

When I first read the Nanji and French research - countless rat experiments, consistent with what human epidemiology there was - showing that high PUFA oils potentiated the progression of alcoholic liver disease, were indeed essential fats if one wanted to develop this condition, I replaced the rice bran oil I had been conned into using with beef fat. One of the first things I noticed, being a clumsy cook, was that my skin stopped blistering when I burned myself. At the worst I might get a short-lived patch of dead skin, but I've had about 2 blisters in the 7 years since then and neither became painful. Then gradually I noticed I wasn't getting burnt in the sun as easily. I wasn't big on the sun in those days, but as I got more exposure to sun and less exposure to linoleic acid my resistance grew. I try to limit exposure, using clothes and shelter, to what seems reasonable, having no desire to turn nut-brown and wrinkled in my dotage, but occasionally I've been caught out for far longer than I intended, and no harm has ensued. In part this has been due to a policy of tanning early and often so that the protective pigment is in full effect once the summer reaches its peak, but dietary choice is a critical factor, as we shall see.

The first experiment I came across showing the photosentising effect of linoleic acid was this one (in hairless mice - obviously you can't use a hairy animal) [1];

However, dietary ALA inhibited the increase in erythema score after UVB irradiation compared with LA. The peroxidizability index of the skin total lipids was significantly higher, but UVB-induced prostaglandin E2 (PGE2) production was significantly lower in the group fed an ALA-rich diet compared with the group fed an LA-rich diet.

There's a lot of this stuff recently, showing that omega-3 fats, and especially the long-chain fish oil ones, are protective - but also that their irradiation puts more strain on the antioxidant defense system, depleting vitamin C and glutathione. The Linus Pauling Institute website has an excellent summary of this research, including human trials, but if you think like me you want to know, is saturated fat protective too? I mean there are people out there exposed to very high UV levels eating not-especially-oily fish and coconut or ghee for generations - are they OK?

The Linus Pauling Institute doesn't tell us, nor does it really warn us about omega-6. The modern idea is just to increase our intake of flaxseed oil and salmon and antioxidant vitamins and minerals. Sounds expensive, for one thing, and I'm not sure our obsession with fish will prove to be sustainable if we're not allowed to eat anything else.

To answer this question we need to go back to the 1990's, when researchers were mostly looking at omega 6 fats and using saturated fats as controls.

We find:

When polyunsaturated fat intake had been increased, tumorigenesis had been exacerbated and a remarkable persistence of immunosuppression remained measurable. There was no difference apparent in the CHS responsiveness in mice fed 20% sunflower oil or saturated fat in the absence of UV irradiation, indicating that the persistent immunosuppression was likely to have been induced by the carcinogenic irradiation regime.[2]

Diet 1 is 20% hydrogenated cottonseed oil, diet 5 is 20% sunflower oil

Now 20% sunflower oil is exactly the kind of exposure you'd get if you replaced other fats with oil in a low fat diet, as the experts want you to. It's an amount of LA that the epidemiologists at Harvard Chan have no problem with, using as they do data collection methods unreliable enough to produce false negatives as well as false positives, and not controlling for UV exposure anyway. Note that the control here - hydrogenated cottonseed oil - is 69.25% trans fat, the rest all SFA.

Here's another, where there are two controls - 12% menhaden oil (basically fish oil) and 0.75% corn oil.[3]
The most interesting finding is that while menhaden oil is protective, crossing over to 12% menhaden oil from 12% corn oil is not; it's about the worst thing you can do; crossing over from 12% corn oil to 0.75% corn oil seems safer.

In summary, we have shown that (1) high dietary level of an omega-6 FA source (corn oil) enhances photocarcinogenic expression, both with respect to tumor latent period and multiplicity; (2) that this lipid-induced exacerbation of cancer expression occurs at the post-UV initiation, or promotion, stage of carcinogenesis; (3) modification of diet to low lipid level (corn oil), after UV-initiation, negates the enhancement of cancer expression exhibited by high level of corn oil; (4) high level of dietary menhaden oil containing omega-3 FA, when compared to an equivalent level of corn oil, inhibits photocarcinogenic expression; and (5) menhaden oil mediated inhibition of UV-carcinogenesis appears to occur during the initiation stage and by a mechanism dissimilar to that exerted by low levels of corn oil.

These data suggest a complexity of dietary lipid effects upon cancer expression that perhaps has not been widely appreciated.

But here's my favourite - finally someone uses butter and ghee as controls.[4]

They're measuring ear swelling in response to a hapten test, which I assume is some sort of irritant. Low swelling means the immune system is suppressed, and this predicts that the risk of cancers is increased, just as it did in the other experiments. Note this took 4 weeks of a 20% fat diet - the protective effect of butter wasn't obvious after only 2 weeks, but the harmful effect of sunflower oil was.

Now, how do we know that this applies to human populations or has anything to do with the high rates of melanoma (the most fatal skin cancer) in New Zealand or Australia?
There is a natural experiment we can look at. NZ, unlike Australia, is not a land of extreme natural sunlight - it's the "land of the long white cloud", so that travel to the tropics greatly increases UV exposure. (However, we do have greater UV variability at our lower latitude, described by NIWA's Richard Mackenzie here.) Kiwis didn't travel much in the past, especially to the tropics, with one important exception; around 140,000 men (mostly) served overseas in WW2, around 10% of the population, and most of them served in places like Greece, Crete, Egypt, Libya, Italy and the Solomon Islands. Wearing shorts and short-sleeved shirts - US naval officials in the Solomons were appalled by the lack of protection the NZ sailor's uniform gave against flash burns - with only a Tommy helmet for shade (too hot and heavy to wear all the time). Sunburn on arrival in the combat zone is mentioned in memoirs - in the Armed Forces you stay where you're told and work where you're told, shelter or not.

Soldiers of the 2nd NZEF, 20th Battalion, C Company marching in Baggush, Egypt, September 1941.

The NZ diet, and British Army rations, at this time were very low in omega 6. In NZ, margarine wasn't even legalised until 1972. We cooked with butter, hydrogenated coconut oil, and beef and lamb dripping - even chicken and pork were unusual foods until the 70's. Some time during that decade the use of oil (mostly soy and corn oil at first) took off and was entrenched by the 1980's.
Now if exposure to the excess UV rays of the tropics, rather than the combination of UV and oil, caused skin cancer we'd expect to see an age-specific curve in skin cancer mortality in NZ that rose after the war (starting in the mid-1950's would match the usual cancer latency) then dropped as that generation began to die off from all causes, and a generation raised on "slip slop slap" UV protection took over.
Instead we see this:

And if you check different age groups in this part of the Mortality Trends website, you find the same pattern (most obvious where there is highest mortality), despite the different rates of overseas service in each age group, and the dying off of each generation - mortality from skin cancer climbs rapidly from the 1970's, when the NZ nutritional transition to high-PUFA oils began, and has not declined at all as the Greatest Generation dies off and the lesser slip, slop, slap-happy generations take its place (melanoma mortality in NZ has remained stable from 2001 to the present, I can't find earlier stats specific for melanoma but of course it is the most lethal skin cancer). This data is a better fit for diet than it is for UV exposure. (Of course there's the ozone hole, dating from the 70's, but "The ozone hole does not have a large effect on the concentration of ozone over New Zealand. However, when the ozone hole breaks up in spring, it can send ‘plumes’ of ozone-depleted air over New Zealand." The relative unimportance of this is mentioned on page 6 of Mackenzie's paper.)
Which is not to say that UV exposure has unlimited safety, of course this is not the case, but that heart-healthy vegetable oil and margarine advice has made even limited exposure more dangerous than it needs to be. Much the same phenomenon we see with alcohol and liver disease (and, who knows, alcohol and the risk of other cancers).
Anyway, if you plan to go out in the sun for long enough to raise some vitamin D and nitric oxide, or drink enough alcohol to get drunk, or especially both, skip anything cooked in or made with a vegetable oil other than coconut or, within reason, olive oil (this includes mayonnaise), [Edit: olive oil is rich in the terpenoid antioxidant squalene, perfectly configured to quench singlet oxygen radicals released by UV exposure, likely to offset risk from its moderate 10-12% linoleic acid content], eat some butter or cheese or full-fat yoghurt, some fatty fish, chocolate, tomatoes and all the other antioxidant-rich foods with some evidence as UV-protective (caffeine seems to help too). Also keep insulin low - that means no refined carbs, intermittent fasting, low carb diet if necessary. Insulin and IGF-1 are important in skin repair and insulin resistance due to excessive insulin response to diet creates all sorts of skin problems, as well as underwriting most of those non-communicable diseases we hear so much about. (it's not easy to get insulin tested here but the TG/HDL ratio after a 12-14 hr fast is a decent proxy for the 2-hour insulin response).

* IMO the vitamin D supplement scepticism in this article is premature - vit D3 works if you use it for the right reason and take enough of it. It's just as good as sunlight for fixing my minor but annoying psoriasis, but I need 10,000 iu a day till it goes away. This only takes 6 days every month or two now - I used to need to take that amount all winter.

References:
1] Takemura N, Takahashi K, Tanaka H, Ihara Y, Ikemoto A, Fujii Y, Okuyama H. Dietary, but not topical, alpha-linolenic acid suppresses UVB-induced skin injury in hairless mice when compared with linoleic acids. Photochem Photobiol. 2002 Dec;76(6):657-63. link

2] Reeve VE, Bosnic M, Boehm-Wilcox C. Dependence of photocarcinogenesis and photoimmunosuppression in the hairless mouse on dietary polyunsaturated fat. Cancer Lett. 1996 Nov 29;108(2):271-9. Full-text link

3] Homer S. Black John I. Thornby Janette Gerguis Wanda Lenger. INFLUENCE OF DIETARY OMEGA‐6, ‐3 FATTY ACID SOURCES ON THE INITIATION AND PROMOTION STAGES OF PHOTOCARCINOGENESIS. Photochemistry and Photobiology Vol. 56, No. 2, pp. 195-199, 1992.
https://doi.org/10.1111/j.1751-1097.1992.tb02147.x

4] Cope RB, Bosnic M, Boehm-Wilcox C, Mohr D, Reeve VE. Dietary butter protects against ultraviolet radiation-induced suppression of contact hypersensitivity in Skh:HR-1 hairless mice. J Nutr. 1996 Mar;126(3):681-92. free full-text

↧

Two important new papers on climate change.

February 19, 2019, 3:37 pm

≫ Next: Gene-diet interactions and the risk of colorectal cancer

≪ Previous: Don't Drink (oil) and Fry (in the sun) - the link between polyunsaturated vegetable oil and skin cancer

Whad'ya mean, this has to last me a year?

People in the LCHF community can be resistant to considering climate change and greenhouse gas levels because this argument can be used to shift the goalposts in a clumsy, overt fashion in order to sidestep the evidence on health and keep everyone eating nutrient-poor diets.
Our critics even use these manufactured opportunities to resuscitate their zombie saturated fat and TMAO hypotheses, knowing that most of the audience for ecological debates has no clue how intellectually bankrupt and scientifically desperate these arguments are and have been for some time.
So people can be forgiven for both hiding their heads in the sand and distrusting all "consensus" authority - in our specific area of health, consensus authority has been damagingly wrong for many people's entire lifetimes. And ironically some of this wrongness, the saturated fat question, has contributed to global warming - we'll discuss how later.

However, I for one believe in keeping a close eye on existential threats, and whether you see climate change as a threat to your access to a diet that will keep you healthy, or merely as a threat to the future of human existence on this planet, I think you should too.
Don't listen to headlines, certainly don't listen to the dodgy and ideologically skewed EAT-Lancet commision, but do listen out for the people doing the hard work; the people working out how we should most accurately measure the things that the usual suspects want us to think were measured most accurately back when the results were more favourable to them.
And try to understand the systems involved.

There are essentially two - the usual cycling of carbon through plants and animals back into the atmosphere, which has shaped our climate through most of our history, with fluctuations due to deforestation and reforestation that mattered (as we shall see) yet did not wipe out life on Earth.
And then there is the geological cycle - carbon from Earth's hothouse youth slowly trapped under the crust as fossil hydrocarbons, which make excellent fuel.
The system of free trade and free travel that fossil fuels allow has replaced warfare since WW2 for most of the world's countries; but it is a potlatch peace, dependent on wasteful gestures, firstly the making and transportation of shit that will either be thrown away, or that in most cases could be made closer to home with lower energy costs, in order to keep wages at a level consistent with a desire for peace, and secondly the transportation of people who will stay in herds or on their phones at the world's beauty spots, only visited for the bragging rights, and for something to do instead of making war against the people who live there.

In the ecological cycle, plants sequester CO2 as they grow, though the soil around them, if very fertile, will release methane (CH4) - recently noted with alarm in the Amazon rainforest, as well as in rice paddies.
CO2 in plants is released by forest or grass fires, and by the metabolism of animals that eat them, which also sequester some of the carbon in their bodies during their lives, mainly in stored fat and protein. When plants and animals rot to return nutrients to the soil this can also release methane, as can the fermentation of plants in the gut by bacteria - the bacteria in the foregut of ruminants are great at processing inedible (to us) fibre to energy substrates, so are high producers of methane (which escapes in burps, not farts).

Our first paper looks at the contribution of methane to the warming effect. CH4 is much more warming than CO2. This is why we hear that 51% of NZ's GHG come from agriculture, when the proportionate amount of CH4 released by ruminants compared to fossil fuel CO2 in NZ each year is much smaller than this - because GHG emissions have, till now, been calculated on the warming effect of each gas. However CO2 lasts for hundreds of years; CH4 has a half-life of only 10 years before turning to CO2. Thus, if we are looking at a 10-year GHG emissions target, half the CH4 should be counted as CO2, and the further out we get, the smaller the difference between CH4 and CO2 gets.
The full model is more complex than this, but the gist of it is the mathematical demonstration that GHG as methane is being badly overestimated whenever the calculation is for a long term impact.

Climate mitigation: An improved emission metric

A new approach allows the temperature forcing of CO2 and short-lived climate pollutants (SLCPs) to be examined under a common cumulative framework. While anthropogenic warming is largely determined by cumulative emissions of CO2, SLCPs—including soot, other aerosols and methane—also play a role. Quantifying their impact on global temperature is, however, distorted by existing methodologies using conventional Global Warming Potentials (GWP) to convert SLCPs to "CO2-equivalent" emissions. A team of international scientists led by Myles Allen at the University of Oxford provide a solution. A modified form of GWP—GWP*, which relates cumulative CO2 emissions with contemporary SLCP emissions—is shown to better represent the future climate forcing of both long- and short-term pollutants. Use of GWP* could improve climate policy design, benefiting mitigation strategies to achieve the Paris Agreement targets.

