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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a paper that cited another paper referring to a 1970’s experiment in which people with insulin-dependent diabetes were withdrawn off insulin and given a peptide called somatostatin by researchers happily free from modern ethics committee constraints.[3] This hormone prevented DKA by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

Friday, 27 March 2015

How To Live Longer, by A. P. Herbert

This poem by A. P. Herbert was published in The Punch Guide to Good Living, under the initials A. P. H. The collection was edited by William Davis and published in 1973, and the selections appear to date from the 60's and early 70's.


                                    HOW TO LIVE LONGER

                            ATTEND. I do not often sing to you

To make you healthier, but now I do.
            The word coronary does not come down
             From cor, the heart, but from corona, crown;
         And I for one pronounce it in this way
       Whatever medical young men might say.
         Thus can the poet get the modern curse
Coronary thrombosis, into verse.
        "Modern," I say. This fashionable bane
             Is not described by Shakespeare - or by Jane.
                It's not a thing those knights in armour had,
Nor is it mentioned in the Iliad.
It is, as many other evils are,
Almost coeval with the motor-car.
But now, they say, it is the reason why
One-fifth of those who die in Britain die.
There are two schools of thought. One tells you flat
It comes of taking too much animal fat.
This breeds Cholesterol; and so they damn
Such lights of life as butter, milk and ham.
The other school insists, with my applause,
That these nutritious foods are not the cause.
They know of Africans who eat and drink
Fats all the time - but always in the pink:
And when they die, which is extremely rare,
You'll find that no Cholesterol is there.
The reason is, these enviable men
Take healthy exercise from 10 to 10.
But we, the best and brightest in the town.
Spend nearly all the daylight sitting down.
Not Sloth, nor Indolence have damped our fires,
But the soft slogging that Success requires.
We sit to work in motor, bus, or train,
Sit at our work, and, homing, sit again:
The "active" man, forever in a fuss,
Must do more sitting than the rest of us.
The more he telephones the more he sits,
Yet exercises nothing but his wits.
At golf they use the little legs no doubt,
But other men must cart the clubs about.
Tycoon or Clerk, accept the same prognosis -
You're heading for coronary thrombosis.
Be your own caddy; be afraid of chairs;
Ignore that lift and saunter up the stairs.
Do not be jet whizz over to Quebec;
But go by ship and march around the deck.
And no retiring to "a life of ease" -
For there's the certainty of heart disease.
It will be best not only for your soul
To weed the garden and bring in the coal.
And pray each evening for a transport strike -
Thus you may live as long as you would like.

                                                                              - A. P. H.

(The Old Humour)


(The New Humour)





Tuesday, 24 March 2015

TG/HDL ratio trumps LDL in untreated patients in the lipid lowering drug trials.




Ivor Cummins, bless him, found this treasure trove of data and broadcast it first on his Fat Emperor blog.
I've decided to write about it here because Ivor, in his magpie style, has scooped it up and dumped it where all can see, with a suitable explanation for those already in the know, but I think it will benefit from additional commentary.

Diet studies show LCHF is especially good for lowering fasting triglycerides and raising HDL, improving the TG/HDL ratio. Other diets are better for lowering LDL.
These are called surrogate endpoints; people don't usually die during weight loss trials (fat modification trials, usually with bigger numbers, are another story). If the diet lowers a "bad" marker or raises a "good" one, that is, markers such as lipids, blood pressure, BMI or HbA1c that are clearly associated with risk and easy to measure, that counts as success. These trials are too difficult and expensive to take much further than that (e.g. till people start dying).

The problem with this approach was vividly and disastrously demonstrated by the US Navy during World War Two.
If you're a US submariner firing a torpedo at a Japanese ship using a contact detonator and a shallow depth setting so it won't miss by running under the target, you'll most likely put a hole in that ship if you hit it, but you may not cause enough structural damage to sink it, and in underwater warfare you might not get a second shot (the Imperial Japanese Navy didn't really have this problem as their torpedoes were bigger and faster than the US equivalent).
The best way to optimize kills is to set the torpedoes to run deep, then explode them using a magnetic trigger that's detonated by passing under the ship's magnetic field. The consequent increased pressure from a proximal explosion in deep water will do more damage and hopefully break the ships back, allowing more ships to be sunk with the limited torpedo supply a submarine can carry on a long Pacific cruise. That's the theory, and the magnetic trigger was developed for the Mark 14 torpedo. Submariners were ordered to use it instead of the contact fuse.
Torpedo after torpedo fired at carefully set-up Japanese targets failed to explode. Boats that would later in the war devastate the Japanese merchant marine and Navy came back from patrol empty handed, their officers accused of cowardice or incompetence. The technology isn't flawed, you're just doing it wrong. The tide was eventually turned by submarine captains breaking orders, removing the magnetic triggers and changing the depth settings, to a predictable, indeed familiar, chorus of outrage and threats.
The Mk 14 torpedo still wasn't perfect (the contact trigger didn't work if it hit the target full-on, the depth setting mechanism was wonky, and so on) but the Japanese started to lose tonnage and the war.
The problem was that the expensive Mk 14 torpedo was developed during the Great Depression by a Navy operating on a minute budget. Habits of parsimony thus learned were continued into wartime.
The Mk 14 torpedo was never tested to detonation in any trial. If it ran deep enough under the dummy targets, and it had a magnetic trigger attached, or if it hit the target with a contact trigger attached, the trial was counted as a success.
In medicine this is called a surrogate endpoint.
And people are rightly sceptical about surrogate endpoints. Any line of evidence that gives new information about their reliability as predictors of death and disease is always welcome.

