Resmetirom (Rezdiffra) -FDA Approved for MASH with Moderate to Advanced Fibrosis

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3/14/24: FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease

An excerpt:

“At 12 months, liver biopsies showed that a greater proportion of subjects who were treated with Rezdiffra achieved NASH resolution or an improvement in liver scarring as compared with those who received the placebo. A total of 26% to 27% of subjects who received 80 milligrams of Rezdiffra and 24% to 36% of subjects who received 100 milligrams of Rezdiffra experienced NASH resolution and no worsening of liver scarring, compared to 9% to 13% of those who received placebo and counseling on diet and exercise…n addition, a total of 23% of subjects who received 80 milligrams of Rezdiffra and 24% to 28% of subjects who received 100 milligrams of Rezdiffra experienced an improvement in liver scarring and no worsening of NASH, compared to 13% to 15% of those who received placebo, depending on each pathologist’s readings.”

“The most common side effects of Rezdiffra included diarrhea and nausea. Rezdiffra comes with certain warnings and precautions, such as drug-induced liver toxicity and gallbladder-related side effects. Use of Rezdiffra should be avoided in patients with decompensated cirrhosis.”

My take: It is good to finally have an FDA-approved medication for MASH (in adults). My speculation is that medications which achieve persistent weight loss will have a more pronounced effect on liver health and overall health.

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Colorado River near Moab, Utah

Jose Garza: What’s New in Motility (Part 2)

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Dr. Jose Garza joined our group in 2013 and has been providing excellent care for children throughout the South with suspected motility disorders. Recently, he gave our group a fabulous update on what’s new in motility.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of his slides.

FLIP -How Distensible is the Esophagus

  • Distensibility index less than 2 mm2/mmHg is considered abnormal.
  • Normal FLIP (presence of RACs and normal Distensibility Index) can obviate need for high resolution esophageal manometry (HREM)
  • FLIP during anesthesia can only be done with certain medications: versed, fentanyl and propofol (no gas)
  • FLIP  is useful  in evaluating if symptoms after achalasia treatment, during achalasia treatment (dilatation or Heller), if symptoms after fundoplication, and if manometry uncertain

IB-Stim

Unable to Belch ( (Retrograde Cricopharyngeus Dysfunction)

Sitz Markers

  • Guideline published suggest single xray on day 5 (usually off treatment). Cleanout recommended (especially if impacted)
  • Useful for non-retentive fecal soiling as well

Vibrating capsule

Fecobionic

  • Emerging technology to help provide more data on defecation dysfunction

Medications:

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.

Jose Garza: What’s New in Motility (Part 1)

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Dr. Jose Garza joined our group in 2013 and has been providing excellent care for children throughout the South with suspected motility disorders. Recently, he gave our group a fabulous update on what’s new in motility.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included some of his slides. His talk had 123 slides; true motilists would be appalled that I haven’t included more of the high resolution tracing slides (though there are a few tomorrow).

Reflux:

Colic:

BRUE:

Laryngomalacia/Thickening:

Impedance

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.

Environmental Impact of Endoscopy

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M Desai et al. Gastroenterol 2024; 166: 496-502. The Environmental Impact of Gastrointestinal Procedures: A Prospective Study of Waste Generation, Energy Consumption, and Auditing in an Endoscopy Unit

This study prospectively collected data on total waste generation, energy consumption, and the role of intraprocedural inventory audit of a single tertiary care academic endoscopy unit over a 2-month period (May–June 2022, 450 procedures).

Key findings:

  • The total waste generated during the study period was 1398.6 kg (61.6% directly going to landfill, 33.3% biohazard waste, and 5.1% sharps), averaging 3.03 kg/procedure.
  • The average waste directly going to landfill was 219 kg per 100 procedures. The estimated total annual waste generation approximated the size of 2 football fields (1-foot-high layered waste). 
  • Endoscope reprocessing generated 194 gallons of liquid waste per day, averaging 13.85 gallons per procedure.
  • Thus, every 100 GI endoscopy procedures (esophagogastroduodenoscopy/colonoscopy) was associated with 303 kg of solid waste and 1385 gallons of liquid waste generation 
  • 20% of total waste consisted of potentially recyclable items (8.6 kg/d) that could be avoided by appropriate waste segregation of these items.

