Surgery 168 (2020) 800e808

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Surgery
journal homepage: www.elsevier.com/locate/surg

Bile Duct/Gallbladder

Association of gallbladder hyperkinesia with acalculous chronic

cholecystitis: A case-control study
Ravishankar Pillenahalli Maheshwarappa, MDa, Yusuf Menda, MDa,
Michael M. Graham, MD, PhDa, Sarag A. Boukhar, MDb, Gideon K.D. Zamba, PhDc,
Isaac Samuel, MDd,*
a
Department of Radiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
b
Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
c
Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA
d
Department of Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA

a r t i c l e i n f o a b s t r a c t

Article history: Background: This is the first case-control study investigating an association between gallbladder hy-
Accepted 9 June 2020 perkinesia and symptomatic acalculous chronic cholecystitis.
Available online 9 July 2020 Methods: This retrospective study in a single academic center compared resolution of biliary pain in
adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction

80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy
(control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of
296 adults without gallstones had an ejection fraction
80%, of whom 46 patients met predetermined
eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity
of pain, and resolution of pain were compared between groups.
Results: Demographics (mean ± standard deviation) in the control group (n ¼ 25) and in the study group
(n ¼ 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/
m2, with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18
of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean
follow-up of 36 ± 28 months (range 10e120 months) (P < .01). Pain resolution with cholecystectomy was
independent of demographic variables, hepatobiliary iminodiacetic acid scan ejection fraction, and
chronicity of pain. The odds of pain resolution was 19.7 times greater with cholecystectomy than without
(odds ratio, 19.7; 95% confidence interval, 4.34, 89.43; P < .01), and remained robust even with the odds
adjusted for each covariate. Gallbladder histopathology confirmed chronic cholecystitis in all 21 chole-
cystectomy specimens.
Conclusion: Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in
adults.
© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction acalculous chronic cholecystitis from gallbladder hypokinesia (also

known as “biliary dyskinesia” defined by hepatobiliary iminodi-
Cholecystectomy is the standard therapy for gallstone-related, acetic acid scan ejection fraction [HIDA EF] <35%e40% with good
acute or chronic cholecystitis,1 but also for selected patients with symptom relief.3e10 Gallbladder hyperkinesia is defined as a HIDA
acalculous acute cholecystitis.2 Furthermore, in recent decades, EF
80%. Although cholecystectomy for treatment of acalculous
cholecystectomy was introduced as appropriate treatment for chronic cholecystitis from gallbladder hyperkinesia is performed in
children,11 this entity of gallbladder hyperkinesia is rarely recog-
nized in adults.5,7,11e15
* Reprint requests: Isaac Samuel, MD, FRCS, FACS, University of Iowa Gallbladder More recently, a few publications of anecdotal case series
Dysfunction Clinic, Professor, Department of Surgery, Roy J. and Lucille A. Carver
College of Medicine, 200 Hawkins Drive, Suite 4625 JCP (Surgery), University of
without a control group for comparison suggest that cholecystec-
Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. tomy often resolves symptoms in adults with gallbladder hyper-
E-mail address: [email protected] (I. Samuel). kinesia.16e18 Although useful corroborative evidence, these

https://doi.org/10.1016/j.surg.2020.06.005
0039-6060/© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 R. Pillenahalli Maheshwarappa et al. / Surgery 168 (2020) 800e808 801

