Immune Dysregulation and Inflammatory Bowel Disease

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At our center, we are fortunate to work with an immune dysregulation clinic (Dr. Shanmuganathan Chandrakasan, Dr. Taylor Fitch) that helps sort out patients with inflammatory bowel disease with underlying monogenetic disorders. This is very important as specific treatments, including hematopoietic stem cell transplants (HCST), may be needed. The likelihood of an underlying monogenetic disorder is much more frequent in the VEO population. A recent talk on this topic by Taylor Fitch was given to our group. Here are some of the slides:

Generally, about 2% of those older than 6 years of age have monogenetic disorders, but it is much higher in those with severe or refractory disease.

This slide shows six major categories of immune defects.

This slide shows the high frequency of extraintestinal manifestations in patients with monogenetic disorders, particularly recurrent infections, skin/hair abnormalities, and autoimmunity. Perianal disease is also frequent in this population.

In the discussion, it was noted that DHR testing is often unreliable, especially if the specimen is not run promptly.

My take: I have had several patients with IBD/immune dysregulation, including a patient with CTLA4 and a patient with TTC7A. Making these diagnoses led to specific treatment recommendations. The patient with CTLA4 is doing well with abatacept therapy.

For those in Atlanta, a referral can be made via EPIC order and/or via contact with immune dysregulation team members. Epic order:

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

No One Would Design U.S. Healthcare System This Way

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S Corlette, CH Monahan. NEJM 2022; 387: 2297-2300.

There are a lot of problems with the U.S. Healthcare system. This article focuses on healthcare coverage.

The U.S. has a patchwork system of health insurance coverage “in which people’s access to services and level of financial protection — not to mention whether they have coverage at all — varies depending on their birthplace, age, job, income, location, and health status…Many people in the United States work for employers that do not offer insurance or do not sufficiently subsidize it, making it unaffordable for lower-income workers.”

“No one would purposefully design the system we have. Unlike many of our peer countries, the United States has never had a centrally planned, cohesive system to help its citizens obtain and pay for health care services. Ours is a system built on happenstance, unintended consequences, and gap filling…”

“The United States has made sporadic efforts at creating a national system of health coverage…These efforts all foundered in the face of opposition from health insurers, the American Medical Association, and other health industry stakeholders, as well as concerns about the proposals’ costs.”

“Americans who have “good” insurance today may be surprised to learn that they, too, are vulnerable. Underinsurance is a growing problem, as fewer and fewer Americans are able to afford their share of costs. Premiums and deductibles continue to increase as health care costs rise, straining the budgets of families, employers, and state and federal governments. Unless and until policymakers curtail the power of health care monopolies to drive up costs and do more to limit health care prices across our array of public and private coverage systems, virtually everyone’s access to affordable care is at risk… the primary reason millions of Americans remain uninsured or have insurance coverage that leaves them financially exposed is the high costs in our health care system. Constraining the growth of costs while reducing inequities in access and outcomes will require new but difficult reforms.” 

My take: There are no simple solutions to the high costs of our health care or to assuring adequate coverage. At every level, there are excessive costs which undermine these goals:

  • Hospitals charge exorbitant fees and try to monopolize markets
  • Insurance companies have split loyalties and often deny expensive but necessary care
  • Pharmaceutical companies charge as much as the market will bear even with older generics. Increasingly, newer medications are very expensive
  • Health care providers have no incentives to constrain costs. Even salaried physicians may feel complicit by being part of systems owned by hospitals and venture capital firms which have excessive charges.
  • Wasteful (low value) practices are widespread

Related article: NY Times, Eric Reinhart 2/5/23: Doctors Aren’t Burned Out From Overwork. We’re Demoralized by Our Health System.

Excerpts:

“For decades, ‌at least tens of thousands of preventable deaths have occurred each year because health care here is so expensive…

Although deaths from Covid have slowed, the ‌disillusionment among health workers has ‌only increased. Recent exposés have further laid bare the structural perversity of our institutions‌‌. For instance, according to an investigation in The New York Times, ostensibly nonprofit‌ charity hospitals have illegally saddl‌ed poor patients with debt for receiving‌‌ care to which they were entitled without cost and have exploited tax incentives meant to promote care for poor communities to turn ‌‌large profits. Hospitals are deliberately understaffing themselves and undercutting patient care while sitting on billions of dollars in cash reserves. Little of this is new, but doctors’ sense of our complicity in putting profits over people has ‌grown more difficult to ignore…

And many physicians are now finding it difficult to quash the suspicion that our institutions, and much of our work inside them, primarily serve a moneymaking machine…Our health care institutions as they exist today are part of the problem rather than the solution.”

