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Thursday, 16 July 2015

Oliver and Boyd 1953 - lessons from the early history of the lipid hypothesis.


The introduction to Hooper et al. 2015 gives a good potted history of the lipid hypothesis. It's well worth reading to get some background as to why this idea that saturated fat causes heart disease took off the way it did. (Hooper 2015)
There's a chain of logic involved. There is cholesterol in atherosclerotic plaques. There was a correlation between high cholesterol and heart disease. Eating saturated fat tends to elevate serum cholesterol. Join the dots.
The assumption is that the high cholesterol that correlates with heart disease and the effect of saturated fat on serum cholesterol are the same thing. 


In 1949 Ryle and Russell in Oxford documented a dramatic increase in coronary heart disease (CHD), and the Registrar General’s Statistical Tables of 1920 to 1955 showed that there had been a 70-fold increase in coronary deaths during this 35-year period (Oliver 2000Ryle 1949). This sudden surge in coronary heart disease sparked research into its causes. A case-control study published in 1953 of 200 post-myocardial infarction patients and age-matched controls established that those with disease had higher low density lipoprotein (LDL) cholesterol levels (Oliver 1953).

The 70 fold rise seen by Ryle and Russell seems to have been mainly due to vagaries in coding cause of deaths during the period, plus a decrease in mortality; in large part, more people were dying of CHD because more people were living to a suitable age, and CHD was becoming a popular diagnosis, replacing other similar causes on death certificates. CHD almost certainly did rise, but probably not nearly so fast. And of course it's ridiculous to think that people didn't eat much saturated fat before the 1920s. There's a small mistake in Hooper et al.'s citation of Oliver and Boyd 1953; this paper doesn't mention LDL cholesterol, just serum cholesterol. The reviewers would have picked this up if they'd been interested in the early history of the lipid hypothesis.The Plasma Lipids in Coronary Artery Disease. Oliver MF, Boyd GS. 
Br Heart J. 1953 Oct;15(4):387-92. Free text.
Oliver and Boyd 1953 does show a significant difference in cholesterol levels between MI patients and case-controls. That's true (except that strangely there was absolutely no correlation in women in the 50-59 age group). Peak decade for MI in men (largest % of cases) was 50-59, for women 60-69. 



The subjects were 200 consecutive admissions with coronary artery disease and 200 miscellaneous inpatient controls. In the coronary artery disease group, there was electrocardiographic confirmation of myocardial infarction in 170, and of ischaemia before or after the Master two-step test in 30 who presented clinically with angina of effort; any subject who lacked cardiographic confirmation of coronary artery disease was excluded. Adequate controls were very difficult to obtain from a hospital population, but were carefully selected from convalescent in-patients, who had no history or clinical features of atherosclerosis, cardiac, hepatic, metabolic, or renal disease, nor of any other condition known to influence the plasma lipids.
The coronary artery disease group was completed first, and the mean age of each decade of both sexes was determined; the control group was then completed so that the mean age, and number of cases in each decade, would correspond with the coronary artery disease group.

Does this study indicate in any way that saturated fat in the diet was linked to the high cholesterol associated with CHD?

In a small pilot study an irregular diurnal variation in plasma cholesterol was observed thus it was decided that all samples should be withdrawn between 8 and 8.30 a.m. in the fasting state. No blood sample taken during anticoagulant therapy has been included in this series. Similarly, no blood sample taken within five weeks of the occurrence of myocardial infarction has been included. All subjects were receiving a light ward or weight-reducing diet. 

So - the MI cases had been receiving the "light ward or weight-reducing diet" for at least 5 weeks. The controls were "convalescent", and as convalescence was still a leisurely process in hospitals in the UK in 1953, we can safely assume their exposure to hospital food was similar. Indeed, the study indicates that there was no age-related obesity in controls: 


Hypertension and obesity are more common after the menopause, but neither would seem 
to influence these observations; all the control subjects had a diastolic pressure of less than 90, and a morphological study employing a ponderal index assessment (Sheldon et al., 1940), did not show any tendency to endomorphy in this decade in the controls.

Though the text is not clear on this, the MI cases were probably more likely to be on the weight reducing diets than controls.

So what does Oliver and Boyd 1953 tell us about saturated fat and heart disease? Surely it demonstrates either 1) that the serum cholesterol level in MI cases has nothing to do with diet, or 2) that the serum cholesterol level in MI cases relates to a response to diet which is unique to MI cases, and which does not go away on light hospital or weight-reducing rations. There are three possible explanations of this; 1) that genetic determinants of serum cholesterol, such as FH phenotype, are related to MI (which seems pretty uncontroversial), 2) that cholesterol is elevated in response to an MI, and that this effect plays out over many weeks, 3) that cholesterol response to diet is influenced by either a recent MI or by genetic conditions predisposing to MI.
That saturated fat can cause heart disease in healthy people doesn't seem a logical conclusion to draw from Oliver and Boyd and is not a possibility mentioned in the text.

Any other explanations? 1953 was one year after the killer smog of London. The Oliver and Boyd study took place in Edinburgh, historically known as Auld Reekie for its air pollution. The Clean Air Act 1956 was the first attempt to limit air pollution in the UK. These and similar later Acts, the publication of and response to Silent Spring (1962), and the decline in cigarette smoking following (in the U.S.) the Surgeon General's report and Consumer Union reports into smoking (1963) seem to match the rapid decline in CHD after 1970 in the English speaking world and those countries that undertook similar public health measures in the same historical period (including Scandinavia and Japan).
Oliver and Boyd didn't ask questions about smoking, which might have been revealing, but they did at least set up their experiment to control for diet. It's just a pity that Keys and Hegsted ignored that.

