Gallbladder Stones – Pathogenesis and Treatment

Abstract

Gallstone disease (GSD) refers to all the patients with symptoms due to gallstones (cholelithiasis). The presence of gallstones is a common problem seen in 10–15% of western population; with 1–4% of the population developing symptoms. The most common presentation of patients of GSD is biliary colic. There are several mechanism for cholelithiasis and all these processes are slow. Cholesterol stones are the most common variety of gallstones. Cholesterol stones cannot form if the gallbladder is completely emptied several times a day. Therefore, the total or partial extension of bile storage due to impaired gallbladder movement seems to be an important factor for cholelithiasis. Gallbladder dysmotility is an important risk factor for the development of GSD. Insufficient gallbladder motility may be associated with many risk factors for cholesterol gallstone formation, such as pregnant women, obese patients, and their rapid weight loss, diabetes mellitus, and patients receiving total parenteral nutrition. Transabdominal ultrasound is the mainstay in the evaluation of patients with GSD. The presence of gallbladder dysfunction can be studied using cholecystokinin (CCK)-stimulated cholescintigraphy to evaluate for gallbladder ejection fraction (GBEF); with values <40% after 30 mins of CCK infusion considered diagnostic. The definitive treatment of GSD is cholecystectomy.

1. Introduction

Gallstone disease (GSD) is one of the most common diseases affecting 10–15% of adult population. Out of this, 80% of the individuals are asymptomatic and the disease is detected incidentally while performing abdominal ultrasound for any other pathology or during screening. The asymptomatic patients may eventually experience symptoms ~2–3% per year, reaching up to 10% by 5 years. The complicated GSD affects 1–2% of patients with GSD [1]. The complications of GSD include cholecystitis, pancreatitis and gallbladder cancer. The incidence of GSD is more in female gender and increases with age. The formation of gallstones are multifactorial. There are some local factors in the gallbladder, which include dysmotility of the gallbladder, inflammation of gallbladder wall and mucin accumulation in the gallbladder. Other local factor is in the bile, which consists of supersaturation of cholesterol. Bile contains mixed micelles which are composed of cholesterol, phospholipid and bile salts. The bile is thermodynamically stable under the action of mixed micelles and cholesterol does not precipitate. There is variation in the relative concentration of cholesterol in bile. When the cholesterol is supersaturated in the bile then precipitation of cholesterol happens, which forms the cholesterol gall stones. Cholesterol stones are the most common variety of gallstones. There are some systemic factors which include expression and activity of nuclear receptors, hormonal factors (insulin resistance), altered cholesterol metabolism, altered intestinal motility and gut microbiota [2]. Surgery is the mainstay in the treatment of symptomatic GSD or gallstones with complications.

2. Risk factors and pathogenesis

The pathogenesis of gallstones are multifactorial including a variety of genetic and environmental factors. The risk factors for gallstones are modifiable and non-modifiable. The age, sex, race, and genetic factors are nonmodifiable whereas metabolic syndrome, intestinal microflora disorders, impaired gallbladder motility, and immune disorders are important modifiable factors. Pathogenesis of gallstones include local factors in the gallbladder and bile, and systemic factors like elevated proinflammatory proteins (interleukin-6,10,12,13) [2, 3, 4]. The local factors in the gall bladder include gallbladder dysmotility, hypersecretion and accumulation of mucin gel in the gall bladder lumen. The local factors in the bile consists of rapid phase transition of cholesterol from supersaturated hepatic bile and local immune mediated inflammation in the gallbladder [2].

2.1 Age and sex

The gallstones are more common in older individuals and in female gender. Increased incidence in female is because of influence of estrogen on cholesterol metabolism.

2.2 Family history

Family history of gallstones increases the risk of development of GSD. A Swedish study done on twins in 43,141 patients showed that 25% of risk of GSD is determined by the underlying genetic predisposition [5]. These studies confirmed specific gene polymorphism in the formation of gallstones but the environmental factors including diet and physical activity have also the crucial role [6, 7, 8, 9, 10, 11].