results of a cholecystokinin (CCK)-stimulated gallbladder ejection

fraction (EF) according to the then-standardized national pro-
tocols10,13 where low EFs are considered abnormal, and greater EFs
are all reported “normal.” Because it was not a recognized condition
during the period of our study, we defined gallbladder hyperkinesia
as an EF
80% as the arbitrary cut-off level, because this level of EF
was used in a 2013 pediatric publication.11 Adults without gall-
stones on ultrasonography, but with gallbladder hyperkinesia, who
satisfied predetermined eligibility criteria (Fig 1) formed the
cohort. Key inclusion criteria comprises adults with right upper
quadrant or epigastric pain suggestive of biliary origin and who had
undergone clinical evaluations that excluded other common
gastrointestinal causes of upper abdominal pain that may cloud
interpretation of the presentation (Fig 1 and Table I).3,7,8 These
elaborate eligibility criteria produced predictably a small sample
size but one refined enough to be recognized as a select cohort of
adults with symptomatic acalculous gallbladder hyperkinesia. Pa-
tients from this cohort who underwent cholecystectomy formed
the study group. Those patients who did not undergo cholecys-
tectomy formed the control group. Being that this is a retrospective
chart review showing a cross-section of the institutional practice,
the authors had no role in patient selection for cholecystectomy
except for the 2 cholecystectomies successfully completed for
gallbladder hyperkinesia by the UI Gallbladder Dysfunction Clinic
in 2018 for HIDA EF of 100% and 92%.
Clinical presentation and follow-up data were obtained from the
electronic medical record. For the purposes of this study, “biliary
pain” was defined as “right upper quadrant or epigastric pain with
Fig 1. Flowchart of eligibility criteria, groups, and summary results shows cohort of 46
one or more of the following associated features: postprandial
adults with symptomatic acalculous gallbladder hyperkinesia who met predetermined
eligibility criteria for the study. Shaded boxes with dotted borders represent the exacerbation of pain, radiation to the back or shoulder, nausea,
excluded groups. These 46 patients had right upper quadrant/epigastric pain recorded vomiting, gaseous symptoms, or diarrhea.” Chronicity of pain was
in the chart suggestive of biliary pain, and routine GI tests when done were negative. defined as the period from earliest onset of pain until resolution of
*GBEF not done: Bile leak, acute cholecystitis, sphincter of Oddi Dysfunction protocol. pain or until persistence of pain last documented in the medical
y
Cholelithiasis: 26 on ultrasonography, 3 at gross pathology. zExclusion criterion A: No
follow-up (Table I). xExclusion criterion B: Associated GI disease (Table I). HIDA, hep-
record up to December 2019, which was the end of the study
atobiliary iminodiacetic acid scan; GBEF, gallbladder ejection fraction; GI, period. Resolution of pain was ascertained after the 30-day post-
gastrointestinal. operative visit with the surgeon by comparison with the charac-
teristics of the preoperative pain from the “History of Presenting
Illness” and “Review of Systems” from multiple clinic visits to pri-
anecdotal reports in the absence of a control group are inherently mary care clinicians and other specialties. Evidence of persistence
observational and have gone largely unnoticed by the medical and of pain was generally available in the “History of Presenting Illness,”
surgical community.16e18 Therefore, we present the first, retro- because it was most often the presenting complaint.
spective, case-control report to test the hypothesis that adults with Within the restrictions imposed by a retrospective approach, our
acalculous chronic cholecystitis associated with gallbladder hy- chart reviews included explorations of the presenting symptoms of
perkinesia will benefit from cholecystectomy. patients with gallbladder hyperkinesia, their biliary findings on ul-
We identified our first two cases of symptomatic gallbladder trasonography and a basic laboratory profile, detection of choleli-
hyperkinesia in adults in 2018 at the Gallbladder Dysfunction Clinic thiasis or sludge in the gallbladder in the gross pathology report,
founded in 2017 at the University of Iowa Health Care (UIHC) documentation of a HIDA scan CCK-provoked reproduction of
medical center (Iowa City, IA), which inspired this 5-y institution- symptoms by a radiologist or a surgeon, possible reasons why control
wide, retrospective analysis. Here, we elucidate a novel associa- group patients may have not undergone cholecystectomy, and the
tion between gallbladder hyperkinesia and symptomatic acalculous potential operative indications for patients offered cholecystectomy
chronic cholecystitis as evidenced by our findings of a much greater in the study group by the operating surgeon of record even though
odds of pain resolution with cholecystectomy compared with a gallbladder hyperkinesia was not as yet a recognized entity in adults.
nonoperated control group. Paraffin-embedded sections of gallbladder specimens were analyzed
by a pathologist with a hematoxylin and eosin or trichrome stain,
Methods using historic normal gallbladder controls (n ¼ 3) for comparative
photomicrography. Digital scanned images were used for histo-
We performed this retrospective, case-control study at the UIHC morphometry to measure thickness of the tunica muscularis.
medical center. This study was based primarily on patient chart The statistical analyses employed the Wilcoxon rank-sum test
reviews (Institutional Review Board Number 200903778). We for continuous variables, c2 test for dichotomous variables, and
analyzed consecutive hepatobiliary iminodiacetic acid (HIDA) scans Firth penalized logistic regressions. We used Firth penalized logistic
performed between January 2013 and September 2018. During regression rather than simple logistic regression to minimize po-
these 5.75 years, our Nuclear Medicine Division performed tential bias induced by small sample size.19 Continuous data are
99m
technetium (Tc-99m)-labelled HIDA scans and reported the presented as mean ± standard deviation.
802 R. Pillenahalli Maheshwarappa et al. / Surgery 168 (2020) 800e808

