Abstract
The hepatic rudiment appears at approximately day 18 of gestation in the human embryo. By day 25 it can be recognized as an endodermal diverticulum, which projects into the mesenchymal septum transversum. By day 30 the hepatic diverticulum enlarges and divides into the pars hepatica, cranially, and the pars cystica, caudally. The pars hepatica forms parenchymal liver components; the pars cystica differentiates into the gallbladder and cystic ducts (Figure 16.1). The gallbladder primordium is a solid structure that later in development becomes cystic, as found in the adult [1].
Embryologic Development of the Gallbladder
The hepatic rudiment appears at approximately day 18 of gestation in the human embryo. By day 25 it can be recognized as an endodermal diverticulum, which projects into the mesenchymal septum transversum. By day 30 the hepatic diverticulum enlarges and divides into the pars hepatica, cranially, and the pars cystica, caudally. The pars hepatica forms parenchymal liver components; the pars cystica differentiates into the gallbladder and cystic ducts (Figure 16.1). The gallbladder primordium is a solid structure that later in development becomes cystic, as found in the adult [1].
Figure 16.1 Representation of a 9 mm embryo (36 days’ gestation) showing the early formation of the bile ducts and gallbladder between the liver and digestive tract.
Congenital Anomalies of the Gallbladder
A variety of structural anomalies of the gallbladder have been described (Table 16.1). Congenital absence of the gallbladder has long been recognized in humans; it was known to Aristotle. Overall, the incidence of agenesis of the gallbladder has been estimated at between one in 7,500 and one in 10,000 among the general population. There are a number of mammalian species, including the horse, camel, deer, rat, and dolphin, lacking a gallbladder. Absence of the gallbladder may occur as an isolated anomaly or in association with other malformations. In the isolated form, absence of the gallbladder is of little clinical significance. It is believed to result from failed development of the pars cystica. Rarely, symptoms develop related to calculi formation in the biliary ductal system.
| Congenital absence (agenesis) of the gallbladder |
| Hypoplasia of the gallbladder |
| Heterotopic tissue in the gallbladder (gastric, hepatic, adrenal, pancreatic, thyroid) |
| Multiple gallbladder formation (double gallbladder, triple gallbladder) |
| Septated gallbladder |
| Diverticuli of the gallbladder |
| Malposition of the gallbladder |
| Pendulous gallbladder (“floating gallbladder”) |
A number of anomalies have been described in association with congenital absence of the gallbladder. Extrahepatic biliary atresia is associated not uncommonly with absence of the gallbladder, situs inversus, asplenia or polysplenia, and complex congenital heart defects frequently accompany this form of biliary atresia. Imperforate anus, genitourinary anomalies, anencephaly, bicuspid aortic valves, and cerebral aneurysms are associated with agenesis of the gallbladder. Absence of the gallbladder also accompanied thalidomide embryopathy.
Hypoplasia of the gallbladder has also been described. As many as one-third of patients with cystic fibrosis may have a small, poorly functioning gallbladder. Gallbladder hypoplasia is also associated with trisomy 18 and Alagille syndrome [2].
Heterotopic tissue may be found within the gallbladder wall with gastric or hepatic tissue being the most common tissue found. Ectopic adrenal, pancreatic, and thyroid tissues also have been found. The cause of heterotopia is poorly understood. Because the ectopic tissues are all of foregut, endodermal origin, localized heteroplastic differentiation during organogenesis has been proposed. These ectopic foci within the gallbladder wall are seldom of clinical significance; however, chemical irritation secondary to “gastric” acid secretion has been reported.
The incidence of a double gallbladder has been estimated between 0.1 and 0.75 per 1,000 in the general population. Gross described 28 patients with gallbladder duplication, which he defined as structures having two separate gallbladder cavities and two cystic ducts. The two cystic ducts may converge into a single duct forming a Y-shaped structure or may enter the biliary ductal system separately. The paired gallbladders may lie in an appropriate position in the gallbladder fossa, or the accessory gallbladder may be located under the left lobe of the liver, draining into the left hepatic ducts. Rarely, it may be found surrounded by hepatic parenchyma.
Developmentally, duplicate gallbladders are presumed to arise as diverticuli of the embryologic cystic, hepatic, or common duct. Such diverticuli commonly are seen in vertebrate embryos. If these ductal buds fail to regress, an accessory gallbladder may form, which drains into the duct from which it originated. The accessory gallbladder may be more prone to pathologic changes than a normal organ. One case report described a double gallbladder draining into the pancreatic duct of Wirsung. Seventeen cases of triple gallbladder have been reported in the literature [3].