2.3 Pregnancy

Pregnancy is a risk factor for the development of cholesterol stones. This is due to change in the bile composition and delayed gallbladder emptying, which promotes the formation of gallstones.

2.4 Metabolic causes

Elevated non-HDL cholesterol (dyslipedemia) is associated with increased risk of gallstones. Diabetes mellitus is also associated with an increased risk of cholesterol gallstones. Insulin resistance appears to be an important cause for GSD [12].

2.5 Obesity

Obesity has been established as a risk factor for the development of cholesterol gallstones. This is due to enhanced cholesterol synthesis and secretion. The risk of development of gallstones seems to be higher in females, especially in those with morbid obesity [13].

2.6 Rapid weight loss

Higher rates of gallstones have been reported to be associated with rapid weight loss; especially those on very low calories (diet with <800 kcal/day) or after gastric bypass. The exact mechanism by which weight loss cause gallstones are not known, however, the levels of biliary mucin and biliary calcium levels have been noted to be much higher compared to the general population; these factors may promote cholesterol nucleation and gallstone formation [14].

2.7 Drugs associated with formation of gallstones

Some drugs are associated with the development of gallstones like fibrates, somatostatin analogues, hormone replacement and OCPs.

2.8 Conditions causing gallbladder stasis

Prolonged fasting and treatment with parenteral nutrition are associated with increased gallbladder stasis. The cause of biliary stasis is attributed to the lack of enteral stimulation of gallbladder and lack of enterohepatic circulation of bile acids in patients with ileal resection. Interruption of the enterohepatic circulation of bile acids results in the reduction of hepatic bile acids and resulting in increased lithogenicity of hepatic bile, which tends to become supersaturated with cholesterol. Normal gallbladder absorbs the water from bile making it concentrated. Due to gallbladder stasis the bile becomes overly saturated with cholesterol, causing gallstone formation.

2.9 Gallbladder dysmotility

This entity is considered as a risk factor for the development of GSD. The cause of gallstone in dysmotility may be attributed to gallbladder stasis. Gallbladder dysmotility in some cases may be attributed to decreased sensitivity of gallbladder to cholecystokinin (CCK) [15]. Defective intrinsic innervation causes marked reduction in the neurons and interstitial cells of cajal like cells (ICLCs) in the gallbladder. They have a role in the motility of the gallbladder. It has been observed that ICLCs density is markedly reduced in the gallbladder with stones. The reduced density of ICLCs decreases the gallbladder motility [16].

2.10 Immune disorders

Cholesterol secretion is increased by inflammatory mediators. These mediators promote lipid secretion and metabolism in liver. It causes cholesterol supersaturation in the bile. Bile contains low concentration of various immunoglobulins including IgA, IgG and IgM. The IgM is most effective in the gallstone formation in supersaturated bile [17].

2.11 Intestinal microflora disorder

Studies showed that the caecum of the patient with gall stones have increased number of gram positive anaerobes with increased 7α-dehydroxylation activity. These causes increased concentration of deoxycholate (secondary bile acid) which is more hydrophobic and lithogenic [18].

3. Types of gallstones

The gallstones are usually composed of a mixture of cholesterol, calcium salts of bilirubinate or palmitate, proteins, and mucin. The gallstones are mainly classified into 3 groups- cholesterol stones, black pigment stones and brown pigment stones. Cholesterol stones are the most common variety of stones usually seen in patients with genetic or environmental predispositions. These stones occur due to the supersaturation of bile with cholesterol and consist of calcium salts of bilirubinate and palmitate. Black pigment stones are usually found in patients with hemolysis and consist primarily of calcium bilirubinate. The brown pigment stones are found in association with bacterial or parasitic infection of the biliary system. They may also be found in the bile ducts due to biliary system manipulation. Regarding the prevalence of the type of gallstones, the most common variety is the cholesterol stones accounting for ~75% of gallstones, black stones accounting for 20% and brown stones accounting for 5% [19].

4. Pathophysiology of gallstone formation

The mechanism of gallstone formation amongst the various types of gallstones are mentioned below.

