We were invited to review The Hyperkinetic Gallbladder for this Special Issue on “Biliary Tract Disease” as we recently published the first statistically analyzed study to show that gallbladder removal surgery has substantially greater odds in relieving symptoms of gallbladder hyperkinesia than in controls where the gallbladder is not removed [1]. In addition to using a control group and performing detailed statistical analyses, another novel aspect of our study included meticulous histological analyses and morphometric studies of the resected gallbladder specimens by a pathologist [1].

The purpose of this publication is to provide an update on Gallbladder Hyperkinesia not only for the medical community but also for a lay audience. Therefore, difficult medical terminology is either avoided or explained. Removal of the gallbladder (cholecystectomy) for chronic cholecystitis (longterm inflammation of the gallbladder) resulting from acalculous* symptomatic gallbladder hyperkinesia is not yet a widely recognized treatment (*calculus: Latin “small stone”; “acalculous” in the present context: in the absence of gallstone formation).

Symptomatic gallbladder hyperkinesia, a chronic malady that presents with biliary symptoms even in the absence of gallstones but where the gallbladder empties too quickly, is not yet an established clinical diagnosis as it has only recently been noticed [1-7]. Within recent years, several publications from different geographical regions suggest that hyperkinetic gallbladders cause biliary symptoms, and the topic is gaining momentum [1-22]. We independently identified symptomatic gallbladder hyperkinesia at the University of Iowa Gallbladder Dysfunction Clinic in 2018 when two severe cases of acalculous biliary pain associated with high gallbladder ejection fractions (92% & 100%) responded impressively to cholecystectomy [1]. The unique focus of our Gallbladder Dysfunction Clinic on diseases of the gallbladder helped us identify these initial patients and to continue our work on the topic. We then published a retrospective study of patients with symptomatic gallbladder hyperkinesia from 2013 to 2018 at our institution where we compared patients who had cholecystectomy (Study Group, n = 21) to those who did not have cholecystectomy (Control Group, n = 25) [1]. Evidence of long-term follow-up with the referring clinician (e.g., gastroenterologist, primary care physician) averaged 3.5 years in the Study Group (range 1 – 76 months) and 3 years in the Control Group (range 10 –120 months). In our study, we found that the odds of the cholecystectomy group showing symptom resolution (18/21 or 86% of patients) were 19.7 times that of the non-cholecystectomy group (only 5/25 or 20% patients showed spontaneous resolution of symptoms over time) [1]. This indicates that 80% of patients will continue to suffer symptoms indefinitely if they do not undergo cholecystectomy. Over the past 5 years, we have gained experience in the clinical presentation, investigation, diagnosis, and treatment of patients with symptomatic gallbladder hyperkinesia.

What is gallbladder hyperkinesia?

The Chronic Acalculous Symptomatic hyPERkinetic (CASPER) gallbladder, or “the excitable gallbladder,” can be explained as the opposite of the Chronic Acalculous Symptomatic hyPOkinetic (CASPO) gallbladder, or “the lazy gallbladder.” Symptomatic hypokinesia of the gallbladder was investigated with a randomized study in 1991, showing cholecystectomy was better than no operation [23], that justified its entry into medical textbooks. In contrast, the condition of symptomatic gallbladder hyperkinesia is a recently described condition that has not yet reached general acceptance as a recognized clinical condition [1- 22]. Simply put, symptomatic gallbladder hyperkinesia consists of a triad of a) biliary symptoms, b) a gallbladder without stones (“acalculous”), and c) a high gallbladder Ejection Fraction on cholescintigraphy (Hepatobiliary Imino-Diacetic Acid scan or HIDA scan) [1]. The HIDA scan is a nuclear medicine scan used to measure gallbladder emptying (Ejection Fraction) after hormonal stimulation or a fatty meal [24-26]. In normal physiology, the gallbladder stores and concentrates bile between meals, and when a meal is eaten the duodenum secretes cholecystokinin (CCK) hormone into the bloodstream making the gallbladder contract and the bile duct sphincter relax, allowing concentrated bile to reach the duodenum and mix with the meal [25]. This explains why biliary pain is typically exacerbated by a meal.

Why is Gallbladder Hyperkinesia not in the standard medical textbooks?

Although gallbladder hypokinesia (often called gallbladder dyskinesia) [27] has been in the textbooks of surgery for several decades, gallbladder hyperkinesia in adults has not yet made its entry into the standard medical textbooks for several reasons. Gallbladder hyperkinesia is also not currently found in the question databases for surgical trainees such as SESAP [Surgical Education & Self-Assessment Program (American College of Surgeons)], the ABS (American Board of Surgery) Certification Examination, and the ABSITE (ABS Inservice Training Examination), while gallbladder hypokinesia is included. Similarly, the Rome IV Diagnostic Criteria for Functional Gallbladder Disorders (see below) recognizes gallbladder hypokinesia as a gallbladder motility disorder but not gallbladder hyperkinesia [28]. Many clinicians may not accept the formalization of a new clinical condition until and unless a randomized controlled clinical trial is conducted. This would require a prospective study where patients with symptomatic gallbladder hyperkinesia are randomly allocated to a cholecystectomy group or a non-cholecystectomy group (diet and analgesia only) and are then evaluated by blinded independent observers for at least one to two years. However, obtaining research funding could be a hurdle. Also, if a randomized study is attempted, most patients needing surgery could be in so much agony that they may refuse randomization and avoid entering the study by choosing early surgical intervention. Furthermore, even if a successful randomized study is completed, the inherent bias amongst many clinicians against motility disorders of the gallbladder may be difficult to overcome [29]. Therefore, it could take many years for this condition to be recognized by the medical community and enter standard medical textbooks. In the meantime, continued publications, as exemplified in the present review [1-22], would help to inform healthcare providers about symptomatic gallbladder hyperkinesia and the favorable effects of cholecystectomy in well-selected patients.

