Associations between Abnormal Quantitative Autonomic Function Test Parameters and Specific Gastrointestinal Symptoms

Autonomic dysfunction has been associated with various gastrointestinal (GI) pathologies, particularly in disorders of gut-brain interaction (DGBI), where patients experience chronic sensory and motility GI symptoms¹. Quantitative autonomic function testing (AFT) comprehensively assesses various domains of autonomic function and serves as the gold standard for diagnosing disorders associated with dysfunction of the autonomic nervous system (ANS)². Despite our longstanding appreciation of the link between GI symptoms and altered autonomic function, many fundamentally important questions such as the prevalence and types of GI symptoms in patients with autonomic dysfunction have not previously been examined in large cohorts. We sought to examine the prevalence and types of GI symptoms in patients who completed AFTs, and to determine whether abnormal AFT parameters may serve as predictors for GI symptoms.

We conducted a cross-sectional study of 2080 patients undergoing quantitative AFT at a tertiary center between 2017–2022. Patients presenting for AFT completed three GI symptom scales (nausea, diarrhea, and constipation) as part of a larger, validated Survey of Autonomic Symptoms³. These GI symptom scales consisted of single-item questions, where participants were asked to rate each symptom on a scale of 0 to 5 (5 being the most severe), with ratings greater than 0 indicating the presence of symptoms and a rating of 0 indicating their absence. Patients lacking GI symptom data were excluded (n=155). We reviewed the medical records of a subset of patients (n=504) who underwent GI endoscopic and/or motility testing in order to determine the correlation between selected abnormal AFT parameters and GI testing results, to assess whether any GI testing could discriminate between the severity of abnormal AFT parameters identified in patients with GI symptoms.

All patients underwent comprehensive AFT, which encompasses the following components (Supplemental Table 1): 1) deep breathing test (DBT), which assesses cardiovagal parasympathetic function, 2) Valsalva maneuver, which uses blood pressure responses in assessing sympathetic adrenergic function, 3) tilt table test, which evaluates the response of ANS to orthostatic stress, measuring both sympathetic adrenergic and parasympathetic cardiovagal orthostatic responses, 4) sudomotor test, which determines the function of nerve fibers that control sweat glands and evaluates postganglionic sympathetic cholinergic function, and 5) skin punch biopsies for evaluation of epidermal sensory and sweat gland fibers. Autonomic function parameters are graded based on the Quantitative Autonomic Reflex and Small Fibers Tests (QASAT) scoring system⁴. Normal function is graded as 0 points, and abnormal parameters are assigned additional points based on the severity of abnormalities (Supplemental Table 1).

Of the 1925 patients, the median age was 45 (IQR, 31–60) and 76% (n=1463) were female. Median BMI was 25.6 (IQR, 22.1–30.3). 83.7% (n=1611) of the patients identified as White, 0.21% (n=4) as American Indian or Alaska Native, 1.5% (n=29) as Asian, 2.18% (n=42) as Black, 3.32% (n=64) as multiple or other races, and 9.1% (n=175) as unknown. Overall, a large proportion (n=1600, 83%) of patients undergoing AFT experienced one or more of the following GI symptoms: nausea (68%), diarrhea (42%), or constipation (62%). We examined the relationship between each of these GI symptoms and abnormal AFT parameters. Patients reporting nausea symptoms were found to have increased heart rate response to tilt, decreased cerebral blood flow velocity (CBFV), and lower end tidal CO₂ during tilt (QASAT score 0.56 vs 1.22, p<0.0001; 3.02 vs 3.56, p<0.001; 1.24 vs 2.07, p< 0.0001 by Mann-Whitney U test, respectively, Table 1). Increased heart rate response to tilt signifies both sympathetic and parasympathetic dysfunction. This is a parameter used for detection and grading of postural orthostatic tachycardia syndrome (POTS). Measurement of CBFV assesses blood flow which is used as a proxy of cerebral perfusion. Of note, decreased CBFV to tilt has been observed in patients with POTS and chronic fatigue syndrome^5,6. Decreased end tidal CO₂ during tilt is indicative of a hypocapnic hyperventilation response to postural challenge. Interestingly, upright hypocapnic hyperventilation has been previously described in POTS patients where hypocapnia may reflect metabolic compensation of central hypovolemia associated with the orthostatic drop in cardiac output⁷. Multivariable logistic regression analyses adjusting for age and sex showed that increased heart rate response to tilt and end tidal CO₂ during tilt were independently associated with the presence of nausea (OR 1.06 [1.01–1.13], p=0.015 and OR 1.09 [1.04–1.14], p<0.0001, respectively). As the cerebral blood flow response to tilt is calculated as the reduction in percent from the supine baseline of a tested individual (Supplemental Table 1), where supine baseline is 100%, this parameter does not vary by age and sex as each value is internally controlled per tested subject. Notably, certain parameters, such as the DBT, sudomotor test, and sweat gland nerve fiber density, were more abnormal in patients without nausea compared to those with nausea. Since AFT evaluates broad ANS functions that regulate multiple organ systems (e.g. cardiovascular, respiratory, GI, bladder, and sexual function, among others), these parameters may have a great relevance to non-GI organ systems, underscoring the complex, multisystem nature of autonomic dysfunction. There were no associations between diarrhea or constipation and abnormal AFT.

Table 1.