The evidence Ivor found concerns 3 lipid markers at baseline. They're not products of an intervention; they relate to diet, genetics, and metabolic health.
LDL, as we know, is raised by some of the saturated fats and lowered when these are replaced by other sources of energy.
TG is elevated (except in very low fat diets) in response to dietary carbohydrate.
HDL is raised by the same saturated fats that raise LDL, and is lowered by chronically elevated insulin levels such as we will see in insulin resistance and the early-to-middle phases of type 2 diabetes.
Someone who is metabolically healthy but eating a high-carbohydrate diet will have high TG, but because their insulin level is normal their HDL will not be depressed, thus the TG/HDL ratio will tend to stay in the normal range. In someone who is hyperinsulinaemic, TG on a high-carbohydrate diet may be even higher, and HDL will be depressed, creating an unfavourable TG/HDL ratio.
Excess insulin (or excess alcohol) will also increase production of unhelpful HDL subtypes, and high carbohydrate will make the LDL subtypes more atherogenic.
Dietary carbohydrate is thus the driver of this type of dyslipidemia, but is it necessarily worse than the high-LDL dyslipidemia that statins target?

The evidence from the trials:
The first set of graph is from a fibrate trial. Fibrates mainly lower TG/HDL, plus have nasty side effects. The black bars are the people who didn't get the drugs. That's who we're interested in in all these papers. HDL (cut-off 1.08) and TG (cut-off 2.3) correlate strongly with events. LDL (cut-off 5 - very generous!) is barely significant.
http://circ.ahajournals.org/content/85/1/37.long




The second set of graphs, from the same trial, shows that high TG is a lesser risk factor in people with higher HDL, and that a high LDL/HDL ratio is especially bad if you have high TG. Despite the lower white bars everywhere (those treated with gemfibrozil had fewer cardiac events) "there was no difference between the [treated and untreated] groups in the total death rate."



The third graph, from a 2013 statin trial, shows that people in the highest quartile for HDL who don't get statins (which did work for others) but get placebo instead do better than anyone taking statins.
http://www.ncbi.nlm.nih.gov/pubmed/23948286




I also found this drug and non-drug study: note cut-off for LDL is now half what it was in the Gemfibrozil study. This shows how much fashions can change in 25 years, but makes no difference to the results.

Low plasma HDL-c, a vascular risk factor in high risk patients independent of LDL-c.http://www.ncbi.nlm.nih.gov/pubmed/19453647
During a median follow up of 3.3 (range 0.1-9.5) years, a total of 465 first new events occurred. Compared with the lowest quintile, the upper quintile of HDL-c levels was associated with a lower risk for new events; Hazard Ratio 0.61 (95% CI 0.43-0.86) irrespective of the localisation of vascular disease and use of lipid-lowering medication. Higher HDL-c levels were associated with comparably lower risks for vascular events in patients with LDL-c levels above and below 2.5 mmol L(-1) (P-values for interaction > 0.05).
Patients with various clinical manifestations of vascular diseases in the highest HDL-c quintile have a lower risk for vascular events compared with patients in the lowest HDL-c quintile. Further, the current results expand the evidence by showing that also in a cohort of patients with various localisations of clinical evident vascular disease, in which statins were widely used, higher HDL-c levels confer a lower risk for developing new vascular events, irrespective of the localisation of vascular disease, use of lipid-lowering medication and plasma LDL-c concentration.

And this:

HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events
http://www.nejm.org/doi/full/10.1056/NEJMoa064278

I pulled these up in a very short search, but without cherry picking - that last example is a less perfect example of the HDL being protective genre, but then everyone in it was taking a statin. Which lowers insulin, according to that latest Finnish "statins cause diabetes" paper. Unfortunately without lowering blood glucose and HbA1c.

I wonder what intervention would naturally lower insulin, fasting glucose, HbA1c, and fasting TG, while promoting higher HDL?
Hmmmn.

Limitations - it is possible (I don't have time to follow this up) that participants in some of the statin trials were excluded if LDL measures were extremely high at baseline. The first study, however, was a primary prevention trial that did include all degrees of dyslipidaemia.
- Surrogate endpoints will never be perfect, but people like NICE are dosing millions on the basis that LDL is especially meaningful. If you're going to play that game, get it right.