4.1 Cholesterol gallstone formation

The main route of cholesterol excretion from the body is via biliary secretion. Cholesterol is a hydrophobic molecule, which is relatively insoluble in bile. Bile salts and phospholipids are incorporated in micelles with cholesterol to increase their solubility. The excess cholesterol is usually kept in vesicles (not in micelle). These vesicles usually contain cholesterol with phospholipids. The vesicle cholesterol nucleation occurs when they get supersaturated with cholesterol. Vesicles are said to be super saturated when the vesicle cholesterol/phospholipid ratio is >1 [20]. The supersaturated vesicles may get aggregated from unilamellar to multilamellar vesicles and later the process of cholesterol crystal nucleation occurs. The bile is concentrated 3–4 folds in the gallbladder due to water absorption and progressively increasing cholesterol in the micelle due to the preferential solubilization of bile salts with phospholipids leaving supersaturated bile cause cholesterol nucleation and this explains why the gallstones are usually seen in gallbladder than anywhere else in the biliary tree. There are some factors that can further promote gallstone formation like IgM, IgG, haptoglobins, alpha-1 acid glycoprotein, alpha-1 antichymotrysin and mucin, based on various invitro and in vivo studies [21]. Gallbladder dysmotility is another important factor for the development of cholesterol nucleation, since it causes stagnation of bile leading to crystal aggregation.

4.2 Black pigment stone formation

The black pigment stones are formed in cases of haemolytic anemia. They are primarily composed of calcium bilirubinate and tend to occur due to high levels of bilirubin (10-fold) which are excreted in bile due to haemolysis [22].

4.3 Brown pigment stone formation

The brown pigment stones are primarily seen in bacterial infection of the bile ducts by organisms such as E. Coli, Bacteroides, Clostridium, Clonorchis sinensis, and Ascaris lumbricoides. These organisms produce the enzyme, Beta glucuronidase, phospholipase A, and bile acid hydrolase which lead to increased amounts of unconjugated bilirubin which combine with calcium resulting in stone formation. The parasites may stimulate stones formation by the presence of calcified eggs, which may serve as a nidus and enhance the precipitation of calcium bilirubinate [23].

5. Clinical features

Most individuals with the presence of gallstones are asymptomatic, usually diagnosed on screening imaging. The most common presenting symptoms of patients of GSD is abdominal pain, termed as biliary colic (Table 1). It typically starts as a dull discomfort in the right upper abdomen, severe in intensity with radiation to the back. It is usually associated with diaphoresis, nausea, and vomiting. The term biliary colic is considered as a misnomer since the pain is usually constant and not colicky. The pain in biliary colic usually lasts 30 minutes, plateauing in an hour and starts to subside. The episode of pain in biliary colic usually lasts <6 hours [24]. The pain is classically triggered by a fatty meal, which causes gallbladder contraction with cystic duct blocked by stones, leading to increase pressure inside the gallbladder. However, this association is not universal [25]. The pain subsides when the gallbladder relaxes, leading to the stones blocking the cystic duct to fall back into the gallbladder. Some individuals can also present with atypical symptoms such as bloating, belching, nausea, vomiting or abdominal distention. Few patients of GSD may also present with complications related to gallstones like cholecystitis, choledocholithiasis, cholangitis, gallstone induced pancreatitis, Mirizzi syndrome or gallstone ileus. The important definitions regarding the presentation of gallstones diseases are mentioned in Table 2.

Pain in the epigastrium or right upper quadrant Increase in severity over 30 minutes Pain plateaus within an hour Duration lasts <6 hours Severe enough to disrupt routine activities or lead to hospital visits Interval of symptoms can be variable. Association with food intake (especially fatty meals)

Table 1.

Features of classical biliary pain in GSD.

Cholelithiasis/cholecystolithiasis	Refers to the presence of stones in the gallbladder
GSD	Refers to gallstones causing symptoms
Uncomplicated GSD	Refers to GSD without gallstone-related complications
Complicated GSD	Refers to the GSD with gallstone-related complications like acute cholecystitis, acute cholangitis, gallstone induced pancreatitis, Mirizzi syndrome and gallstone ileus.

Table 2.

Definitions related to gallstones used in clinical practice.