Dr Michelle Cain explains the meaning of this paper in this twitter thread and this short YouTube video.

You can't get fossil fuels off the hook. The billionaire owners of EAT-Lancet make their money from a hotel chain. No doubt the hotels are eco-friendly and serve vegan meals. But you can't fill hotels without jet aircraft and cars and cruise ships. Without unnecessary travel, that is - because people with sounder reasons to travel tend to stay with family or friends. A successful hotel chain today is a prime symptom of the fossil fuel binge-for-gold mentality that is breaking the planet.

Our second paper looks at the effects of reforestation on the climate after 56 million mesolithic farming peoples died following the colonisation of the New World.[2] It supplies the evidence for an earlier claim that when their disused cropland was overtaken by forest regrowth, the additional retention of CO2 carbon involved in the creation of standing forests caused the Little Ice Age. Animal numbers are not mentioned in the paper but it is extremely unlikely that ruminant numbers in the Americas declined as a result of the tragic deaths, mainly through introduced diseases, of much of the human population that hunted them. Any additional methane release during forest regrowth also did not stop the Ice Age.

Again, this paper revises the estimates used in GHG calculations - the retention of carbon in forests was missed before - again a case of early GHG formulas missing the all-important effect of time scaling.

Now, let's do some modelling of our own. It's silly, I admit, but no sillier than anything EAT-Lancet have proposed. We have an obesity epidemic; a 2012 estimate of the extra food needed to maintain that extra weight was, that biomass due to obesity was 3.5 million tonnes, the equivalent of 56 million people of average body mass (1.2% of human biomass globally).[3] In other words, if the obesity epidemic could be entirely reversed, the food savings would be roughly equivalent to the annual food consumption of Australia and Canada combined (minus that of little New Zealand).
The reduction in biomass would also be exactly the same as the population drop that caused the Little Ice Age.

In our model all the weight lost is lost because of a reduction in wheat, corn, rice and sugar consumption, and their cropland is replaced by permanent forest (not forestry). Of course farming today is more intensive, and thus causes more harm to biodiversity, soil health, and marine health, so the total hectarage saved will be less - but we can compensate for that if we also tell people they can eat the fat from the animals they eat instead of soy oil or palm oil. This will reduce demand for the two human foods that most drive deforestation. If palm and soy plantations collapse as a result and the Indonesian and Brazilian rainforest takes back the land, so much the better.
Of course, the Adam Curtis voiceover should be telling you about now, "but it was a fantasy". But it was a fantasy that demonstrates how misguided public health experts and their inability to correct error on the saturated fat question have helped to change the climate. We can afford to eat meat, we just can't afford to keep eating lean meat and avoiding the fat-and-cholesterol rich parts of the animal. We can't afford to keep cooking exclusively with vegetable oil (and then often throwing it away). Keep on crowbarring that rubbish advice into climate change statements and no-one but vegans will ever believe you.

References

[1] Myles R. Allen, Keith P. Shine, Jan S. Fuglestvedt, Richard J. Millar, Michelle Cain, David J. Frame & Adrian H. Macey. A solution to the misrepresentations of CO2-equivalent emissions of short-lived climate pollutants under ambitious mitigation. NPJ Climate and Atmospheric Science volume 1, Article number: 16 (2018).

[2] Alexander Kocha, Chris Brierley, Mark M.Maslina, Simon L.Lewis. Earth system impacts of the European arrival and Great Dying in the Americas after 1492. Quaternary Science Reviews
Volume 207, 1 March 2019, Pages 13-36. https://doi.org/10.1016/j.quascirev.2018.12.004

[3] Walpole SC, Prieto-Merino D, Edwards P, Cleland J, Stevens G, Roberts I. The weight of nations: an estimation of adult human biomass. BMC Public Health. 2012;12:439. Published 2012 Jun 18. doi:10.1186/1471-2458-12-439 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408371/

↧

Gene-diet interactions and the risk of colorectal cancer

August 22, 2019, 7:13 pm

≫ Next: The Official COVID-19 protocol from Shanghai, China, in English

≪ Previous: Two important new papers on climate change.

There's nothing like a bit of cognitive dissonance to get the brain working if you steel yourself against the instinct to invoke protective stupidity. It's much like Marx's internal stresses of capitalism (or communism for that matter), awareness of contradictions may be the birth-pangs of the next state of existence/awareness, or it may just be the subconscious motivation for repression and consequent dysfunction (it's uncanny how Marxist and Freudian terminologies overlap here, but I digress).

When you join the keto cult, first you have to overcome cognitive dissonance just to entertain the idea that eating high fat can do you some good, and try it. God knows that's hard enough, well done everyone. But that's the beta effect (short term results); what about the alpha effects, i.e. longevity and disease resistance? We know risk markers improve, and why do we have risk markers? Because doctors prefer to diagnose diseases from blood tests, and not your stories about what you had for dinner. Your lipids, BP. HbA1c are measured with considerably more accuracy that saturated fat ever was in any FFQ, so if you have to trust epidemiology trust biomarker epidemiology, and get with the lipid triad and LMHR news over at cholesterolcode.com.

And as for saturated fat and cardiovascular disease in epidemiology, read em and weep saturophobes - latest, biggest meta-analysis the other month, very good methodology, and SFA is beginning to look just a little bit protective.[1]

Cancer though - doesn't that have a biodiversity that's harder to predict than a metabolic disease? Well, most of the common cancers, including colorectal cancer, have a very strong, Bradford Hill strong, association with hyperinsulinaemia (and/or the IGF1/IGFBP3 axis), and we've taken care of that. But still - you read papers where processed meat (way too heterogenous a set of stuff to combine as if it were homogenous, but nutrition epidemiology is what it is, a very blurry snapshot that you need to squint at hard to see anything at all really) is mildly associated with CRC but unprocessed meat isn't, or vice versa, or only in one sex, or in the other, etc etc etc and wonder if there still could be anything in it.
If nothing else, it's good for refuting accusations of orthorexia,

One tool I've found recently that seems to let you look a bit more closely at the murk is the epidemiology of gene-diet interactions. It still doesn't tell you if residual confounding is at play, but it does let you see the spread of association in a population and can help to validate plausible mechanisms, another Bradford Hill criteria. One thing that impresses me is that it's rather full of null results. Dietary patterns are baloney, so they have no interaction with any genes associated with BMI in this Chinese-Singaporean population, (study pulled at random, fairly typical so far of this sort of question). Interestingly there's an interaction with cholesterol, which seems like the opposite of what's happened in the West, maybe just the diets of the wealthy in Singapore, but there it is.[2]

So anyway, to the subject in hand - I looked up gene-diet interactions for CRC and it turns out processed meat (I know, I know) is the only one in this large pooled case-control study.
Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer.[3]

Our results provide strong evidence for a gene-diet interaction and colorectal cancer risk between a genetic variant (rs4143094) on chromosome 10p14 near the gene GATA3 and processed meat consumption (p = 8.7E-09).

Now, this gene has nothing to do with nitrate metabolism as far as I can see - it seems to be a cell proliferation gene. So we could still be seeing residual confounding, because there's no absolute way to adjust for the huge effect of hyperinsulinaemia on this cancer and processed meat is what you have on a pizza or in a sandwich. And the people who clean up chemical spills for you are unlikely to be vegan and/or rich, so processed meat is kind of their thing. But still.

The study wasn't designed to implicate carbs, by the way (but the fibre results will be interesting)

In this large combined analysis using GECCO from 10 case-control and nested cohort studies comprising 9,287 colorectal cancer cases and 9,120 controls, we build upon these previous reports [13], [14] to examine over 2.7 million common polymorphisms for multiplicative interactions with selected dietary factors (red meat, processed meat, fiber, fruit and vegetables) and risk of colorectal cancer.

Of the 7 studies listed here, the association goes the other way in 2 - NHS and HPFS. This helps to validate it according to my bias, which is that NHS and HPFS are the last place to look if you want results that correspond to reality.
If, on the other hand, you love Harvard epidemiology, then eat more bacon (I know, I know).

There are 3 significant loci and they all have positive interactions. Nothing good.

And here's the spread. This stuff interests me:

Stratified by genotype, the risk for colorectal cancer associated with each increasing quartile of processed meat was increased in individuals with the rs4143094-TG and -TT genotypes (OR = 1.20, 95% CI = 1.13–1.26 and OR = 1.39, 95% CI = 1.22–1.59, respectively) and null in individuals with the rs4143096-GG genotype (OR = 1.03, 95% CI = 0.98–1.07, Table 2). Results are very similar for minimal and multivariable adjusted ORs.

Only 6% of these populations had TT, most people had GG. So all the risk is in one corner. (you could get tested for this these days, but who knows what other genetic factors also influence it at the personal level).

What about red meat etc?

With the other dietary factors evaluated, no interactions using the conventional case-control logistic regression analysis reached the genome-wide significance threshold.

So I dug down into the supplementary data and found this amazing table.

If you have the most significant interactive allele for red meat, you get a 10% higher cancer risk if you don't eat enough. If you have one of the other 2, you get an 11% increased risk from too much.
And look at fibre - it's pretty much the same.
This helps to explain the Polyp Prevention Trial, doesn't it?[4]
I've long suspected that something like this goes on - that null or near-null results can disguise a mild 2-tailed effect - a little extra harm in one corner of the population and a similar-sized protective effect in another.
If any of this is real - insulin is, as always, the elephant in the room, as are the true carcinogens, which you'll find in the storeroom. But surely it has a bit more validity than the naked FFQ epidemiology it's based on?

Anyway, this seems like a useful reality check, and there are others - does the epidemiology of bowel movements support the motility part of the fibre hypothesis? Not really.[5] Does the epidemiology of aspirin (a drug that notoriously leaches blood into the gut, even when vegans take it) support the heme iron hypothesis? Not really.[6] Maybe this seems like nonsense to some, but if people want to draw drastic conclusions from FFQ epidemiology, they need to get outside the box more.

Oh, and why do people want to draw drastic conclusions from FFQ epidemiology anyway?
Adam Curtis has the best take on how this happened here.

[1] Zhu Y, Bo Y, Liu Y. Dietary total fat, fatty acids intake, and risk of cardiovascular disease: a dose-response meta-analysis of cohort studies. Lipids Health Dis. 2019;18(1):91. Published 2019 Apr 6. doi:10.1186/s12944-019-1035-2

[2] Chang X, Dorajoo R, Sun Y, et al. Gene-diet interaction effects on BMI levels in the Singapore Chinese population. Nutr J. 2018;17(1):31. Published 2018 Feb 24. doi:10.1186/s12937-018-0340-3

[3] Figueiredo JC, Hsu L, Hutter CM, et al. Genome-wide diet-gene interaction analyses for risk of colorectal cancer. PLoS Genet. 2014;10(4):e1004228. Published 2014 Apr 17. doi:10.1371/journal.pgen.1004228

[4] Schatzkin A, Lanza E, Corle D, Lance P, Iber F, Caan B, Shike M, Weissfeld J, Burt R, Cooper MR, Kikendall JW, Cahill J. Polyp Prevention Trial Study Group.

Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. N Engl J Med. 2000 Apr 20;342(16):1149-55.

[5] Kojima M, Wakai K, Tokudome S, et al. Bowel movement frequency and risk of colorectal cancer in a large cohort study of Japanese men and women. Br J Cancer. 2004;90(7):1397–1401. doi:10.1038/sj.bjc.6601735

[6] Qiao Y, Yang T, Gan Y, et al. Associations between aspirin use and the risk of cancers: a meta-analysis of observational studies. BMC Cancer. 2018;18(1):288. Published 2018 Mar 13. doi:10.1186/s12885-018-4156-5

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The Official COVID-19 protocol from Shanghai, China, in English

March 10, 2020, 12:32 pm

≫ Next: You can't Boost your Immunity? or, Debunking the COVID-19 Skeptics.

≪ Previous: Gene-diet interactions and the risk of colorectal cancer

This detailed protocol, which appeared online last week on an official Chinese Govt website, includes high-dose Vitamin C within the SOC drug recommendations. So far, when this has been pointed out to anyone in the "evidence-based medicine" community who has been busy online dismissing nutrient protocols for viral illnesses, they have pretended not to notice. Nor does there seem to be any reporting or discussion in the western mainstream media.
What about prophylaxis? The blood concentrations of vitamin C from IV use are higher than we can get from oral dosing.
I think, if you read the Cochrane reviews of vitamin C for the common cold or pneumonia, there is a clinically significant advantage in high-risk subcategories (people stressed by cold or rigorous exercise for cold, seriously ill elderly for pneumonia). There is heterogeneity in exposure methods, some of which will replicate natural coronavirus exposure better than others. And the general advantages - reduced symptoms and duration - are reductions in COVID-19 transmission factors that could have a meaningful impact at a population level. Read them closely, don't just look for the first limitation that you think might allow you to dismiss a whole body of evidence.
https://www.ncbi.nlm.nih.gov/pubmed/23925826/
https://www.ncbi.nlm.nih.gov/pubmed/23440782
"Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them."

If you disagree that EBM, for a lot of proponents, stands for emotionally biased medicine, consider this: New Zealand has had to ration acetaminophen (Panadol, Tylenol) prescriptions due to a run on pharmacy stocks.
There is no human RCT of the safety of acetaminophen in pneumonia (we know vitamin C is safe from the Cochrane review), but antipyretics, including acetaminophen, cause a 37% increased risk of mortality in animal models.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951171/
Yet there is no EBM push online to warn about this and to mock the people buying or prescribing antipyretics.
EBM - it ought to be essential, it's lovely in theory, yet it seems to be toxic at the level of science communication.

I can't tell you what to do, but here's what I'm doing, besides all the washing and contact common sense stuff - I'm making sure I'm replete in selenium, zinc, retinol, and vitamin D. I'm taking 500mg vitamin C a day. If I start to get ill, I'll take a standardised elderberry extract and a standardised andrographis extract. I may increase the dose of vitamin C.

The Shanghai Protocol, from https://mp.weixin.qq.com/s/bF2YhJKiOfe1yimBc4XwOA

[Editor's note]

On March 1st, the Chinese Journal of Infectious Diseases, which was hosted by the Shanghai Medical Association, pre-published the "Expert Consensus on Comprehensive Treatment of Coronavirus in Shanghai 2019" (http://rs.yiigle.com/m/yufabiao/1183266 .htm), which has attracted widespread attention in the industry. Shanghai TV also reported on the news last night. This consensus was reached by 30 experts representing the strongest medical force in the treatment of new-type coronavirus pneumonia in Shanghai. Through the research and summary of more than 300 clinical patients, and fully drawing on the treatment experience of colleagues at home and abroad, the "Shanghai Plan" was finally formed. At the end of the article, the list of 30 subject experts (18 writing experts and 12 consulting experts) from various medical institutions in Shanghai is attached.