[Edit P.S. 27/03/15] - makes sense of these stunning charts, from 
http://www.nejm.org/doi/full/10.1056/nejm199604113341504




Friday, 6 March 2015

What, exactly, is the Dietary Guidelines for Americans Committee's case against saturated fat?

[Edit 7/04/2015]

This analysis of the observational evidence cited in support of the US Dietary Guidelines recommendation to limit saturated fat to 10% or less replaces the version I posted earlier, but I have kept that version and you can still read it lower down this post.

Dietary Guidelines for Americans Committee Report 2015

Critique of the evidence for restricting saturated fat, with emphasis on the evidence from meta-analysis (including prospective cohort studies and RCTs) of substitution of saturated fat with other sources of energy.

1) The claim that the evidence for substituting PUFA for SFA is “strong and consistent”, which refers to the first two Bradford Hill criteria, is incorrect.

"Strong and consistent evidence from RCTs and statistical modeling in prospective cohort studies shows that replacing SFA with PUFA reduces the risk of CVD events and coronary mortality.
For every 1 percent of energy intake from SFA replaced with PUFA, incidence of CHD is reduced by 2 to 3 percent."
(Part D. Chapter 6: Cross-Cutting Topics of Public Health Importance. Lines 603-606)

Bradford Hill defined a strong association as having a factor of 2 or more; the association between CHD mortality and PUFA for SFA substitution in meta-analysis is, at best, approximately 0.80. The claim of consistency is also not accurate; meta-analysis of this question pools studies which have shown both positive and negative associations between PUFA and CHD mortality and/or events. The existence of more than one study, within each meta-analysis, in which increasing PUFA and decreasing SFA was associated with increased CHD, refutes the claim of consistency.

2) The method of sub-group meta-analysis which was given particular emphasis by the Committee is less than 6 years old and its interpretation is still an open question.

“Regarding saturated fat, Question 5 was answered using the NHLBI systematic review and related AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk, which focused on randomized controlled trials (RCTs), as well as existing SRs (systematic reviews) and MA (meta-analysis) addressing this question published in peer-reviewed literature between January 2009 and August 2014.
Particular emphasis was placed on reviews that examined the macronutrient replacement for saturated fat.”
(Part D. Chapter 6: Cross-Cutting Topics of Public Health Importance. Lines 84-89)

As noted by the Committee, meta-analysis of prospective cohort studies and RCTs shows no independent association between SFA and CHD mortality; the method of sub-group meta-analysis which instead compares stepwise substitutions of PUFA for other nutrients dates from the 2009 study by Jakobsen et al.[1] The post-script of the Skeaff and Miller meta-analysis, 2009, testifies to the novelty of the Jakobsen et al. methodology, and how it was welcomed by two experienced epidemiologists who could not within their own analysis find evidence to support their anti-SFA position.[2] PUFAs are essential nutrients with countless bioactive metabolites, and are not just energy sources, and those energy sources that lack essentiality – SFA, MUFA, and CHO – seem to all stand in much the same relation to PUFA in these meta-analyses. The results of these meta-analyses may reflect both the essentiality and functionality of PUFA, and the effect of a reduction in energy from other sources, rather than the harmfulness of these energy sources per se.

3) Notwithstanding the 2 previous points, the evidence from meta-analysis of energy substitution, taken at face value, does not support a limit on SFA.

“Farvid et al. found dietary LA intake is inversely associated with CHD risk in a dose-response manner: when comparing the highest to the lowest category of intake, LA was associated with a 15 percent lower risk of CHD events (pooled RR = 0.85; 95% CI = 0.78 to 0.92; I²=35.5%) and a 21% lower risk of CHD deaths (pooled RR = 0.79; 95% CI = 0.71 to 0.89; I²=0.0%). A 5 percent of energy increment in LA intake replacing energy from SFA intake was associated with a 9 percent lower risk of CHD events (RR = 0.91; 95% CI = 0.86 to 0.96) and a 13 percent lower risk of CHD deaths (RR = 0.87; 95% CI = 0.82 to 0.94).”
(Part D. Chapter 6: Cross-Cutting Topics of Public Health Importance. Lines 577-589)

The Committee’s report quotes Farvid et al. selectively (above). The Farvid et al. meta-analysis found that 5 percent energy intake from LA replacing the same amount of energy from carbohydrates was associated with a 13% reduction in CHD mortality.[3] This is exactly the same as the reduction in CHD mortality associated with 5% energy intake from LA replacing the same amount of energy from SFA. A similar conclusion can be drawn from Jakobsen et al. and Mozaffarian et al. with regard to total PUFA (in fact this exact point – that PUFA can be substituted for either SFA or carbohydrate - is made by Dariush Mozaffarian in presentations).[4]
There are two additional notes relating to the substitution meta-analyses so far; the substitution of PUFA for carbohydrate is for all carbohydrate, a mixture of refined and unrefined, and the substitution of PUFA for CHO is slightly superior to substitution of PUFA for SFA with regard to some endpoints.
The Farvid et al. analysis is not cited as evidence in the section relating to carbohydrate. If energy substitution sub-group meta-analysis is considered meaningful evidence in favour of SFA restriction, why is it not discussed in the context of carbohydrate?

