Controversy and reflection on the clinical diagnosis and treatment of asymptomatic gallstones

Authors: Zheng Yamin, Gu Liguo, Xu Chen

Source: International Journal of Surgery, 2023, 50(8)

summary

Gallstones are a common and frequent clinical disease, which can be secondary to cholecystitis, cholangitis, pancreatitis and gallbladder cancer. Many patients with gallstones do not have obvious clinical symptoms such as biliary colic. Some patients do not have obstruction of gallstones, have no accompanying inflammation of the gallbladder, and are indeed in the asymptomatic period. However, some patients have no symptoms because they are unconscious, and mistakenly think that stomach pain, enteritis, etc.; or due to insensitivity to pain or disease interference, etc., insufficient perception of gallstone symptoms; In other patients, the gallbladder is morphologically and structurally abnormal, and the gallbladder is non-functional, causing no cramping pain. Clarifying the concept, diagnosis, and classification of asymptomatic gallstones according to pathophysiological stages is conducive to the development of individualized management strategies. There are many controversies in the management of asymptomatic gallstones, including regular follow-up, drug treatment, surgical excision or gallstone preservation, etc., and more in-depth basic research evidence is needed for reasonable personalized diagnosis and treatment.

Gallstones are common all over the world, and Zhang et al. [1] reported that the prevalence of gallstones increases with age, ranging from 5.9%~21.9% in Europe, 4%~15% in Asia, and 3%~11% in China. Gallstones can be secondary to acute abdomen such as acute cholecystitis, acute obstructive cholangitis and severe pancreatitis, which can endanger the health of patients. If gallbladder cancer is secondary to it, the prognosis is very poor and can be life-threatening. With the deepening of research and the accumulation of experience in clinical practice, the diagnosis and treatment of gallstones are becoming more and more standardized [2,3,4]. However, the treatment of asymptomatic gallstones remains highly controversial, including observational follow-up, medical therapy, surgical excision, or different management of gallstone-sparing [3]. Based on the research results of gallstone formation mechanism and pathophysiological progression, combined with clinical diagnosis and treatment practice, this article explores the reasonable diagnosis and treatment strategy of asymptomatic gallstones.

1 Concept of asymptomatic gallstones

Gallstones refer to the stone-like foreign body in the gallbladder bile, which is mainly composed of cholesterol, bilirubin, calcium, protein, etc. Patients with gallstones generally do not have symptoms such as abdominal pain if they do not have stone incarceration or obstruction of bile emptying, which leads to many people only finding gallstones during physical examination and hepatobiliary ultrasound. The typical symptom of gallstones is biliary colic, which is usually precipitated by a high-fat diet, with strong gallbladder contraction, incarceration of the gallstone in the cystic duct, and obstruction of bile drainage, resulting in increased gallbladder tone and biliary spasm [5]. Biliary colic is characterized by crampy pain in the right upper quadrant, radiating to the back of the right shoulder, lasting from a few minutes to ten minutes, and if the obstruction is relieved, the symptoms are immediately relieved; If the obstruction is not relieved, abdominal pain will persist and worsen, and will be followed by acute cholecystitis, and even gallbladder wall ischemia, gangrene, suppuration, and perforation. In a broad sense, the symptoms of gallstones also include atypical epigastric pain, bloating, acid reflux, bitter mouth, early satiety and other biliary dyspepsia symptoms associated with gallstones. These symptoms need to rule out whether the patient has other medical conditions, such as gastroenteritis, upper gastrointestinal ulcers, duodenal diverticulitis, gastrointestinal spasms, and gastroesophageal reflux.