Is a prospective, randomized, controlled study essential to justify cholecystectomy for symptomatic gallbladder hyperkinesia?

Not every treatment for every medical condition has undergone a prospective randomized study with a control group prior to general acceptance. In fact, gastric bypass surgery for severe obesity was performed internationally from the 1960s onwards [30] for almost half a century based entirely upon retrospective studies [31-34] until the first prospective randomized study in 2012 showed that surgery was better than medical treatment for diabetes associated with obesity [34-36]. Before 2012, most published bariatric surgery studies were observational (retrospective) and only a limited number of them had nonsurgical control groups [34]. Ethical considerations may have inhibited performing randomized control trials and so the central hypothesis that bariatric surgery is more effective than medical treatment for weight loss in the severely obese remained untested for half a century. But even then, bariatric surgery continued a relentless expansion for almost 50 years despite the lack of randomized studies [31-34].

Interestingly, in 1926 the legendary American surgeon Dr. Allen O. Whipple published a series of 217 consecutive cholecystectomies with post-operative follow-up of up to 10 years [37]. Of these, 170 (78%) were for calculous disease and 47 (22%) were for acalculous disease showing 89.4% and 76.6% symptom relief, respectively [37]. It is reasonable to suggest that some of these 47 patients with acalculous biliary symptoms had either gallbladder hypokinesia or hyperkinesia.

If gastric bypass for severe obesity and cholecystectomy for acalculous biliary pain were performed in the 20th century without randomized studies, then is a randomized study essential to justify cholecystectomy for symptomatic gallbladder hyperkinesia in the 21st century?

What is the current definition of gallbladder hyperkinesia?

The essential features of symptomatic gallbladder hyperkinesia are [1-2]:

Clinical presentation suggestive of biliary symptoms,

No gallstones on radiologic imaging, and

High gallbladder Ejection Fraction on HIDA scan.

a) Clinical presentation suggestive of biliary symptoms: This is a clinical diagnosis and is quite dependent on the person taking the history, as history taking is a science and an art. Unfortunately, recent reliance on innovative technology has blunted classical attention to detail of a well-taken history. Modern clinicians often prefer to look at a radiological image or read a report rather than listen to the patient and ask probing questions. To help guide a useful clinical history-taking in the evaluation of gallbladder hyperkinesia, we provide a detailed list (see below) garnered during 5 years of experience at our Gallbladder Dysfunction Clinic. The most common symptoms suggestive of a biliary cause are nonspecific: upper abdominal pain, nausea and vomiting, and gaseous symptoms such as bloating [1-22,28].

b) No gallstones on radiologic imaging: If an ultrasound shows gallbladder stones, it will support a diagnosis of calculous chronic cholecystitis and additional studies of gallbladder motility (HIDA scan) may not be needed. If only a small amount of gallbladder sludge is seen on ultrasound in a symptomatic patient, a HIDA scan could provide additional justification to consider cholecystectomy if it shows either gallbladder hypokinesia or hyperkinesia ? as then, the odds of cholecystectomy relieving the presenting symptoms are increased. It is important to remember that ultrasound is the gold standard for the diagnosis of gallbladder stones as diagnostic modalities using X-rays (e.g., plain X-ray or CT scan) may miss up to 80-90% of gallstones as only about 10-20% of gallstones contain sufficient calcium to show up on X-ray images [38].

c) High Ejection Fraction of the gallbladder on HIDA scan: When radioisotope cholescintigraphy was introduced in the 1950s, 131Iodine-Rose Bengal dye given intravenously was taken up by the liver, secreted into the biliary tract, and then reached the duodenal lumen while also filling the gallbladder [39]. Its initial use was to test hepatobiliary function, identify non-filling gallbladders to confirm acute cholecystitis, or to investigate biliary leaks. In 1981, the first gallbladder Ejection Fractions were calculated when gallbladders that filled after IV 99Technitium-HIDA radioisotope administration were stimulated with a CCK analog, and gallbladder emptying was recorded [24]. This technological advancement led to the first functional evaluations of gallbladder motility. Therefore, from the early 1900s until 1981, surgeons were removing acalculous symptomatic gallbladders based entirely on symptoms and signs without any information about gallbladder ejection efficiency [37]. From 1981, after gallbladder ejection fraction data became available, the focus for many years was the slowly emptying gallbladder (hypokinesia) causing biliary symptoms [23,40]. Now, several studies emphasize a new-found interest in the rapidly emptying gallbladder (hyperkinesia) that was generally considered to be normal until recent reports [1-22]. Currently, most clinicians use the 80% Ejection Fraction as the cut-off level to define gallbladder hyperkinesia, but there is no scientific justification yet for the selection of this percentage number.

