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Tuesday 24 September 2013

Gluten and Cross-Sensitivity as a Factor in Post-Interferon Malaise and Autoimmune Syndromes of Chronic Hep C

(Music: Charlie Parker 
Live at Storyville, 1953)

Coeliac and non-coeliac gluten sensitivity, conditions which can cause (apart from the classic syndrome) cirrhosis of the liver independent of viruses or alcohol, are hard to treat by simple removal of gluten grains, because gliadin sensitivity creates cross-sensitivity to peptides found in other foods.
(Hat-tip to Suppversity for posting about this).

Gliadin (Wheat), Casein (Milk), Secalin (Rye), Avenin (Oat), Kafirin (Sorghum), and Zein (Corn) peptides are prolamines (peptides with Pro-Pro bonds). But why does instant coffee feature at all? Well, coffee is a seed, but it doesn't appear to be a source of prolamines.
All of these cross-sensitivity prolamine allergens are also active at endorphin receptor sites; they are what is called exorphins. Wheat and milk can be addictive to persons who should be avoiding them, another reason coeliac is difficult to diagnose and treat. And roasted coffee beans also contain a compound which has endorphin receptor activity - except that it is an endorphin antagonist, and not a prolamine but a lactone formed from one of coffee's antioxidants.
There is no record of a link between coeliac disease and endorphins (at least, none that the cursory Google search that easily supplies all my other evidential links has uncovered), beyond the helpfulness of LDN (low dose Naltrexone) in CD recovery.
However, opioids (at least, the pharmaceutical ones) have two modes of action, one via the endorphin system, one via the immune system and TRL4 activity. Naltrexone is both an opioid antagonist and a TLR4 antagonist; and TLR4 is implicated in coeliac disease via non-gluten components of wheat, trypsin inhibitors.
(At about this point, the trail went cold. It would have been nice to link exorphins and TLR4, I had even dreamed about TLR4 antagonism and the benefits of coffee drinking, but it was not to be...)
Edit: here is a link between coffee and TLR4 inhibition, it's not about the exorphin, but there's hope for me yet.

Enlarged picture here

Coeliac and non-coeliac gluten sensitivity may be associated with Hepatitis C, and anecdotally a great many people with the virus find their health improves when avoiding the cross-reactive foods. Both coeliac disease (OR 3.1) and chronic HCV infection (OR 2-4) are associated with an increased rate of non-Hodgkin's lymphoma, and the autoimmune conditions commonly associated with coeliac are virtually identical to the extra-hepatic HCV syndrome. As an intracellular virus, HCV triggers the production of interferons, and interferon-alpha has a causitive role in coeliac. Coeliac disease has been triggered by INF-alpha treatment for HCV. However, gluten sensitivities are hard to diagnose and exist on a spectrum, with a significant proportion of people having some potential for sensitivity, and gluten sensitivity diseases may take time to develop. On average, cases of coeliac disease take 13 years to diagnose. This is plenty of time for someone to develop serious health problems or indeed die, without the involvement of gluten sensitivity being noticed.
(I have never been a fan of Interferon treatment for HCV; in my experience people who have avoided Interferon and treated themselves with diet and supplements tend to stay healthier overall than people who have done interferon but failed to respond to it. Indeed, I know people with chronic hepatitis C who stay healthy with no effort at self-treatment whatsoever. So far, the people I have known with HCV who have died of liver disease or needed transplants, other than alcoholics, are people who have taken Interferon but failed to clear the virus. People who do respond to Interferon can certainly improve, but this means that doctors prescribing Interferon need to be selective about who they offer it to. If it is prescribed to someone with no symptoms, or a low possibility of clearance, or a high risk of side effects on the basis that this is better than doing nothing, this is unlikely to be the case. Thankfully this question is becoming moot with the arrival of interferon-free treatments with a high rate of efficacy and minimal side-effects. Here is a grueling account of post-interferon problems.)