The concept of asymptomatic gallstones refers primarily to the presence of gallstones on imaging without typical symptoms of biliary colic or the onset of acute cholecystitis. Because the identification of abdominal pain depends on the patient's self-perception, it is affected by factors such as the level of pain area, health status, level of disease cognition, and comorbidities. For patients with gallstones who think they are asymptomatic, especially those with atypical epigastric discomfort, in-depth communication, medical history, detailed physical examination, and combined with the results of auxiliary examinations, a comprehensive assessment and judgment should be carried out to determine whether there are clinical symptoms caused by gallstones. The formation of gallstones is a gradual process, and the formation of gallstones is associated with a variety of risk factors, including genetic factors [6], congenital diseases, age, sex [7], body mass index [8], dietary patterns, lifestyle habits, inactivity [4], drug damage [9], lipid metabolism [10], abnormal gallbladder morphological function, gut microbiota [11], liver disease [12], and a history of some surgeries [13]. The mechanism of gallstone formation has not been fully elucidated, resulting in a lack of targeted preventive measures, and patients need to pay attention to the lack of asymptomatic after the discovery of gallstones.

2 Classification of causes of asymptomatic gallstones

A strategy for the management of asymptomatic gallstones should be developed on the premise that the patient's systemic status and local pathophysiology changes are identified. There is significant individual variation in the clinical presentation and timing of symptom onset, and biliary obstruction leading to abdominal pain and secondary pathology increases if survival is long enough. It is necessary to pay attention to the presence of asymptomatic illusions in some patients in clinical diagnosis and treatment, and identify the causes of asymptomatic gallstones, which is helpful for choosing a reasonable treatment.

2.1 Asymptomatic stems from unawareness

Due to a lack of medical expertise, patients do not have an accurate understanding of the symptoms of gallstones. Some patients do not know that they have gallstones without medical examination or medical treatment, and mistakenly regard biliary colic as other diseases; Even though some patients know that they have gallstones, they still attribute abdominal pain to concomitant gastric ulcers, enteritis, and even lumbar disc herniation. There are also some patients who are asymptomatic, but in fact only have a remission or intermittent period of acute biliary colic or cholecystitis attacks; In addition, some patients with gallstones have biliary colic attacks, but they are not severe or atypical, and they are ignored because the symptoms are quickly relieved.

2.2 Asymptomatic stems from inadequate perception

Everyone's sensitivity to pain is different, and some people have a high pain threshold and are not sensitive to abdominal pain, resulting in neglect of abdominal pain caused by gallstones. Patients with diabetes mellitus, distal gastrectomy, and high paralysis are insensitive to biliary colic due to gallstones, due to dysesthesia due to gallbladder-related nerve damage. This lack of perception can easily cause patients to miss the optimal time for treatment, and start treatment only when cholangitis, severe pancreatitis, or gallbladder cancer are caused by common bile duct stone obstruction. Some pain-causing disorders, such as right-sided urinary stones and gastroduodenal disease, are more common than sickle cell anemia and often mask symptoms of biliary colic caused by gallstones.

2.3 Asymptomatic stems from abnormal morphological structure and function of the gallbladder

Some patients with gallstones have gallbladder malformation, atrophy, dilation, luminal stones, or magnetization of the cyst wall, at which point the gallbladder has lost its normal morphological structure and function of storing, concentrating, and emptying bile. Weakening or loss of the contractile function of the gallbladder rarely induces the spasmodic effect of gallbladder obstruction and causes symptoms of biliary colic. Acute or chronic obstruction of gallstones can lead to ischemia, bacterial infection, secondary inflammation, and fibrous hyperplasia, resulting in abnormal gallbladder morphological structure and function. Abnormal gallbladder morphology, such as non-pear-shaped structures such as gourd or cast, will cause bile flow disorders during contraction, resulting in cholestasis, cholesterol precipitation, and stone formation. The gallbladder with abnormal morphological structure and function is not a true asymptomatic gallbladder, but a secondary lesion of gallstones, which has an increased risk of cancer, and it is recommended to have surgery as soon as possible.

2.4 Asymptomatic due to non-obstructive inflammation

The real asymptomatic gallbladder stones should be a period when the shape, structure and function of the gallbladder remain basically intact, the stones are not obstructed, and the cyst wall is not inflamed. This condition is likely to persist for a long time, but as people live longer and the risk of secondary damage from stones increases, there is a greater academic debate about how to manage these patients more rationally [14,15,16]. It is not advisable to let gallstones in the asymptomatic stage go unchecked, and it is not uncommon for cases of gallbladder cancer secondary to asymptomatic stones to be detected at an advanced stage. The authors suggest that asymptomatic gallstones should be treated individually according to the specific situation of the patient.

