Are Gastroparesis and Functional Dyspepsia Part of the Same Problem?

A recent post (Is A Gastric Emptying Study Helpful in Children?) reviewed data in children indicating that gastric emptying study (GES) results did not correlate with symptom severity in children with functional dyspepsia (FD) symptoms.

Now a 12-year study in adults (n=944) (PJ Pasricha et al. Gastroenterol 2021; 160; 2006-2017. Full text: Functional Dyspepsia and Gastroparesis in Tertiary Care are Interchangeable Syndromes With Common Clinical and Pathologic Features) shows that FD is similar to gastroparesis in terms of clinical and pathological features and that diagnosis of these disorders were NOT fixed. Many patients with FD developed criteria of gastroparesis and many with gastroparesis were later reclassified as FD after followup GES.

Key findings:

  • At 48-weeks, 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis
  • In a subset of patients, full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206+ macrophages in both groups compared with obese controls.
  • The 48-week clinical outcomes were similar. Symptom severity remained “on average unchanged despite the change in gastric-emptying status”

My take (borrowed from authors): This study shows that “patients initially classified as one or the other are not distinguishable by clinical features or by follow-up assessment of gastric emptying…both disorders are unified by characteristic pathologic features, best summarized as a macrophage-driven “cajalopathy” of the stomach.”

While the authors state that a GES lacks reliability, the associated editorial argues that a GES may still be useful (J Tan et al. pg 1931. Full text: Gastroparesis: A Dead-end Street After All?) As individuals with delayed GE “fail to benefiit” from neuromodulators, a GES may influence treatment. However, they note that ACG guidelines indicate that a GES is not needed and all patients with dyspepsia symptoms can be treated in a “uniform sequence of proton pump inhibitors, tricyclic antidepressants and prokinetics as third-line therapy.”

Related blog posts:

Islamorada, FL

Gastric Emptying in Diabetes, Plus Two

Briefly noted: RK Goyal. NEJM 2021; 384: 1742-1751. Gastric Emptying Abnormalities in Diabetes Mellitus

This article provides insight into the topic of gastric emptying with a focus on patients with diabetes. A few key points:

  • Gastric emptying affects glucose homeostasis in patients with diabetes; delayed gastric emptying in patients with type 2 diabetes could have beneficial effects in this regard.
  • Delayed gastric emptying occurs in 40-47% of adults with diabetes; rapid emptying occurs in 20-22%.
  • Upper GI symptoms do NOT correlate with gastric emptying. Prevalence of these symptoms is highest in those with normal gastric emptying (43-52% in those with normal emptying compared with 19-28% with delayed emptying, and 20-37% with rapid emptying)
  • “Functional dyspepsia-like symptoms in gastroparesis may arise not through motility changes but rather through the parallel effects of oxidative stress and inflammation on nocireceptors and on other afferents that produce the symptoms.”

My take: Knowing how quickly the stomach empties rarely helps management. In this review, Dr. Goyal states that “the effective treatment of symptoms in diabetic gastroparesis may be similar to the treatment of functional dyspepsia.”

Also, noted in same issue of NEJM:

TB Corcoran et al. NEJM 2021; 384: 1731-1741. Dexamethasone and Surgical-Site Infection Key finding: A single dose of dexamathosone (8 mg) did not increase the risk of surgical site infection; this is in contrast to long-term glucocorticoid therapy which is a risk factor for infection and wound dehiscence.

J Salwa et al. NEJM 2021; 384: 1684-6. Designing an Independent Public Health Agency. This article makes compelling arguments for separating health agencies from political influence. The FDA, the CDC, and HHS in the previous administration were pressured and undermined. In contrast, the Federal Reserve Board, which has 14 year terms that require ‘removal only for cause,’ was “reliably [able to] exert federal power because of its institutional features as an independent agency.”