6. Investigations

The main investigation for the diagnosis of GSD is transabdominal ultrasonography. Endoscopic ultrasonography is an alternative investigation done for cases where the sensitivity of transabdominal ultrasound in low (gallstones <3 mm). Computed tomography, oral cholecystography and cholescintigraphy (HIDA scan) are tests which are done in some special circumstance, like those planned for dissolution therapy (Table 3).

Imaging modality	Salient features
USG abdomen	Preliminary investigation of choice Smaller stones (<3 mm) may be missed
Computed tomography	Non-contrast CT can assess the stone composition. Floating stones (buoyancy) indicates high cholesterol concentration [26]. Low density (black holes) suggests cholesterol stones. Stones with density < 75 HU are susceptible to dissolution; whereas stones >100 HU dissolve poorly [27]. Highly calcified stones are unlikely to dissolve. If gallstones are not visualized on CT, it means the stones are isodense to bile. CT density of bile in these cases helps predict the outcome.
Oral cholecystography	Can help in the assessment of number, size, buoyance, cystic duct patency and gallbladder concentration ability. Oral contrast agents (eg: iopanoic acid) are administered the night before. Visualization of the gallbladder suggests adequate intestinal absorption, secretion into bile by the liver and concentration in the gallbladder. Can indirectly measure motor function by the reduction in the size of the gallbladder on serial radiographs after a fatty meal. Gallstone buoyancy can be seen as suggestive of cholesterol stones
Cholescintigraphy (HIDA scan)	Can be used to identify cystic duct patency. Mucosal function cannot be assessed as the concentration of the tracer in the gallbladder is not needed for visualization, unlike oral cholecystography.

Table 3.

Summary of investigations to be done before gallstone dissolution therapy.

6.1 Transabdominal ultrasound

Transabdominal ultrasound is the most common investigation performed for the diagnosis of GSD. It is readily available, non-invasive, and does not subject the patient to the harmful effects of ionizing radiation. Overnight fasting or fasting for 8 hours before the ultrasound evaluation of the gallbladder is recommended for distension of the gallbladder with bile. This helps in better visualization of gallstones. The stones are visible as echogenic contents within the lumen of the gallbladder with posterior acoustic shadowing (Figure 1). These tend to be usually mobile and deposit according to gravity. Biliary sludge is usually echogenic, but does not cast posterior acoustic shadows. Gallbladder polyps on the other hand have a similar appearance as gallstones but do not cast posterior acoustic shadow. The sensitivity of detecting gallstones by USG is 76–99% and specificity is 99% [28]. However, it has been noted that the sensitivity of gallstones reduces to 50–60% for gallstones <3 mm in size [29].

Figure 1.

Shows the presence of gallstones in the gallbladder. Echogenic foci in the gallbladder with posterior acoustic shadowing.

6.2 Endoscopic ultrasound

Endoscopic ultrasound (EUS) is useful in select few cases of GSD. It is a useful investigation to detect small gallstones (<3 mm) which may be missed on transabdominal ultrasound and in obese patients with difficult visualization of gallstones. EUS also has the added benefit of visualization of the gastric and duodenal mucosa which helps in the diagnosis of peptic ulcer disease, which may mimic the symptoms of GSD. The sensitivity of EUS for the detection of GSD is 96% and the specificity is 86% [30].

7. Prevention of gallstone disease

7.1 Dietary and lifestyle modification

The aim is to maintain the ideal body weight and maintain healthy lifestyle. The following are recommended:

• Eating three well balanced diet containing adequate fiber and low in saturated fats. Regular meal timing prevents gallbladder stasis of bile and ensures adequate emptying.

• Gradual weight reduction of <1.5 kg/month is recommended for obese individuals. Diet containing <800 kcal/day is not recommended.

• Regular exercise will help to maintain the body weight.

• Enteral feeds are always recommended over parenteral. Patients who are on parenteral nutrition should be periodically assessed for the resumption of enteral nutrition.

• Diets rich in poly and monounsaturated fats inhibits cholesterol gallstone formation and thus reduce the risk of the development of gallstones [31].