3 Diagnostic basis for asymptomatic gallstones

According to the basic research on the formation and pathogenesis of gallstones, the pathophysiological progression of gallstones can be divided into four stages[17]:(1) the stage of gallstone formation; (2) Asymptomatic and non-obstructive period of gallstones; (3) Acute inflammation of gallstones; (4) Secondary lesion stage of gallbladder stones. True asymptomatic gallstones belong to the asymptomatic, non-obstructive phase of gallstones. At this stage, gallstones were mainly found through imaging examinations, but the patient had no obvious symptoms, no obstruction of the cystic duct, no obvious inflammation of the gallbladder wall, the contractile function of the gallbladder was basically normal, and the gallstones were in a resting state. The pathophysiological basis of this stage is that the gallbladder morphology, structure, and function are good, and the formation of stones is caused by bile or extragallbladder factors; The function of the gallbladder to store, concentrate, and empty bile remains relatively normal. The stones did not block the cystic duct, and the patient did not have symptoms such as biliary colic. Gallstones have not yet caused significant secondary damage to the gallbladder wall and have a significant inflammatory response.

The author believes that the diagnostic criteria for asymptomatic gallstones include three aspects: (1) gallstones found by imaging examination, and the gallbladder size, morphology and structure are normal, and the gallbladder function is normal; (2) The patient has no obvious symptoms of biliary colic, no history of acute cholecystitis, and may have dyspeptic symptoms such as epigastric discomfort, abdominal distension, and belching; (3) Patients with epigastric pain have a clear cause other than gallbladder stones that can be explained, and the cause is significantly relieved or the abdominal pain disappears after etiological treatment.

4 Treatment strategies for asymptomatic gallstones

At present, the management of asymptomatic gallstones is controversial and needs to be further studied and discussed. Combined with the clinical diagnosis and treatment guidelines and consensus at home and abroad, the treatment at this stage mainly includes the following views: (1) the traditional concept is that patients can be rechecked and observed regularly, and then treated if symptoms appear; (2) There is a consensus on drug treatment recommendations for litholysis, lithotripsy, and stone expulsion [18]; (3) Multiple guidelines and consensus point out that asymptomatic patients with gallstones such as large stones, long course of disease, accompanied by diabetes, elderly patients and other special conditions should have their gallbladder surgically removed; (4) In view of the high risk of malignant transformation of stones, more and more experts are inclined to perform gallbladder resection surgery at this stage; (5) Some physicians believe that the gallbladder has a function at this stage and can be operated with cholelithotomy.

4.1 Observational follow-up of asymptomatic gallstones

In the past, it was generally believed that asymptomatic gallstones could be observed first and followed up regularly, which is also the recommendation of most medical textbooks in mainland China, and has been widely implemented in clinical practice. The rationale for this management is that some patients with gallstones may remain asymptomatic for life and have no serious secondary lesions, which are only discovered after postmortem autopsy. If gallstones are asymptomatic, they can be followed up with regular observation, and there is still no recognized effective drug to completely remove them. At follow-up, if the patient has clear symptoms related to gallstones, prompt surgical resection is required. Symptomatic gallstones are often accompanied by cholecystitis, dysfunction, and high risk of cancer, and removal of the diseased gallbladder is recognized as a reasonable and effective treatment.