What should be the cut-off Ejection Fraction level for a diagnosis of gallbladder hyperkinesia?

Although gallbladder Ejection Fractions above 80% are widely considered as the diagnostic criterion for gallbladder hyperkinesia, this cut-off level has been arbitrarily chosen without scientific investigations [1-22]. The 80% Ejection Fraction level seems to have taken root in the scientific literature by mere repetition in several papers. At our Gallbladder Dysfunction Clinic, using our clinical judgement in select patients, we have gone down to Ejection Fractions of 74% based upon clinical necessity and found a good response to biliary pain with cholecystectomy. There is one paper that reported a range of 71% to 99% in a series of patients with gallbladder hyperkinesia that responded well to cholecystectomy, where they used an arbitrary cut-off of 65% for their definition of hyperkinesia [10]. Therefore, until and unless extensive detailed clinical studies are undertaken, patients with Ejection Fractions in the borderline gray area between 70% and 80% will have to be considered on a case-by-case basis. If clinically indicated (intolerable symptoms), cholecystectomy in patients with Ejection Fractions between 65% and 80% can be justified by referencing the publication that offered surgery to symptomatic adults with Ejection Fractions above 65% [10]. There are some studies that used a 75% Ejection Fraction as their cut-off [7,12].

Is gallbladder hyperkinesia a new disease entity or merely a marker of disease?

Clinicians opposing the belief that symptomatic gallbladder hyperkinesia is a real entity cite evidence that a certain percentage of normal people that go through their daily lives without any symptoms will have a high gallbladder ejection fraction if a HIDA scan is done. The counter-argument would be that a good percentage of normal people that go through their daily lives without any symptoms will have gallstones in their gallbladder if an ultrasound is done [38]. Therefore, if gallstone formation is a pathologic entity even if the person is asymptomatic, then gallbladder hyperkinesia can also be an asymptomatic pathologic entity and symptoms could develop over time in a certain percentage of individuals, just as up to 30% of patients with gallstones can become symptomatic over time but as many as 70% may go through life without any symptoms [41]. On the other hand, it is quite possible that hyperkinesia of the gallbladder is not in itself a disease entity but only a marker of an underlying poorly understood disease.

What is the pathogenesis of gallbladder hyperkinesia?

At the present time, the pathogenesis of how gallbladder hyperkinesia develops and progresses to becoming symptomatic is not known. As gallbladder hyperkinesia has not yet gained acknowledgment as a recognized disease entity, investigations into its pathogenesis are still pending. Most studies of symptomatic gallbladder hyperkinesia show a female preponderance, [1-22] similar to that of gallstone disease [41]. Therefore, one can only speculate that the pathogenesis of symptomatic gallbladder hyperkinesia may have some correlation to the female hormones and their effect on the biliary tract. For example, the increased incidence of cholesterol gallstones in females is thought to be related to the effect of female hormones on the liver metabolism of cholesterol [41]. In our recent study, we presented novel data where a pathologist studied the surgically resected gallbladder histology in 21 patients with symptomatic gallbladder hyperkinesia and found a prominent increase in the thickness of the smooth muscle layer within the gallbladder wall in many of these patients [1]. The reasons as to why this smooth muscle hypertrophy occurs, and its relevance to the pathogenesis of gallbladder hyperkinesia, remain unknown. In our study, we showed fibrosis and lymphocytes in the submucosal area of the gallbladder wall suggestive of mild to moderate chronic cholecystitis that indicates a long-term inflammatory process [1].

What are the non-surgical treatment options for the CASPER gallbladder?

At the present time, the only non-surgical management for symptomatic gallbladder hyperkinesia is a low-fat diet with appropriate painkillers used on an “as per need” basis. At our Gallbladder Dysfunction Clinic, non-surgical management has been used in a small number of patients who had mild symptoms not affecting their quality of life and therefore opted to defer surgery unless exacerbations developed. If symptoms are mild and the patient is compliant with diet, surgery could be postponed or even avoided. In our retrospective study, we showed that only 20% of patients with symptomatic gallbladder hyperkinesia who did not receive cholecystectomy improved spontaneously over a period of years.

Other treatments may exist but have not been researched to provide proof of benefit for symptomatic gallbladder hyperkinesia [1-22]. Most pharmacological agents tried are those usually used for irritable bowel syndrome [antispasmodic dicyclomine (can cause giddiness) and peppermint oil (IBgard)].

What are the various investigations that patients undergo before a diagnosis of gallbladder hyperkinesia is entertained?