Corona virus disease 2019 (COVID-19) was first reported on December 31, 2019 in Wuhan, Hubei Province. COVID-19, as a respiratory infectious disease, has been included in the Class B infectious diseases stipulated in the Law of the People's Republic of China on the Prevention and Control of Infectious Diseases and managed as a Class A infectious disease.

With the deepening of understanding of the disease, COVID-19 has accumulated a certain amount of experience in the prevention and control of COVID-19. The Shanghai New Coronary Virus Disease Clinical Treatment Expert Group follows the National New Coronary Virus Pneumonia Diagnosis and Treatment Program and fully draws on the treatment experience of colleagues at home and abroad to improve the success rate of clinical treatment and reduce the mortality rate of patients, prevent the progress of the disease, and gradually reduce the disease The proportion of patients with severe disease improves their clinical prognosis. Based on the continuous optimization and refinement of the treatment plan, expert consensus has been formed on the relevant clinical diagnosis and treatment.

I. Etiology and epidemiological characteristics

2019 novel coronavirus (2019-nCoV) is a new coronavirus belonging to the genus β. On February 11, 2020, the International Committee on Taxonomy of Viruses (ICTV) named the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with COVID-19 and asymptomatic infection can transmit 2019-nCoV. Respiratory droplet transmission is the main route of transmission and can also be transmitted through contact. There is also the risk of aerosol transmission in confined enclosed spaces. COVID-19 patients can detect 2019-nCoV in stool, urine, and blood; some patients can still test positive for fecal pathogenic nucleic acid after the pathogenic nucleic acid test of respiratory specimens is negative. The crowd is generally susceptible. Children, infants, and young children also develop disease, but the condition is relatively mild.

Clinical characteristics and diagnosis

(A) clinical characteristics

The incubation period is 1 to 14 d, mostly 3 to 7 d, with an average of 6.4 d. Main symptoms are fever, fatigue, and dry cough. May be accompanied by runny nose, sore throat, chest tightness, vomiting and diarrhea. Some patients have mild symptoms, and a few patients have no symptoms or pneumonia.

The elderly and those suffering from basic diseases such as diabetes, hypertension, coronary atherosclerotic heart disease, and extreme obesity tend to develop severe illness after infection. Some patients develop symptoms such as dyspnea within 1 week after the onset of the disease. In severe cases, they can progress to acute respiratory distress syndrome (ARDS) and multiple organ dysfunction. The time to progression to severe illness was approximately 8.5 days. It is worth noting that in the course of severe and critically ill patients, there may be moderate to low fever, even without obvious fever. Most patients have a good prognosis, and deaths are more common in the elderly and those with chronic underlying disease.

The early CT examination showed multiple small patches or ground glass shadows, and the internal texture of the CT scans was thickened in the form of grid cables, which was obvious in the outer lung zone. A few days later, the lesions increased and the scope expanded, showing extensive lungs, multiple ground glass shadows, or infiltrating lesions, some of which showed consolidation of the lungs, often with bronchial inflation signs, and pleural effusions were rare. A small number of patients progressed rapidly, with imaging changes reaching a peak on days 7 to 10 of the course. Typical "white lung" performance is rare. After entering the recovery period, the lesions are reduced, the scope is narrowed, the exudative lesions are absorbed, part of the fiber cable shadow appears, and some patients' lesions can be completely absorbed.

In the early stage of the disease, the total number of white blood cells in the peripheral blood was normal or decreased, and the lymphocyte count was reduced. Some patients may have abnormal liver function, and the levels of lactate dehydrogenase, muscle enzyme, and myoglobin may increase; troponin levels may be increased. Most patients had elevated CRP and ESR levels and normal procalcitonin levels. In severe cases, D-dimer levels are elevated, other coagulation indicators are abnormal, lactic acid levels are elevated, peripheral blood lymphocytes and CD4 + T lymphocytes are progressively reduced, and electrolyte disorders and acid-base imbalances are caused by metabolic alkalosis See more. Elevated levels of inflammatory cytokines (such as IL-6, IL-8, etc.) may occur during the disease progression stage.

(Two) diagnostic criteria

1. Suspected case: Combined with the following epidemiological history and clinical manifestations. Suspected cases were diagnosed as having any one of epidemiological history and meeting any two of the clinical manifestations, or having no clear epidemiological history but meeting three of the clinical manifestations. ① Epidemiological history: travel history or residence history of Wuhan City and surrounding areas, or other communities with case reports within 14 days before the onset; history of contact with 2019-nCoV infection (positive nucleic acid test) within 14 days before the onset ; Patients with fever or respiratory symptoms from Wuhan and surrounding areas or from communities with case reports within 14 days before the onset of the disease; cluster onset. ② Clinical manifestations: fever and / or respiratory symptoms; with the above-mentioned imaging features of the new coronavirus pneumonia; the total number of white blood cells is normal or decreased in the early stage of onset, and the lymphocyte count is reduced.

2. Confirmed cases: Those with one of the following etiology evidence are diagnosed as confirmed cases. ① Real-time fluorescent reverse transcription PCR detected 2019-nCoV nucleic acid positive. ② Viral gene sequencing revealed high homology with the known 2019-nCoV. ③ Except for nasopharyngeal swabs, take sputum as much as possible. Patients undergoing tracheal intubation can collect lower respiratory tract secretions and send viral nucleic acid test positive.

(Three) differential diagnosis

It is mainly distinguished from other known viral pneumonias such as influenza virus, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, human metapneumovirus, severe acute respiratory syndrome (SARS) coronavirus, etc. , Different from Mycoplasma pneumoniae, Chlamydia pneumonia and bacterial pneumonia. In addition, it must be distinguished from non-infectious diseases such as pulmonary interstitial lesions and organizing pneumonia caused by connective tissue diseases such as vasculitis and dermatomyositis.

(Four) clinical classification

1. Mild: The clinical symptoms are slight, and no pneumonia manifestations on imaging examination.

2. Ordinary type: fever, respiratory tract symptoms, etc. Pneumonia manifestations on imaging examination.

Early warning of severe cases of common patients should be strengthened. Based on current clinical studies, elderly (aged> 65 years) with underlying diseases, CD4 + T lymphocyte count <250 2="" 3="" and="" blood="" days="" found="" il-6="" imaging="" increased="" lesions="" levels="" lung="" on="" progress="" significant="" significantly="" to="" were="">50 %, lactic dehydrogenase (LDH)> 2 times the upper limit of normal value, blood lactic acid ≥ 3 mmol / L, metabolic alkalosis, etc. are all early warning indicators of severe disease.250>

3. Heavy: Any one of the following. ① Shortness of breath, respiratory rate ≥ 30 times / min; ② In resting state, arterial oxygen saturation (SaO2) ≤ 93%; ③ arterial partial pressure of oxygen, PaO2) / fraction of inspired oxygen (FiO2) ≤ 300 mmHg (1 mmHg = 0.133 kPa). At high altitudes (above 1 000 m), PaO2 / FiO2 should be corrected according to the following formula: PaO2 / FiO2 × [Atmospheric Pressure (mmHg) / 760].

Pulmonary imaging examination showed that the lesions progressed significantly within 24 to 48 hours, and those with more than 50% of the lesions were managed as severe.

4. Dangerous: A person who meets any of the following conditions can be judged as critical. ① Respiratory failure occurs and requires mechanical ventilation; ② Shock occurs; ③ Combined with other organ failure, ICU monitoring and treatment is required.

(5) Clinical monitoring

The patient's clinical manifestations, vital signs, fluid volume, gastrointestinal function and mental state are monitored daily.

All patients were dynamically monitored for terminal blood oxygen saturation. For critically ill and critically ill patients, timely blood gas analysis is performed according to the changes in the condition; blood routine, electrolytes, CRP, procalcitonin, LDH, blood coagulation function indicators, blood lactic acid, etc. are tested at least once every 2 days; liver function, kidney function , ESR, IL-6, IL-8, lymphocyte subsets, at least once every 3 days; chest imaging examination, usually every 2 days. For patients with ARDS, routine ultrasound examination of the heart and lungs at the bedside is recommended to observe extravascular lung water and cardiac parameters. For monitoring of extracorporeal membrane oxygenation (ECMO) patients, refer to the implementation section of ECMO.

Treatment plan

(A) antiviral treatment

You can try hydroxychloroquine sulfate or chloroquine phosphate, or Abidol for oral administration, interferon nebulization and inhalation, interferon κ is preferred, and interferon α recommended by the national scheme can also be applied. It is not recommended to use 3 or more antivirals at the same time. The viral nucleic acid should be stopped in time after it becomes negative. The efficacy of all antiviral drugs remains to be evaluated in further clinical studies.

For patients with severe and critical viral nucleic acid positives, recovery patients can be tested for recovery plasma. For detailed operation and management of adverse reactions, please refer to the "Clinical Treatment Program for Recovery of New Coronary Pneumonia Patients During Recovery Period" (trial version 1). Infusion within 14 days of the onset may be more effective. If the viral nucleic acid is continuously detected at the later stage of the disease, the recovery period of plasma treatment can also be tried.

(Two) treatment of light and ordinary patients

Supportive treatment needs to be strengthened to ensure sufficient heat; pay attention to water and electrolyte balance to maintain internal environment stability; closely monitor patient vital signs and finger oxygen saturation. Give effective oxygen therapy in time. Antibacterials and glucocorticoids are not used in principle. The patient's condition needs to be closely monitored. If the disease progresses significantly and there is a risk of turning into severe, it is recommended to take comprehensive measures to prevent the disease from progressing to severe. Low-dose short-course glucocorticoids can be used with caution (see the application section of glucocorticoids for specific protocols) ). Heparin anticoagulation and high-dose vitamin C are recommended. Low-molecular-weight heparin 1 to 2 per day, continued until the patient's D-dimer level returned to normal. Once fibrinogen degradation product (FDP) ≥10 µg / mL and / or D-dimer ≥5 μg / mL, switch to unfractionated heparin. Vitamin C is administered at a dose of 50 to 100 mg / kg per day, and the continuous use time is aimed at a significant improvement in the oxygenation index. If lung lesions progress, it is recommended to apply a large-dose broad-spectrum protease inhibitor, ulinastatin, at 600 to 1 million units / day until the pulmonary imaging examination improves. In the event of a "cytokine storm", intermittent short veno-venuous hemofiltration (ISVVH) is recommended.

(III) Organ function supportive treatment for severe and critically ill patients

1. Protection and maintenance of circulatory function: implement the principle of early active controlled fluid replacement. It is recommended to evaluate the effective volume and initiate fluid therapy as soon as possible after admission. Severe patients can choose intravenous or transcolonic fluid resuscitation depending on the conditions. The preferred supplement is lactated Ringer's solution. Regarding vasoactive drugs, noradrenaline and dopamine are recommended to maintain vascular tone and increase cardiac output. For patients with shock, norepinephrine is the first choice. It is recommended to start low-dose vasoactive drugs at the same time as fluid resuscitation to maintain circulation stability and avoid excessive fluid infusion. Cardioprotective drugs are recommended for severe and critically ill patients, and sedative drugs that inhibit the heart are avoided as much as possible. For patients with sinus bradycardia, isoprenaline can be used. For patients with sinus rhythm, a heart rate of <50 80="" about="" and="" at="" beats="" dopamine="" font="" heart="" hemodynamic="" instability="" intravenous="" is="" isoproterenol="" low-dose="" maintain="" min.="" min="" of="" or="" pumping="" rate="" recommended="" the="" to="">50>

2. Reduce pulmonary interstitial inflammation: 2019-nCoV leads to severe pulmonary interstitial lesions that can cause pulmonary function deterioration. It is recommended to use a large dose of a broad-spectrum protease inhibitor ulinastatin.

3. Protection of renal function: Reasonable anticoagulant therapy and appropriate fluid therapy are recommended as soon as possible. See chapter "Cytokine storm" for prevention, protection and maintenance of circulatory function.

4. Protection of intestinal function: Prebiotics can be used to improve the intestinal microecology of patients. Use raw rhubarb (15-20 g plus 150 ml warm boiling water) or Dachengqi decoction for oral administration or enema.

5. Nutritional support: parenteral nutrition is preferred, via nasal feeding or via jejunum. The whole protein nutrient preparation is preferred, and the energy is 25 to 35 kcal / kg (1 kcal = 4.184 kJ) per day.

6. Prevention and treatment of cytokine storm: It is recommended to use large doses of vitamin C and unfractionated heparin. Large doses of vitamin C are injected intravenously at a dose of 100 to 200 mg / kg per day. The duration of continuous use is to significantly improve the oxygenation index. It is recommended to use large doses. Dose of the broad-spectrum protease inhibitor ulinastatin, given 1.6 million units, once every 8 h, under mechanical ventilation, when the oxygenation index> 300 mmHg can be reduced to 1 million units / d. Anticoagulation The treatment protects endothelial cells and reduces the release of cytokines. When FDP ≥ 10 µg / mL and / or D-dimer ≥ 5 μg / mL, anticoagulation is given to unfractionated heparin (3 to 15 IU / kg per hour). Heparin is used for the first time. The patient's coagulation function and platelets must be re-examined 4 h later. ISVVH is used for 6 to 10 h every day.

7. Sedation and artificial hibernation: Patients undergoing mechanical ventilation or receiving ECMO need to be sedated on the basis of analgesia. For patients with severe man-machine confrontation during the establishment of an artificial airway, short-term application of low-dose muscle relaxants is recommended. Hibernation therapy is recommended for severe patients with oxygenation index < 200 mmHg. Artificial hibernation therapy can reduce the body's metabolism and oxygen consumption, and at the same time dilate the pulmonary blood vessels to significantly improve oxygenation. It is recommended to use continuous intravenous bolus medication, and the patient's blood pressure should be closely monitored. Use opioids and dexmedetomidine with caution. Because severely ill patients often have elevated IL-6 levels and easily cause abdominal distension, opioids should be avoided; 2019-nCoV can still inhibit sinus node function and cause sinus bradycardia, so it should be used with caution on Inhibitory sedatives. In order to prevent the occurrence and exacerbation of lung infections, and to avoid prolonged excessive sedation, try to withdraw muscle relaxants as soon as possible. It is recommended to monitor the depth of sedation closely.

