What We Don’t Know About Toxic Exposures is a Lot and Dangerous

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TJ Woodruff. NEJM 2024; 390: 922-933. Health Effects of Fossil Fuel–Derived Endocrine Disruptors

Initially, I was tempted to title this post ‘Burying the Evidence and the Bodies from Pollution.’ That sounded too alarmist, though. That said, this review article asserts that “chemical pollution is estimated to be responsible for at least 1.8 million deaths each year…This number is probably an underestimate, since less than 5% of approximately 350,000 chemicals registered for use globally have been adequately studied.1”  (90% of pollution-related deaths occurring in low- and middle-income countries).

In addition, “polluting industries [are] “weaponizing” scientific uncertainty to foster distrust in scientific findings and lobbying for weaker regulations.71 For example, previously secret industry documents show that the industries knew about the health harms of PFAS decades before the scientific and public health community did.72” The science behind pollution is hampered by the inability (unethical) to conduct randomized trials of pollution exposure.

This article focuses on Endocrine Disruptors Chemicals (EDCs).

Health Effects of Fossil Fuel–Derived Endocrine Disruptors

  • Fossil fuels contribute to chemical pollution through production of petrochemicals, many of which interfere with hormonal function (endocrine-disrupting chemicals [EDCs]). Examples include perfluoroalkyl and polyfluoroalkyl substances in food packaging and fabrics and phthalates in plastics and consumer products.
  • Petrochemical production is increasing, and people are exposed through contaminated air, water, food, and manufactured products (e.g., plastics, pesticides, building materials, and cosmetics).
  • EDCs can increase several health risks, including cancer, neurodevelopmental harm, and infertility.
  • Risks are higher with exposures during fetal and child development and with exposure to multiple EDCs and occur at low exposure levels. Exposures are higher in communities of color and low-income communities and contribute to health inequities.
  • Clinicians can provide advice to patients toward reducing some exposures, but policy change is needed to establish legal requirements for comprehensive safety testing and to reduce health threats from petrochemicals. Clinicians are important advocates for these changes.

Figure 2 reviews the potential individual modifiers to the effects of pollution as well as the increased adverse health effects.

Table 2 provides recommendations for reducing exposures including diet/food preparation, cleaning/use of cleaning products, minimizing occupational exposures, and advocacy.

My take: There are limited steps that individuals can take to reduce their exposures. In order to make our environment safer, this requires policy changes. Most individuals do not even know if they are being exposed to dangerous pollutants and would have limited ability to move away from unsafe areas.

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Increased Risk of Irritable Bowel Before and After the Diagnosis of Celiac Disease

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K Marild et al. Clin Gastroenterol Hepatol 2024; Open Access (PDF)! Association Between Celiac Disease and Irritable Bowel Syndrome: A Nationwide Cohort Study

Methods: Using Swedish histopathology and register-based data, we identified 27,262 patients with CD diagnosed in 2002–2017 and 132,922 age- and sex-matched general population comparators.

Key Findings:

  • During an average of 11.1 years of follow-up, 732 celiac patients (2.7%) were diagnosed with IBS vs 1131 matched general population comparators (0.9%).
  • Compared with siblings (n= 32,010), celiac patients (n = 19,211) had >/= 2-fold risk of later IBS (aHR, 2.42)
  • Compared with celiac patients with mucosal healing, those with persistent villus atrophy on follow-up biopsy were less likely to be diagnosed with IBS (aHR, 0.66)

Interpretation of findings:

“We found celiac patients with persistent villus atrophy on follow-up biopsy less likely to be
diagnosed with IBS than those with mucosal healing. Traditionally, physicians have hesitated to diagnose IBS in patients with an organic gastrointestinal disorder (eg, CD), possibly underestimating the observed IBS risk in CD. This reluctance to diagnose IBS may be particularly true for celiac patients who have not achieved mucosal healing, because persistent villus atrophy may indicate that ongoing symptoms are due to gluten exposure
instead of IBS.”

“Surveillance bias is another challenge of studies associating IBS with CD. From the outset of diagnosing and managing these conditions, they are often mutually excluded (eg, CD-specific serology tests are often part of the workup of IBS-like symptoms). Consequently, the
strength of the association between these conditions may be overestimated.” This is why the authors focused on IBS events beyond the first year of CD diagnosis and there continue to be an increased risk of IBS 10 years of follow-up.

