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Acquired biliary diseases in children
SYMPOSIUM: HEPATOLOGY
Acquired biliary diseases in children
exact prevalence of gallstones in children is not known. European studies in pediatric patients estimated an overall prevalence of 0.13% to 0.2% for gallstone disease in children up to 19 years of age. In Japan, the prevalence of gallstone disease is reported to be less than 0.13% of children. In a recent study, however, the prevalence of gallstones among obese children and adolescents was shown to be quite high (2% of 493 children). Studies on cholelithiasis in children have shown a bimodal distribution, with a small peak in infancy and a steady rising incidence from early adolescence onward. Boys and girls are similarly affected in early childhood, but as in adults, a clear female preponderance emerges during adolescence. A unique subset is those with chronic hemolytic disease. Interestingly in this condition cholelithiasis is not seen commonly before the age of 5 and thereafter the incidence increases progressively with age. In sickle-cell disease the prevalence of pigment gallstones is 10% to 15% in children under 10 years of age and it increases to 40% in those aged 10e18 years. In hereditary spherocytosis the prevalence of gallstones is 10% to 20% and in thalassemia the figure is 10% to 15%.
Ujjal Poddar Winita Hardikar
Abstract Acquired biliary diseases are far less common in children than in adults and include gallstones, acalculous cholecystitis, biliary dyskinesia, primary sclerosing cholangitis (PSC) and benign biliary strictures. Gallstones have been increasingly diagnosed in children in recent years mainly due to increasing use of ultrasonography. The etiologies of cholelithiasis are hemolytic (20%e50%), other known etiology (30%e40%) such as total parenteral nutrition, ileal disease, congenital biliary diseases and idiopathic (20%). Spontaneous resolution of gallstones is frequent in infants and hence a period of observation is recommended even for choledocholithiasis. Children with gallstones can present with typical biliary symptoms (50%), nonspecific symptoms (25%), be asymptomatic (20%) or complicated (5%e10%). Cholecystectomy is useful in children with typical biliary symptoms but is not recommended in those with nonspecific symptoms. Prophylactic cholecystectomy is recommended in children with hemolytic disorders. Biliary dyskinesia is characterized by biliary colic without the presence of gallstones. Management is controversial. In PSC immunosuppressive therapy helps children with PSC with autoimmune hepatitis features.
Pathogenesis Gallstones are either cholesterol gallstones (pure and mixed) or pigment stones (black or brown). Cholesterol supersaturation of bile with stasis predisposes to cholesterol gallstone formation. Mixed cholesterol gallstones are the commonest stones in adults and in adolescent girls. However, pigment stones are more common in children. Black pigment stones are formed due to supersaturation of bile with calcium bilirubinate and are seen in hemolytic disorders and in association with total parenteral nutrition. Brown pigment stones are associated with infection and biliary stasis and form more often in the bile ducts than in the gallbladder. Biliary sludge is composed of mucin, calcium bilirubinate and cholesterol crystals. It is commonly associated with prolonged fasting, total parenteral nutrition, pregnancy, sickle-cell disease, treatment with ceftriaxone or octreotide. The natural history of biliary sludge is variable; it may disappear spontaneously or may progress to gallstone development. Persistent sludge may give rise to biliary complications (such as obstruction or infection). Etiologically cholelithiasis (Table 1) in children can be divided into three groups; hemolytic, other known etiology and idiopathic. Almost 20% to 50% of all gallstones in children are due to hemolytic diseases such as sickle-cell disease, hereditary spherocytosis and thalassaemia. In around 30% to 40% of cases, gallstones are due to another known etiology such as total parenteral nutrition, prolonged fasting, ileal disease or ileal resection, frusemide therapy, congenital biliary diseases such as choledochal cyst, chronic liver disease and progressive familial intrahepatic cholestasis (PFIC). Around 20% of cases are idiopathic. As in adults, gallstones in adolescent girls are more often idiopathic.
Keywords acalculous cholecystitis; biliary dyskinesia; cholelithiasis; LPAC; sclerosing cholangitis
Overall biliary diseases are far less common in children than in adults and those that do occur are usually congenital such as biliary atresia and Alagille Syndrome. Among the acquired biliary diseases, gallstones, acalculous cholecystitis, biliary dyskinesia, primary sclerosing cholangitis and benign biliary strictures will be discussed.