See also: 
Flaws, Fallacies and Facts: Reviewing the 
Early History of the Lipid and Diet/Heart
Hypotheses. Elliott J. Food and Nutrition Sciences, 2014, 5, 1886-1903
http://dx.doi.org/10.4236/fns.2014.519201

Tuesday, 23 June 2015

Lee Hooper et al., 2015 - the latest Cochrane meta-analysis of saturated fat reduction RCTs

A new Cochrane meta-analysis of saturated fat reduction trials by Lee Hooper et al. has barely made a splash in the blogosphere, and my mention of it on Twitter barely merited a retweet.
This is a pity, because this is a question that is not really resolved.
A matter of particular interest to me about RCT meta-analysis is whether it agrees with prospective cohort meta-analysis. Another feature of Hooper's work that's instructive, which I intend to discuss, is her ongoing disagreement with Dariush Mozzafarian's analysis of fatty acid substitution.

Reduction in saturated fat intake for cardiovascular disease, The Cochrane Library, June 10 2015. Hooper L, Martin N, Abdelhamid A, Smith GD. DOI: 10.1002/14651858.CD011737

We include 15 randomised controlled trials (RCTs) (17 comparisons, ˜59,000 participants), which used a variety of interventions from providing all food to advice on how to reduce saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.72 to 0.96, 13 comparisons, 53,300 participants of whom 8% had a cardiovascular event, I² 65%, GRADE moderate quality of evidence), but effects on all-cause mortality (RR 0.97; 95% CI 0.90 to 1.05; 12 trials, 55,858 participants) and cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 12 trials, 53,421 participants) were less clear (both GRADE moderate quality of evidence). There was some evidence that reducing saturated fats reduced the risk of myocardial infarction (fatal and non-fatal, RR 0.90; 95% CI 0.80 to 1.01; 11 trials, 53,167 participants), but evidence for non-fatal myocardial infarction (RR 0.95; 95% CI 0.80 to 1.13; 9 trials, 52,834 participants) was unclear and there were no clear effects on stroke (any stroke, RR 1.00; 95% CI 0.89 to 1.12; 8 trials, 50,952 participants). These relationships did not alter with sensitivity analysis. Subgrouping suggested that the reduction in cardiovascular events was seen in studies that primarily replaced saturated fat calories with polyunsaturated fat, and no effects were seen in studies replacing saturated fat with carbohydrate or protein, but effects in studies replacing with monounsaturated fats were unclear (as we located only one small trial). Subgrouping and meta-regression suggested that the degree of reduction in cardiovascular events was related to the degree of reduction of serum total cholesterol, and there were suggestions of greater protection with greater saturated fat reduction or greater increase in polyunsaturated and monounsaturated fats. There was no evidence of harmful effects of reducing saturated fat intakes on cancer mortality, cancer diagnoses or blood pressure, while there was some evidence of improvements in weight and BMI.

In other words, no benefit from reducing SFA per se (some non-significant trends towards small benefits) on mortality and hard endpoints such as heart attacks. Non-significant trends and even null associations have been written up here as if they are meaningful. The Cochrane Collaboration surely wouldn't allow this in a review of drug trials, so why is it okay here?
Beneficial association between reduced SFA and cardiovascular events (17% RR), which is dependent on what SFA is replaced with, i.e. only PUFA. Because there is no reduction in individual classes of serious events, it's possible that the symptomatic relief of angina is the main benefit being shown here, but those figures aren't presented. In any case, this is almost certainly an effect of higher PUFA intakes and not SFA reduction.

An interesting point here is that this is the opposite of the prospective cohort data. Jakobsen et al. and Farvid et al. state that replacing SFA with PUFA (5%E) is associated with a 13% lower rate of CHD mortality, yet has (in Farvid et al.) non-significant effects on cardiovascular events in the randomised model. Non-randomised results from Farvid et al.:


“When the highest category was compared with the lowest category, dietary LA was associated with a 15% lower risk of CHD events (pooled RR, 0.85; 95% confidence intervals, 0.78-0.92; I(2)=35.5%) and a 21% lower risk of CHD deaths (pooled RR, 0.79; 95% confidence intervals, 0.71-0.89; I(2)=0.0%). A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% confidence intervals, 0.87-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% confidence intervals, 0.82-0.94).”

Results from Jakobsen et al.

“For a 5% lower energy intake from SFAs and a concomitant higher energy intake from PUFAs, there was a significant inverse association between PUFAs and risk of coronary events (hazard ratio: 0.87; 95% CI: 0.77, 0.97); the hazard ratio for coronary deaths was 0.74 (95% CI: 0.61, 0.89).”

Subgroup analysis reveals that this effect on cardiovascular events in Hooper et al. 2015 is specific to PUFA and, though it is related to LDL, it depends on PUFA, not CHO, being the LDL-lowering replacement for SFA.

"
We found no important effects of reducing SFA compared to usual or control diets on mortality when we subgrouped studies by SFA replacement (with PUFA, MUFA, CHO, or protein), mean duration, baseline SFA intake, or difference in SFA between intervention and control arms, decade of publication, or degree of reduction of serum total cholesterol. "
"There was a reduction in LDL in participants with reduced SFA compared to usual diet (MD -0.19 mmol/L, 95% CI -0.33 to -0.05, I² 37%, 5 RCTs, 3291 participants, P 0.006). There was no clear differential effect on LDL depending on the replacement for SFA (PUFA, MUFA, CHO or a mixture). "

yet
- " the subgroup of studies which achieved a reduction in serum total cholesterol of at least 0.2 mmol/L reduced cardiovascular events by 26%, while studies that did not achieve this cholesterol reduction showed no clear effect."

and

"When we subgrouped according to replacement for SFA, the PUFA replacement group suggested a 27% reduction in cardiovascular events, while there were no clear effects of other replacement groups."


