Gallbladder stones – how to recognize, diagnose, and treat – a literature review

Full article

https://doi.org/10.53453/ms.2025.6.6

Gallbladder stones: how to recognize, diagnose, and treat - a

literature review

Ieva Bružaitė

, Linas Prapiestis

, Aistė Česnulevičienė

Faculty of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania

Lithuanian University of Health Sciences, Kaunas Clinics, Department of Family Medicine Kaunas, Lithuania

Abstract

Background. Gallstone disease is a prevalent digestive disorder, affecting 10–15% of adults worldwide. Although

the disease is usually asymptomatic, in certain cases, it can cause severe complications that require urgent

treatment.

Aim. To evaluate current knowledge on cholelithiasis, including its epidemiology, risk factors, pathogenesis,

diagnostic approaches, treatment options, and preventive strategies.

Material and Methods. A comprehensive literature review was conducted using the PubMed database, focusing

on English-language studies published between 2015 and 2025. Studies were selected based on relevance to

epidemiology, pathogenesis, risk factors, diagnosis, and treatment.

Results. Cholelithiasis develops due to an interplay of modifiable and non-modifiable risk factors. Cholesterol

supersaturation, bile stasis and inflammation contribute to gallstone formation. Ultrasound remains the first-line

diagnostic tool. Treatment ranges from conservative management to laparoscopic cholecystectomy, which is the

gold standard for symptomatic cases. Preventive strategies include lifestyle modifications and pharmacological

interventions in high-risk patients.

Conclusion. Gallstone disease remains a major global health concern due to its high prevalence and potential

complications. Advances in imaging and surgical techniques have improved outcomes, but prevention through

lifestyle modifications remains crucial. Future research should focus on personalized risk assessment and novel

therapeutic strategies.

Keywords: gallstones, cholelithiasis, biliary tract diseases, gallbladder diseases, laparoscopic cholecystectomy.

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Medical Sciences 2025 Vol. 13 (4), p. 65-75, https://doi.org/10.53453/ms.2025.6.6

1. Introduction

Gallstone disease, otherwise known as

cholelithiasis, is one of the most prevalent

digestive disorders on a global scale, affecting

millions of individuals each year. While the

mortality rate is relatively low, the high

incidence of the condition gives rise to

significant healthcare concerns (1). The

prevalence of gallstones in adults ranges from

10% to 15% in the United States and Europe,

with similar rates observed in Lithuania (2). The

majority of gallstones form within the

gallbladder; however, in some cases, gallstones

can migrate through the cystic duct into the bile

ducts, leading to conditions such as

choledocholithiasis and hepatolithiasis.

Although many cases remain asymptomatic,

gallstones can lead to severe complications,

including acute cholecystitis and pancreatitis,

necessitating timely medical intervention (3).

Given the high incidence of the disease and its

potential for serious outcomes, there is a clear

need for the advancement of diagnostic methods,

the improvement of treatment options, and the

development of effective prevention strategies,

in order to reduce the burden on both patients

and healthcare systems (4).

2. Methods

A comprehensive literature review was

conducted using the PubMed database to

identify relevant studies on cholelithiasis, its

epidemiology, risk factors, pathogenesis,

diagnostic approaches, treatment options, and

preventive strategies. The search strategy

employed a combination of keywords, including

"gallstones", "cholelithiasis", "gallbladder

stones" and "gallstone disease."

Inclusion criteria:

• Articles published between 2015 and 2025 to

ensure the inclusion of recent and up-to-date

findings.

• Publications written in English.

• Peer-reviewed original research articles,

systematic reviews, meta-analyses, and

clinical guidelines.

• Studies focused on the epidemiology, risk

factors, pathogenesis, diagnosis, treatment,

or prevention of gallstone disease

(cholelithiasis).

• Studies involving human subjects.

Exclusion criteria:

• Articles published in languages other than

English.

• Studies published prior to 2015.

• Case reports, conference abstracts, editorials,

and opinion pieces.