Table I
Patients with gallbladder ejection fraction (GBEF)
80% excluded from the study cohort of 46 patients

Exclusion criterion A n ¼ 103 Example/explanation

No follow up after HIDA scan

Outside referrals 16 (15%) Returned to referring physician with HIDA scan reported as
“normal”
No follow-up 87 (85%) No UI hospital visits after HIDA scan reported as “normal”

Exclusion criterion B n ¼ 147 Example/explanation

Associated GI disease

Abnormal EGD 45 (30%) Uncontrolled GERD or APD

Previous open upper abdominal 23 (16%) Potential pain from postoperative adhesions or abdominal surgical
operation(s) scar
Untreated carbohydrate intolerance 17 (12%) Glucose/lactulose/fructose/lactose intolerance
Clinical diagnosis of irritable bowel 14 (9%) Diagnosed by gastroenterologist
syndrome
Inflammatory bowel disease 12 (8%) Crohn’s disease, ulcerative colitis
Liver disease 11 (7%) Mass, hepatitis
Small intestinal bacterial overgrowth 7 (5%) Tendency for recurrences
Nonspecific symptoms 7 (5%) Generalized abdominal pain undiagnosed by gastroenterologist
Chronic pancreatitis 4 (3%) Diagnosed by gastroenterologist
Narcotic abuse 4 (3%) Drug-seeking behavior
Malabsorption syndromes 3 (2%) Celiac disease, etc

Of 1,477 HIDA scans in 5 years, GBEF was not measured in 658 (Fig 1). After excluding GBEF < 80%, children, and cholelithiasis
cases, there were 296 adults with acalculous gallbladder hyperkinesia. This Table shows categories of predetermined
exclusion criteria to arrive at the final study cohort of 46 patients so that other GI causes of abdominal pain potentially
indistinguishable from a biliary source of pain may not compromise the analysis of the primary outcome.
HIDA, hepatobiliary iminodiacetic acid scan; n, number; UI, University of Iowa; GI, gastrointestinal; EGD, esophagogas-
troduodenoscopy; GERD, gastroesophageal reflux disease; APD, acid peptic disease.

Results diarrhea in 1 patient. Chronicity of pain was decreased in patients

whose pain resolved (P < .01; Table II). The 3 postcholecystectomy
Patients patients with nonresolution of pain had follow-up of 6, 30, and 40
months, and none were found to have an alternative diagnosis in
Of 1,477 HIDA scans performed during these 5.75 years, a total of spite of several investigations by various specialties including at
1,181 (80%) were excluded because of other indications for a HIDA other hospitals. All 46 patients had documented follow-up in the
scan where the EF was not done, the HIDA EF was <80%, the age was medical record for a minimum of 6 months by non-surgical spe-
less than 19 y, or cholelithiasis was documented at ultrasonography cialties, such as primary care clinicians or specialists, except 1 pa-
or pathology (Fig 1). Of the remaining 296 adults with a HIDA EF tient who was lost to follow-up after the 30-day

80%, 46 (16% of 296) met our clinical eligibility criteria (Table I). postcholecystectomy visit at which time pain had resolved.
Within this final cohort, 21 (46%) underwent cholecystectomy
(study group) and 25 (54%) did not (control group).
Odds of pain resolution with cholecystectomy
Demographics and HIDA EF
The univariate Firth penalized logistic regression analysis
demonstrated that the odds in favor of pain resolution were 19.7
Values in the control and study groups, respectively, were age 40
times as great with cholecystectomy than without (odds ratio, 19.7;
± 16 years and 39 ± 14 years, body mass index 28.9 ± 5.2 and 29.1 ±
95% confidence interval, 4.34, 89.43; P < .01), and that the odds of
7.1 kg/m2, HIDA EF 93% ± 6% and 91% ± 6%, with 15 (60%) and 18
pain resolution were independent of demographic variables
(86%) females in each group. Demographic and HIDA EF variables
(Table III). Even after adjusting for each covariate separately, the
between patients whose pain did or did not resolve were not
adjusted odds were strongly in favor of pain resolution after cho-
different (Wilcoxon rank-sum test and c2 test, P > .05, Table II).
lecystectomy (Table IV).