I think it entirely plausible that the post-treatment effects some people experience from Interferon therapy for HCV are mediated by the induction of sensitivity to wheat, milk, yeast, corn and other foods, and that the extra-hepatic and autoimmune syndromes of chronic hepatitis C have the same cause. This could include a wide variety of auto-immune conditions, not just gut disorders.
On the other hand, I am not in favour of eliminating so many foods from the diet that nutrition is compromised. Removing the main offenders - grains, legumes (also a source of trypsin inhibitors), yeast (bread and beer are the main sources of yeast), and milk (some dairy products low in casein, such as butter, may be OK), supplementing vitamin D and probiotics, and eating nutrient-dense foods mainly of animal origin for a while seems to be the best way to both heal the gut and reduce autoimmunity.

Another problem with grains, and with milk in people who are lactose intolerant, is SIBO, or an excess of bacteria in the small intestine. This is associated with progression of NASH and cirrhosis, and also with Vitamin B12 deficiency. It's a good fibre/bad fibre situation, with good fibres being those that ferment in the colon (large intestine).
Micheal Eades has just blogged about SIBO in the context of GERD, a common cause of eosophagitis (acid reflux, sore throat, difficulty swallowing, increased cancer risk).
Reading first the introduction to a vitamin primer, and then Protein Power, by Drs Michael and Mary Dan Eades first awakened me to the possibilities of low-carb, high fat diets for the treatment of inflammation and autoimmune disease. I'd like to thank the Drs Eades for writing books that became popular enough to become ubiquitous (and thus arrive at the Op Shops I get my books from) while remaining readable.

Here's one of my favourite NASH papers, just an abstract from a poster presentation at a conference - but how on earth does anyone get an omega 3:6 ratio of 1:144? Note that no-one here had 3:6 in or near the adaptive range of 1:1 - 1:5. 


S. Caldwell*, C. Argo, A. Al-Osaimi, N. Shah, H. Lothamer, C. Harmon, J. Rodriguez
University of Virginia, Charlottesville, VA, USA. *

Introduction and aim: Essential dietary polyunsaturated fatty acids (PUFA) include omega-6 (n-6) linoleic acid (18:2) which is metabolized to arachidonic acid (AA) and omega-3 (n-3) linolenic acid (18:3) which is metabolized to eicosapentanoic acid (EPA). Imbalance in secondary eicosanoids and prostaglandin metabolites of n-6 and n-3 PUFA are implicated in disorders related to the metabolic syndrome. Skeletal muscle PUFA influences systemic insulin sensitivity (Borkman 1993) and diets rich in omega-3 fatty acids are associated with diminished histological injury in NASH (Musso 2003). Erythrocyte membrane lipids reflect dietary intake of essential fatty acid over preceding months. We measured erythrocyte n-6:n-3 ratio in a cohort of patients as part of a larger study of omega-3 fatty acid therapy of NASH. 

Methods: 15 patients (10 female) underwent analysis of erythrocyte lipid composition using capillary gas chromatography (Metametrix, Duluth, GA) to determine the AA:EPA ratio. The mean age was 50 ± 13 years all with liver biopsy NAS score ≥ 5 and a range of non-cirrhotic fibrosis stages of stage 1 (n = 6), stage 2 (n = 5) and stage 3 (n = 4). 

Results: The mean AA:EPA was 65 ± 34 reflecting a relative excess of n-6 PUFA overall. However, a broad range was noted from 15 to 144 AA:EPA. Dividing the group into quintiles of the reference range, 9 of the patients fell into the highest (5th) quintile (AA:EPA = 84 ± 30) compared to the remaining 6 patients (AA:EPA = 36 ± 16, p = 0.001). There was no statistically significant difference in the histological stage between these groups (fibrosis score = 2 ± 0.9 versus 1.7 ± 0.8) although the higher AA:EPA group was significantly older (55±12 versus 39±12, p=0.01). 

Conclusion: There is heterogeneity of AA:EPA in non-cirrhotic NASH patients and an age-related increase in n-6 to n-3 PUFA evident in the AA:EPA ratio of erythrocyte lipids. Further work is needed to understand if this reflects dietary differences and how this might influence response to omega-3 fatty acid therapy.

Here is a discussion of changing omega 3:6 in the US food supply: "The ratio of total n−6 to n−3 was 5.4 in 1909 and 9.6 in 1999". Average intake of omega 6 has always been sufficient but has become excessive, intake of omega 3 has always been inadequate.

