Who are you? Who am I? | Week 19

May | Health and Fitness | Week 19 | 5/14/2023
A dissertation on Crohns and Colitis

Introduction | On many occasions I have sat, quieted my mind, and documented the history of my disease, looking for a pattern, an origin story, and a silver bullet. I never found that silver bullet, no switch I could flip that would end the suffering. But along the way, I did uncover many interesting things about the history of my disease and fascinating correlations. In fact, I found enough interesting things that I have developed a working theory of IBD, which I'm excited to finally compile. As an aside, most, if not all of the information I'm going to present here was never surfaced to me by my physicians, part of a deeper problem in our health system. For example, there is a statistical correlation between colder climates and autoimmune disease (my ancestors are from the hills of Ireland). There is data linking a lack of breast feeding to the onset of autoimmune disease (I wasn't breastfed). Finally, there is a correlation between testosterone levels and autoimmune disease (mine were low as a 27 year old, and I have tell-tale signs of low in-utero testosterone). If it weren't for Autodidactism, reading books on nutrition, published studies from the NIH, and querying my doctors to research and get back to me, the information I have come to understand would not be possible. I'll do my best to be concise and thorough on the plethora of credible theories for what gives rise to Crohns and Ulcerative Colitis. I'll attempt to simplify the panaceas of data both at the fringe and in the mainstream. And I'll focus on my experience. Hopefully, this may one day prove relatable and helpful for others. 

Family History | My Irish great grandfather can be spotted in pictures taken in the early 1930's,  hunched over, not in the arthritic way that is common with older individuals, but in a way I know very well. This ever-so-slight, permanent hunch is indicative of a man crippled by a perennial stomach pain. Slightly hunching over, I found, would help to ease the pain. His son, my grandfather would not inherit the disease, but his grandson (my father) and his great grandson (me) would. Interestingly, the disease progression worsened with each generation. My great grandfather suffered from what we believe to have been a mild case of the disease. He did not die early, nor did he ever receive treatment. My father suffered with a moderate to severe case, but ultimately reached remission with the aid of the first monoclonal antibody treatment to hit the market, Remicade. I suffered with a particularly rare and severe form of the disease known as indeterminate Crohn's Colitis - diagnosed at age 6 with Ulcerative Colitis, failure of 10 on-market medications, large intestine removal at age 24, and active Crohn's at age 27. Anecdotally, en masse, disease severity is increasing over time. Factually, disease incidence is increasing over time. 

Multifactorial Theory on the Proliferation of IBD 

Common Narrative | Like most autoimmune disease, I do believe IBD derives from a genetic basis. But that is far from the whole story. More than 200 genes have been traced to having a influence on the incidence of Crohn's disease. According to the Human Genome project we have around 22,000 genes. 200 genes among 22,000 is ~1% of total genes. Statistically isolating an issue to 1% of total potential causality is an achievement and should be seen as a major accomplishment, but it misses something critical in my mind about genetic inheritability, for which we claim Crohn's and Colitis to be the sort of disease. If I recall my days working on punnett squares, the basic tenet of gene expression was that both parents had to either carry the gene and/or express the gene themselves for it to make itself known in the offspring. The statistical likelihood of two parents with matching or carrying genetic variations of 200 genes amidst 22,000 genes, is so low its not worth even stating. If the disease was truly reliant on a single mutation, in a disease like cycle-cell anemia, the math makes sense why it would show up in a steady population over time. But in 200 expressions, the math is exponential. 

My Conclusions

[1] Statistics | Due to the statistical significance of IBD in western society versus the statistical insignificance of inheriting 200 genetic mutations from two parents, IBD symptomology can triggered by many isolated or combination of these 200 genetic variations. This makes sense anecdotally given how many people show variation in their Ulcerative Colitis and Crohn's symptoms and severity. This inherently means that the disease exists on a spectrum, it is not binary. It's worth noting here that the highest incidence of IBD is in Jewish females. The Jewish ethnicity is said to be carried on the female side (in order to be Jewish, your mother has to be Jewish), and the Jewish people keep genetic lineages much closer than other ethnic groups - leading to higher statistical likelihood of more combinations of the 200 genes being homozygous. 

[2] Interrelatedness | Other inflammatory autoimmune diseases like RA, Psoriasis, and Lupus, which are treated with the same medications as Crohn's and Colitis (monoclonal antibody-derived treatments targeting specific inflammatory proteins like Interleukin and TNF) must also be a part of this web of genetic variations, which probably amasses to well over 200 genes.. Let's do basic math: Since 1 disease (Crohn's) can be triggered by 200 genes, then 5 diseases could be triggered by 1000 genes. Now we're talking almost 5% of the human genome. Which brings me to conclusion three.

