Figure 9.1 Number of cholecystectomies in children (≤16 years) in England in 1997–2012 according to gender. (Reproduced with permission from Khoo AK, et al., Journal of Pediatric Surgery 2014, 49: 284–288.)

9.4    PATHOPHYSIOLOGY OF BILE (SEE CHAPTER 3)

Bile has both an excretory function (predominantly bile acids, fatty acids, cholesterol and bilirubin) and a nutritional role (absorption of lipids and fat-soluble vitamins D, A, K and E) within metabolism. It is mainly composed of water (>90%), with the remaining constituents shown in Table 9.1.

9.4.1  Molecular mechanisms of bile formation

The biliary canalicular membrane of the hepatocyte contains numerous transport proteins termed ATP-binding cassette (ABC) transporters, and four are involved in the formation of bile:

1.  ABCB4 (i.e. ABC, subfamily B, member 4) – previously known as multi-drug-resistant 3-P-glycoprotein (MDR3)

•  Transports phospholipids, predominantly phosphatidylcholine

2.  ABCB11 transporter – previously bile salt export pump (BSEP)

•  Exports bile salts

3.  ABCG5 and ABCG8

•  Exports cholesterol

4.  ABCC2 – previously known as multidrug resistance–associated protein 2 (MRP2)

•  Exports bilirubin

Bile acids form simple micelles within the biliary canaliculus, which in turn activates ABCB4, and ABCG5 and ABCG8 to secrete phospholipids and cholesterol, respectively. Cholesterol in its native form is only mildly soluble in aqueous bile. Therefore, it forms mixed micelles with bile salts (ionised form of bile acids) and phospholipids (mainly phosphatidylcholine), thus enabling the secretion of cholesterol into the intestine.

9.5    CLASSIFICATION OF GALLSTONES

The types and proportions of gallstones found in children differs from those seen in adults (Figure 9.2). Four types are described depending on the predominant chemical composition (Table 9.2) [8,9]:

1.  Cholesterol

2.  Black pigment

3.  Brown pigment

4.  Calcium carbonate

Figure 9.2 Gallstone composition: adults and children in North of England. (Adapted from data in Stringer MD, et al., Journal of Pediatric Surgery 2007, 42: 1677–1682.)

Table 9.1 Solute concentration in bile

Note: Concentrations vary with fluctuating nutritional status.

^a Percentages represent ratio to solute concentration (mg/mL).

Table 9.2 Classification of gallstones

Note: LPAC, low phospholipid-associated cholelithiasis.

^a  Taken from Stringer MD, et al., Journal of Pediatric Surgery 2007, 42: 1677–1682.

This classification may also be extended to a fifth sub-type, recently termed microliths.

9.5.1  Cholesterol stones (Figure 9.3)

The main pathway for cholesterol excretion is by the formation of bile acids (cholic and chenodeoxycholic acid) from the oxidation of cholesterol within the hepatocyte. When there is an excess of cholesterol, then bile becomes super-saturated, and this may be quantified as the cholesterol saturation index (CSI), which is defined as the ‘ratio of actual biliary cholesterol concentration and the maximal concentration that would be soluble at phase equilibrium in model bile with equal lipid composition’ [10].

When the CSI > 1, monohydrate crystals of cholesterol aggregate, forming inspissated bile and microliths which can progress to form intra- and extrahepatic gallstones. A high CSI can be the result of hypersecretion of cholesterol or hyposecretion of bile salts and phospholipids. Hypersecretion, the most common, usually results from increased hepatic uptake of cholesterol derived from excess dietary intake mediated by the scavenger receptor B-1 for high-density lipoproteins (HDLs), the apolipoprotein B/E receptor for low-density lipoproteins (LDLs) and the LDL receptor-related protein for chylomicron remnants.

Figure 9.3 Multiple multifaceted cholesterol stones in 14-year-old girl with a 6-month history of intermittent abdominal pain. Her mother had a gallbladder removed at age 30 years.