From TikTok -twitter feed: The GI Bleeding Paradox (58 secs -humor) @DGlaucomflecken#Gastroenterology#GI#MedTwitter

Gastric Electrical Stimulation For Refractory Vomiting, IBD Resources & MMWR COVID-19 Report

A recent yard sign from my wife for neighborhood walkers during the pandemic

P Ducrotte el al (Gastroenterol 2020; 158: 506-14, editorial 461-3) examined the use of an implanted gastric electrical stimulation (GES) in 172 patients in a randomized crossover trial (mean age 45 years).  GES device was implanted and left unactivated until patients were randomized in a double-blind manner to receive stimulation (for 4 months) or not.  Patients had vomiting that was either idiopathic, postsurgical or associated with diabetic gastroparesis (n=72).

Key findings:

  • A significant decrease in vomiting occurred with the device on based on a nonvalidated vomiting score.  During the ON period, vomiting was improved with score of 2.2 compared to vomiting score of 1.8 with device off.  30.6% of patients reported at least a 1 point improvement with device ON compared to device OFF.  However, 16.5% of patients reported improvement with device OFF compared to device ON.
  • Gastric emptying was not accelerated during treatment (device on) compared to no treatment
  • GES was NOT associated with increased quality of life
  • GES was not associated with improved nutritional parameters
  • Adverse effects included pain (n=26) or infection (n=16) at the insertion site of GES; 3 patients required GES removal.

My take (from editorial): “Taking into account the modest magnitude of therapeutic benefit, the cost of the treatment and the potential for adverse events with GES, it seems advisable to exhaust all (symptomatic) therapeutic options” beforehand.

Related blog posts:

IBD Resources (from David Rubin, MD):

COVID-19 March 2020: MMWR Report (Link to report from Bryan Vartabedian 33mail)

  • March 1-28 2020, 84% of hospitalized U.S. patients had underlying diseases -he most common being obesity, hypertension, chronic lung disease, diabetes mellitus, and cardiovascular disease.
  • Hospitalization rates increased with age, with a rate of 0.3 (per 100,000) in persons aged 0–4 years, 0.1 in those aged 5–17 years, 2.5 in those aged 18–49 years, 7.4 in those aged 50–64 years, and 13.8 in those aged ≥65 years

 

Trying to Understand Gastroparesis

…all I know is that I know nothing. –Socrates

Perhaps Socrates was a gastroenterologist.  So much of what we think we know, we are finding out is poorly understood.  This applies to gallbladder dyskinesia, sphincter of Oddi dysfunction and now gastroparesis.

A recent study (PJ Pasricha et al. Gastroenterol 2015; 149: 1762-74, commentary 1666-68) and commentary show how little we understand about gastroparesis.

The study was a large prospective surgery of 262 adult patients with gastroparesis (either diabetic or idiopathic).

Key findings:

  • 28% had improvement in the gastroparesis cardinal symptom index (GCSI) at 48 weeks.  Beyond 48 weeks, there were no significant reductions through week 192.
  • Favorable characteristics: male gender, age 50 and older, initial infectious prodrome (18% of cohort), antidepressant usage, and 4-hour gastric retention greater than 20%.
  • Unfavorable characteristics: obesity, smoking, use of pain modulators, moderate to severe abdominal pain, severe reflux, and moderate to severe depression.

The commentary suggests that those with the higher GCSI improved, in part, because of a regression toward the mean bias.  Other important commentary:

  • “More severely delayed gastric emptying was associated with a greater likelihood of improvement”
  • “There was no differences in outcome between diabetic or idiopathic gastroparesis.”
  • Gastric emptying tests are not reliable:  “Pathophysiologic tests are useful in clinical practice if they are reproducible, explain the symptoms, guide therapeutic choices, and determine response to therapy and long-term prognosis.  Despite its popularity, the gastric emptying test scores low on most of these criteria.”
  • “A metaanalysis found no correlation between the change in gastric emptying rate and the symptom response during prokinetic therapy…A 5-year prospective follow-up study of …functional dyspepsia…found that more than 50% improved…with no relation to the presence of delayed gastric emptying.”
  • “Using the term gastroparesis also can lead to premature closure in our efforts to understand the pathophysiology of symptoms…can lead to botulinum injections into the pylorus or placement of gastric stimulators (formerly called gastric pacemakers) for gastroparesis, both of which have been shown to be nonefficacious in controlled trials.”