4) There is no discussion of an upper limit to benefit from PUFA.

The current average intake of LA by Americans is over 7% of energy, and this would likely be higher were it not for the restrictions on total fat recommended by previous DGA Committees. The average intake of SFA is, at 11%, close to the recommendation of 10% or less. A 5 percent substitution of energy from LA for energy for SFA would result in an LA intake of over 12% and a SFA intake of 6%.
There are countries in the world that have long had similar fat intakes, and these are the countries of the former Soviet Union, where sunflower oil has been the main cooking fat since Tsarist times.
These countries have some of the highest incidences of CHD mortality in the world.[5] In Poland, a former satellite of the Soviet Union, the replacement of sunflower oil with rapeseed oil was followed by a sharp reduction in coronary mortality. Although the abstract of the epidemiological study that reports this change suggests this effect has been due to an increased intake of ALA, the change also saw a significant reduction (estimated reduced by one half to two thirds) of the total PUFA in cooking oil and of its LA content (reduced by two thirds or more). This study was co-authored by Walter Willet of Harvard School of Public Health, who also co-authored the Farvid et al. and Jakobsen et al. meta-analyses.[6]
The suggestion is that there may be evidence relating to the upper limit of LA safety available, and that this is a subject for discussion, not only with regard to CHD mortality but also with regard to non-CHD and all-cause mortality.

5) There is no evidence of a benefit from fat substitution on all-cause mortality.

If substitution of PUFA for saturated fat reduces CHD without adverse effects on other outcomes, we would expect overall mortality to be reduced. Death is measured with less error than any other disease-specific outcomes. Focus on overall mortality avoids the risk of concluding that an intervention improves one endpoint, but, in reality, is offset by harm to another. For example, a treatment may reduce CHD but increase cancer incidence, so that the effect on overall mortality is neutral. This is possible in those meta-analyses of energy substitution where only CHD endpoints are reported.[7] The 2012 Cochrane review by Hooper et al., of randomised studies designed to test the hypothesis that saturated fat influences CVD, showed no association between treatment arm and overall mortality (pooled relative risk 0.98, 95%CI: 0.93–1.04, 71,790 participants, 4292 deaths). The analysis by Mozaffarian et al. found discordance between CHD mortality (RR 0.80) and total mortality (RR 0.98, non-significant). The question of whether the reduction in CHD mortality associated with substitution of energy from PUFA for an equivalent amount of energy from SFA is also associated with an increase in non-CHD mortality from all causes should be resolved.
The Government may not have a mandate for decreasing the rate of morbidity and mortality from one disease by a recommendation that increases morbidity and mortality from other causes; the evidence for, and the legal and ethical implications of this question should be part of the discussion.

6) The explanation given for the lack of benefit from substituting MUFA for SFA in meta-analysis is not supported by evidence and amounts to special pleading.

“Evidence is limited regarding whether replacing SFA with MUFA confers overall CVD (or CVD endpoint) benefits. One reason is that the main sources of MUFA in a typical American diet are animal fat, and because of the co-occurrence of SFA and MUFA in foods makes it difficult to tease out the independent association of MUFA with CVD.
However, evidence from RCTs and prospective studies has demonstrated benefits of plant sources of monounsaturated fats, such as olive oil and nuts on CVD risk.”
(Part D. Chapter 6: Cross-Cutting Topics of Public Health Importance. Lines 617-621)

The use of “one reason” and “because of” incorrectly implies that the claim has been tested. These explanations are not given in the meta-analyses of Jakobsen et al. or Mozaffarian et al. which found a lack of evidence of benefit for replacing SFA with MUFA, but were first proposed as unsupported speculation in Martijn Katan’s 2009 editorial response to the Jakobsen meta-analysis, which is more nuanced than the Committee’s statement above, including a discussion of the confounding factors associated with animal fat consumption.[9] That there are evident benefits from both olive oil and nuts, traditional foods which supply bioactive components other than fats, should not be interpreted as evidence that the results of meta-analysis of the cohort studies available are more unreliable with regard to MUFA than with regard to SFA, PUFA, or other macronutrients.




[1] Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Jakobsen MU1, O'Reilly EJ, Heitmann BL, et al. Am J Clin Nutr. 2009 May;89(5):1425-32. doi: 10.3945/ajcn.2008.27124.

[2] Dietary Fat and Coronary Heart Disease: Summary of Evidence from Prospective Cohort and Randomised Controlled Trials. Skeaff CM, Miller J. Ann Nutr Metab. 2009;55:173–201 DOI: 10.1159/000229002

[3] Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Farvid MS, Ding M, Pan A. et al. Circulation. 2014 Oct 28;130(18):1568-78. doi: 10.1161/CIRCULATIONAHA.114.010236.

[4] Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. Mozaffarian D, Micha R, Wallace S.  PLoS Med. 2010 Mar 23;7(3):e1000252. doi: 10.1371/journal.pmed.1000252.