Resolution of pain and follow-up data

Histopathology
The majority of patients in the control group (20/25 or 80%)
continued to have pain even after a mean follow-up of 36 ± 28 Histopathologic examination of gallbladders from all 21 chole-
months (range 10e120 months). In the control group, 5 out of 25 cystectomies displayed chronic cholecystitis (Figs 2 and 3) as evi-
patients (20%) had spontaneous resolution of pain, which did not denced by mild to moderate lymphocytic infiltration (21/21, 100%),
recur after a mean follow-up of 39 ± 14 months (range 23e61 transmural fibrosis (21/21, 100%), and thickened tunica muscularis
months). In comparison, 18 out of 21 patients (86%) in the study (18/21, 86%). Surrogate markers of chronic cholecystitis, such as
group had resolution of pain after cholecystectomy (P < .01; cholesterolosis (7/21, 33%), Rokitansky-Aschoff sinuses (5/21, 24%),
Table II) for the most part by the 30-day postoperative surgical visit, and epithelial pyloric metaplasia (3/21, 14%) were also seen. His-
lasting even after a mean postoperative follow-up of 41 ± 21 toric normal gallbladder controls displayed only occasional focal
months (range 1e76 months). Resolution of pain after cholecys- lymphocytic infiltration without evidence of fibrosis, thickened
tectomy was associated with improvement of associated symp- muscularis, or surrogate markers of inflammation. Mean thickness
toms, except mild reflux-like pain symptoms in 2 patients and of the tunica muscularis by histomorphometry was 193 ± 118
 R. Pillenahalli Maheshwarappa et al. / Surgery 168 (2020) 800e808 803

Table II
Wilcoxon rank-sum test or c2 test

Covariates Statistics Level Pain resolved Y/N P value

N (n ¼ 23) Y (n ¼ 23)

Demographics
Age (y) n 23 23 .68*
Mean (SD) 40.9 (15.4) 38.6 (14.9)
Median (range) 41 (19e73) 33 (19e66)
Sex n (row %) F 15 (47) 17 (53) .52y
n (row %) M 8 (57) 6 (43)
BMI (kg/m2) n 23 23 .39*
Mean (SD) 29.5 (5.6) 28.5 (6.6)
Median (range) 30.7 (19.6e38.7) 28.5 (17.6e44.1)
Gallbladder kinetics
HIDA EF (%) n 23 23 .41*
Mean (SD) 92 (6) 92 (5)
Median (range) 95 (80e99) 93 (84e100)
Clinical outcomes
Chronicity of pain (months) n 23 23 < .01*
Mean (SD) 33 (27) 25 (38)
Median (range) 25 (5e120) 7 (1e144)
Cholecystectomy Yes/No n (row %) N 20 (80) 5 (20) < .01y
n (row %) Y 3 (14) 18 (86)

Y, yes; N, no; n, number; F, female; M, male; SD, standard deviation.

Statistically significant P values are indicated in bold.
*
Wilcoxon rank-sum test.
y
c2 test.

Table III
Univariate Firth penalized logistic regression

Covariate Level n Odds of pain resolved (Y)

Odds ratio 95% CI P value

Demographics
Age (y) Units ¼ 1 46 0.99 0.95 1.03 .63
Sex F 32 1.48 0.42 5.23 .55
M 14 Ref - -
BMI (kg/m2) Units ¼ 1 46 0.98 0.89 1.07 .60
Gallbladder kinetics
HIDA EF (%) Units ¼ 1 46 0.97 0.88 1.08 .61
Clinical outcomes
Chronicity of pain (months) Units ¼ 1 46 0.99 0.98 1.01 .46
Cholecystectomy Yes/No Y 21 19.70 4.34 89.43 < .01
N 25 Ref - -

Apart from cholecystectomy, none of the other covariates increased the odds of resolution of pain.
CI, confidence interval.
Statistically significant P value are indicated in bold.

Table IV
Adjusted odds for each of the covariates separately

Adjusted for Effect Odds of pain resolved (Y)

Odds ratio 95% CI P value

Age (y) Cholecystectomy Y versus N 18.09 4.05 80.73 < .01

Sex Cholecystectomy Y versus N 25.73 4.55 145.4 < .01
BMI (kg/m2) Cholecystectomy Y versus N 19.70 4.22 92.04 < .01
HIDA EF (%) Cholecystectomy Y versus N 18.00 4.03 80.47 < .01
Chronicity of pain (months) Cholecystectomy Y versus N 18.82 3.99 88.81 < .01

The Firth penalized logistic regression was used to estimate the adjusted odds in favor of pain resolution after
adjusting for each variable separately.
CI, confidence interval.
Statistically significant P values are indicated in bold.