• Studies focusing exclusively on pediatric

populations or rare genetic disorders unless

directly relevant to gallstone disease.

• Articles lacking accessible full text.

In total, 40 articles were included in the review

based on their compliance with the established

inclusion criteria. This systematic approach

provides a detailed and current review of the

existing knowledge and developments in the

management of cholelithiasis.

3. Results

3.1. Ethiology

The formation of gallstones is influenced by a

complex interplay of modifiable and non-

modifiable risk factors (5). Among the

modifiable risk factors, conditions such as

dyslipidemia, obesity, metabolic syndrome,

smoking, type 2 diabetes, and the use of certain

medications – including ceftriaxone, estrogens,

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and thiazide diuretics – have been strongly

associated with an increased risk of gallstone

formation (6). Conversely, non-modifiable risk

factors encompass female sex, pregnancy, and a

family history of gallbladder disease (5). The

incidence of gallstones rises sharply with age,

with individuals aged 40 to 69 experiencing a

fourfold higher risk compared to younger adults

(7). Furthermore, the presence of certain medical

conditions, including cirrhosis, Crohn's disease,

and hyperbilirubinemia, has been identified as a

risk factor for gallstone formation (8) .

One of the key mechanisms by which obesity

contributes to gallstone formation is through

increased hepatic cholesterol synthesis and

secretion into bile, leading to cholesterol

supersaturation (9). Moreover, obesity is

frequently associated with insulin resistance,

which can further compromise bile acid

metabolism and gallbladder function (10). It is

also noteworthy that rapid weight loss, whether

due to extreme dieting or bariatric surgery, can

also predispose individuals to gallstones by

reducing gallbladder motility and impairing bile

clearance (8). The association between

dyslipidemia and gallstone disease has been well

documented (10). Elevated levels of non-high-

density lipoprotein (non-HDL) cholesterol have

been demonstrated to be associated with a higher

incidence of gallstones, thereby underscoring the

role of abnormal lipid metabolism in the

pathogenesis of cholelithiasis (6).

Hormonal factors have been demonstrated to be

particularly relevant in the formation of

gallstones, especially among women of

reproductive age, who have been shown to be

four times more likely to develop gallstones than

men (11). However, this gender disparity

narrows after menopause (7). The role of

estrogen is particularly significant in this regard,

as it has been demonstrated to increase

cholesterol secretion into bile while decreasing

bile salt secretion (12). This, in turn, results in

cholesterol supersaturation and, consequently,

gallstone formation. Conversely, progesterone

exerts a detrimental effect by reducing

gallbladder motility, leading to bile stasis and,

consequently, an elevated risk of stone

development (13).

Diabetes mellitus is another significant

contributing factor to gallstone formation,

primarily due to autonomic neuropathy-induced

gallbladder dysfunction (14). Gallbladder stasis,

a prevalent complication in diabetes, results in

impaired bile emptying and elevated bile

lithogenicity (13). A study of 51 diabetic

subjects, categorized into those with no

neuropathy, diabetic peripheral neuropathy, and

diabetic autonomic neuropathy, demonstrated

that patients with autonomic neuropathy

exhibited significantly reduced gallbladder

ejection fractions, thereby underscoring the

association between diabetes and gallstone

disease (15).

It is therefore vital to understand these diverse

risk factors and their underlying mechanisms if

we are to achieve early prevention, risk

stratification, and effective management of

gallbladder stone disease. The identification of

individuals at high risk and the implementation

of preventive measures can lead to a significant

reduction in the burden of gallstone disease on

individuals and healthcare systems (16).

3.2. Pathogenesis

Gallstones are categorized into three distinct

types: cholesterol stones, pigment stones, and

mixed stones, which are characterized by their

own unique mechanisms of formation (17). The

development of gallstones is influenced by a

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combination of genetic predisposition,

metabolic imbalances, biliary stasis, gut

microbiota, and infections (18). These factors

contribute to the crystallization and aggregation

of stone-forming substances in bile (19).