So - lowering LDL has no association with benefit except when PUFA is increased, and no association with mortality even so.


This is not evidence of harms from SFA. 

This is consistent with an effect of the PUFA foods (possibly confounded by anti-atherogenic effects of their significant alpha-tocopherol, gamma-tocopherol, and Co-enzyme q10 content, and the anticoagulant effects of the hydrogenated vitamin K analogues formed during oil processing) being distinct from the effects of SFA lowering.

A substitution of PUFA for SFA in the context of a diet high in refined carbohydrate, which was the norm for most trials in Hooper at al., would produce a less atherogenic lipoprotein protein - less ApoCIII, for example (See anything by Ron Krauss). You would get the same effect by reducing carbohydrate without cutting SFA (ditto), which is why substitution of PUFA for CHO, even the small increments measured in prospective cohort meta-analysis, shows more benefit than substitution of PUFA for SFA . But substituting PUFA for CHO wasn't the (intentional) plan of any of the studies in Hooper et al. though it may well have happened incidentally as a result of calorie lowering or better food choices due to the educational aspect of these trials. (N.B. trials included were potentially biased by the intervention arms having education and support not available to controls, and by the SFA-lowering advice meaning less cakes, biscuits, more fish, veges, but the Finnish Mental Hospital trial where controls were handicapped by cardiotoxic drugs was excluded - EDITED - Excellent discussion of this paper by Steve Hamley here).


"The number of cardiovascular deaths was relatively small (1096), so while we can be quite confident in reporting a reduction in cardiovascular events (4377 events) with SFA reduction, and a lack of effect on total mortality (3276 deaths) within the studies' time scales, the effect on cardiovascular mortality is less clear. The risk ratio of 0.95 (95% CI 0.80 to 1.12) may translate into a small protective effect, but this is unclear. The lack of effect on individual cardiovascular events is harder to explain; there were 1714 MIs, 1125 strokes and 1348 non-fatal MIs, 2472 cancer deaths, 3342 diabetes diagnoses and 5476 cancer diagnoses. Lack of clear effects on any of these outcomes is surprising, given the effects on total cardiovascular events, but may be due to the relatively short timescale of the included studies, compared to a usual lifespan during which risks of chronic illnesses develop over decades."

By the same token, harmful effects of higher PUFA intakes may also take years to develop.

Where is the table for all-cause non-CHD mortality? Trend for cancer diagnoses = 0.94 (NS), trend for cancer deaths = 1.00 - no sub-group analysis. 

"One surprising element of this review is the lack of ongoing trials. In all previous reviews we have been aware of ongoing trials, the results of which were likely to inform the review, but for this review we have not noted any new trials on the horizon and so perhaps the current evidence set is as definitive as we will achieve during the 'statin era'."

Wow.
I predict that towards the end of the "statin era" we will begin to see RCTs of LCHF and Paleo diets in the primary and secondary prevention of CVD/CHD. And I predict that, given the very low bar set by SFA restricted diets - which seem here to be not much better for you than the rubbish people normally eat before they end up in hospital, which was after all the composition of the control diets - LCHF and Paleo diets will do pretty well in this regard.

Hooper disputes Mozzafarian's exaggerated analysis still.  "A recent review by Mozaffarian 2010, which again included very similar studies to the last version of this review, with the Finnish Mental Hospital study and Women's Health Initiative data added, stated that their findings provided evidence that consuming PUFAs in place of saturated fat would reduce coronary heart disease. However, their evidence for this was limited and circumstantial, as they found that modifying fat reduced the risk of myocardial infarction or coronary heart disease death (combined) by 19% (similar to our result). As the mean increase in PUFAs in these studies was 9.9% of energy, they infer an effect of increasing PUFAs by 5% of energy of 10% reduction in risk of myocardial infarction or coronary heart disease death. "

According to Hooper's 2010 editorial she thinks this back-dated evidence, from times when PUFA baselines were lower than today, justifies current PUFA intakes - it does not necessarily warrant an increase on the scale suggested by Mozaffarian.

"Mozaffarian and colleagues go further in presenting
their results as a 10% risk reduction for each additional
5% of PUFA consumption, although they present no evidence
of a dose-response relationship (not presenting
subgrouping or meta-regression by PUFA intake) and do
not explain how much of the PUFA consist of ω-3 fats
in each trial.
This review addresses an important question and
re-opening the debate on the effectiveness of replacing saturated
by polyunsaturated fats on coronary heart disease
is very welcome. However, dietary patterns have changed
over the 20–50 years since these studies ware carried out.
It would be useful to examine the full data set, including
more recent trials before concluding, as the abstract does,
that “a shift toward greater population PUFA consumption
in place of SFA would significantly reduce rates of CHD.”
Such a shift has already occurred since these trials were

carried out, and further shifts may be unhelpful."

Hooper L. Meta-analysis of RCTs finds that increasing consumption of polyunsaturated fat as a replacement for saturated fat reduces the risk of coronary heart disease. Evid Based Med2010;15:108–109doi:10.1136/ebm1093.




C-enzyme Q10 and tocopherols as confounders in PUFA oils

Coenzyme Q10 consumption promotes ABCG1-mediated macrophage cholesterol efflux: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

This shows that consumption of Co-Q10 improves HDL functionality, e.g. is anti-atherogenic. There is likely a separate effect on oxLDL as well.
Dose was 100mg 2x daily.

