Idiopathic Gastroparesis

Complex MONDO:0034150 Pathograph 19 Show in embeddings browser Gastroparesis

Idiopathic gastroparesis is a chronic gastric neuromuscular disorder in which upper gastrointestinal symptoms (cardinally nausea and vomiting, with early satiation, postprandial fullness, bloating and abdominal pain) occur with objectively delayed gastric emptying of a solid meal, in the absence of mechanical obstruction and after exclusion of diabetes, prior gastric surgery, medications and other identifiable causes. It is the largest etiological category of gastroparesis in referral series and predominantly affects young and middle-aged women. Full-thickness gastric biopsies show loss and ultrastructural injury of interstitial cells of Cajal, reduced nitrergic (nNOS) innervation, loss of anti-inflammatory CD206+ muscularis macrophages with a pro-inflammatory immune signature, and altered smooth muscle contractile gene expression, although how consistently these lesions explain delayed emptying or symptoms in the idiopathic form is unsettled. A subgroup begins acutely after a viral-like illness and usually improves over months; most other cases run a chronic course. Clinical and pathological features overlap extensively with functional dyspepsia, and treatment is largely symptomatic (dietary modification, metoclopramide or erythromycin, antiemetics, and gastric electrical stimulation or pyloric interventions for refractory disease). Diabetic gastroparesis, which shares the ICC and macrophage lesions, is outside the scope of this entry.

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7
Pathophys.
11
Phenotypes
3
Hypotheses
3
Gaps
19
Pathograph
9
Medical Actions
2
Subtypes
1
Deep Research
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Subtypes

2
Post-infectious (post-viral) gastroparesis
Gastroparesis beginning acutely after a viral-like illness (fever, myalgia, gastroenteritis) in a previously healthy person, sometimes with a documented agent such as cytomegalovirus or Epstein-Barr virus. It is regarded as a subgroup of idiopathic gastroparesis, is often accompanied by autonomic dysfunction, and usually improves or resolves over weeks to months.
Show evidence (2 references)
PMID:17716347 SUPPORT Human Clinical
"Post-infectious gastroparesis (PIGP) is a subgroup of idiopathic gastroparesis."
Case series establishing post-infectious gastroparesis as a subgroup of idiopathic gastroparesis.
PMID:2348727 SUPPORT Human Clinical
"postviral gastroparesis is uncommon, is frequently associated with autonomic dysfunction, and is associated with an apparently excellent prognosis"
Retrospective series describing the autonomic dysfunction and favorable course that distinguish the post-viral subgroup.
Chronic (insidious-onset) idiopathic gastroparesis
Idiopathic gastroparesis without an infectious prodrome, typically of insidious onset and running a slowly progressive or persistent course with greater symptom burden than the post-infectious subgroup.
Show evidence (1 reference)
PMID:9317072 SUPPORT Human Clinical
"Idiopathic gastroparesis is a more slowly progressive illness, and patients remain significantly more symptomatic for a longer period of time."
Comparison of viral and non-viral idiopathic gastroparesis showing the chronic, slowly progressive course of the non-viral group.
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Mechanistic Hypotheses

3
Loss of cytoprotective muscularis macrophages permits oxidative and inflammatory injury of interstitial cells of Cajal and nitrergic neurons
macrophage_oxidative_icc_injury EMERGING
Evidence balance 1 support
In diabetic mouse models, gastric muscularis macrophages that fail to sustain heme oxygenase-1 expression and shift to an inflammatory phenotype release reactive oxygen species and cytokines (IL-6, TNF) that injure interstitial cells of Cajal and reduce nNOS expression, producing delayed gastric emptying. Human idiopathic gastroparesis tissue shows the matching static lesions (CD206+ macrophage loss, ICC loss, reduced HMOX1 mRNA), so the same chain is proposed for the idiopathic form, but the causal steps have not been demonstrated in idiopathic disease.
Pathograph links
Muscularis Macrophage Phenotype Shift -> Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress INDIRECT UNKNOWN INTERMEDIATES Muscularis macrophages are the cells that upregulate heme oxygenase-1 in the diabetic stomach; loss of that upregulation raises reactive oxygen species. Shown in diabetic mice; inferred for idiopathic disease.
Muscularis Macrophage Phenotype Shift -> Interstitial Cell of Cajal Loss and Injury INDIRECT KNOWN INTERMEDIATES Inflammatory macrophage products (IL-6, TNF) damage ICC in cultured mouse gastric muscularis, and restoring macrophages to macrophage-deficient diabetic Csf1op/op mice with CSF1 led to delayed emptying and damaged ICC in most of them. Human biopsies show a correlation between CD206+ cell and ICC numbers across patients and controls, but the correlation was not found within the idiopathic group in the gastric body.
Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress -> Interstitial Cell of Cajal Loss and Injury DIRECT Inhibiting heme oxygenase-1 causes loss of Kit-positive ICC and delayed emptying, and inducing it restores Kit expression, in diabetic mice.
Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress -> Nitrergic Enteric Neuron Loss DIRECT Heme oxygenase-1 induction restores nNOS expression together with Kit in diabetic mice.
Show evidence (1 reference)
PMID:32718570 SUPPORT Other
"More recently, in animal models, macrophages have also been identified to play a central role in development of delayed gastric emptying. Activation of macrophages leads to loss of ICC. In human gastroparesis, loss of anti-inflammatory macrophages in gastric muscle has been shown."
Review summarizing the animal-model macrophage mechanism and the corresponding human biopsy finding.
Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
delayed_emptying_symptom_model CANONICAL
Evidence balance 1 support
The classical definition attributes nausea, vomiting, early satiety and fullness to delayed emptying of the stomach. It underlies the diagnostic requirement for a 4-hour gastric emptying test and the use of prokinetic and pyloric therapies.
Pathograph links
Interstitial Cell of Cajal Loss and Injury -> Impaired Gastric Neuromuscular Function DIRECT Loss of ICC networks disrupts slow-wave pacemaking. Restoring ICC networks normalizes slow waves and emptying in diabetic mice; in human idiopathic gastroparesis, ICC counts did not correlate with gastric retention although KIT transcript levels did.
Nitrergic Enteric Neuron Loss -> Impaired Gastric Neuromuscular Function DIRECT Loss of nitrergic input impairs pyloric relaxation and gastric emptying; shown in nNOS-deficient mice, where restoring nNOS-expressing neurons in the pylorus improves emptying.
Smooth Muscle Contractile Protein and PDGFRA+ Cell Loss -> Impaired Gastric Neuromuscular Function UNKNOWN Reduced contractile protein expression is expected to weaken antral contraction. No study has shown that this change delays emptying in idiopathic gastroparesis; the transcript changes correlated only weakly with fullness and satiety scores.
Impaired Gastric Neuromuscular Function -> Delayed Gastric Emptying DIRECT Disordered gastric neuromuscular function slows emptying of a solid meal.
Delayed Gastric Emptying -> Delayed gastric emptying on scintigraphy DIRECT
Delayed Gastric Emptying -> Vomiting INDIRECT UNKNOWN INTERMEDIATES Severe emptying delay is associated with worse vomiting in idiopathic gastroparesis; the association is modest and prokinetic acceleration of emptying does not predict symptom relief.
Delayed Gastric Emptying -> Poor appetite INDIRECT UNKNOWN INTERMEDIATES
Delayed Gastric Emptying -> Early satiety UNKNOWN Early satiety is a classic symptom attributed to gastric retention; impaired accommodation may contribute independently of emptying rate.
Delayed Gastric Emptying -> Postprandial fullness UNKNOWN Postprandial fullness is attributed to gastric retention, but correlates poorly with emptying rate.
Delayed Gastric Emptying -> Nausea UNKNOWN Nausea is the most common symptom and is related to meals in most patients, but symptom relief does not track acceleration of emptying.
Show evidence (1 reference)
PMID:39674226 SUPPORT Other
"This consensus defined idiopathic gastroparesis as the presence of symptoms associated with delayed gastric emptying in the absence of mechanical obstruction."
International consensus definition built on delayed emptying as the defining physiological abnormality.
Idiopathic gastroparesis is a gastric sensorimotor disorder on a spectrum with functional dyspepsia
gastric_sensorimotor_spectrum ALTERNATIVE
Evidence balance 2 support
Gastric emptying status is labile and correlates poorly with symptoms or with response to prokinetics, while idiopathic gastroparesis and functional dyspepsia share clinical features and the ICC and CD206+ macrophage lesions. This view places impaired accommodation, visceral hypersensitivity and gut-brain interaction alongside or in place of delayed emptying as the source of symptoms.
Show evidence (2 references)
PMID:33548234 SUPPORT Human Clinical
"FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders."
Consortium cohort showing that functional dyspepsia and gastroparesis are clinically and pathologically indistinguishable after a year.
PMID:24005344 SUPPORT REVIEW SYNTHESIS Human Clinical
"In this review, no evidence of a relationship between SI and GE was identified for different drugs used for the treatment of gastroparesis."
Meta-regression across prokinetic trials finds that symptom improvement does not track acceleration of gastric emptying.
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Discussions and Knowledge Gaps

3
What initiates the loss of interstitial cells of Cajal and the macrophage phenotype shift in idiopathic gastroparesis, where there is no hyperglycemia to drive oxidative stress?
KNOWLEDGE GAP OPEN ig_cause_of_icc_loss
Attached to
pathophysiology#Muscularis Macrophage Phenotype Shift pathophysiology#Interstitial Cell of Cajal Loss and Injury
The upstream trigger in diabetic gastroparesis is hyperglycemia-associated oxidative stress. No equivalent trigger is established for the idiopathic form. Candidates include antecedent viral infection (the post-infectious subgroup), autoimmunity (antinuclear antibodies in about 16% of idiopathic patients) and unrecognized neuropathic processes, none of which has been connected to the tissue lesion.
Show evidence (2 references)
PMID:34595805 SUPPORT Human Clinical
"Positive ANA was seen in 148 of 893 (17%) patients with gastroparesis, being similar in idiopathic (16% of 536 patients), T1DM (16% of 162), T2DM (18% of 147), and postfundoplication (19% of 48 patients) gastroparesis."
Autoimmune serology is present in a minority of idiopathic patients but is not specific to that etiology.
PMID:27344315 SUPPORT Human Clinical
"Gastric EV infection was frequently detected (82 %) in patients undergoing investigation for IGP."
Small uncontrolled series proposing gastric enterovirus infection as a trigger; it has not been replicated.
Does the macrophage, heme oxygenase-1 and oxidative-stress mechanism shown in diabetic mice operate in human idiopathic gastroparesis?
HUMAN MODEL MISMATCH OPEN ig_diabetic_model_extrapolation
Attached to
pathophysiology#Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress mechanistic_hypotheses#macrophage_oxidative_icc_injury
Every causal step of the macrophage to ICC chain was demonstrated in streptozotocin or NOD diabetic mice. Human idiopathic tissue reproduces the static lesions only partly: CD206+ macrophages are reduced and HMOX1 mRNA is lower, but the CD206-ICC correlation seen in diabetic patients was absent in idiopathic patients, a transcript study found no loss of KIT or ANO1, and ICC counts did not track gastric retention in idiopathic disease. There is no model of idiopathic gastroparesis itself.
Proposed experiments
Single-cell profiling of idiopathic gastroparesis muscularis
ig_muscularis_single_cell
Single-cell and spatial transcriptomics of full-thickness gastric biopsies from idiopathic gastroparesis, diabetic gastroparesis, functional dyspepsia and controls, measuring macrophage heme oxygenase-1 expression and oxidative-stress signatures next to ICC.
Would support
pathophysiology#Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress
Supporting outcome
  • Idiopathic tissue shows HO-1-deficient, inflammatory macrophages adjacent to injured ICC, with oxidative-stress signatures, as in diabetic models.
Refuting outcome
  • Idiopathic tissue shows ICC injury without macrophage HO-1 loss or oxidative-stress signatures.
Show evidence (1 reference)
PMID:25041465 SUPPORT Human Clinical
"Depletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes."
The human evidence for macrophage cytoprotection of ICC is specific to diabetic patients.
Is delayed gastric emptying the cause of symptoms in idiopathic gastroparesis, or a labile marker of a broader gastric sensorimotor disorder shared with functional dyspepsia?
CONTROVERSY OPEN ig_emptying_symptom_correlation
Attached to
pathophysiology#Delayed Gastric Emptying mechanistic_hypotheses#gastric_sensorimotor_spectrum
About 40% of patients change between the gastroparesis and functional dyspepsia categories on repeat emptying testing within a year without any change in symptoms, 86% of idiopathic gastroparesis patients meet functional dyspepsia criteria, and acceleration of emptying by prokinetics does not predict symptom relief.
Show evidence (2 references)
PMID:33548234 SUPPORT Human Clinical
"The 48-week clinical outcome was also similar but at this time 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."
Gastric emptying category is unstable on retesting.
PMID:20965184 SUPPORT Human Clinical
"A total of 86% met criteria for functional dyspepsia, primarily postprandial distress syndrome."
Most idiopathic gastroparesis patients also meet functional dyspepsia criteria.
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Pathophysiology