My take: The huge amount of trash (solid and liquid) generated by endoscopy is difficult to fathom. It is incumbent for gastroenterologists to consider this hidden extra cost. Recycling could help in a modest way. Trying to limit low-value procedures is another step. Long-term alternative diagnostic procedures will need to be developed/utilized which reduce the environmental impact.

Atlanta Botanical Gardens

Genetic Testing for Pediatric Acute Liver Failure of Indeterminate Origin

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D Lenz et al. Hepatology 2024; 79: 1075-1087. Open Access! Genetic landscape of pediatric acute liver failure of indeterminate origin

Background: ” In US and European cohorts, the underlying etiology [of PALF] remained unclear in about half of cases, hampering clinical management including disease-specific therapies, particularly decision-making regarding liver transplantation.” The associated editorial (pg 970-972) by Squires and Horslen note that standardized evaluation of PALF can lower the indeterminate cases to ~30%.

This study had 96 authors! (I think). In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. 

Key findings:

  • Whole-exome sequencing (WES) established a genetic diagnosis in 37% of cases (97/260)
  • Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%)
  • Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. The underlying pathophysiologies in those with abnormal WES were mitochondrial diseases (45%) and disorders of vesicular trafficking (28%)

Discussion points:

  • 55% of patients in this series had no evidence of an underlying genetic disorder. “According to Squires et al,32 the fraction of PALF cases with unknown etiology is particularly high in the first 3 years of life, which is the age range in which our study demonstrates the highest molecular diagnostic yield by WES.”
  • Rapid turnaround of genetic testing is essential in order to have an important clinical impact. A “short period of time as the clinical situation typically is critical and decisions are time-sensitive.” Yet the editorial noted that “rapid” testing in most laboratories require 1-6 months.

My take: Genetic testing is important for indeterminate PALF and may help in determining whether to proceed with a liver transplant.

Related blog post: Bookmark This Article on Pediatric Acute Liver Failure

Dale Chihuly Glass Art
This is a cup that Jay Hochman made!

How Trientine and Penicillamine Work: Cool Visual Study

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FT Kirk et al. Hepatology 2024; 79: 1065-1074. Open Access! Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64Cu PET/CT study in healthy humans

Background: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN.

Key findings and conclusions:

  • “TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI.”
  • ” TRI (n=8) reduced hepatic 64Cu activity 1 hour after 64Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p<0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p<0.02, indicating strong inhibition of intestinal 64Cu absorption.”
  • “PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p<0.04.”
  • “The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.”

My take: This is a cool study!

Related blog post: Practice Guidance on Wilson Disease (AASLD) (2023)

Cost Transparency Rules Not Implemented for GI Procedures

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GastroEndoNews 3/28/24: (Open Access!) Mandated Cost Transparency Requirement For GI Procedures Is Not Being Met

Excerpts:

Three years after the Hospital Price Transparency Rule was implemented by the Centers for Medicare & Medicaid Services, a large proportion of hospitals are not complying when it comes to gastrointestinal services, according to two studies presented at the 2023 annual meeting of the American College of Gastroenterology.

When institutions do list their prices, they are often hard to find, and the wide variety of charges are frequently listed in a format that is “not patient-friendly,” according to investigator Kevin Brittan, MD, an internal medicine resident at the University of Nebraska Medical Center, in Omaha…

All hospitals are expected to be in compliance with the rule and report prices for these and other procedures as of Jan. 1, 2021. However, in one study, Dr. Brittan and his co-investigators found that only two of 25 [top-rated] hospitals surveyed (8%) reported costs for all eight procedures evaluated (abstract P4083). In the other study, from Howard University researchers, 14 of 30 hospitals (47%) provided some costs for four procedures, but only 10 (30%) provided cost information for all of them (abstract P4091)...

[They] also found “extreme variance” between institutions in the costs cited, raising the question of whether the reported data are even reliable. “There was a 51-fold difference found in the price for an upper endoscopy and a greater than 80-fold difference for a colonoscopy,” Dr. Bhayana reported. Self-pay colonoscopy prices, for example, ranged from $440 to more than $36,000...

Approximately 11 million colonoscopies and 6.1 million upper endoscopies performed each year in the United States, Dr. Brittan said. He calculated that the price differences would equate to billions of dollars if procedures were performed at top centers offering the lowest prices relative to top centers asking the highest prices.