8. Oxygen therapy and respiratory support: ① nasal cannula or mask oxygen therapy, SaO2 ≤93% under resting air condition, or SaO2 < 90% after activity, or oxygenation index (PaO2 / FiO2) 200-300 mmHg; With or without respiratory distress; continuous oxygen therapy is recommended. ② High-flow nasal cannula oxygen therapy (HFNC), receiving nasal cannula or mask oxygen therapy for 1-2 hours, oxygenation fails to meet treatment requirements, and respiratory distress does not improve; or hypoxemia during treatment And / or exacerbation of respiratory distress; or an oxygenation index of 150 to 200 mmHg; HFNC is recommended. ③ Noninvasive positive pressure ventilation (NPPV), receiving 1 to 2 h of HFNC oxygenation does not achieve the treatment effect, and there is no improvement in respiratory distress; or hypoxemia and / or exacerbation of respiratory distress during treatment; or When the oxygenation index is 150 ～ 200 mmHg; NPPV can be selected. ④ Invasive mechanical ventilation, HFNC or NPPV treatment does not meet the treatment requirements for 1 to 2 hours of oxygenation, and respiratory distress does not improve; or hypoxemia and / or exacerbation of respiratory distress during treatment; or oxygenation index <150 a="" are="" as="" be="" body="" considered.="" core="" font="" ideal="" invasive="" kg="" mass="" ml="" mmhg="" preferred.="" protective="" should="" small="" strategies="" the="" tidal="" ventilation="" volume="" with="">150>

9. Implementation of ECMO: Those who meet one of the following conditions may consider implementing ECMO. ① PaO2 / FiO2 < 50 mmHg for more than 1 h; ② PaO2 / FiO2 < 80 mmHg for more than 2 h; ③ Arterial blood pH < 7.25 with PaCO2 > 60 mmHg for more than 6 h. ECMO mode is preferred for intravenous-venous ECMO.

(4) Special problems and treatment in treatment

1. Application of glucocorticoids: Use glucocorticoids with caution. Imaging showed significant progress in pneumonia. Patients with SaO2 ≤ 93% or shortness of breath (respiratory frequency ≥ 30 breaths / min) or oxygenation index ≤ 300 mmHg in the state of no oxygen inhalation. Glucocorticoids can be added at the risk of intubation. Patients are advised to withdraw promptly from glucocorticoid use when intubation or ECMO support can maintain effective blood oxygen concentrations. For non-severe patients using methylprednisolone, the recommended dose is controlled at 20 to 40 mg / d, severe patients are controlled at 40 to 80 mg / d, and the course of treatment is generally 3 to 6 days. Can be increased or decreased according to the body weight.

2. Use of immunoregulatory drugs: Subcutaneous injection of thymosin 2 to 3 times per week has certain effects on improving patients' immune function, preventing the disease from becoming worse, and shortening the time of detoxification. Due to the lack of specific antibodies, high-dose intravenous immunoglobulin therapy is currently not supported. However, some patients have low levels of lymphocytes and the risk of co-infection with other viruses. Human immunoglobulin can be infused intravenously at 10 g / d for 3 to 5 days.

3. Accurate diagnosis and treatment of combined bacterial and fungal infections: clinical microbiological monitoring of all severe and critically ill patients. The sputum and urine of the patients are kept daily for culture, and the patients with high fever should be cultured in time. All patients with suspected sepsis who have indwelling vascular catheters should be sent for peripheral venous blood culture and catheter blood culture at the same time. All patients with suspected sepsis may consider collecting peripheral blood for molecular diagnostic tests for etiology, including PCR-based molecular biology testing and next-generation sequencing.

Elevated procalcitonin levels have implications for the diagnosis of sepsis / septic shock. When patients with new type of coronavirus pneumonia get worse, there is an increase in the level of CRP, which is not specific for the diagnosis of sepsis caused by bacterial and fungal infections.

Critically ill patients with open airways are often prone to bacterial and fungal infections at a later stage. If sepsis occurs, empirical anti-infective treatment should be given as soon as possible. For patients with septic shock, empirical antibacterial drugs can be used in combination before obtaining an etiological diagnosis, while covering the most common Enterobacteriaceae, Staphylococcus and Enterococcus infections. Patients with infection after hospitalization can choose β-lactamase inhibitor complex. If the treatment effect is not good, or the patient has severe septic shock, it can be replaced with carbapenem drugs. If considering enterococci and staphylococcal infections, glycopeptide drugs (vancomycin) can be added for empirical treatment. Daptomycin can be used for bloodstream infections, and linezolid can be used for lung infections. Attention should be paid to catheter-related infections in critically ill patients, and treatment should be empirically covered with methicillin-resistant staphylococci. Glycopeptide drugs (vancomycin) can be used for empirical treatment. Candida infection is also more common in critically ill patients. Candida should be covered empirically when necessary. Echinocin drugs can be added. With the length of hospitalization of critically ill patients, drug-resistant infections have gradually increased. At this time, the use of antibacterial drugs must be adjusted according to drug sensitivity tests.

4. Nosocomial infection prevention and control: ① In accordance with the Basic System for Infection Prevention and Control of Medical Institutions (Trial) of the National Health and Health Commission in 2019, actively implement evidence-based infection prevention and control clustering intervention strategies to effectively prevent ventilator-related pneumonia and intravascular Multidrug-resistant bacteria and fungal infections such as catheter-related bloodstream infections, catheter-related urinary tract infections, carbapenem-resistant gram-negative bacilli. ② Strictly follow the National Health and Health Commission's "Technical Guide for the Prevention and Control of New Coronavirus Infection in Medical Institutions (First Edition)", "Guidelines for the Use of Common Medical Protective Products in the Prevention and Control of Pneumonitis Due to New Coronavirus (Trial)" During the epidemic period, the technical guidelines for protection of medical personnel (trial implementation), strengthened process management, correctly selected and used personal protective equipment such as masks, gowns, protective clothing, eye masks, protective masks, gloves, and strict implementation of various disinfection and isolation measures Minimize the risk of nosocomial infections and prevent 2019-nCoV infections in hospitals by medical staff.

5. Treatment of infants and young children: Only mild symptomatic oral treatment is needed for mild children. In addition to symptomatic oral administration for children with common type, treatment with syndrome differentiation can be considered. If combined with bacterial infection, antibacterial drugs can be added. Severely ill children are mainly symptomatic and supportive treatment. Ribavirin injection was given antiviral therapy empirically at 15 mg / kg (2 times / day). The course of treatment did not exceed 5 days.

(V) Treatment plan of integrated traditional Chinese and western medicine

The combination of traditional Chinese and western medicine for the treatment of new coronavirus pneumonia can improve the synergistic effect. For adult patients, the condition can be improved through TCM syndrome differentiation. For light patients, those with a syndrome of wind-heat type are given the traditional Chinese medicine Yinqiaosan plus and minus treatment; those with gastrointestinal symptoms and those with damp-wetting and yang-type syndrome are given the addition and subtraction of Zhipu Xialing Decoction and Sanren Decoction. For ordinary patients, those with syndromes of hot and evil stagnation of lungs can be treated with Chinese medicine Ma Xing Shi Gan Decoction; those with syndromes of dampness and stagnation of lungs can be treated with traditional Chinese medicine Da Yuan Yin, Gan Lu Fang Dan, etc., which can be controlled to some extent Progression of the disease, reducing the occurrence of common to severe; for anorexia, nausea, bloating, fatigue, anxiety and insomnia, the addition and subtraction of Chinese medicine Xiao Chai Hu Tang can significantly improve symptoms. For severe patients, if the fever persists, or even the high fever, bloating, and dry stools are closed, and those who are heat-tolerant and the lungs are closed, give the Chinese medicine Dachengqi Decoction enema to relieve fever or reduce fever, or use Chinese medicine. The treatment of Baihu Decoction, Shengjiang San and Xuanbai Chengqi Decoction were added and subtracted to cut off the condition and reduce the occurrence of heavy to critical illness. Children with light patients, when the disease belongs to the defender, can be added or subtracted from Yinqiaosan or Xiangsusan. Ordinary children, those with damp heat and closed lungs, are given Ma Xing Shi Gan Decoction and Sanren Decoction; those with moderate scorching dampness and heat such as bloating and vomiting with abdominal distension can be added or subtracted without changing Jinzhengqi San. For severe patients with epidemic and closed lung (currently rare in the country), please refer to adult Xuanbai Chengqi Decoction and Manna Disinfection Danjiao; if the poison is hot, the gas can't pass, and the medicines are not good, the Rhubarb Decoction is given to enema for emergency.

(6) Discharge standards

Patients who meet the following conditions at the same time can be considered for discharge: ①The body temperature returns to normal > 3 d; ②Respiratory symptoms are significantly improved; ③ Imaging examination of the lungs shows that the acute exudative lesions are significantly improved; At least 1 d); ⑤ After the nucleic acid test of the respiratory specimen is negative, the fecal pathogen nucleic acid test is also negative; ⑥ The total disease course exceeds 2 weeks.

(VII) Health management of discharged patients

1. For discharged patients, close follow-up is still required. Follow-up is recommended from 2 weeks and 4 weeks after discharge to the designated follow-up clinic.

2. When the patient is discharged from the hospital, the place of residence and address in the city should be specified.

3. Patients should rest at home for 2 weeks after leaving the hospital, avoid activities in public places, and must wear masks when going out.

4. According to the patient's address (including hotel or hotel), the relevant district health and health committee will organize the corresponding medical institution to do a good job of health management. Professionals will visit the patient's temperature twice a day for 2 weeks, ask their health status, and carry out related health education.

5. If fever and / or respiratory symptoms recur, the corresponding medical institution shall report to the District Health and Health Commission and the District Centers for Disease Control and Prevention in a timely manner, and assist in sending them to the designated medical institution in the area for treatment.

6. After receiving the report, the District Health and Health Committee and the District Centers for Disease Control and Prevention report to the superior department in a timely manner.

↧

You can't Boost your Immunity? or, Debunking the COVID-19 Skeptics.

March 25, 2020, 4:03 pm

≫ Next: Probiotics for the prevention of Upper Respiratory Tract infections - a back-of-the-envelope Bradford Hill analysis

≪ Previous: The Official COVID-19 protocol from Shanghai, China, in English

Kate's elderberry concoction, photograph by Hayley Theyers

Is there anything as useless as the professional Skeptic community in a health crisis? Some people are paid to be roadblocks, others are educated professionals going well outside their lanes after the witches they despise for getting in their lanes at other times, others are just the sort of people who get an existential thrill from negating what they don't understand, or journalists with a "tough" reputation to uphold and a grab-bag of empty rhetoric.
In the history of science no-one has been wrong more often than the skeptic. What we usually call scepticism in the scientific method is just BEING CAREFUL.
"The first principle is that you must not fool yourself and you are the easiest person to fool." Richard P. Feynman
This is nothing like rushing into print with a negative opinion and a few pejoratives on a subject you haven't studied until now so you're either linking to the first blog that agrees with you on an emotional level, instead of looking at the literature, or you're scanning the literature quickly for reasons to dismiss it.

It's far more useful to point to what we DO know. And the first thing to be said, quite clearly, is that you CAN boost your immune system. See the evidence below. And a fast-acting, broad-spectrum immune response is how we get on top of new pathogens.
Straight up, it needs to be stated that COVID-19 is a new virus, with some specific features. Not everything that applies to previous colds, flus, or pneumonial diseases may apply. So all older evidence needs to be evaluated carefully. But it's not completely new, this isn't smallpox in the New World, it's a nasty variation on the cold viruses we've seen before and the healthiest immune systems can usually react appropriately, as we see when we consider the high rate of mild cases and the low symptom load in the very young. The pattern so far is characteristic of other pandemics; people with no or light symptoms seem to have had a strong initial immune response and are producing antibodies to COVID-19. Here is a COVID-19 immunological case study of a mild infection, which concludes:
“our study indicates that robust multi-factorial immune responses can be elicited to the newly emerged virus SARS-CoV-2 and, similar to the avian H7N9 disease, early adaptive immune responses might correlate with better clinical outcomes.“
https://www.nature.com/articles/s41591-020-0819-2.pdf

In humans, we can test whether a compound (or organism) improves the recognition of new pathogens by giving it with a vaccine.
Consistently, acetaminophen (tylenol, paracetamol) suppresses this function in infants.
https://www.ncbi.nlm.nih.gov/pubmed/19837254Effects are dose- and drug-dependent - low-dose aspirin doesn't impair immunity in elderly given flu vaccine, ibuprofen doesn't impair it compared with paracetamol in infants.
Probiotics enhance it.
https://www.sciencedirect.com/science/article/pii/S0264410X17311672

We know that probiotics enhance the immune response in vaccinated infants, but we can't take those infants and then expose them to the disease to learn how significant this is - herd immunity means that the risk is low in a vaccinated population even for people whose vaccines didn't work. We can however do this in animals.
Here's an experiment where zebrafish were vaccinated against a bacterial pathogen, Flavobacterium columnare, then bathed in said pathogen, with varying amounts of echinacea purpurea in their diets.
It's a tough test with, you might think, little possibility of a placebo effect.
The first point is that this vaccine doesn't really work. Only 5% of vaccinated fish are surviving exposure to Flavobacterium columnare. But add the echinacea to their feed, and we see survival climb dose-dependently. 5g echinacea per Kg is the same as none - 5% survival. 10g/Kg = 6%. 20g/Kg = 30%. 30g/Kg = 36%.
https://www.ncbi.nlm.nih.gov/pubmed/25638970
That link is down at sci-hub, so here is a similar study by the same team - without the vaccine.
https://www.researchgate.net/publication/230257632_Effect_of_Echinacea_purpurea_on_growth_and_survival_of_guppy_Poecilia_reticulata_challenged_with_Aeromonas_bestiarum

You're not going to get ethics approval to try this in humans, so make of this what you can. Firstly, why echinacea? The active ingredient is a polysaccharide, and it likely activates a variety of TLR and NOD receptors much as pathogen lipopolysaccharides do.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140398/
Similarly with probiotic cell wall lysates. A company I worked for tested a lysate from a lactobacillus rhamnosus strain many years ago and found it had ligand activity at TLRs 2,4,7,9, and NOD2, which latter is a gamma-interferon pathway.
This is going to enhance the response to a pathogen, which relies on you recognising quickly that it IS a pathogen via PAMPs and DAMPs (q.v.), a signal which compounds with such activity are amplifying.
This is well-known in human vaccine research - such compounds are called adjuvants and play a poorly-understood role in establishing immunodominance (the identification and proliferation of the "right" antibody-producing (B, Th2) immune cell).