[5] European Cardiovascular Disease Statistics: British Heart Foundation Health Promotion Research Group, 2008. Allender S, Scarborough P, Peto V, Rayner M.

[6] Rapid declines in coronary heart disease mortality in Eastern Europe are associated with increased consumption of oils rich in alpha-linolenic acid. Zatonski W, Campos H, Willett W. Eur J Epidemiol. 2008;23(1):3-10. Epub 2007 Oct 23.

[7] Chewing the saturated fat: should we or shouldn't we? Thornley S, Henderson G, Schofield G. N Z Med J. 2014 May 23;127(1394):94-6.

[8] Reduced or modified dietary fat for preventing cardiovascular disease. Hooper L, Summerbell CD, Thompson R, et al. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD002137. doi: 10.1002/14651858.CD002137.pub2.

[9] Omega-6 polyunsaturated fatty acids and coronary heart disease. Katan MB. Am J Clin Nutr. May 2009 vol. 89 no. 5 1283-1284.doi: 10.3945/​ajcn.2009.27744. 

[original version]

The 2015 DGA committee has released a 571 page document which is meant to inform the next dietary guidelines.[1] Changes are that % fat vs carbohydrate is no longer prescribed and cholesterol is no longer subject to a limit.
However, the old limit of 10% energy from saturated fat remains in place. Low fat or no fat dairy is the only dairy you're allowed. Meat? However poor or aged you may be, you should eat less of it. Although consumption of added sugars and refined grains is of concern, it always takes secondary place to the established evils of saturated fat and sodium.
Most of the document is dreadfully written and repetitively displays a circular logic. The healthy diet pattern (there are three of these, but they are interchangeable) is healthy (because it outperforms, slightly, a dummy version of the SAD diet); the healthy diet pattern avoids certain foods; ergo, these foods are not part of a healthy diet (even though they weren't an important part of the dummy SAD diet either).
Thus the verdict is repeated many, many times, and the prosecution does its summing up, and only then is the evidence presented. I'm familiar with this evidence. It's presented dishonestly.

Firstly, there is a nolo contendere acceptance of the evidence that saturated fat does not independently correlate with cardiovascular disease.
Regarding saturated fat, Question 5 was answered using the NHLBI systematic review and related AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk, which focused on randomized controlled trials (RCTs), as well as existing SRs (systematic reviews) and MA (meta-analysis) addressing this question published in peer-reviewed literature between January 2009 and August 2014.
 Particular emphasis was placed on reviews that examined the macronutrient replacement for saturated fat.
The analysis of these pretends to be applying a truncated version of the Bradford Hill criteria. There's a good summary of these criteria and examples of their application here. There are 9 criteria and the first two are Strength of the Association and Consistency.


"Strong and consistent evidence from RCTs and statistical modeling in prospective cohort studies shows that replacing SFA with PUFA reduces the risk of CVD events and coronary mortality.
For every 1 percent of energy intake from SFA replaced with PUFA, incidence of CHD is reduced by 2 to 3 percent."
Part D. Chapter 6. page 16. (p451 doc)

Problem #1 - The evidence is not strong; in the meta-analysis by Dariush Mozaffarian et al., which is a meta-analysis supportive of substitution with PUFA, the average reduction in coronary mortality for 5% substitution was 0.80.[2]

Nowhere does the correlation attain the strength that Bradford Hill asked for, a factor of two or greater.
When the correlation is closest to one, as here, it can only be called weak. In fact it is even weaker than that, because the effect in primary prevention is not significant.
Emphasizing the benefits of replacement of saturated with polyunsaturated fats, Mozaffarian et al., 2010 found in a MA of 8 trials (13,614 participants with 1,042 CHD events) that modifying fat reduced the risk of myocardial infarction or coronary heart disease death (combined) by 19 percent (RR = 0.81; 95% CI = 0.70 to 0.95; p = 0.008), corresponding to 10 percent reduced CHD risk (RR = 0.90; 95% CI = 0.83 to 0.97) for each 5 percent energy of increased PUFA. This magnitude of effect is similar to that observed in the Cochrane MA. In secondary analyses restricted to CHD mortality events, the pooled RR was 0.80 (95% CI = 0.65 to 0.98). In subgroup analyses, the RR was greater in magnitude in the four trials in primary prevention populations but non-significant (24 percent reduction in CHD events) compared to a significant reduction of 16 percent in the four trials of secondary prevention populations.
From Ramsden et al. BMJ 2013 
Problem #2 - The evidence is not consistent, because there is more coronary mortality in some PUFA substitution studies, less in others, and no difference in others again.
You cannot use meta-studies as evidence of consistency!