Sunday 8 September 2013

The Elegant Solution

Peter D has been running a fantastic series on PUFAs and cancer. Lots of references to linoleic acid promoting the growth of hepatoma cells.

"In the lab situation rapid hepatoma tumour growth needs either arachidonic or linoleic acids. The acids must be taken up in to the hepatoma cells, they must be acted on by lipoxygenase to produce 13-hydroxyoctadecadienoic acid, better known as 13-HODE. 13-HODE appears to be the mitogen which promotes rapid cancer growth. 13-HODE looks like a repair signal gone wrong in cancer cells."

Wonderful stuff in line with all the other deleterious effects of excess (seed oil amounts) of linoleate on liver function, and with the benefits of omega 3's.

This passage also caught my eye:
omega 3 fatty acids, in a G-protein coupled receptor manner, completely turn off the uptake of ALL fatty acids in to hepatoma cells. 
If, and it's quite a big "if", the same effects apply to hepatocytes as well as hepatoma cells, we then have a very straightforward mechanism for the protective effects of omega 3 fish oils on hepatic lipidosis."
(or for that matter, steatosis).

This interests me because, in Hep C research, HCV can only be cultured in hepatoma cells. You can't culture it in normal hepatocytes. And this provides an answer to an old question - why do viruses cause cancer? What's the benefit, given the risk of killing the host? Because, there is something about the cancer phenotype of a cell that makes the cell a better host to the virus. Obviously it doesn't want to push carcinogenesis all the way (which is why only a small minority of chronic HCV cases end up as HCC), but it does want to tweak the cell a little in that direction. Hence activities like sequestering selenium. Better not give that virus-infected cell too much linoleate to play with.

In the middle of this discussion, Purposelessness dropped this 2008 mouse paper:

cAMP-dependent Signaling Regulates the Adipogenic Effect of n-6 Polyunsaturated Fatty Acids

This is great science thinking about the obesity epidemic. Why are high-carb diets only generally productive of obesity when linoleate is added, and not, say, in Kitava (where most fat comes from coconut and some from fish?). If it's the linoleate, how come low-carb dieters loose weight on cupfuls of nuts and olive oil - or even canola oil - with everything?

The effect of dietary fat on human health is not solely a matter of quantity but depends also on the nature of the fatty acids. The current recommendation is to replace saturated fat by polyunsaturated fatty acids (PUFAs).5 Today, more than 85% of the total dietary PUFA intake in Western diets is n-6 PUFAs, mainly linoleic acid, a precursor of arachidonic acid, whereas the consumption of n-3 PUFAs has declined (1). Since the high intake of n-6 has been associated with childhood obesity, concerns regarding this matter have been raised (2). However, animal studies have yielded conflicting results, with some studies demonstrating that a diet enriched in n-6 PUFAs decreases adipose tissue mass (34), whereas others have associated intake of n-6 PUFAs with an increased propensity for obesity (5-7).

So, we have a paradox. And a solution.

In the present study, we present data that reconcile and explain the disparate effects of n-6 PUFAs on adipocyte differentiation in vitro and in vivo. We demonstrate that cAMP signaling plays a pivotal role controlling the production of antiadipogenic prostaglandins. In vivo, the obesigenic action of n-6 PUFAs is determined by the balance between dietary carbohydrates and protein. A high carbohydrate/protein ratio translated into a high plasma insulin/glucagon ratio, and in this setting, dietary n-6 PUFAs promoted strongly adipose tissue expansion. Conversely, a high protein/carbohydrate ratio translated into a high plasma glucagon/insulin ratio and enhanced cAMP-dependent signaling. In this setting, COX-mediated prostaglandin synthesis was enhanced, and dietary n-6 PUFAs decreased white adipose tissue mass.

Don't try this last bit at home; those prostaglandins might not be liver-friendly, but you can do much the same job with omega 3s.

This bit is for all the calorie nerds:

The decreased obesigenic action ofn-6 PUFAs in mice fed a protein-rich diet did not result from increased dissipation of energy by uncoupled respiration but rather reflected increased energy expenditure in relation to gluconeogenesis and urea formation.