7
Muscularis Macrophage Phenotype Shift
The gastric muscularis propria of patients with idiopathic gastroparesis shows loss of anti-inflammatory CD206+ macrophages in the circular muscle and myenteric plexus without a fall in total CD45+ immune cells, with an immune infiltrate containing macrophages and enrichment of transcripts associated with pro-inflammatory (M1) macrophages.
Loss of cytoprotective muscularis macrophages permits oxidative and inflammatory injury of interstitial cells of Cajal and nitrergic neurons
CD206+ anti-inflammatory muscularis macrophage CL:0000890 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD206+ anti-inflammatory muscularis macrophage, annotated with M2 macrophage (CL:0000890). CL:0000890 is a cell type from the Cell Ontology. pro-inflammatory muscularis macrophage CL:0000863 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pro-inflammatory muscularis macrophage, annotated with M1 macrophage (CL:0000863). CL:0000863 is a cell type from the Cell Ontology.
macrophage activation GO:0042116 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated macrophage activation (GO:0042116). GO:0042116 is a biological process from the Gene Ontology. ↕ DYSREGULATED
gastric antrum muscularis UBERON:0001165 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in gastric antrum muscularis, annotated with pyloric antrum (UBERON:0001165). UBERON:0001165 is an anatomical location from the Uberon multi-species anatomy ontology. myenteric plexus UBERON:0002439 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myenteric plexus, annotated with myenteric nerve plexus (UBERON:0002439). UBERON:0002439 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress Muscularis macrophages are the cells that upregulate heme oxygenase-1 in the diabetic stomach; loss of that upregulation raises reactive oxygen species. Shown in diabetic mice; inferred for idiopathic disease. Loss of cytoprotective muscularis macrophages permits oxidative and inflammatory injury of interstitial cells of Cajal and nitrergic neurons
Interstitial Cell of Cajal Loss and Injury Inflammatory macrophage products (IL-6, TNF) damage ICC in cultured mouse gastric muscularis, and restoring macrophages to macrophage-deficient diabetic Csf1op/op mice with CSF1 led to delayed emptying and damaged ICC in most of them. Human biopsies show a correlation between CD206+ cell and ICC numbers across patients and controls, but the correlation was not found within the idiopathic group in the gastric body. Loss of cytoprotective muscularis macrophages permits oxidative and inflammatory injury of interstitial cells of Cajal and nitrergic neurons
Nausea In idiopathic gastroparesis, patients with a myenteric immune infiltrate have more severe nausea and overall symptoms than those without one; the mechanism linking the infiltrate to nausea is unknown.
Show evidence (4 references)
PMID:28066953 SUPPORT Human Clinical
"Overall immune cell population (CD45) was unchanged but there was a loss of anti-inflammatory macrophages (CD206) in circular muscle"
Full-thickness antral biopsies from diabetic and idiopathic gastroparesis show loss of CD206+ macrophages with unchanged total immune cells.
PMID:30086735 SUPPORT Human Clinical
"Immune profile analysis revealed that genes associated with M1 (pro inflammatory) macrophages were enriched in tissues from idiopathic gastroparesis tissues compared to controls (p < 0.05)."
RNA sequencing of gastric body biopsies shows a pro-inflammatory macrophage signature specifically in idiopathic gastroparesis.
PMID:21300066 SUPPORT Human Clinical
"The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers."
NIDDK consortium biopsy study (20 idiopathic, 20 diabetic) reporting a macrophage-containing immune infiltrate.
+ 1 more reference
Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress
Failure to maintain heme oxygenase-1 expression in the gastric muscularis leaves the tissue exposed to reactive oxygen species. HMOX1 mRNA is reduced in the muscularis externa of idiopathic gastroparesis; the oxidative-stress consequence has been demonstrated in diabetic mice.
Loss of cytoprotective muscularis macrophages permits oxidative and inflammatory injury of interstitial cells of Cajal and nitrergic neurons
HMOX1 hgnc:5013 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HMOX1 (hgnc:5013). hgnc:5013 is a gene from the HUGO Gene Nomenclature Committee.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↕ DYSREGULATED
gastric muscularis externa UBERON:0008856 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in gastric muscularis externa, annotated with stomach muscularis externa (UBERON:0008856). UBERON:0008856 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Interstitial Cell of Cajal Loss and Injury Inhibiting heme oxygenase-1 causes loss of Kit-positive ICC and delayed emptying, and inducing it restores Kit expression, in diabetic mice. Loss of cytoprotective muscularis macrophages permits oxidative and inflammatory injury of interstitial cells of Cajal and nitrergic neurons
Nitrergic Enteric Neuron Loss Heme oxygenase-1 induction restores nNOS expression together with Kit in diabetic mice. Loss of cytoprotective muscularis macrophages permits oxidative and inflammatory injury of interstitial cells of Cajal and nitrergic neurons
Show evidence (2 references)
PMID:29052298 SUPPORT Human Clinical
"There was also a significant decrease in mRNA-encoding platelet-derived growth factor receptor α (PDGFRα) and its ligand PDGFB and in Heme oxygenase 1 in idiopathic gastroparesis subjects."
Reduced heme oxygenase-1 transcript in idiopathic gastroparesis muscularis externa.
PMID:18926825 SUPPORT Model Organism
"Loss of HO-1 up-regulation increased levels of reactive oxygen species."
In diabetic mice, loss of heme oxygenase-1 upregulation raises reactive oxygen species in the stomach.
Interstitial Cell of Cajal Loss and Injury
Kit-immunoreactive interstitial cells of Cajal, the pacemaker cells of the gastric slow wave, are reduced in number in gastric body and antral biopsies, and electron microscopy shows injury of the remaining ICC that is more severe in idiopathic than in diabetic gastroparesis. Not every study agrees: a muscularis externa transcript study found no reduction in KIT or ANO1 mRNA in idiopathic gastroparesis.
Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
interstitial cell of Cajal CL:0002088 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves interstitial cell of Cajal (CL:0002088). CL:0002088 is a cell type from the Cell Ontology.
body of stomach UBERON:0001161 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in body of stomach (UBERON:0001161). UBERON:0001161 is an anatomical location from the Uberon multi-species anatomy ontology. gastric antrum UBERON:0001165 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in gastric antrum, annotated with pyloric antrum (UBERON:0001165). UBERON:0001165 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Impaired Gastric Neuromuscular Function Loss of ICC networks disrupts slow-wave pacemaking. Restoring ICC networks normalizes slow waves and emptying in diabetic mice; in human idiopathic gastroparesis, ICC counts did not correlate with gastric retention although KIT transcript levels did. Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Show evidence (4 references)
PMID:21300066 SUPPORT Human Clinical
"The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity."
Full-thickness gastric body biopsies from 20 idiopathic and 20 diabetic patients show loss of ICC.
PMID:28066953 SUPPORT Human Clinical
"Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls"
Antral ICC counts are reduced in idiopathic gastroparesis.
PMID:21914127 SUPPORT Human Clinical
"However, the ultrastructural changes in ICC and nerves differed between diabetic and idiopathic gastroparesis and were more severe in idiopathic gastroparesis."
Transmission electron microscopy shows ICC injury that is more severe in idiopathic gastroparesis.
+ 1 more reference
Nitrergic Enteric Neuron Loss
Expression of neuronal nitric oxide synthase in gastric myenteric nerves is reduced, and was reduced in more idiopathic (40%) than diabetic (20%) patients in the NIDDK consortium biopsies. Nitrergic neurons mediate inhibitory relaxation of the pylorus and fundus.
Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
nitrergic myenteric neuron CL:0020058 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves nitrergic myenteric neuron, annotated with nitrergic neuron of myenteric plexus (CL:0020058). CL:0020058 is a cell type from the Cell Ontology.
NOS1 hgnc:7872 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOS1 (hgnc:7872). hgnc:7872 is a gene from the HUGO Gene Nomenclature Committee.
nitric oxide biosynthetic process GO:0006809 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nitric oxide biosynthetic process (GO:0006809). GO:0006809 is a biological process from the Gene Ontology. ↓ DECREASED
myenteric plexus UBERON:0002439 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myenteric plexus, annotated with myenteric nerve plexus (UBERON:0002439). UBERON:0002439 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Impaired Gastric Neuromuscular Function Loss of nitrergic input impairs pyloric relaxation and gastric emptying; shown in nNOS-deficient mice, where restoring nNOS-expressing neurons in the pylorus improves emptying. Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Show evidence (1 reference)
PMID:21300066 SUPPORT Human Clinical
"On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading."
Reduced nNOS expression is more frequent in idiopathic than diabetic gastroparesis biopsies.
Smooth Muscle Contractile Protein and PDGFRA+ Cell Loss
The gastric muscularis externa in idiopathic gastroparesis has reduced transcripts for smooth muscle contractile proteins (MYH11, MYLK1) and for PDGFRA and its ligand PDGFB, consistent with altered smooth muscle contractile capacity and loss of PDGFRA+ interstitial cells. Electron microscopy shows fibrosis, particularly around nerves, in idiopathic cases.
Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
gastric smooth muscle cell CL:4047034 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves gastric smooth muscle cell, annotated with smooth muscle cell of stomach (CL:4047034). CL:4047034 is a cell type from the Cell Ontology.
MYH11 hgnc:7569 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYH11 (hgnc:7569). hgnc:7569 is a gene from the HUGO Gene Nomenclature Committee. MYLK hgnc:7590 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYLK (hgnc:7590). hgnc:7590 is a gene from the HUGO Gene Nomenclature Committee. PDGFRA hgnc:8803 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PDGFRA (hgnc:8803). hgnc:8803 is a gene from the HUGO Gene Nomenclature Committee.
gastric muscularis externa UBERON:0008856 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in gastric muscularis externa, annotated with stomach muscularis externa (UBERON:0008856). UBERON:0008856 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Impaired Gastric Neuromuscular Function Reduced contractile protein expression is expected to weaken antral contraction. No study has shown that this change delays emptying in idiopathic gastroparesis; the transcript changes correlated only weakly with fullness and satiety scores. Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Show evidence (2 references)
PMID:29052298 SUPPORT Human Clinical
"Smooth muscle tissue from idiopathic gastroparesis patients had decreased expression of mRNAs encoding several contractile proteins, such as MYH11 and MYLK1."
Quantitative RT-PCR of idiopathic gastroparesis muscularis externa shows reduced contractile protein transcripts.
PMID:21914127 SUPPORT Human Clinical
"A thickened basal lamina around smooth muscle cells and nerves was characteristic of diabetic gastroparesis whereas idiopathic gastroparetics had fibrosis, especially around the nerves."
Ultrastructural fibrosis around nerves distinguishes idiopathic from diabetic gastroparesis.
Impaired Gastric Neuromuscular Function
Combined failure of slow-wave pacemaking, inhibitory nitrergic relaxation and smooth muscle contraction produces disordered gastric motility, including impaired antral contractility and antropyloric coordination.
Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
gastric motility GO:0035482 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gastric motility (GO:0035482). GO:0035482 is a biological process from the Gene Ontology. ↓ DECREASED
stomach UBERON:0000945 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stomach (UBERON:0000945). UBERON:0000945 is an anatomical location from the Uberon multi-species anatomy ontology. pylorus UBERON:0001166 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pylorus (UBERON:0001166). UBERON:0001166 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Delayed Gastric Emptying Disordered gastric neuromuscular function slows emptying of a solid meal. Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Show evidence (2 references)
PMID:21914127 SUPPORT Human Clinical
"In conclusion, in all the patients TEM showed abnormalities in ICC, nerves and smooth muscle consistent with the delay in gastric emptying."
Ultrastructural abnormalities of all three neuromuscular components are present in every patient studied.
PMID:22626059 SUPPORT Other
"the most common intrinsic defects are being recognized in the interstitial cells of Cajal (ICC-opathy) and with immune infiltration and neuronal changes (intrinsic neuropathic gastroparesis)"
Review framing idiopathic and diabetic gastroparesis as intrinsic ICC and neuropathic disorders of the gastric wall.
Delayed Gastric Emptying
Objectively delayed emptying of a solid meal without mechanical obstruction, defined on 4-hour scintigraphy or a gastric emptying breath test. Retention at 4 hours is on average lower in idiopathic than in diabetic, postsurgical or connective tissue gastroparesis, and emptying status is labile on retesting.
Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
gastric emptying GO:0035483 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gastric emptying (GO:0035483). GO:0035483 is a biological process from the Gene Ontology. ↓ DECREASED
stomach UBERON:0000945 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stomach (UBERON:0000945). UBERON:0000945 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Delayed gastric emptying on scintigraphy Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Vomiting Severe emptying delay is associated with worse vomiting in idiopathic gastroparesis; the association is modest and prokinetic acceleration of emptying does not predict symptom relief. Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Poor appetite Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Early satiety Early satiety is a classic symptom attributed to gastric retention; impaired accommodation may contribute independently of emptying rate. Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Postprandial fullness Postprandial fullness is attributed to gastric retention, but correlates poorly with emptying rate. Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Nausea Nausea is the most common symptom and is related to meals in most patients, but symptom relief does not track acceleration of emptying. Neuromuscular injury delays gastric emptying, and retained gastric contents produce the symptoms
Show evidence (2 references)
PMID:39674226 SUPPORT Other
"Diagnosis requires the presence of these symptoms alongside delayed gastric emptying, measured by a 4 h scintigraphy or gastric emptying breath test of a mixed composition meal in the absence of mechanical obstruction."
International consensus requires objectively delayed emptying for the diagnosis.
PMID:36730846 SUPPORT Human Clinical
"Gastric retention at 4 hours was significantly greater in patients with diabetic (39.3±25.7% P <0.001), postsurgical (41.3±24.0% P =0.002), and connective tissue gastroparesis (37.8±20.0% P =0.049) compared with patients with idiopathic gastroparesis (25.5±17.6%)."
The degree of emptying delay is on average milder in idiopathic gastroparesis.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Idiopathic Gastroparesis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Digestive 7
Delayed gastric emptying on scintigraphy OBLIGATE Gastroparesis HP:0002578 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is delayed gastric emptying, annotated with Gastroparesis (HP:0002578). HP:0002578 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39674226 SUPPORT Other
"Diagnosis requires the presence of these symptoms alongside delayed gastric emptying, measured by a 4 h scintigraphy or gastric emptying breath test of a mixed composition meal in the absence of mechanical obstruction."
Delayed emptying on a 4-hour test is a defining diagnostic requirement.
Nausea VERY_FREQUENT HP:0002018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nausea (HP:0002018). HP:0002018 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27350152 SUPPORT Human Clinical
"Of 159 gastroparesis patients (107 IG, 52 DG), 96% experienced nausea, whereas 65% experienced vomiting."
Registry cohort (two thirds idiopathic) in which nausea was nearly universal.
PMID:39674226 SUPPORT Other
"Nausea and vomiting were identified as cardinal symptoms."
International consensus names nausea as a cardinal symptom of idiopathic gastroparesis.
Vomiting FREQUENT HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27350152 SUPPORT Human Clinical
"Vomiting was more common in DG (81%) compared to IG (57%; p = 0.004)."
Vomiting occurred in 57% of idiopathic gastroparesis patients.
Early satiety HP:0033842 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Early satiety (HP:0033842). HP:0033842 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21871247 SUPPORT Human Clinical
"Patients with DG had more severe retching and vomiting than those with IG, whereas patients with IG had more severe early satiety and postprandial fullness subscores."
NIDDK registry comparison (254 idiopathic patients) showing prominent early satiety in idiopathic gastroparesis.
PMID:36730846 SUPPORT Human Clinical
"In PSGp, diabetic and idiopathic causes, the main symptoms were early satiety and postprandial fullness"
Early satiety is a main symptom in idiopathic gastroparesis.
Postprandial fullness HP:0033843 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postprandial fullness (HP:0033843). HP:0033843 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21871247 SUPPORT Human Clinical
"Patients with DG had more severe retching and vomiting than those with IG, whereas patients with IG had more severe early satiety and postprandial fullness subscores."
Postprandial fullness subscores were higher in idiopathic gastroparesis.
Bloating Abdominal distention HP:0003270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is bloating, annotated with Abdominal distention (HP:0003270). HP:0003270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20965184 SUPPORT Human Clinical
"Overweight patients had more bloating and gastric retention at 2 hours but less severe loss of appetite."
Bloating is a feature of idiopathic gastroparesis, more severe in overweight patients.
Poor appetite HP:0004396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is loss of appetite, annotated with Poor appetite (HP:0004396). HP:0004396 is a phenotype from the Human Phenotype Ontology.
Sequelae: Weight loss
Show evidence (1 reference)
PMID:20965184 SUPPORT Human Clinical
"Patients with severely delayed gastric emptying had worse vomiting and more severe loss of appetite and overall gastroparesis symptoms."
Loss of appetite is a graded symptom of idiopathic gastroparesis.
Nervous System 2
Anxiety FREQUENT HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20965184 SUPPORT Human Clinical
"Severe anxiety and depression were present in 36% and 18%, respectively."
Frequency of severe anxiety in 243 idiopathic gastroparesis patients.
Depression OCCASIONAL HP:0000716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depression (HP:0000716). HP:0000716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20965184 SUPPORT Human Clinical
"Severe anxiety and depression were present in 36% and 18%, respectively."
Frequency of severe depression in 243 idiopathic gastroparesis patients.
Constitutional 1
Abdominal pain HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20965184 SUPPORT Human Clinical
"Predominant presenting symptoms were nausea (34%), vomiting (19%), an abdominal pain (23%)."
Abdominal pain was the predominant presenting symptom in 23% of idiopathic gastroparesis patients.
PMID:22626059 SUPPORT Other
"We conclude that idiopathic and diabetic gastroparesis has similar initial presentations and manifestations, except that idiopathic gastroparesis tends to be associated more frequently with pain."
Review concluding that pain is more frequent in idiopathic gastroparesis.
Growth 1
Weight loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28721575 SUPPORT Other
"The most frequently reported symptoms of gastroparesis include nausea, vomiting, epigastric pain, early satiety, and unintentional weight loss."
Review listing unintentional weight loss among the common features of gastroparesis.
PMID:39674226 SUPPORT Other
"Dietary adjustments, nutritional support (per guidelines from the European Society for Clinical Nutrition and Metabolism for substantial weight loss or intractable vomiting), and opioid cessation were recommended by a consensus opinion."
The idiopathic gastroparesis consensus recognizes substantial weight loss as an indication for nutritional support.
💊