Vegetable oils are among the richest dietary sources of CoQ10.
the amount is much lower than in the experiment above, but enough to boost intake for most people. Absorption of coenzyme Q10 decreases with increasing supplemental dose.


Do oils raise serum co-Q10 levels?
Serum Co-Q10, alpha-tocopherol, and gamma-tocopherol are associated in women

"CoQ10 was significantly and positively correlated to α- and γ-tocopherol, and BMI was positively associated with CRP and γ-tocopherol in both groups."
Gamma tocopherol is generally considered to be a reliable marker of soy and corn oil consumption; soy and corn oils supply all 3 nutrients. It is most likely that the increase in Co-Q10 has the same origin as the increase in tocopherols. And maybe the same origin as the increased BMI, i.e. those of these oils that are highest in gamma-tocopherol - soy and corn.



Thursday, 4 June 2015

Statins and cancer stories - the stupidest thing you'll read this week.

If this isn't the stupidest thing I've read since that "high-protein diets kill mice fed lots of casein, ergo humans shouldn't eat paleo diet (which a priori eliminates casein)" story last week.

Statins 'could halve the risk of dying from cancer'


Apparently, people taking statins have much lower rates of cancer mortality. Cue more research and RCTs aimed at proving a new use for this class of drugs and sell even more prescriptions.

However, there are reasons why this claim (or carefully couched suggestion) amounts to quackery of the "false hope" sort. False hope for gullible GPs especially.

The studies did not show statins would prevent cancer. But they suggest taking them daily could save thousands of lives, by slowing the spread of diseases.
Doctors said it was not clear why they had such an effect, but the drugs reduce cholesterol, which is known to help the spread of disease.

Please do not bang your head quite so hard on your desk, no doctor recommends that (yet).

There are some basic things these "experts", and I use the inverted commas wisely, don't seem to know, or at least don't admit to knowing in a press release.

I summed up two of them in a letter to the Herald yesterday (unpublished so far).

Dear Sir/Ma'am,

According to a study reported in yesterday's Herald, people who take statin drugs are less likely to die from cancer. However, this effect has not been seen in 27 randomised, controlled trials. Statins are prescribed to people with high cholesterol. People with low cholesterol have an increased risk of cancer, and a greatly decreased likelihood of being prescribed statins. This might help to explain what is being presented as a possible protective effect of statins against cancer.


Yours sincerely,

George Henderson

References: (who includes references in letters to the Editor? I do. Maybe that's why they don't get published)

Serum cholesterol and cancer risk: an epidemiologic perspective.


http://www.ncbi.nlm.nih.gov/pubmed/1503812

Lack of Effect of Lowering LDL Cholesterol on Cancer: Meta-Analysis of Individual Data from 175,000 People in 27 Randomised Trials of Statin Therapy


http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029849

I wanted to save space to increase the odds of publication, so left out two other confounders;

1) People who take statins are goodie-goods. If the doctor tells them to take pills, they take them. If the doctor tells them to stop smoking, they stop. And so on. In fact doctors are less likely to prescribe statins to smokers.

2) Lots of people stop taking statins because of their side effects. Side effects - the inability to tolerate statins - could signify underlying diseases of ageing or nutritional deficiencies that also increase cancer risk or mortality.

If statins reduced cancer mortality an effect would be seen in RCTs. Statins cannot reduce cancer mortality by lowering LDL cholesterol, which is a protective risk factor for many common cancers, and for non-coronary mortality in ageing populations.

I'm not ruling out a cytotoxic effect of statins in certain cancers or a potentiating effect with specific cancer meds, but that's not what's being touted here, and were there a general effect of this sort with regard to more common cancers it would have shown in the RCTs.
.

Monday, 1 June 2015

Japanese epidemiology puts another hole in the lipid hypothesis



Everyone is reading this masterful analysis (PDF) of the lipid hypothesis from Japan, a country where it doesn't even seem true, which hasn't stopped the Japanese authorities from recommending cholesterol limits. The whole thing is worth reading, and sections of it are particularly congruent with the reverse lipid hypothesis of hepatology - that saturated fat protects the liver.




That this reversal comes from Japan is particularly interesting, because Japan is the poster boy of the lipid hypothesis - low intake of saturated fat (2.2%E in the Seven Countries Study), low CHD mortality, and has long been used to support the pious hope that if our SFA intakes were only low enough we'd see a comparable reduction in CHD. The reason there's no correlation between SFA and CHD in meta-analysis is, so they say, because we all eat too much SFA, except for the Japanese (oh, and the people of the former USSR and its satellites, who have fantastically high CHD mortality, but let's ignore that). The limbo argument - you can't get under the CHD bar if you're not low enough - is one of those last-ditch defenses of lipid hypothesis epidemiology.
Another is the undisputable truth that in many countries, the ones we know best, CHD mortality did fall at around the same time that SFA intakes declined. Steven Hamley makes the valid point that this SFA was in practice mostly replaced with refined carbohydrate, which no epidemiologist would predict to have lowered CHD based on any data we have. I'll link to this post of Steven's here and recommend regular reading of his blog for anyone interested in this topic.

Here's the mortality trend graph for the USA, typical of NZ, Australia, Canada, Finland and other big dairy and meat countries. SFA goes down a little, CHO goes up, CHD goes down a lot and keeps falling after 1972. Okay.



Here's the same data for Japan.