In contrast to multiple gallbladders, a single gallbladder may be divided into multiple chambers by longitudinal septa, presumably secondary to incomplete resolution of its solid phase. Conversely, small diverticuli off the body of the gallbladder may be seen. Because these diverticuli promote bile stasis, gallstones may form.
A normally formed, single gallbladder may be malpositioned. Gallbladders have been described lying beneath the left lobe of the liver, horizontally in the transverse fissure, embedded within hepatic parenchyma, and suprahepatic. Malposition of the gallbladder may be caused by one of two mechanisms: abnormal migration of the pars cystica could result in an aberrant gallbladder location. Alternatively, a ductal diverticulum forming a “second gallbladder,” in conjunction with failed genesis of the pars cystica, could result in a single malpositioned gallbladder. Anomalous gallbladder position is clinically silent unless accompanied by cholelithiasis and cholecystitis. An increased frequency of gallstone formation in association with malposition of the gallbladder is suspected, although it has not been studied systematically.
An uncommon occurrence that may be of clinical significance is the so-called floating gallbladder. This is a gallbladder with a peritoneal coat suspending it from the undersurface of the liver. The embryogenesis is unknown, but a gallbladder-supporting membrane of this type has been seen in approximately 5% of routine post-mortem examinations. This “mesentery” may cover the entire length of the gallbladder creating a stable structure. On occasion, however, it surrounds only the cystic duct, creating a pendulous gallbladder. With this anatomic arrangement, torsion of the gallbladder may occur.
Torsion of the gallbladder is a rare clinical entity but may present a surgical emergency. Elderly women are at greatest risk, although pediatric cases have been reported. The presentation is with abrupt onset of severe, right upper quadrant abdominal pain, with nausea and vomiting. The patient is usually afebrile. On physical examination there is marked right upper quadrant tenderness and often a palpable mass. Peritoneal signs may be present. Shock may ensue. Surgical intervention reveals an infarcted gallbladder on a twisted pedicle containing the cystic duct and artery. Rarely has the diagnosis been presumed preoperatively.
Acalculous Gallbladder Disease
Gallbladder disease in the absence of gallstones is being recognized with increasing frequency with the availability of newer and better techniques of ultrasonography. Classically, acute noncalculous gallbladder disease has been classified as either hydrops or acalculous cholecystitis; the distinction between the two syndromes may be unclear. These conditions may represent a spectrum of disease ranging from transient gallbladder distension with spontaneous resolution to acute acalculous cholecystitis with necrosis of the gallbladder wall.
Hydrops of the Gallbladder
Acute hydrops is defined by marked gallbladder distension in the absence of calculi, bacterial infection, or congenital gallbladder anomaly associated with a normal-caliber extrahepatic biliary ductal system. The absence of a significant inflammatory component and its typically benign prognosis are the features that distinguish hydrops from acalculous cholecystitis.
Etiology and Pathogenesis
Hydrops most commonly is recognized associated with Kawasaki syndrome. The incidence of gallbladder hydrops complicating Kawasaki syndrome ranges from 5% to 20%. In the most extensive series, abdominal ultrasonographic images were obtained in 117 children diagnosed with Kawasaki syndrome, and hydrops was identified in 16 (13.7%). The typical presentation included abdominal pain, vomiting, and right upper quadrant mass superimposed on the clinical features of Kawasaki syndrome (fever for longer than five days, conjunctivitis, oral mucosal changes, rash, and cervical adenopathy). A mild, direct hyperbilirubinemia also may be present. Gallbladder hydrops also has been discovered by screening ultrasonography in patients with Kawasaki syndrome in the absence of significant abdominal complaints. In the vast majority of patients, gallbladder distension is self-limited, resolving without surgical intervention. Complications of gallbladder necrosis and perforation, however, have been reported in patients with Kawasaki syndrome. Serial clinical and ultrasonographic examinations are suggested to monitor for resolution.
The hydrops in this disorder is believed to be secondary to a vasculitic process in the gallbladder wall with cystic duct obstruction. Perivascular leukocytic infiltration with vascular congestion has been described on pathologic examination of a hydropic gallbladder from a child with Kawasaki syndrome. Bile cultures are sterile. Enlarged lymph nodes surrounding, and perhaps obstructing, the cystic duct also have been reported. As depicted in Table 16.2, hydrops of the gallbladder has been reported in association with a variety of disorders.