Quantitative autonomic function testing parameters comparing patients witn ana witnout specific gastrointestinal symptoms

AFT parameters	No symptomsa	Positive symptoms	P-value b
Nausea	N = 612	N = 1313
Deep breathing test	0.79 (0 – 3)c,d	0.52 (0 – 3)	1.31E-07*
Valsalva maneuver	1.29 (0 – 3)	1.13 (0 – 3)	1.05E-03
Tilt table test – increased heart rate response	0.56 (0 – 7)	1.22 (0 – 10)	1.66E-09*
Tilt table test - cerebral blood flow velocity	3.02 (0 – 10)	3.56 (0 – 10)	3.71E-04*
Tilt table test - decline in end tidal CO2	1.24 (0 – 10)	2.07 (0 – 10)	2.34E-08*
Sudomotor test – electrochemical skin conductance	2.53 (0 – 6)	1.96 (0 – 6)	1.34E-09*
Epidermal nerve fiber density	2.28 (0 – 8)	2.25 (0 – 8)	0.66
Sweat gland nerve fiber density	1.82 (0 – 8)	1.4 (0 – 8)	3.97E-04*
Diarrhea	N = 1107	N = 818
Deep breathing test	0.61 (0 – 3)	0.6 (0 – 3)	0.93
Valsalva maneuver	1.19 (0 – 3)	1.16 (0 – 3)	0.48
Tilt table test – increased heart rate response	0.9 (0 – 9)	1.15 (0 – 10)	0.05
Tilt table test - cerebral blood flow velocity	3.34 (0 – 10)	3.46 (0 – 10)	0.40
Tilt table test - decline in end tidal CO2	1.71 (0 – 10)	1.93 (0 – 10)	0.07
Sudomotor test – electrochemical skin conductance	2.1 (0 – 6)	2.2 (0 – 6)	0.38
Epidermal nerve fiber density	2.18 (0 – 8)	2.35 (0 – 8)	0.17
Sweat gland nerve fiber density	1.44 (0 – 8)	1.62 (0 – 8)	0.17
Constipation	N = 729	N = 1196
Deep breathing test	0.58 (0 – 3)	0.62 (0 – 3)	0.15
Valsalva maneuver	1.16 (0 – 3)	1.19 (0 – 3)	0.61
Tilt table test – increased heart rate response	0.95 (0 – 9)	1.04 (0 – 9)	0.30
Tilt table test - cerebral blood flow velocity	3.1 (0 – 10)	3.57 (0 – 10)	3.36E-03
Tilt table test - decline in end tidal CO2	1.6 (0 – 10)	1.93 (0 – 10)	0.02
Sudomotor test – electrochemical skin conductance	2.21 (0 – 6)	2.09 (0 – 6)	0.14
Epidermal nerve fiber density	2.35 (0 – 8)	2.2 (0 – 8)	0.17
Sweat gland nerve fiber density	1.66 (0 – 8)	1.45 (0 – 8)	0.03

^a.“No symptoms” refers to patients who do not exhibit the specified GI symptoms (i.e. nausea, diarrhea, or constipation)

^b.The p-value cutoff for significance was determined to be 5.43x10⁻⁴ using alpha =0.05 with a Bonferroni correction.

^c.All values listed are scores based on Quantitative Autonomic Reflex and Small Fibers Tests (QASAT) scoring system⁶. Supplemental Table 1 includes interpretations and scoring rubrics for each parameter.

^d.Values represent means (2.5% - 97.5% quantiles).

Of the 1925 patients, 324 (16.8%) patients met the diagnostic criteria for POTS, namely a combination of sustained increased heart rate response to tilt test without orthostatic hypotension⁸. Patients with POTS were more likely to experience nausea than patients without POTS (82% vs 65%, p< 0.0001). There was no significant difference in the prevalence of diarrhea or constipation in patients with or without POTS.

A subset of patients (n=504) underwent GI testing: EGD, colonoscopy, esophageal manometry, pH impedance testing, 4-hour gastric emptying study, upper GI series, Sitz marker test, anorectal manometry, and wireless motility capsule. Examination of the medical records of these patients demonstrated no associations between rates of abnormal GI testing and the severity of specific abnormal AFT parameters identified above as being associated with GI symptomology (Supplemental Table 2).

To the best of our knowledge, this study contains the largest cohort to date where GI symptoms, standard GI tests, and comprehensive AFT parameters were evaluated concurrently. We found GI symptoms to be highly prevalent (83%) among those undergoing AFT, with a suggestion that specific autonomic system dysfunctions (sympathetic, parasympathetic, and metabolic) may be linked to certain GI symptoms. These findings appear to correlate most strongly with nausea rather than constipation or diarrhea. Standard GI diagnostic testing failed to discriminate the severity of abnormal autonomic testing parameters, suggesting that abnormal autonomic function—rather than structural abnormalities or dysmotility—may underlie the pathophysiology of some GI sensory symptoms (i.e. nausea). Study limitations include the fact that only a subset of GI symptoms was queried (e.g. data on abdominal pain were not collected) and the cross-sectional study design. Future longitudinal studies examining a broader array of symptoms are needed.

Abbreviations:

AFT

autonomic function testing

ANS

autonomic nervous system

CBFV

cerebral blood flow velocity

DBT

deep breathing test

DGBI

disorders of gut-brain interaction

GI

gastrointestinal

POTS

postural orthostatic tachycardia syndrome

QASAT

Quantitative Autonomic Reflex and Small Fibers Tests