“The risk associated with multiple cancers, cardiovascular disease, diabetes, and all-cause mortality is decreased in individuals who meet the current recommendations for physical activity…Over time, the associated metabolic stress of each individual exercise bout provides the basis for long-term adaptations across tissues, including the cardiovascular system, skeletal muscle, adipose tissue, liver, pancreas, gut, and brain. Therefore, regular exercise is associated with a plethora of benefits throughout the whole body, including improved cardiorespiratory fitness, physical function, and glycemic control. Overall, we summarize the exercise-induced adaptations that occur within multiple tissues and how they converge to ultimately improve cardiometabolic health.”
JCT Lai et al. NEJM 2023; 389: 2377-2385. Case 39-2023: A 43-Year-Old Woman with Chronic Diarrhea, Hair Loss, and Nail and Skin Changes
This case presents a polyposis disorder seen in adults and provides a useful differential diagnosis: autoimmune disorders including IBD, vasculitis, and celiac, primary adrenal insufficiency, heavy metal poisoning, amyloidosis, and cancer. This rare disorder has a reported “5-year mortality of 55%, mostly due to complications such as sepsis and gastrointestinal bleeding”
A few of the images from Figure 2:
Numerous sessile polyps in colonFrom Stomach
ChatGPT’s explanation of Cronkhite-Canada Syndrome:
Cronkhite-Canada syndrome (CCS) is a rare, noninherited, sporadic gastrointestinal polyposis syndrome that affects various parts of the digestive system. It is characterized by the presence of multiple polyps in the stomach and colon, as well as other distinctive features.
Epidemiology: Cronkhite-Canada syndrome is a very rare disorder, with only a few hundred cases reported worldwide. It typically affects older adults, with an average age of onset around 60 years, and there is no known genetic predisposition.
Clinical Presentation: Patients with Cronkhite-Canada syndrome often present with a combination of gastrointestinal and dermatological symptoms. The gastrointestinal manifestations include diarrhea, abdominal pain, weight loss, and protein-losing enteropathy. The dermatological symptoms consist of characteristic changes such as nail atrophy, hyperpigmentation, alopecia (hair loss), and skin hyperpigmentation.
Gastrointestinal Findings:
Polyposis: Multiple [hamartomotous] polyps are found in the stomach and colon. These polyps can vary in size and number.
Diarrhea and Abdominal Pain: Chronic diarrhea and abdominal pain are common symptoms due to the involvement of the digestive tract.
Dermatological Findings:
Nail Changes: Nail atrophy, ridges, and splitting are commonly observed.
Skin Changes: Hyperpigmentation of the skin, especially on the palms and soles, is a distinctive feature.
Alopecia: Hair loss is often present.
Laboratory Findings: Patients with Cronkhite-Canada syndrome may exhibit laboratory abnormalities, including hypoalbuminemia (low levels of albumin in the blood), hypoproteinemia, and electrolyte imbalances due to protein loss in the gastrointestinal tract.
Diagnosis: Diagnosis is based on a combination of clinical presentation, endoscopic findings, and pathology results from biopsies of the affected gastrointestinal tissue.
Treatment: Management of Cronkhite-Canada syndrome involves a multidisciplinary approach. Nutritional support is essential, and patients may require supplementation of protein and nutrients. Corticosteroids are often used to suppress inflammation, and immunosuppressive agents may be considered in refractory cases. Regular surveillance endoscopy is necessary to monitor polyp growth and assess response to treatment.
This study analyzed “pH impedance testing in the NICU in 516 infants with symptoms of arching and irritability. A nurse was assigned to document episodes of arching and irritability during the study.”
Key findings:
Acid reflux and impedance bolus characteristics were not significantly different between infants with >72 and ≤72 arching/irritability events (P ≥ .05)
Arching/irritability events had an 8% sensitivity for reflux (3062/39,962). The specificity of arching/irritability for NOT being reflux was 94% (246,462/262,534)
Oral feeding was associated with more arching and irritability than tube feeding
“The study found that <10% of the clinical episodes were associated with acid reflux but episodes of arching and irritability were more common in infants with preterm birth, neurologic injury, or chronic lung disease.”
My take (in part, borrowed from authors): “Acid GER disease is unlikely the primary cause of arching/irritability and empiric treatment should not be used when arching/irritability is present.” Unfortunately, getting physicians to curtail the use of ineffective acid blockers in infants is a not making headway (Unfavorable Trends in Reflux Management of Infants) There is definitely enough material with reflux to devote a whole MythBusters show.
