Gallstones Unveiled: A Comprehensive Review Of Formation, Diagnosis, And Management

Abstract

Gallstones are hardened deposits of bile that form in the gallbladder, ranging from the size of a grain of sand to that of a golf ball. The prevalence of gallstones varies by population, with higher rates in American Indians and Mexican-American women, and lower rates in African and Asian populations. Gallstones are classified into three biochemical types: black pigment stones, brown pigment stones, and cholesterol stones. Black pigment stones are associated with hemolytic disorders, while brown pigment stones are linked to bacterial infections and bile stasis, commonly found in Asian populations. Cholesterol stones, the most common, are linked to dietary factors and impaired gallbladder function. Risk factors for gallstone formation include non-modifiable variables such as age, gender, and genetics, as well as modifiable factors like obesity, diet, and medications. Gallstones may present asymptomatically in 70% of cases or cause symptoms like biliary colic, jaundice, and acute cholecystitis. Diagnosis primarily involves ultrasound imaging, with additional tools like CT, MRI, and nuclear medicine techniques aiding in complex cases. Management of gallstones includes lifestyle modifications, pharmacological interventions, and surgical options. Ursodeoxycholic acid (UDCA) is a pharmacological agent used to dissolve cholesterol gallstones, though recurrence rates remain high. Surgical intervention is typically recommended for symptomatic cases. This review provides an overview of the classification, risk factors, clinical presentations, diagnostic approaches, and management strategies for gallstone disease, emphasizing a multidisciplinary approach to optimize patient outcomes.

Keywords

Introduction

Gallstones are hardened deposits of the digestive fluid bile, that can form within the gallbladder. They vary in size and shape from as small as a grain of sand to as large as a golf ball. Gallstones occur when there is an imbalance in the chemical constituents of bile that result in precipitation of one or more of the components. [1] Ultrasound studies indicate mean prevalence rates of 10–15% in adult European, and of 3–5% in African and Asian populations. In the US, the prevalence rates range from 5% for non-Hispanic black men to 27% for Mexican-American women. In American Indians, gallstone disease is epidemic and found in 73% of adult female Pima Indians, and in 30% of male and 64% of female in other American Indians [2].

CLASSIFICATION OF GALLSTONES

1. BIOCHEMICAL CLASSIFICATION OF GALL STONES

1. Black pigment stones

A black pigmented stone contains predominately bile. Super saturation of bile along with calcium bilirubinate lead to formation of black pigment stones. Black pigment stones are composed of less than 30% cholesterol. These are present in patients associated with Hemolytic Jaundice, Sickle Cell Disease, Cystic Fibrosis, Hereditary Spherocytosis, Gilbert Syndrome and in Illeal Crohn’s Disease. Increased entero-hepatic circulation of bilirubin also contributes to the formation of black pigment stones. In West 30% of gall stones comprise of black pigment stones. Patients having black pigment stones commonly do not have bacterial infection and mostly these stones are present in gall bladder. Black pigment stones commonly show amorphous appearance. In sickle cell anemia risk of black pigment stones increases due to increase in unconjugated bilirubin which leads to precipitation of calcium bilirubinate. This type of precipitation of calcium bilirubinate leads to formation of black pigment stones.

2. Brown pigment stones

Brown pigment stones are also known as bile pigment stones, bilirubin stones, earthy stones or muddy stones. On average 43 % of cholesterol content is found in brown pigment stones. In addition brown pigment stones also have amorphous material and mucous glycoprotein. These stones are primarily present in bile ducts and are associated with bacterial infection or parasitic infection and bile stasis. In brown pigment stones, intrahepatic and extra hepatic gallstones are different in composition from each other.  Their surface has various shapes from round to faceted and exhibit various colors like yellowish brown, greenish brown and black brown. Brown stones are frequently found in Asian population.

3. Cholesterol stones

These are most commonly found gall stones which contain up to 70% of cholesterol content. In addition, they also contain bile pigment, glycoprotein and calcium salts. Patients with cholesterol gall stones have decreased bile salt synthesis and increased biliary secretion of cholesterol due to increase cholesterol intake. Patients with cholesterol gall stones also have impaired gall bladder emptying in postprandial state. [4] Their color varies from light yellow to dark green. They are usually oval in shape and each often have a dark central spot of about 2-3 cm long. [3]

2. ANATOMICAL CLASSIFICATION OF GALL STONES

1. Cholelithiasis

Formation of stones within in the gall bladder is known as cholelithiasis. 88-94% patients suffering from gall stones have stone in gall bladder. Stones may be black pigment stones, brown pigment stones or cholesterol stones. [5]

2. Choledocholithiasis

In this type, the stones are located in the common bile duct. 6-12% patients suffering from gall stones have stone in common bile duct (CBD) and their presence in CBD increases with age.