Most patients coming to our Gallbladder Dysfunction Clinic to evaluate symptomatic gallbladder hyperkinesia have been referred by gastroenterologists or primary care physicians and have already undergone various investigations. In effect, at the present time, symptomatic gallbladder hyperkinesia is generally considered a diagnosis of exclusion. Such an approach is clinically sound as diseases of the gastrointestinal tract have much overlap in symptoms and signs and differentiating between them based on history and examination alone can be challenging. Hepatic function panel and pancreatic enzymes have usually been already evaluated and are normal (except transaminase elevations related to a fatty liver), and should be a basic part of the evaluation in all these patients to exclude bile duct obstruction and pancreatic disease.

The following is a list of most common investigations done on symptomatic gallbladder hyperkinesia patients before they come to our Gallbladder Dysfunction Clinic, but we do not mean to imply that every patient needs to undergo each and every one of these studies as the choice would be left to the clinical judgement of the healthcare provider evaluating the patient:

1. Esophagogastroduodenoscopy (EGD)
2. CT scan of abdomen and pelvis
3. Colonoscopy
4. Radioisotope gastric emptying study
5. Hydrogen & methane breath test for small intestinal bacterial overgrowth (using glucose, lactulose, or fructose) or lactose intolerance (using lactose).
6. Esophageal manometry and pH studies
7. Helicobacter pylori tests
8. Tests for celiac disease
9. Trial of anti-acid treatment such as several months of proton pump inhibitor treatment
10. Psychological or psychiatric assessments.

What are some conditions that patients with undiagnosed gallbladder hyperkinesia are labelled with?

As HIDA scans reporting high gallbladder ejection fractions are at present mostly reported as “normal” at many institutions, and as visceral symptoms are poorly localized, symptomatic gallbladder hyperkinesia patients are often given a variety of different diagnoses:

• Irritable bowel syndrome (IBS)
• Acid peptic disease (APD)
• Gastroesophageal reflux disease (GERD)
• Gastroparesis (Slow gastric emptying),
• Small intestinal bacterial overgrowth (SIBO)
• Constipation
• Cardiac or rib causes for chest pain
• Psychiatric disorder
• Malingering
• Or, they are simply told, “We do not know what is wrong with you.”

What are the symptoms and signs of gallbladder hyperkinesia?

Over the past five years, we have evaluated several patients with gallbladder hyperkinesia and have distilled a list of signs and symptoms that patients present with. Often, patients have at least half of the signs or symptoms listed here, but occasionally ? in an atypical presentation ? only one or two.

1. Pain: right upper quadrant, epigastric, or upper abdominal.
2. Onset of pain after a meal (post-prandial pain), varying from a short time to a few hours after a meal. However, although abdominal pain is typically post-prandial in gallstone-biliary colic, it may not always follow a meal in gallbladder hyperkinesia patients, as it can sometimes come on randomly, or even become constant with occasional or frequent waves of exacerbation.
3. Certain foods especially are known to initiate the pain: deep fried food, whole milk, milk products (cheese, cream, butter), or fatty meats. Also, large meals.
4. Pain radiates to the flank, back, shoulder blade, or shoulder, most often to the back, occasionally travelling along the left side or upwards to the chest or neck.
5. Post-prandial nausea with or without overt vomiting
6. Post-prandial gaseous symptoms such as bloating, with burping, belching, or flatulence.
7. Waking up at night with pain, especially after a late meal or a large meal.
8. An unusual sensation in the right upper quadrant, likened to a “tense balloon about to burst,” a “clenching fist,” or a “cramping pain,” located over the gallbladder region.
9. Exacerbation of pain in the right upper quadrant with postural movements that increase intra-abdominal pressure, such as bending down to pick something from the ground or rising from the sitting position.
10. Post-prandial urgency for a bowel movement, most often within a few to 60 minutes.
11. Diarrhea, after a meal, but often even between meals.
12. Localized tenderness directly over the anatomical location of the gallbladder.

Regarding the 12 symptoms and signs listed above, not all 12 needs to be present in any patient as occasionally only a few symptoms or even only one symptom may be present. Although abdominal pain is the most common presenting symptom, some patients do not experience pain but only have uncomfortable abdominal bloating, intolerable nausea, or mainly urgency for a bowel movement with diarrhea after eating. The post-prandial temporal relation of symptoms such as abdominal pain, nausea and vomiting, gaseous symptoms, or diarrhea, is not always present and the symptoms can occur at any time even without a meal and can even exacerbate to reach a state that is continuous. Additional complaints that we have heard occasionally from patients that reversed after cholecystectomy include weight loss due to insufficient nutrition (excess pain and vomiting with attempted meals), sporadic fainting, tachycardia, and fatigue. Patients should always be cautioned that not all their symptoms might be improved with cholecystectomy as there can be overlap of symptoms with different upper gastrointestinal diseases. Occasionally, some patients may have no benefit at all from cholecystectomy if they had asymptomatic gallbladder hyperkinesia with symptoms from other undiagnosed conditions. In difficult-to-diagnose cases, the only way to find out is by performing cholecystectomy and seeing what happens (an interrogative cholecystectomy). Such difficulties in diagnosis arise as the visceral symptoms of upper gastrointestinal diseases are often vaguely demarcated and various investigations can turn out to be negative. Therefore, most cases-series of cholecystectomy for the CASPER gallbladder can be expected to have a certain percentage of failure of surgical treatment, [1-22] just as in the case of the CASPO gallbladder.