Table 16.2 Conditions Associated with Gallbladder Hydrops
| Infants and children |
| Kawasaki syndrome |
| Mesenteric adenitis |
| Viral hepatitis |
| Streptococcal pharyngitis |
| Staphylococcal infection |
| Henoch–Schonlein purpura |
| Hypokalemia |
| Sjögren syndrome |
| Nephrotic syndrome |
| Sinusoidal obstruction syndrome |
| Neonates |
| Sepsis |
| Total parenteral nutrition |
| α1-antitrypsin deficiency |
| Fasting |
Hydrops may accompany staphylococcal or streptococcal infection, with associated toxin production. A number of cases of gallbladder hydrops have been described in young children with antecedent upper respiratory infection (or no clear antecedent illness) in whom surgical intervention revealed enlarged mesenteric lymph nodes. Whether cystic duct obstruction secondary to adenopathy played a role in the pathogenesis of the hydrops is unclear.
Single cases of gallbladder hydrops have been reported in infants and children with Sjögren syndrome, Henoch–Schonlein purpura, viral hepatitis, and hypokalemia secondary to Bartter syndrome. A recent retrospective study suggests that gallbladder hydrops may be a feature of early sinusoidal obstruction syndrome following hematopoietic stem cell transplant [4].
Clinical Features
The child with hydrops of the gallbladder typically presents with abdominal pain and a tender right upper quadrant mass. Vomiting, fever, and stigmata of an associated illness commonly are found. The clinical picture may mimic intussusception or acute appendicitis.
The diagnosis of hydrops generally is made by ultrasonography demonstrating a markedly distended, echo-free gallbladder and a normal caliber biliary tree (Figure 16.2). Prior to the routine use of ultrasonography, the diagnosis typically was encountered as an unsuspected finding at laparotomy.
The mainstay of therapy is supportive, with fluid resuscitation and therapy aimed at an associated illness, if indicated (such as antibiotics for streptococcus). Serial ultrasonographic examination is useful to confirm resolution. Surgery should be reserved for the exceedingly rare complication of gallbladder perforation. Symptomatic abdominal pain can resolve after one to two days.
Transient gallbladder distension has been recognized with increasing frequency in neonates as well. Typically, the presentation is as a right upper quadrant abdominal mass in a sick neonate or premature infant. Associated conditions have included sepsis, prolonged fasting, and administration of total parenteral nutrition (TPN), likely related to the reduced cholecystokinin secretion and impaired gallbladder contraction. Gallbladder distension in neonates with cystic fibrosis (perhaps secondary to inspissation of bile) and α1-antitrypsin deficiency (perhaps secondary to cystic duct hypoplasia) have been reported.
Ultrasonography is used to confirm that the abdominal mass is the gallbladder. Typically, with the institution of feeding, transient gallbladder distension of the neonate resolves spontaneously. It is important to remember, however, that a number of cases of culture-proven acalculous cholecystitis in neonates have been documented. Because there are no reliable ultrasonographic criteria for distinguishing inflammation from benign distension (thickening of the gallbladder wall is neither entirely sensitive nor specific for inflammation), failure of the abdominal mass to resolve or clinical deterioration should warrant further investigations. Surgical intervention may be required in some patients.
Acalculous Cholecystitis
Acalculous cholecystitis, characterized by distension and inflammation of the gallbladder, is uncommon in infants and children. It is an important entity to recognize, however, because it may present as an abdominal emergency.
Etiology and Pathogenesis
Acalculous cholecystitis has been reported at all ages from neonates to adolescents. Acalculous cholecystitis in adults commonly accompanies serious illness or trauma. Predisposing factors for the development of acalculous cholecystitis have been identified in 50% of pediatric patients and include previous surgical procedure, burns, multiple transfusions, trauma, and systemic infection (Table 16.3). A case of acalculous cholecystitis in an adolescent male with Crohn disease has been described.