Another commonly used herbal supplement, andrographis, has similar adjuvant effects given with vaccines in animal experiments
https://www.ncbi.nlm.nih.gov/pubmed/17321475.

Elderberry has AFAIK not been tested as an adjuvant but has direct antiviral effects in mice exposed to human influenza A.
https://pdfs.semanticscholar.org/8850/575f0665e98360dc6386ad828e66f573d270.pdf

So what is the human evidence? Elderberry (sambucus) is effective for seasonal URT infections in a meta-analysis. The studies only add up to n=180, but the effect is large and consistent (you don't need a high-powered study when something has a decent effect - we're not counting crumbs here, there's a loaf on the table).
https://www.ncbi.nlm.nih.gov/pubmed/30670267

This is likely due to cytokine effects, and some people might ask "what about cytokine storm?"
https://pubmed.ncbi.nlm.nih.gov/11399518/

Cytokines early in infection are the immune system's alert response. If viral levels are controlled early, there is a lower risk of cytokine storm.
The analogy here is the phase one insulin response, which, if inadequate to manage glucose levels, may be followed by an exaggerated and hyperinsulinaemic phase 2 response.
There is some question as to whether COVID-19 mortality is really due to cytokine storm, as in SARS or swine flu, or due to a direct effect of the virus on the lung, where cells producing pulmonary surfactant (Type II alveolar epithelial cells) are damaged by the virus and reduce normal lung function.

Andrographis is effective for reducing cough.
https://www.karger.com/Article/FullText/442111
It has an opposite effect on TNF-alpha from sambucus, so if you are worried that sambucus is too inflammatory use a combined supplement, in my experience these are effective enough for easing the misery and shortening the course of the usual cold and flu.
https://www.ncbi.nlm.nih.gov/pubmed/22026410

An AI-type analysis of data found that andrographis suppressed ACE2 expression most; sambucus and the TCM staple astragalus (another adjuvant) were also on the list.
https://www.preprints.org/manuscript/202002.0047/v1

Now, you may not want ACE2 suppressed if you are in extremis. It is a normal feature of lung function, and vitamin D supplementation (25 ug/Kg) increases ACE2 expression but prevents LPS-induced lung injury in this Wistar rat example.
https://www.researchgate.net/publication/316630691_Effect_of_Vitamin_D_on_ACE2_and_Vitamin_D_receptor_expression_in_rats_with_LPS-induced_acute_lung_injury
The jury is very much still out on ACE inhibitors (which may increase ACE2 expression) and risk.
https://jamanetwork.com/journals/jama/fullarticle/2763803

However - if you use these medicines, the idea is to use them around exposure, or PRN for symptoms, as advised. If they work, the disease will be less serious, if they don't and you do experience pneumonia you're not going to be taking them in the ICU.
Never keep taking something that makes you feel worse.

Interestingly, echinacea, which is a star in the animal studies, has only weak effects in human trials.
https://www.ncbi.nlm.nih.gov/pubmed/24554461
Yet these studies were just as small and had the same potential for bias as the elderberry and andrographis trials. That quite distinct effects or strength of effect appears consistently when different compounds are tested answers the specificity test of a Bradford Hill analysis of the "immune boosting" question. In fact every Bradford Hill criteria is being well-met, whatever the limitations of the human research.

The weak effects of echinacea may be due to its relative fragility and variation as an extract, inadequate dosage, or to the timing of its use as a prophylactic. I use these extracts only when I am either obviously exposed, "coming down with something", or actually sick. My opinion, not necessarily what the science says and just the voice of experience, is that echinacea and elderberry, if good extracts in adequate doses, both work if taken soon enough (elderberry was very effective taken within 24 hours in the swine flu but had no effect when given more than 48 hours after symptoms started). Perhaps echinacea is better for colds and sambucus for flus, but even if that were true COVID-19 is not necessarily playing by all rules. I also use Sanderson's Viramax, a mixed supplement of sambucus, andrographis, echinacea and olive leaf extract when I'm sick for PRN symptom relief, on the basis of past satisfaction with its effects. There is some evidence for olive leaf extract, but the active ingredient seems to be found in extra virgin olive oil.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412187/

Apart from herbs and probiotics, what else is there evidence for?

Malnutrition impairs antibody production, obviously, so eat a sensible diet that includes minimally processed animal products, including meat, if you're skeptical about supplements.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033455/

Apart from that, it's well worth supplementing selenium (by Brazil nuts or supplements). A pre-2019 coronavirus encoded for 60 selenocysteine residues per core protein. This is a common viral adaptation and protects the stability of the viral genome (a good thing) while depressing host immunity (a bad thing).
https://www.sciencedaily.com/releases/2001/06/010608081506.htm
Wuhan, Northern Italy, the UK and NZ are all low-selenium areas where deficiency is common. Check the data for your region or county, which is usually available online.

The jury's still out on supplementary vitamin C, and I seemed to stop responding to it when my metabolic health improved, but it's cheap and can't hurt.
Update: high dose vitamin C is being used in New York hospitals.
https://www.dailymail.co.uk/news/article-8149191/New-York-hospitals-treating-corona-patients-6000-milligrams-VITAMIN-C.html
It's the end of winter in the Northern hemisphere so I'd be supplementing vitamin D3 if I lived there.
Inorganic zinc lozenges (especially zinc acetate) seem to have a role to play here, but may be a lot of trouble to maintain for the duration. It might be worth it depending on your level of risk, as the effect is strong enough.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418896/

The spread and virulence of viral infections is in large part a numbers game. Needlestick exposures to HCV had a higher clearance rate than exposures to contaminated blood transfusions. Every line of defense matters, and every proven or even just most-likely barrier to the pathogen establishing dominance over the immune system can be worth investment.

↧

Probiotics for the prevention of Upper Respiratory Tract infections - a back-of-the-envelope Bradford Hill analysis

April 2, 2020, 4:56 pm

≫ Next: My Letter to Cochrane on the Hooper 2020 saturated fat meta

≪ Previous: You can't Boost your Immunity? or, Debunking the COVID-19 Skeptics.

“With most people, disbelief in a thing is founded on a blind belief in something else"
G. C. Lichtenberg

The Cochrane Collaboration found low-quality evidence that probiotics prevent UTRIs, and moderate-quality evidence that probiotics reduce antibiotic prescriptions for UTRI.
Because the antibiotic finding is most robust (aside from bearing the higher-quality GRADE score, it's also not a self-reported outcome), we'll take this as our baseline and see if it is strengthened or weakened by a Bradford Hill analysis.

1) Strength of association: for antibiotic use, RR 0.65 (0.45 to 0.94), n=1184.[1]
The true association is subject to type 2 confounding by two factors - by intention-to-treat analysis, and potentially by the random consumption of yogurt and other fermented foods supplying similar effects.

2) Consistency of association: the association is consistent, with similar (but slightly larger) effect sizes for all other measures of URTI. The association is reasonably consistent between different trials (there is no major contradiction). The association is strongly consistent with the effects of probiotics on vaccination immunity (RCTs using independently measured serum makers so more robust than the UTRI trials). The association is consistent with results for sambucus (effect size 1.717) (see 9, "analogy").[1,2,3,4]

3) Specificity: Probiotics have had no consistent association with several other outcomes predicted for them. Probiotic treatment of mothers during pregnancy only results in better immunity after vaccine for mother, not infant, consistent with dendrite cell pathway for effect.[2]

4) Temporality: Implicit in trial design

5) Biological gradient: dose-reponse is seldom tested in probiotic experiments perhaps because of assumption that a living organism can replicate, however a dose-response for duration of treatment is seen in the vaccine studies.[3] The analogous effect of echinacae purpurea in zebrafish is strongly dose-dependent.[5]

6) Plausibility: effect of probiotic on immune tone is well-studied, insofar as the immune system is currently understood the effect is plausible. Increased innate immunity around infection improves the acquired immune response. "A significant property of these bacteria is their ability to mimic natural infections, while intrinsically possessing mucosal adjuvant properties".[6] Dendrite cell presentation provides plausible pathway.[7]

7) Coherence - laboratory and field work are strongly coherent, animal experiments support human, herbs with similar immune effects to probiotics in experiments tend to have similar associations with URTIs in RCTs.[4]

8) Experiment - the association is experimental, the mechanism holds across a wide range of experiment types, including those with lowest risk of confounding or placebo effect.

9) Analogy - herbal effects are analogous, as when plant polysaccharides mimic bacterial lipopolysaccharides. Vaccine adjuncts are also analogous. Probiotics and herbal antivirals are researched as adjuvants.

Bradford Hill analysis allows us to see an association within its complete scientific context, to test whether it is causal.
It was originally designed to test the low-quality evidence that arises from purely observational, non-interventional studies, but is also useful to test the results of experiments where one considers these inadequate by themselves.

Here's what I think is the parsimonious way to explain the association: In the vaccine research, probiotics double the odds of lasting immunity after vaccination. Many infections are "repeats" of infections we have had before but lost immunity to. If probiotics prevent "repeat" infections by maintaining antibody responses, this can account for the effect, even without a direct effect on immunity to any new pathogen (although this is also plausible).
Immunologists are currently worried that many exposed to COVID-19 have not had a sufficient or lasting antibody response and are at risk of re-infection. The less re-infectious COVID-19 is, the sooner we can safely end our current economic restrictions, which will also take a toll on human life if maintained indefinitely.

1] Cochrane Database of Systematic Reviews. Q Hao, RB Dong, T Wu.
Probiotics for preventing acute upper respiratory tract infections
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006895.pub3/full

2] Zimmermann P, Curtis N. The influence of probiotics on vaccine responses - A systematic review.
Vaccine. 2018 Jan 4;36(2):207-213. doi: 10.1016/j.vaccine.2017.08.069. Epub 2017 Sep 18.
https://www.ncbi.nlm.nih.gov/pubmed/28923425

3] Lei WT, Shih PC, Liu SJ, Lin CY, Yeh TL. Effect of Probiotics and Prebiotics on Immune Response to Influenza Vaccination in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2017;9(11):1175. Published 2017 Oct 27. doi:10.3390/nu9111175
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707647/

4] Hawkins J, Baker C, Cherry L, Dunne E. Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complement Ther Med. 2019 Feb;42:361-365. doi: 10.1016/j.ctim.2018.12.004. Epub 2018 Dec 18.

5] Guz L, Puk K, Walczak N, Oniszczuk T, Oniszczuk A.
Effect of dietary supplementation with Echinacea purpurea on vaccine efficacy against infection with Flavobacterium columnare in zebrafish (Danio rerio). Pol J Vet Sci. 2014;17(4):583-6.

6] Benef Microbes. 2020 Mar 27:1-14. doi: 10.3920/BM2019.0121. [Epub ahead of print]
Immune modulatory capacity of probiotic lactic acid bacteria and applications in vaccine development.
Mojgani N, Shahali Y, Dadar M.

7] Gallo PM, Gallucci S. The dendritic cell response to classic, emerging, and homeostatic danger signals. Implications for autoimmunity. Front Immunol. 2013;4:138. Published 2013 Jun 10. doi:10.3389/fimmu.2013.00138

↧

My Letter to Cochrane on the Hooper 2020 saturated fat meta

May 27, 2020, 2:56 pm

≫ Next: A Reading List, and I Shill for a New Cookbook

≪ Previous: Probiotics for the prevention of Upper Respiratory Tract infections - a back-of-the-envelope Bradford Hill analysis

I submitted this on the Cochrane form at
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011737.pub2/comment

Others will have points to add about study quality and other factors, I have stuck to what I know (not wanting to waste my life battling an opponent who can obviously be reanimated an unlimited number of times).

The introduction to this meta-analysis includes an error uncorrected from the 2015 version.
Oliver 1953 measured total cholesterol, not LDL cholesterol. Further, it is relevant that every subject in Oliver 1953 had been eating the same hospital diet for at least 5 weeks before the cholesterol samples were taken, which does not support a diet-heart interpretation of the results.[1] (The presence of FH in the sample, and/or survivorship bias, are probably more reasonable interpretations)

[1] The Plasma Lipids in Coronary Artery Disease. Oliver MF, Boyd GS. Br Heart J. 1953 Oct;15(4):387-92.

The section headed "Agreements and disagreements with other studies or reviews" has not addressed any written after 2014, meaning that this section has not been updated. There are several analyses of the diet heart trials since 2015 that should have been addressed (indeed, that should have been read before the current Cochrane review was designed). Some are listed below.[2,3.4]

[2] Hamley, S. The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials. Nutr J 16, 30 (2017). https://doi.org/10.1186/s12937-017-0254-5

[3] Thornley S, Schofield G, Zinn C, Henderson G. How reliable is the statistical evidence for limiting saturated fat intake? A fresh look at the influential Hooper meta-analysis. Intern Med J. 2019;49(11):1418‐1424. doi:10.1111/imj.14325

[4] Jeffery L Heileson, Dietary saturated fat and heart disease: a narrative review, Nutrition Reviews, Volume 78, Issue 6, June 2020, Pages 474–485, https://doi.org/10.1093/nutrit/nuz091

The discussion of Siri-Tarino 2010 in "Agreements and disagreements with other studies or reviews" claims that adjustment for lipids has confounded its null result, however Siri-Tarino at al had already addressed this by isolating studies not adjusted for lipids with no difference in their null result. This is quite understandable as adjusting for lipids also means adjusting for TG and HDL, cardiometabolic risk markers which can be beneficially infuenced by saturated fat and worsened by carbohydrate.
Studies which do not adjust for lipids can be favourable to saturated fat, for example the Malmo DCS, a high-quality observational study using a 7-day food diary and more rigorous exclusion criteria than is usual, or the 2019 dose-response meta-analysis of observational studies by Zhe et al.[5,6]

[5] Leosdottir M, Nilsson PM, Nilsson JA, Månsson H, Berglund G. Dietary fat intake and early mortality patterns--data from The Malmö Diet and Cancer Study. J Intern Med. 2005;258(2):153‐165. doi:10.1111/j.1365-2796.2005.01520.x

[6] Zhu, Y., Bo, Y. & Liu, Y. Dietary total fat, fatty acids intake, and risk of cardiovascular disease: a dose-response meta-analysis of cohort studies. Lipids Health Dis 18, 91 (2019). https://doi.org/10.1186/s12944-019-1035-2

The claim that greater lowering of LDL in trials being associated with greater reduction of events supports the diet-heart hypothesis may be unsound. Persons in good metabolic health are at significantly lower risk of CVD events despite other risk factors.[7] Persons who are obese, have diabetes, or the metabolic syndrome do not usually experience drops in LDL cholesterol when fat in the diet is changed; the subjects in the feeding studies cited, who did experience such drops, were healthy volunteers.[8,9,10]

[7] Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Low triglycerides-high high-density lipoprotein cholesterol and risk of ischemic heart disease. Arch Intern Med. 2001;161(3):361‐366. doi:10.1001/archinte.161.3.361

[8] Flock MR, Green MH, Kris-Etherton PM; Effects of Adiposity on Plasma Lipid Response to Reductions in Dietary Saturated Fatty Acids and Cholesterol, Advances in Nutrition. 2011;2,(3):261–274, https://doi.org/10.3945/an.111.000422

[9] Benatar JR, Sidhu K, Stewart RAH. Effects of High and Low Fat Dairy Food on Cardio-Metabolic Risk Factors: A Meta-Analysis of Randomized Studies. Tu Y-K, ed. PLoS ONE. 2013;8(10):e76480. doi:10.1371/journal.pone.0076480.