Ignore the glitch in the coding; it's obvious that CHD mortality fell from about 1970 or 1971. What happened to Japanese fat intake? Saturated fat intake doubled between 1965 and 1975, kept climbing thereafter. Serum cholesterol levels have been going up too.
What we see here is exactly the same CHD mortality pattern in two countries with directly opposing saturated fat and serum cholesterol trends. Two countries which were placed by Keys et al. at opposite extremes, kept apart by their difference in SFA intakes and serum cholesterol.

There are two or three possible explanations. One is that there is an optimal SFA intake, higher than 1965 Japan, lower than 1965 USA, pretty much where both countries are today. This has a certain biological plausibility (though it does require belief in Paleo just-so-stories), but it doesn't match other epidemiology (replacing dietary SFA with CHO elevates serum SFA, reduces LDL particle size, increases CHD events, and doesn't alter CHD mortality. Which higher or lower SFA doesn't correlate with anyway within any population band, be it Japan or Finland).

The second explanation is an improvement in treatment. This is usually countered with the objection that statins weren't available till the 1980's. So - warfarin, nitrates, beta-blockers - were those all being prescribed for no reason? Sure they didn't lower cholesterol, but if that isn't the dominant factor in CHD it's plausible that they had a significant effect as doctors got better at using them.

The third explanation is that this was an epidemic with an unknown or unappreciated cause, and it passed like historical epidemics do. For example, a pathogen wiped out by vaccination or other changes. Smoking, which does fit the trends and which does get some credit. Smog and industrial and agricultural pollution; the mortality trends closely match the beginnings of environmental and workplace regulation of pollutant exposure in both the USA and Japan. Silent Spring was published in 1962 and the period 67-72 represents a tipping point during which restrictions on household smoke, industrial emissions, agricultural residues, workplace exposures, and vehicular emissions began, and after which they became increasingly strict. Another consideration is that 1972 or thereabouts marked the end of national conscription in many western countries. After that date there was a growing expectation that people wouldn't and couldn't be expected to do things any longer if they didn't want to. Turn on, tune in, drop out. The decline of the stress-driven West began, though how this played out in Japan I have no idea. Micronutrition also improved, with the availability of out-of-season foods, new cultivars and imports. Increased PUFA intakes should be seen as part of this trend - the PUFA aspect of the lipid hypothesis was really a proposal for nutrient megadosing to achieve a pharmacological effect not seen, according to Keys et al., with normal intakes of PUFA.

What are we left with today as primary causes of CHD? A significant residue of chemical atherogenesis from pollution and smoking; the effects of malnutrition and the oxidative stress of deficiency, made worse by high-energy diets and the adulterants and contaminants of food processing technology; and above all the effects of metabolic diseases - MetSyn, hyperinsulinaemia, type 2 diabetes, and so on.
The disease patterns of the present are not just those of the past repeated with more or less intensity.





Friday, 22 May 2015

How a high fat ketogenic diet prevents diabetic ketoacidosis – somatostatin


Karl Petren 1868-1927
How a high fat ketogenic diet prevents diabetic ketoacidosis – somatostatin




It is pretty well-accepted now that nutritional ketosis and diabetic ketoacidosis are quite different things, but it is not yet understood how nutritional ketosis prevents diabetic ketoacidosis. That it does so was clear in 1923; both Newbugh and Marsh[1] and Karl Petren[2] reported in that year from their respective diabetes clinics that a diet high in fat, restricted in protein, and very low in carbohydrate, fed to diabetic patients, including (certainly in the case of Newburgh and Marsh) those with juvenile-onset, or type 1 diabetes, prior to the introduction of insulin, resulted in no cases of DKA developing. Newburgh and Marsh also reported DKA developing in a fasting case, so the inhibition of DKA was not a result of carbohydrate restriction alone.
DKA is the result of the unrestrained action of glucagon, which stimulates lipolysis and proteolysis, flooding the liver with substrates for ketogenesis (fat and ketogenic amino acids) and gluconeogenesis (glycerol and glucogenic amino acids), in the absence of insulin. Glucose, in the absence of insulin, is also a glucogenic substrate and increases both glucagon release and hepatic gluconeogenesis. The combination of hyperglycaemia and hyperketonaemia that ensues produces a loss of fluid volume and a life-threatening acidosis.
How might feeding fat prevent this?

Raphi Sirt, in response to my restatement of this question recently, tweeted a paper that cited another paper referring to a 1970’s experiment in which people with insulin-dependent diabetes were withdrawn off insulin and given a peptide called somatostatin by researchers happily free from modern ethics committee constraints.[3] This hormone prevented DKA by inhibiting glucagon release from the pancreatic alpha-cells. Somatostatin exists in two main forms in human metabolism, as 14 and 28 length peptides, and somatostatin 28 is released from the delta cells of the gut and pancreas proportionately in response to the ingestion of fat; there is a partial response to protein and no response to carbohydrate, making the somatostatin 28 ratio of macronutrients the inverse of the insulin ratio.[4]
In normal metabolism somatostatin inhibits both insulin and glucagon release. It is probably responsible for mediating the slower digestive response needed when fat is consumed in a meal. But if you have no insulin to begin with, somatostatin is just a glucagon inhibitor. If you have too much insulin and low insulin sensitivity (and hence too much hepatic glucagon activity) it’s probably helpful too, as long as you aren’t also eating carbohydrate.

Unusually I could not find full-text version of references 3 and 4, so there are still some very unanswered questions. Did Gerich et al. know of the findings of Newburgh and Marsh in designing their experiment? What was the form of somatostatin they used? And, did the serum concentrations of somatostatin approximate those that might be attained with high fat feeding? If not, does the paracrine release of somatostatin 28 that inhibits glucagon necessarily result in such high serum levels?
All your help, as always, is appreciated.