| Postoperative state |
| Burns |
| Trauma |
| Multiple transfusions |
| Escherichia coli infection of the gallbladder in neonates |
| Systemic infection |
| Sepsis |
| Leptospirosis |
| Rocky Mountain spotted fever |
| Typhoid fever |
| Cryptosporidium |
| Giardia |
| Epstein–Barr virus |
| Cytomegalovirus |
| Candida |
| Aspergillus |
| Immunocompromised host |
| Hemophagocytic lymphohistiocytosis |
The pathophysiology of acalculous cholecystitis is poorly understood. In the postoperative or severely ill patient, the lack of enteral feeding, the administration of TPN, and the use of opiates result in gallbladder stasis. In some patients, congenital narrowing or local inflammation of the cystic duct has been demonstrated at the time of surgical intervention. Obstruction of the cystic duct with gallbladder distention and secondary bacterial invasion may lead to cholecystitis. Episodic ischemia or hypoperfusion also could play a role in the development of acalculous cholecystitis in the patient in intensive care.
Acalculous cholecystitis has been described in association with systemic infectious illness. Ternberg and Keating described three patients with leptospirosis presenting as fever, pharyngitis, cervical adenopathy, and rash, in whom tender abdominal masses were found [5]. At laparotomy, an inflamed distended gallbladder was found in each of the three patients. Therapy included tube cholecystostomy with good results. In a review of the experience with leptospirosis at St. Louis Children’s Hospital, five of nine cases were complicated by acalculous cholecystitis requiring surgical drainage [6].
In one review of neonates with acalculous cholecystitis, eight of ten infants had systemic infection [7]. Bile cultures grew Escherichia coli, Streptococcus viridans, Serratia, and Pseudomonas. The two infants in whom there was no evidence of sepsis had congenital anomalies of the biliary tree with cystic duct obstruction. Another report of two neonates, one premature and one term, reported nonspecific symptoms including irritability and ileus. In each case, exploratory laparotomy revealed gallbladder necrosis and cultures from the gallbladder grew Escherichia coli. Both infants fully recovered following cholecystectomy [8].
Gallbladder inflammation has been described with Rocky Mountain spotted fever, with rickettsial organisms demonstrated in a surgically resected gallbladder. The course of typhoid fever frequently has been complicated by acalculous cholecystitis; the first cholecystostomy was performed for acute gallbladder inflammation secondary to typhoid fever in 1901. Children with hemophagocytic lymphochistiocytosis (HLH) may present with a constellation of ultrasound findings including hepatosplenomegaly, ascites, pleural effusion, periportal echogenicity, and gallbladder wall thickening.
Associated illness or anomaly is not necessary for the development of acalculous cholecystitis in the pediatric population. None of the seven patients in the series reported by Holcomb and colleagues had an associated predisposing illness or documented systemic infection. Cholecystectomy was performed in all seven without postoperative complication.
Opportunistic infection may occur in the gallbladder of an immunocompromised host. Adult patients with HIV disease or after orthotopic liver transplant have been reported to have cholecystitis secondary to cytomegalovirus. Fungal infections of the gallbladder with Candida, Torulopsis, and Aspergillus have been described. Additionally, parasitic infestation of the gallbladder with Giardia and Cryptosporidium has occurred in association with HIV infection and other immunodeficiency states.
Clinical Features
Patients with acalculous cholecystitis classically present with right upper quadrant abdominal pain, nausea, vomiting, and fever. Physical examination reveals right upper quadrant or generalized abdominal tenderness. A mass may be palpable. Leukocytosis is an inconsistent finding. Signs and symptoms may be less readily apparent in the neonate or the severely ill patient. The clinical presentation may be dominated by the findings of an associated illness, such as trauma or a systemic infectious process.