Another limitation of this study: “a large proportion of IBS patients are cared for in
primary care or never seek care at all, and hence our study may have had a low sensitivity for IBS, particularly mild IBS.”

My take: While recurrent symptoms in patients with CD could indicate ongoing gluten exposure, recurrent symptoms can also be due to IBS which can occur even with mucosal healing.

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Mike Farrell and The Role of The Consultant

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Jose Garza recently shared this lecture from one of our mentors, Mike Farrell. I really enjoyed being able to hear and see him. This lecture discusses the role of being a consultant and how many things have changed over the years. It is amazing that Mike has been at Cincinnati for 50 years and has instructed so many residents, clinicians as well as GI trainees. The main task is still providing assistance to our colleagues in a respectful manner. I’ve included some of his slides.

Link: The Consultation: An Ancient and Venerable Process in the Modern Age

Often, the person requesting the consult does not know exactly why they are requesting a consult.
Dr. Farrell recommended documentation with phone consultation that patient
was not examined and to please call back if needed and patient could be seen.
Dr. Farrell says he often starts a visit with a family by asking ‘How Can I Help You?’
On the left: Dr. Schubert (one of Dr. Farrell’s mentors).
On the right: Christine Heubi, Jim Heubi, Mike Farrell and Peter Farrell.

On a separate note, Mike was honored recently by Cincinnati Children’s with the Drake Medal. Link: Mike Farrell, Recipient of Drake Medal Some of the accomplishments noted in this article:

  • Among the first to study the relationship between infantile apnea and gastroesophageal reflux
  • Helped define the hepatobiliary complications associated with parenteral nutrition
  • Participated in important studies defining vitamin D, calcium and phosphorus requirements in infant parenteral nutrition solutions
  • Invented the Farrell Valve Enteral Gastric Pressure Relief System, aka the Farrell bag—a disposable plastic bag that is connected to vent a feeding tube, which is now used nationwide.
  • Presented with the 2007 Murray Davidson Award from the American Academy of Pediatrics (AAP)

Improved Efficacy with Vonoprazan for Severe Esophagitis

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Briefly noted:

Q Zhuang et al. The American Journal of Gastroenterology  :10.14309/ajg.0000000000002714, March 22, 2024. Comparative Efficacy of P-CAB vs Proton Pump Inhibitors for Grade C/D Esophagitis: A Systematic Review and Network Meta-analysis

In this meta-analysis, 24 studies met criteria. Key findings:

  • Vonoprazan (20 mg) had the lowest rates of treatment failure: 6% in the initial treatment phase, and 21% in the maintenance phase of healing of grade C/D esophagitis
  • Vonoprazan had similar risk of incurring adverse events, severe adverse events, and withdrawal to drug when compared with PPI.

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Tofacitinib vs Ustekinumab -Which is Better for Ulcerative Colitis?

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RS Dalal et al. Inflammatory Bowel Diseases, Volume 30, Issue 3, March 2024, Pages 395–401. 1-Year Comparative Effectiveness of Tofacitinib vs Ustekinumab for Patients With Ulcerative Colitis and Prior Antitumor Necrosis Factor Failure

In this real-world cohort of anti-TNF-exposed patients with ulcerative colitis, tofacitinib (n=69) and ustekinumab (n=97) demonstrated similar effectiveness in achieving steroid-free clinical remission (SCFR) at 12 and 52 weeks. The median follow-up was 88.0 and 62.0 week, respectively. 35 of 66 in the tofacitinib cohort had dose reduction from the starting dose of 10 mg twice daily. This reduction occurred at a mean of 144 days. 59 of 97 in the ustekinumab cohort received either Q4W dosing (n=43) or Q6W (n=16).

Key findings:

  • 53% of patients receiving tofacitinib and 32% of patients receiving ustekinumab achieved SFCR at 12 weeks. Tofacitinib-treated patients had higher baseline Mayo endoscopic subscores and CRPs.
  • At 52 weeks, approximately 50% of patients in both treatment groups achieved SFCR. There were also high proportions (>60%) of patients in both treatment groups who had endoscopic response within 52 weeks.
  • Both drugs were well-tolerated, as only 1 patient in each treatment group discontinued therapy due to an AE during >260 patient-years of follow-up.

My take: This shows similar response to either tofacitinib and ustekinumab in a cohort that had refractory disease as patients were anti-TNF failures and most had prior vedolizumab as well.