• Coffee consumption has been associated with decreased risk of developing gallstones. The exact mechanism is not known, probably attributed its effect on cholesterol gallstone formation [32].

7.2 Ursodeoxycholic acid supplementation

Ursodeoxycholic acid (UDCA) is recommended for the prevention of gallstones due to rapid weight loss in patients undergoing bariatric procedures. A dose of 600 mg/day is usually given in two divided doses. Studies suggest a significant reduction in the rate of gallstone formation in such patients from ~28% in the placebo group to 3% in patients on 600 mg/day of the drug [33]. UDCA acts by reducing the intestinal absorption of cholesterol and improving gallbladder emptying. It is also used for gallstone dissolution because of its ability to dissolve the cholesterol in gallstones [34].

7.3 Vitamin C supplementation

Vitamin C may have a protective effect on gallstones. The exact mechanism of action is not known but it is postulated to be due to its effects on the conversion of cholesterol to bile acid [35].

8. Management of gallstone disease

All patients with symptomatic gallstones are advised for laparoscopic cholecystectomy, this includes both uncomplicated and complicated GSD. The timing of surgery is maybe decided based on individual patient and surgeon preferences. The debate on the management of patients with asymptomatic gallstones rages on. The current consensus is to perform cholecystectomy for asymptomatic patients who are at increased risk of gallbladder cancer (Table 4) [37]. The patients who are unwilling for surgery or those not fit for surgery may be considered for non-surgical management. The details of this are mentioned in the subsequent section.

Gallbladder adenomas Large gallstones (>3 mm) Porcelain gallbladder Longer duration (>40 years) Regions with higher incidence like Chile, Bolivia, South Korea, China and North India [36]

Table 4.

Gallstones with increased risk of gallbladder cancer.

8.1 Non-surgical management

Non-surgical management of GSD is mainly done in asymptomatic patients whereas cholecystectomy is the treatment of choice in symptomatic gallstones. Non-surgical management of gallstones is theoretically safer owing to the avoidance of general anesthesia and surgical risk; however, these need patients to follow up at regular intervals, high rates of treatment failure and recurrences and the dissolution therapy for gallstones mainly works for cholesterol stones. The candidates for successful gallstone dissolution therapy are mentioned in Table 5. Prospective multicentre trials done on gallstone dissolution in South Korea shows a response rate of close to 50% in 6 months with the administration of UDCA [38]. Pre-treatment imaging is recommended before the initiation of dissolution therapy. The main aim of the imaging is to evaluate the composition of gallstones, number and size of the stones, patency of cystic duct and the concentrating capacity of the gallbladder. Radioluscency is an important factor for the decision of dissoluation therapy. CT scan is important before the start of dissolution therapy, since <50% of gallstones which were radioluscent on abdominal radiograph, turn out to be hyperdense on CT; thereby not fit for gallstone dissolution therapy. The summary of pre-treatment imaging in mentioned in Table 3.

Small gallstones (<1 cm) Cholesterol stones Radiolucent on plane abdominal X-ray Uncomplicated GSD Patent cystic duct Normal functioning gallbladder

Table 5.

Gallstone dissolution therapy.