Medical Actions

9
Dietary Modification
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
Small-particle, low-fat, small frequent meals, with nutritional support (enteral feeding) for substantial weight loss or intractable vomiting, and cessation of opioids. Recommended by consensus opinion rather than by trials in idiopathic gastroparesis.
Show evidence (1 reference)
PMID:39674226 SUPPORT Other
"Dietary adjustments, nutritional support (per guidelines from the European Society for Clinical Nutrition and Metabolism for substantial weight loss or intractable vomiting), and opioid cessation were recommended by a consensus opinion."
Consensus recommendation for dietary adjustment and nutritional support in idiopathic gastroparesis.
Metoclopramide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: metoclopramide CHEBI:107736 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metoclopramide (CHEBI:107736). CHEBI:107736 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Dopamine D2 receptor antagonist with prokinetic and antiemetic effects; the only drug approved in the United States for gastroparesis, conditionally recommended as initial therapy, with a boxed warning for tardive dyskinesia.
Mechanism Target:
MODULATES Delayed Gastric Emptying — Prokinetics, metoclopramide among them, generally accelerate gastric emptying, but symptom relief does not track the acceleration.
Show evidence (1 reference)
PMID:24005344 SUPPORT REVIEW SYNTHESIS Human Clinical
"Even though most drugs concomitantly improved symptoms and accelerated GE, no study reported a significant correlation between SI and GE."
Meta-regression including six metoclopramide trials shows prokinetics accelerate emptying without correlated symptom benefit.
Show evidence (2 references)
PMID:40976635 SUPPORT Other
"There are conditional recommendations for the use of metoclopramide and erythromycin in patients with gastroparesis."
AGA guideline, covering idiopathic and diabetic gastroparesis, conditionally recommends metoclopramide.
PMID:28721575 SUPPORT Other
"Metoclopramide is the only medication currently approved for the treatment of gastroparesis; however, it is associated with adverse effects in a sizable proportion of patients."
Regulatory status and adverse-effect burden of metoclopramide.
Erythromycin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: erythromycin CHEBI:48923 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses erythromycin (CHEBI:48923). CHEBI:48923 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Macrolide antibiotic acting as a motilin receptor agonist; conditionally recommended as initial prokinetic therapy, typically short term because of tachyphylaxis.
Show evidence (1 reference)
PMID:40976635 SUPPORT Other
"There are conditional recommendations for the use of metoclopramide and erythromycin in patients with gastroparesis."
AGA guideline conditionally recommends erythromycin.
Domperidone
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: domperidone CHEBI:31515 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses domperidone (CHEBI:31515). CHEBI:31515 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Peripheral dopamine D2 receptor antagonist used off label, with restricted access in the United States. In a consortium cohort in which most patients had idiopathic gastroparesis it produced moderate symptom improvement; the AGA guideline advises against it as first-line therapy.
Show evidence (2 references)
PMID:34089855 SUPPORT Human Clinical
"Utilizing the method of pragmatic modeling to evaluate long-term treatment of GP in a large GpCRC database, DOM treatment resulted in moderately but significantly improved GP."
Observational consortium cohort (63% idiopathic) showing moderate benefit of domperidone.
PMID:40976635 SUPPORT Other
"Conditional recommendations were issued against the use of domperidone, prucalopride, aprepitant, nortriptyline, buspirone, and cannabidiol as first-line therapies."
AGA guideline advises against domperidone as first-line therapy.
Tradipitant
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tradipitant CHEBI:747212 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tradipitant (CHEBI:747212). CHEBI:747212 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Neurokinin-1 receptor antagonist tested for nausea in idiopathic and diabetic gastroparesis. A phase 2 trial met its nausea endpoint; the phase 3 trial did not meet its primary endpoint in the intention-to-treat population. Investigational.
Mechanism Target:
INHIBITS Nausea
Show evidence (2 references)
PMID:32693185 SUPPORT Human Clinical
"Tradipitant resulted in statistically and clinically meaningful improvements in nausea and reduced vomiting, compared with placebo, in patients with idiopathic or diabetic gastroparesis."
Phase 2 randomized trial showing reduced nausea.
PMID:38237696 REFUTE Human Clinical
"The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12"
The phase 3 trial did not confirm the nausea benefit in the intention-to-treat analysis.
Show evidence (2 references)
PMID:32693185 SUPPORT Human Clinical
"Tradipitant resulted in statistically and clinically meaningful improvements in nausea and reduced vomiting, compared with placebo, in patients with idiopathic or diabetic gastroparesis."
Phase 2 evidence for tradipitant in idiopathic and diabetic gastroparesis.
PMID:38237696 REFUTE Human Clinical
"The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12"
Negative primary result of the phase 3 trial.
Nortriptyline
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: nortriptyline CHEBI:7640 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses nortriptyline (CHEBI:7640). CHEBI:7640 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Tricyclic antidepressant used as a neuromodulator for nausea and pain. The NORIG randomized trial in idiopathic gastroparesis found no benefit over placebo, and the AGA guideline advises against it as first-line therapy.
Show evidence (2 references)
PMID:24368464 REFUTE Human Clinical
"Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms."
Randomized placebo-controlled trial in 130 idiopathic gastroparesis patients refutes symptomatic benefit.
PMID:40976635 SUPPORT Other
"Conditional recommendations were issued against the use of domperidone, prucalopride, aprepitant, nortriptyline, buspirone, and cannabidiol as first-line therapies."
AGA guideline advises against nortriptyline as first-line therapy.
Intrapyloric Botulinum Toxin Injection
Action: endoscopic intrapyloric injectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is endoscopic intrapyloric injection, annotated with Therapeutic Endoscopic Procedure (NCIT:C64958). NCIT:C64958 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Endoscopic Procedure NCIT:C64958
Agent: botulinum toxin type A CHEBI:3160 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses botulinum toxin type A (CHEBI:3160). CHEBI:3160 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Other
Endoscopic injection of botulinum toxin A into the pylorus to reduce pyloric resistance. Open-label series were encouraging, but a randomized placebo-controlled trial found no benefit over saline.
Show evidence (1 reference)
PMID:18070232 REFUTE Human Clinical
"At 1-month follow-up, 37.5% randomized to botulinum toxin and 56.3% randomized to placebo achieved improvement as defined by this study."
Randomized double-blind trial in idiopathic and diabetic gastroparesis found no benefit over placebo.
Gastric Electrical Stimulation
Action: gastric electrical stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gastric electrical stimulation (NCIT:C157862). NCIT:C157862 is a clinical intervention from the NCI Thesaurus. Ontology label: Gastric Electrical Stimulation NCIT:C157862
Platform: Device
Implanted high-frequency gastric electrical stimulator, reserved for refractory nausea and vomiting. It reduces vomiting in diabetic and non-diabetic patients without accelerating gastric emptying.
Mechanism Target:
INHIBITS Vomiting
Show evidence (1 reference)
PMID:31647902 SUPPORT Human Clinical
"In a randomized crossover study, we found that GES reduced the frequency of refractory vomiting in patients with and without diabetes, although it did not accelerate gastric emptying or increase of quality of life."
Double-blind crossover trial including idiopathic patients shows reduced vomiting without faster emptying.
Show evidence (2 references)
PMID:31647902 SUPPORT Human Clinical
"In a randomized crossover study, we found that GES reduced the frequency of refractory vomiting in patients with and without diabetes, although it did not accelerate gastric emptying or increase of quality of life."
Randomized evidence for gastric electrical stimulation in refractory vomiting, including idiopathic gastroparesis.
PMID:40976635 SUPPORT Other
"In addition, conditional recommendations were issued against the routine initial use of gastric per-oral endoscopic pyloromyotomy or gastric electrical stimulation in patients with gastroparesis, reserving these treatments for select patients with symptoms refractory to medical therapies."
AGA guideline reserves gastric electrical stimulation for selected patients with symptoms refractory to medical therapy.
Gastric Peroral Endoscopic Pyloromyotomy (G-POEM)
Action: gastric peroral endoscopic pyloromyotomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gastric peroral endoscopic pyloromyotomy, annotated with Therapeutic Endoscopic Procedure (NCIT:C64958). NCIT:C64958 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Endoscopic Procedure NCIT:C64958
Platform: Surgery
Endoscopic division of the pyloric muscle for severe refractory gastroparesis. In a sham-controlled trial it improved symptoms and gastric retention overall; the idiopathic subgroup was small and the result in it not conclusive. Reserved for selected refractory patients.
Mechanism Target:
BYPASSES Delayed Gastric Emptying
Show evidence (1 reference)
PMID:35470243 SUPPORT Human Clinical
"Median gastric retention at 4 hours decreased from 22% (95% CI 17 to 31) to 12% (5-22) after G-POEM and did not change after sham"
Sham-controlled trial showing reduced gastric retention after pyloromyotomy.
Show evidence (2 references)
PMID:35470243 SUPPORT Human Clinical
"In severe gastroparesis, G-POEM is superior to a sham procedure for improving both symptoms and gastric emptying 6 months after the procedure. These results are not entirely conclusive in patients with idiopathic and postsurgical aetiologies."
Randomized sham-controlled trial (11 idiopathic of 41 patients) supporting G-POEM, with an explicit caveat for the idiopathic subgroup.
PMID:40976635 SUPPORT Other
"In addition, conditional recommendations were issued against the routine initial use of gastric per-oral endoscopic pyloromyotomy or gastric electrical stimulation in patients with gastroparesis, reserving these treatments for select patients with symptoms refractory to medical therapies."
AGA guideline reserves G-POEM for selected patients with symptoms refractory to medical therapy.
🌍

Environmental Factors

1
Antecedent acute viral illness
acute viral infection ECTO:3000001 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is acute viral infection, annotated with exposure to virus (ECTO:3000001). ECTO:3000001 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
An acute viral-like illness (fever, fatigue, myalgia, with or without diarrhea) precedes symptom onset in about one fifth of patients with idiopathic gastroparesis and defines the post-infectious subgroup. Cytomegalovirus, Epstein-Barr virus and gastric enterovirus infection have been reported in individual patients; no single agent is established.
Show evidence (2 references)
PMID:20965184 SUPPORT Human Clinical
"The mean age of 243 patients with IG studied was 41 years; 88% were female, 46% were overweight, 50% had acute onset of symptoms, and 19% reported an initial infectious prodrome."
In the NIDDK registry, 19% of idiopathic gastroparesis patients reported an infectious prodrome.
PMID:17716347 SUPPORT Human Clinical
"A specific virus was identified in two patients (one cytomegalovirus [CMV] and one Epstein-Barr virus [EBV])."
Identifies cytomegalovirus and Epstein-Barr virus as documented agents in individual post-infectious cases.
Mechanism Target:
TRIGGERS Delayed Gastric Emptying — Delayed gastric emptying develops within days of resolution of the viral illness. The intermediate cellular lesion is not established; autonomic neuropathy was documented in the patients tested.
Show evidence (1 reference)
PMID:2348727 SUPPORT Human Clinical
"A mean of 4.5 days after spontaneous resolution of the viral illness, persistent nausea, vomiting, and epigastric pain developed in these patients. In all seven patients, delayed emptying of the gastric contents was substantiated."
Temporal association of a viral illness with the onset of objectively delayed gastric emptying.
🔬

Diagnosis

2
Four-hour solid-meal gastric emptying scintigraphy
Gastric emptying scintigraphy of a standardized low-fat solid meal over 4 hours is the reference test; 4-hour testing is recommended over 2-hour testing. A gastric emptying breath test of a mixed meal is an accepted alternative.
gastric emptying scintigraphy NCIT:C62667 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40976635 SUPPORT Other
"A conditional recommendation was issued against using 2-hour gastric emptying testing and in favor of 4-hour testing in patients with suspected gastroparesis."
AGA guideline recommendation for 4-hour gastric emptying testing.
Upper endoscopy to exclude mechanical obstruction
Mechanical gastric outlet obstruction must be excluded, usually by upper gastrointestinal endoscopy or radiology, before delayed emptying is attributed to gastroparesis.
upper gastrointestinal endoscopy NCIT:C78144 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39674226 SUPPORT Other
"This consensus defined idiopathic gastroparesis as the presence of symptoms associated with delayed gastric emptying in the absence of mechanical obstruction."
Absence of mechanical obstruction is part of the consensus definition, which requires it to be excluded.
📈

Progression

2
Acute post-infectious onset with spontaneous improvement
Post-infectious Duration: 4 weeks to 12 months in most reported cases
Show evidence (1 reference)
PMID:17716347 SUPPORT Human Clinical
"In four out of seven patients, symptoms resolved spontaneously within 4 weeks to 12 months, three patients had improved but were still symptomatic at the time of the writing of this work."
Documents the self-limiting course of most post-infectious cases.
Chronic fluctuating course
Chronic idiopathic
In the NIDDK consortium registry only about a quarter of gastroparesis patients improved by at least one GCSI point over 48 weeks.
Show evidence (1 reference)
PMID:41833524 SUPPORT Human Clinical
"Of 555 patients followed over 48 weeks, GCSI improved by ≥ 1 in 26% overall"
Registry follow-up (idiopathic and diabetic gastroparesis) showing that most patients remain symptomatic over a year.
📊

Prevalence

4
Olmsted County, Minnesota, women (definite gastroparesis, all etiologies)
Point Prevalence 37.8 per 100,000 (23.3–52.4) 1–9 per 10,000
Age-adjusted prevalence of definite gastroparesis on 1 January 2007, 37.8 per 100,000 women (95% CI 23.3 to 52.4). All etiologies, not idiopathic gastroparesis alone.
Show evidence (1 reference)
PMID:19249393 SUPPORT Human Clinical
"The age-adjusted prevalence of definite gastroparesis per 100,000 persons on January 1, 2007, was 9.6 (95% CI, 1.8-17.4) for men and 37.8 (95% CI, 23.3-52.4) for women."
Population-based Rochester Epidemiology Project estimate of gastroparesis prevalence in women.
Olmsted County, Minnesota, men (definite gastroparesis, all etiologies)
Point Prevalence 9.6 per 100,000 (1.8–17.4) 1–9 per 100,000
Age-adjusted prevalence of definite gastroparesis on 1 January 2007, 9.6 per 100,000 men (95% CI 1.8 to 17.4). All etiologies, not idiopathic gastroparesis alone.
Show evidence (1 reference)
PMID:19249393 SUPPORT Human Clinical
"The age-adjusted prevalence of definite gastroparesis per 100,000 persons on January 1, 2007, was 9.6 (95% CI, 1.8-17.4) for men and 37.8 (95% CI, 23.3-52.4) for women."
Population-based estimate of gastroparesis prevalence in men, about one quarter of the rate in women.
Olmsted County, Minnesota, women, 1996-2006 (definite gastroparesis, all etiologies)
Annual Incidence 9.8 per 100,000 (7.5–12.1) person-years 1–9 per 100,000 per year
Age-adjusted incidence of definite gastroparesis, 9.8 per 100,000 person-years in women (95% CI 7.5 to 12.1). All etiologies.
Show evidence (1 reference)
PMID:19249393 SUPPORT Human Clinical
"The age-adjusted (to the 2000 US white population) incidence per 100,000 person-years of definite gastroparesis for the years 1996-2006 was 2.4 ... 1.2-3.8) for men and 9.8 (95% CI, 7.5-12.1) for women."
Population-based incidence of gastroparesis in women.
Olmsted County, Minnesota, men, 1996-2006 (definite gastroparesis, all etiologies)
Annual Incidence 2.4 per 100,000 (1.2–3.8) person-years 1–9 per 100,000 per year
Age-adjusted incidence of definite gastroparesis, 2.4 per 100,000 person-years in men (95% CI 1.2 to 3.8). All etiologies.
Show evidence (1 reference)
PMID:19249393 SUPPORT Human Clinical
"The age-adjusted (to the 2000 US white population) incidence per 100,000 person-years of definite gastroparesis for the years 1996-2006 was 2.4 ... 1.2-3.8) for men and 9.8 (95% CI, 7.5-12.1) for women."
Population-based incidence of gastroparesis in men.
{ }