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Autoimmune Hepatitis, Horseshoes and Hand Grenades

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“Close don’t count in baseball. Close only counts in horseshoes and hand grenades.” –Frank Robinson 1973.

This study used the the International Autoimmune Hepatitis Group retrospective registry (IAIHG-RR), a web-based platform. This retrospective, observational, multicenter study analyzed 2559 patients; however, only 1700 had adequate follow-up. A complete biologic response (CBR) was defined as normalization of aminotransferases and serum IgG within 6 months; only 706 had serial results of these parameters to assess for a CBR.

Key findings:

  • Among the 706 with adequate data, 68.5% achieved a CBR.
  • Non-White ethnicity (HR 4), cirrhosis (HR 3.5), variant syndrome with primary sclerosing cholangitis (PSC) (HR 3.1), and lack of complete biochemical response within 6 months (HR 5.7) were independent prognostic factors.
  • Patients with a CBR had a greater actuarial survival over a 20-year period (91%) compared to those without a CBR (61%). Lack of a CBR at 6 months conferred a 3.6-fold higher risk of progression to cirrhosis.
  • Even in patients with cirrhosis, a CBR increased long-term survival: 82% versus 34%.

My take: A CBR is associated with the best long-term outcomes. My suspicion is that a biochemical response is actually similar to horseshoes. Improvement with treatment is likely beneficial but not as good as hitting the stake (the target).

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Algae and Liver Cancer

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M Ledenko, SO Antwi, T Patel. Hepatology 2024; 79: 575-588. Geospatial analysis of cyanobacterial exposure and liver cancer in the contiguous United States

Cyanobacteria are commonly found in water bodies and their production of hepatotoxins can contribute to liver damage.

Methods: Across the contiguous United States, regions with high cyanobacteria exposure (CE) counts in water bodies were identified using satellite remote sensing data. The data were geospatially mapped to county boundaries, and disease mortality and incidence rates were analyzed.

Key findings:

  • There was a highly significant spatial association between CE, liver disease, and liver cancer. In Figure 4, the counties in the top half of CE had higher liver cancer. The mean CE 569.6 in the top half compared with median counts of CE of 319.5 in the bottom half of CE
  • Counties with CE exceeding the 80Th percentile for >8 or more years had as significantly higher liver cancer age-adjusted incidence rate (mean 9.48) compared with that did so for 5 or fewer years (mean=8.79)
  • Hot spots of CE and mortality were identified along the Gulf of Mexico, eastern Texas, Louisiana, and Florida, and cold spots across the Appalachians. 
  • Cyanotoxins were detected in 62% of US counties using remote sensing.

My take: This study shows an association between areas with higher CE exposure and increased risk of liver cancer. This could be mediated via contaminated water exposure.

What Is Driving Hospitals’ Acqui$ition of Physician Practices?

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D Khullar et al. NEJM 2024; 390: 965-967. Vertical Integration and the Transformation of American Medicine

This article examines the growing trend of hospital acquisition of physician practices.

Some excerpts:

  • “From July 2012 through January 2018, the share of practices owned by a hospital increased from 14% to 31%, according to data from the Physicians Advocacy Institute; from January 2019 to January 2022, hospitals acquired 4800 additional practices, and about 58,000 more physicians became hospital employees.”
  • “In theory, vertical integration (the combining of organizations operating at different levels of production into a single entity) in health care can lead to improved patient outcomes — for example, by promoting care coordination, information exchange, and economies of scale. To date, however, the most consistent documented effect of such transactions has been an increase in prices.”
  • Increased prices are due to multiple factors including strengthened negotiating position, “facility fees” that are added to services delivered by hospital-owned practices.1, increased tests and procedures in hospital settings, higher payor rates, and in many cases discounted outpatient drug prices (for those qualified in 340B program)
  • “The limited research in this area suggests that vertical integration doesn’t tend to result in meaningful improvements in quality of care, with some studies finding that it may lead to poorer quality, if health systems take resources away from unprofitable services and redistribute them to more lucrative ones.2“
  • “Hospital acquisitions of physician practices have gone largely unreviewed by agencies such as the Federal Trade Commission (FTC) and the Department of Justice (DOJ)…In December 2023, the FTC and the DOJ issued new antitrust guidelines that could strengthen the agencies’ approach to vertical integration in health care “
  • “Many clinicians may be satisfied after their practice is acquired; they may, for example, have an improved work–life balance, receive greater administrative support, and be relieved of managing the business-related aspects of medicine. Alternatively, they may work longer hours, have less autonomy and constrained job mobility, and experience more burnout or moral injury.”
  • “The rapid acquisition of physician practices by hospitals highlights an important tension in health care — between the possibility that integration can promote efficiency and improved quality and the concern that it distorts markets and can worsen health and financial outcomes.”