8.1.1 Gallstone dissolution therapy

After the proper selection of patients for dissolution therapy (Table 5), treatment with UDCA is initiated. It is given at a dose of 10 mg/kg daily in 2 divided doses. It acts by dissolving the cholesterol from both the surface and the center of the gallstone. It also inhibits the intestinal absorption of cholesterol and improves the gallbladder emptying functions [34]. The calcium in the stones disintegrates subsequently and is expelled by the contraction of the gallbladder. The cystic duct must be patent for the drug to enter the gallbladder. Normal gallbladder mucosa must be functional to absorb the water and to concentrate the drug in the gallbladder; needed for its ability to dissolve the gallstone. Adequate contraction of the gallbladder is needed for the dissolve cholesterol and the stone debris to be expelled from the gallbladder. The dosage of UDCA is given in divided doses since it helps maintain the drug biliary concentration levels and help in increased stone dissolution. A study done comparing UDCA and a combination of UDCA with Cheno-deoxycholic acid (CDCA) in Korea shows comparable results for gallstone dissolution [39]. CDCA also has more incidence with diarrhea, hypercholesterolemia and an increase in liver transaminase levels [40]. Hence, UDCA is the recommended drug of choice for gallstone dissolution therapy. The follow-up of patients on dissolution therapy is kept every 6 months to 1 year to assess for its response. It must be remembered that most gallstones dissolve from the inside out, hence the size of follow-up may not decrease drastically before the external shell of the gallstone disintegrates. The drug is also continued for 6 months after the complete dissolution of gallstones. The standard rate of gallstone dissolution is 1 mm/month [41]. Multiple small stones dissolve faster than a single large stone due to greater surface area. In a typical patient planned for dissolution therapy (noncalcified small cholesterol stones with functioning gallbladder), the dissolution rates are >90% [42]. However, only 10% of individuals with gallstones are fit for dissolution therapy. Multicentric studies by the British-Italian Gallstone study group found a mean dissolution of 47% in 6 months and at 12 months. Complete dissolution of gallstones was found in around 30% of patients by 1 year [40].

8.2 Surgical treatment: cholecystectomy

8.2.1 Surgical anatomy of gallbladder

The gallbladder is located below segment IVb and V of liver. It is a pear-shaped organ which accommodates ~30 cc of bile but can collect upto ~50 cc of bile. The gallbladder normally has three parts—fundus, body, and the neck (infundibulum). The surface landmark of the gallbladder is at the 9th costal cartilage; at the junction of lateral border of rectus abdominis and the costal margin. The neck of the gallbladder opens into the cystic duct, which in turn open into the bile duct. A pathological part of gallbladder is known as the hartmann’s pouch which is an outpouching of the neck of the gallbladder due to gallstones. The cystic duct is about 2–4 cm long and 1–3 mm wide; it is <2 cm in length in 20% of individuals [43]. The mucosa of cystic duct is spirally folded to form the valves of heister. These valves are thought to provide support to the wall of cystic duct and prevent its collapse [44]. Sphincter of the cystic duct is called the sphincter of lutkens; which help to regulate the flow of bile from the gallbladder. The gallbladder is supplied by the cystic artery, branch of right hepatic artery. Moynihan’s hump is seen in ~15% of individuals, where the right hepatic artery forms a loop and is found close to the gallbladder, thereby mistaking it for cystic artery (Figure 2) [45]. Various variations in biliary and vascular anatomy have been described.

Figure 2.

Shows the presence of Moynihan’s hump with short cystic artery. (The right hepatic artery can be easily mistaken for the cystic artery and divided.)

8.2.2 Laparoscopic cholecystectomy

Laparoscopic cholecystectomy is considered as the gold standard surgery for cholelithiasis. Indications for cholecystectomy have been illustrated in Table 6. the procedure is done under general anesthesia. Nasogastric tube decompression is done, and bladder emptying is ensured.

Symptomatic cholelithiasis Asymptomatic cholelithiasis in patients with increased risk of complications/malignancy. Acalculous cholecystitis Gallbladder polyp >10 mm Porcelain gallbladder

Table 6.

Indications of cholecystectomy.

The standard port positions in laparoscopic cholecystectomy are shown in Figure 3. The umbilical port is placed either by the veress needle technique or the open technique. The other three ports are placed under direct vision after the creation of the pneumoperitoneum. The position of the patient is then turned to reverse Trendelenburg position with the right side up.

• In North America, the surgeon stands at the patient’s left and the assistant to the right of the patient. The camera person stands to the left of the operating surgeon.

• In Europe, the patient is in a supine position with abducted legs. The surgeons stand between the legs of the patient, the camera person stands to the left and the assistant stands to the right of the patient.

Figure 3.

Shows the port placement in laparoscopic cholecystectomy.

Dissection steps:

1. Gallbladder exposure—The gallbladder is dissected from adhesions to the omentum, duodenum, and colon. The assistant retracts the gallbladder superior and laterally using a grasper. If the gallbladder is distended and difficult to aspiration; a wide bore needle is inserted into the gallbladder and the bile is aspirated.