Cholelithiasis (Gallstone disease) in children Epidemiology Little is known about the epidemiology of cholelithiasis in children. Cholelithiasis and choledocholithiasis were considered to be uncommon in infants and children but have been increasingly diagnosed in recent years. This phenomenon may be attributed to better medical imaging (especially ultrasonography) and its usage in investigating children with unexplained abdominal pain and/or a genuine increase in the incidence of cholelithiasis. The
Ujjal Poddar MD DM Gastroenterology Fellow Department of Paediatric Gastroenterology & Nutrition, Royal Children Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
Total parenteral nutrition and cholelithiasis Total parenteral nutrition (TPN) impairs enterohepatic circulation and cholecystokinin induced gallbladder contraction resulting in biliary stasis, sludge and stones. The longer the duration of TPN therapy, the higher the risk of developing cholelithiasis. The risk of developing gallstones in children on prolonged TPN therapy is increased if there is concomitant ileal resection or disease. In
Winita Hardikar MBBS PhD FRACP is Head of Hepatology, Department of Paediatric Gastroenterology & Nutrition, Royal Children Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
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SYMPOSIUM: HEPATOLOGY
Etiology of gallstones in children Type of gallstones
Proportion of all gallstones in children
Etiology
1. 2.
Hemolytic Non-hemolytic
20% 40% to 50%
3.
Idiopathic
30e40%
Sickle-cell disease, hereditary spherocytosis, thalassemia major TPN, prolonged fasting, ileal disease (like Crohn’s disease) or resection, prematurity, frusemide therapy, cardiopulmonary bypass, congenital biliary malformations, PFIC, chronic liver disease, cystic fibrosis, OCP, teenage pregnancy No predisposing factor
TPN: total parenteral nutrition, PFIC: progressive familial intrahepatic cholestasis, OCP: oral contraceptive pills.
Table 1
a study of 21 children on prolonged TPN (more than 3 months) Roslyn et al. have shown that 43% of children developed gallstones but this figure was 64% in children with ileal resection or disease. Sludge develops more rapidly in neonates than in adults after a mean time of TPN infusion in neonates of 10 days, as compared with more than 6 weeks in adults. In a prospective study of 41 neonates, Matos et al. have shown that gallbladder sludge appeared in 18 (44%) of those infants who had received TPN infusion for a mean period of 10 days. In 12 infants, the sludge cleared within one week of resuming enteral feeding but two of the remaining infants went on to develop asymptomatic gallstones. Spontaneous resolution occurred in one of these two infants by 6 months while the calculi persisted in the other baby.
phosphatidylcholine, bile becomes supersaturated with cholesterol and predisposes to gallstone formation. This condition is more frequent in females than in males (3:1). Apart from a family history of cholesterol gallstones amongst first degree relatives, intrahepatic hyperechoic foci (cholesterol crystal deposits in intrahepatic bile ducts) are a characteristic sign of the LPAC syndrome. The typical biliary symptoms experienced by these patients are probably due to cholesterol crystal deposits and bile duct inflammation as symptoms recur in more than half of the cases after cholecystectomy. Ursodeoxycholic acid (UDCA) appears to relieve biliary symptoms long before the dissolution of intrahepatic stones. Clinical presentation According to the age of presentation, children can be divided into three groups; infants (0 to 2 years), children (2 to 14 years) and adolescents (14 to 18 years) (Table 2).
Low phospholipid associated cholelithiasis (LPAC) Gallstones in the adolescent age group with a strong family history of gallstones under the age of 40 years, intrahepatic cholestasis of pregnancy or a cholestatic reaction to oral contraception should raise the suspicion of a rare condition called low phospholipid associated cholelithiasis (LPAC). The underlying cause is a mutation in MDR3, a gene which encodes the ABCB4 transporter. This protein is responsible for the translocation of phosphatidylcholine across the canalicular membrane of hepatocytes which then solubilises cholesterol in bile. In the absence of
Cholelithiasis in infancy Cholelithiasis is uncommon in infants but more and more cases are reported in recent years mainly due to increasing use of ultrasonography (US). Gallstones have even been detected in the fetus. Gallstones in infancy are usually asymptomatic but occasionally can present with cholestatic jaundice, transient acholic stools, sepsis and abdominal pain.
Clinical presentations of gallstones in children Age group
Proportion of all gallstones in children
Clinical presentations
1.
Infants
10%
2.
Children
40%
3.