The DGA committee also draw on the Harvard et al. meta-analysis by Farvid et al.[3]|
Consistent with the benefits of replacing SFA with PUFA for prevention of CHD shown in other studies, Farvid et al., 2014 conducted an SR and MA of prospective cohort studies of dietary linoleic acid (LA), which included 13 studies with 310,602 individuals and 12,479 total CHD events (5,882 CHD deaths). Farvid et al. found dietary LA intake is inversely associated with CHD risk in a dose-response manner: when comparing the highest to the lowest category of intake, LA was associated with a 15 percent lower risk of CHD events (pooled RR = 0.85; 95% CI = 0.78 to 0.92; I²=35.5%) and a 21% lower risk of CHD deaths (pooled RR = 0.79; 95% CI = 0.71 to 0.89; I²=0.0%). A 5 percent of energy increment in LA intake replacing energy from SFA intake was associated with a 9 percent lower risk of CHD events (RR = 0.91; 95% CI = 0.86 to 0.96) and a 13 percent lower risk of CHD deaths (RR = 0.87; 95% CI = 0.82 to 0.94).
Once again, the word "consistent" is abused. Individual studies are not consistent, and this is a meta-analysis (which is supposed to include all the relevant studies) so the concept of consistency does not apply. In what sense is an average consistent?

However an even larger deception is taking place in this selective quotation from Farvid et al., because that paper also concludes that a 
5 percent of energy increment in LA intake replacing energy from carbohydrate intake is associated with similar benefits as replacing SFA.
Every meta-analysis that tells you that there is no benefit from replacing SFA with CHO, but a benefit from replacing SFA with PUFA, is saying the same thing, but Farvid et al. finally spelled it out.




9 cohort studies evaluating substitution of LA for carbohydrate showed that substituting 5% energy intake from LA for carbohydrates lowered risk by about 10%. A slightly lower risk benefit was seen for substitution of LA for SFA.This systematic review and meta-analysis suggests that risk of CHD decreases with higher dietary LA intake, when replacing either carbohydrate or saturated fat.



As a third criticism, how plausible is this claim - "for every 1 percent of energy intake from SFA replaced with PUFA, incidence of CHD is reduced by 2 to 3 percent"? With no safe upper limit set or implied.

For every 1 percent? Is the reduction the same for the 1st% and the 20th%?* And what of the observation that higher PUFA % intakes (like lower SFA % intakes) tend to be reported by those under-reporting calories? Is the correlation the same for absolute intakes (grams/day)?How is the suggestion to be placed in context? The calculations begin at 1%E as LA, yet the average dietary intake of LA in the USA was over 7% in 1999.[4] Is the case against saturated fat now to be based on chasing a PUFA target that for all practical purposes has already been met?

The graphic from Farvid et al. above shows that there is less data above 6-7% LA and correlations become less reliable. As Ancel Keys would have predicted - dietary intake of LA above 7% is not a usual part of natural human diets, and the range of intakes in the 7 Countries study was 3-7%. 
We are still in the "weak" range of correlation, meaning there could always be another explanation for what we are seeing. And we do not have all the data. The countries of the former Soviet Union have very low SFA intakes (6-7%) and very high LA intakes (unknown, but sunflower oil is the main cooking fat), and these countries have some of the highest rates of CHD mortality in the world. If we had reliable cohort data from these countries, what then?
And what of the elephant in the room of PUFA celebration - the lack of any association with all-cause, age-adjusted mortality? If PUFA substitution prevents CHD deaths, and CHD deaths are a major part of all deaths, then PUFA substitution should reduce all deaths. If it doesn't, then either the reduction in CHD mortality is illusory, or PUFA (or something associated with it) is causing more death from other causes. It doesn't.[5] Well there is a small, non-significant reduction, and the theory is that if this were multiplied to infinity by more and more studies it would attain significance and be interpreted as saving thousands of lives. As long as the new studies didn't come from parts of the world like Azerbaijan and, well, most of the rest of the world. But that the idea that a tiny association magnified means anything in a world of uncertainty, unreliability, and alternative explanations (known and hidden confounders) is nothing but clutching at straws.
Has all this effort and expense and messing with peoples' lives only had the result of sweeping the problem of CHD under the carpet of death from other causes?

There is also the following curious passage on MUFA. Remember that the lipid hypothesis recommends replacing saturated with unsaturated fats.

Evidence is limited regarding whether replacing SFA with MUFA confers overall CVD (or CVD
endpoint) benefits. One reason is that the main sources of MUFA in a typical American diet are
animal fat, and because of the co-occurrence of SFA and MUFA in foods makes it difficult to
tease out the independent association of MUFA with CVD.
However, evidence from RCTs and prospective studies has demonstrated benefits of plant sources of monounsaturated fats, such as olive oil and nuts on CVD risk.

That's some special pleading. Suddenly the methods used to separate SFA and PUFA, which the argument has depended on so far, are not good enough to separate SFA and MUFA, because they do not give the desired results. (The use of the words "one reason" and "because" above implies that these explanations have been tested; they have not; they appear in the literature as speculations). Animal fats - pork, and especially chicken - are a major source of PUFA in the US diet. Canola and other high oleic oils are sources of MUFA.
Nuts and olive oil, real high-fat foods, do seem to show benefits that don't show up when MUFA alone is measured. MUFA has been a big disappointment to epidemiologists, it lowers cholesterol when substituted for SFA, but this is not associated with a reduction in coronary disease. So the bogey of animal fat is invoked, without much justification and without the whiff of a mechanism to explain why oleic acid from canola oil should differ from oleic acid from beef (after all, cholesterol has just been acquitted). 