2. Dissection of hepatocystic triangle—The hepatocystic triangle is bounded by the cytstic duct, inferior edge of liver and the common hepatic duct. All the fibrofatty tissue is cleared from the triangle. If a large stone is blocking the neck of gallbladder, it may be pushed into the gallbladder for easier dissection. The operating surgeon must hold the infundibulum and retract it infero-laterally. The posterior dissection will need the surgeon to retract the infundibulum supero-medially. The rouvier’s sulcus is a fissure between the right lobe and the caudate process of liver. This corresponds to the level of porta where the right pedicle enters the liver. The recommendation is to stay superior the rouvier sulcus for safety [46]. R4U line has been described by Gupta and Jain [47], connecting the rouvier sulcus, base of segment IV up to the umbilical fissure. The dissection is recommended to be done above this line for safety (Figure 4).

3. Achieving the critical view of safety—The critical view of safety by proposed by Strasberg in 1995 to promote the accurate recognition of structures during laparoscopic cholecystectomy and to prevent the occurrence of bile duct injury [48]. It is also recognized as part of Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and incorporated in the “Safe cholecystectomy program”. The details of critical view of safety have been shown in Table 7, (Figure 5). The operating surgeon should be aware of the common variations in the bilio-vascular anatomy.

4. Division of the cystic artery and duct—The cystic artery and the cystic duct are fully dissected. The cystic artery is first clipped and divided (two clips proximally and one clip distally towards the gallbladder). The cystic artery gives of an anterior and posterior branch, usually close to the gallbladder; however, in some cases the branching takes place proximally, in such cases the anterior branch may be divided instead of posteriorly. Hence the posterior branch must be looked, if not appreciated can result in troublesome bleeds during cholecystectomy. The cystic duct is then milked retrograde to push any stones if present in the cystic duct into the gallbladder. The cystic duct is clipped and divided. Intraoperative cholangiography can be done at this step if any doubt in the biliary anatomy exists. Some of the tips shown in Table 8 that can be followed in difficult situations during laparoscopic cholecystectomy.

5. Dissection of the gallbladder from liver bed- the gallbladder is then dissected away from the liver bed using hook or spatula cautery. If the dissection is done in the correct plane, there is usually minimal bleeding. Prior to detachment of gallbladder from the liver bed, the liver is inspected for any bleeding or bile leak. The right upper quadrant is irrigated and suctioned. The gallbladder is then fully detached from the liver surface.

6. Gallbladder extraction: the gallbladder is extracted either from the 10 mm epigastric port or the 10 mm umbilical port. An extraction bag may be used if the gallbladder is inflamed, friable or perforated. After the extraction, the right upper quadrant maybe further irrigated and suctioned. Hemostasis and no bile leak is ensured. The trocars are removed under direct vision and the 10 mm trocar sites are closed using appropriate sutures. The skin is approximated using sutures or staplers. The access sites local anesthesia may be used.

Figure 4.

Show the R4U line connecting the rouviere’s sulcus to base of segment IV until the umbilical fissure. The dissection is recommended to be done above this plane.

There are three components to the critical view of safety: Hepatocystic triangle is cleared of fibrofatty tissue (to note: the CBD and the CHD do not have to be exposed). Lower third of gallbladder is separated from the cystic plate. Two and only two structures should be seen entering the gallbladder.

Table 7.

Critical view of safety.

Figure 5.

Duplet view of critical view of safety: (a) anterior; (b) posterior.

Tips to follow in difficult situations

Thorough knowledge of the anatomy and variation must be known. A good vision by a good laparoscope Obtain critical view of safety whenever possible. Recognize the safe and unsafe areas. Make liberal use of cholangiography whenever required. Intraoperative momentary pause before clipping or dividing. Get help from colleague or seniors in difficult situations.

Table 8.

Tips to followed during laparoscopic cholecystectomy.