The Rome Foundation [42] is a private not-for-profit organization that supports international collaboration to understand functional disorders of the gastrointestinal tract (Disorders of Gut-Brain Interaction or DGBIs). The Rome IV Criteria of 2016 for “Gallbladder and Sphincter of Oddi Disorders” focus on symptoms of acalculous biliary disease and only mention gallbladder hypokinesia (and sphincter of Oddi dysfunction) and have not yet recognized gallbladder hyperkinesia as a clinical condition [42]. The 12 symptoms and signs that we have associated with gallbladder hyperkinesia and have listed above show several differences when compared to the Rome IV Diagnostic Criteria for “Functional Gallbladder Disorders” or “Biliary Pain” [42]. Notably, the Rome IV Criteria document only four symptoms: biliary pain as the main symptom, with three supportive criteria – a) nausea and vomiting, b) radiation of pain to the back and/or right infra-subscapular region, and c) waking from sleep due to pain. The presence of biliary pain is an essential requirement to satisfy the Rome IV criteria, and the pain: a) reaches a steady level lasting at least 30 minutes, b) is not daily, c) is severe enough to interrupt daily activities or need an emergency department visit, d) is not significantly related to bowel movement, and e) is not significantly relieved by postural change or acid suppression.

As we independently identified symptomatic gallbladder hyperkinesia in 2018 at the University of Iowa Gallbladder Dysfunction Clinic, and over the past five years saw several referrals for assessment for cholecystectomy, we intentionally deviated from the Rome IV Criteria for Functional Gallbladder Disorder to autonomously characterize the symptoms and signs of this novel clinical condition. Such an autonomous approach was justified as the Rome IV Criteria for Functional Gallbladder Disorders do not acknowledge symptomatic gallbladder hyperkinesia as a clinical disorder [42].

Exacerbation of abdominal pain during the HIDA scan after the administration of CCK analog is commonly considered a positive indicator of gallbladder disease by many clinicians [43] but this topic is controversial as CCK administered intravenously to anyone can potentially cause pain and nausea [44]. Therefore, we have not included CCK-induced reproduction of symptoms in our current list of symptoms of the CASPER gallbladder.

Post-operatively, most patients appreciate the impact of cholecystectomy on their gallbladder hyperkinesia symptoms within 1 to 5 days, as the laparoscopic incisional pain, carbon-dioxide gas-related referred shoulder pain, and anesthetic effects fade away. Some patients need a few weeks, as each patient reacts differently to cholecystectomy. Patients are best advised to remain on broth the first night after laparoscopic cholecystectomy, and to then advance steadily onto a low-fat diet such as the BRAT diet (Bananas, Rice, Applesauce, Toast). Adventurous consumption of a cheeseburger few days after surgery can result in an Emergency Department visit with abdominal pain. Tolerance of a general diet and resolution of post-cholecystectomy diarrhea happen in a few weeks as the body acclimatizes to the lack of a gallbladder.

Summary of literature published on symptomatic gallbladder hyperkinesia

We have identified a total of 29 scientific works, including 7 peer-reviewed national conference abstract presentations (Table 1) [45-51] and 22 peer-reviewed papers (Table 2) [1- 22] published in the literature on the topic of symptomatic gallbladder hyperkinesia. Conference abstract presentations that were published later as full-length papers are excluded from Table 1, but are included in Table 2. Historically, to our knowledge, the first description of gallbladder hyperkinesia was only in abstract form in 1999 (Table 1), and we could not identify the same study published as a full manuscript. The first full-length article publishing a study on the topic was in 2012, [7] and the total number of papers have presently reached 22 (Table 2). In effect, symptomatic gallbladder hyperkinesia is a condition brought into focus only in the 21st Century, especially in the past decade [1-22].

Except for one paper from the UK, [4] which was a metaanalysis of 13 previous studies, all the other 28 publications were from the USA (Tables 1&2). Invariably, the 22 published articles were all studies led by surgeons that performed cholecystectomy for gallbladder hyperkinesia showing evidence that cholecystectomy is useful in mitigating the associated biliary symptoms in a substantial percentage of patients. When data was provided, there was female gender predominance in adults (Table 2). Success of cholecystectomy for relief of symptoms with symptomatic gallbladder hyperkinesia ranged from 65% to 100% in adults (Table 2). The meta-analysis from 13 previous studies involved data from 332 patients and concluded that cholecystectomy was successful in ameliorating symptoms in more than 90% of patients with the hyperkinetic gallbladder [4]. Some of these publications mentioned the histology report findings, but did not present a detailed descriptive characterization of all the histology slides performed by a single pathologist.

Our study was the only one that showed statistical data indicating that the odds of symptom improvement were substantially higher (19.7 times greater) with cholecystectomy than without. Such a sizeable Odds Ratio advantage of cholecystectomy over nonsurgical treatment suggests that it could be unethical not to offer surgery to a patient suffering intolerably with symptoms from gallbladder hyperkinesia.