My take: There are clear financial incentives for hospitals to acquire physician practices. This trend leaves patients facing higher costs and clinicians dealing with less autonomy. Regulatory efforts face a difficult task to limit this widespread anti-competitive practice which at this point is akin to extracting a large trichobezoar from the stomach.

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AGA Guidance: Nutritional Therapies for Inflammatory Bowel Disease

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JG Hashash et al.Gastroenterology 166; 521-532. Open Access! AGA Clinical Practice Update on Diet and Nutritional Therapies in Patients With Inflammatory Bowel Disease: Expert Review

There are 12 “best practice” recommendations. Here are a few of them:

  • Best Practice Advice 1: Unless there is a contraindication, all patients with IBD should be advised to follow a Mediterranean diet rich in a variety of fresh fruits and vegetables, monounsaturated fats, complex carbohydrates, and lean proteins and low in ultraprocessed foods, added sugar, and salt for their overall health and general well-being. No diet has consistently been found to decrease the rate of flares in adults with IBD. A diet low in red and processed meat may reduce ulcerative colitis flares, but has not been found to reduce relapse in Crohn’s disease.
  • Best Practice Advice 3: Exclusive enteral nutrition using liquid nutrition formulations is an effective therapy for induction of clinical remission and endoscopic response in Crohn’s disease, with stronger evidence in children than adults. Exclusive enteral nutrition may be considered as a steroid-sparing bridge therapy for patients with Crohn’s disease.
  • Best Practice Advice 6: In patients with IBD who have an intra-abdominal abscess and/or phlegmonous inflammation that limits ability to achieve optimal nutrition via the digestive tract, short-term parenteral nutrition may be used to provide bowel rest in the preoperative phase to decrease infection and inflammation as a bridge to definitive surgical management and to optimize surgical outcomes.
  • Best Practice Advice 7: We suggest the use of parenteral nutrition for high-output gastrointestinal fistula, prolonged ileus, short bowel syndrome, and for patients with IBD with severe malnutrition when oral and enteral nutrition has been trialed and failed or when enteral access is not feasible or contraindicated.
  • Best Practice Advice 10: All patients with IBD should be monitored for vitamin D and iron deficiency. Patients with extensive ileal disease or prior ileal surgery (resection or ileal pouch) should be monitored for vitamin B12 deficiency.
  • Best Practice Advice 12: Breastfeeding is associated with a lower risk for diagnosis of IBD during childhood. A healthy, balanced, Mediterranean diet rich in a variety of fruits and vegetables and decreased intake of ultraprocessed foods have been associated with a lower risk of developing IBD.

AGA has a summary and video here: What you need to know about diet and nutritional therapies for IBD patients

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End of the Line for Probiotics for Preterm Infants

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9/29/23 FDA: Risk of Invasive Disease in Preterm Infants Given Probiotics Formulated to
Contain Live Bacteria or Yeast

“The FDA cautions that microorganisms contained in probiotics have been reported in the medical literature as causing bacteremia or fungemia, sometimes with a severe clinical course, in very preterm or very low birthweight (VLBW) infants.”

“Moreover, the American Academy of Pediatrics states ‘Given the lack of FDA-regulated pharmaceutical grade products in the United States, conflicting data on safety and efficacy, and potential for harm in a highly vulnerable population, current evidence does not support the routine, universal administration of probiotics to preterm infants, particularly those with a birth weight of <1000 g.’”

“The FDA is also reminding healthcare providers that FDA has not approved any probiotic product for use as a drug or biological product in infants.”

My take: Despite promising studies (over the last 20 years) indicating that probiotics reduce the risk of necrotizing enterocolitis and death, this appears to be the end of the line for the use of probiotics for preemies in the U.S. To change course, there would need to be a pharmaceutical-grade probiotic and proof that it was a reliable high-quality agent meeting FDA standards along with subsequent studies showing this probiotic was effective.

Reference: Poindexter B. Use of probiotics in preterm infants. Pediatrics 2021;147(6):June 2021:e2021051485. https://publications.aap.org/pediatrics/article/147/6/e2021051485/180282/Use-of-Probiotics-in-PretermInfants

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