Source YAML

click to show 
name: Idiopathic Gastroparesis
creation_date: "2026-09-30T19:45:00Z"
category: Complex
disease_term:
  preferred_term: idiopathic gastroparesis
  term:
    id: MONDO:0034150
    label: idiopathic gastroparesis
description: >-
  Idiopathic gastroparesis is a chronic gastric neuromuscular disorder in which
  upper gastrointestinal symptoms (cardinally nausea and vomiting, with early
  satiation, postprandial fullness, bloating and abdominal pain) occur with
  objectively delayed gastric emptying of a solid meal, in the absence of
  mechanical obstruction and after exclusion of diabetes, prior gastric
  surgery, medications and other identifiable causes. It is the largest
  etiological category of gastroparesis in referral series and predominantly
  affects young and middle-aged women. Full-thickness gastric biopsies show loss
  and ultrastructural injury of interstitial cells of Cajal, reduced nitrergic
  (nNOS) innervation, loss of anti-inflammatory CD206+ muscularis macrophages
  with a pro-inflammatory immune signature, and altered smooth muscle
  contractile gene expression, although how consistently these lesions explain
  delayed emptying or symptoms in the idiopathic form is unsettled. A subgroup
  begins acutely after a viral-like illness and usually improves over months;
  most other cases run a chronic course. Clinical and pathological features
  overlap extensively with functional dyspepsia, and treatment is largely
  symptomatic (dietary modification, metoclopramide or erythromycin, antiemetics,
  and gastric electrical stimulation or pyloric interventions for refractory
  disease). Diabetic gastroparesis, which shares the ICC and macrophage lesions,
  is outside the scope of this entry.
synonyms:
- IG
- IGP
parents:
- Gastroparesis
categories:
- Gastrointestinal Motility Disorder
notes: >-
  MONDO:0034150 has no causal gene; idiopathic gastroparesis is not a Mendelian
  disorder, and no GeneReviews chapter names it. The Olmsted County prevalence
  and incidence figures recorded under prevalence are for definite gastroparesis
  of all etiologies; no population-based rate specific to the idiopathic form
  was found. In referral series the idiopathic form is the largest single
  etiology (149 of 256 patients, 58.2%, in PMID:36730846). Most of the
  mechanistic evidence linking macrophages, heme oxygenase-1 and oxidative
  stress to interstitial cell of Cajal loss comes from diabetic mouse models,
  and the human idiopathic tissue data are cross-sectional.
has_subtypes:
- name: Post-infectious
  display_name: Post-infectious (post-viral) gastroparesis
  description: >-
    Gastroparesis beginning acutely after a viral-like illness (fever, myalgia,
    gastroenteritis) in a previously healthy person, sometimes with a documented
    agent such as cytomegalovirus or Epstein-Barr virus. It is regarded as a
    subgroup of idiopathic gastroparesis, is often accompanied by autonomic
    dysfunction, and usually improves or resolves over weeks to months.
  evidence:
  - reference: PMID:17716347
    reference_title: "Post-infectious gastroparesis: clinical and electerogastrographic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post-infectious gastroparesis (PIGP) is a subgroup of idiopathic gastroparesis."
    explanation: Case series establishing post-infectious gastroparesis as a subgroup of idiopathic gastroparesis.
  - reference: PMID:2348727
    reference_title: "Gastroparesis after a presumed viral illness: clinical and laboratory features and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "postviral gastroparesis is uncommon, is frequently associated with autonomic dysfunction, and is associated with an apparently excellent prognosis"
    explanation: Retrospective series describing the autonomic dysfunction and favorable course that distinguish the post-viral subgroup.
- name: Chronic idiopathic
  display_name: Chronic (insidious-onset) idiopathic gastroparesis
  description: >-
    Idiopathic gastroparesis without an infectious prodrome, typically of
    insidious onset and running a slowly progressive or persistent course with
    greater symptom burden than the post-infectious subgroup.
  evidence:
  - reference: PMID:9317072
    reference_title: "Viral gastroparesis: a subgroup of idiopathic gastroparesis--clinical characteristics and long-term outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Idiopathic gastroparesis is a more slowly progressive illness, and patients remain significantly more symptomatic for a longer period of time."
    explanation: Comparison of viral and non-viral idiopathic gastroparesis showing the chronic, slowly progressive course of the non-viral group.
prevalence:
- population: Olmsted County, Minnesota, women (definite gastroparesis, all etiologies)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 37.8
  rate_low: 23.3
  rate_high: 52.4
  rate_denominator: POPULATION
  notes: >-
    Age-adjusted prevalence of definite gastroparesis on 1 January 2007, 37.8
    per 100,000 women (95% CI 23.3 to 52.4). All etiologies, not idiopathic
    gastroparesis alone.
  evidence:
  - reference: PMID:19249393
    reference_title: "The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age-adjusted prevalence of definite gastroparesis per 100,000 persons on January 1, 2007, was 9.6 (95% CI, 1.8-17.4) for men and 37.8 (95% CI, 23.3-52.4) for women."
    explanation: Population-based Rochester Epidemiology Project estimate of gastroparesis prevalence in women.
- population: Olmsted County, Minnesota, men (definite gastroparesis, all etiologies)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 9.6
  rate_low: 1.8
  rate_high: 17.4
  rate_denominator: POPULATION
  notes: >-
    Age-adjusted prevalence of definite gastroparesis on 1 January 2007, 9.6 per
    100,000 men (95% CI 1.8 to 17.4). All etiologies, not idiopathic
    gastroparesis alone.
  evidence:
  - reference: PMID:19249393
    reference_title: "The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age-adjusted prevalence of definite gastroparesis per 100,000 persons on January 1, 2007, was 9.6 (95% CI, 1.8-17.4) for men and 37.8 (95% CI, 23.3-52.4) for women."
    explanation: Population-based estimate of gastroparesis prevalence in men, about one quarter of the rate in women.
- population: Olmsted County, Minnesota, women, 1996-2006 (definite gastroparesis, all etiologies)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 9.8
  rate_low: 7.5
  rate_high: 12.1
  rate_denominator: PERSON_YEARS
  notes: >-
    Age-adjusted incidence of definite gastroparesis, 9.8 per 100,000
    person-years in women (95% CI 7.5 to 12.1). All etiologies.
  evidence:
  - reference: PMID:19249393
    reference_title: "The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age-adjusted (to the 2000 US white population) incidence per 100,000 person-years of definite gastroparesis for the years 1996-2006 was 2.4 ... 1.2-3.8) for men and 9.8 (95% CI, 7.5-12.1) for women."
    explanation: Population-based incidence of gastroparesis in women.
- population: Olmsted County, Minnesota, men, 1996-2006 (definite gastroparesis, all etiologies)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.4
  rate_low: 1.2
  rate_high: 3.8
  rate_denominator: PERSON_YEARS
  notes: >-
    Age-adjusted incidence of definite gastroparesis, 2.4 per 100,000
    person-years in men (95% CI 1.2 to 3.8). All etiologies.
  evidence:
  - reference: PMID:19249393
    reference_title: "The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age-adjusted (to the 2000 US white population) incidence per 100,000 person-years of definite gastroparesis for the years 1996-2006 was 2.4 ... 1.2-3.8) for men and 9.8 (95% CI, 7.5-12.1) for women."
    explanation: Population-based incidence of gastroparesis in men.
progression:
- phase: Acute post-infectious onset with spontaneous improvement
  subtype: Post-infectious
  duration: 4 weeks to 12 months in most reported cases
  evidence:
  - reference: PMID:17716347
    reference_title: "Post-infectious gastroparesis: clinical and electerogastrographic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In four out of seven patients, symptoms resolved spontaneously within 4 weeks to 12 months, three patients had improved but were still symptomatic at the time of the writing of this work."
    explanation: Documents the self-limiting course of most post-infectious cases.
- phase: Chronic fluctuating course
  subtype: Chronic idiopathic
  notes: >-
    In the NIDDK consortium registry only about a quarter of gastroparesis
    patients improved by at least one GCSI point over 48 weeks.
  evidence:
  - reference: PMID:41833524
    reference_title: "Predominant Symptom in Gastroparesis: Relationships to Quality of Life, Treatments, and Outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 555 patients followed over 48 weeks, GCSI improved by ≥ 1 in 26% overall"
    explanation: Registry follow-up (idiopathic and diabetic gastroparesis) showing that most patients remain symptomatic over a year.
environmental:
- name: Antecedent acute viral illness
  presence: risk factor
  description: >-
    An acute viral-like illness (fever, fatigue, myalgia, with or without
    diarrhea) precedes symptom onset in about one fifth of patients with
    idiopathic gastroparesis and defines the post-infectious subgroup.
    Cytomegalovirus, Epstein-Barr virus and gastric enterovirus infection have
    been reported in individual patients; no single agent is established.
  exposure_term:
    preferred_term: acute viral infection
    term:
      id: ECTO:3000001
      label: exposure to virus
  evidence:
  - reference: PMID:20965184
    reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age of 243 patients with IG studied was 41 years; 88% were female, 46% were overweight, 50% had acute onset of symptoms, and 19% reported an initial infectious prodrome."
    explanation: In the NIDDK registry, 19% of idiopathic gastroparesis patients reported an infectious prodrome.
  - reference: PMID:17716347
    reference_title: "Post-infectious gastroparesis: clinical and electerogastrographic aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A specific virus was identified in two patients (one cytomegalovirus [CMV] and one Epstein-Barr virus [EBV])."
    explanation: Identifies cytomegalovirus and Epstein-Barr virus as documented agents in individual post-infectious cases.
  influences_mechanisms:
  - target: Delayed Gastric Emptying
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Delayed gastric emptying develops within days of resolution of the viral
      illness. The intermediate cellular lesion is not established; autonomic
      neuropathy was documented in the patients tested.
    evidence:
    - reference: PMID:2348727
      reference_title: "Gastroparesis after a presumed viral illness: clinical and laboratory features and natural history."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A mean of 4.5 days after spontaneous resolution of the viral illness, persistent nausea, vomiting, and epigastric pain developed in these patients. In all seven patients, delayed emptying of the gastric contents was substantiated."
      explanation: Temporal association of a viral illness with the onset of objectively delayed gastric emptying.
mechanistic_hypotheses:
- hypothesis_group_id: macrophage_oxidative_icc_injury
  hypothesis_label: >-
    Loss of cytoprotective muscularis macrophages permits oxidative and
    inflammatory injury of interstitial cells of Cajal and nitrergic neurons
  status: EMERGING
  description: >-
    In diabetic mouse models, gastric muscularis macrophages that fail to
    sustain heme oxygenase-1 expression and shift to an inflammatory phenotype
    release reactive oxygen species and cytokines (IL-6, TNF) that injure
    interstitial cells of Cajal and reduce nNOS expression, producing delayed
    gastric emptying. Human idiopathic gastroparesis tissue shows the matching
    static lesions (CD206+ macrophage loss, ICC loss, reduced HMOX1 mRNA), so
    the same chain is proposed for the idiopathic form, but the causal steps
    have not been demonstrated in idiopathic disease.
  evidence:
  - reference: PMID:32718570
    reference_title: "Gastric Biopsies in Gastroparesis: Insights into Gastric Neuromuscular Disorders to Aid Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More recently, in animal models, macrophages have also been identified to play a central role in development of delayed gastric emptying. Activation of macrophages leads to loss of ICC. In human gastroparesis, loss of anti-inflammatory macrophages in gastric muscle has been shown."
    explanation: Review summarizing the animal-model macrophage mechanism and the corresponding human biopsy finding.
- hypothesis_group_id: delayed_emptying_symptom_model
  hypothesis_label: >-
    Neuromuscular injury delays gastric emptying, and retained gastric
    contents produce the symptoms
  status: CANONICAL
  description: >-
    The classical definition attributes nausea, vomiting, early satiety and
    fullness to delayed emptying of the stomach. It underlies the diagnostic
    requirement for a 4-hour gastric emptying test and the use of prokinetic
    and pyloric therapies.
  evidence:
  - reference: PMID:39674226
    reference_title: "Rome Foundation and international neurogastroenterology and motility societies' consensus on idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This consensus defined idiopathic gastroparesis as the presence of symptoms associated with delayed gastric emptying in the absence of mechanical obstruction."
    explanation: International consensus definition built on delayed emptying as the defining physiological abnormality.
- hypothesis_group_id: gastric_sensorimotor_spectrum
  hypothesis_label: >-
    Idiopathic gastroparesis is a gastric sensorimotor disorder on a spectrum
    with functional dyspepsia
  status: ALTERNATIVE
  description: >-
    Gastric emptying status is labile and correlates poorly with symptoms or
    with response to prokinetics, while idiopathic gastroparesis and functional
    dyspepsia share clinical features and the ICC and CD206+ macrophage lesions.
    This view places impaired accommodation, visceral hypersensitivity and
    gut-brain interaction alongside or in place of delayed emptying as the
    source of symptoms.
  evidence:
  - reference: PMID:33548234
    reference_title: "Functional Dyspepsia and Gastroparesis in Tertiary Care are Interchangeable Syndromes With Common Clinical and Pathologic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly \"organic\" gastric neuromuscular disorders."
    explanation: Consortium cohort showing that functional dyspepsia and gastroparesis are clinically and pathologically indistinguishable after a year.
  - reference: PMID:24005344
    reference_title: "The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In this review, no evidence of a relationship between SI and GE was identified for different drugs used for the treatment of gastroparesis."
    explanation: Meta-regression across prokinetic trials finds that symptom improvement does not track acceleration of gastric emptying.
pathophysiology:
- name: Muscularis Macrophage Phenotype Shift
  description: >-
    The gastric muscularis propria of patients with idiopathic gastroparesis
    shows loss of anti-inflammatory CD206+ macrophages in the circular muscle
    and myenteric plexus without a fall in total CD45+ immune cells, with an
    immune infiltrate containing macrophages and enrichment of transcripts
    associated with pro-inflammatory (M1) macrophages.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: CD206+ anti-inflammatory muscularis macrophage
    term:
      id: CL:0000890
      label: M2 macrophage
  - preferred_term: pro-inflammatory muscularis macrophage
    term:
      id: CL:0000863
      label: M1 macrophage
  biological_processes:
  - preferred_term: macrophage activation
    modifier: DYSREGULATED
    term:
      id: GO:0042116
      label: macrophage activation
  locations:
  - preferred_term: gastric antrum muscularis
    term:
      id: UBERON:0001165
      label: pyloric antrum
  - preferred_term: myenteric plexus
    term:
      id: UBERON:0002439
      label: myenteric nerve plexus
  evidence:
  - reference: PMID:28066953
    reference_title: "Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall immune cell population (CD45) was unchanged but there was a loss of anti-inflammatory macrophages (CD206) in circular muscle"
    explanation: Full-thickness antral biopsies from diabetic and idiopathic gastroparesis show loss of CD206+ macrophages with unchanged total immune cells.
  - reference: PMID:30086735
    reference_title: "Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immune profile analysis revealed that genes associated with M1 (pro inflammatory) macrophages were enriched in tissues from idiopathic gastroparesis tissues compared to controls (p < 0.05)."
    explanation: RNA sequencing of gastric body biopsies shows a pro-inflammatory macrophage signature specifically in idiopathic gastroparesis.
  - reference: PMID:21300066
    reference_title: "Cellular changes in diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers."
    explanation: NIDDK consortium biopsy study (20 idiopathic, 20 diabetic) reporting a macrophage-containing immune infiltrate.
  - reference: PMID:31482734
    reference_title: "Proteomics in gastroparesis: unique and overlapping protein signatures in diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both DG and IG, \"Role of Macrophages, Fibroblasts and Endothelial Cells\" was the most statistically significant altered pathway"
    explanation: Tissue proteomics identifies macrophage-related signaling as the most altered pathway in idiopathic gastroparesis.
  downstream:
  - target: Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - macrophage_oxidative_icc_injury
    description: >-
      Muscularis macrophages are the cells that upregulate heme oxygenase-1 in
      the diabetic stomach; loss of that upregulation raises reactive oxygen
      species. Shown in diabetic mice; inferred for idiopathic disease.
    evidence:
    - reference: PMID:18926825
      reference_title: "Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In early stages of diabetes, HO-1 was up-regulated in gastric macrophages and remained up-regulated in all mice that were resistant to development of delayed gastric emptying."
      explanation: Places the protective heme oxygenase-1 response in gastric macrophages in the NOD diabetic mouse.
  - target: Interstitial Cell of Cajal Loss and Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - macrophage_oxidative_icc_injury
    description: >-
      Inflammatory macrophage products (IL-6, TNF) damage ICC in cultured
      mouse gastric muscularis, and restoring macrophages to
      macrophage-deficient diabetic Csf1op/op mice with CSF1 led to delayed
      emptying and damaged ICC in most of them. Human biopsies
      show a correlation between CD206+ cell and ICC numbers across patients
      and controls, but the correlation was not found within the idiopathic
      group in the gastric body.
    evidence:
    - reference: PMID:29501441
      reference_title: "Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Medium conditioned by macrophages previously exposed to oxidative injury caused damage to ICC in cultured gastric muscularis propria from Csf1op/op mice; neutralizing antibodies against IL6R or TNF prevented this damage to ICC."
      explanation: Macrophage-derived IL-6 and TNF are sufficient to damage ICC ex vivo in cultured mouse gastric muscularis.
    - reference: PMID:29501441
      reference_title: "Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "11 of 15 diabetic mice given CSF1 developed delayed gastric emptying and had damaged ICC."
      explanation: Restoring macrophages to macrophage-deficient diabetic Csf1op/op mice with CSF1 led to ICC damage and delayed emptying in vivo in most animals.
    - reference: PMID:28066953
      reference_title: "Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There was correlation between the number of ICC and CD206-positive cells (r=.55, P=.008)."
      explanation: In antral biopsies pooled across diabetic, idiopathic and control subjects, CD206+ macrophage and ICC counts correlate.
    - reference: PMID:25041465
      reference_title: "Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "There was a significant correlation between the number of CD206+ cells and ICC in DG and DC patients, but not in C and IG"
      explanation: In gastric body biopsies the CD206-ICC correlation was absent within the idiopathic group, which argues against assuming the diabetic mechanism operates in idiopathic disease.
  - target: Nausea
    causal_link_type: UNKNOWN
    description: >-
      In idiopathic gastroparesis, patients with a myenteric immune infiltrate
      have more severe nausea and overall symptoms than those without one; the
      mechanism linking the infiltrate to nausea is unknown.
    evidence:
    - reference: PMID:22339929
      reference_title: "Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall clinical severity and nausea in IG is associated with a myenteric immune infiltrate."
      explanation: NIDDK biopsy cohort associating the myenteric immune infiltrate with nausea severity in idiopathic gastroparesis.
- name: Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress
  description: >-
    Failure to maintain heme oxygenase-1 expression in the gastric muscularis
    leaves the tissue exposed to reactive oxygen species. HMOX1 mRNA is reduced
    in the muscularis externa of idiopathic gastroparesis; the oxidative-stress
    consequence has been demonstrated in diabetic mice.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: DYSREGULATED
    term:
      id: GO:0006979
      label: response to oxidative stress
  genes:
  - preferred_term: HMOX1
    term:
      id: hgnc:5013
      label: HMOX1
  locations:
  - preferred_term: gastric muscularis externa
    term:
      id: UBERON:0008856
      label: stomach muscularis externa
  evidence:
  - reference: PMID:29052298
    reference_title: "Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was also a significant decrease in mRNA-encoding platelet-derived growth factor receptor α (PDGFRα) and its ligand PDGFB and in Heme oxygenase 1 in idiopathic gastroparesis subjects."
    explanation: Reduced heme oxygenase-1 transcript in idiopathic gastroparesis muscularis externa.
  - reference: PMID:18926825
    reference_title: "Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of HO-1 up-regulation increased levels of reactive oxygen species."
    explanation: In diabetic mice, loss of heme oxygenase-1 upregulation raises reactive oxygen species in the stomach.
  downstream:
  - target: Interstitial Cell of Cajal Loss and Injury
    causal_link_type: DIRECT
    hypothesis_groups:
    - macrophage_oxidative_icc_injury
    description: >-
      Inhibiting heme oxygenase-1 causes loss of Kit-positive ICC and delayed
      emptying, and inducing it restores Kit expression, in diabetic mice.
    evidence:
    - reference: PMID:18926825
      reference_title: "Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Inhibition of HO-1 activity in mice with normal gastric emptying caused a loss of Kit expression and development of diabetic gastroparesis."
      explanation: Loss-of-function experiment showing heme oxygenase-1 activity is required to preserve ICC.
  - target: Nitrergic Enteric Neuron Loss
    causal_link_type: DIRECT
    hypothesis_groups:
    - macrophage_oxidative_icc_injury
    description: >-
      Heme oxygenase-1 induction restores nNOS expression together with Kit in
      diabetic mice.
    evidence:
    - reference: PMID:18926825
      reference_title: "Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Induction of HO-1 by hemin decreased reactive oxygen species, rapidly restored Kit and neuronal nitric oxide synthase expression, and completely normalized gastric emptying in all mice."
      explanation: Rescue experiment linking oxidative stress to loss of neuronal nitric oxide synthase expression.
- name: Interstitial Cell of Cajal Loss and Injury
  description: >-
    Kit-immunoreactive interstitial cells of Cajal, the pacemaker cells of the
    gastric slow wave, are reduced in number in gastric body and antral
    biopsies, and electron microscopy shows injury of the remaining ICC that is
    more severe in idiopathic than in diabetic gastroparesis. Not every study
    agrees: a muscularis externa transcript study found no reduction in KIT or
    ANO1 mRNA in idiopathic gastroparesis.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: interstitial cell of Cajal
    term:
      id: CL:0002088
      label: interstitial cell of Cajal
  locations:
  - preferred_term: body of stomach
    term:
      id: UBERON:0001161
      label: body of stomach
  - preferred_term: gastric antrum
    term:
      id: UBERON:0001165
      label: pyloric antrum
  evidence:
  - reference: PMID:21300066
    reference_title: "Cellular changes in diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity."
    explanation: Full-thickness gastric body biopsies from 20 idiopathic and 20 diabetic patients show loss of ICC.
  - reference: PMID:28066953
    reference_title: "Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls"
    explanation: Antral ICC counts are reduced in idiopathic gastroparesis.
  - reference: PMID:21914127
    reference_title: "Ultrastructural differences between diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the ultrastructural changes in ICC and nerves differed between diabetic and idiopathic gastroparesis and were more severe in idiopathic gastroparesis."
    explanation: Transmission electron microscopy shows ICC injury that is more severe in idiopathic gastroparesis.
  - reference: PMID:29052298
    reference_title: "Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Conversely, there was no significant change in mRNAs characteristic of interstitial cells of Cajal (ICCs) such as KIT or ANO1."
    explanation: A transcript-level study found no overall reduction of ICC markers in idiopathic gastroparesis, contrasting with the immunohistochemical studies.
  downstream:
  - target: Impaired Gastric Neuromuscular Function
    causal_link_type: DIRECT
    hypothesis_groups:
    - delayed_emptying_symptom_model
    description: >-
      Loss of ICC networks disrupts slow-wave pacemaking. Restoring ICC
      networks normalizes slow waves and emptying in diabetic mice; in human
      idiopathic gastroparesis, ICC counts did not correlate with gastric
      retention although KIT transcript levels did.
    evidence:
    - reference: PMID:27795979
      reference_title: "Interleukin 10 Restores Gastric Emptying, Electrical Activity, and Interstitial Cells of Cajal Networks in Diabetic Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This response is associated with up-regulation of HO1 and repair of connectivity of ICC networks."
      explanation: Repair of ICC networks accompanies normalized slow-wave activity and gastric emptying in diabetic mice.
    - reference: PMID:29052298
      reference_title: "Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "KIT expression showed a significant correlation with gastric emptying"
      explanation: In idiopathic gastroparesis muscularis, KIT expression tracks gastric emptying.
    - reference: PMID:22339929
      reference_title: "Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "Interstitial cells of Cajal counts inversely correlated with 4 h gastric retention in DG but not in IG"
      explanation: In the NIDDK biopsy cohort, ICC counts did not correlate with gastric retention in idiopathic gastroparesis.
- name: Nitrergic Enteric Neuron Loss
  description: >-
    Expression of neuronal nitric oxide synthase in gastric myenteric nerves is
    reduced, and was reduced in more idiopathic (40%) than diabetic (20%)
    patients in the NIDDK consortium biopsies. Nitrergic neurons mediate
    inhibitory relaxation of the pylorus and fundus.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: nitrergic myenteric neuron
    term:
      id: CL:0020058
      label: nitrergic neuron of myenteric plexus
  biological_processes:
  - preferred_term: nitric oxide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006809
      label: nitric oxide biosynthetic process
  genes:
  - preferred_term: NOS1
    term:
      id: hgnc:7872
      label: NOS1
  locations:
  - preferred_term: myenteric plexus
    term:
      id: UBERON:0002439
      label: myenteric nerve plexus
  evidence:
  - reference: PMID:21300066
    reference_title: "Cellular changes in diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading."
    explanation: Reduced nNOS expression is more frequent in idiopathic than diabetic gastroparesis biopsies.
  downstream:
  - target: Impaired Gastric Neuromuscular Function
    causal_link_type: DIRECT
    hypothesis_groups:
    - delayed_emptying_symptom_model
    description: >-
      Loss of nitrergic input impairs pyloric relaxation and gastric emptying;
      shown in nNOS-deficient mice, where restoring nNOS-expressing neurons
      in the pylorus improves emptying.
    evidence:
    - reference: PMID:16344050
      reference_title: "Neural stem cell transplantation in the stomach rescues gastric function in neuronal nitric oxide synthase-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Gastric emptying was significantly increased in mice that received NSCs as compared with vehicle-injected controls (49.67% vs 35.09%; P < .01 by Student t test)."
      explanation: Transplanted neural stem cells that become nNOS-expressing neurons improve gastric emptying in nNOS-deficient mice, a genetic model of gastroparesis.
- name: Smooth Muscle Contractile Protein and PDGFRA+ Cell Loss
  description: >-
    The gastric muscularis externa in idiopathic gastroparesis has reduced
    transcripts for smooth muscle contractile proteins (MYH11, MYLK1) and for
    PDGFRA and its ligand PDGFB, consistent with altered smooth muscle
    contractile capacity and loss of PDGFRA+ interstitial cells. Electron
    microscopy shows fibrosis, particularly around nerves, in idiopathic cases.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: gastric smooth muscle cell
    term:
      id: CL:4047034
      label: smooth muscle cell of stomach
  genes:
  - preferred_term: MYH11
    term:
      id: hgnc:7569
      label: MYH11
  - preferred_term: MYLK
    term:
      id: hgnc:7590
      label: MYLK
  - preferred_term: PDGFRA
    term:
      id: hgnc:8803
      label: PDGFRA
  locations:
  - preferred_term: gastric muscularis externa
    term:
      id: UBERON:0008856
      label: stomach muscularis externa
  evidence:
  - reference: PMID:29052298
    reference_title: "Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Smooth muscle tissue from idiopathic gastroparesis patients had decreased expression of mRNAs encoding several contractile proteins, such as MYH11 and MYLK1."
    explanation: Quantitative RT-PCR of idiopathic gastroparesis muscularis externa shows reduced contractile protein transcripts.
  - reference: PMID:21914127
    reference_title: "Ultrastructural differences between diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A thickened basal lamina around smooth muscle cells and nerves was characteristic of diabetic gastroparesis whereas idiopathic gastroparetics had fibrosis, especially around the nerves."
    explanation: Ultrastructural fibrosis around nerves distinguishes idiopathic from diabetic gastroparesis.
  downstream:
  - target: Impaired Gastric Neuromuscular Function
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - delayed_emptying_symptom_model
    description: >-
      Reduced contractile protein expression is expected to weaken antral
      contraction. No study has shown that this change delays emptying in
      idiopathic gastroparesis; the transcript changes correlated only weakly
      with fullness and satiety scores.
- name: Impaired Gastric Neuromuscular Function
  description: >-
    Combined failure of slow-wave pacemaking, inhibitory nitrergic relaxation
    and smooth muscle contraction produces disordered gastric motility,
    including impaired antral contractility and antropyloric coordination.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: gastric motility
    modifier: DECREASED
    term:
      id: GO:0035482
      label: gastric motility
  locations:
  - preferred_term: stomach
    term:
      id: UBERON:0000945
      label: stomach
  - preferred_term: pylorus
    term:
      id: UBERON:0001166
      label: pylorus
  evidence:
  - reference: PMID:21914127
    reference_title: "Ultrastructural differences between diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, in all the patients TEM showed abnormalities in ICC, nerves and smooth muscle consistent with the delay in gastric emptying."
    explanation: Ultrastructural abnormalities of all three neuromuscular components are present in every patient studied.
  - reference: PMID:22626059
    reference_title: "What are the important subsets of gastroparesis?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the most common intrinsic defects are being recognized in the interstitial cells of Cajal (ICC-opathy) and with immune infiltration and neuronal changes (intrinsic neuropathic gastroparesis)"