3. CLINICAL CLASSIFICATION OF GALL STONES 

1. Asymptomatic Gall Stones

The percentage of asymptomatic gall stones among the patients suffering from cholelithiasis is about 70 % and the patients with the progression of asymptomatic to symptomatic are about 10 to 20%. However, the majority of patients show symptoms before going towards the complexity of disease. [6]

2. Symptomatic Gall Stones

The symptomatic gallstones present with symptoms of recurrent attacks of pain, nausea and vomiting. The pain in epigastric region or in right upper quadrant may radiate backward towards shoulder. The character of recurrent pain plays an important role in diagnosis of symptomatic gallstones. [7]

RISK FACTORS

The causes of gallbladder disease are multifactorial. Factors that affect hepatic production of cholesterol, gall bladder function (stasis or inflammation),bile acid production, or intestinal absorption of cholesterol and bile acids are all possible contributors to the formation of gallstones. Risk factors include both modifiable and non-modifiable variables [8]

Non-modi?able Risk Factors

• Age older than 40 years increases the risk of developing gallbladder disease by 4- to 10fold.[9,10]
• Individuals are at a 5 times greater risk of developing gall bladder disease if they have a family history of gallbladder disease.
• Women of child bearing age are approximately twice as likely as men to form gallstones.
• Once menopause occurs, the incidence in women is close to that of men.[9]

Modi?able Risk Factors

• Obesity, particularly abdominal obesity, is associated with the development of gallstones. [9] Approximately 25% of persons who are morbidly obese show evidence of gallbladder disease. [10] Obesity is also a primary factor associated with metabolic syndrome and non alcoholic fatty liver disease, both of which are associated with an increased incidence of gallstone formation. [11]
• Weight loss of more than 1.5 kg per week after bariatric surgery increases the risk of gallstone formation.[10]
• The increased risk of gall stone formation related to rapid weight loss may be related to an increase in the ratio of cholesterol to bile salts or occurrence of bile stasis because of decreased gall bladder motility.[12]
• Diets high in vegetables, fruit, and fiber may reduce the risk of gallstone formation, whereas those high in animal protein, carbohydrates, and cholesterol increase the risk.[9]
• Medications such as ceftriaxone (Rocephin), thiazide diuretics, and estrogen may also increase the risk of gallstone formation, whereas 3-hydroxy-3-methyl glutaryl coenzyme reductase inhibitors (also referred to as statins) can reduce risk by decreasing  cholesterol synthesis in the liver. [10]

Additional Risk Factors for Cholelithiasis

• People with diabetes generally have high levels of fatty acids called triglycerides. These fatty acids may increase the risk of gallstones. Gallbladder function is impaired in the presence of diabetic neuropathy, and regulation of hyperglycaemia with insulin seems to raise the lithogenic index. [13] A lack of melatonin could significantly contribute to gallbladder stones, as melatonin inhibits cholesterol secretion from the gallbladder, enhances the conversion of cholesterol to bile, and is an antioxidant, which is able to reduce oxidative stress to the gallbladder. [14]
• In all populations of the world, regardless of overall gallstone prevalence, women during their fertile years are almost twice as likely as men to experience cholelithiasis. This preponderance persists to a lesser extent into the postmenopausal period, but the sex difference narrows with increasing age.
• Increased levels of the hormone estrogen, as a result of pregnancy or hormone therapy, or the use of combined (estrogen?containing) forms of hormonal contraception, may increase cholesterol levels in bile and also decrease gallbladder movement, resulting in gallstone formation.[3]