The formation of cholesterol gallstones has been

linked to genetic factors, as variations in genes

involved in cholesterol metabolism and bile acid

regulation can increase susceptibility to

gallstone formation (2). Research suggests that

mutations in the ATP-binding cassette G8

(ABCG8) and cytochrome 7A1 (CYP7A1)

genes affect cholesterol transport and bile acid

synthesis, leading to supersaturated bile and a

higher risk of gallstone development (18).

Furthermore, excessive hepatic cholesterol

secretion can lead to bile supersaturation, a

primary factor in cholesterol crystallization (20).

Pigment stones, which are primarily composed

of calcium bilirubinate, are classified as black or

brown stones. Black pigment stones typically

develop in conditions involving chronic

hemolysis, such as sickle cell disease and

hereditary spherocytosis, which result in

excessive bilirubin production and its

subsequent accumulation in bile (20). In

contrast, brown pigment stones are strongly

associated with biliary infections, particularly

those involving anaerobic bacteria, which

produce β-glucuronidase, an enzyme that

hydrolyses conjugated bilirubin, leading to

calcium bilirubinate precipitation (21).

A pivotal factor in gallstone formation is

cholestasis, which results in impaired bile flow

and the accumulation of stone-forming

substances (18). Biliary obstruction, infections

or hepatobiliary dysfunction can alter bile

composition, increasing the likelihood of

gallstone development (21). The formation of

gallstones is a multifaceted process influenced

by a complex interplay of genetic, metabolic, gut

microbiota, and bile flow dynamics (18).

3.3. Diagnostics

3.3.1. Symptoms

In most cases, gallstones remain asymptomatic

and are detected incidentally during imaging for

unrelated abdominal conditions (11). Research

indicates that merely 20% of patients with

asymptomatic gallstones progress to clinically

significant complications (8). The hallmark

symptom of gallstone disease is biliary colic,

characterized by acute and rapidly escalating

pain in the right upper quadrant or epigastric

region (22). The pain often radiates to the right

shoulder or the area between the scapulae, a

phenomenon known as Collins' sign (23).

Patients may also complain of nausea, vomiting,

bloating, and diaphoresis. The pain is typically

triggered by the consumption of fatty meals, as

gallbladder contractions attempt to expel bile

past an obstructing stone (24). The duration of

these episodes can range from several minutes to

a few hours (25). In more severe cases, there may

be progression to acute cholecystitis, presenting

with persistent right upper quadrant pain, fever

and leukocytosis, which often requires surgical

intervention (24). When a gallstone blocks the

common bile duct, the condition is referred to as

choledocholithiasis, which may manifest with

symptoms such as jaundice, dark urine, pale

stools, and increased liver enzyme levels (26).

Rarely, gallstones may also result in gallstone

pancreatitis, manifesting as epigastric pain

radiating to the back, severe nausea, and

systemic inflammation (24).

3.3.2. Diagnostic tests

The National Institute for Health and Care

Excellence (NICE) has provided guidelines

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advising that patients who show symptoms

indicative of gallstone disease should have blood

tests conducted to evaluate liver function

parameters. These parameters include bilirubin,

alkaline phosphatase, gamma-glutamyl

transferase (GGT), alanine aminotransferase

(ALT), lipase, and inflammatory markers (11).

The conclusive diagnosis of cholelithiasis is

established through imaging methods, with

ultrasound, magnetic resonance

cholangiopancreatography (MRCP), and

endoscopic ultrasound (EUS) being the most

frequently used techniques (27).

Ultrasound is the preferred imaging technique

for diagnosing gallstones because it is widely

available, cost-effective, and non-invasive (11).

Typically, gallstones manifest as hyperechoic

structures, casting acoustic shadows, and their

mobility can be assessed by repositioning the

patient (20). The sensitivity and specificity of

ultrasound for detecting gallstones range from

81% to 83%, but increase significantly when

performed by an experienced radiologist, thus

making it the gold standard for gallbladder stone

diagnosis (11).