    explanation: Review framing idiopathic and diabetic gastroparesis as intrinsic ICC and neuropathic disorders of the gastric wall.
  downstream:
  - target: Delayed Gastric Emptying
    causal_link_type: DIRECT
    hypothesis_groups:
    - delayed_emptying_symptom_model
    description: >-
      Disordered gastric neuromuscular function slows emptying of a solid meal.
- name: Delayed Gastric Emptying
  description: >-
    Objectively delayed emptying of a solid meal without mechanical
    obstruction, defined on 4-hour scintigraphy or a gastric emptying breath
    test. Retention at 4 hours is on average lower in idiopathic than in
    diabetic, postsurgical or connective tissue gastroparesis, and emptying
    status is labile on retesting.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: gastric emptying
    modifier: DECREASED
    term:
      id: GO:0035483
      label: gastric emptying
  locations:
  - preferred_term: stomach
    term:
      id: UBERON:0000945
      label: stomach
  evidence:
  - reference: PMID:39674226
    reference_title: "Rome Foundation and international neurogastroenterology and motility societies' consensus on idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis requires the presence of these symptoms alongside delayed gastric emptying, measured by a 4 h scintigraphy or gastric emptying breath test of a mixed composition meal in the absence of mechanical obstruction."
    explanation: International consensus requires objectively delayed emptying for the diagnosis.
  - reference: PMID:36730846
    reference_title: "Atypical Causes of Gastroparesis: Prevalence, Gastric Emptying, and Clinical Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastric retention at 4 hours was significantly greater in patients with diabetic (39.3±25.7% P <0.001), postsurgical (41.3±24.0% P =0.002), and connective tissue gastroparesis (37.8±20.0% P =0.049) compared with patients with idiopathic gastroparesis (25.5±17.6%)."
    explanation: The degree of emptying delay is on average milder in idiopathic gastroparesis.
  downstream:
  - target: Delayed gastric emptying on scintigraphy
    causal_link_type: DIRECT
    hypothesis_groups:
    - delayed_emptying_symptom_model
  - target: Vomiting
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - delayed_emptying_symptom_model
    description: >-
      Severe emptying delay is associated with worse vomiting in idiopathic
      gastroparesis; the association is modest and prokinetic acceleration of
      emptying does not predict symptom relief.
    evidence:
    - reference: PMID:20965184
      reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with severely delayed gastric emptying had worse vomiting and more severe loss of appetite and overall gastroparesis symptoms."
      explanation: In 243 idiopathic gastroparesis patients, severe delay was associated with worse vomiting.
  - target: Poor appetite
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - delayed_emptying_symptom_model
    evidence:
    - reference: PMID:20965184
      reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with severely delayed gastric emptying had worse vomiting and more severe loss of appetite and overall gastroparesis symptoms."
      explanation: Severe delay was associated with more severe loss of appetite.
  - target: Early satiety
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - delayed_emptying_symptom_model
    description: >-
      Early satiety is a classic symptom attributed to gastric retention;
      impaired accommodation may contribute independently of emptying rate.
  - target: Postprandial fullness
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - delayed_emptying_symptom_model
    description: >-
      Postprandial fullness is attributed to gastric retention, but correlates
      poorly with emptying rate.
  - target: Nausea
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - delayed_emptying_symptom_model
    description: >-
      Nausea is the most common symptom and is related to meals in most
      patients, but symptom relief does not track acceleration of emptying.
    evidence:
    - reference: PMID:24005344
      reference_title: "The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Even though most drugs concomitantly improved symptoms and accelerated GE, no study reported a significant correlation between SI and GE."
      explanation: Across prokinetic trials, accelerating emptying did not correlate with symptom improvement, weakening a direct emptying-to-symptom link.
phenotypes:
- category: Gastrointestinal
  name: Delayed gastric emptying on scintigraphy
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Retention above the normal limit on 4-hour solid-meal gastric emptying
    scintigraphy, or delay on a gastric emptying breath test, is required for
    the diagnosis.
  phenotype_term:
    preferred_term: delayed gastric emptying
    term:
      id: HP:0002578
      label: Gastroparesis
  evidence:
  - reference: PMID:39674226
    reference_title: "Rome Foundation and international neurogastroenterology and motility societies' consensus on idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis requires the presence of these symptoms alongside delayed gastric emptying, measured by a 4 h scintigraphy or gastric emptying breath test of a mixed composition meal in the absence of mechanical obstruction."
    explanation: Delayed emptying on a 4-hour test is a defining diagnostic requirement.
- category: Gastrointestinal
  name: Nausea
  frequency: VERY_FREQUENT
  description: >-
    A cardinal symptom present in nearly all patients, usually meal-related,
    and the predominant presenting symptom in about a third of idiopathic
    cases.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: PMID:27350152
    reference_title: "Nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 159 gastroparesis patients (107 IG, 52 DG), 96% experienced nausea, whereas 65% experienced vomiting."
    explanation: Registry cohort (two thirds idiopathic) in which nausea was nearly universal.
  - reference: PMID:39674226
    reference_title: "Rome Foundation and international neurogastroenterology and motility societies' consensus on idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nausea and vomiting were identified as cardinal symptoms."
    explanation: International consensus names nausea as a cardinal symptom of idiopathic gastroparesis.
- category: Gastrointestinal
  name: Vomiting
  frequency: FREQUENT
  description: >-
    Present in just over half of idiopathic gastroparesis patients, less often
    and less severe than in diabetic gastroparesis.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:27350152
    reference_title: "Nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vomiting was more common in DG (81%) compared to IG (57%; p = 0.004)."
    explanation: Vomiting occurred in 57% of idiopathic gastroparesis patients.
- category: Gastrointestinal
  name: Early satiety
  description: >-
    Early satiation, with postprandial fullness, is among the main symptoms and
    is more severe in idiopathic than in diabetic gastroparesis.
  phenotype_term:
    preferred_term: Early satiety
    term:
      id: HP:0033842
      label: Early satiety
  evidence:
  - reference: PMID:21871247
    reference_title: "Similarities and differences between diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with DG had more severe retching and vomiting than those with IG, whereas patients with IG had more severe early satiety and postprandial fullness subscores."
    explanation: NIDDK registry comparison (254 idiopathic patients) showing prominent early satiety in idiopathic gastroparesis.
  - reference: PMID:36730846
    reference_title: "Atypical Causes of Gastroparesis: Prevalence, Gastric Emptying, and Clinical Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In PSGp, diabetic and idiopathic causes, the main symptoms were early satiety and postprandial fullness"
    explanation: Early satiety is a main symptom in idiopathic gastroparesis.
- category: Gastrointestinal
  name: Postprandial fullness
  description: >-
    Postprandial fullness is a main symptom and is more severe in idiopathic
    than in diabetic gastroparesis.
  phenotype_term:
    preferred_term: Postprandial fullness
    term:
      id: HP:0033843
      label: Postprandial fullness
  evidence:
  - reference: PMID:21871247
    reference_title: "Similarities and differences between diabetic and idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with DG had more severe retching and vomiting than those with IG, whereas patients with IG had more severe early satiety and postprandial fullness subscores."
    explanation: Postprandial fullness subscores were higher in idiopathic gastroparesis.
- category: Gastrointestinal
  name: Abdominal pain
  description: >-
    Abdominal pain, often epigastric, is more often the symptom prompting
    evaluation in idiopathic than in diabetic gastroparesis.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:20965184
    reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Predominant presenting symptoms were nausea (34%), vomiting (19%), an abdominal pain (23%)."
    explanation: Abdominal pain was the predominant presenting symptom in 23% of idiopathic gastroparesis patients.
  - reference: PMID:22626059
    reference_title: "What are the important subsets of gastroparesis?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We conclude that idiopathic and diabetic gastroparesis has similar initial presentations and manifestations, except that idiopathic gastroparesis tends to be associated more frequently with pain."
    explanation: Review concluding that pain is more frequent in idiopathic gastroparesis.
- category: Gastrointestinal
  name: Bloating
  description: >-
    Abdominal bloating is common and is more pronounced in overweight patients.
  phenotype_term:
    preferred_term: bloating
    term:
      id: HP:0003270
      label: Abdominal distention
  evidence:
  - reference: PMID:20965184
    reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overweight patients had more bloating and gastric retention at 2 hours but less severe loss of appetite."
    explanation: Bloating is a feature of idiopathic gastroparesis, more severe in overweight patients.
- category: Gastrointestinal
  name: Poor appetite
  description: >-
    Loss of appetite is more severe in patients with severely delayed emptying.
  phenotype_term:
    preferred_term: loss of appetite
    term:
      id: HP:0004396
      label: Poor appetite
  evidence:
  - reference: PMID:20965184
    reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with severely delayed gastric emptying had worse vomiting and more severe loss of appetite and overall gastroparesis symptoms."
    explanation: Loss of appetite is a graded symptom of idiopathic gastroparesis.
  sequelae:
  - target: Weight loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced oral intake from poor appetite, satiety and vomiting leads to
      weight loss that can require nutritional support.
- category: Constitutional
  name: Weight loss
  description: >-
    Unintentional weight loss occurs in gastroparesis; substantial weight loss
    or intractable vomiting is the indication for nutritional support.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:28721575
    reference_title: "Gastroparesis: Medical and Therapeutic Advances."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most frequently reported symptoms of gastroparesis include nausea, vomiting, epigastric pain, early satiety, and unintentional weight loss."
    explanation: Review listing unintentional weight loss among the common features of gastroparesis.
  - reference: PMID:39674226
    reference_title: "Rome Foundation and international neurogastroenterology and motility societies' consensus on idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dietary adjustments, nutritional support (per guidelines from the European Society for Clinical Nutrition and Metabolism for substantial weight loss or intractable vomiting), and opioid cessation were recommended by a consensus opinion."
    explanation: The idiopathic gastroparesis consensus recognizes substantial weight loss as an indication for nutritional support.
- category: Psychiatric
  name: Anxiety
  frequency: FREQUENT
  description: >-
    Severe anxiety was present in 36% of registry patients with idiopathic
    gastroparesis. It is recorded as a comorbidity; no causal edge to it is
    asserted.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:20965184
    reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe anxiety and depression were present in 36% and 18%, respectively."
    explanation: Frequency of severe anxiety in 243 idiopathic gastroparesis patients.
- category: Psychiatric
  name: Depression
  frequency: OCCASIONAL
  description: >-
    Severe depression was present in 18% of registry patients with idiopathic
    gastroparesis. It is recorded as a comorbidity; no causal edge to it is
    asserted.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:20965184
    reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe anxiety and depression were present in 36% and 18%, respectively."
    explanation: Frequency of severe depression in 243 idiopathic gastroparesis patients.
diagnosis:
- name: Four-hour solid-meal gastric emptying scintigraphy
  description: >-
    Gastric emptying scintigraphy of a standardized low-fat solid meal over 4
    hours is the reference test; 4-hour testing is recommended over 2-hour
    testing. A gastric emptying breath test of a mixed meal is an accepted
    alternative.
  diagnosis_term:
    preferred_term: gastric emptying scintigraphy
    term:
      id: NCIT:C62667
      label: Radionuclide Imaging
  evidence:
  - reference: PMID:40976635
    reference_title: "AGA Clinical Practice Guideline on Management of Gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A conditional recommendation was issued against using 2-hour gastric emptying testing and in favor of 4-hour testing in patients with suspected gastroparesis."
    explanation: AGA guideline recommendation for 4-hour gastric emptying testing.
- name: Upper endoscopy to exclude mechanical obstruction
  description: >-
    Mechanical gastric outlet obstruction must be excluded, usually by upper
    gastrointestinal endoscopy or radiology, before delayed emptying is
    attributed to gastroparesis.
  diagnosis_term:
    preferred_term: upper gastrointestinal endoscopy
    term:
      id: NCIT:C78144
      label: Esophagogastroduodenoscopy
  evidence:
  - reference: PMID:39674226
    reference_title: "Rome Foundation and international neurogastroenterology and motility societies' consensus on idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This consensus defined idiopathic gastroparesis as the presence of symptoms associated with delayed gastric emptying in the absence of mechanical obstruction."
    explanation: Absence of mechanical obstruction is part of the consensus definition, which requires it to be excluded.
treatments:
- name: Dietary Modification
  description: >-
    Small-particle, low-fat, small frequent meals, with nutritional support
    (enteral feeding) for substantial weight loss or intractable vomiting, and
    cessation of opioids. Recommended by consensus opinion rather than by
    trials in idiopathic gastroparesis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:39674226
    reference_title: "Rome Foundation and international neurogastroenterology and motility societies' consensus on idiopathic gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dietary adjustments, nutritional support (per guidelines from the European Society for Clinical Nutrition and Metabolism for substantial weight loss or intractable vomiting), and opioid cessation were recommended by a consensus opinion."
    explanation: Consensus recommendation for dietary adjustment and nutritional support in idiopathic gastroparesis.
- name: Metoclopramide
  description: >-
    Dopamine D2 receptor antagonist with prokinetic and antiemetic effects; the
    only drug approved in the United States for gastroparesis, conditionally
    recommended as initial therapy, with a boxed warning for tardive
    dyskinesia.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metoclopramide
      term:
        id: CHEBI:107736
        label: metoclopramide
  target_mechanisms:
  - target: Delayed Gastric Emptying
    treatment_effect: MODULATES
    description: >-
      Prokinetics, metoclopramide among them, generally accelerate gastric
      emptying, but symptom relief does not track the acceleration.
    evidence:
    - reference: PMID:24005344
      reference_title: "The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Even though most drugs concomitantly improved symptoms and accelerated GE, no study reported a significant correlation between SI and GE."
      explanation: Meta-regression including six metoclopramide trials shows prokinetics accelerate emptying without correlated symptom benefit.
  evidence:
  - reference: PMID:40976635
    reference_title: "AGA Clinical Practice Guideline on Management of Gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are conditional recommendations for the use of metoclopramide and erythromycin in patients with gastroparesis."
    explanation: AGA guideline, covering idiopathic and diabetic gastroparesis, conditionally recommends metoclopramide.
  - reference: PMID:28721575
    reference_title: "Gastroparesis: Medical and Therapeutic Advances."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Metoclopramide is the only medication currently approved for the treatment of gastroparesis; however, it is associated with adverse effects in a sizable proportion of patients."
    explanation: Regulatory status and adverse-effect burden of metoclopramide.
- name: Erythromycin
  description: >-
    Macrolide antibiotic acting as a motilin receptor agonist; conditionally
    recommended as initial prokinetic therapy, typically short term because of
    tachyphylaxis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: erythromycin
      term:
        id: CHEBI:48923
        label: erythromycin
  evidence:
  - reference: PMID:40976635
    reference_title: "AGA Clinical Practice Guideline on Management of Gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are conditional recommendations for the use of metoclopramide and erythromycin in patients with gastroparesis."
    explanation: AGA guideline conditionally recommends erythromycin.
- name: Domperidone
  description: >-
    Peripheral dopamine D2 receptor antagonist used off label, with restricted
    access in the United States. In a consortium cohort in which most patients
    had idiopathic gastroparesis it produced moderate symptom improvement; the
    AGA guideline advises against it as first-line therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: domperidone
      term:
        id: CHEBI:31515
        label: domperidone
  evidence:
  - reference: PMID:34089855
    reference_title: "Effect of Domperidone Therapy on Gastroparesis Symptoms: Results of a Dynamic Cohort Study by NIDDK Gastroparesis Consortium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Utilizing the method of pragmatic modeling to evaluate long-term treatment of GP in a large GpCRC database, DOM treatment resulted in moderately but significantly improved GP."
    explanation: Observational consortium cohort (63% idiopathic) showing moderate benefit of domperidone.
  - reference: PMID:40976635
    reference_title: "AGA Clinical Practice Guideline on Management of Gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Conditional recommendations were issued against the use of domperidone, prucalopride, aprepitant, nortriptyline, buspirone, and cannabidiol as first-line therapies."
    explanation: AGA guideline advises against domperidone as first-line therapy.
- name: Tradipitant
  description: >-
    Neurokinin-1 receptor antagonist tested for nausea in idiopathic and
    diabetic gastroparesis. A phase 2 trial met its nausea endpoint; the phase 3
    trial did not meet its primary endpoint in the intention-to-treat
    population. Investigational.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tradipitant
      term:
        id: CHEBI:747212
        label: tradipitant
  target_mechanisms:
  - target: Nausea
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:32693185
      reference_title: "Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tradipitant resulted in statistically and clinically meaningful improvements in nausea and reduced vomiting, compared with placebo, in patients with idiopathic or diabetic gastroparesis."
      explanation: Phase 2 randomized trial showing reduced nausea.
    - reference: PMID:38237696
      reference_title: "The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12"
      explanation: The phase 3 trial did not confirm the nausea benefit in the intention-to-treat analysis.
  evidence:
  - reference: PMID:32693185
    reference_title: "Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tradipitant resulted in statistically and clinically meaningful improvements in nausea and reduced vomiting, compared with placebo, in patients with idiopathic or diabetic gastroparesis."
    explanation: Phase 2 evidence for tradipitant in idiopathic and diabetic gastroparesis.
  - reference: PMID:38237696
    reference_title: "The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12"
    explanation: Negative primary result of the phase 3 trial.
- name: Nortriptyline
  description: >-
    Tricyclic antidepressant used as a neuromodulator for nausea and pain. The
    NORIG randomized trial in idiopathic gastroparesis found no benefit over
    placebo, and the AGA guideline advises against it as first-line therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nortriptyline
      term:
        id: CHEBI:7640
        label: nortriptyline
  evidence:
  - reference: PMID:24368464
    reference_title: "Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms."
    explanation: Randomized placebo-controlled trial in 130 idiopathic gastroparesis patients refutes symptomatic benefit.
  - reference: PMID:40976635
    reference_title: "AGA Clinical Practice Guideline on Management of Gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Conditional recommendations were issued against the use of domperidone, prucalopride, aprepitant, nortriptyline, buspirone, and cannabidiol as first-line therapies."
    explanation: AGA guideline advises against nortriptyline as first-line therapy.
- name: Intrapyloric Botulinum Toxin Injection
  description: >-
    Endoscopic injection of botulinum toxin A into the pylorus to reduce
    pyloric resistance. Open-label series were encouraging, but a randomized
    placebo-controlled trial found no benefit over saline.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: endoscopic intrapyloric injection
    term:
      id: NCIT:C64958
      label: Therapeutic Endoscopic Procedure
    therapeutic_agent:
    - preferred_term: botulinum toxin type A
      term:
        id: CHEBI:3160
        label: Botulinum toxin type A
  evidence:
  - reference: PMID:18070232
    reference_title: "Botulinum toxin A for the treatment of delayed gastric emptying."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "At 1-month follow-up, 37.5% randomized to botulinum toxin and 56.3% randomized to placebo achieved improvement as defined by this study."
    explanation: Randomized double-blind trial in idiopathic and diabetic gastroparesis found no benefit over placebo.
- name: Gastric Electrical Stimulation
  description: >-
    Implanted high-frequency gastric electrical stimulator, reserved for
    refractory nausea and vomiting. It reduces vomiting in diabetic and
    non-diabetic patients without accelerating gastric emptying.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: gastric electrical stimulation
    term:
      id: NCIT:C157862
      label: Gastric Electrical Stimulation
  target_mechanisms:
  - target: Vomiting
    treatment_effect: INHIBITS
    evidence:
    - reference: PMID:31647902
      reference_title: "Gastric Electrical Stimulation Reduces Refractory Vomiting in a Randomized Crossover Trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a randomized crossover study, we found that GES reduced the frequency of refractory vomiting in patients with and without diabetes, although it did not accelerate gastric emptying or increase of quality of life."
      explanation: Double-blind crossover trial including idiopathic patients shows reduced vomiting without faster emptying.
  evidence:
  - reference: PMID:31647902
    reference_title: "Gastric Electrical Stimulation Reduces Refractory Vomiting in a Randomized Crossover Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a randomized crossover study, we found that GES reduced the frequency of refractory vomiting in patients with and without diabetes, although it did not accelerate gastric emptying or increase of quality of life."
    explanation: Randomized evidence for gastric electrical stimulation in refractory vomiting, including idiopathic gastroparesis.
  - reference: PMID:40976635
    reference_title: "AGA Clinical Practice Guideline on Management of Gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In addition, conditional recommendations were issued against the routine initial use of gastric per-oral endoscopic pyloromyotomy or gastric electrical stimulation in patients with gastroparesis, reserving these treatments for select patients with symptoms refractory to medical therapies."
    explanation: AGA guideline reserves gastric electrical stimulation for selected patients with symptoms refractory to medical therapy.
- name: Gastric Peroral Endoscopic Pyloromyotomy (G-POEM)
  description: >-
    Endoscopic division of the pyloric muscle for severe refractory
    gastroparesis. In a sham-controlled trial it improved symptoms and gastric
    retention overall; the idiopathic subgroup was small and the result in it
    not conclusive. Reserved for selected refractory patients.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastric peroral endoscopic pyloromyotomy
    term:
      id: NCIT:C64958
      label: Therapeutic Endoscopic Procedure
  target_mechanisms:
  - target: Delayed Gastric Emptying
    treatment_effect: BYPASSES
    evidence:
    - reference: PMID:35470243
      reference_title: "Endoscopic pyloromyotomy for the treatment of severe and refractory gastroparesis: a pilot, randomised, sham-controlled trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Median gastric retention at 4 hours decreased from 22% (95% CI 17 to 31) to 12% (5-22) after G-POEM and did not change after sham"
      explanation: Sham-controlled trial showing reduced gastric retention after pyloromyotomy.
  evidence:
  - reference: PMID:35470243
    reference_title: "Endoscopic pyloromyotomy for the treatment of severe and refractory gastroparesis: a pilot, randomised, sham-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In severe gastroparesis, G-POEM is superior to a sham procedure for improving both symptoms and gastric emptying 6 months after the procedure. These results are not entirely conclusive in patients with idiopathic and postsurgical aetiologies."
    explanation: Randomized sham-controlled trial (11 idiopathic of 41 patients) supporting G-POEM, with an explicit caveat for the idiopathic subgroup.
  - reference: PMID:40976635
    reference_title: "AGA Clinical Practice Guideline on Management of Gastroparesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In addition, conditional recommendations were issued against the routine initial use of gastric per-oral endoscopic pyloromyotomy or gastric electrical stimulation in patients with gastroparesis, reserving these treatments for select patients with symptoms refractory to medical therapies."
    explanation: AGA guideline reserves G-POEM for selected patients with symptoms refractory to medical therapy.
discussions:
- discussion_id: ig_cause_of_icc_loss
  prompt: >-
    What initiates the loss of interstitial cells of Cajal and the macrophage
    phenotype shift in idiopathic gastroparesis, where there is no
    hyperglycemia to drive oxidative stress?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Muscularis Macrophage Phenotype Shift
  - pathophysiology#Interstitial Cell of Cajal Loss and Injury
  rationale: >-
    The upstream trigger in diabetic gastroparesis is hyperglycemia-associated
    oxidative stress. No equivalent trigger is established for the idiopathic
    form. Candidates include antecedent viral infection (the post-infectious
    subgroup), autoimmunity (antinuclear antibodies in about 16% of idiopathic
    patients) and unrecognized neuropathic processes, none of which has been
    connected to the tissue lesion.
  evidence:
  - reference: PMID:34595805
    reference_title: "Prevalence and clinical correlates of antinuclear antibody in patients with gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Positive ANA was seen in 148 of 893 (17%) patients with gastroparesis, being similar in idiopathic (16% of 536 patients), T1DM (16% of 162), T2DM (18% of 147), and postfundoplication (19% of 48 patients) gastroparesis."
    explanation: Autoimmune serology is present in a minority of idiopathic patients but is not specific to that etiology.
  - reference: PMID:27344315
    reference_title: "Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastric EV infection was frequently detected (82 %) in patients undergoing investigation for IGP."
    explanation: Small uncontrolled series proposing gastric enterovirus infection as a trigger; it has not been replicated.
- discussion_id: ig_diabetic_model_extrapolation
  prompt: >-
    Does the macrophage, heme oxygenase-1 and oxidative-stress mechanism shown
    in diabetic mice operate in human idiopathic gastroparesis?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress
  - mechanistic_hypotheses#macrophage_oxidative_icc_injury
  rationale: >-
    Every causal step of the macrophage to ICC chain was demonstrated in
    streptozotocin or NOD diabetic mice. Human idiopathic tissue reproduces the
    static lesions only partly: CD206+ macrophages are reduced and HMOX1 mRNA is
    lower, but the CD206-ICC correlation seen in diabetic patients was absent in
    idiopathic patients, a transcript study found no loss of KIT or ANO1, and
    ICC counts did not track gastric retention in idiopathic disease. There is
    no model of idiopathic gastroparesis itself.
  evidence:
  - reference: PMID:25041465
    reference_title: "Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Depletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes."
    explanation: The human evidence for macrophage cytoprotection of ICC is specific to diabetic patients.
  proposed_experiments:
  - experiment_id: ig_muscularis_single_cell
    name: Single-cell profiling of idiopathic gastroparesis muscularis
    description: >-
      Single-cell and spatial transcriptomics of full-thickness gastric
      biopsies from idiopathic gastroparesis, diabetic gastroparesis,
      functional dyspepsia and controls, measuring macrophage heme
      oxygenase-1 expression and oxidative-stress signatures next to ICC.
    would_support:
    - pathophysiology#Loss of Heme Oxygenase-1 Cytoprotection and Oxidative Stress
    supporting_outcome:
    - >-
      Idiopathic tissue shows HO-1-deficient, inflammatory macrophages adjacent
      to injured ICC, with oxidative-stress signatures, as in diabetic models.
    refuting_outcome:
    - >-
      Idiopathic tissue shows ICC injury without macrophage HO-1 loss or
      oxidative-stress signatures.
- discussion_id: ig_emptying_symptom_correlation
  prompt: >-
    Is delayed gastric emptying the cause of symptoms in idiopathic
    gastroparesis, or a labile marker of a broader gastric sensorimotor
    disorder shared with functional dyspepsia?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Delayed Gastric Emptying
  - mechanistic_hypotheses#gastric_sensorimotor_spectrum
  rationale: >-
    About 40% of patients change between the gastroparesis and functional
    dyspepsia categories on repeat emptying testing within a year without any
    change in symptoms, 86% of idiopathic gastroparesis patients meet
    functional dyspepsia criteria, and acceleration of emptying by prokinetics
    does not predict symptom relief.
  evidence:
  - reference: PMID:33548234
    reference_title: "Functional Dyspepsia and Gastroparesis in Tertiary Care are Interchangeable Syndromes With Common Clinical and Pathologic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 48-week clinical outcome was also similar but at this time 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."
    explanation: Gastric emptying category is unstable on retesting.
  - reference: PMID:20965184
    reference_title: "Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 86% met criteria for functional dyspepsia, primarily postprandial distress syndrome."
    explanation: Most idiopathic gastroparesis patients also meet functional dyspepsia criteria.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Idiopathic Gastroparesis · 2026-09-30T20:26:22Z · View source