4.2 Medical treatment of asymptomatic gallstones

In the past, drug treatment of gallstones mainly focused on the dissolution or passage of gallstones, especially asymptomatic gallstones without the need for symptomatic treatment. Oral ursodeoxycholic acid and other bile acid litholytic drugs are not ideal, the effective rate is only about 20%, and the medication time is long, and the recurrence rate is as high as 50% in 5 years. If the gallbladder stones are embedded in the cystic duct or discharged into the common bile duct during the stone removal process, it will cause obstruction of the outlet of the bile duct and pancreatic duct, resulting in acute obstructive purulent cholangitis and acute severe pancreatitis. MT perfusion can dissolve cholesterol stones, but percutaneous injection into the gallbladder is an invasive procedure with a risk of overflow into the common bile duct, liver, and intestines, and is mostly experimental. The author believes that the drug treatment of gallbladder stones should be controlled in a small area where cholesterol stones, fine sediment stones, and excretion stones are not risk-free. Drug prophylaxis for people at high risk of stones and patients in the stone stage is the direction of future drug treatment research.

4.3 Special types of asymptomatic gallstones are recommended for surgical excision

In some patients with asymptomatic gallstones, gallbladder removal is positive if they are at greatly increased risk of serious secondary lesions. In patients with cystic duct dilation, distal bile duct stricture, or parapapillary duodenal diverticulum, gallstone drainage into the extrahepatic bile duct is often secondary to acute obstructive suppurative cholangitis and acute severe pancreatitis, with a high mortality rate. Patients with gallstones that are too large, have been ill for too long, have polyps, inflammation, wall thickness, calcification, and glandular hyperplasia have a higher risk of gallbladder cancer. Older adults, patients with diabetes mellitus, and immunocompromised gallstones have more difficult biliary tract infections to control, and emergency surgery has higher morbidity and mortality. Previous experts and scholars have conducted a large number of studies from many aspects, and it is recommended to undergo gallbladder removal treatment for asymptomatic gallstones with high-risk patients.

In recent years, studies on the high-risk risk of asymptomatic gallstones have emerged [18], and surgical treatment is recommended in the following situations: (1) gallstones with a maximum diameter of more than 3 cm; (2) Imaging examination of porcelain gallbladder; (3) Diabetic; (4) Calculi combined with gallbladder polypoid lesions; (5) Those with a family history of cholangiocarcinoma; (6) Gallbladder atrophy, gallbladder expansion or obvious thickening of the gallbladder wall, especially local thickening; (7) gallbladder malformation; (8) The stone is embedded in the neck of the gallbladder; (9) Female patients who are older than 50 years old and have a disease duration of more than 5 years; (10) Patients with immunocompromised or immunodeficiency diseases; (11) Patients with duodenal diverticulum near the distal end of the bile duct or abnormal biliary and pancreatic duct confluence; (12) Those whose gallbladder function test shows severe gallbladder dysfunction or no function; (13) The elderly, especially those with cardiopulmonary dysfunction. The treatment of these patients reflects the development trend of modern medical concepts, and pays more attention to personalization and precision on the basis of standardized diagnosis and treatment.

4.4 Asymptomatic gallstones are indications for surgical resection

According to the 2021 edition of the Chinese Expert Consensus on the Surgical Treatment of Benign Gallbladder Diseases, the Biliary Surgery Group of the Chinese Society of Surgery and the Biliary Surgeon Committee of the Surgeon Branch of the Chinese Medical Doctor Association pointed out that cholecystectomy is the only curative means for benign gallbladder diseases, regardless of whether gallstones are asymptomatic or asymptomatic [16]. The consensus points out that the gallbladder mucosa is repeatedly stimulated by stones and inflammation for a long time, and the process of "metaplasia-dysplasia-carcinogenesis" of epithelial cells will occur. Most of the patients in the early stage of gallbladder cancer have no obvious symptoms, most patients are in the advanced stage when they visit the clinic, only 10%~30% of patients can get the opportunity of radical surgery, and the 5-year overall survival rate is only about 5%. Previous studies have reported at least a six-fold increase in the incidence of gallbladder cancer in patients with gallstones, particularly in older patients with gallstones who are at higher risk of cancerization [19]. In addition, it has been reported that during the follow-up of patients with gallstones, 6.6%~25.8% of patients developed secondary biliary complications, and 2.4%~8% of patients developed secondary gallbladder cancer [20].