Adolescents
50%
1. Symptomatic: Cholestatic jaundice, transient acholic stools, abdominal pain, and sepsis 2. Asymptomatic: incidental detection. 1. Typical biliary symptoms (40%e50%): right upper quadrant or epigastric pain with or without nausea, vomiting and fat intolerance 2. Non-specific abdominal pain (20%e30%) 3. Acute abdomen (5%e10%): due to acute cholecystitis, pancreatitis or cholangitis 4. Asymptomatic (20%) Same as in children but right upper quadrant pain and fatty food intolerance are more common in adolescents than in children
Table 2
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SYMPOSIUM: HEPATOLOGY
In symptomatic infants, gallstones are more often associated with stones in the common bile duct (CBD) than stones in the gallbladder alone. In a series of 13 cases of cholelithiasis in infants, St-Vil et al. have reported that 11 were asymptomatic and detected by US done for unrelated problems. In another series of 40 cases of cholelithiasis in infancy, Debray et al. have shown that 6 had isolated gallstones and were asymptomatic whereas 34 had bile duct obstruction and all were symptomatic.
Bruch SW et al. followed 41 children with non-specific or no symptoms for 21 months. Of these, 50% remained or became asymptomatic, 32% experienced definite improvement in symptoms, 18% had continued symptoms but none had any biliary complications. Wesdorp et al. have substantiated this observation in their study of 82 children with cholelithiasis who were followed up for a mean period of 4.6 years. The suggested treatment algorithm for gallstones in children is given in Figure 1. Children with gallstones should be divided into two groups. Those with typical symptoms (right upper quadrant or epigastric pain, nausea, vomiting and fatty food intolerance) should have their gallbladders removed. Asymptomatic children or children with nonspecific symptoms can undergo safe follow up. These children will require observation into adulthood to determine their lifetime risk of developing symptoms. In recent years, laparoscopic cholecystectomy has become the treatment of choice in the surgical management of children with cholelithiasis. It has the advantage of being less invasive with lower morbidity and mortality and shorter hospital stay over conventional open cholecystectomy. The role of dissolution therapy in the management of gallstones in children remains to be defined. The only study of UDCA therapy for gallstones in children by Gamba et al. has shown disappointing results. Of 15 children with radiolucent stones (<10 mm) and a functional gallbladder treated for one year, stones disappeared completely in only two cases but returned later in both. Extracorporeal shock-wave lithotripsy for gallstones in children has been successful in a single case report.
Cholelithiasis in children Children with gallstones can present with acute abdominal pain due to cholecystitis, cholangitis or pancreatitis. However, an acute presentation is uncommon (5% to 10% of cases only). Most commonly, children with cholelithiasis present with typical right upper quadrant pain (50%) or non-specific abdominal symptoms (25%) including poorly localized abdominal pain and nausea. Around 20% of cases are asymptomatic (incidentally detected stones). Gallstones in children are more often (60%) symptomatic than in adults (20%). The type of symptoms depend on the age of presentation, older children (6 years or more) often localize pain in the right upper quadrant whereas younger children (5 years or less) tend to present with nonspecific symptoms. Fatty food intolerance, a typical symptoms of gallstone disease in adults, tends to be reported by older children. Cholelithiasis in adolescents In this age group, the symptoms are similar to those generally found in adults. Patients are more often girls who are overweight and have a positive family history. Fatty food intolerance, biliary colic and acute or chronic cholecystitis are usual presenting features of symptomatic patients.
The approach to cholelithiasis in infancy is different as spontaneous resolution has been reported in a significant proportion of cases (cholelithiasis almost 50% and choledocholithiasis 30%). Spontaneous resolution within 6 months is more common with idiopathic gallstones than in patients with known predisposing factors. Based on limited information, it can be recommended that asymptomatic infants with idiopathic cholelithiasis be observed for spontaneous resolution. Even for choledocholithiasis an observation period of one to two weeks is recommended before active therapy as there is a chance of spontaneous resolution. Cholecystectomy is indicated for symptomatic cholelithiasis, asymptomatic cholelithiasis persisting beyond 12 months and radiopaque calculi.
Diagnosis The most universally used and the most accurate diagnostic aid in detecting the presence of gallstones is ultrasonography. Gallstones are usually mobile, single or multiple and characteristically cast an acoustic shadow. Biliary sludge though appearing echogenic on ultrasound, does not cast an acoustic shadow. A stone, as small as 1.5 mm, can be detected by ultrasonography. The sensitivity and specificity of ultrasonography exceeds 95% for gallbladder cholelithiasis, but this figure is only 50%e75% for choledocholithiasis. In children 20% to 50% gallstones are radiopaque. Cholescintigraphy, with technetium 99 m labeled diisopropyl iminodiacetic acid (DISIDA), is the most accurate method of diagnosing acute cholecystitis. Nonvisulization of the gallbladder in an otherwise patent biliary system suggests acute cholecystitis. Magnetic resonance cholangiopancreatography (MRCP) is being used increasingly to investigate complicated gallstone disease. Endoscopic retrograde cholangiopancreatography (ERCP) offers the additional advantage of therapeutic intervention in common bile duct stones.
