Liver In The Coalmine

Is it just me, or is everything getting worse? 

Each time I stumble on a new interest and start digging up the epidemiology of some health condition or other, the picture is nearly always the same. Gout, BPH, diabetes, chronic pain, cancer, depression, allergy, preeclampsia, Parkinsonism, infertility, autism, essential hypertension, kidney disease, trauma-induced brain damage – I could go on – all are occurring in larger numbers of people, and, with the obvious exception of autism, in progressively younger ones. 

The pharmaceutical industry, a notoriously corrupt and unethical business¹, has been wildly successful in one metric at least, namely its own growth and commercial success. When it comes to the ongoing decay in our public health, however, which some might think more important, it has failed, utterly.

Allow me to introduce Dr John Scott Haldane. Physiologist, philosopher, self-experimenter, father of oxygen therapy and the even more remarkable JBS Haldane, whose sister Lady Naomi Mitchison occasionally looked after me when my mother was overseas, he was a brilliant and deeply moral man who believed, unlike Big Pharma, that science should primarily benefit society. 

Having ascertained that in colliery accidents most miners did not die of trauma but from carbon monoxide poisoning, Haldane devised an elegant and effective early warning system; the coalmine canary². Due to the bird’s small size and high metabolic rate, a canary exposed to carbon monoxide would fall unconscious about 20 minutes before humans did. This gave miners enough time, with luck, to escape.

The incoming tide of non-communicable diseases indicates that toxins are accumulating in our diet and environment, and that we need a new and different kind of canary. While there are several potential candidates, I nominate the liver. 

A healthy liver naturally contains a small amount of lipids. When these exceed 5% by weight it is termed fatty liver disease. Initially benign and reversible, this condition tends to proceed to non-alcoholic steatohepatitis (NASH) which can be life-threatening, and then to liver cancer which is generally lethal. 

The major causes of NAFLD are rather well understood. They include excessive intakes of sucrose and glucose which drive intrahepatic lipogenesis, as do obesity and type 2 diabetes probably via hyperinsulinaemia; dysbiosis, which floods the liver with pro-inflammatory endotoxins; an excessively sedentary lifestyle, which inhibits autophagy; choline deficiency; and a generally pro-inflammatory diet³.

Two years ago, when I last visited this topic³, the global incidence of NAFLD was reckoned to be 25%⁴. New data revises this figure upwards, and it is now estimated to affect 32%⁵ of the world’s population. Revised methods of calculation account for only a part of this, and on current trends we will hit 50% by 2033⁶.

Le et al ’22. (4).

These are not just self-indulgent adults. The frankly appalling statistics imply that significant and increasing numbers of children are being affected. In 2006 NAFLD was found in 10% of children⁷, between 20 and 40% of whom had progressed to NASH⁸. If we go by the graph, the numbers of affected children may be as high as 15% by now.

These alarming trends mean that the numbers of patients progressing to NASH, heart disease and liver cancer will continue to spiral upwards, and that many of them will hit those buffers earlier in life. And all this as we move, inexorably, towards increased healthcare rationing^{9, 10}.

I suggest that the liver is the canary in our coal mine. The increasing numbers of people with liver damage is telling us that something is disastrously wrong with our diet and lifestyle, and that we need to find a way out, urgently.

Buried in a maze of visceral tunnels, the liver is the organ most immediately affected by what we eat. Ingested nutrients, drugs, supplements and toxins all pass through the portal vein and enter the liver in high concentrations before they can reach other parts of the body, where they will in most cases be diluted.

This is why the liver has such a striking capacity for repair. It is designed in such a way that if/when it is damaged by acute exposure to a toxin or even to trauma, in most cases it rapidly recovers both form and function. In rats, if the bulk of the liver is removed, it will grow back to full size within a week¹¹. 

This is a complex exercise involving an enormous amount of inter-cellular communication and cooperation. Almost immediately after damage occurs, non-affected liver cells switch on growth-related genes and start dividing until they recognise that the liver has regained its overall size and function. Division halts and the liver is back to where it started, hardly missing a metabolic beat. 

With the exception of the epithelia, no other tissue can recover so promptly and so effectively from damage.