PATHOPHYSIOLOGY

The gallbladder is located under the liver on the right side of the abdomen. Gallstones are formed from bile that has been concentrated in the gallbladder. These stones form when the constituents of bile are not in balance and one or more precipitates into a solid compound. There are 2 categories of gallstones: cholesterol and pigment. Pigment stones are further classified as either black or brown stones and are primarily composed of calcium bilirubinate. Black stones are hard because of polymerization and are formed in sterile gall bladder bile. The primary risk factor for black pigment stones is hyperbilirubinemia, and these stones are more common in persons with hemolytic disorders such as sickle cell anemia secondary to hemolysis and overproduction of bilirubin. Brown stones, which are unpolymerized and soft, can be found anywhere in the biliary tract but are rarely found in the gall bladder. Brown stones are associated with anaerobic bacterial infections and result from obstruction or stasis.[15] The majority of gallstones (approximately 80%) that are diagnosed in persons who reside in the United States are composed primarily of cholesterol. These stones occur when the cholesterol concentration becomes higher than the ability of bile to keep it in solution. [9] When gallstones obstruct the common bile duct, the individual may begin to experience painful spasms in the right upper quadrant of the abdomen, which is referred to as biliary colic. This obstruction can cause bile to reflux into the liver, which may damage hepatocytes. Damage to the pancreas can also occur secondary to release of pancreatic enzymes that cause autodigestion. [16] Cholesterol stones may be precipitated by the hormones estrogen and progesterone. Estrogen increases cholesterol secretion and decreases the secretion of bile salts. Progesterone reduces the production of bile salts and slows gallbladder emptying secondary to smooth muscle relaxation resulting in stasis of the gallbladder. [10,17] This increase in cholesterol production and stasis due to delayed gallbladder emptying may resulting all stone formation. The pathophysiology that explains the association between diabetes and gallbladder disease appears to be related to autonomic neuropathy, which may cause gallbladder stasis, thereby increasing the risk of gallstone formation

CLINICAL PRESENTATIONS

• The clinical presentations of gall stones include acute cholecystitis and febrile illness with pain and tenderness in the right upper quadrant (Murphy Sign).
• Persistent pain, fever and jaundice may also be present and are collectively known as Charcot’s triad and if this triad is associated with septic shock and altered level of consciousness then it is collectively known as Raynaud’s pentad.
• The clinical manifestations of gall stones also include biliary colic, jaundice and acute pancreatitis.
• Leukocytosis, sepsis, transient alcoholic or clay-colored stools, fatty food intolerance, chills, nausea and vomiting are also included in clinical presentations of gall stones.
• General weakness and loss of weight can also be considered as generalized symptoms of gall bladder stones.
• Mild rise in alkaline phosphatase level (ALP) may be the indicative of severe form of gall stone disease. [3] 

DIAGNOSIS

1. Ultrasound is by far the most common and useful imaging modality in assessing gallstones within the gallbladder (cholelithiasis) and associated gallbladder pathology and has the added benefit of no radiation dose to the patient.

• With ultrasound, gallstones are characteristically echogenic and demonstrate posterior acoustic shadowing regardless of the gallstone composition.
• As ultrasound is a bedside dynamic study, stone mobility can be demonstrated with patient manoeuvering, and this can help in differentiating gallstones from gallbladder polyps, which can mimic cholelithiasis sonographically.
• Another principle advantage of ultrasound over other imaging techniques in the investigation of acute cholecystitis is the ability to evaluate for a sonographic Murphy’s sign, which can be a reliable indicator of acute cholecystitis with a high sensitivity [18].

2. Plain radiography is limited in the diagnosis of gallstones as only 15–20% of gallstones are radio-opaque on X-ray.

• The classical radiographic appearance is the “Mercedes Benz sign” which is an outer radioopaque rim with a radiolucent centre which is caused by calcification of the gallstone rim and gas fissuring within the gallstone.
• Calcification of gallstones occurs with increased calcium in bile

3. On CT, a high percentage of cholesterol stones are hypoattenuating relative to bile and calcified stones are hyperattenuating relative to bile.

• Dual-energy CT has been shown to improve detection of gallstones with low KV imaging and base substance imaging, such as calcium-based and lipid-based imaging, which is more sensitive at detecting gallstones than traditional higher KV imaging.

4. MRI is another very effective tool for diagnosing gallstones and associated pathological processes.

• Magnetic resonance cholangiopancreatography (MRCP) is typically performed using heavily T2-weighted sequences, supplemented by fat-saturated T1- and T2weighted MRI, and with steady-state gradient-echo acquisitions.
• Heavily T2-weighted image sequences are particularly helpful in delineating ductal anatomy. Gallstones typically appear as low signal or signal void on T2-weighted imaging surrounded by T2 hyperintense bile.
• MRCP has largely replaced endoscopic retrograde cholangiopancreatography (ERCP) as the gold standard for diagnosing choledocholithiasis due to its high sensitivity of 90– 94% and specificity of 95–99% without the use of ionising radiation or ERCP-related complications such as pancreatitis which can result in significant morbidity and even mortality [19, 20].