8.2.3 SILS cholecystectomy

Single incision laparoscopic surgery (SILS) cholecystectomy makes use of a single incision for the surgery. Laparoscope with specially made instruments are used for this procedure. This was first reported by Navarra et al. [49] in 1997 using transabdominal sutures to retract the gallbladder. For retraction traction sutures may be used according to the surgeon discretion. The steps of cholecystectomy are like the standard 4 port cholecystectomy and the specimen is extracted using a specimen retraction bag via the umbilical port. The facial defect must be carefully closed to prevent incisional hernia in future [50]. A preliminary study done in 2012 comparing the SILS to traditional laparoscopic cholecystectomy shows slightly longer operative time (~65 minutes) compared to 4 port laparoscopic cholecystectomy which may be attributable to the learning curve of the procedure. Metanalysis done in 2022 comparing SILS to the standard laparoscopic cholecystectomy shows less immediate post-operative pain in the group; but similar pain on days 1 and 2 of the procedure, longer operative time, and more complications than in conventional 4 port laparoscopic cholecystectomy. Complications including bile leak, intra-abdominal collection, and surgical site wound infection were found to be higher in the SILS group. Conversion from laparoscopy to open surgery was similar in both groups [51]. Hence, this is an alternative technique of laparoscopic cholecystectomy and further studies are warranted for the evolution of the technique.

8.2.4 NOTES cholecystectomy

Natural orifice transluminal endoscopic surgery (NOTES) cholecystectomy, via transvaginal approach, has gained some popularity in recent years. Ricardo Zorron from Brazil in 2007 published the first report on transvaginal hybrid notes [52]. The procedure is done by placing the laparoscope (10 mm) via the posterior vagina and 5 mm umbilical port. The access may be done through the stomach, urinary bladder, or colon. The critical view of safety may be slightly different compared to a standard 4-port laparoscopic cholecystectomy owing to a different viewing angle. However, the cystic artery and the duct are dissected and clipped like the laparoscopic technique. It must be noted some challenges might be encountered during specimen extraction from the vagina using the specimen retrieval bag. Meta-analysis comparing the NOTES cholecystectomy with the laparoscopic cholecystectomy shows no significant difference regarding the safety of the procedure or wound complications. It was noted that the operating time for NOTES cholecystectomy was significantly longer than laparoscopic cholecystectomy by around 34 minutes; however, the postoperative pain was less in the NOTES cholecystectomy group [53]. Hence, this is an alternative technique of cholecystectomy, however, needs good procedural training, specially designed surgical instruments, and further studies to validate for general use.

8.2.5 Robotic surgery (robotic assisted cholecystectomy)

Robotic surgery has many advantages including the 3D view, enhanced instrument articulation, intraoperative fluorescence imaging and precise movements. Docking of the robot is done, and the steps of surgery are like the laparoscopic surgery. Studies done comparing laparoscopy with robotic surgery show longer operative time for robotic surgery with comparable conversion and complication rates. There was also no significant difference in the length of hospital stay, surgical site infection or readmissions. However, it has to be mentioned that the hospital costs of robotic surgery are significantly higher than that of laparoscopic surgery [54].

9. Conclusion

GSD is one of the most common diseases affecting 10-15% of adult population. Eighty percent of these individuals are asymptomatic. Biliary colic is the most common presentation. Pathogenesis of the gallstones are multifactorial which include non-modifiable and modifiable factors. Cholesterol stones are the most common variety of gallstones. Cholesterol gallstones cannot form if the gallbladder is completely emptied several times a day. Therefore, gallbladder dysmotility seems to be an important factor for cholelithiasis. Gallbladder dysmotility may be attributed to decreased sensitivity of the gallbladder to CCK. It has been observed that ICLCs density is markedly reduced in the gallbladder with stones. The reduced density of ICLCs decreases the gallbladder motility. Transabdominal ultrasound is the mainstay in the evaluation of patients with GSD. The presence of gallbladder dysfunction can be studied using CCK-stimulated cholescintigraphy to evaluate for gallbladder ejection fraction (GBEF); with values <40% after 30 mins of CCK infusion considered diagnostic. The definitive treatment of GSD is cholecystectomy and laparoscopic cholecystectomy is considered as gold standard.

Conflict of interest

The authors declare no conflict of interest.