When we see so many people developing chronic liver damage, which is a sign that the liver’s uniquely potent repair kit is being overwhelmed, we can be sure that other less robust tissues are also being damaged, and in ways that they are intrinsically less able to recover from.

Our livers are warning us that our milieu interieur has become dangerously toxic, which helps to explain the proliferating pandemics of chronic degenerative disease listed in the first paragraph.

Pharmers have responded to the oncoming tide of NAFLD / NASH by developing a range of new drugs and re-purposing old ones, but not a single one of these has yet received regulatory approval. Most do not progress beyond stage 2 trials, ie they fail basic safety and efficacy.

There are several reasons for these failures. Measuring the impact of a new drug on a slowly developing condition, and where biopsy data are generally required, is not easy. And it is not yet possible to identify those most likely to progress to NASH. However, if there was a drug that was actually effective in treating NAFLD / NASH, well-conducted longer-term (ie 12 months and over) studies should have been able to find it by now.

I don’t think they will. Given the multiplicity of pathogenic mechanisms that lead towards NAFLD / NASH, such patients are a heterogynous group who merely share a common set of symptoms. Monotherapy seems intrinsically unlikely to show efficacy within the constraints of a Phase 2 or 3 trial, let alone work in the community. 

A drug designed to slow NAFLD driven by excessive intra-hepatic lipogenesis will probably not be very effective in cases of NAFLD driven predominantly by dysbiosis, reduced autophagy or chronic inflammatory stress.

What is the medical take on this? Not, I submit, a very healthy one. Besotted with drugs as they are, they bemoan the current dearth of suitable medicines and dream of more precise monitoring systems, more specific patient populations, more polypharmacy. Statins, glitazones, GLP-1 agonists and PCSK9 inhibitors, with a pinch of vitamin E on the side, and all of these together still not particularly effective. 

In the real world, the way to a healthier liver seems quite straightforward. Reduced intake of sugars and sugar-sweetened drinks^{3, 12}, more physical exercise, a blended prebiotic, an anti-inflammatory dietary regime and a choline supplement should do the trick.

Most of these factors were already known in the 19^th century^13-15 and choline was added in 1949¹⁶, so there is nothing radical about this. The prebiotics are a newer addition, but still go back to 2113¹⁷.

(Choline in supplements has been reported to increase platelet reactivity and levels of the cardiotoxic compound TMAO¹⁸, but consuming choline in foods such as eggs does NOT do this¹⁸ and can be considered safe.) 

In addition to the above protocol, there is recent evidence that anyone with fatty liver would do well to minimize exposure to the weedkiller glyphosate^{19, 20}. In the event that the problem persists there is a case for adding milk thistle extract to the hepato-protective regime; its polyphenol component silymarin cycles through the liver and provides additional antioxidant and anti-inflammatory support²¹.

Why has the medical profession not promoted this route? I think you know why.

Copyright of the pictures: www.bobocong94.tistory.com, https://www.liverpoolecho.co.uk/

Next week: Thanks for all the fish oil. (A hitchhiker’s guide to nutrition)

References

1. Https://drpaulclayton.eu/blog/highly-evolved/
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3. https://drpaulclayton.eu/blog/foie-gras/
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10. https://www.definitivehc.com/blog/5-reasons-why-healthcare-costs-are-rising  Accessed 12.5.23
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17. Correia-Sá I, de-Sousa-Lopes H, Martins MJ, Azevedo I, Moura E, Vieira-Coelho MA. Effects of raftilose on serum biochemistry and liver morphology in rats fed with normal or high-fat diet. Mol Nutr Food Res. 2013 Aug;57(8):1468-72.
18. Wilcox J, Skye SM, Graham B, Zabell A, Li XS, Li L, Shelkay S, Fu X, Neale S, O’Laughlin C, Peterson K, Hazen SL, Tang WHW. Dietary Choline Supplements, but Not Eggs, Raise Fasting TMAO Levels in Participants with Normal Renal Function: A Randomized Clinical Trial. Am J Med. 2021 Sep;134(9):1160-1169.e3.
19. Mills PJ, Caussy C, Loomba R. Glyphosate Excretion is Associated With Steatohepatitis and Advanced Liver Fibrosis in Patients With Fatty Liver Disease. Clin Gastroenterol Hepatol. 2020 Mar;18(3):741-743.
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