[3] Epigenetics | If 5% of the human genome is 'corrupted' for modern society, then there is something much bigger going on here. We have an epidemic of epigenetics. Our modern environment is triggering the onset of disease. We can prove this too. The incidence rate of IBD and autoimmune disease on aggregate in the developing world is near 0. Additionally, why would disease severity increase down generations from my great grandfather to myself if the mating pool became larger and more sexually diverse? That should in theory dilute the 200+ genes which trigger disease onset, but instead, it got more significant. 

Hypothesized Causes of Increasing Incidence

[Cause A] The Western Diet

Despite disagreeing with him about the efficacy of COVID vaccine, my ex girlfriend's father was a gifted pediatrician and I'll always be grateful to him for a book he recommended to me; The China Study by Dr. Campbell. The book centered around the differences in the western diet and the eastern diet as THE major source of inflammatory disease, metabolic disease, cancer and a host of other ailments that we experience disproportionately in the west. It was quite convincing. While I take some issue with the focus on meat (bad) and grain (good), it appears to be spot on about a variety of other concepts. [1] High fructose corn syrup. [2] Seed oils. [3] Ultra-processing (dyes, preservatives, chemicals). [4] Treated-meats (hormones, antibiotics, farming factories). And [5] the composition of our diet. We give our children sugary, ultra-processed breakfasts, instead of eggs, vegetables, fruit and natural yogurt. We give them high-fructose gummies, fried, farmed chicken for lunch. We give them cheap meat, with nutrient-less white potatoes for dinner. Our diet consists of 85% meat, diary and carbohydrates when it should consist of 60% fruits and vegetables. We don't eat nearly enough fish, and the fish we do eat is farmed. We drink coffee 5 minutes after waking and beer 5 minutes before sleeping. We lack the polyphenols in green tea, the flavonoids and carotenoids from colorful fruits and vegetables, the magnesium in leafy greens, and the fiber from whole foods. Thus, from a young age, we create acidic, non-motile, dehydrated, micronutrient deficient guts, with microbiomes that produce excess gas, starve us of serotonin, and prop up chronic illness.   

[Cause B] EDC's, BPA's and Phthalates

Perhaps the most important book in a half century is Countdown by Dr. Shana Swan. The main concept of this book is that we're seeing massive drops in fertility and normal hormone regulation due to a variety of unnatural compounds and chemicals in our everyday environment. Dr. Swan briefly touches on metabolic and physical health, outside of fertility, for someone with sub par hormone composition, which is the piece I want to draw attention to. The literature is quite clear when it comes to IBD, low testosterone correlates strongly with inflammatory bowel disease. There is a question about the chicken and the egg - does inflammation reduce testosterone? Likely yes, through the mechanism of cortisol. But does low testosterone trigger inflammation? I believe it does. The scientific community is well aware of the fact that healthy levels of testosterone stave off age-related diseases such as Alzheimer's and arthritis, but the consensus is becoming ever clearer, that it's not limited to just these, it extends to multimorbitity, including cardiovascular disease, pulmonary disease and diabetes. If a normal hormone profile has negative correlation to multimorbitity over a long period of time, then it stands to reason that a sub normal hormone profile could have a positive correlation to chronic illness expression of the inherited type, i.e.: Crohns, Colitis, Type 1 Diabetes, RA, etc. These EDC's, particularly BPA's and Phthalates, reduce in-utero levels of testosterone and estrogen, which could explain the uptick in disease incidence. This is classic epigenetics. 

[Cause C] Leaky Gut

Since 2017, Harvard, the Cleveland Clinic, and the NIH have published essays and studies on Leaky Gut Syndrome. What used to exist at the fringe has now entered the medical Overton Window. The general consensus at this point is that our intestinal permeability varies person to person, but that for those with IBD and Celiac disease, intestinal permeability is reduced. The thought is that this is caused by inflammation and is therefore a symptom rather than a cause. My theory is that our guts are getting leakier and leakier from items A and B on this list. Inflammation then perpetuates the leakiness and creates an exponential death spiral. One factor of Leaky Gut with high consensus is that when a gut becomes 'leaky', certain compounds that otherwise wouldn't have been able to pass through the intestinal lining, are now able to. Compounds like the items in Cause B (Phthalates and the sort). But what if those compounds, in-utero, actually create a leakier gut due to the fact that the Mother is consuming them whilst the gut itself is being developed. Pile on top of that genetic predisposition, and the acidic, non-motile, dehydrated, micronutrient deficient guts I mentioned earlier, which we create with particular expertise in our youth, and you get a leaky gut by age 6 (the age I was diagnosed with UC).