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IBD Updates: Low Lymphoma Risk, Fewer Biopsies for Ulcerative Colitis, MRE Distinguishes Backwash Ileitis, Beta-Fructans and IBD Activity

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M Egberg et al. AJC 2023: 118: 354-359. Low Risk of Lymphoma in Pediatric Patients Treated for Inflammatory Bowel Disease

Key finding:

  • Using a database with 10,777 pediatric patients (2007-2018) with more than 28,000 patient years, there were 5 lymphomas reported. 4 had received thiopurines and none received anti-TNF monotherapy.

My take: This is a very reassuring study for the safety of anti-TNF agents.

AE Mikolajczyk et al. Inflamm Bowel Dis 2023; 29: 222-227. Assessment of the Degree of Variation of Histologic Inflammation in Ulcerative Colitis

  • In this retrospective study with 92 patients (182 colonoscopies), the authors found “minimal variability between degree of inflammation among biopsy fragments within and among different colorectal segments in UC, suggesting that even a single biopsy would adequately reflect the inflammation of the entire colorectum.”

My take: This study suggests that taking biopsies from every segment of the colon (when it looks uniform) is usually not needed, unless the purpose is to look for dysplasia. Also, it is worth recognizing that individuals with primary sclerosing cholangitis often have greater histologic activity in the right colon.

References only:

Understanding the Laxative Effects of Coffee

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V Mehta et al. JPGN 2023; 76: 20-24. Open Access! Effect of Caffeine on Colonic Manometry in Children

Methods: A prospective study of pediatric patients (N=16) undergoing standard colonic motility testing that were able to consume caffeinated coffee, decaffeinated coffee, and caffeine tablet during colonic manometry (with normal response to bisacodyl)

Key findings:

  • Caffeinated coffee resulted in a higher AUC, motility index (MI), and time to HAPC compared with decaffeinated coffee (P < 0.05).
  • Urge to defecate, or actual bowel movement in 100% (n = 16) of patients after intraluminal bisacodyl (IB), compared to 81% (n = 13) after caffeinated coffee (CC), 56% (n= 9) after caffeine tablet (CT), and 50% (n = 8) after decaffeinated coffee (DC)
  • Based on AUC between T = 1 and T = 60 minutes after each agent, the response of the colon to IB was more robust, relative to other agents (P < 0.05). Both CC and DC had resulted in a higher AUC compared to CT (P < 0.05), but no significant difference between CC and DC 
  • Caffeine is indeed a colonic stimulant; however, other components of caffeinated and non-caffeinated beverages likely induce colonic response as well
  • Limitation: Study population: patients required motility testing for refractory chronic constipation Therefore, they do not represent a normal population

My take: As with adult patients, coffee (both caffeinated and decaffeinated) acts as a colonic stimulant. Though, it is relatively weak compared to bisacodyl

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Weight Gain If Semaglutide Stopped

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This article discusses several conditions like Prader-Willi and pregnancy that can result in increase hunger and then elaborates on genetic tendency towards obesity in an age of abundant ultra-processed high calorie foods. Excerpts:

A famous 1990 study of identical twins born in Sweden showed that pairs who were separated at birth and adopted had weights more similar to each other than to their adoptive families…The ability to sense such fullness — and hunger — varies, the result of genetic differences in brain circuits that control appetite.

The new drugs are the first to manipulate the hormonal regulatory systems governing energy balance. The drugs simulate the action of our native GLP-1 but with longer-lasting effects, amplifying the fullness signal inside the body…At the very least, though, the way the drugs work can teach us that people who are larger did not necessarily choose to be, just as people who are smaller did not — and are not morally superior. This “isn’t a free pass, either to individuals who do have the capacity to choose better, nor does it take the heat off of food industries,” said a University of Sydney nutritional biologist, Stephen Simpson, but it’s “evidence that obesity isn’t a personal lifestyle choice.”