[10] Lefevre M, Champagne CM, Tulley RT,et al. Individual variability in cardiovascular disease risk factor responses to low-fat and low-saturated-fat diets in men: body mass index, adiposity, and insulin resistance predict changes in LDL cholesterol. Am J Clin Nutr. 2001;82(5):957–963, https://doi.org/10.1093/ajcn/82.5.957

It is also relevant that from 2004 the Swedish population began to reject diet-heart advice, to such an extent that butter sales rose and margarine sales dropped; cholesterol levels also rose.[11] Yet as recently as 2018 mortality from, and incidence of, AMI was continuing to decline in Sweden. In fact incidence of AMI had stayed stable from 1987 to 2005, after which it began to drop from 42,263 PA to 25,789 PA in 2018.[12]

[11] Johansson I, Nilsson LM, Stegmayr B, Boman K, Hallmans G, Winkvist A. Associations among 25-year trends in diet, cholesterol and BMI from 140,000 observations in men and women in Northern Sweden. Nutr J. 2012;11:40.

[12] Data accessed from Swedish Social Registry website 28/05/20 https://sdb.socialstyrelsen.se/if_hji/resultat.aspx

↧

A Reading List, and I Shill for a New Cookbook

July 2, 2020, 3:54 pm

≫ Next: Selenium reduces COVID-19 risk - a back-of-the-envelope Bradford Hill analysis.

≪ Previous: My Letter to Cochrane on the Hooper 2020 saturated fat meta

It's been a time for reading lists; in lockdown I enjoyed discovering the books of T.H. White (The Goshawk and The Age of Scandal) and Evan S. Connell (Mrs Bridges) and reading Hillary Mantel's memoir (Giving Up the Ghost).
Sam Kriss also has a great reading list in Damage magazine, which features some of the best political writing I've read in ages - kind of a Leftist Spectator, if you get my drift, i.e. an honest journal, in a time when honesty is a rare and dangerous thing.

This is a reading list I compiled for PreKure a while back, of books most worth reading if you're interested in the nutrition-and-health ideas this blog has covered over the years.

The Perfect Health Diet, Paul and Shou-Ching Jaminet, 2012

This was one of the first “Paleo” books I read and, in my opinion, still one of the best. There are all sorts of sensible ideas, lots of references, and it’s not exclusively low carb. Some of their theoretical objections to keto diets haven’t come to much, and can be taken with a grain of salt, but there’s so much of value here to compensate. As far as population health goes, this is a clever and coherent interpretation of the evidence.

The Daughter of Time, Josephine Tey, 1951

This amusing 1950’s British detective story is a “research thriller”. The action, such as it is, takes place in a hospital bed as an injured detective sends his friends to libraries in search of the evidence in the case of a well-known historical mystery. Tey’s genius, and the lasting appeal of this book (Christopher Hitchens called it one of the most important ever written) is to show us how the most cherished received beliefs can be based – if we look closely – on lies and hearsay, the suppression of evidence, and self-serving propaganda. (*cough* saturated fat *cough*) And when Tey’s detective comes around to her alternative hypothesis, he oversells it – we suspect the author’s bias by now, and already know the evidence is too corrupt to accept; so its very flaws help to make this book perfect. If you want to inoculate young adults against fake news without getting mired in any modern controversies, convince them to read The Daughter of Time.

Foods of the Foreign Born in Relation to Health, Bertha M. Wood, 1922

Wood was a US dietitian and wrote this book at a time when the US was receiving migrants and refugees from all over Europe, as well as Mexico and the Middle East; some had brought political terrorism with them, xenophobia was if anything more extreme than it is today, and in this climate Wood wanted to familiarise nursing and dietetic students with the variety of immigrant diets so that they could help these populations in what we would today call a culturally appropriate manner. Thanks to her research we can learn about the real Mediterranean diets of 100 years ago, and that Hungarians gave children whiskey instead of milk on their cereal. A feature of this book is that Wood tells us how to adapt each population’s diet for diabetics by removing the starchy carbs. Foods of the Foreign Born is available free online at https://archive.org/details/foodsforeignbor00woodgoog/page/n6

Biochemistry. Mathews, van Holde, Ahern. 3rd edition. 2000.

This is a second-hand biochemistry textbook. I recommend older editions like this, which you can sometimes find in op shops, because they give less space to the biochemistry of the genome, which isn’t useful information if you’re interested in nutrition, and thus have more nuts-and-bolts detail than whatever they’re selling today. It also says on page 841 that “Adult onset diabetes can often be controlled by dietary restriction of carbohydrate”. Only experts in biochemistry were allowed to tell us something that simple and true in 2000 - the rest of the world back then only cared about saturated fat and felt that the Mediterranean Diet was quite daring.
This book is, amongst other things, your essential guide to what functions vitamins and minerals really perform in the body. Disclaimer – I understand few of the many mathematical formulas in this book that are an essential part of a real biochemistry education, but enjoyed this book nonetheless, making especial use of the index.

The Meat Fix: How a Lifetime of Healthy Living Nearly Killed Me! John Nicholson, 2012

This is a light, funny read by a UK sports journalist who wrecked his gut and metabolic health by trying to be a good vegetarian. I recommend it as a consumer’s eye view of the path many are on today, and also an insight into what popular low-carb science looks like to an ordinary convert – a bit pseudoscientific from our perspective, but still thoroughly effective.

And, of course, The Big Fat Surprise (Nina Teicholz) and Why We Get Fat (Gary Taubes) – these are the books that best explain how we got to where we are today.

Now, I've never run advertising on this blog. I did try at one stage, when I ran out of money, but Google weren't interested. Their loss, my escape.

However, given a chance to sell out in a good cause, in a time when paid work ain't what it used to be, I've leapt at it.

Ally Houston from PaleoCanteen has written "Low Carb on a Budget" with chef John Meechan and this is the book I've long meant to write but never had time for.
Lower income people are most likely to suffer from the conditions for which low carb is the specific cure, from metabolic syndrome to obesity to type 2 diabetes to depression, anxiety and chronic pain.
Yet low-carb cookbooks are often written by foodies and include a wide variety of expensive, hard to find, and - not to put too fine a point on it - unnecessary - ingredients. Even without these, there is still some extra cost over white bread, sugar, margarine and processed meat, but nothing you won't soon make back from your dentist, doctor, pharmacy and snack bills.
Low Carb on a Budget gets high praise from those most worth listening to in the UK diet-and-public health debate; if you don't know the names of some of those praising it, check out their work.
Another great selling point is that I'll get a pound, whatever that is, for every copy sold through the link above, and the Public Health Collaboration, a very effective lobby group in the UK, will get 50p.

↧

Selenium reduces COVID-19 risk - a back-of-the-envelope Bradford Hill analysis.

August 30, 2020, 8:20 pm

≫ Next: Mauritius - When the effects of saturated fat replacement failed to conform to the modelling, no-one cared.

≪ Previous: A Reading List, and I Shill for a New Cookbook

Bradford Hill introduced a checklist for assessing the strength of epidemiological evidence for causality, which is useful in the current pandemic when nutritional factors have been insufficiently tested by experiment in favour of drugs with, so far, relatively weak effects.[1]
Remember, a long time has passed and a lot of people have died while Evidence-Based Medicine was facing the wrong way.

And asking the wrong question. "What new treatment will save more lives in the ICU?" is an important question, but one with few answers and no great ones - "What can stop people who catch SARS-CoV-2 coming to the ICU?" is a better one in a pandemic, and one that might also lead to better treatment protocols.

Selenium reduces COVID-19 mortality: A Bradford Hill analysis

1) Strength of association. Very Strong.

1) On inspection of the Hubei data, it is notable that the cure rate in Enshi city, at 36.4%, was much higher than that of other Hubei cities, where the overall cure rate was 13.1% (Supplemental Table 1); indeed, the Enshi cure rate was significantly different from that in the rest of Hubei (P < 0.0001). Enshi is renowned for its high selenium intake and status [mean ± SD: hair selenium: 3.13 ± 1.91 mg/kg for females and 2.21 ± 1.14 mg/kg for males]—compare typical levels in Hubei of 0.55 mg/kg (10)—so much so that selenium toxicity was observed there in the 1960s. Selenium intake in Enshi was reported as 550 µg/d in 2013.

Similar inspection of data from provinces outside Hubei shows that Heilongjiang Province in northeast China, a notoriously low-selenium region in which Keshan is located, had a much higher death rate, at 2.4%, than that of other provinces (0.5%; P < 0.0001). The selenium intake was recorded as only 16 µg/d in a 2018 publication, while hair selenium in the Songnen Plain of Heilongjiang was measured as only 0.26 mg/kg (Supplemental Table 2).

Finally, we found a significant association between cure rate and background selenium status in cities outside Hubei (R2 = 0.72, F test P < 0.0001; Figure 1, Supplemental Table 2).[2]

Correlation between COVID-19 cure rate in 17 cities outside Hubei, China, on 18 February, 2020 and city population selenium status (hair selenium concentration) analyzed using weighted linear regression (mean ± SD = 35.5 ± 11.1, R2 = 0.72, F test P < 0.0001). Each data point represents the cure rate, calculated as the number of cured patients divided by the number of confirmed cases, expressed as a percentage. The size of the marker is proportional to the number of cases.

2) Serum samples (n = 166) from COVID-19 patients (n = 33) were collected consecutively and analyzed for total Se by X-ray fluorescence and selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong correlation (r = 0.7758, p < 0.001), pointing to an insufficient Se availability for optimal selenoprotein expression. In comparison with reference data from a European cross-sectional analysis (EPIC, n = 1915), the patients showed a pronounced deficit in total serum Se (mean ± SD, 50.8 ± 15.7 vs. 84.4 ± 23.4 µg/L) and SELENOP (3.0 ± 1.4 vs. 4.3 ± 1.0 mg/L) concentrations. A Se status below the 2.5th percentile of the reference population, i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L, was present in 43.4% and 39.2% of COVID samples, respectively.
The Se status was significantly higher in samples from surviving COVID patients as compared with non-survivors (Se; 53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; 3.3 ± 1.3 vs. 2.1 ± 0.9 mg/L), recovering with time in survivors while remaining low or even declining in non-survivors.[3]

2) Consistency - Strong

All epidemiological data about selenium and COVID-19 is consistent in direction and effect size. However, tests that could be done comparing COVID-19 risk in high and low selenium regions of Brazil and the USA would establish consistency further.

3) Specificity - Very Strong

Selenium has much weaker or less consistent associations with other diseases, except those caused by other RNA viruses, e.g. when risk of hepatocellular cancer in viral hepatitis patients is compared with risk of osteoporosis.[4, 5]

4) Temporality - Strong

Prospective ecological comparisons are temporal by design.[2] In the German study, the temporal association between low serum selenium levels and COVID-19 symptom severity was closely tracked.[3]

Nutrients 12 02098 g003 550

5) Dose-response gradient - Very Strong

A strong, consistent dose-response is seen, even at levels where the risk of selenium toxicity exists, and despite the fact that toxic levels of soil selenium are often a legacy of industrial pollution in China.[2]

6) Plausibility - Very High

Reading references 2 and 3, as well as this review of the evidence written before reference 2 was published, should be persuasive.[6] See also ref 17 for antiviral effects. This one goes up to 11.

7) Coherence - Very High

Selenium is well-studied and nothing in its story seems to contradict the idea that higher intakes will protect against COVID-19 mortality and reduce the severity of disease.
Dexamethasone, a drug which can reduce COVID-19 mortality in the ICU, enhances 1α,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription.[7]
Selenium sufficiency is essential for the function of vitamin D in peripheral blood monocytes.[8] Vitamin D status also correlates with COVID-19 survival.[9]

8) Experiment - Weak (Insufficient)

This is an area of neglect, but overlaps with the next section as there are several trials of selenium supplementation in other viral diseases, and animal experiments in analogous conditions, and many mechanistic experiments that are non-specific. However the interaction between SARS-CoV-2 and selenoproteins has been confirmed by experiment.[10]

9) Analogy - Strong

Selenium intake is protective, and selenium supplementation has been useful, in other viral illnesses.
However, the protective effect of high selenium intakes before infection in epidemiology appears stronger than the protective effect of selenium as a late intervention in disease.[6, 11]

10)Risk - Weak, Well-Established

We can add the most relevant of extra questions to any given set of criteria - "strength of the alternative hypothesis" would be a good one for any lipid hypothesis.
Bradford Hill stated that some interventions are easier to justify than others.

On fair evidence we might take action on what appears to be an occupational hazard, e.g. we might change from a probably carcinogenic oil to a non-carcinogenic oil in a limited environment and without too much injustice if we are wrong. But we should need very strong evidence before we made people burn a fuel in their homes that they do not like or stop smoking the cigarettes and eating the fats and sugar that they do like. In asking for very strong evidence I would, however, repeat emphatically that this does not imply crossing every ‘t’, and swords with every critic, before we act.

With nutrient intakes there is often an identifiable risk, with a J-shaped curve. With selenium the risk is selenosis, which is a condition that requires chronic high exposure (I have given myself mild selenosis with around 900mcg selenium a day and it was not a terrible condition to experience and was reversible). There could be other risks. Luckily we have an experiment that tells us where the limit is.
In a low selenium country, like New Zealand or Denmark, you don't want to take more than 200mcg of extra selenium long term.[12] Pity the low dose arms here weren't retained in the intervention.

fx1

During 6871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis, the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 µg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 µg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar.