[Update 23-05-15] The somatostatin that prevents DKA in the Gerich study is somatostatin 14, whereas that which is elevated by dietary fat is somatostatin 28. How might this work? Somatostatin 14 has a higher affinity for the distribution of receptors on alpha cells, somatostatin 28 for that in beta cells. So in normal physiology somatostatin 28 is mainly inhibiting insulin, more so than glucagon. However, in physiology without functioning beta cells, the weaker effect on alpha cells is all that there is, and somatostatin 28 is inhibiting glucagon.


[1] Further observations on the use of a high fat diet in diabetes mellitus. Newburgh LH and Marsh PL. Archives of Internal Medicine April 1923 Vol. 31 No. 4.

[2] Über Eiweissbeschränkung in der Behandlung des Diabetes gravis, Petren K, 1923 - On protein restriction in the treatment of diabetes gravis. Cited in: A Substance in Animal Tissues which stimulates Ketone-Body Excretion, Stewart FB and Young HG, Nature 1952; 170, 976 - 977 doi:10.1038/170976b0


[3] Prevention of Human Diabetic Ketoacidosis by Somatostatin — Evidence for an Essential Role of Glucagon. Gerich JE, Lorenzi M, Bier DM et al. N Engl J Med 1975; 292:985-989. DOI: 10.1056/NEJM197505082921901

[4] Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans. Ensinck JW, Vogel RE, Laschansky EC, Francis BH. Gastroenterology 1990 Mar;98(3):633-8

Tuesday, 5 May 2015

Chemical Atherogenesis - the alternative hypothesis.



In 1977, when I was 19, and shortly before I cut my hair and joined a punk group, I worked as an apple picker in Upper Moutere, near Mapua, in the Tasman district of New Zealand.
The orchard was an eerie pace - no insects, no weeds, it even seemed that birds didn't fly over it, they certainly never ate the fruit. The fruit we picked had a white film on it. One of the guys I worked with drove the spray tractor, and he complained that he was loosing his vision due to the effects of the spray. None of us had protective gear. Our fires at night, fueled with cut-down apple trees, smelled like burning tyres. The factory that made some chemicals, including DDT, DDD, and which processed others, including 2,4,5-T and 2,4-D, was only 8 kilometres away, as the crow flies. Crows were probably the only thing that flew there.
There is a short report on this factory here. You can see that environmental standards were non-existent in New Zealand during the heyday of the persistent organochlorine pesticides and herbicides, which were used on the food everyone ate. Those who lived near or worked on farms were exposed to the highest levels, and urban workers were not exempt because PCBs were used in multiple industries and very similar organochlorine chemicals were added to petrol as "anti-knock" agents (they were, and probably still are, used in proprietary formulations such as STP).
My boss was a fit and hard-working guy, a non-smoker, who looked to be about 50. He was completely positive about the pesticides; it was as if he had a death-wish, or even an addiction. If Apocalypse Now had been released back then, I can imagine him saying "I love the smell of Dieldrin in the morning!" on a daily basis. I always assumed he sprayed Dieldrin for insects, because DDT was becoming less popular by 1977, even in New Zealand. He used to stand in the orchard while we worked and sneeze, loudly and often. He'd tell us how good sneezing made him feel - "like an orgasm!" - as he stood there in his shorts and plaid shirt, braced with his hands to his sides, like a jolly scoutmaster.
I only worked there for a month or so, but shortly after I left I had problems with recurrent flus, chronic fatigue, and headaches that lasted a long time. After a year or two I got word that my employer had died of a heart attack.
It never occurred to me for a moment that the butter in his diet had killed him. Obviously his blithe disregard for the dangers inherent in pesticide use had done him in.

Here is the NZ graph for mortality trends in CHD among people in their 50s. This is the historical ecological data cited by epidemiologists like Rod Jackson to make the case against saturated fat.


Saturated fat consumption in NZ increased between 1950 and 1970, but saturated fat consumption was always high - the increase did not represent a huge spike, and besides atherosclerosis is supposed to take 20 years or more. And women also ate more saturated fat - we are talking about the end of rationing and a new prosperity - yet the spike in CHD for women is minute - and this was the period when women started smoking in greater numbers. Sugar consumption skyrocketed at the end of rationing in 1950, polyunsaturated fats (and vitamin E) began to increase during the 1970's, selenium began to increase during the 1980's. I remember that women in the 1960's and 1970's often avoided sugar - saccharine and other artificial sweeteners were popular products specifically marketed to women in those days.

Meanwhile there was a growing awareness of the dangers of persistent pesticide use, the dangers of smoking, and the dangers of air pollution. New Zealand, despite its socialist politics, was completely dependent on primary industry - agriculture and manufacturing. The tourism and film industries, which benefit from pristine natural reputation, were insignificant. Not to put too fine a point on it, the situation was a messy scandal which few people want to go near even today. Proper records were not kept, guidelines were not followed, laws were ignored. It was only cleaned up slowly by a combination of a groundswell of increasing "green" criticism, the exposure of the Agent Orange scandal in South East Asia (involving the same chemicals we used for agricultural weed control in New Zealand) and, perhaps more important than any other factor, the rise of Monsanto, who had new and less persistent toxins to sell, and were actually in a position to convince the die-hards that the old poisons needed replacing.