The differential diagnosis includes appendicitis, intussusception, infectious hepatitis, choledochal cyst, and diffuse peritonitis. Ultrasonography can demonstrate gallbladder distension, with thickening of the gallbladder wall (Figure 16.3) and echogenic intraluminal debris. Thickening of the gall bladder wall can also be demonstrated by axial CT scans (Figure 16.4). The reliability of excessive thickness of the gallbladder wall as an indicator of acute inflammation has been questioned. In a report by Sanders, a thickened gallbladder wall was present in 45% of adult patients with acute calculous and noncalculous cholecystitis studied by ultrasound [9]. In a series of 793 consecutively studied infants and children, Patriquin and co-workers reported that 20 patients were identified as meeting ultrasound criteria for a thick gallbladder wall (defined as greater than 3 mm) [10]. Of these 20 patients, 16 had hypoalbuminemia, two had ascites, one had physiologic thickening associated with contraction of the gallbladder wall, and one had heart disease with associated systemic venous hypertension. None of the patients had clinical findings suggestive of acute cholecystitis. Of five patients with surgically proven acute cholecystitis who underwent ultrasonographic examinations during the study period, none had a thickened gallbladder wall. Jeffrey and Sommer evaluated 14 adult patients with clinically suspected acute acalculous cholecystitis but inconclusive initial abdominal ultrasounds [11]. Four of the patients with normal gallbladder walls demonstrated progressive thickening on subsequent studies, and three of these patients had acute acalculous cholecystitis as a surgical finding. Six patients had thickened gallbladder walls at the initial ultrasonographic examination, but only one of these patients required a cholecystectomy after continuing to have symptoms consistent with acute acalculous cholecystitis. Another recent analysis of 94 adults with hematologic malignancy and signs/symptoms suggestive of cholecystitis (fever, right upper quadrant pain or tenderness, abnormal liver enzymes) showed that 41% of patients without initial ultrasonographic evidence of acute acalculous cholecystitis went on to develop suggestive imaging evidence within one week of the negative ultrasound [12]. These data suggest that repetitive sonography may be helpful in diagnosing acute acalculous cholecystitis. Gallbladder wall thickening may represent a local inflammatory response or may be a reflection of a systemic process; a thickened gallbladder wall depicted by ultrasonography must be interpreted in the context of the clinical setting.
The diagnosis of acute acalculous cholecystitis requires a high index of clinical suspicion. Radiographic techniques can provide strong supportive evidence in the appropriate clinical setting. Ultrasonographic findings consistent with acute acalculous cholecystitis, however, such as gallbladder distention, gallbladder wall thickening, lack of calculi, and a poor response to cholecystokinin, also can be seen in gallbladder hydrops. Radioisotope studies with technetium-labeled mebrofenin can be used to demonstrate patency (or lack thereof) of the cystic duct. Non-filling of the gallbladder, in the presence of good hepatic uptake and intestinal excretion of radioisotope, suggests cholecystitis. Swayne demonstrated that technetium cholescintigraphy has a high sensitivity for biliary obstruction in a retrospective study of adults with clinically suspected acute acalculous cholecystitis [13]. Another study showed that scintigraphy was not specific compared with both ultrasonography and computerized tomography. False-positive scintigraphic results have been seen in alcoholism or in patients receiving parenteral nutrition.
Definitive therapy for acalculous cholecystitis remains controversial. Surgical intervention with tube cholecystostomy, or preferably cholecystectomy, is considered prudent, in order to prevent complications such as gangrenous necrosis of the gallbladder wall, perforation, and bile peritonitis. In a series of 12 patients, Imamoglu et al. performed cholecystectomy on three with resolution, without operative intervention in the other nine [14].
Other Acalculous Entities of the Gallbladder
Another category of acalculous disease that is becoming more commonly diagnosed is gallbladder dyskinesia, also known as biliary colic. Patients presenting with this disorder often are female and have a history of right upper quadrant pain and fatty food intolerance that may have been present for longer than one year. Often a family history of cholelithiasis is present. Ultrasonography does not show gallstones, and ultrasonography or scintigraphy with cholecystokinin stimulation shows a decreased biliary ejection fraction. Dumont and Caniano examined 42 children with abdominal pain and abnormal gallbladder emptying (contractility less than 50%) diagnosed by either ultrasonography or scintigraphy with cholecystokinin [15]. All patients were treated with cholecystectomies, and all but one improved after surgery after a mean follow-up period of 20 months. Almost half of removed gallbladders had chronic inflammation. A retrospective analysis by Vegunta et al. revealed that among 107 consecutive cholecystectomies in children at a single medical center, 62 were performed for biliary dyskinesia. Short-term relief of symptoms was observed in 85% of patients with a preoperative diagnosis of dyskinesia and approximately half of the removed gall bladders had chronic cholecystitis [16]. Another retrospective study showed a much higher incidence of chronic cholecystitis in such patients.
Gallbladder motility has been shown to be impaired in children with Down syndrome and children and adolescents with type I diabetes mellitus. Fasting gallbladder volumes are increased in both conditions and contraction after a meal stimulus is reduced in Down syndrome. These abnormalities may predispose to the known increased gallstone formation in both conditions.