De novo curation of idiopathic gastroparesis (MONDO:0034150), replacing the skeleton and the stub. No other gastroparesis entry exists in kb/disorders; diabetic gastroparesis is left out of scope. Deep research: OpenScientist report research/Idiopathic_Gastroparesis-deep-research-openscientist.md (32/32 references resolved, 0 off topic, 24 on topic, 8 undecided; no needs_review key and no trigger met). Its term validation flagged UBERON:0006909 as mislabelled (lumen of digestive tract, not muscularis); that CURIE was not used and UBERON:0008856 stomach muscularis externa was looked up instead. just preflight-dr returned SKIP because MONDO records no causal gene for this term; identity was checked by hand: MONDO:0034150 carries no OMIM xref (Orphanet:558411, GARD, UMLS only) and the report is about idiopathic gastroparesis throughout. The report's statement that PMID:25041465 found CD206+ counts correlating with ICC counts is not true for the idiopathic group; the entry cites that paper as REFUTE on the macrophage-to-ICC edge. The report's SCN5A lead comes from an IBS cohort (PMID:24613995) and was not curated. Additional references beyond the report were found by PubMed search (GpCRC biopsy, transcriptome and proteome studies; NORIG, tradipitant phase 2 and 3, botulinum toxin, GES and G-POEM trials; post-viral case series). Mechanistic edges from the macrophage/heme oxygenase-1/oxidative-stress axis are cited to diabetic mouse models, grouped under an EMERGING hypothesis and a HUMAN_MODEL_MISMATCH discussion; human IG studies that do not reproduce parts of the chain are recorded as REFUTE items. Olmsted County prevalence and incidence are all-etiology gastroparesis rates with measure_type and rate_denominator set. No module conformance: no gastrointestinal motility, ICC or enteric neuromuscular module exists. GeneReviews check: NO_CHAPTER for GeneReviews and StatPearls. Validation: just validate, validate-terms, count-verified-snippets (85/85), check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes, snippet gates, validate-disorders all pass. Four phenotypes (abdominal pain, bloating, anxiety, depression) are intentionally left without a causal in-edge because no source ties them to a node. Review round 1 (PR 13290): added reference_title to all 90 evidence items, copied by script from the title frontmatter of each references_cache file. On the Muscularis Macrophage Phenotype Shift to Interstitial Cell of Cajal Loss and Injury edge, the PMID:29501441 conditioned-medium snippet was regraded from MODEL_ORGANISM to IN_VITRO because it is an explant result, a separate MODEL_ORGANISM item now quotes the in vivo result (11 of 15 diabetic Csf1op/op mice given CSF1 developed delayed emptying and damaged ICC), and the edge description was reworded to state those two results instead of claiming that mice lacking macrophages are protected. PMID:40976635 (AGA guideline) evidence was added for the recommendations against domperidone and nortriptyline as first-line therapies and for reserving gastric electrical stimulation and G-POEM for refractory patients. The three PMID:24005344 items (a systematic review and meta-regression of human prokinetic trials) were regraded from OTHER to HUMAN_CLINICAL with quote_role REVIEW_SYNTHESIS. After these changes validate, validate-terms, count-verified-snippets (90/90), check-snippet-grading, check-reference-titles, check-title-snippets, check-snippet-length, validate-disorders and check_gene_activity_grounding all pass.