(range 103e326) mm in historic controls and 478 ± 180 (range Additional findings
190e921) mm in the study group (P < .02).
Presenting symptoms and findings
The presenting symptomatology in the control group and the
Complications study group were essentially similar (Table V). Liver function tests
(except those with fatty liver), white blood cell count, and serum
All 21 cholecystectomies were performed laparoscopically with lipase were essentially within normal limits. Ultrasonography re-
no mortality and only two minor wound complications. ports of three patients from the study group noted a “small
804 R. Pillenahalli Maheshwarappa et al. / Surgery 168 (2020) 800e808

Fig 2. Gallbladder hyperkinesia: Histopathology of the wall. (A, B) Gallbladder wall from a symptomatic patient with gallbladder hyperkinesia shows thickened tunica muscularis
(black bracket) within a thick gallbladder wall, compared with normal control. Adventitial fibrosis (green bracket) also contributes to gallbladder wall thickening. (C, D) Histo-
morphometric measurement of the tunica muscularis from digital scanned images of the gallbladder wall shows a thickness of 151 mm in a control sample, and 921 mm in the
patient with gallbladder hyperkinesia with the thickest tunica muscularis measurement in the group range. (E, F) Fibrous tissue (collagen) stains blue and muscle tissue stains red
with trichrome stain. Adventitial fibrosis (green bracket) is seen in gallbladder hyperkinesia. Fibrosis of the lamina propria and the interstitium of the hypertrophied tunica
muscularis is also prominent in gallbladder hyperkinesia (yellow bracket). The dense blue staining of connective tissue across the entire wall seen in gallbladder hyperkinesia,
relative to control, underlines the pathologic transmural fibrotic change related to the disease process. H&E, hematoxylin and eosin; , original magnification.

amount” of gallbladder sludge, but the pathology reports of the comment on the remaining 43. Documentation of the absence or
surgical specimen did not confirm any sludge. Only one patient in presence of CCK-provoked pain that reproduced the patients’
the control group was reported as having a “small amount” of typical pain was not often recorded during imaging. The national
sludge on ultrasonography. Interdisciplinary Panel Consensus Recommendations of 2011 also
did not encourage reporting this because of insufficient evidence to
CCK-provocation response during a HIDA scan justify diagnostic interpretations and treatment decisions.14 At the
HIDA scan reports recorded CCK-provoked pain in only 2/21 and preoperative surgical visit, an additional 10 patients in the chole-
1/25 patients in the study and control groups, respectively, without cystectomy group indicated a positive CCK-provocation response
 R. Pillenahalli Maheshwarappa et al. / Surgery 168 (2020) 800e808 805

Fig 3. Gallbladder hyperkinesia: Histopathology of the mucosal lining. (A, B) Magnified mucosal view shows lamina propria fibrosis (black arrows) extending into interstitial spaces
(yellow arrows) between muscularis SM bundles in gallbladder hyperkinesia subjects, compared with the control group. (C, D) Moderate lymphocytic infiltration in the lamina
propria (arrows) is seen in gallbladder hyperkinesia, compared with a few lymphocytes occasionally seen in the control group. (E) Clusters of lipid laden histiocytes (cholesterolosis)
within the lamina propria (arrows) seen in cases of gallbladder hyperkinesia. (F) Gallbladder hyperkinesia specimen showing epithelial pyloric metaplasia (arrow). SM, smooth
muscle; H&E, Hematoxylin and Eosin; , original magnification.

with a HIDA scan. Because the CCK-provocation response in the frequency distribution histogram indicates that the peak distribu-
remaining 33 patients is unknown, the available data are insuffi- tion of gallbladder EF is above 90% (Fig 4).
cient for correlative analysis.
Reasons for selection for cholecystectomy in the study group
Distribution of HIDA EF HIDA scans were reported as “normal” even with EF
80%,
The 819 HIDA scans with EF measured during the 2013 to 2018 satisfying the Society of Nuclear Medicine Practice Guideline of
study period were ordered to investigate abdominal pain to eval- 201013 and the Interdisciplinary Panel Consensus Recommenda-
uate for gallbladder hypokinesia. Of these, 183 (22%) fell into the tions of 201114 that only recognized low EFs as abnormal. In the 2
hypokinesia group, 278 (34%) into the normokinesia group, and the patients seen at the UI Gallbladder Dysfunction Clinic in 2018, the
remaining 358 (44%) into the hyperkinesia group (Fig 1). The documented operative indication for cholecystectomy was
806 R. Pillenahalli Maheshwarappa et al. / Surgery 168 (2020) 800e808