Other Inflammatory Lesions of the Gallbladder
Rarely, lesions of the gallbladder accompany other systemic inflammatory disorders. A characteristic granulomatous inflammatory lesion has been demonstrated in the gallbladder wall of a patient with Crohn disease. Malacoplakia involving the gallbladder, with the formation of Michaelis–Gutmann bodies, has been reported as well. The gallbladder may be affected in patients with polyarteritis nodosa.
Tumors of the Gallbladder
Neoplastic disorders of the gallbladder occur uncommonly in childhood. Adenoma of the gallbladder, a benign polypoid lesion, has been described in a pediatric patient. It may present with symptoms of biliary colic; ultrasonography may allow visualization of a gallbladder polyp (Figure 16.5). Resection is recommended because of malignant potential and association with acute acalculous cholecystitis. Gallbladder polyps also have been reported in association with Peutz–Jegher syndrome. Adenomyomatosis is a benign hyperplasia of the muscularis mucosa with intramucosal diverticula formation. This condition may lead to abdominal pain. Although there is no consensus regarding an association with malignancy, most clinicians would recommend cholecystectomy.
Primary malignant neoplasms of the gallbladder are exceedingly uncommon in the pediatric age group. Presenting as obstructive jaundice, embryonal rhabdomyosarcoma is the most frequently encountered malignancy arising from the gallbladder and biliary tree. The prognosis is dismal because the tumor is poorly responsive to surgical and chemotherapeutic intervention.
Miscellaneous Conditions
There are a number of disorders characterized by accumulation of lipids or calcium salts intraluminally or intramurally within the gallbladder. These disorders are more common in the adult population.
Porcelain gallbladder, an entity characterized by calcification of the gallbladder wall, occurs in association with chronic inflammation. Two cases have been described that were associated with extrahepatic bile duct obstruction [17, 18]. Cholecystectomy is advised, because of the high frequency of gallbladder carcinoma reported in adult patients with porcelain gallbladder.
A single case of “milk of calcium” bile has been reported in the pediatric literature [19]. For unknown reasons, excessive quantities of calcium carbonate accumulate in gallbladder bile; the gallbladder is radiopaque on plain film, which appears much like a cholecystogram.
Cholesterolosis of the gallbladder involves deposition of triglycerides and cholesterol esters in macrophages within the lamina propria of the gallbladder wall. It may occur as a diffuse or localized phenomenon.
Calculous Gallbladder Disease
Approximately 20 to 25 million North American adults have gallstones. Based upon the Framingham study, it is estimated that 12 million females and six million males have gallstones. Cholelithiasis is relatively uncommon in infancy and childhood; however, gallstones have been detected in utero as early as after 30 weeks’ gestation, and in newborns. One newborn has been described with clinical and ultrasonographic evidence of acute calculous cholecystitis.
Few studies have been performed that examined the incidence or prevalence of gallstone disease in children. The prevalence of gallstones among 1,502 Italian males and females, 6 to 19 years of age, screened with ultrasound was 0.13% overall (0.27% in females) [20]. This compares with a prevalence of 2.9% and 1.1% among Italian females and males, respectively, between 18 and 29 years of age [21]. The incidence of gallbladder disease remains negligible in males throughout childhood and adolescence; in females there is a remarkable increase in incidence between 11 and 13 years of age [22] (Figure 16.6). The true prevalence of gallstones has been evaluated in adult Caucasians by survey with ultrasonography or oral cholecystography (Figure 16.7). For both males and females, there is an increasing prevalence of gallstones with increasing age. At all ages from puberty until menopause, women have a higher frequency of stones than men [21, 23, 24]. Clear differences in gallstone frequency exist among ethnic backgrounds. The frequency is exceedingly low (near 0%) among Canadian Eskimos and East and West African Natives; it reaches 30–70% among American Indians, Swedish, and Czechs [25]. The type of stones also varies with geographic region. Cholesterol gallstones predominate in Western cultures; pigment stones are more common among Asian populations.
Figure 16.6 Incidence of gallstones among hospitalized Swedish children younger than 16 years of age. Note minimal incidence for both boys and girls before 11 years of age, with a sharp increase in incidence in girls and a minimal increase in boys.
Figure 16.7 Prevalence of gallstones by surveys using ultrasonography or oral cholecystography in Caucasian women (A) and men (B) from Europe and Canada. Gallstones are more common in women and increase in frequency with increasing age.