I know anecdotal evidence  has low admissibility, but all evidence is evidence of something. All over the internet and print media people will tell you that eating a lot less carbohydrate and more fat, sometimes more saturated fat, has improved their lives and their health. Doctors are saying this about their patients too.
Where are the blogs where people rave about how replacing butter with margarine has fixed their health problems? Millions of people take statins - where are the stories from statin users about the improvements to their lives? You will find more negative stories from statin users online. You might find stories of improved cholesterol, but where is the increased vitality and reversal of obesity and type 2 diabetes? Oh, wait.
You might conclude from this that any association between improvements in cholesterol and improvements in health is not necessarily a linear or temporal one. There is perhaps stronger evidence for the idea that improvements in health are temporally associated with improvements in cholesterol.

The DGAC are a bunch of brainy people, familiar with the evidence (some of them anyway), presenting a summary of this evidence to non-specialists - the 
Secretaries of the U.S. Department of Health and Human Services (HHS) and the U.S. Department of Agriculture (USDA).
How honest is their case?
They present the observational evidence as being stronger than it is, and they suppress an important finding of this evidence which would contradict their saturated fat recommendation.
After all, if 7% PUFA is where the benefit lies (which is endlessly debateable and certainly not a case I'd personally want to make, especially in light of the all-cause mortality association), who eating either a standard American diet or one of the healthy "Healthy" DGA diets doesn't have a few % CHO to spare? And in that case, if you're willing to trade some sugar for some nuts, then where is the evidence against SFA? The observational evidence, weak though it was in terms of consistency and strength of association, just flew out the window.

Bye bye.



*Appendix 1

Walter Willet of Harvard, co-author of the Farvid et al. study, also put his name to this study, about a decline in CHD mortality in Eastern Europe where rapeseed oil has been substituted for sunflower oil.[6] Sunflower oil is about 44-75% PUFA, as LA, rapeseed oil supplies 15-30% PUFA, 15-20% LA.[7,8] This is evidence for the hypothesis that restricting PUFA or LA reduces CHD mortality.
Consistency.

Appendix 2

The following PUFA recommendations are listed on the website of the Linus Pauling Institute.

Upon request of the European Commission, the European Food Safety Authority (EFSA) proposed adequate intakes (AI) for the essential fatty acids LA and ALA, as well as the long-chain omega-3 fatty acids EPA and DHA (62). EFSA recommends an LA intake of 4% of total energy and an ALA intake of 0.5% of total energy; an AI of 250 mg/day is recommended for EPA plus DHA.
(note: this is about the average NZ intake)
The World Health Organization recommends an acceptable macronutrient distribution range (AMDR) for omega-6 fatty acid intake of 6-11% of energy and for omega-3 fatty acid intake of 0.5-2% of energy. Their AMDR for EPA plus DHA is 0.250-2 g/day (the upper limit applying to the secondary prevention of CHD).
(note - this requires use of seed oils and intensive fishing. The WHO are zealots for the diet-heart hypothesis).
The International Society for the Study of Fatty Acids and Lipids (ISSFAL) recommends for healthy adults an LA intake of 2% energy, ALA intake of 0.7% energy, and a minimum of 500 mg/day of EPA plus DHA for cardiovascular health.





[1] 
Scientific Report of the 2015 Dietary Guidelines Advisory Committee. link
[2] 
Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. Mozaffarian D, Micha R, Wallace S.  PLoS Med. 2010 Mar 23;7(3):e1000252. doi: 10.1371/journal.pmed.1000252.

[3] 
Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Farvid MS, Ding M, Pan A. et al. Circulation. 2014 Oct 28;130(18):1568-78. doi: 10.1161/CIRCULATIONAHA.114.010236.

[4] Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Blasbalg TL, Hibbeln
JR, Ramsden CE, et al. 
Am J Clin Nutr. 2011 May;93(5):950-62. doi: 10.3945/ajcn.110.006643. 

[5] Chewing the saturated fat: should we or shouldn’t we? Thornley S, Henderson G, Schofield G. NZMJ 23 May 2014, Vol 127 No 1394; ISSN 1175 8716

[6]  Rapid declines in coronary heart disease mortality in Eastern Europe are associated with increased consumption of oils rich in alpha-linolenic acid. Zatonski W1Campos HWillett WEur J Epidemiol. 2008;23(1):3-10. Epub 2007 Oct 23.

[7] 
http://www.chempro.in/fattyacid.htm

[8] 
Chemical composition and stability of rapeseed oil produced from various cultivars grown in Lithuania. Dainora Gruzdienė, Edita Anelauskaitė.
http://www.icef11.org/content/papers/epf/EPF278.pdf

Monday, 23 February 2015

Why the High-Fat Hep C Diet? Rationale and n=1 results.