Endoscopic ultrasound (EUS) represents a

sophisticated technique with a high sensitivity of

94–98% for detecting small gallstones or biliary

sludge in patients with biliary pain but normal

abdominal ultrasound findings (20). It is

particularly useful in patients with unexplained

acute or recurrent pancreatitis, where

microlithiasis (biliary sludge) might be the cause

(24). However, it is important to note that EUS

cannot be performed in patients with previous

gastric surgeries that alter normal

gastrointestinal anatomy (20).

Furthermore, the role of computed tomography

scan (CT) and magnetic resonance imaging

(MRI) in diagnosing cholelithiasis is limited. CT

is not generally recommended for the detection

of gallbladder stones due to its relatively low

sensitivity for small, radiolucent cholesterol

stones, which may not be visible on standard

imaging procedures (28). Research by Peter J.

Fagenholz and others shows that CT fails to

identify cholelithiasis in 40% of cases, while

Joss R. Wertz and others found that CT may fail

to detect up to 20% of patients with gallstones

(29,30). Furthermore, CT is unable to effectively

visualize bile composition, thus rendering it a

suboptimal diagnostic modality in comparison to

ultrasound for routine gallbladder stone

detection (28).

Conversely, MRI, including Magnetic

Resonance Cholangiopancreatography (MRCP),

is not a primary imaging technique for

gallbladder stones. While MRCP has been found

to have a high sensitivity for bile duct stones

(choledocholithiasis), its role in detecting

gallbladder stones is limited (26). The visibility

of small gallstones may be compromised, and

the cost-effectiveness of MRI in comparison to

ultrasound for routine cholelithiasis diagnosis is

questionable (31).

3.4 Complications

It is estimated that between 1 - 3% of patients

diagnosed with gallstones experience a

gallstone-related complication each year (32).

This risk is evident in both symptomatic and

asymptomatic individuals. Patients with a

history of gallstone symptoms have a higher 10-

year cumulative risk of complications (6%)

compared to those who were previously

asymptomatic (3–4%) (11). Studies indicate that

up to 72% of symptomatic gallstone patients

develop ongoing biliary pain or serious

complications, including acute cholecystitis, an

inflammatory condition caused by cystic duct

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obstruction; gallstone pancreatitis, which results

from stones blocking the pancreatic duct, leading

to pancreatic inflammation (33). Moreover,

biliary tract obstruction can lead to jaundice and

liver dysfunction, while advanced gallbladder

inflammation may result in emphysematous

cholecystitis and perforation, increasing the risk

of sepsis and peritonitis (34). Post-surgical

complications are reported in approximately

11% of patients, with 2% requiring further

treatment for major complications (35). Beyond

acute complications, gallstones are recognized

as a major risk factor for gallbladder, pancreatic,

and colorectal cancers (5).

3.5 Treatment

For asymptomatic individuals, a watch-and-wait

strategy is generally preferred, as the risk of

complications remains low. However, in high-

risk patients, including those with a porcelain

gallbladder, large gallstones (>3 cm), or

underlying hematologic disorders such as sickle

cell disease, prophylactic cholecystectomy may

be indicated (11). Furthermore,

immunocompromised patients, individuals with

diabetes, and certain ethnic groups—such as

Native Americans, Hispanics, and Latinos—are

predisposed to gallstone-related complications

and may benefit from early surgical intervention

(36). It is important to emphasize that the

primary objective of management should be the

prevention of gallstone formation. The most

effective issues for prevention are lifestyle

modifications, such as maintenance of a healthy

body mass index, regular physical activity, and a

balanced diet (11). Although pharmacological

prevention is not routinely recommended,

ursodeoxycholic acid (UDCA) has demonstrated

effectiveness in decreasing the formation of

gallstones among high-risk individuals,

especially those experiencing rapid weight loss

after bariatric surgery (36). It is crucial to note

that the effectiveness of UDCA is limited to

cholesterol gallstones and treatment typically

requires a prolonged duration of 6 to 24 months,

and that this medication does not show efficacy

against pigment or calcified stones (23).