In addition to not being the main reason for arching,
Reflux is not a frequent reason for BRUEs
Reflux cannot be reliably-identified by ENTs. Red airway appearance is NOT indicative of reflux (poor specificity, poor sensitivity)
Reflux in infants does not improve with PPIs (more than placebo)
Fundoplication does not result in fewer hospitalizations or improve pulmonary outcomes
Treating reflux does not improve asthma and probably does not help throat symptoms either
Many kids (and adults) with “reflux” don’t have reflux
T Watson, C Robertson. NEJM 2023; 389; 25: 2312-2314. Silencing the FDA’s Voice — Drug Information on Trial
Recently (9/1/23), “a panel of the Fifth Circuit Court of Appeals allowed a case to proceed against the Food and Drug Administration (FDA) concerning its public statements on the use of ivermectin for treating Covid-19.1“ Even though a district court had dismissed the suit due to “sovereign immunity,” the Fifth Court stated the FDA had exceeded its authority.
Some excerpts from this commentary:
Between August 2021 and April 2022, however, the agency released several public messages about ivermectin and Covid-19 — including an informal consumer update titled “Why You Should Not Use Ivermectin to Treat or Prevent COVID-19”…
Three physicians who prescribed and promoted ivermectin for Covid-19 treatment sued the FDA, alleging that its statements interfered with their ability to practice medicine and harmed their professional reputations, even though they hadn’t been named by the FDA. One doctor claimed the agency’s statements had caused him to be referred to his state medical board; the others claimed to have lost admitting privileges at a hospital and a role at a medical school.
According to the Fifth Circuit, the FDA “has authority to inform, announce, and apprise — but not to endorse, denounce, or advise”….
The Fifth Circuit panel’s opinion is puzzling in light of the FDA’s long-standing and generally unquestioned role as a public health educator. The agency routinely releases consumer-directed information; for example, its website instructs consumers about the appropriate use of antibiotics and includes related clinical information. The opinion suggests the FDA may need to reevaluate each of these communications — an impractical proposition.
The opinion is also in tension with a long-standing constitutional principle known as the government speech doctrine, according to which the government can itself be a speaker, like any person or corporation, and isn’t required to be neutral when it expresses an opinion..
The Fifth Circuit’s holding reflects suspicion of agency influence, even in matters in which the agency is an expert speaking directly about products it regulates. The court’s interpretation of the FDA’s proper role may permit only narrow forms of expression...
Subsequent courts could use the Fifth Circuit’s logic to disempower other agencies with health-related missions, such as the Centers for Disease Control and Prevention and the Environmental Protection Agency… Meanwhile, “junk science” pervades social media and harms public health.2
My take: It is hard to believe that the justification for this challenge comes from three physicians prescribing ivermectin. It turns out the FDA’s advice was spot on and that these physicians were offering an ineffective therapy. This is a worrisome trend in which the judicial branch seeks
To limit government agencies without explicit line-by-line authorization by a dysfunctional congress
And to substitute its judgement over matters in which it has little expertise over governmental agencies tasked with protecting our country (eg. FDA, CDC, EPA, and others)
This research utilized 40 studies which met the eligibility criteria, including over 288 million participants and 147,668 patients with EoE from 15 countries across the five continents.
Key findings:
The global pooled incidence and prevalence of EoE were 5.31 cases per 100,000 inhabitant-years and 40.04 cases per 100,000 inhabitant-years, respectively.
The pooled prevalence and incidence of EoE were higher in high-income countries, males, and North America.
The pooled prevalence and incidence of EoE have increased from 1976 to 2022.
Time trends of incidence (A) and prevalence (B) of EoE, 1976 to 2022. Pooled estimates, cases per 100,000 inhabitant-years.
“This review summarizes the data leading to FDA approval for dupilumab and provides a practical approach for clinical use of dupilumab.” Dupilumab, a humanized monoclonal antibody that blocks interleukin (IL)-4 receptor alpha, is currently the only FDA-approved medication for EoE. It is noted that in the trials leading to FDA approval, all patients were PPI refractory and ~70% had received topical steroids (with about half either intolerant or nonresponsive).
Dosing: 300 mg weekly injection with a single-dose prefilled autoinjector pen or a syringe with a needle shield. It is recommended that refrigerated medicine is brought to room temperature for at least 45 minutes prior to injection. It “can remain unrefrigerated up to 14 days.”
In Figure 1, the articles details positioning of use of dupilumab in EoE management algorithm:
New diagnosis, patient preference
Additional atopic condition with approved dupilumab use (strong indication)
Lack of response to current treatment (diet, PPI, swallowed steroids) or adverse effects from current treatment (strong indications)
“It is reasonable to repeat endoscopy with biopsy 24 weeks after initiation of dupilumab in many patients…However, endoscopy may be completer earlier” in selected patients.
At least 5 other biologics are in phase 2 or phase 3 studies (listed in Table 1).
My take: EoE is increasing in prevalence and new therapies (often expensive) are emerging.
Also, there is a fairly good patient education 7-page pamphlet from the makers of Dupixent encouraging patients with symptoms suggestive of EoE to speak with their physicians.
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.