Howsoever that may be, taking extra selenium above 200mcg per day may yet be advised if one becomes ill with Covid, but an inorganic salt of selenium like sodium selenite (which is anyhow probably safer than the selenomethionine form long-term, as I'll discuss below) is preferable, according to the selenovirus expert, Ethan Will Taylor.
(this video link does not show in the mobile version of this post but can be reached through the web view option at the bottom)

[Edit: 1/09/20] There is also very good evidence that intravenous high dose selenite is safe in the ICU setting.

Totally 19 RCTs involving 3341 critically ill patients were carried out in which 1694 participates were in the selenium supplementation group, and 1647 in the control. The aggregated results suggested that compared with the control, intravenous selenium supplement as a single therapy could decrease the total mortality (RR = 0.86, 95% CI: 0.78–0.95, P = .002, TSA-adjusted 95% CI = 0.77–0.96, RIS = 4108, n = 3297) and may shorten the length of stay in hospital (MD −2.30, 95% CI −4.03 to −0.57, P = .009), but had no significant treatment effect on 28-days mortality (RR = 0.96, 95% CI: 0.85–1.09, P = .54) and could not shorten the length of ICU stay (MD −0.15, 95% CI −1.68 to 1.38, P = .84) in critically ill patients.[13]

This, and an earlier analysis which found less benefit, did not single out viral illnesses as a subgroup - this is only evidence for safety - but the earlier analysis did find a) slightly lower mortality in trials without an initial bolus dose, b) no increased risk in patients with renal disease.[14]

I will hypothesize briefly on selenium increasing mortality at 300 mcg/day in the Danish intervention study, a dose far too low to cause selenosis. This trial used selenium yeast, which supplies selenium as selenomethionine. This is somewhat more effective at raising selenoprotein activity than selenite over the short-term (Brazil nuts are more effective than both). However, if selenomethionine intake is in excess of the body's ability to convert it to selenocysteine by transmethylation, and especially if methionine intake is low, then selenomethionine will be incorporated into proteins instead of methionine, causing these proteins to lose some functionality. Because mammals cannot synthesize methionine de novo, but can synthesize selenocysteine, this risk does not exist with selenite.[15] (Selenite itself also plays a role in signalling that might be critical in SARS-CoV-2 infections.) If much of the selenium in high-selenium regions is present as inorganic selenium in drinking water, and selenocysteine in the flesh of animals that have processed the extra selenomethionine in local plants, this explains a higher selenium tolerance than seen in the Danish study.
(The conventional signs of selenosis result from selenocysteine replacing cysteine in proteins, and the relative weakness of the Se-Se bond compared with the S-S bond.)
It makes sense to me that selenomethionine, very useful as it will increase selenoprotein levels quickly if you don't have much time, should be replaced with sodium selenite for long-term coverage.
Brazil nuts are a variable quantity, a sample of nuts sold in NZ in 2008 had an average of 19 mcg per nut and increased selenoprotein levels more than selenomethionine.[16]

Plasma selenium increased by 64.2%, 61.0%, and 7.6%; plasma GPx by 8.3%, 3.4%, and -1.2%; and whole blood GPx by 13.2%, 5.3%, and 1.9% in the Brazil nut, selenomethionine, and placebo groups, respectively. Change over time at 12 wk in plasma selenium (P < 0.0001 for both groups) and plasma GPx activity in the Brazil nut (P < 0.001) and selenomethionine (P = 0.014) groups differed significantly from the placebo group but not from each other. The change in whole blood GPx activity was greater in the Brazil nut group than in the placebo (P = 0.002) and selenomethionine (P = 0.032) groups.

[Edit 02/09/20] - thanks to Mike Angell for this link; while all selenium sources are probably protective against death and ongoing harm from COVID-19, only selenite is likely to have an additional antiviral effect, and has low toxicity.[17]

All scientific work is incomplete - whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time.

Austin Bradford Hill, 1965.

References:

[1] Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295-300.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1898525/pdf/procrsmed00196-0010.pdf

[2] Jinsong Zhang, Ethan Will Taylor, Kate Bennett, Ramy Saad, Margaret P Rayman, Association between regional selenium status and reported outcome of COVID-19 cases in China, The American Journal of Clinical Nutrition, Volume 111, Issue 6, June 2020, Pages 1297–1299, https://doi.org/10.1093/ajcn/nqaa095

[3] Moghaddam, A.; Heller, R.A.; Sun, Q.; Seelig, J.; Cherkezov, A.; Seibert, L.; Hackler, J.; Seemann, P.; Diegmann, J.; Pilz, M.; Bachmann, M.; Minich, W.B.; Schomburg, L. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients 2020, 12, 2098.

[4] Yu MW, Horng IS, Hsu KH, Chiang YC, Liaw YF, Chen CJ. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. Am J Epidemiol. 1999;150(4):367-374. doi:10.1093/oxfordjournals.aje.a010016

[5] Wang, Y., Xie, D., Li, J. et al. Association between dietary selenium intake and the prevalence of osteoporosis: a cross-sectional study. BMC Musculoskelet Disord 20, 585 (2019). https://doi.org/10.1186/s12891-019-2958-5

[6] Bermano, G., Méplan, C., Mercer, D., & Hesketh, J. (2020). Selenium and viral infection: Are there lessons for COVID-19? British Journal of Nutrition, 1-37. doi:10.1017/S0007114520003128
https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/selenium-and-viral-infection-are-there-lessons-for-covid19/BE3AC78D5C92725BE83C4E474ECBB548

[7] Hidalgo AA, Deeb KK, Pike JW, Johnson CS, Trump DL. Dexamethasone enhances 1alpha,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription. J Biol Chem. 2011;286(42):36228-36237. doi:10.1074/jbc.M111.244061

[8] Schütze N, Fritsche J, Ebert-Dümig R, et al. The selenoprotein thioredoxin reductase is expressed in peripheral blood monocytes and THP1 human myeloid leukemia cells--regulation by 1,25-dihydroxyvitamin D3 and selenite. Biofactors. 1999;10(4):329-338. doi:10.1002/biof.5520100403

[9] Martín Giménez, V.M., Inserra, F., Ferder, L. et al. Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2. J Hum Hypertens (2020). https://doi.org/10.1038/s41371-020-00398-z

[10] Wang, Y et al. SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, ER stress and DNA synthesis. Preprint, 2020/07/31. 10.1101/2020.07.31.230243

https://www.researchgate.net/publication/343365020_SARS-CoV-2_suppresses_mRNA_expression_of_selenoproteins_associated_with_ferroptosis_ER_stress_and_DNA_synthesis

[11] Steinbrenner H, Al-Quraishy S, Dkhil MA, Wunderlich F, Sies H. Dietary selenium in adjuvant therapy of viral and bacterial infections. Adv Nutr. 2015;6(1):73-82. Published 2015 Jan 15. doi:10.3945/an.114.007575

[12] Rayman MP, Winther KH, Pastor-Barriuso R, et al. Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial. Free Radic Biol Med. 2018;127:46-54. doi:10.1016/j.freeradbiomed.2018.02.015

[13] Zhao Y, Yang M, Mao Z, et al. The clinical outcomes of selenium supplementation on critically ill patients: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2019;98(20):e15473. doi:10.1097/MD.0000000000015473

[14] Manzanares W, Lemieux M, Elke G, Langlois PL, Bloos F, Heyland DK. High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis. Crit Care. 2016;20(1):356. Published 2016 Oct 28. doi:10.1186/s13054-016-1529-5

[15] Xu X-M, Carlson BA, Mix H, Zhang Y, Saira K, Glass RS, et al. (2007) Biosynthesis of Selenocysteine on Its tRNA in Eukaryotes. PLoS Biol 5(1): e4. https://doi.org/10.1371/journal.pbio.0050004

[16] Thomson CD, Chisholm A, McLachlan SK, Campbell JM. Brazil nuts: an effective way to improve selenium status. Am J Clin Nutr. 2008;87(2):379-384. doi:10.1093/ajcn/87.2.379
https://academic.oup.com/ajcn/article/87/2/379/4633360

[17] Kieliszek M, Lipinski B. Selenium supplementation in the prevention of coronavirus infections (COVID-19) [published online ahead of print, 2020 May 24]. Med Hypotheses. 2020;143:109878. doi:10.1016/j.mehy.2020.109878
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246001/

↧

Mauritius - When the effects of saturated fat replacement failed to conform to the modelling, no-one cared.

November 16, 2020, 12:00 pm

≫ Next: Letter – Selenium supplementation may improve COVID-19 survival in sickle cell disease.

≪ Previous: Selenium reduces COVID-19 risk - a back-of-the-envelope Bradford Hill analysis.

There may be no country in the world in which a suggested limit on saturated fat has not been followed by a relatively rapid increase in the incidence of diabetes and obesity.

Of course this is a matter of observation not experiment, but so is most of the evidence that various dietary guidelines organizations have relied on over the years.

A particularly egregious case seems to have occurred in Mauritius, after the Mauritian Government changed the fat content of ration oil, a cheap cooking oil used by most of the population, by decree. In 1987 it had been 75-100% (median 87.5%) palm oil, with (by then) some soybean oil – overnight this was changed to 100% soybean oil. This change was based on predictions from the research of Ancel Keys into heart disease, in particular the 7 Countries study and the intervention in East Finland.

This took PUFA intakes (almost all linoleic acid) to 8.6%E for men and 8.8%E for women, and lowered SFA intakes to 7%E and 7.5%E respectively. These were, as reported, not high fat diets, and it may be relevant that Mauritius is a sugar-producing nation.[1,2]

5 years later, in 1992, researchers, including experts from Finland and the WHO, measured the changes in fat intake and cholesterol in the Mauritian population, focusing on Hindu Indians.

"In the 5-year survey of lipids and other biomarkers, mean population serum total cholesterol concentration fell appreciably from 5.55 mmol/l to 4.7 mmol/l (P<0.001). The prevalence of overweight or obesity increased, and the rates of glucose intolerance changed little."[1]

However, in a letter to the BMJ, N Chandrasekharan, a consultant chemical pathologist and Kalyana Sundram, senior research officer of the Palm Oil Research Institute of Malaysia disputed these findings -

"On the purported fall in serum cholesterol concentration from 5.7 mmol/l in 1987 to 4.6 mmol/l in 1992, it is not evident whether the samples were from the same subjects.

The data for 1992 on the per caput fat intake of 56.2 g per day based on a 24 hour dietary recall is a far cry from the 73.7 g reported by the Food and Agriculture Organisation. The figures for edible oil intake seem erroneous. In 1987 palm oil accounted for only 27.5% of the edible oils consumed and its saturated fatty acids contributed 1.89% of the total energy intake and this fell to 0.33% in 1992."[3]

However, we have previously found FAO fat consumption estimates to be unreliable, overestimating NZ butter consumption in recent years by a factor of 4. And Chandrasekharan and Sundram’s letter contains this statement:

"Although we are also concerned about the need to reduce the prevalence of noncommunicable diseases in Mauritius, we disagree on the kind of simplistic thinking and draconian measures advocated."[3]

In other words, whatever the effect on fat intakes or cholesterol, the change was a radical one. It put more linoleic acid into the Mauritian food supply, and as in other places, the change in mandated fats would have been accompanied by voluntary changes along the same lines. We may doubt whether cholesterol levels changed, but not that people began to consume more soybean oil.

So what happened? The 1987 intervention included several good ideas – exercise more, smoke less, drink less – as well as less certain ones – eat less salt, eat less saturated fat and more soybean oil.

However, it seems unlikely that CVD went down – circulatory mortality as a percentage of mortality increased after 1987. [4]

"Over 1981–2004 the proportion of circulatory disease mortality rose from 44% to 49% in males, and from 46% to 57% in females."

Mauritius is now #2 in the world for diabetes mortality. However, a coding change in 2004 meant that much of what had been recorded as circulatory disease mortality was shifted to diabetes mortality. What we do know is that diabetes prevalence increased, as has incidence of pre-diabetes.

"The prevalence of Type 2 diabetes increased significantly during the period studied, from 12.8% in 1987, to 15.2% in 1992, and 17.9% in 1998."[5]

Note that this contradicts the 1992 claim – by some of the same authors – that “the rates of glucose intolerance changed little” between 1987 and 1992, a discordance not mentioned in the 2002 paper.[1]

"The age-standardized prevalence of diabetes in 2009 was 22.3% (95% CI 20.0–24.6) among men and 20.2% (18.3–22.3) among women, representing an increase since 1987 of 64 and 62% among men and women, respectively".[6]

The Mauritius fat change paper has been cited just 17 times in 25 years, and not one of the citing papers includes any follow up on the consequences of the change there. For example, an AHA paper mentions the Mauritius change in glowing terms without following up whether benefit or harm ensued, beyond the claimed 5-year drop in cholesterol.[7] Palm oil reduction was modelled for India in 2013, and a doubled palm oil tax has been implemented in Fiji since, all in papers citing the 1987-1992 Mauritius cholesterol drop.[8, 9]
But none follows that citation up with any hard outcomes.

Conversely, none of the papers on health in Mauritius since 1992, charting worsening trends, and in which the Finns still feature as authors, mentions the oil change of 1987. However, the earlier paper had contained a warning:[2]

"Whether the replacement of palm oil by soya bean oil, rich in n-6 polyunsaturated fatty acids, is the optimal dietary change may be questioned... the consumption of fats high in polyunsaturated fatty acids may lead to increased concentrations of free radicals and oxidised low-density lipoprotein, which may promote the progression of atherosclerosis. Therefore, notwithstanding the apparent success of the intervention in Mauritius, an oil high in monounsaturated fatty acids, such as olive oil or rapeseed oil, might be preferable if such an oil substitution were currently being planned."

It appears now that both saturated fat in the diet, and a low intake of omega 6 linoleic acid, are beneficial in terms of the incorporation of the omega 3 fatty acids EPA and DHA into circulating lipids and cells.[10, 11, 12, 13] EPA in particular is anti-inflammatory, and is an approved drug for the prevention of CVD.[14]

"These observations indicate that the efficacy of n-3 fatty acids in reducing arachidonic acid level is dependent on the linoleic acid to saturated fatty acid ratio of the diet consumed."[11]

"The results suggest that dietary substitution of SFA with n-6PUFA, despite maintaining low levels of circulating cholesterol, hinders n-3PUFA incorporation into plasma and tissue lipids."[13]

The conversion of linoleic acid to arachidonic acid, and the peroxidation of arachidonic acid to aldehydes which interfere with insulin signaling, as well as its conversion to cannabinoids which increase adipocyte growth, in a context of decreased omega 3 availability from high LA and low SFA diet, are pathways that may explain the eventual adverse outcomes in Mauritius, especially in a population with high sugar availability.[15,16]

"Our recent finding that sucrose and other high glycemic index carbohydrates abrogate the antiobesity effect of n-3 PUFAs might, at least in part, provide an explanation to the apparent discrepancy between human and rodent intervention studies, and the lack of effect in some human trials. In addition to the amount and type of carbohydrates, the levels of n-6 PUFAs, linoleic acid in particular, in the background diet might influence the antiobesogenic effect of n-3 PUFAs."[15]

It seems that, in the matter of diet, public health experts cannot be relied on to investigate the possibility that they have made a mistake. They control the narrative so that a (questionable) historical change in cholesterol within a 5-year period is considered evidence that a lifetime intervention is valuable, yet a nation-wide worsening of hard endpoints after that intervention can be ignored. Certainly the diabetes disaster in Mauritius can have had many causes, but the possibility that the soya bean oil intervention was one of them has not even registered in the medical literature over a 30 year period, let alone been tested.