Nomenclature

Many publications have referred to gallbladder motility disorders associated with a low ejection fraction as “gallbladder dyskinesia” which means “abnormal motility of the gallbladder” [27,29]. However, now that gallbladder hyperkinesia has entered the scene, labelling low Ejection Fraction gallbladders as “gallbladder dyskinesia” would be a misnomer, and the term “gallbladder hypokinesia” would be more appropriate as “gallbladder hyperkinesia” is also “dyskinesia” of the gallbladder. Similarly, the term “biliary dyskinesia” [12,13,16,29,40] should not be used synonymously with “gallbladder hypokinesia” or “gallbladder hyperkinesia” as the term “biliary” can refer to anatomical areas outside the gallbladder such as the sphincter of Oddi (sphincter of Oddi dysfunction) or any segment of the biliary tract.

Social media engagement

Modern technology has brought to the forefront world-wideweb sites and services such as social media internet platforms where patients seeking information, help, or emotional peer support have been able to connect and interact. A Facebook. com private group called “Hyperkinetic Gallbladders” was started in 2017, collected 500 members by 2020, and surpassed 1300 members by early 2023 [52]. Patients discuss their symptoms, diagnosis, and experiences, and assist each other. An experience mentioned regularly is of patients being diagnosed with gallbladder hyperkinesia but being refused surgery by consultant surgeons due to nonrecognition of the condition. In response, this Facebook Group has accumulated a list of surgeons that recognize and offer cholecystectomy for symptomatic gallbladder hyperkinesia from Canada, the United Kingdom, New Zealand, Turkey, and the United States, and the list of surgeons and countries continually grows. Twitter.com shows 16 tweets about “gallbladder hyperkinesia” from 2020 onwards, 4 of them from surgeons posting our 2020 Surgery journal article [1] and the remaining from symptomatic patients [53]. Twitter.com also shows 25 tweets about the “hyperkinetic gallbladder” from 2012 onwards that includes a discussion between surgeons, and has several tweets from symptomatic patients seeking advice or help [54]. Therefore, social media internet platforms serve as an interface to facilitate interactions between patients, between surgeons, and between patients and surgeons. The momentous global reach of the internet and its ubiquity are strengths that aid the exchange of new information and that initiate unexpected collaborations.

Potential future directions for the CASPER Gallbladder

Clinicians from different specialties and geographical regions should publish their experience regarding the diagnosis and treatment of the CASPER Gallbladder. Ideally, retrospective studies should include patients that did not have cholecystectomy as a control group and include statistical odds ratios for chances of improvement with cholecystectomy versus no cholecystectomy, as in our recent study [1].

If possible, well-designed prospective studies should be conducted where patients with the CASPER Gallbladder are randomized into a cholecystectomy group and a diet-andanalgesia group and followed for one to two years by blinded observers. However, ethical considerations may imply that withholding surgical options for the Control Group patients that may be in agony cannot be justified.

Standardization of cholescintigraphy methodology and evaluations of reproducibility should continue [26,55]. A gallbladder Ejection Fraction cut-off level to define gallbladder hyperkinesia needs well-executed statistical interrogations.

Detailed studies of pathological changes of the CASPER Gallbladder by gastrointestinal pathologists need to be undertaken [1].

Basic science research into motility disorders of the gallbladder ? both the CASPER Gallbladder and the CASPO Gallbladder ? need to be initiated. Contractility studies of the gallbladder smooth muscle, inquiries into the possible activation of inflammatory pathways in the gallbladder wall, and autonomic neuromuscular responses of the gallbladder smooth muscle would be reasonable areas to begin bench-top investigations using fresh cholecystectomy specimens from patients with symptomatic gallbladder motility disorders. This may potentially open avenues for pharmacological therapeutic options useful for the amelioration of symptoms.

Engagement of the patient population suffering from symptomatic gallbladder hyperkinesia via social media networks to help them understand their condition, assist them to find surgeons that will offer surgery to deserving patients, and make available to them publications on the topic that will facilitate health insurance coverage and surgeon involvement for their surgical treatment [52-54].

Taken together, these wide-ranging initiatives could result in symptomatic gallbladder hyperkinesia being introduced into the Rome V Criteria for Functional Gallbladder Disorders targeted for 2026 [56], serving as a first step in the potential formal recognition of this novel clinical entity.

Symptomatic gallbladder hyperkinesia is a new clinical condition, either a disease or a marker for disease, that is steadily gaining validation among patients and clinicians as a new clinical indication for cholecystectomy in well-selected patients.