Patients diagnosed with nonerosive gastroesophageal reflux disease did not have a higher incidence of esophageal adenocarcinoma than the general population in a new study published in the BMJ.
This extensive population-based cohort study leveraged data spanning over three decades from national healthcare registries in Denmark, Finland and Sweden, known for their broad scope and high quality…
The incidence rate of EAC [esophageal adenocarcinoma] among 285,811 patients with nonerosive GERD (no esophagitis, Barrett’s esophagus or other esophageal condition), was 11.0 per 100,000 person-years, similar to that of the general population (BMJ 2023;382:e076017). Moreover, the rate remained stable regardless of the length of follow-up…
Harish K. Gagneja, MD, FACG, AGAF, FASGE, who was not involved in the research, commented that “patients with nonerosive GERD don’t require additional follow-up endoscopies unless they have alarm symptoms such as dysphagia, weight loss or anemia, etc.”…
The findings will need to be confirmed in well-designed studies from other countries. But the large sample size, population-based design, substantial duration of follow-up and inclusion of a contrasting erosive GERD cohort for validation are just some of the study’s strengths, supporting the validity of its findings.
My take: This study indicates that nonerosive reflux was not associated with an increased risk of esophageal adenocarcinoma.
Hydroxychloroquine (HCQ) was used off-label for COVID-19 during the first wave despite the absence of evidence documenting its clinical benefits. A recent study has estimated that it resulted in an increase death rate of 11%. ”The number of hydroxychloroquine related deaths in hospitalized patients is estimated at 16,990 in six countries.” Ref: Open Access! A Pradelle et al. Biomedicine & Pharmacotherapy 2024; 171: 116055. Deaths induced by compassionate use of hydroxychloroquine during the first COVID-19 wave: an estimate
Florida’s surgeon general on Wednesday called for a halt to the use of Covid vaccines, citing widely debunked concerns that contaminants in the vaccine can permanently integrate into human DNA.
Dr. Ladapo’s latest contention is “very irresponsible,” said John Wherry, a vaccine expert and director of the Institute for Immunology at the University of Pennsylvania. “He has, however, demonstrated a tenuous grasp of science and medicine in general over the course of the pandemic so this is not surprising,” Dr. Wherry said….
For Dr. Ladapo’s claim to be true, humans would need to have an enzyme that can incorporate foreign DNA into their genomes. “We don’t have one,” said Dr. Eric Rubin, a member of the F.D.A.’s vaccine advisory committee and the editor in chief of the New England Journal of Medicine.
My take: The first article estimates the number of deaths due to the bad advice of using hydroxychloroquine. Perhaps in a few years, researchers will be able to calculate the number of deaths and hospitalizations that occur due to the bad advice of Florida’s surgeon general.
Bernadette, my nurse, joined me and my wife at this year’s CCFA Torch Gala. Bernadette and I have worked together for more than 26 years -pretty soon she will have me trained.
Chen H, et al. NEJM 2023; 389: 1649-1659. Thalidomide for Recurrent Bleeding Due to Small-Intestinal Angiodysplasia
In this multicenter, double-blind, randomized, placebo-controlled trial, 150 adult patients underwent randomization: 51 to the 100-mg thalidomide group, 49 to the 50-mg thalidomide group, and 50 to the placebo group. Thalidomide has antiangiogenic activity, with inhibition of VEGF. It also has many adverse effects of thalidomide including peripheral neuropathy, fatigue, and teratogenic effects.
Key finding:
The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively
Discussion points -(from the associated editorial by Loren Laine): The data for thalidomide for small-intestinal angiodysplasia is “of higher quality than evidence for any other therapy for this indication. In addition,….thalidomide may be disease-modifying, with efficacy persisting after discontinuation. However, many clinicians will still use somatostatin analogues first” due to convenience and safety.
My take: I am glad this is a rare problem in pediatrics. I am not at all excited about using thalidomide.
The authors performed population pharmacokinetic (popPK) simulations to determine optimal dosing recommendations.
Key points:
Infliximab: “The Q2W SC dosing regimen of infliximab has been selected with the purpose of exceeding a C,trough,ss of 5 mg/L.” This tends to align with 5 mg/kg Q8W IV dosing.
Infliximab: “Patients on Q6W or Q8W IV infliximab can safely switch to Q2W SC infliximab…only patients on Q4W IV infliximab need Q1W SC dosing”
Vedolizumab: “Only patients on Q4W IV vedolizumab should switch to Q1W SC dosing”
Both agents: “Switching 4 instead of 8 weeks after the last IV dose can hit SS[steady state] faster, thereby avoiding the risk of temporary underexposure.”
My take: It is still important to see how switching from IV to SC route affects clinical outcomes in real-world cohorts. This study, though, does provide a good starting point when trying to provide the right dose frequency to achieve good therapeutic troughs.
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.
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