5. Nuclear medicine imaging with scintigraphy and with SPECT/CT can be used to dynamically assess the gallbladder.

• Technicium-99 labeled mebrofenin is administered and taken up by bile producing cells and subsequently excreted into the biliary system. The patient is typically imaged at 1h and at 4h post-administration of radioisotope. A normal gallbladder will be well delineated as it fills with radioactive bile. In cases of cholecystitis or gallbladder obstruction due to an impacted stone in the cystic duct, the gallbladder will not be visualised as the radioactive will not accumulate within the gallbladder. If the gallbladder is not visualised, morphine analogues can be given to induce sphincter of Oddi contraction and aid gallbladder filling.
• Cholescintigraphy for acute cholecystitis has a sensitivity of 97% and a specificity of 94%.

6. There is an increasing role for interventional radiology (IR) in gallstone-related diseases.

• Percutaneous cholecystostomy can be used as a temporizing measure in critically ill patients who are too sick to proceed to immediate surgery and cholecystectomy.
• In patients who have had a cholecystostomy placed, cholangiograms can be performed to demonstrate resolution of or ongoing obstruction of the biliary tree by assessing for filling defects (gallstones) within the biliary system
• Percutaneous transhepatic cholangiography (PTC) with biliary stenting is a very effective treatment to decompress the biliary system in the case of obstructing choledocholithiasis, most often in cases not amenable to ERCP. [18]

MANAGEMENT

Management of cholelithiasis depends on the symptomatology and presence of absence of complications. In general, management is multifactorial and includes lifestyle and dietary modification and medication. Pharmacologic management alone is appropriate for individuals with infrequent episodes of right upper quadrant pain and those whose symptoms are mild. In persons with recurrent right upper quadrant pain or those who have signs and symptoms of acute cholecystitis, referral for surgical evaluation is indicated. Pharmacologic management consists of pain control, antiemetics, and, if indicated, dissolution agents. In persons with symptomatic cholelithiasis, surgical intervention is usually recommended.

1. Lifestyle and Dietary Modi?cation

All individuals with symptomatic cholelithiasis, regardless of severity and frequency of symptoms, should be advised to avoid fatty foods and, if indicated, reduce total caloric intake. The clinician should encourage the individual to diet responsibly and avoid fasting or starvation. A generally accepted weight loss goal of 1 to 2 pounds per week is safe and reasonable. Individuals should also be encouraged to exercise regularly. Persons with asymptomatic cholelithiasis should be encouraged to eat a diet high in fruits, vegetables, and total fiber, which may reduce the risk of further gallstone formation and gall bladder disease. Diets high in animal protein, cholesterol, and carbohydrates should be avoided. Exercise is recommended because it is theorized to potentiate gallbladder emptying via release of cholecystokinin (the enzyme that stimulates release of bile acids into the intestine) and increase gallbladder motility

2. Pharmacologic Management

Acute biliary colic pain may be managed with nonsteroidal anti-inflammatory medications (NSAIDs) or opioids depending on severity. NSAIDS are the first choice for pain control in biliary colic. Evidence suggests that NSAIDs control biliary colic with the same efficacy as opioids and result in a decreased number of individuals with severe complications such as acute cholecystitis, cholangitis, or acute pancreatitis. Antiemetics can be used to relieve nausea and vomiting. Gallstone dissolution agents suppress hepatic secretion and inhibit intestinal absorption of cholesterol. Once the gallstone dissolution agent reaches a steady state, the bile environment changes to one that is favorable to solubilization of cholesterol. Individuals who have established cholesterol gallstones may benefit from this type of medication. Ursodeoxycholic acid (UDCA) is a bile acid that reduces gallstones by dissolution. It has been shown to reduce biliary colic, the need for surgical intervention, and the incidence of acute cholecystitis. 23 UDCA is given over 6 to18 months at a dose of 8 to10mg/kg per day divided into 2 or 3 times daily dosing. The recurrence rate in individuals who are treated with gallstone dissolution agents is 50% within 5 years. UDCA is contraindicated for persons with acute cholecystitis, variceal bleeding, liver or bile duct abnormalities, inflammatory bowel disease, calcified gallstones, chronic hepatic disease, or complete biliary obstruction. Liver function tests should be performed prior to initiation of this medication regimen and repeated regularly for the first few months to ensure normal liver function. Side effects may include diarrhea, immune suppression, rash, thrombocytopenia, interstitial lung disease, pruritus, portal hypertension, and liver failure.38 Persons using this medication should be monitored appropriately. Antibiotics should be considered for all individuals with acute cholecystitis, especially those who delay surgical intervention or who are undergoing observation. Continuous bile stasis can lead to a secondary infection that may progress to sepsis if not treated prophylactically with antibiotics. The clinician should consider local antibiotic resistance and the most likely pathogens when choosing an antibiotic regimen. Antibiotics commonly used to treat acute cholecystitis include piperacillin/tazobactam (Zosyn), tigecycline (Tygacil), amoxicillin/clavulanate (Augmentin),ciprofloxacin (Cipro), ampicillin/sulbactam (Unasyn), cefepime (Maxipime), levofloxacin (Levaquin), penicillin (BicillinL-A),and imipenem and cilastin (Primaxin).39