OpenScientist ▸
Idiopathic Gastroparesis: A Comprehensive Disease Characteristics Report
openscientist-autonomous 30 citations 2026-09-30T19:46:07.927489

Idiopathic Gastroparesis: A Comprehensive Disease Characteristics Report

Disease: Idiopathic Gastroparesis (IGP) MONDO ID: MONDO:0034150 · ICD-10: K31.84 · MeSH: D018589 (Gastroparesis) Category: Complex / multifactorial gastric neuromuscular (sensorimotor) disorder Report type: Multi-iteration literature synthesis (12 confirmed findings, 52 papers reviewed)

Summary

Idiopathic gastroparesis (IGP) is a chronic, female-predominant gastric neuromuscular disorder defined by the presence of upper-gastrointestinal symptoms — cardinally nausea and vomiting, frequently accompanied by early satiation, postprandial fullness, bloating, and abdominal pain — in the setting of objectively delayed gastric emptying without mechanical obstruction and after exclusion of secondary causes (diabetic, post-surgical, medication-induced, connective-tissue, neurological). It is the single largest etiologic category of gastroparesis, accounting for roughly 58% of cases in tertiary series. The authoritative 2025 Rome Foundation/international consensus (PMID: 39674226) codified this definition and requires demonstration of delayed emptying by 4-hour scintigraphy or gastric emptying breath test of a mixed-composition meal.

The hallmark cellular lesion, established through full-thickness gastric biopsy studies from the NIDDK Gastroparesis Clinical Research Consortium, is loss of interstitial cells of Cajal (ICC) — the pacemaker cells that generate gastric slow waves — accompanied by depletion of anti-inflammatory CD206+ (M2) muscularis macrophages and downregulation of smooth-muscle contractile genes. Animal-model evidence (largely diabetic but mechanistically shared) knits these observations into a coherent causal axis: loss of cytoprotective, heme oxygenase-1 (HO-1)–expressing M2 macrophages permits unchecked oxidative stress, which destroys ICC and nitrergic (nNOS) enteric neurons, degrading slow-wave activity, gastric accommodation, and antropyloric coordination — the functional substrate of delayed emptying. Macrophage-deficient mice are protected from the lesion, and HO-1/IL-10 induction reverses it, demonstrating that the macrophage–HO-1–oxidative-stress module is both necessary and sufficient in models.

IGP is multifactorial, not Mendelian: there is no established causal gene, no OMIM entry, and no pathogenic-variant classification; the strongest molecular-genetic lead is the SCN5A/NaV1.5 sodium-channelopathy, a candidate susceptibility factor expressed by ICC and smooth muscle. A recognized post-infectious subgroup follows acute viral illness and is often self-limiting, while the majority of cases run a chronic, fluctuating course. Management remains largely symptomatic and only modestly effective — metoclopramide (the sole FDA-approved agent, boxed warning for tardive dyskinesia) and erythromycin are conditionally recommended, with G-POEM, gastric electrical stimulation, and intrapyloric botulinum toxin reserved for refractory disease — and roughly one-third of patients remain refractory. The strong ~4:1 to ~9:1 female predominance is biologically underpinned by the physiologically slower gastric emptying of healthy women and the inhibitory effects of estrogen and progesterone on gastric motility.

Key Findings

1. Disease Definition, Cardinal Symptoms, and Diagnostic Criteria (F001)

The 2025 Rome Foundation/international neurogastroenterology consensus defined IGP as "the presence of symptoms associated with delayed gastric emptying in the absence of mechanical obstruction," with nausea and vomiting as cardinal symptoms and early satiation/postprandial fullness frequently co-existing (PMID: 39674226). Diagnosis requires these symptoms plus delayed gastric emptying demonstrated on 4-hour scintigraphy or a gastric emptying breath test of a mixed-composition meal. Idiopathic disease is the largest category of gastroparesis — 149 of 256 patients (58.2%) in a 2023 tertiary series were idiopathic, versus 23.4% diabetic and 11.3% postsurgical (PMID: 36730846).

Key identifiers: MONDO:0034150 · ICD-10 K31.84 · MeSH D018589 (Gastroparesis). There is no OMIM entry (IGP is not monogenic). Synonyms/alternative names: idiopathic delayed gastric emptying; idiopathic gastric stasis; the disorder is increasingly reconceptualized as a gastric sensorimotor disorder on a spectrum with functional dyspepsia. Information is drawn from both aggregated disease-level resources (consensus guidelines, registries) and individual-patient sources (full-thickness biopsy cohorts, EHR/registry studies).

2. Core Cellular Pathophysiology: ICC Loss and CD206+ (M2) Macrophage Depletion (F002)

Full-thickness gastric biopsy studies remain the decisive evidence. Grover et al. 2017 (PMID: 28066953) quantified ICC in the antral muscularis: counts were reduced in idiopathic (2.53/hpf) and diabetic (2.28/hpf) gastroparesis versus controls (6.05/hpf), P = 0.004. Anti-inflammatory CD206+ (M2) macrophages were lost in circular muscle (IG 4.16 vs control 6.59, P = 0.04) and myenteric plexus (IG 3.59 vs control 7.46, P = 0.004), while overall CD45+ immune cell counts were unchanged — implying a shift in macrophage phenotype, not a global immune depletion. Bernard et al. 2014 (PMID: 25041465) confirmed ICC loss in the gastric body and found CD206+ counts correlated with ICC counts. Herring et al. 2018 (PMID: 29052298) showed decreased muscularis-externa mRNA for contractile and regulatory genes — MYH11, MYLK1, PDGFRA, PDGFB, and HMOX1 (HO-1) — in IG, with preserved KIT/ANO1.

"Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean/hpf: diabetic, 2.28; idiopathic, 2.53; controls, 6.05; P=.004)." — PMID: 28066953

Suggested ontology terms: ICC (CL:0002088); M2/muscularis macrophage (CL:0000235); smooth muscle cell (CL:0000192); GO: macrophage activation (GO:0042116), regulation of smooth muscle contraction (GO:0006940).

3. Demographics and Clinical Features — NIDDK GpCRC Registry (F003)

Parkman et al. 2011 (PMID: 20965184) characterized 243 IG patients: mean age 41 years; 88% female; 46% overweight; 50% acute symptom onset; 19% reported an initial infectious prodrome (the post-viral subset). Severe emptying delay (>35% retention at 4 h) occurred in 28%. Predominant presenting symptoms were nausea (34%), abdominal pain (23%), and vomiting (19%); women had more severe nausea, satiety, and constipation. Psychiatric comorbidity was prominent — severe anxiety in 36% and depression in 18% — and 86% met criteria for functional dyspepsia (predominantly postprandial distress syndrome), underscoring the overlap with FD.

"The mean age of 243 patients with IG studied was 41 years; 88% were female, 46% were overweight, 50% had acute onset of symptoms, and 19% reported an initial infectious prodrome." — PMID: 20965184

4. Epidemiology and Strong Female Predominance (F004)

The Olmsted County, Minnesota population study (Jung et al. 2009, PMID: 19249393) provides the foundational epidemiology:

Metric (per 100,000) Men Women Ratio
Age-adjusted incidence (per person-year) 2.4 (95% CI 1.2–3.8) 9.8 (7.5–12.1) ~4:1 F:M
Age-adjusted prevalence (Jan 1, 2007) 9.6 (1.8–17.4) 37.8 (23.3–52.4) ~4:1 F:M

Overall diagnosed prevalence was ≈24.2/100,000 (Rey et al. 2012, PMID: 22323986), and community modeling suggested up to ~1.8% of adults may harbor undiagnosed ("hidden") delayed gastric emptying — the gastroparesis "iceberg." Overall survival in the Olmsted cohort was reduced relative to the age- and sex-matched expected population.

5. Treatment Landscape — AGA 2025 Guideline (F005)

The AGA Clinical Practice Guideline on Management of Gastroparesis (2025, PMID: 40976635) issued 12 GRADE recommendations: conditionally FOR metoclopramide and erythromycin, and AGAINST domperidone, prucalopride, aprepitant, nortriptyline, buspirone, and cannabidiol as first-line therapies; it favored 4-hour over 2-hour scintigraphy. Metoclopramide (dopamine D2 antagonist / 5-HT4 agonist) is the only FDA-approved drug (PMID: 28721575) and carries a boxed warning for tardive dyskinesia, with risk elevated by continuous dosing (0.77% continuous vs 0.55% intermittent in a gastroparesis cohort; PMID: 42702756). Refractory options include gastric electrical stimulation, intrapyloric botulinum toxin, and endoscopic pyloromyotomy (G-POEM) (PMID: 36970885). Foundational care — dietary modification (small, low-fat, low-fiber meals), nutritional support, glycemic control, opioid cessation, and antiemetics — remains central (PMID: 39674226).

"There are conditional recommendations for the use of metoclopramide and erythromycin in patients with gastroparesis. Conditional recommendations were issued against the use of domperidone, prucalopride, aprepitant, nortriptyline, buspirone, and cannabidiol as first-line therapies." — PMID: 40976635

Suggested NCIT terms: Metoclopramide (C62035); Erythromycin (C557); Domperidone; Botulinum Toxin; Gastric Electrical Stimulation.

6. Mechanistic Causal Axis — Macrophage Polarization, HO-1/Oxidative Stress, ICC and nNOS Loss (F006)

Mouse-model evidence establishes the neuromuscular-injury axis (largely from NOD/streptozotocin diabetic models but mechanistically shared with IGP, which exhibits the same ICC/CD206 lesions):

  1. Choi et al. 2008 (PMID: 18926825): loss of HO-1 upregulation in gastric macrophages → increased reactive oxygen species → loss of Kit (ICC) and nNOS → delayed gastric emptying. HO-1 induction by hemin restored Kit/nNOS and normalized emptying; HO-1 inhibition caused gastroparesis in normal mice.
  2. Cipriani et al. 2018 (PMID: 29501441): macrophage-deficient Csf1op/op mice do not develop delayed emptying or ICC damage when made diabetic — proving muscularis macrophages are necessary for the injury.
  3. Choi et al. 2016 (PMID: 27795979): IL-10 activates M2/cytoprotective macrophages and induces HO-1, restoring gastric emptying, slow-wave activity, and ICC networks in diabetic mice.

"Induction of HO-1 by hemin decreased reactive oxygen species, rapidly restored Kit and neuronal nitric oxide synthase expression, and completely normalized gastric emptying... Inhibition of HO-1 activity in mice with normal gastric emptying caused a loss of Kit expression and development of diabetic gastroparesis." — PMID: 18926825

Suggested GO terms: response to oxidative stress (GO:0006979), heme oxygenase activity (GO:0004392), nitric oxide biosynthetic process (GO:0006809), macrophage activation (GO:0042116). CHEBI: heme (CHEBI:30413), nitric oxide (CHEBI:16480), reactive oxygen species (CHEBI:26523).

7. Etiology and Risk Factors (F007)

IGP is a diagnosis of exclusion — of diabetic, post-surgical/iatrogenic, medication-induced, connective-tissue, neurological, and identifiable post-viral causes (PMID: 30385743; PMID: 36970885). A recognized post-infectious/post-viral subgroup (PIGP) follows acute viral illness (CMV, EBV documented) and is typically self-limiting — 4 of 7 PIGP patients resolved spontaneously within 4 weeks–12 months (Naftali et al. 2007, PMID: 17716347); ~19% of registry patients reported an infectious prodrome. Key non-genetic risk associations: female sex (~4:1 to ~9:1), overweight status (46%), anxiety/depression (36%/18%), overlap with functional dyspepsia (86%), and a suggested bidirectional relationship with eating disorders (nondiabetic gastroparesis carries higher malnutrition/mortality; Fagan et al. 2026, PMID: 41638531). There is no established Mendelian cause.

"Gastroparesis can have idiopathic, diabetic, iatrogenic, post-surgical or post-viral aetiologies." — PMID: 30385743

"Post-infectious gastroparesis (PIGP) is a subgroup of idiopathic gastroparesis." — PMID: 17716347

8. Diagnostic Evaluation (F008)

Diagnosis requires objective delayed gastric emptying without mechanical obstruction. Gastric emptying scintigraphy (GES) is the gold standard: a standardized 4-hour solid-meal (low-fat egg-white "EggBeaters" meal) protocol, key threshold >10% retention at 4 hours (and/or >60% at 2 h); severe delay is >35% at 4 h (Rao et al. 2011 ANMS/ESNM position paper, PMID: 21138500). AGA 2025 recommends 4-hour over 2-hour testing (PMID: 40976635). Validated alternatives include the ¹³C-breath test (spirulina/octanoate) and the wireless motility capsule, which correlate with scintigraphy but lack full standardization (PMID: 41128532). Mechanical obstruction is excluded by upper endoscopy/imaging. Research/specialist tools: EndoFLIP (pyloric distensibility), electrogastrography, antroduodenal manometry, full-thickness gastric biopsy. No blood biomarker or genetic test is diagnostic.