[Cause D] Hygiene Hypothesis

Out of the Covid pandemic arose an important conversation that again laid dormant at the fringe. How good is our immune system? Do we need a vaccine for everything? Are we over prescribing antibiotics and antivirals? And what are the consequences of an increasingly 'clean', germ-free environment? The answer appears quite clear from the literature and the multifactorial picture in front of us. The first point, in which the literature is clear, examines children with peanut allergies. An allergy is an immune response to a given stimulus. If children, both predisposed to peanut allergy and who already have the allergy are given small doses of the allergen at a very young age, it virtually eliminates/prevents all peanut allergy incidence. Another strong piece of evidence supporting the hypothesis is that of first generation immigrants from developing nations. According to epidemiological data, immigrants coming from low-incidence country (developing nation) to a high-incidence country (developed nation) acquire the autoimmune and allergy related diseases with as high incidence as a first generation. There's a strong argument to suggest that this speaks to our environment, items A and B on this list, but there may be something more pernicious going on here. Our levels of vaccination and antibiotic prescription, particularly for young children are the highest in the world, a factor of 10 higher than the developing world. In fact, according to the NIH, antibiotic exposure both in-utero and childhood has a statistical correlation to developing IBD. 

Conclusion

When you put these four components together, our diet, our environment, their effects on the gut and the state of medicine in the West, you get a recipe for autoimmune disease, in particular IBD. As I said at the outset, I do believe there is a genetic linkage, but the math doesn't add up, Given the number of genes with connection to immune disorder, the likelihood that this is an epidemic of pure inheritance is low. Just like Climate Change, the debate is not whether the phenomenon is occurring, the debate is about the extent to which we're contributing to it. And in this case, I believe it's extremely significant. 

My experience and advice

[A] How to (try to) prevent it 

If you're reading this as a young adult and potential parent, I have a few pieces of advice on how to avoid an IBD diagnosis in your children. [1] Get checked. Cheaper services like 23&Me will likely add Crohns and UC to their genetic predispositions in the future. However, there is also genetic screening that can be done at various fertility clinics and medical practices. If you and your partner are carriers or there is a family history present, take special care to reduce risk from the above four items. [2] Read Dr. Shana Swan's book, Countdown, and begin to remove various EDCs from your lifestyle, ASAP. [3] Remove processed foods from your diet and engage with more of an Eastern Diet (except Soy). [4] Finally, if and when the kids do arrive, don't over-vaccinate (particularly COVID and HPV) and avoid antibiotics in the first few years of life, unless absolutely necessary. All in all, breast-feed children if possible, let them play in the dirt, avoid feeding them processed sugar, and make sure they get plenty of sunlight. 

[B] How to spot it  

Much of this section is based on what my parents told me about my childhood. There were 3 main habits and characteristics I had, which I think correlate either to IBD. [1] Constipation and anal retention. This one is more egg than chicken. It appears obvious that anal retention is one way in which bacterial overgrowth can develop in the colon. That dysregulation in the gut microbiome can trigger IBD. Snuff this out as soon as possible. [2] Latent Stress. This one could be chicken or egg. It's hard to say whether adolescent stress and anxiety causes IBD, is a cause of latent IBD or is a coincidental personality trait of those with IBD. One thing is clear, as a teen and young adult, stress can exacerbate symptoms quite significantly and even lead to flare-up, so it's reasonable to assume that the same is true for children. If you spot latent stress and anxiety in children it can lead to anal retention and/or lower immune function. Pay close attention for it. [3] Anger. It's not uncommon to see a 3-year old in a fit of anger, but be on the watch for an unreasonably frustrated kid. As is the case with any infant or toddler, expressing emotions clearly and drawing focus to the source of pain is virtually impossible. Therefore, if your child is expressing anger and frustration, more than one would reasonably predict, there may be stomach pain at play.  

[C] How to treat it

I'm no physician but I've spent over 10 years actively fighting Crohn's and Colitis, so hopefully this section can provide a brief summary of how to treat IBD if given the diagnosis. First things first, before any non-ceasing medication, experiment with diet, exercise, and stress regulation. The latter two are self explanatory so let me linger on the first. 