Table V
Symptom comparison between control and study groups

Control group (n ¼ 25) (no cholecystectomy) Study group (n ¼ 21) (cholecystectomy)

RUQ/Epigastric pain 25 (100%) 21 (100%)

Postprandial exacerbation 20 (80%) 17 (81%)
Radiation to back or shoulder 15 (60%) 15 (71%)
Nausea 16 (64%) 16 (76%)
Vomiting 9 (36%) 8 (38%)
Gaseousness 8 (32%) 6 (29%)
Diarrhea 11 (44%) 9 (43%)
Tenderness over gallbladder 2 (8%) 2 (10%)
ED visit (at least 1/patient) 14 (56%) 9 (43%)

Presenting symptoms and ED visits were compared between the control group and study group and found to be similar. Clinical
presentation suggestive of biliary pain prompted the clinicians to order a HIDA scan when ultrasonography failed to show
cholelithiasis.
ED, Emergency department.

Discussion

In this first case-control study, we demonstrate that the majority

of patients (80%) with symptomatic acalculous chronic cholecystitis
associated with gallbladder hyperkinesia who did not have chole-
cystectomy continued to experience pain; however, most of those
(86%) who underwent cholecystectomy had resolution of their
pain. This substantial and statistically significant difference in
outcomes between the patients in the control group and the pa-
tients who had cholecystectomy, independent of demographic
variables, supports our central hypothesis that adults with symp-
tomatic acalculous chronic cholecystitis associated with gall-
bladder hyperkinesia will benefit from cholecystectomy. Our
finding that gallbladders from cholecystectomy patients demon-
strated histologic evidence of chronic cholecystitis, especially with
conspicuous hypertrophy of the tunica muscularis, adds credence
to this central hypothesis. Moreover, we demonstrate that the odds
of pain resolution with cholecystectomy are greater than without
cholecystectomy, even with the odds adjusted for each covariate.
Taken together, these findings indicate that symptomatic gall-
bladder hyperkinesia may be a new indication for cholecystectomy
Fig 4. Frequency distribution of gallbladder ejection fraction from 0% to 100% in all 819
in adults. Randomized multicenter trials to test this hypothesis
patients referred for the HIDA scan 2013 to 2018 for evaluation of abdominal pain. Each
bin represents an interval of 5%. with larger sample sizes are needed.
Gallbladder contraction after a meal is a neurohormonal
response involving cholinergic and CCK pathways.20 Being a largely
“gallbladder hyperkinesia,” with a reference to the 2013 pediatric unrecognized clinical entity,5,7,11e18 detailed histologic character-
publication.11 In the remaining 19 patients, seen by 7 other general ization of the hyperkinetic gallbladder has, to our knowledge, not
surgeons, the documented indication for cholecystectomy was: (1) been published.16e18,21,22 In the present study, the histopathologic
a positive CCK-provocation during HIDA scan (n ¼ 12), (2) persis- findings of thickening of the muscularis layer is suggestive of
tent biliary pain (n ¼ 4), (3) sludge on ultrasonography (n ¼ 2), or gallbladder hyperstimulation, the lymphocytic infiltration seems to
(4) a small polyp (n ¼ 1). be a nonspecific response to chronic inflammation, and the fibrosis
is a reaction to chronic tissue injury (possibly from hyperstimula-
tion of the contractile activity). The prominent hypertrophy of the
tunica muscularis layer and the extent of fibrosis, in the absence of
Reasons for not doing cholecystectomy in the control group gallstones, supports the concept that gallbladder hyperkinesia is
Because the HIDA scan was reported as “normal,” 9 out of 25 in associated with chronic cholecystitis and is congruent with our
the control group sent for surgical consultation did not receive observation that cholecystectomy resolves pain in the majority of
cholecystectomy and, for the same reason, the remaining 16 were these patients. Speculative mechanisms of disease pathogenesis
not offered surgical referrals. would include hypersensitivity of the gallbladder wall to stimula-
tion (increase in CCK or cholinergic receptor number or sensitivity),
a heightened neurohormonal postprandial gut response, unknown
changes in the composition of bile, specific dietary habits or
Cholecystectomy in the excluded group changes, or malfunction of the interstitial cells of Cajal considered
In the 147 patients excluded from our cohort because of clini- to be the “pacemaker” of the gastrointestinal system.22
cally important associated gastrointestinal comorbidities (Table I), Symptoms of gallbladder hyperkinesia include right upper
4 eventually underwent cholecystectomy, 2 of whom had pain quadrant or epigastric pain often with postprandial exacerbation,
resolution, and 2 did not (The n was too small for statistical anal- radiation to the back or shoulder, nausea, vomiting, gaseous
ysis; needs prospective study). symptoms, or diarrhea (Table V). The Rome Criteria for biliary pain
 R. Pillenahalli Maheshwarappa et al. / Surgery 168 (2020) 800e808 807