All this would be moot if there was no evidence that organochlorines cause atherosclerosis. However, it is quite clear that they do.
This lovely document came out last year:


Review

Chemical Atherogenesis: Role of Endogenous and Exogenous Poisons in Disease Development.  MK AT, LC. Toxics 2014, 2(1), 17-34; doi:10.3390/toxics2010017


Chemical atherogenesis is an emerging field that describes how environmental pollutants and endogenous toxins perturb critical pathways that regulate lipid metabolism and inflammation, thus injuring cells found within the vessel wall. Despite growing awareness of the role of environmental pollutants in the development of cardiovascular disease, the field of chemical atherogenesis can broadly include both exogenous and endogenous poisons and the study of molecular, biochemical, and cellular pathways that become dysregulated during atherosclerosis. This integrated approach is logical because exogenous and endogenous toxins often share the same mechanism of toxicity. Chemical atherogenesis is a truly integrative discipline because it incorporates concepts from several different fields, including biochemistry, chemical biology, pharmacology, and toxicology. This review will provide an overview of this emerging research area, focusing on cellular and animal models of disease.
[N.B. the authors mention saturated fat as an endogenous atherogenic factor - not a dietary one. However their reference 18, cited to support this claim, a tasty review of ApoE knockout mouse research, doesn't really back it up - maybe because the experiments it cites rely on dietary fat, not endogenoous SFA].

So here we have the alternative hypothesis to explain the late 20th century rise and fall in CHD mortality. As cities and the countryside became more polluted, with particulate pollution, smoking, and organochlorines in agriculture and industry, which seeped into the food supply and home furnishings, heart disease rose. It rose significantly more in men because men - almost exclusively - worked in the industries, and at the automotive and electronic hobbies, that increased exposure to these pollutants the most. A few years after the publication of Silent Spring, as use of the most egregious pesticides lessened, it began to fall. As the rate of use, and the persistence of these chemicals fell further, CHD rates steadily dropped. The Clean Air Acts and improving Vehicle Emissions Standards of the 1970's-2000's, and the invention of the catalytic converter gradually reduced exposure to particulates and anti-knock additives, and lead was eliminated from petrol and paint. Better antioxidant and other micronutrition and the war against smoking also played an important role in its decline, and we can only hope that medicine was improving too, because some of the atherogenic chemicals were likely to have been drugs in common use - this is still a problem with SSRIs and antipsychotics today.

What is the role of sugar? Still not likely to be good. Not everyone had heart attacks from pollutant exposure; the dietary and hormonal drivers still operate. What about saturated fat?
This is likely to be bidirectional. Hence there is no association in prospective population studies. Saturated fat, when it increases LDL-cholesterol, is giving more hostages to fortune; but it is also less prone to oxidation than other lipids (though MUFA is no slouch in this regard), and it decreases gut permeability, reducing uptake of some swallowed atherogenic factors, and makes the liver less sensitive to toxins. Thus it can help some and harm others, so that the net effect is a wash-out at a population level. Maybe. A further factor is, that the atherogenic organochlorines were all lipid-soluble, and perhaps accumulated in animal fat (though the amount left on bought fruits and vegetables was sometimes visible to the naked eye), and at least one of the atherogenic factors, acrolein, is formed from the glycerol in burning fat - possibly helping to account for the differential CHD associations of meat SFA (always cooked, often burnt) vs. dairy SFA (usually eaten uncooked, and rarely burnt).

And this is my picture.

Tuesday, 31 March 2015

The Acute Porphyrias, and other Contraindications for Very Low Carbohydrate Diets and Fasting.

From the Department of Due Diligence...
Contraindications for Ketogenic and Very Low Carbohydrate Diets

This list of medical conditions which may cause adverse reactions to ketogenic diets or fasting may not be complete and is intended to be updated as necessary.


Acute Intermittent Porphyria and Acute Variegate Porphyria

The possibility of uncovering undiagnosed cases of these related disorders should always be borne in mind by those prescribing or experimenting with carbohydrate-restricted diets or fasting.

Acute Intermittent Porphyria (AIP) - Genetic disorder of incomplete heme synthesis due to deficiency of porphobilinogen deaminase with incidence 5-10 per 100,000.

 Acute Variegated Porphyria (AVP) - Genetic disorder reducing heme synthesis by 50% due to mutation of protoporphyrinogen oxidase, with incidence 1 in 300 (South Africa) to 1 in 75,000 (Finland).

True incidence may be greater as some cases are only diagnosed when triggered by low-carbohydrate diets or fasting.

- Some new cases of AIP and AVP were diagnosed at the height of Atkins diet popularity in the 1970s and this can be expected to recur during current popularity of LCHF diets.[1]

Symptoms may include:

Abdominal pain which is severe and poorly localized (most common, 95% of patients experience)
Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine)
(Note: urine turning dark after exposure to sunlight or UV light is useful diagnostic sign)
Peripheral neuropathy (patchy numbness and paresthesias)
Proximal motor weakness (usually starting in upper extremities which can progress to include respiratory impairment and death)
Autonomic nervous system involvement (circulating catecholamine levels are increased, may see tachycardia, hypertension, sweating, restlessness and tremor)
Neuropsychiatric symptoms (anxiety, agitation, hallucination, hysteria, delirium, depression)
Electrolyte abnormalities (Hyponatremia may be due to hypothalamic involvement leading to SIADH that may lead to seizures).
AIP can also present as acute pancreatitis [2, 3, 4]
Rash is not typically seen in AIP, but in AVP skin can be overly sensitive to sunlight. Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth. Exposed skin becomes fragile and is easily damaged.