9.5.2  Black pigment stones

Black pigment stones are commonly seen in children with haemolytic disorders, namely, sickle cell disease, thalassaemia and hereditary spherocytosis. They occur due to excess amounts of unconjugated bilirubin and ionised calcium in the form of calcium bilirubinate ± calcium carbonate.

Elevated unconjugated hyperbilrubinaemia may be secondary to a reduced activity of the enzyme bilirubin diphosphate-glucuronyltransferase (UGT1-A1), which conjugates bilirubin (as seen clinically in Gilbert^* syndrome), or by overloading of the hepatocyte with bilirubin conjugation (i.e. haemolytic anaemias), an increased endogenous β-glucuronidase activity or a reduction in the bile salt pool [11–13].

Children with Gilbert syndrome have a fourfold increased risk of developing gallstones due to the combined effect of increased bilirubin production and reduced bilirubin diphosphate-glucuronyltransferase activity mediated by the UGT1-A1 gene [13–15]. Conditions affecting the terminal ileum (Crohn’s^† disease or following surgical resection) also result in black pigment stones because of the reduction in bile salt reabsorption, leading to solubilisation and uptake of unconjugated bilirubin into the enterohepatic circulation via the colon [16].

Gallstones, ‘sludge’ and microliths are detected by ultrasound in 45% of children with sickle cell disease, with a third of these in the <10-year age group. Paradoxically, only 5% of children with hereditary spherocytosis will develop stones by their 10th birthday.

9.5.3  Brown pigment stones

These are formed in the presence of bacterial or helminthic infection within the biliary tract. The microbial β-glucuronidase enzyme, unlike the human enzyme, deconjugates bilirubin conjugates, altering the solubility of calcium bilirubinate, which precipitates out to form stones. Their formation is also associated with biliary duct dilatation and biliary stasis, and they are much more commonly seen in the Far East. Interestingly, they can be found in the CBD years after a cholecystectomy.

9.5.4  Calcium carbonate stones

About 20% of paediatric series of gallstones are made up of calcium carbonate, much higher than the equivalent 2%–4% seen in adults [9]. The reasons for this are obscure, although they appear predominantly in boys. There does not appear to be any dietary, geographic or genetic explanation. Some authors have suggested a link with intermittent cystic duct obstruction and increased mucin production as a result. This changes calcium buffering, encouraging calcium precipitation.

9.5.5  Microlithiasis and inspissated bile syndrome

Microliths are defined as gallstones of <3 mm in size and are seen within the intra- and extrahepatic biliary tree. They may explain ongoing symptoms of biliary colic, cholecystitis and pancreatitis following cholecystectomy [17]. Due to their small size, diagnosis can be challenging and adjuvant techniques such as endoscopic ultrasound, endoscopic retrograde cholangiopancreatography (ERCP) and nasobiliary aspiration may be required in addition to traditional transabdominal ultrasound [18].

Inspissated bile or sludge is most commonly found in children with systemic infections, those receiving parenteral nutrition (formed within 3 weeks in ~6% of patients) [19], rapid weight loss, prolonged fasting, poor gallbladder contractility, biliary stasis and third-generation cephalosporins (e.g. ceftriaxone) [5]. They are composed of precipitates of cholesterol monohydrate crystals, calcium bilirubinate, calcium phosphate, calcium carbonate and calcium salts of fatty acids which embed into biliary mucin to form sludge [20].

The formation of sludge may be transient, lasting only a few days, and is usually treated conservatively, or may be more persistent and recurrent, causing duct dilatation necessitating treatment with ursodeoxycholic acid (UDCA) or ERCP ± sphincterotomy to relieve any obstruction. In smaller children and neonates, where ERCP is not practical, percutaneous transhepatic cholangiogram (PTC) to flush the biliary tract may be necessary (Figure 9.4).

Figure 9.4

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