Fig 5. Clinical paradigm for biliary pain associated with gallbladder hyperkinesia. The flowchart for the management of symptomatic gallbladder hyperkinesia and hypokinesia have
much in common.

and functional gallbladder disorders specifies pain lasting at least gallbladder that is emptying efficiently, and ingrained biases
30 minutes and associations with nausea, vomiting, and radiation, against gallbladder motility disorders23 being a cause of biliary
etc.12,14 The Rome Criteria, however, have not been evaluated in pain. Of note, our data indicate that gallbladder hyperkinesia may
relation to gallbladder hyperkinesia, because an entity of gall- in fact be more prevalent than hypokinesia in symptomatic patients
bladder hyperkinesia is not as yet formally recognized.12,14 For with abdominal pain sent for a HIDA scan (Figs 1 and 4). A funda-
instance, diarrhea and postprandial exacerbation of symp- mental public health responsibility is to identify a disease that has
tomsdseen in close to 40% and 80% of patients in our study, remained elusive for a long time, to characterize its presentation
respectivelydare not listed in the Rome Criteria.12,14 Some of the and histopathologic changes, to investigate potential treatment
gallbladder hyperkinesia case series draw a link between CCK modalities to relieve this patient population of debilitating symp-
provocation during a HIDA scan and reproduction of toms, and to improve their quality of life. Our investigation of
symptoms.16e18 Well-designed, prospective studies are needed for gallbladder hyperkinesia is novel because it is the first study to
the following reasons: to determine whether a positive CCK prov- demonstrate the following:
ocation predicts better outcomes with cholecystectomy, to evaluate
reproducibility of HIDA scan measurements in the context of high  To characterize its histologic changes,
EFs, and to systematically determine whether the cut-off reading  To present statistical evidence to support the hypothesis and the
for gallbladder hyperkinesia should be 80% or 70%, or even less. The conclusions, and
presenting symptomatology of gallbladder hyperkinesia and its  To show that most patients will suffer indefinitely if they do not
response to cholecystectomy should also be characterized pro- have cholecystectomy.
spectivelydpreferably in comparisons with gallbladder hypo-
kinesia and calculous biliary pain. Our observations have potentially important clinical implica-
Although symptomatic gallbladder hypokinesia was defined in tions across various disciplines. Specialists (gastroenterologists,
1991, with a randomized clinical trial that showed substantial emergency department physicians, and cardiologists) and primary
benefit from cholecystectomy,3 the clinical entity of gallbladder care clinicians must be aware that these patients might benefit
hyperkinesia has remained elusive or even not recognized for from surgical evaluation. Radiologists must be able to recognize
almost 3 decades.5,7,11e18 Initial reports of gallbladder hyperkinesia adult gallbladder hyperkinesia as abnormal and report it accord-
occurred in 2013 in children11 and in 2018 to 2019 in adults.16e18 ingly, which suggests that the Society of Nuclear Medicine Practice
Some of the possible reasons why gallbladder hyperkinesia has Guidelines of 201013 and the Interdisciplinary Panel Consensus
eluded us for so long are related to several observations, including Recommendations of 201114,24 may need to be revisited. Surgeons
its relative rarity compared with biliary colic from gallstones, the must realize that these patients must be counseled, suggesting that
intuitive assumption that a high EF automatically implies a they may benefit from cholecystectomy. Otherwise, symptomatic
808 R. Pillenahalli Maheshwarappa et al. / Surgery 168 (2020) 800e808

gallbladder hyperkinesia will continue to be an unrecognized dis- References

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