Diet | There is much conflicting research as to what causes inflammation in the gut. 4 diets I'd recommend researching and attempting, in order of increasing difficulty are [1] Eastern, [2] Mediterranean, [3] Paleo, and [4] Carnivore. As I mentioned earlier, the [1] Eastern diet has many correlations to overall health. It indexes heavily on fish, rice and vegetables. Raw vegetables may irritate the IBD, due to difficulty digesting. The [2] Mediterranean diet is also higher in fish and lower in red meat, but introduces more nuts and olive oil. This diet has become a source of recommendation among physicians. Nuts may irritate the IBD due to the high fat and fiber content with digesting. The [3] Paleo diet is more restrictive than both and the low glycemic index foods tend to make one feel less full. Finally, the [4] Carnivore diet is hyper restrictive (look into Mikhalia Peterson's Lion Diet) but in rare cases of autoimmunity it has shown fantastic, and increasingly scientific results. The typical diet prescribed by physicians for IBD is called Low FODMAP. This diet removes lactose, high fructose, raw/gaseous vegetables, soy products, beans, and recommends essentially an Eastern Diet high in fruit, rice, cooked vegetables, fish and eggs. It is a great starting place. If you remember anything, remember this -- remove coffee and alcohol immediately, and don't look back. 

Medications | The traditional classes of medications to treat UC and Crohns are the following: [1] 5-ASA (mesalamine), [2] Corticosteroids (prednisone, budesonide, uceris), [3] immunosuppressants (6MP, azathioprine, methotrexate), and [4] biologics (Remicade, Humira, Simponi Entyvio, Enbrel, Stelara, Xeljanz). In most cases, when inflammation is noticed in bloodwork (C-Reactive Protein elevation and/or Sed Rate elevation), intra-stool blood is seen, or colonoscopy exam shows symptoms, a patient will be given some form of mesalamine. Prescription names here are Asocal, Delzicol or Lialda. From the literature, it appears to slightly decrease inflammatory activity with low side effect. If inflammation continues, particularly continued blood loss, a patient will be put on a corticosteroid, which is a potent and fast-acting anti-inflammatory. The basic, but reliable drug here is Prednisone. Prednisone comes with a host of side effects, but at doses above 30mg daily it is highly effective. At one point in the hospital I was on 80mg intravenously. If symptom severity can be managed with a less potent anti-inflammatory, I'd opt for budesonide or uceris. Both of these are delayed release and therefore mostly impact the gastrointestinal track only, therefore reducing side effects. For many years, due to limited market availability of drugs, many traditional immunosuppressants and chemotherapy agents were deployed to combat life-threatening inflammation, such as 6-mercaptopurine, azathioprine and methotrexate. At all costs, avoid these drugs. As we know well, chemotherapies work to deactivate the entire immune system and come with a litany of problems if any real duration is needed. Fortunately, through the work of monoclonal antibodies the IBD community has been prolific in producing medications that are much safer and more effective. Each medication in the biologic class targets different inflammatory proteins such as TNF Alpha, Interleukins, or Janus Kinase which enables treatment based on the particularity of Crohns or Colitis that an individual possesses. I found the most success on Entyvio and Stelara, and the market tends to agree that these are the most effective in clinical study. 

 

[D] How to live with it 

This is a section that I could write something of a short novel on, but will refrain from today. For the sake of concision, I'll narrow the challenges of living with IBD to three categories, [1] Pain [2] Lifestyle and [3] Fortitude. 

Living with [1] chronic pain is a challenge to say the least, but hopefully I have some helpful recommendations. First is to take advantage when there is a lack of pain. In moments of clarity and ease of symptoms, the natural inclination is to relax. Instead, get out and move, try to exercise, try to get sunlight. It will limit the effects of cortisol in your blood. Second, be diligent about diet, sleep and stress. Finally, utilize pain medication and antispasmodics. Bentyl and Tramadol were my drugs of choice. Bentyl makes you feel quite drowsy but it relaxes the body. Tramadol makes you feel quite awake and it numbs the pain differently than harder drugs like Hydrocodone and Oxycodone. 

Understanding [2] lifestyle alterations is important. Society suddenly looks different. Drinking at a party becomes a tradeoff of consequences beyond just a hangover. Being out of range of a bathroom becomes a a calculated risk. Whether it's in remission, in the midst of a flare-up or post-operation with a stoma, life changes. Resisting the confinement of your disease is noble, but fighting reality is foolish. Embrace change and work with it, be honest about it, and accept it. But don't let it define you. You are not it. It is not you.