Phew, we didn't break the laws of thermodynamics, so the CICO police are not after us.

We observed a remarkable difference in feed efficiency between mice fed the protein-enriched versus the carbohydrate-enriched diet. In the high protein group, 467.8 kcal were needed to produce a weight gain of 1 g, whereas the high carbohydrate group only needed 67.8 kcal to produce the same weight gain, which almost exclusively represented an increase in adipose tissues. Increased cAMP signaling is known to induce adaptive thermogenesis by inducing expression of PGC-1α and UCP1 in brown adipose tissue (30), but the fact that heat production and oxygen consumption as well as expression of UCP1 in intracapular brown adipose tissue were similar in the two groups of mice indicated that decreased feed efficiency of the protein group was not due to increased uncoupled respiration. Furthermore, no increase in genes involved in fatty acid oxidation in muscle and liver was observed in the mice fed the protein-enriched diet, and the total physical activity of the carbohydrate and the protein group did not differ. Expression of UCP1 and genes involved in β-oxidation was, however, induced in the inguinal fat pad, but the relatively low expression of these genes compared with interscapular brown adipose tissue suggested that such a contribution to whole body metabolism was limited.

Oh no, not DNL too, I though that was all debunked, sorry folks

A hallmark of PUFA action is the ability to increase catabolism by enhancing ketogenesis and peroxisomal and mitochondrial fatty acid oxidation and to suppress expression of genes involved in lipogenesis in rodents (36). It is worth noting that the hepatic expression of rate-limiting enzymes involved in fatty acid catabolism was similar in mice fed corn oil supplemented with protein and sucrose. In contrast, expression of genes involved in lipogenesis was significantly lower in liver of mice fed corn oil and protein compared with corn oil and sucrose. Thus, despite high dietary intake of fatty acids, expression of genes involved in de novo synthesis of fatty acid continued when dietary corn oil was combined with sucrose.

In conclusion: 

In conclusion, we have shown that the adipogenic potential of n-6 PUFAs is modulated by cAMP signaling both in vivo and in vitro. Differences in culture conditions and feeding regimes affecting the glucagon/insulin ratio provide an explanation for the contradictory results published in the literature. Today's diets are abundant in n-6 fatty acids from vegetable oils (corn, sunflower, safflower, and soybeans) that are used in industrially prepared food. In addition, industrially produced animal feed is also rich in grains containing n-6 PUFAs, leading to meat enriched in n-6 PUFAs at the expense of n-3 fatty acids (39). n-6 PUFAs, predominantly linoleic acid, are now the predominant source of PUFAs in Western diets (23). PUFAs have been considered less harmful to human health than saturated fat, and substitution of saturated fat with PUFAs in general has been recommended by dieticians. If the background diet determines the adipogenic potential of n-6 PUFAs also in humans, this is of great concern, since the intake of refined sugars from sources such as soft drinks has increased dramatically during recent decades (40).

Background diet? Insulin-elevating carbohydrate. Result? Adiposity. Culprit? Linoleic acid.

I like this model because it provides a face-saving formula for many factions currently locked in bitter dispute, and because it seems to reflect the various realities we see around us. It's certainly not my job to help solve the obesity epidemic, but every now and then one can't help but take an interest, because the science gets good.
What will happen when fat, with normal protein, is substituted for carbohydrate? Less protein metabolism energy loss, different body composition, less COX-mediated prostaglandin but maybe the cAMP will still be elevated. On to the next experiment then.
Now about that proposed Kiwi saturated fat tax, supposed to increase our PUFA intake without decreasing our intake of carbs?
There's a thing called Unintended Consequences. I like this example, reminds me of the good old days:

Theobald Mathew's temperance campaign in 19th-century Ireland (in which thousands of people vowed never to drink alcohol again) led to the consumption of diethyl ether, an intoxicant much more dangerous due to its high flammability, by those seeking to become intoxicated without breaking the letter of their pledge.
(Ether in Ireland, from Psychology Today; Ether in Silesia, a fascinating J. Medical History article from PubMed)

The only thing that really worried me was the ether. There is nothing in the world more helpless and irresponsible and depraved than a man in the depths of an ether binge
    - Hunter S. Thompson