My take: So far, the hospital price transparency has been ineffective. Patients should be able to find out more readily what the costs are prior to receiving a bill. Unfortunately, this appears to be years away. To implement price transparency will require either enforcement (penalties) and/or litigation.

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Long Duration of Eosinophilic Esophagitis Associated with a Stiff Esophagus

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IK Araujo et al. Clin Gastroenterol Hepatol 2024; 22: 513-522. The Severity of Reduced Esophageal Distensibility Parallels Eosinophilic Esophagitis Disease Duration

This study of 171 adult patients (mean age 38 years) who had FLIP at time of an EGD determined the degree of esophageal distensibility and its association with eosinophilic esophagitis disease duration.

Key findings:

  • The median symptom duration was 8 (interquartile range, 3–15) years and diagnostic delay was 4 (interquartile range, 1–12) years
  • Symptom duration and diagnostic delay were negatively correlated with distensibility plateau (DP) (rho = –0.326 and –0.309; P values < .001)
  • Abnormal esophageal distensibility (DP ≤17 mm) was more prevalent with increased duration of symptoms (P < .004): 23% at <5 years to 64% at ≥25 years
  • Patients with ≥15 eos/hpf had significantly lower DP with greater symptom duration (P = .004), while there was not a significant difference among patients with <15 eos/hpf (P = .060).

My take: Longer duration of disease increases the risk of esophageal fibrosis and lack of distensibility. We need better tools to predict who is at most risk for developing fibrosis.

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Pictograms for Gastroduodenal Symptoms Fall Short

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G Humphrey et al. J Pediatr 2024; 267: 113922. Open Access! Designing, Developing, and Validating a Set of Standardized Pictograms to Support Pediatric-Reported Gastroduodenal Symptoms

The authors attempted to develop useful pictograms to help enable standardization of symptom reporting in children with gastroduodenal disorders.

Figure 2: Pediatric gastroduodenal symptom pictograms. A, stomach burn; B, upper gut pain; C, heartburn; D, nausea; E, reflux; F, vomiting; G, belching; H, bloating; I, excessively full; and J, early satiety. (The same images were used to create the animated set).

Key findings:

  • Face and content validity were higher for the pediatric static and animated pictogram sets compared with pre-existing adult pictograms (78% vs 78% vs 61%).
  • Participants with worse gastric symptoms had superior comprehension of the pediatric pictograms (χ2 [8, N = 118] P < .001)
  • “Little significant comprehension was gained by having the animated pictograms.”

My take: Some research while worthwhile does not pan out. This is what I was thinking when I read this study. Upper GI symptoms are difficult to convey in pictures; in addition, some patients will have multiple overlapping symptoms. This is why the validity percentages are not higher. I don’t foresee using these pictograms in clinical practice.

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Upadacitinib vs Ustekinumab for Ulcerative Colitis

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RS Dalal et al. Clin Gastroenterol Hepatol 2024; 22: 666-668. Comparative Effectiveness of Upadacitinib vs Ustekinumab for Ulcerative Colitis: A Multicenter Retrospective Cohort Study

This was a multicenter retrospective cohort study of adults with ulcerative colitis comparing upadacitinib (n=70) to ustekinumab (n=148). The upadacitinib-treated patients were all bio-exposed, had more advanced therapy failures, and higher baseline SCCAI (simple clinical colitis activity index).

Key findings:

  • Upadacitinib-treated patients had better outcomes: Clinical response of 82.9% vs. 63.5%, Steroid-free clinical remission 62.1 % vs. 34.7%, improvement in arthralgia 64.3% (9 of 14) vs 23.4% (11 of 47), and endoscopic remission 37.5% (9 of 24) compared with 15.9% (7 of 44).
  • The odds ratio (OR) after inverse probability of treatment-weighting were in favor of upadacitinib: Clinical response OR 2.39, SFCR OR 3.17, and endoscopic remission OR 5.10
  • Similar amounts of adverse effects were reported in each group

My take: Upadacitinib had better response rates within 52 weeks even though the patients receiving this medication had more advanced therapy failures. However, it is important to keep in mind the limitations of this retrospective study. The improved outcomes are in contrast to a study comparing another JAK inhibitor (tofacitinib) to ustekinumab in which the outcomes appeared equivalent (Tofacitinib vs Ustekinumab -Which is Better for Ulcerative Colitis?).

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Heron at Azalea Park (Sandy Springs, GA)