My take: It is unclear “when to consider gastric emptying testing and how to use it in patient management.”  For the pediatric population, gastroparesis is more likely to be associated with a prodromal infection which increases the likelihood of recovery.

Related blog posts:

Banning Mills

Banning Mills

A 6-Year Study of Amitriptyline, Escitalopram, and Functional Dyspepsia

A recent theme on this blog has been the difficulty of studying inexpensive therapies.  The issue is that there are not strong incentives for pharmaceutical companies to invest in treatment trials when the potential for profits is meager.  Fortunately, there are other funding mechanisms.  A recent study (NJ Talley et al. Gastroenterol 2015; 149:340-9), sponsored by the NIH, still was challenging.  One of the reasons is that when medicines are already approved by the FDA that can be used off-label and this can undermine recruitment.

Due to difficulty with enrollment, the researchers of this current study expanded to a total of 8 sites (initially 5) and settled for 292 patients rather than their goal of 400.  After a baseline washout of 2- to 4-week with assessment, patients with Rome II criteria for functional dyspepsia (FD) were assigned in a randomized, double-blind trial to either placebo, amitriptyline 50 mg, or escitalopram 10 mg for 10 weeks.

Exclusion criteria:

  • History of depression and not using antidepressants.
  • Anxiety
  • Symptom resolution with antisecretory therapy (eg. proton pump inhibitors)
  • History of esophagitis, ulcers, or organic gastrointestinal disease
  • Major physical illness
  • Drug/alcohol abuse
  • Nonsteroidal anti-inflammatory drugs

Inclusion criteria:

  • Required: previous normal EGD within 5 years
  • 18-75 years

Key terms:

  • “ulcer-like dyspepsia” pain centered in the upper abdomen is the predominant symptom
  • “dysmotility-like dyspepsia” non pain symptom predominates: fullness, bloating, early satiety, and nausea

Key Findings:

  • Adequate relief was noted in 40% of placebo-treated, 53% of amitriptyline-treated, and 38% of escitalopram-treated patients
  • Ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief compared with placebo for odds ratio of 3.1
  • Delayed gastric emptying was associated with being less likely to report adequate relief with an odds ratio of 0.4
  • Safety: while adverse effects were common, “there was no overall difference between the 3 arms (except in neurologic symptoms, with highest rates in the escitalopram arm) suggesting that…TCAs will be generally well tolerated at low doses.”

The associated editorial (pages 270-2) notes that the overall benefits of amitriptyline were modest.  They also reviewed the NORIG study (JAMA 2013; 310: 2640-9) which examined nortriptyline and placebo for idiopathic gastroparesis (n=130).  Similar to this study from Talley et al, the NORIG study found a lack of response to tricyclic antidepressants in this cohort with delayed gastric emptying and dysmotility; “the lack of efficacy in patients with dyspepsia with delayed gastric emptying suggests the possible utility of scintigrahic testing to select patients” for amitriptyline therapy.

Bottomline: This well-designed study supports the use of amitriptyline, but not escitalopram for the use of FD, mainly in those with pain-predominant symptoms.

Related blog posts:

Mt Washburn, Yellowstone

Mt Washburn, Yellowstone

What to do with delayed gastric emptying/gastroparesis

More information for pediatric patients with the perplexing problem of poor gastric emptying is available in three articles:

JPGN 2012; 55: 166-72, 185-90, & 194-199.

The first study by Waseem et al describes the “Spectrum of Gastroparesis:”

  • Retrospective chart review included 239 eligible children with mean age of 7.9 years.  Nearly equal numbers of males and females. .
  • Time to empty half of solid or liquid considered abnormal if more than 45-90 minutes for solid and more than 60 minutes for liquid (labelled pediasure)
  • Etiology: idiopathic 70%, drug-induced 18%, postsurgical 12%
  • Treatment in 74% diet and erythromycin (74%)
  • Over 24 months, 60% had significant improvement regardless of treatment

The second study by Rodriguez et al is titled “Clinical Presentation, Response to Therapy, and Outcome of Gastroparesis in Children.”