H/T Louise Stephen @LouiseStephen9 author of 'Eating Ourselves Sick' for bringing this intervention to my attention.

Postscript: it will be obvious to students of evidence-based medicine that the quality of evidence used to create this argument has left much to be desired. With the exception of the date and intent of the intervention and the diabetes incidence data, nothing here tells us quite what we want to know. For example, circulatory disease as a percentage of mortality is a suggestive but imperfect measure, even before the coding change. So there will be those who read this article and feel justified in dismissing the need for it.
But I ask them to look at things another way - the data in this page is, to the best of my knowledge, the sum total of the published, peer-reviewed evidence on the subject. The Mauritius intervention - a legal disruption of the saturated fat supply to replace it with unsaturated fat within an entire community, in a way designed to target its most vulnerable members - has been the masturbation fantasy of a certain type of public health epidemiologist for as long as I can remember. There is a constant supply of peer-reviewed publications modelling the long-term effect of such an intervention on the putatively preventable causes of mortality, and there have been none directly investigating the impact on those causes in this case - where the long-planned intervention actually happened.
The reasons for this neglect are a matter for conjecture; we may hear future tales of suppressed data and publication bias as we did with the Sydney Heart Study and Minnesota Coronary Experiment studies (both of which also involved changes of fat products given to a population, rather than the less certain changes of mere advice given in most other diet-heart studies)[17] but the conclusion ought surely to be that the modelling should stop until the facts have been checked.

References

[1] Dowse GK, Gareebo H, Alberti KGMM, Zimmet P, Tuomilehto J, Purran A, et al. Changes in population cholesterol concentrations and other cardiovascular risk factor levels after five years of the noncommunicable disease intervention programme in Mauritius. BMJ 1995;311:12259.

[2] Uusitalo U, Feskens EJM, Tuomilehto J, Dowse G, Haw U, Fareed D, et al. Fall in total cholesterol concentration over five years in association with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey. BMJ 1996;313:10446.

[3] Chandrasekharan N, Sundram K. Fall in cholesterol after changes in composition of cooking oil in Mauritius. BMJ. 1997;314(7079):516. doi:10.1136/bmj.314.7079.516

[4] Morrell, S., Taylor, R., Nand, D. et al. Changes in proportional mortality from diabetes and circulatory disease in Mauritius and Fiji: possible effects of coding and certification. BMC Public Health 19, 481 (2019) doi:10.1186/s12889-019-6748-7

[5] Söderberg S, Zimmet P, Tuomilehto J, de Courten M, Dowse GK, Chitson P, Gareeboo H, Alberti KG, Shaw JE. Increasing prevalence of Type 2 diabetes mellitus in all ethnic groups in Mauritius. Diabet Med. 2005 Jan;22(1):61-8.

[6] Magliano DJ, Söderberg S, Zimmet PZ, et al. Explaining the increase of diabetes prevalence and plasma glucose in Mauritius. Diabetes Care. 2012;35(1):87–91. doi:10.2337/dc11-0886

[7] Mozaffarian D, Afshin A, Benowitz NL, et al. Population approaches to improve diet, physical activity, and smoking habits: a scientific statement from the American Heart Association. Circulation. 2012;126(12):1514–1563. doi:10.1161/CIR.0b013e318260a20b

[8] Basu S, Babiarz KS, Ebrahim S, Vellakkal S, Stuckler D, Goldhaber-Fiebert JD. Palm oil taxes and cardiovascular disease mortality in India: economic-epidemiologic model. BMJ. 2013;347:f6048. Published 2013 Oct 22. doi:10.1136/bmj.f6048

[9] Coriakula J, Moodie M, Waqa G, Latu C, Snowdon W, Bell C. The development and implementation of a new import duty on palm oil to reduce non-communicable disease in Fiji. Global Health. 2018;14(1):91. Published 2018 Aug 29. doi:10.1186/s12992-018-0407-0

[10] Gibson, Robert A. Musings about the role dietary fats after 40 years of fatty acid research. Prostaglandins, Leukotrienes and Essential Fatty Acids, Volume 131, 1 – 5

[11] Garg ML, Thomson ABR, and Clandinin M T. Interactions of saturated, n-6 and n-3 polyunsaturated fatty acids to modulate arachidonic acid metabolism.

The Journal of Lipid Research, February 1990 , 31, 271-277.

[12] Dabadie H, Motta C, Peuchant E, LeRuyet P, Mendy F. Variations in daily intakes of myristic and alpha-linolenic acids in sn-2 position modify lipid profile and red blood cell membrane fluidity. Br J Nutr. 2006 Aug;96(2):283-9.

[13] Dias Cintia B, Wood LG, and Garg Manohar L. Effects of dietary saturated and n-6 polyunsaturated fatty acids on the incorporation of long-chain n-3 polyunsaturated fatty acids into blood lipids. European Journal of Clinical Nutrition. 2016; 70: 812-818

[14] Budoff M, Brent Muhlestein J, Le VT, May HT, Roy S, Nelson JR. Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: Rationale and design of the EVAPORATE study. Clin Cardiol. 2018;41(1):13–19. doi:10.1002/clc.22856

[15] Madsen L, Kristiansen K. Of mice and men: Factors abrogating the antiobesity effect of omega-3 fatty acids. Adipocyte. 2012;1(3):173–176. doi:10.4161/adip.20689

[16] Clark TM, Jones JM, Hall AG, Tabner SA, Kmiec RL. Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users. Cannabis Cannabinoid Res. 2018;3(1):259-271. Published 2018 Dec 21. doi:10.1089/can.2018.0045

[17] Ramsden Christopher E, Zamora Daisy, Majchrzak-Hong Sharon, Faurot Keturah R, Broste Steven K, Frantz Robert P et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73) BMJ 2016; 353 :i1246
https://www.bmj.com/content/353/bmj.i1246

↧

Letter – Selenium supplementation may improve COVID-19 survival in sickle cell disease.

March 4, 2021, 4:03 pm

≫ Next: Zombies of the Risk Society

≪ Previous: Mauritius - When the effects of saturated fat replacement failed to conform to the modelling, no-one cared.

Further to Ulfberg and Stehlik’s letter of Sept 29^th, further evidence supports the role of selenium in COVID-19 virulence.[1]

In their pre-print analysis by machine learning of Medicare patients Dun et al. found that the leading comorbidity associated with COVID-19 mortality, adjusted for age and race, was sickle cell disease (aOR, 1.73; 95% CI, 1.21-2.47), followed by chronic kidney disease (aOR, 1.32; 95% CI, 1.29-1.36).[2]

Both SCD and kidney disease can lower selenium levels by decreasing tubular selenium resorption, and are associated with deficient selenium status.[3,4]

Selenium status or intake has been correlated with COVID-19 outcomes, including mortality and recovery rates, in four patient groups in China, Germany, South Korea, and southern India.[5,6,7,8] SARS-CoV-2, like other RNA viruses, sequesters selenium causing selenium levels to drop during infection.[6,9] SARS-CoV-2 may infect cells in bone marrow, suppressing red blood cell formation.[10] Selenium status is inversely associated with haemolysis in SCD, and selenium may both inhibit haemolysis and enhance erythropoiesis in SCD.[3,11]

Selenium is required for the actions of both vitamin D and dexamethasone.[12,13] Selenite infusion is safe, including in critically ill and dialysis patients, and selenium supplementation has had favourable effects in other RNA virus infections.[14,15,16]

It should be noted that vitamin C and magnesium are also commonly deficient nutrients and are required for the activation of vitamin D3 by hydroxylation.[17,18,19] Deficiency of ascorbate has been associated with COVID-19 and COVID-19 outcomes in hospital populations.[20]

Selenium, supplemented if necessary with its cofactors in vitamin D metabolism, is proposed to be an important protective factor in the general population, but has the potential to reduce mortality from SARS CoV-2 infection in the sickle cell disease population to an even greater extent.

[1] Ulfberg, J., & Stehlik, R. (2020). Finland’s handling of selenium is a model in these times of coronavirus infections. British Journal of Nutrition, 1-2. doi:10.1017/S0007114520003827

[2] Dun C, Walsh CM, Bae S et al. A Machine Learning Study of 534,023 Medicare Beneficiaries with COVID-19: Implications for Personalized Risk Prediction. medRxiv 2020.10.27.20220970; doi: https://doi.org/10.1101/2020.10.27.20220970

[3] Delesderrier E, Cople-Rodrigues CS, Omena J, et al. Selenium Status and Hemolysis in Sickle Cell Disease Patients. Nutrients. 2019;11(9):2211. Published 2019 Sep 13. doi:10.3390/nu11092211

[4] Iglesias P, Selgas R, Romero S, Díez JJ. Selenium and kidney disease. J Nephrol. 2013 Mar-Apr;26(2):266-72. doi: 10.5301/jn.5000213. Epub 2012 Sep 18. PMID: 23023721.

[5] Zhang J, Taylor EW, Bennett K, Saad R, Rayman MP. Association between regional selenium status and reported outcome of COVID-19 cases in China, The American Journal of Clinical Nutrition, Volume 111, Issue 6, June 2020, Pages 1297–1299, https://doi.org/10.1093/ajcn/nqaa095

[6] Moghaddam A, Heller RA, Sun Q et al. L. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients 2020, 12, 2098.

[7] Im, JH et al. Nutritional status of patients with coronavirus disease 2019 (COVID-19) Int J Infectious Diseases, August 11, 2020

[8] Majeed, M et al. An Exploratory Study of Selenium Status in Normal Subjects and COVID-19 Patients in South Indian population: Case for Adequate Selenium Status: Selenium Status in COVID-19 Patients. Nutrition. Available online 11 November 2020, 11105

[9] Wang, Y et al. SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, ER stress and DNA synthesis. Preprint, 2020/07/31. 10.1101/2020.07.31.230243

[10] Reva, I., et al. Erythrocytes as a Target of SARS CoV-2 in Pathogenesis of Covid-19. Archiv EuroMedica. 2020. doi.org/10.35630/2199-885X/2020/10/3.1

[11] Jagadeeswaran R, Lenny H, Zhang H et al. The Impact of Selenium Deficiency on a Sickle Cell Disease Mouse Model. Blood 2018; 132 (Supplement 1): 3645. doi: https://doi.org/10.1182/blood-2018-99-111833

[12] Schütze N, Fritsche J, Ebert-Dümig R, et al. The selenoprotein thioredoxin reductase is expressed in peripheral blood monocytes and THP1 human myeloid leukemia cells--regulation by 1,25-dihydroxyvitamin D3 and selenite. Biofactors. 1999;10(4):329-338. doi:10.1002/biof.5520100403

[13] Rock C, Moos PJ. Selenoprotein P regulation by the glucocorticoid receptor. Biometals. 2009;22(6):995-1009. doi:10.1007/s10534-009-9251-2

[14] Zhao Y, Yang M, Mao Z, et al. The clinical outcomes of selenium supplementation on critically ill patients: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2019;98(20):e15473. doi:10.1097/MD.0000000000015473

[15] Manzanares W, Lemieux M, Elke G, Langlois PL, Bloos F, Heyland DK. High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis. Crit Care. 2016;20(1):356. Published 2016 Oct 28. doi:10.1186/s13054-016-1529-5

[16] Steinbrenner H, Al-Quraishy S, Dkhil MA, Wunderlich F, Sies H. Dietary selenium in adjuvant therapy of viral and bacterial infections. Adv Nutr. 2015;6(1):73-82. Published 2015 Jan 15. doi:10.3945/an.114.007575

[17] Cantatore FP, Loperfido MC, Magli DM, Mancini L, Carrozzo M. The importance of vitamin C for hydroxylation of vitamin D3 to 1,25(OH)2D3 in man. Clin Rheumatol. 1991 Jun;10(2):162-7. doi: 10.1007/BF02207657. PMID: 1655350.

[18] Dai Q, Zhu X, Manson JE, et al. Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial. Am J Clin Nutr. 2018;108(6):1249-1258. doi:10.1093/ajcn/nqy274

[19] Cooper ID, Crofts CAP, DiNicolantonio JJ, et al. Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management. Open Heart. 2020;7(2):e001356. doi:10.1136/openhrt-2020-001356

[20] Carr, A.C.; Rowe, S. The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19. Nutrients 2020, 12, 3286.

[3] Delesderrier E et al. Selenium Status and Hemolysis in Sickle Cell Disease Patients. Nutrients. 2019;11(9):2211. Published 2019 Sep 13. doi:10.3390/nu11092211

[4] Iglesias P et al. Selenium and kidney disease. J Nephrol. 2013 Mar-Apr;26(2):266-72. doi: 10.5301/jn.5000213. Epub 2012 Sep 18. PMID: 23023721.

[5] Zhang J et al. Association between regional selenium status and reported outcome of COVID-19 cases in China, The American Journal of Clinical Nutrition, Volume 111, Issue 6, June 2020, Pages 1297–1299, https://doi.org/10.1093/ajcn/nqaa095

[6] Moghaddam A et al. L. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients 2020, 12, 2098.

[7] Im, JH et al. Nutritional status of patients with coronavirus disease 2019 (COVID-19) Int J Infectious Diseases, August 11, 2020

[9] Wang, Y et al. SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, ER stress and DNA synthesis. Preprint, 2020/07/31. 10.1101/2020.07.31.230243

[10] Reva, I., et al. Erythrocytes as a Target of SARS CoV-2 in Pathogenesis of Covid-19. Archiv EuroMedica. 2020. doi.org/10.35630/2199-885X/2020/10/3.1

[11] Jagadeeswaran R et al. The Impact of Selenium Deficiency on a Sickle Cell Disease Mouse Model. Blood 2018; 132 (Supplement 1): 3645. doi: https://doi.org/10.1182/blood-2018-99-111833

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