I wonder whether the French will celebrate Bastille Day with an uprising against President Macron’s decree that all children will be vaccinated. Just a thought.
Anyway – back to leptin. My further interest was piqued by an article in “The Times” on the 12th July headlined “Hormones found in fat may help against prostate cancer”. It reported a 3 year study suggesting that people (surely that should be men? – Ed) with a BMI of more than 30 had a 10% higher survival rate than thinner patients. The patient group was highly selected being patients with metastatic disease that was resistant to medical castration. You can find a summary of the conference presentation at https://www.eurekalert.org/pub_releases/2021-07/eaou-ois070721.php.
Now many years ago, BIBG (before Internet, Before Google) I was asked to review a paper reporting three cases of reflex sympathetic dystrophy following herpes zoster infection. RSD is also known as Sudek’s atrophy after the physician who first described it. The authors stated that their cases were the first reported with this trigger in the English literature.
I thought this was surprising, so I went to the library to search the giant volumes of “Index Medicus” which most young folk won’t have heard of, but which contained the titles and authors of all medical papers arranged by author and by category. Nowadays you just type your search terms into Google and up pop the relevant things, but this was a lengthy manual process, and once you had found what you thought might be useful you had to order a copy through the library staff. In the list I found a review article with a vast list of references, but no mention of zoster. However one of the references was to Sudek’s original paper and thought it would be interesting to read, relevant or not. It was in German, so it took me a while to go through it. You can guess that I found a mention of cases triggered by zoster. Of course the new paper had been specific in saying that their finding was the first in the English literature, but the fact that Sudek himself had described it meant that it was far from new – about 100 years late, in fact. No publication followed.
You may also need to look for original documents. Having a passing interest in phalloplasty (penile reconstruction) after discovering the case file of the first ever female to male surgical transition I investigated the history of the procedure, which in all of the literature was attributed to a Russian surgeon, Nikolai Bogoraz. Now Harold Gillies (the surgeon in my case) had written a paper in the 1940s which described a case he had performed. All the references to Bogoraz’ work mentioned this, but gave the surgical date as the date of the paper; reading between the lines it was clear it had been done earlier. But no-one had read between the lines (indeed I wonder whether many authors had done more than find the reference, and quoted it without reading the paper itself – a common fault). A bit of research in the archives of St Bartholomew’s hospital found the relevant details in the admissions and operating theatre books, and as a result that attribution of “the first” has moved to Gillies. There’s an abstract at https://link.springer.com/article/10.1007/s00238-019-01539-5. In similar vein to the Sudek story the invention of the tube pedicle (the basis of early phalloplasty) was almost simultaneous in England, Germany and Russia, but the issues of translation obscured this for a long time.
The moral of this tale is that you need to search the literature for precedents, and read it properly. This is vital if you have a research idea. Then decide whether you really want to do the study, or if you do it, refer to anything contradictory that has appeared before (because you need to postulate a mechanism for why your study shows something different).
What, you ask, is the relevance of this? Well, I was intrigued by the reference to fat hormones, of which leptin is one, so I had a look to see whether any work had been done before. You too can play this game; type “leptin prostate cancer” into Google and see what happens. In case you cannot be bothered – it has been done. Much of the research suggests that high leptin levels (which occur in the obese) are a risk factor for the development of prostate cancer. So far from being protective, fat hormones may in fact be detrimental. This work is 20 years old. I use this example to show that science can be completely contradictory. That said, I concede that the new study is looking at outcomes in established prostate cancer, not at the risk factors in its development.
Take a look at one of the papers that appears in the search results: Ribeiro, R., Lopes, C. & Medeiros, R. The link between obesity and prostate cancer: the leptin pathway and therapeutic perspectives. Prostate Cancer Prostatic Dis 9, 19–24 (2006). https://doi.org/10.1038/sj.pcan.4500844 (or go straight to https://www.nature.com/articles/4500844). There you will read:
“Tumor and host produced proinflammatory cytokines (IL-6, IL-1, TNFα) upregulate the OB gene in adipose tissue, while leptin induces IL-6 and IGF-I production. This self-perpetuating loop allows tumor growth, involving leptin and other adipocytic molecules, contributing for tumor progression to advanced disease.”
Do you see where I am going? No? So look again at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846344/ – “Role of Leptin in the Activation of Immune Cells”. This one is only 10 years old. It says, among the complex and almost impenetrable analysis, “The overall leptin action in the immune system is a proinflammatory effect, activating proinflammatory cells, promoting T-helper 1 responses, and mediating the production of the other proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-2, or IL-6.”, and concludes “… leptin plays a role in the activation of the immune system, and it is a mediator of inflammation. In this context, leptin may be one of the mediators responsible for the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis, which is associated with obesity, especially central obesity. Therefore, leptin may be considered as a therapeutic target in some clinical situations, such as proinflammatory states or autoimmune diseases, to control an excess of immune response, as well as in other clinical situations, such as starving, to control an excess of exercise, or immune deficiencies, to improve the impaired immune response. That is why the investigation of the role of leptin in the regulation of the immune response remains a challenge for the future.”
Actually I quoted this before – in Blog 19, on 1st May 2020… I had forgotten that!
Hypothesis: Covid-19 is a disease of hyperimmunity – a cytokine storm. Leptin levels are higher in the obese. Leptin stimulates the immune system. Therefore Covid-19 is more likely in people with high leptin levels, viz the obese.
Observation: obesity is a known risk factor for Covid-19. Q.E.D.
Conclusion: It is worth investigating the possible role of leptin antagonists as an additional way of damping the immune response (we already use a generic suppressant – steroids – and an IL-6 antagonist – tocilizumab).
I have previously suggested using an IL-1 antagonist which is quicker and possibly safer (anakinra) which is already used in a childhood mirror condition, Kawasaki disease.
Now do you see where I was going? From a report on the possible role of fat hormones on prostate cancer, through the mechanism of action of leptin, back to its possible role in Covid-19, which I flagged over a year ago. Also have a look at https://www.acpjournals.org/doi/full/10.7326/L21-0062 and https://www.acpjournals.org/doi/10.7326/L21-0064
Time someone did a study?