My take: For those who benefit from GLP-1 medications, it is important to recognize that weight gain is likely when the medications are discontinued; this indicates once treatment is started, the goal would be to use indefinitely –until something better comes along.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Briefly Noted: Kiwi for IBS-C

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R Gearry et al. AJG 2022. DOI: 10.14309/ajg.0000000000002124.Open Access! Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort—Results of an International Multicenter Randomized Controlled Trial

Participants included healthy controls (n = 63), patients with functional constipation (FC, n = 60), and patients with constipation-predominant irritable bowel syndrome (IBS-C, n = 61). Mean age 35 years.

Key findings: Consumption of green kiwifruit was associated with a clinically relevant increase of ≥ 1.5 CSBM (complete spontaneous bowel movement) per week (Functional constipation; 1.53, P < 0.0001, IBS-C; 1.73, P = 0.0003) and significantly improved measures of GI comfort (GI symptom rating scale total score) in constipated participants (FC, P < 0.0001; IBS-C, P < 0.0001)

Related blog post: Small Study: Kiwi For Constipation

What I Don’t Want to See: Catastrophic Antiphospholipid Syndrome

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SA Kahn et al. NEJM 2023; 388: 358-368. Case 3-2023: A 16-Year-Old Girl with Abdominal Pain and Bloody Diarrhea

This case report of a girl presenting with abdominal pain and diarrhea identifies a rare etiology, catastrophic antiphospholipid syndrome (CAPS). CAPS can result in ischemic colitis. This patient underwent a colonoscopy which was normal in rectum but then became abnormal in the sigmoid colon:

“CAPS is thought to result from the binding of antiphospholipid antibodies to cell surfaces, which activates endothelial cells, monocytes, and platelets and leads to inflammation, complement activation, and thrombosis. The formation of thrombi in patients with antiphospholipid antibodies is thought to be a multihit process.7 The presence of antiphospholipid antibodies in the blood is the first event, but the antibodies typically do not cause disease until another event occurs.”

Management of antiphospholipid antibodies: “Thrombotic disease manifestations are important in guiding therapy. For patients with antiphospholipid antibodies and no history of clotting, anticoagulation for primary thromboprophylaxis is generally not recommended…For patients with antiphospholipid antibodies and a history of unprovoked thrombosis (e.g., patients with APS), long-term thromboprophylaxis is recommended…For patients with more severe presentations — such as this patient, who had CAPS with thrombosis in multiple organs — treatment is more aggressive and involves targeting multiple steps within the CAPS cascade.”

From ChatGPT

My take: This 16 yo had a severe presentation and the case is a reminder that there are multiple reasons besides IBD for a teenager to have bloody diarrhea and abdominal pain.

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How Low Can You Go with Split Livers?

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Z Wang et al. Liver Transplantation 2023; 29: 58-66. Outcome of split-liver transplantation from pediatric donors weighing 25 kg or less

DJ Stoltz et al. Liver Transplantation 2023; 29: 3-4.(Editorial) Open Access! Exploring the lower weight limit of splitable liver grafts for pediatric recipients

From the editorial:

“In this issue of Liver Transplantation, Wang et al.7 describe the results of an innovative strategy to increase organ availability, particularly for low‐weight pediatric recipients, by utilizing a low‐weight donor population (≤25 kg) that historically has been avoided in pediatric split‐liver transplantation (SLT)…They found no significant differences in perioperative data, postoperative complications, patient survival, or graft survival between SLTs from donors ≤25 kg and the other three groups.”

Implications of study findings:

  • Splitting livers from donors weighing less than 25 kg will increase the pediatric donor pool and could improve waitlist mortality
  • Split smaller livers may mitigate “the clinical consequences of large‐for‐size syndrome and subsequent graft dysfunction”
  • “This approach requires a substantial level of surgical expertise to achieve comparable outcomes with more conventional operative techniques”
  • “1‐year graft survival for pediatric recipients receiving technical variant grafts was significantly worse at low‐volume centers performing an average of <5 pediatric liver transplantations per year” compared with high‐volume centers (89.9% vs. 95.3%; p < 0.001)
  • Limitations: Retrospective study. Also, only 22 of the split livers were from <25 kg donors

My take: Making the best use of this precious resource is a solemn responsibility. This study provides another reason for more transplants to be done in centers with a high level of expertise and more reasons to continue to use split livers. In those with sufficient expertise, even smaller livers can save two lives instead of one.

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