Finally, [3] fortitude. This it the most important of all. This disease is not a sprint, it is a marathon. It is incurable. Battles can be short or long winded, lasting weeks or years. It is critical to batten down the hatches and prepare for war. It sounds macabre, but being truthful about reality is the first step to dealing with it in the most productive way possible. The first Noble Truth of Buddhism is that Life is Suffering. That suffering can come from many sources, greed, pride, addiction, and disease. It is not that we chose our means of suffering, but instead that everyone has their cross to bear. The third Noble Truth is that there can be an end to suffering, the cessation of craving, of attachment, of ego. Of course we cannot suddenly wish away pain and physical suffering, but we can do what is in our power to curb it's influence on our life. We can create strong, meaningful relationships. We can ground ourselves to a higher purpose. We can be kind, helpful, altruistic, and loving. And we can engage the full power of our fortitude to help us carry our cross. When the doors finally close on this life, we will have fought the good fight, turning an acerbic affliction into an admirable affiliation. 

[E] How to (try to) fix it 

Notice here I have the word fix, not cure. Technically, there are no cures, unlike a bacterial infection or a fungal overgrowth, there is no single antidote to cure the problem. The problem, in part, is the body itself, and we cannot get new bodies (yet). But there are 4 ways in which to try to fix the problem. The [1] first is out of our control, but has shown some relative success, growing out of it. The diagnosis window for UC and Crohns is biphasic, typically occurring between very young adulthood (16 - 25) and very late adulthood (60+). It perfectly coincides with the onset of hormonal changes in both cases (my opinion, not scientific conclusion). This speaks specifically for the diagnosis, but I think it also applies to the symptomology. It appears that symptoms reduce in severity and frequency during the 30 - 50 age window, probably because of mostly steady state hormones (although I don't know how this relates to pregnant women). In other words, try to weather the storm and you may find that things clear up quite quickly after the first window. [2] is diet. Earlier I spoke about the various diets that have shown clinical improvements in disease. Particularly there is some shocking evidence coming out of elimination diets. People start with sugar, then gluten, then slowly but surely have arrived at a diet composed of solely meat (Carnivore diet). For whatever reason, there is profound anecdotal data suggesting that this can be a fix for autoimmune disease. Start down the track of Eastern Diet and Mediterranean Diet first, then move to elimination diet if success isn't found. [3] is medication. Thankfully, the profit motive has been there for autoimmune research in the last 20 years and what's come out of it has been remarkable. There are over 10 biologic immunotherapies available on the market for the treatment of UC, Crohns, RA, Psoriasis and Lupus. And as I mentioned earlier, they overlap in treatment purviews. In fact, they're getting better in efficacy too, the newest drugs on market are performing better than the older ones, due mostly to their increased specificity. The final note on medication is that the long term consequences of taking them are relatively low given the immunocompromization. Have hope. [4] I am hesitant to mention, as it may only impact a select few, but I am living proof of it's success - Surgery. There are two types of surgery. For Crohns, because the disease is present throughout the gastrointestinal tract, surgery is used to remove parts of the large or small bowel in order to preserve the rest of the bowel. I don't personally know the efficacy of this, but I would be cautious to agree, given the potential recurring nature of the surgery. The second type of surgery is for Ulcerative Colitis. In theory, UC is relegated to the large intestine (colon) and the rectum. If you remove them, then there is no place for the UC to occur. The fine print is that, you must replace them with something unless you get a permanent ostomy. That replacement mechanism has a statistically significant recidivism rate for IBD of some sort, whether it be Crohns or chronic pouchitis. Fortunately, given the first three fixes (aging, diet, and medication), relative remission can be found eventually with a J Pouch. I am here to attest. The body is incredibly adaptive, and the J Pouch is an adaptation. 

A Note on IBD

In the long course of history, IBD appears to be a new foe. Some wicked combination of environmental factors, biologic maladaptation, and genealogic unluckiness has seen to it that we rise to the occasion and battle once more, against the unfairness of the human condition. But we are prepared for such a battle. And we are in the early days. We, the patients, must all do our part to investigate our individual incidence of the disease, document our learnings and contribute to the pool of knowledge that is gathering on this topic. That is how we fight, leveraging the collective information of millions, and having faith in the wisdom and imagination of the few. It is a good fight, a noble fight. If you are drafted by fate, become a soldier, as your ancestors have before you, so that your progeny might not have to.