  • Restrospective study with 230 children, mean age 9 years.  In adolescents, female gender was more common (77%) whereas in infants (n=36), male gender was more common (61%).  Most common causes were postviral in 42%, mitochondrial in 18%, and diabetes in 5%.
  • Delayed gastric emptying was defined as having solids or liquids emptying <40% of the meal at one hour.
  • Resolution occurred in 22% at 6 months, 53% at 18 months, and 61% at 36 months.  Median time to resolution was 14 months; though among resolvers, 84% did so by 12 months.
  • Presence of longer duration of symptoms and mitochondrial disorder was associated with lower rates of resolution.
  • Younger age and response to promotility agents increased likelihood of resolution
  •  Treatment with proton pump inhibitors (PPIs) were used in 79% as first-line agents; only 3% reported resolution of symptoms with PPIs.
  • Prokinetics: Domperidone (0.1-0.2mg/kg/dose qid to max of 10mg) in 33 patients. Tegaserod in 20 patients.  Metoclopropramide in 142 patients. Erythromycin (EES) in 40 patients (3-10 mg/kg/dose qid).  Of these agents, metoclopropramide was inferior with an 80% failure rate.  In contrast, EES was associated with symptom resolution in 5% and symptom improvement in 46%.  Domperidone was associated with symptom resolution in 26% and symptom improvement in 48%.

The third study by Bhardwaj et al highlights “Impaired Gastric Emptying and Small Bowel Transit in Children with Mitochondrial Disorders.”

  • Prospective study enrolled 26 subjects from mitochondrial clinic.  58 patients were screened but the majority were not eligible; the most common reasons included the following: 14 were receiving enteral feedings, 1 was receiving parenteral nutrition, 6 had no GI symptoms.
  • Delayed gastric emptying was considered if >50% at 90 minutes of a solid meal was present, at 60 minutes for semisolid, and at 40 minutes for liquid meal. For small bowel transit, delayed transit was considered if radiotracer had not reached cecum within 4 hours.  Severely prolonged transit was diagnosed if transit time exceeded 6 hours.
  • In this cohort, 18 (69%) had delayed gastric emptying and 12 (46%) had prolonged small bowel transit.  Common symptoms included abdominal pain and vomiting.
  • In the small numbers of patients who received prokinetics,there was a poor response.  One of three patients with bethanecol and two of five patients with metoclopropramide had normalized GE time; one patient treated with azithromycin continued with abnormal GE time

Additional references:

  • -Gastroenterol 2011; 140: 101.  Clinical features -mostly females, often incr BMI.  Defined as severe gastroparesis if >35% at 4hrs, moderate if 20-35%, and mild if <20%.
  • -Clincal Gastro & Hep 2011; 9: 5.  Review of diabetic gastroparesis & mgt.
  • -Clin Gastro & Hep 2009; 7: 823. Radiation from gastric emptying is ~10mrad, CXR is 12mrad, yearly background is 300mrad.
    Norms:
    1 hr 37-90%
    2 hr 30-60%
    4 hr 0-10%
  • -Gastroenterol 2009; 136: 1526.  Tests of gastric emptying -review.
  • -Clin Gastro & Hep 2008; 6: 1309. algorithm for nausea & delayed GE.  REC;
    1. small meals, low fiber/fat
    2. prokinetic: reglan, EES, ?domperidone
    3. Antiemetics: zofran, prochloroperazine
    4. TCA
    5. ?Botox injection
    6. jejunal feeds
  • -Gastroenterol 2009; 136: 1526.  Tests of gastric emptying -review.  Consider domperidone, reglan, ?gastric stimulation, ?surgery, discusses novel Rxs.
  • -Gastroenterol 2009; 136: 1225.  Review of prevalence and outcomes in Olmsted County.
  • -Am J Gastro 2008; 103: 416-23.  Botox is NOT effective for gastroparesis/delayed GE.
  • Need to distinguish delayed gastric emptying from rumination. Treatment for rumination and belching