1. Pillenahalli Maheshwarappa R, Menda Y, Graham MM, Boukhar SA, Zamba GKD, Samuel I. Association of gallbladder hyperkinesia with acalculous chronic cholecystitis: A case-control study. Surgery. 2020; 168: 800-8.
2. Saurabh S, Green B. Is hyperkinetic gallbladder an indication for cholecystectomy? Surg Endosc. 2019; 33: 1613-7.
3. Gazzetta J, Fan B, Bonner P, Galante J. Cholecystectomy for Biliary Hyperkinesia. Am Surg. 2019; 85: 219-22.
4. Eltyeb HA, Al-Leswas D, Abdalla MO, Wayman J. Systematic review and meta-analyses of cholecystectomy as a treatment of biliary hyperkinesia. Clin J Gastroenterol. 2021; 14: 1308-17.
5. Nasri B, Glass T, Singh K, Saxe J. Biliary hyperkinesia: an indication for cholecystectomy? Surg Endosc. 2021; 35: 3244-8.
6. Pihl KD, Jones MW, Deppen JG, Ferguson TM, Hanses SM. Effects of laparoscopic cholecystectomy in normokinetic biliary dyskinesia. Am J Surg. 2018; 215: 116-9.
7. DuCoin C, Faber R, Ilagan M, Ruderman W, Wier D. Normokinetic biliary dyskinesia: a novel diagnosis. Surg Endosc. 2012; 26: 3088-93.
8. Lindholm EB, Alberty JB, Hansbourgh F, Upp JR, Lopoo J. Hyperkinetic gallbladder: an indication for cholecystectomy? Am Surg. 2013; 79: 882-4.
9. Huckaby L, Timmapuri S, Prasad R. Biliary hyperkinesia: A potentially surgically correctable disorder in adolescents. J Pediatr Surg Case Rep. 2013; 1: 314-6.
10. Greenberg JJ. What is Biliary Hyperkinesia? Global Surgery. 2018; 4: 1-3.
11. Steele J, Wayne M, Iskandar M, Wolmer T, Bratcher J, Cooperman A. Biliary pain, no gallstones--remove the gallbladder, anyway? J FamPract. 2014; 63: 421-3.
12. Alexida L, Tiesenga FM. Laparoscopic cholecystectomy for biliary dyskinesia in patient with an extended spectrum of ejection fraction on hepatobiliaryiminodiacetic acid scan. Int Arch Integr Med. 2017; 4: 14-7.
13. Bates JA, Dinnan K, Sharp V. Biliary hyperkinesia, a new diagnosis or misunderstood pathophysiology of dyskinesia: A case report. Int J Surg Case Rep. 2019; 55: 80-3.
14. Dekonenko C, Sujka JA, Dorman RM, Oyetunji TA, St Peter SD. Selfreported Outcomes After Cholecystectomy for Pediatric Hyperkinetic Biliary Dyskinesia. J Surg Res. 2020; 246: 73-7.
15. Williford ML, Fay KT, Simpson FJ, Defnet AM, Schuster DM, Sethi I, et al. Optimal Management of the Hyperkinetic Gallbladder: A Comparison of Outcomes Between Operative and Nonoperative Approaches. Am Surg. 2021; 87: 903-9.
16. Bosley ME, Jacobson J, Gaffley MWG, Beckwith MA, Pandya SR, Davis JS, et al. Biliary hyperkinesia in adolescents-it isn’t all hype! Transl Gastroenterol Hepatol. 2021; 6: 36.
17. Singh JP. Role of Cholecystectomy in Symptomatic Hyperkinetic Gallbladder Patients. Case Rep Surg. 2021; 2021: 5569850.
18. Hart R, Senapathi H, Satchell E, Mandal S, McAndrew M, Scharf M, et al. The Role of Cholecystectomy in Hyperkinetic Gallbladder: A Retrospective Cohort Study in a Rural Hospital. Cureus. 2022; 14: e29778.
19. Whitaker LF, Bosley ME, Refugia JM, Powell MS, McNatt SS, Westcott CJ, et al. Outcomes After Laparoscopic Cholecystectomy in Hyperkinetic Biliary Dyskinesia. Am Surg. 2022; 88: 1983-7.
20. Falco GM, Condon FJ, Yheulon CG. Biliary Hyperkinesia: A Potentially Overlooked Source of Abdominal Pain Following Bariatric Surgery. Am Surg. 2020: 3134820973736.
21. Sadek AA, Higgins RM. Hyperkinetic Biliary Dyskinesia in Adults: Cholecystectomy as a Treatment Option. 2021.
22. Wright RC, Thach N, Peffer H, Robles R, Wright RJ. Surgical outcome in patients with biliary colic and atypical workup findings. Am J Surg. 2019; 217: 986-9.
23. Yap L, Wycherley AG, Morphett AD, Toouli J. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology. 1991; 101: 786-93.
24. Krishnamurthy GT, Bobba VR, Kingston E. Radionuclide ejection fraction: a technique for quantitative analysis of motor function of the human gallbladder. Gastroenterology. 1981; 80: 482-90.
25. Krishnamurthy S, Krishnamurthy GT. Biliary dyskinesia: role of the sphincter of Oddi, gallbladder and cholecystokinin. J Nucl Med. 1997; 38: 1824-30.
26. Ziessman HA, Tulchinsky M, Lavely WC, Gaughan JP, Allen TW, Maru A, et al. Sincalide-stimulated cholescintigraphy: a multicenter investigation to determine optimal infusion methodology and gallbladder ejection fraction normal values. J Nucl Med. 2010; 51: 277-81.
27. Dave RV, Pathak S, Cockbain AJ, Lodge JP, Smith AM, Chowdhury FU, et al. Management of gallbladder dyskinesia: patient outcomes following positive 99mtechnetium (Tc)-labelled hepatic iminodiacetic acid (HIDA) scintigraphy with cholecystokinin (CCK) provocation and laparoscopic cholecystectomy. Clin Radiol. 2015; 70: 400-7.