I originally started this blog to publicise the hypothesis that a diet low in carbohydrate and linoleic acid, but high in saturated fat and long-chain PUFA, will inhibit HCV replication.

The blog header with the pig above is the abstract for this hypothesis.

I first worked this out in 2010 after reading Dr Atkins New Diet Revolution while studying HCV replication. The lipid patterns in low-carb dieters - low TG and VLDL, high HDL, normal or high LDL - are those associated with lower viral load and improved response to treatment in HCV cases.
The mechanics of HCV replication and infection support this link.


HCV inhibits PPAR-a, a ketogenic diet reverses this inhibition

I wrote a fairly comprehensive version of the hypothesis in 2012:
http://hopefulgeranium.blogspot.co.nz/2012/02/do-high-carbohydrate-diets-and-pufa.html

Recently I was sent a link to an article that cited this paper:
http://www.journal-of-hepatology.eu/article/S0168-8278(11)00492-2/pdfHCV and the hepatic lipid pathway as a potential treatment target. Bassendine MF, Sheridan DA , Felmlee DJ, et al. Journal of Hepatology 2011 vol. 55 j 1428–1440

This review compiles a great deal of supporting evidence regarding the interaction between HCV and lipids, and between lipids and HCV. The only thing missing is the role of carbohydrate. It mentions multiple lipid synthetic pathways as targets for indirect-acting antiviral drugs (IDAA), pathways which are also well documented as targets of low carbohydrate ketogenic diets, or of saturated fat in the diet (in the case of the LDL-receptor complex).

From 2012:
A little n=1 experimental data; 4 years ago (2008) my viral load was 400,000 units, now after 2 years of low carb dieting and intermittent mild ketosis (2012) it is 26,000.

Later in 2012:
Total Cholesterol:  6.7  H     
Triglyceride:          0.8         
HDL:                     1.63              (63.57)
LDL (calc.)            4.7   H    
Chol/HDL ratio:     4.1          

HCV viral load on this day (21st May 2012): 60,690 IU/mL (4.78 log)



Lipid panel from 07 Feb 2012, during ketogenic diet phase (non-fasting)

Total Cholesterol: 8.9   HH  (347.1)
Triglyceride:         1.3          (115.7)
HDL:                    1.65         (64.35)
LDL (calc):           6.7    H    (261.3)
Chol/HDL ratio:     5.4   H

HCV viral load on this day: 25,704 IU/mL (4.41 log)

From 2014:
On a personal note, I have started an 8-week trial of Sofosbuvir and GS-5816 (Vulcan). It is day 11 and it seems tolerable so far.
A pre-trial blood test on 22nd October was normal except for these counts:
AST 74
ALT 174

and viral load was 600,419 (log 5.78), counts consistent with the tests I've had done this last year.

But the day the trial started, 18th November, before my first dose, things were different:
AST 21

ALT 32
Viral load 27,167 (log 4.43)

The low viral load is easy to explain; I get a consistent 1 log drop (to 14,000-60,000*) when I try to eat very low carb (50g/day or lower) and an elevation to 400-600,000 when my carbohydrate intake is over 50g/day. When I ate very high carb (but took antioxidant supps) it was as high as it was on 22nd October. So for me the tipping point seems to be where ketosis begins, and other variations don't have much effect; it's an on/off switch, not a dial (and the name of that switch is PPAR-alpha).
[edit: though the very low scores are at ketogenic, or nearly so, carb intakes, the exact increase in carbohydrate needed to cause a significant increase in viral load seemed to vary]
(I do however, according to CAPSCAN elastography, have zero excess fat in my liver, which is an effect of low carb in general, as well as avoiding vegetable seed oils).

My belief is that my viral load was much higher than any of these counts previous to 2003. This was the year I started taking antioxidant supplements, eating a bit better (in a normal, confused "healthy eating" pattern), and using herbal antivirals like silybin. Prior to that I was seriously ill, and I believe that my viral load would have reflected my extra autoimmune symptoms, signs of liver failure, and elevated enzymes. Unfortunately in those days one didn't get a PCR unless one was considering donating one's body to interferon, which I was not.

* I don't seem to have a record of the date of the 14,000 VL reading, but will include it when I find it.

Summary:
A very low carbohydrate ketogenic diet, without enough PUFA to lower LDL artificially, had a significant inhibitory effect on HCV viraemia in my case.
Effective DAA drugs for HCV infection are now available. There is a ~98% SVR rate at present. These drugs are expensive, they sometimes have side effects (though much less so than interferon + ribavirin), and interferon + ribavirin is still being used.
If my results are more generally applicable, VLCKD diet offers an adjunct therapy for patients with a high viral load, steatosis that relates to diet and lifestyle as well as HCV infection, or a need to postpone treatment. In people who oppose or cannot complete or afford treatment, it offers a way to manage the disease, and in particular to reverse the autoimmune syndromes caused by immune complexes when viraemia is excessive.