The idea of "reducing the incidence of gallbladder cancer and treating asymptomatic gallstones with cholecystectomy" has attracted extensive academic discussions, including the timing of resection surgery, risk prognosis assessment, and selection of surgical methods [16]. At present, the surgical treatment of asymptomatic gallstones in mainland China may still need to be comprehensively considered in combination with local medical resources and patient wishes. The rapid increase in the number of surgeries is bound to increase the pressure on medical institutions. For some patients with asymptomatic stones, it is difficult to give up the gallbladder due to emotion, or because of fear of surgery, and it is recommended to follow up closely on a regular basis for patients who do not undergo surgery, and if there are clinical symptoms, secondary lesions and high-risk factors for cancer, gallbladder removal should be carried out in time.

4.5 Controversy over the use of gallstones for asymptomatic gallstones

For asymptomatic gallstones with abnormal gallbladder morphology, structure and function, cholecystectomy should be performed, and a consensus can be reached in the industry. There is a great deal of academic controversy about whether gallstones from asymptomatic gallbladder with good gallbladder function can be taken with gallstones conserved. Many people have the traditional concept of preserving their organs, and there is a large demand for gallstones. The mechanism of gallstone formation is not fully elucidated, and there are various hypotheses and conjectures about stone formation. The theoretical basis for gallbladder removal treatment is mainly the "hotbed theory" of gallstone formation. A variety of factors cause abnormal gallbladder morphological structure and function, cholestasis, bacteria, proteins, crystals, etc. as the core of stone, cholesterol precipitation and aggregation, bile pigment precipitation and attachment, and gradually form gallstones, so the treatment is to remove the gallbladder and remove the hotbed. The theoretical basis for the treatment of gallstones is the "theory of abnormal bile composition" formed by stones, the relative deficiency of bile acid in bile, the precipitation and aggregation of cholesterol supersaturation, and the combination of bile pigments and other factors to form stones. If the gallbladder is still functioning, the patient may benefit from gallbladder preservation by removing stones and supplementing with bile acids. It should be noted that there is no accepted diagnostic standard for the normal morphological structure and function of the gallbladder, and it is difficult to accurately judge the nature of the stone and the proportion of bile acid before surgery, and it is also difficult for the individual to determine the specific cause of the formation of the stone.

Studies in Europe and the United States on laparotomy and calculus removal as early as the 20th century have shown that the recurrence rate of gallstones is more than 30%, so there are few studies and guidelines in Europe and the United States that cholelithotomy is rarely used as an alternative for the treatment of gallstones [21]. In recent years, some medical institutions in China have carried out minimally invasive cholelithotomy surgeries such as laparoscopy, choledoscopy, and endoscopy, and have published the Guidelines for Endoscopic Cholelithotomy (2021 Edition) [15]. In view of the great controversy surrounding this surgical method, it is necessary to control it within the scope of academic research and should not be widely promoted. The Guidelines for the Diagnosis and Treatment of Gallbladder Cancer (2019 Edition) formulated by the Surgical Branch of the Chinese Medical Association clearly oppose cholelithotomy, arguing that it may miss potential early cancerous changes in the gallbladder mucosa, and that the gallbladder is a high-risk factor for gallbladder cancer after surgery.

5 Conclusion

In short, for asymptomatic gallstones, it is first necessary to clarify whether the patient is truly asymptomatic, and exclude unawareness, insufficient perception, and abnormal gallbladder shape and function to prevent delaying treatment. It is recommended that physicians determine the pathophysiological stage of gallstones according to clinical manifestations, combined with imaging examinations such as ultrasound, CT, magnetic resonance cholangiopancreatography, etc., which is helpful for personalized treatment. There is great controversy in the management of gallstones in the asymptomatic and non-obstructive period, including regular follow-up, drug treatment, surgical excision, or cholelithotomy. The author believes that asymptomatic gallstones require reasonable and personalized diagnosis and treatment, and gallbladder surgical resection in high-risk patients is necessary.

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