28. Cotton PB, Elta GH, Carter CR, Pasricha PJ, Corazziari ES. Rome IV. Gallbladder and Sphincter of Oddi Disorders. Gastroenterology. 2016; 150: 1420-9.
29. Bielefeldt K, Saligram S, Zickmund SL, Dudekula A, Olyaee M, Yadav D. Cholecystectomy for biliary dyskinesia: how did we get there? Dig Dis Sci. 2014; 59: 2850-63.
30. Mason EE, Ito C. Gastric bypass in obesity. Surg Clin North Am. 1967; 47: 1345-51.
31. Sjostrom CD, Lissner L, Wedel H, Sjostrom L. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. 1999; 7: 477-84.
32. Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004; 351: 2683-93.
33. Adams TD, Gress RE, Smith SC, Halverson RC, Simper SC, Rosamond WD, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007; 357: 753-61.
34. Wolfe BM, Kvach E, Eckel RH. Treatment of Obesity: Weight Loss and Bariatric Surgery. Circ Res. 2016; 118: 1844-55.
35. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012; 366: 1567-76.
36. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, et al. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. N Engl J Med. 2014; 370: 2002-13.
37. Whipple AO. Surgical criteria for cholecystectomy. Bull N Y Acad Med. 1926; 2: 302-6.
38. O’Connor OJ, Maher MM. Imaging of cholecystitis. AJR Am J Roentgenol. 2011; 196: W367-74.
39. Taplin GV, Meredith OM, Jr., Kade H. The radioactive (I131 tagged) rosebengal uptake-excretion test for liver function using external gamma-ray scintillation counting techniques. J Lab Clin Med. 1955; 45: 665-78.
40. Clark CJ. An Update on Biliary Dyskinesia. Surg Clin North Am. 2019; 99: 203-14.
41. Sakorafas GH, Milingos D, Peros G. Asymptomatic cholelithiasis: is cholecystectomy really needed? A critical reappraisal 15 years after the introduction of laparoscopic cholecystectomy. Dig Dis Sci. 2007; 52: 1313-25.
42. TheRomeFoundation.Org. Appendix A: Rome IV Diagnostic Criteria for Functional Gastro-Intestinal Disorders - E) Gallbladder and Sphincter of Oddi Disorder.
43. Morris-Stiff G, Falk G, Kraynak L, Rosenblatt S. The cholecystokin provocation HIDA test: recreation of symptoms is superior to ejection fraction in predicting medium-term outcomes. J Gastrointest Surg. 2011; 15: 345-9.
44. Ziessman HA. Sincalide: A Review of Clinical Utility, Proper Infusion Methodology, and Alternative Cholecystogogues. J Nucl Med Technol. 2019; 47: 210-2.
45. Cook CH, Kisner J, Melvin WS, Olsen J, Pozderac R, Martin LC. Biliary hyperkinesia: A new indication for cholecystectomy.(Abstract) Society for Surgery of the Alimentary Tract (SSAT) Annual Meeting, 1999.
46. Holes-Lewis K, Hakim S, Rehman F, Nabi H, Uhde T. CCK-induced gall bladder hyperkinesia: An indication for cholecystectomy and brainGI connectivity research.(Abstract) Society of Nuclear Medicine (SNM) Annual Meeting, 2009.
47. Law JK, Antoniou A, Kalloo AN, Shin EJ. The Hyperkinetic Gallbladder - An Ignored Cause of Abdominal Pain. (Abstract) American Gastroenterological Association (AGA) Annual Meeting. 2014.
48. Diarra C, Ho S, Lynsue J, Pauli EM, Rogers AM. Outcomes of cholecystectomy in gastric bypass and normal anatomy patients with biliary symptoms but normal diagnostic studies.(Abstract) Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Annual Meeting, 2015.
49. Cetrulo LN, Joshi A, Trang A. Management of the hyperkinetic gallbladder in adults: A case series.(Abstract) Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Annual Meeting, 2016.
50. Melvin JC, Ibendahl E, Perna M, Rawlings AL. Symptomatic hyperkinetic biliary dyskinesia: A predictor of successful outcomes after cholecystectomy.(Abstract) Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Annual Meeting, 2017.
51. Pallapothu R, Protas M, Prier T, Brustein J, Anne N. Biliary hyperkinesia: Is it a true indication for cholecystectomy?(Abstract)
    Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Annual Meeting, 2017.
52. Facebook.com. Private Facebook Group: “Hyperkinetic Gallbladders”.
53. Twitter.com. Gallbladder Hyperkinesia.
54. Twitter.com. Hyperkinetic Gallbladder.
55. Tulchinsky M, Ciak BW, Delbeke D, Hilson A, Holes-Lewis KA, Stabin MG, et al. SNM practice guideline for hepatobiliaryscintigraphy 4.0. J Nucl Med Technol. 2010; 38: 210-8.
56. TheRomeFoundation.org. Rome V, Disorders of Gut-Brain Interaction 5th Edition.