Classification of Gallstones
Stones may be divided into two major categories (Figure 16.8). Cholesterol stones contain more than 50% cholesterol by weight, with variable amounts of protein and calcium salts. Pigment stones (black and brown) are complex mixtures of insoluble calcium salts including calcium bilirubinate, calcium phosphate, and calcium carbonate. Cholesterol content in pigment stones ranges from less than 10% in black stones to 10–30% in brown pigment stones.
Approximately 25–33% of stones removed during cholecystectomy in adults are pigment stones; as many as 72% in children are pigment stones. Less than 10% of gallstones obtained during cholecystectomy during adolescence are pigment stones; by the seventh decade of life, pigment stones are more common than cholesterol stones. Black and white adults have similar frequencies of pigment stones. Obesity does not appear to predispose to pigment stone formation.
Causes of Gallstones in Children
Several series have reported the cause of gallstones in children and adolescents [26, 27, 28, 29, 30, 31–41). Few have addressed carefully the issue of the type of stone associated with certain conditions. Friesen and Roberts [27] reviewed their hospital’s experience and a total of 693 cases of pediatric gallstones reported in the literature. Based on their experience, 72% of stones were pigmented, 17% cholesterol, and in 11% the composition was unknown. Over the entire series, pigment stones predominated in infants and children up to the age of five years, with cholesterol stones found more commonly between six and 21 years of age. Unfortunately, the composition of the stones was unknown in the majority of studies, and determination of composition was based on visual inspection rather than chemical analysis. Hemolytic disease was considered the cause of gallstones in 30% of the entire series. The cause of and conditions associated with stones from the entire series are illustrated in Table 16.4. In a second smaller study, Stringer et al. examined stone type obtained from 64 consecutive cholecystectomies for cholelithiasis in children. Of the 63 with a sample available for analysis, 32 had pigment stones, 13 had cholesterol stones and 15 had calcium carbonate stones [28]. These findings suggest that the stone composition in children is different from adults, particularly the finding of calcium carbonate stones. These stones appear to have a similar composition to pigment stones but lack bilirubinate salts. Many, but not all, had received parenteral nutrition which may provide a potential explanation for the high frequency of calcium carbonate stones in this series.
Table 16.4 Associated Conditions by Age for 693 Patients with Cholelithiasis Reported in the Literature [27], Expressed as Percentage of Total Cases in Age Group
| 0–12 months | 1–5 years | 6–11 years |
|---|---|---|
| None (36.4%) | Hepatobiliary disease (28.6%) | Pregnancy (37.2%) |
| TPN (29.1%) | Abdominal surgery (21.4%) | Hemolytic disease (22.5%) |
| Abdominal surgery (29.1%) | Artificial heart valve (14.3%) | Obesity (8.1%) |
| Sepsis (14.8%) | None (14.3%) | Abdominal Surgery (5.1%) |
| Bronchopulmonary dysplasia (12.7%) | Malabsorption (7.1%) | None (3.4%) |
| Hemolytic disease (5.5%) | Hepatobiliary disease (2.7%) | |
| Malabsorption (5.5%) | TPN (2.7%) | |
| Necrotizing enterocolitis (5.5%) | Malabsorption (2.8%) | |
| Hepatobiliary disease (3.6%) |
Pigment Gallstones
There are two major types of pigment stones, “black” and “brown.” In both types, pigment is present as calcium bilirubinates. In black pigment stones, pigment is cross-linked to form a black polymer that is insoluble in all solvents. In contrast, in brown pigment stones the cross-linked polymers are present in low concentrations and the pigments are soluble in most organic solvents. Black pigment stones are found in sterile gallbladder bile. About 50% of black pigment stones appear to be radiopaque with conventional radiographic techniques. Two thirds of all opaque stones are pigment stones, because of their high content of calcium carbonates and phosphates. Brown pigment stones generally are found in infected bile in intra- and extrahepatic bile ducts. They are usually radiolucent, because they contain smaller amounts of calcium phosphate and carbonate than black pigment stones. Brown stones contain more cholesterol than black stones, because the bile in which they develop tends to be continuously supersaturated with cholesterol. Black pigment stones are shiny, like anthracite chips, or dull, like asphalt, and relatively hard and spiculated. Brown pigment stones are soft and soap-like or greasy in consistency.