3. Surgical Management

Surgical intervention is not recommended for persons who are asymptomatic because potential risk exceeds potential benefit. However, persons with asymptomatic cholelithiasis who also have calcified, or porcelain, gallbladder, which is a result of chronic gallbladder inflammation, are the exception, and these individuals should be managed surgically. Studies have found that a relatively high number of individuals with porcelain gallbladders develop gallbladder carcinoma without prophylactic cholecystectomy. Other exceptions include persons with spinal cord injuries and those with sickle cell anemia. Prophylactic cholecystectomy should be considered in individuals with sickle cell anemia because the chronic hemolysis associated with this disorder creates increased bilirubin secretion and black pigment gallstones, which may result in obstruction of the common bile duct. Other populations who might benefit from elective cholecystectomy include those with cirrhosis, portal hypertension, or diabetes or those who are transplant candidates. 40 Laparoscopic cholecystectomy is the treatment of choice for symptomatic or complicated cholelithiasis. Individuals who present with symptomatic cholelithiasis should be evaluated by a surgeon or gastroenterologist within a week of initial presentation. Laparoscopic methods allow for shorter hospital stays and recovery times than open cholecystectomy. Absolute contraindications for laparoscopic cholecystectomy include gall bladder cancer, inability to undergo general anesthesia, and uncontrolled coagulopathy.

4. Special Considerations in Pregnancy

Physiologic changes during pregnancy increase the risk of gallstones. These changes include decreased gallbladder contractility due to increased progesterone levels, which leads to increased gallbladder volume and, ultimately, stasis and impaired gall bladder emptying. This biliary stasis promotes the formation of biliary sludge, a precursor to gallstone formation. The risk of gallstone formation in pregnancy is most prevalentinthesecondandthirdtrimesters.41 The incidence of gallstone formation increases with parity: 5.1?ter the first pregnancy, 7.6?ter 2 pregnancies, and 12.3?ter 3 or more pregnancies. Maternal mortality in women with uncomplicated cholelithiasis during pregnancy is rare, and fetal loss is less than 5%. Symptomatic gallstones not treated surgically that occur during pregnancy have a reoccurrence rate of up to 92% when onset is in the first trimester, 64% in the second trimester, and 44% when symptoms begin the third trimester. As in non pregnant individuals, ultrasound is the gold standard for diagnosis of gallbladder disease during pregnancy. Conservative management may be considered in pregnant women with biliary colic who do not have cholecystitis. Conservative management consists of intravenous hydration, correction of electrolytes if indicated, and bowel rest. [8]

CONCLUSION:

Gallstone disease remains a prevalent and multifaceted condition, with both genetic and lifestyle factors contributing to its development. Advances in diagnostic imaging have improved the ability to detect and characterize gallstones, facilitating better treatment decisions. While many individuals with gallstones remain asymptomatic, timely management of symptomatic cases is crucial to prevent complications such as acute cholecystitis and pancreatitis. Pharmacological approaches, particularly the use of ursodeoxycholic acid, offer non-invasive treatment options for some patients, but surgical intervention remains the definitive solution for those with recurrent or severe symptoms. Ultimately, prevention through lifestyle modification and early detection remains key in managing gallstone disease and reducing its associated morbidity.

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