The choice between conservative treatment and

surgical intervention for symptomatic gallstone

disease depends on the severity of the symptoms,

the likelihood of recurrence, and the potential for

complications (23). Patients with mild, transient

biliary colic may be managed conservatively

with analgesics and lifestyle modifications (37).

Common medications employed in this context

include nonsteroidal anti-inflammatory drugs

(NSAIDs) (e.g., ibuprofen), paracetamol,

opioids, and antispasmodics such as

butylscopolamine (23). However, it is important

to recognize that up to 50% of patients who are

managed conservatively for gallstone disease

may necessitate surgical intervention within five

years because of recurrence of symptoms or

complications (37). For patients who are not

suitable for immediate surgical intervention,

alternative treatment options such as

extracorporeal shock wave lithotripsy (ESWL)

are available (38). Nevertheless, the utilization

of these treatments has diminished due to their

limited efficacy and high incidence of

recurrence. ESWL demonstrates optimal

efficacy for solitary, radiolucent cholesterol

stones with a diameter of up to 2 cm; however,

recurrence rates exceed 50% within a five-year

timeframe (23).

When surgical treatment is indicated,

laparoscopic cholecystectomy remains the gold

standard due to its minimally invasive technique,

shorter hospital stay and lower postoperative

complication rate (39). Several studies have

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demonstrated that laparoscopic cholecystectomy

reduces postoperative morbidity, pneumonia

risk, and wound infections in comparison with

open cholecystectomy (25). However, it is

important to note that conversion to open surgery

is necessary in 2% to 15% of cases due to severe

inflammation, unclear anatomy, or previous

adhesions (39). The Critical View of Safety

technique is imperative in preventing bile duct

injury, a grave complication that occurs in 0.3–

0.7% of cases (40). A small subset of patients (5–

40%) experience persistent digestive symptoms

after cholecystectomy, a condition known as

post-cholecystectomy syndrome (PCS). The

symptoms associated with this condition include

dyspepsia, diarrhea, bloating, and right upper

quadrant pain, and are often attributed to biliary

dyskinesia, retained stones, or sphincter of Oddi

dysfunction. While the majority of cases do

resolve over time, some patients require further

dietary modifications, medications, or additional

interventions (34).

4. Discussion

Gallbladder disease presents several clinical

challenges, primarily due to its often-silent

progression - many patients remain

asymptomatic until complications arise. These

complications - such as acute cholecystitis,

choledocholithiasis, or gallstone pancreatitis—

can be severe and require urgent intervention.

Diagnostic difficulties also pose a challenge, as

small stones or biliary sludge may be missed on

standard imaging, and symptoms can mimic

other gastrointestinal disorders. Even after

surgical treatment, a subset of patients

experience post-cholecystectomy syndrome,

leading to ongoing digestive issues. Managing

high-risk patients, including those with diabetes

or multiple comorbidities, requires careful

planning due to increased surgical risks.

Additionally, the growing prevalence of obesity

and metabolic disorders contributes to a rising

burden on healthcare systems, emphasizing the

need for improved prevention, early detection,

and personalized treatment strategies.

5. Conclusions

1. Many cases are asymptomatic. Additionally,

gallstones can lead to severe conditions such as

acute cholecystitis, choledocholithiasis, and

pancreatitis, requiring timely medical

intervention.

2. The interplay of genetic predisposition,

metabolic factors, and bile composition

alterations plays a crucial role in gallstone

formation.

3. Ultrasound remains the gold standard for

diagnosing gallstones, while MRCP and EUS are

valuable for assessing bile duct involvement.

4. Conservative management is an option for

mild cases, laparoscopic cholecystectomy

remains the definitive treatment for symptomatic

gallstone disease due to its minimally invasive

technique and lower risk of complications.

5. Preventive strategies, including lifestyle

modifications and selective pharmacological

interventions, can reduce gallstone formation,

particularly in high-risk individuals.

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Gallbladder stones – how to recognize, diagnose, and treat – a literature review