Unconjugated bilirubin (UCB) is the major bile pigment in gallstones. Typically, the major components of bile are bilirubin diglucuronides and two bilirubin monoglucuronide isomers. The glucuronides generally bind calcium as soluble complexes. UCB ordinarily makes up only a small fraction of normal bile pigment (1%). Most UCB derives from endogenous enzymatic (β-glucuronidase) or nonenzymatic hydrolysis of conjugated bilirubins. Unlike the conjugates, UCB is very sensitive to precipitation with ionized calcium. Although the process is still poorly understood, polymers of cross-linked bilirubin tetrapyrroles are formed in bile that serve as the basis for stone formation. The chemical initiators of the polymerization process are not known. It seems likely that polymerization is initiated by free radicals or singlet oxygen, possibly produced by the liver and secreted in bile or by macrophages or neutrophils in the gallbladder mucosa.
Calcium carbonate and phosphate are the major components of most black pigment stones; brown pigment stones do not contain appreciable amounts of these substances. Precipitation of these salts is determined by bile pH. Insoluble calcium salt formation is enhanced markedly in alkaline bile, and it is likely that black pigment stones containing calcium carbonates only form in alkaline bile. Fatty acid salts (calcium soaps) are important components of brown pigment stones. Palmitate and stearate are principal sn-1 salts of fatty acids of biliary lecithin. They generally are not found free in bile and are produced by bacterial phospholipase A1 hydrolysis of lecithin.
Mucin glycoproteins are the framework on which pigment stones grow. Mucin is produced in the gallbladder crypts. Mucin hypersecretion by the gallbladder may play an important role in pigment stone formation.
In black pigment stone disease, bile should be supersaturated with calcium bilirubinates, calcium carbonate, and calcium phosphate. This may result from an absolute increase in the amount of UCB or ionized calcium. Increased biliary UCB may derive from increased pigment production and excretion in bile. In humans, the output and proportion of UCB in bile may increase after a load of hemoglobin or bilirubin. Patients with spontaneous hemolysis have no more than 3% of total biliary bilirubin as UCB. Increased UCB also may result from increased enzymatic (β-glucuronidase) hydrolysis of bilirubin conjugates or reduced amounts of an inhibitor of β-glucuronidase, glutaric acid. Potential causes of increased levels of ionized calcium are increased amounts of plasma-ionized calcium or reduced biliary calcium binders such as micellar bile salts and lecithin–cholesterol vesicles. Increased ionization of normal amounts of UCB and increased [CO3−2] occurs in alkaline biliary pH. Decreased biliary bile salts and cholesterol concentrations found in cirrhotic patients may lead to increased levels of ionized calcium in bile, as well as reduced levels of micellar bile salt and vesicle deficiency.
Brown pigment stones require both stasis and infection. Bacterially derived β-glucuronidase, phospholipase A1, and bile salt deconjugase produce UCB, fatty acids, and unconjugated bile acids. All of these products are insoluble and precipitate as calcium salts. Ductal precipitation of these compounds together with cholesterol and mucin form soft, greasy stones shaped like the bile ducts.
Conditions Predisposing to Black Pigment Stone Formation
Chronic Hemolytic Disease
The risk of black pigment stone formation is increased in patients with chronic hemolytic disorders including congenital spherocytosis, sickle cell (S-S and S-C) disease, thalassemia major and minor, pyruvate kinase deficiency, glucose-6-phosphate dehydrogenase deficiency, and autoimmune hemolytic disease. The prevalence of pigment stones in patients with hemolytic disorders increases with age, as illustrated by the age-related frequencies of gallstones in sickle cell anemia. In children younger than ten years of age, the frequency is 14%. In 10- to 20-year-olds, the frequency increases to 36%. At age 22 years, the frequency is 50%, and by age 33 years it is between 60% and 85% [42–44]. Despite the identification of gallstones in over half of a cohort of patients with sickle cell disease, few are symptomatic at the time of ultrasound identification of stones. Elective laparoscopic cholecystectomy is encouraged for patients with sickle cell disease who have gallstones identified by ultrasonography. Studies have suggested a 12-day reduction in hospital stay with elective laparoscopic cholecystectomy compared to those undergoing emergent surgery (four vs. 16 days).
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Chapter 5 – Cirrhosis and Chronic Liver Failure in Children
Chapter 13 – Familial Hepatocellular Cholestasis
Chapter 14 – Alagille Syndrome
Chapter 26 – Cystic Fibrosis Liver Disease in Children
Chapter 32 – Lysosomal Storage Disorders in Children
Chapter 43 – Liver Transplantation in Children: Indications and Surgical Aspects
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