"The tests include measurements of: gastric emptying with scintigraphy, wireless motility capsule, and (13)C breath tests." — PMID: 21138500

9. Prognosis, Quality of Life, and Disease Course (F009)

IGP is typically chronic; spontaneous remission is uncommon except in the post-viral subset. In a multicenter GpCRC registry (Parkman et al. 2026, PMID: 41833524; N=1013, 607 idiopathic), predominant symptoms were nausea (31%), vomiting (20%), abdominal pain (20%). Abdominal pain was more often predominant in idiopathic (vs vomiting in diabetic) and that group had the lowest quality-of-life scores. Over 48 weeks, GCSI improved by ≥1 point in only 26% overall — more often with predominant nausea (32%) or bloating (35%), less often with fullness (13%) or abdominal pain (15%), indicating modest, symptom-dependent improvement. Complications include malnutrition, dehydration, electrolyte disturbance, weight loss, bezoar formation, impaired glycemic control, frequent hospitalization, and reduced QoL. Overall survival is reduced (PMID: 19249393). QoL instruments: PAGI-SYM, GCSI, SF-12/SF-36, EQ-5D, GIQLI.

"Of 555 patients followed over 48 weeks, GCSI improved by ≥ 1 in 26% overall, more often in patients with initial PrS of nausea (32%) and bloating (35%) and less often for initial PrS of fullness (13%) or abdominal pain (15%)." — PMID: 41833524

10. Genetic/Molecular Basis — No Mendelian Cause; SCN5A/NaV1.5 as Candidate (F010)

IGP has no established causal gene, OMIM entry, or pathogenic-variant classification — it is complex/multifactorial and is not listed as monogenic in OMIM/ClinVar. The strongest molecular-genetic lead across GI neuromuscular motility disorders is SCN5A, encoding the voltage-gated sodium channel NaV1.5 expressed by ICC and smooth muscle. Beyder et al. 2014 (PMID: 24613995) found SCN5A missense mutations in 13/584 (2.2%) IBS patients, 10/13 disrupting NaV1.5 function (9 loss-of-function, 1 gain-of-function); mexiletine restored function and normalized bowel habits in a p.A997T carrier. Verstraelen et al. 2015 (PMID: 25898860) review NaV1.5 channelopathy in GI motility disorders. At the tissue level, IGP shows decreased muscularis-externa mRNA for MYH11, MYLK1, PDGFRA, PDGFB, and HMOX1 (PMID: 29052298) and macrophage-based immune-gene dysregulation on transcriptomic/proteomic profiling (Chikkamenahalli et al. 2020, PMID: 32718570; datasets GEO GSE115601, single-cell GSE252126). No recurrent chromosomal abnormality, epigenetic signature, or founder effect is established.

"Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands)." — PMID: 24613995

Suggested gene annotations: SCN5A (HGNC:10593, candidate); HMOX1 (HGNC:5013); NOS1/nNOS (HGNC:7872); KIT (HGNC:6342); ANO1 (HGNC:21625); PDGFRA (HGNC:8803).

11. Animal/Model Systems and the Nitrergic-Oxidative-Stress Axis (F011)

Principal model systems (mostly mouse/rat):

Model Key feature Reference
nNOS-deficient (Nos1⁻/⁻) mice Established genetic model; delayed emptying, impaired pyloric relaxation. Neural stem cell transplant → nNOS+ neurons, improved emptying (49.7% vs 35.1%, P<0.01) PMID: 16344050
NOD / streptozotocin diabetic mice Delayed emptying + ICC loss, reversible by HO-1/IL-10 PMID: 18926825, PMID: 27795979
Csf1op/op macrophage-deficient mice Protected from delayed emptying/ICC damage PMID: 29501441
Kit mutant (W/Wv) mice Model ICC deficiency —
ApoE-knockout mice Hyperlipidemia/oxidative-stress model; reduced nitrergic relaxation with decreased nNOS, GCH-1, NRF2 (NFE2L2) PMID: 22302246

"nNOS-/- mice, a well-established genetic model of gastroparesis... Gastric emptying was significantly increased in mice that received NSCs as compared with vehicle-injected controls (49.67% vs 35.09%; P < .01)." — PMID: 16344050

In vitro/cellular models: isolated ICC, muscularis macrophage cultures, and human full-thickness gastric biopsy tissue. Limitation: most causal-mechanism models are diabetic; no dedicated, validated idiopathic genetic model exists.

12. Anatomy, Hormonal Basis of Female Predominance, and Temporal Features (F012)

ANATOMY: Primary organ is the stomach (UBERON:0000945), especially the antrum (UBERON:0001165) and pylorus (UBERON:0001166), within the digestive system (UBERON:0001007). The lesion localizes to the muscularis propria/externa (UBERON:0006909): circular/longitudinal smooth muscle (CL:0000192), myenteric (Auerbach) plexus (UBERON:0002439), ICC (CL:0002088), nitrergic/nNOS enteric neurons (CL:0000540), and muscularis macrophages (CL:0000235). Extrinsic vagal/autonomic innervation and the brain-gut axis are implicated.

FEMALE PREDOMINANCE & HORMONES: Healthy women physiologically empty solids and liquids more slowly than men ("postprandial physiologic gastroparesis"; Caballero-Plasencia et al. 1999, PMID: 10499477); sex steroids (progesterone, estrogen) inhibit gastric emptying (Hutson et al. 1989, PMID: 2909416) — a biological basis for the ~4:1–9:1 female predominance.

"These findings support the hypothesis that sex steroid hormones have variable inhibitory effects on gastric emptying of a mixed meal." — PMID: 2909416

TEMPORAL: Adult-onset (mean ~41 y), can be childhood-onset; onset acute in ~50% (often post-infectious) or insidious; course typically chronic and fluctuating/episodic, lifelong in most, but self-limiting in the post-viral subset over weeks–months.

Mechanistic Model / Interpretation

Ordered Causal Chain (initiating lesion → clinical manifestation)

[Initiating triggers — branch point]
  ├─ Acute viral infection (CMV/EBV) ─┐         (post-infectious subtype; ~19% of cases)
  ├─ Unknown idiopathic trigger ───────┤
  └─ Candidate SCN5A/NaV1.5 ───────────┘  (inferred susceptibility, not proven causal)
    │
    ▼
(1) Loss of cytoprotective CD206+ / HO-1+ (M2) muscularis macrophages
│  (demonstrated in human IGP biopsy: CD206 IG 4.16 vs 6.59, P=0.04)
▼  "leads to"
(2) Failure of HO-1–mediated antioxidant defense
│  (HMOX1 mRNA reduced in IGP muscularis; model-proven axis)
▼  "results in"
(3) Unchecked oxidative stress (↑ reactive oxygen species) in muscularis propria
│  (direct in diabetic models; INFERRED in idiopathic)
▼  "causes"
(4) Injury/loss of interstitial cells of Cajal (ICC)  ──┐
    and loss of nitrergic (nNOS) enteric neurons  ──────┤  (ICC IG 2.53 vs 6.05/hpf, P=0.004)
│                                                │
▼                                                ▼
(5) Impaired gastric slow-wave pacemaking     Loss of nitrergic pyloric relaxation
    + downregulated contractile genes          + impaired accommodation
    (MYH11, MYLK1, PDGFRA/B)                    (antropyloric dyscoordination)
│                                                │
└───────────────┬────────────────────────────────┘
        ▼  "results in"
(6) Delayed gastric emptying + gastric sensorimotor dysfunction
        ▼  "manifests as"
(7) Nausea, vomiting, early satiety, postprandial fullness, bloating, abdominal pain
    (modulated by visceral hypersensitivity, gut-brain axis, anxiety/depression)

Upstream vs downstream. The macrophage phenotype shift (M2/HO-1 depletion) is the most upstream demonstrable node; oxidative stress is the central effector; ICC and nNOS loss are the proximate lesions producing the downstream physiology of delayed emptying. The female-predominant epidemiology sits alongside this chain as a permissive modifier: hormonally slower baseline emptying lowers the threshold at which neuromuscular injury becomes symptomatic.

Important caveat on evidence strength. The human IGP data are strongest for the static histological endpoints (ICC loss, CD206 loss, contractile-gene downregulation). The dynamic causal links (macrophage → HO-1 → ROS → ICC/nNOS loss) are proven chiefly in diabetic/oxidative-stress mouse models; their application to idiopathic disease is a well-supported inference grounded in the shared histological lesion, not a directly demonstrated mechanism in humans. A parallel, increasingly emphasized view reframes IGP as a sensorimotor disorder on a spectrum with functional dyspepsia (PMID: 33548234; PMID: 42235947), in which delayed emptying correlates poorly with symptoms and gut-brain/visceral-hypersensitivity mechanisms carry substantial weight.

Evidence Base

PMID Title (abbrev.) Role in this report
39674226 Rome Foundation consensus on IGP Authoritative definition + diagnostic criteria (F001)
36730846 Atypical causes of gastroparesis IGP = 58.2% of cases (F001)
28066953 CD206 macrophage loss in gastroparesis Quantifies ICC + M2 macrophage loss (F002)
29052298 Transcriptional changes in IGP muscularis Contractile/HMOX1 gene downregulation (F002, F010)
25041465 CD206 & ICC in gastric body Confirms ICC loss + CD206 correlation (F002)
20965184 Clinical features of IG (NIDDK) Demographics, 88% female, prodrome (F003, F007)
19249393 Olmsted County epidemiology Incidence/prevalence, female predominance, survival (F004, F009)
22323986 Hidden gastroparesis "iceberg" Overall diagnosed prevalence 24.2/100k (F004)
40976635 AGA 2025 guideline Pharmacotherapy + 4-h scintigraphy (F005, F008)
28721575 Gastroparesis therapeutic advances Metoclopramide sole FDA-approved agent (F005)
42702756 TD with metoclopramide Continuous > intermittent TD risk (F005)
36970885 2023 clinical management update Refractory interventions; etiologic categories (F005, F007)
18926825 HO-1 protects ICC Core HO-1/ROS/ICC/nNOS axis (F006)
29501441 Macrophages & delayed emptying Csf1op/op mice protected — macrophages necessary (F006)
27795979 IL-10 restores gastric emptying M2/HO-1 activation reverses lesion (F006)
30385743 Gastroparesis (Nat Rev Dis Primers) Etiologic classification (F007)
17716347 Post-infectious gastroparesis PIGP subgroup, self-limiting course (F007)
21138500 ANMS/ESNM transit position paper GES/breath test/WMC diagnostics (F008)
41128532 Pediatric GES review Breath test + WMC alternatives (F008)
41833524 Predominant symptom & QoL Modest, symptom-dependent improvement (F009)
41638531 Nondiabetic gastroparesis diet review Higher malnutrition/mortality (F007, F009)
24613995 NaV1.5 channelopathy in IBS SCN5A candidate susceptibility (F010)
25898860 SCN5A channelopathy review NaV1.5 in ICC/smooth muscle (F010)
32718570 Gastric biopsies review Macrophage immune dysregulation, omics (F010)
16344050 NSC transplant in nNOS⁻/⁻ mice nNOS⁻/⁻ genetic model; rescue (F011)
22302246 ApoE-KO gastric nitrergic/NRF2 Oxidative-stress model (F011)
10499477 Gastric emptying & menstrual cycle Physiologic slower emptying in women (F012)
2909416 Gender/menopause & gastric emptying Sex steroids inhibit emptying (F012)
33548234 FD & gastroparesis interchangeable Spectrum/sensorimotor reframing (interpretation)
42235947 GESA position statement on IGP Sensorimotor-disorder reconceptualization (interpretation)

Supporting vs challenging. The biopsy and animal-model literature support the ICC/macrophage/oxidative-stress mechanistic core. The functional-dyspepsia-overlap and GESA sensorimotor papers challenge a purely "delayed-emptying" framing — noting that emptying rates correlate poorly with symptoms and are labile (37–42% of patients reclassify between FD and gastroparesis over a year; PMID: 33548234). Both perspectives are integrated above.

Sections With Limited or Not-Applicable Data

  • Causal genes / pathogenic variants / ACMG classification (Section 4): None established. No OMIM entry; not in ClinVar as monogenic. SCN5A/NaV1.5 is a candidate susceptibility factor only.
  • Epigenetics, chromosomal abnormalities, founder effects, carrier frequency, inheritance pattern, penetrance, anticipation, consanguinity (Sections 4, 9): Not applicable / none established — IGP is multifactorial, not Mendelian.
  • Infectious agents (Section 5): Only the post-infectious subtype has documented triggers (CMV, EBV); no single causative pathogen.
  • Other species / natural disease / veterinary relevance / zoonosis (Section 14): No naturally occurring idiopathic gastroparesis is described in companion animals or wildlife; relevant data are limited to induced laboratory rodent models (Section 15). Orthologous genes exist (e.g., mouse Nos1, Hmox1, Kit, Scn5a) but no OMIA natural-disease entry corresponds to human IGP.
  • Gene therapy, cell therapy, RNA-based therapy, immunotherapy, pharmacogenomics (Section 12): No approved advanced therapeutics; IL-10/HO-1 induction and neural stem cell transplantation are experimental (model-stage only).

Limitations and Knowledge Gaps

  1. Mechanism is inferred, not proven, in humans. The macrophage→HO-1→ROS→ICC/nNOS causal chain is demonstrated primarily in diabetic mouse models; human IGP evidence is largely cross-sectional histology. The direction of causation and the initiating trigger in idiopathic disease remain unknown.
  2. Poor symptom–physiology correlation. Gastric emptying rate correlates weakly with symptom severity and is labile over time, undermining delayed emptying as a unifying pathophysiological endpoint and blurring the boundary with functional dyspepsia.
  3. No molecular diagnostic or biomarker. Diagnosis rests on a functional test (scintigraphy) with imperfect reproducibility; no blood/genetic biomarker exists.
  4. Heterogeneous entity. IGP almost certainly aggregates several distinct pathophysiologies (post-viral, sensorimotor/FD-overlap, eating-disorder-associated, channelopathy-related), limiting the generalizability of any single mechanism.
  5. Modest, refractory treatment landscape. Only ~26% achieve meaningful symptom improvement; ~one-third are refractory; the sole FDA-approved drug carries a serious neurological risk.
  6. No dedicated idiopathic animal model. Existing genetic models (nNOS⁻/⁻, Kit-mutant) recapitulate lesions but not the idiopathic etiology.
  7. Sex-difference mechanism underexplored. The estrogen/progesterone contribution is established physiologically but not mechanistically linked to the ICC/macrophage lesion.

Proposed Follow-up Experiments / Actions

  1. Human muscularis single-cell + spatial transcriptomics (extend GSE252126) comparing IGP, diabetic gastroparesis, FD, and controls to test whether the M2/HO-1 macrophage-depletion axis operates in idiopathic tissue and to resolve disease subtypes.
  2. Prospective post-viral cohort with serial GES, biopsy, and viral serology to define which triggers produce self-limiting vs chronic disease and to capture the earliest cellular events.
  3. Targeted SCN5A/NaV1.5 sequencing in a well-phenotyped IGP registry (mirroring the IBS 2.2% finding) with functional electrophysiology of variants, and a pilot of mexiletine in loss-of-function carriers.
  4. Translational HO-1/IL-10 or NRF2-activator trial (e.g., dimethyl fumarate) targeting the oxidative-stress node validated in ApoE-KO and diabetic models.
  5. Sex-hormone mechanistic studies linking estrogen/progesterone signaling to ICC survival and macrophage polarization, to explain female predominance.
  6. Biomarker discovery (serum proteomics/metabolomics; circulating macrophage-phenotype or ICC-injury markers) to replace or complement scintigraphy.
  7. Redefinition initiative — adopt the sensorimotor-spectrum framework (PMID: 42235947; PMID: 39674226) with symptom-plus-physiology endpoints in future trials rather than emptying rate alone.

Report compiled from 12 confirmed findings and 52 reviewed papers across 5 investigation iterations. Evidence source types are indicated throughout: human clinical (registry/biopsy), model organism (mouse/rat), in vitro (isolated ICC/macrophage), and computational (transcriptomic/proteomic datasets).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 32
Resolved 32
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 32
On topic 24
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 25
Resolved 19
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 6
Terms whose name was checked 10
Terms named correctly 6
Terms named as a different term 1
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • UBERON:0006909 (1 mention) - the report calls it "muscularis propria/externa"; UBERON calls it lumen of digestive tract

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0004392 (1 mention) - the report calls it "heme oxygenase activity"; GO calls it heme oxygenase (decyclizing) activity, and lists "heme oxygenase activity" among its other names
  • UBERON:0001165 (1 mention) - the report calls it "antrum"; UBERON calls it pyloric antrum, and lists "antrum" among its other names
  • UBERON:0002439 (1 mention) - the report calls it "myenteric (Auerbach) plexus"; UBERON calls it myenteric nerve plexus