Patients with acute porphyrias are commonly misdiagnosed with psychiatric diseases. Subsequent treatment with anti-psychotics increases the accumulation of porphobilinogen, thus aggravating the disease enough that it may prove fatal.
10% glucose infusion or high-carbohydrate diet used in treatment. Hematin and heme arginate can shorten attacks and reduce the intensity of an attack but are not without side effects [5]
Carbohydrate restriction is not a factor in the common porphyria, porphyria cutanea tarda.

Question: does dietary heme as well as dietary glucose play a protective role in AIP and AVP?

[Edit: a first hand account of what it is like to have an undiagnosed porphyria - http://ahha.org/articles.asp?Id=119
Note it can be triggered by many common diet components including in this case corn fed to animals.
Beta carotene is an effective treatment for photosensitivity of acute variegate porphyria -
 http://www.rarediseasesnetwork.org/porphyrias/patients/treatment/index.htm 
]

Systemic primary carnitine deficiency (SPCD) [6]

This syndrome, and others below, is almost certain to be diagnosed in infancy.
- also known as carnitine uptake defect, carnitine transporter deficiency (CTD) or systemic carnitine deficiency
- an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving carnitine across the plasma membrane.
- can be treated with high-dose l-carnitine supplementation
- although it is usually thought that MCTs do not require carnitine transport for beta-oxidation, tests with affected individuals have shown that MCTs are poorly metabolised in SPCD [7]
- Incidence: 1 per 100,000 except in Faroe Islands 1 per 1,000.

Other disorders that impair fatty acid oxidation and ketogenesis

A person with one of these disorders will have impaired metabolism of fatty acids when fasting, and will not produce ketones. Unless the condition is one treatable with l-carnitine, they may require a low-fat, high-carbohydrate diet.
Paradoxically a CPT1A defect is highly preserved in Arctic populations who evolved on a high-fat diet – this mutation suppresses ketosis and instead increases gluconeogenesis and heat generated from uncoupled fatty acid oxidation.[8]  The population of the Faroe Islands also traditionally ate a low-carbohydrate, high seafood diet; this would seem to suggest that CPT1A and perhaps SPCD defects are not true contraindications for such a diet.

Incomplete list of various fatty-acid metabolism disorders [9]

Carnitine Transporter Defect
Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Carnitine Palmitoyl Transferase I & II (CPT I & II) Deficiency
2,4 Dienoyl-CoA Reductase Deficiency
Electron Transfer Flavoprotein (ETF) Dehydrogenase Deficiency (GAII & MADD)
3-Hydroxy-3 Methylglutaryl-CoA Lyase (HMG) Deficiency
Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency)
Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)
Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD deficiency)
Short-chain acyl-coenzyme A dehydrogenase deficiency (SCAD deficiency)
3-hydroxyacyl-coenzyme A dehydrogenase deficiency (M/SCHAD deficiency)

“Inborn errors in the enzymes involved in lipid metabolism: from mitochondrial membrane long-chain fatty acids transport mechanism to beta-oxidation and Krebs cycle could be potentially fatal during fasting or KDs. Thus, carnitine deficiency, carnitine palmitoyltransferase (CPT) I or II deficiency, carnitine translocase deficiency, b-oxidation defects, or pyruvate carboxylase deficiency should be screened before initiating the KD treatment.”[10] 

Note:  The most frequently occurring mitochondrial respiratory disorders impair glucose, rather than fatty acid oxidation and are identified as indications for ketogenic diets.[11]

[1] Acute variegate porphyria following a Scarsdale Gourmet Diet. Quiroz-Kendall E, Wilson FA, King LE Jr. J Am Acad Dermatol. 1983 Jan;8(1):46-9. PMID: 682680

[2] Acute intermittent porphyria presenting as acute pancreatitis and posterior reversible encephalopathy syndrome. Shen FC, Hsieh CH, Huang CR, et al. Acta Neurol Taiwan. 2008 Sep;17(3):177-83.

[3] A case of acute intermittent porphyria with acute pancreatitis. Shiraki K, Matsumoto H, Masuda T, et al. Gastroenterol Jpn. 1991 Feb;26(1):90-4.

[4] Acute intermittent porphyria with relapsing acute pancreatitis and unconjugated hyperbilirubinemia without overt hemolysis. Kobza K, Gyr K, Neuhaus K, Gudat F. Gastroenterology. 1976 Sep;71(3):494-6.

[5] Adapted from Wikipedia, retrieved 14/11/2014 http://en.wikipedia.org/wiki/Acute_intermittent_porphyria

[6] Systemic Primary Carnitine Deficiency. El-Hattab A W. http://www.ncbi.nlm.nih.gov/books/NBK84551/

[7] Medium-chain triglyceride loading test in carnitine-acylcarnitine translocase deficiency: insights on treatment. Parini R. et al. J Inherit Metab Dis. 1999 Aug;22(6):733-9. PMID: 10472533

[8] A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. Clemente F. J et al. American Journal of Human Genetics Volume 95, Issue 5, p584–589, 6 November 2014

[9] retrieved from Wikipedia 14/11/2014 http://en.wikipedia.org/wiki/Fatty-acid_metabolism_disorder

[10] Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases. Paoli, A. et al. BioMed Research International Volume 2014 (2014), Article ID 474296, 10 pages http://dx.doi.org/10.1155/2014/474296

[11] Safe and Effective Use of the Ketogenic Diet in Children with Epilepsy and Mitochondrial Respiratory Chain Complex Defects. Kang, H-C et al. 2006. Epilepsia, DOI: 10.1111/j.1528-1167.2006.00906.x

Compiled by George Henderson, Research Assistant, Human Potential Centre, Auckland University of Technology.
Any suggestions to improve this resource should be sent to the author at puddleg@gmail.com