Management of cholelithiasis in hemolytic disease: In this group of children, screening with US is recommended at around 5 years of age. Screening is also recommended before splenectomy as both splenectomy and cholecystectomy can be combined in presence of gallstones and it confers a survival benefit over splenectomy alone in hereditary spherocytosis. However, there is no advantage of doing cholecystectomy during splenectomy if there are no gallstones as these patients are not at an increased risk of cholelithiasis after splenectomy. In sickle-cell disease, prophylactic cholecystectomy is recommended even for asymptomatic gallstones as it is difficult to differentiate an acute abdominal crisis from acute cholecystitis, and the morbidity and mortality of emergency cholecystectomy in this setting is much higher than in elective cholecystectomy. To avoid sickling during the perioperative period it is recommended that hemoglobin S be
Management Management of gallstones depends on the symptoms and age of the patient. Symptomatic gallstones need cholecystectomy and same is true for complicated gallstones but there is no consensus about the management of asymptomatic gallstones in children. In a prospective study of children with non-pigmented gallstones,
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Management algorithm for gallstones in children Gallstones in infants
Gallstones in children
Symptomatic
Asymptomatic
Observe for 1–2 weeks
Non-calcified
Stone passed spontaneously
No improvement
No treatment
Symptomatic
Asymptomatic
Gallstones in haemolytic disease
Symptomatic
Asymptomatic
Calcified
Observe for 12 months
± splenectomy
Observation
Persistence beyond 12 months
Cholecystectomy
Figure 1
decreased to at least 30% and total hemoglobin be increased to at least 11 g/dL. During the operation and recovery period, hypotension, dehydration, hypoxia, hypothermia and acidosis should be prevented.
computed tomography after a Lipomul challenge. Pediatricians have reported BD as a cause of chronic abdominal pain in children since the mid-1990s and several authors have reported the benefit of cholecystectomy in relieving symptoms in BD. As a result BD has become the commonest indication of cholecystectomy in the United States. Laparoscopic cholecystectomy has been shown to completely resolve symptoms in nearly 80% to 90% of adult patients with biliary dyskinesia but the results in children are not so encouraging. Haricharan et al. have shown complete relief or marked improvement of symptoms after short term follow up following laparoscopic cholecystectomy in 87% of 23 children with BD but on long term follow-up (median 2.7 years) this figure decreased to 67%. Similarly Vegunta et al. in a study of 62 children with BD have shown a good response (85%) to LC in the short term, but more than half of the patients have residual or recurrent symptoms at long term follow up. In another study, Nelson et al. have followed up two groups of children with BD for two years. One group (n ¼ 35) after LC and the other group (n ¼ 20) without cholecystectomy. At the end of two years, improvement of symptoms was similar in both groups (74% in the cholecystectomy group and 75% in the non-operative group). Hence, the utility of laparoscopic cholecystectomy for the treatment of biliary dyskinesia is controversial at best.
Choledocholithiasis Most often common bile duct (CBD) stones are associated with gallstones except in hemolytic conditions where these may be primary stones. Overall CBD stones are uncommon in children (only 10% of all gallstones), but infants have a higher incidence. Clinical presentation of CBD stones comprises jaundice, cholangitis, and gallstone pancreatitis. A CBD stone should also be suspected in a patient with gallstones with hyperbilirubinemia (total bilirubin >1.3 mg/dL) and/or a dilated CBD on US (>6 mm). The most appropriate method of investigation and management of CBD stones seems to be laparoscopic cholecystectomy (LC) with intraoperative cholangiogram (IOC) followed by ERCP. In a study of 48 cases of suspected CBD stones, Mah et al. have compared preoperative ERCP followed by LC with LC þ IOC followed by ERCP. The diagnostic yield of ERCP in detecting CBD stone was just 23% with the former approach compared with 100% with the latter approach.
Biliary dyskinesia Acute acalculous cholecystitis in children
Biliary dyskinesia (BD) is characterized by symptomatic biliary colic without evidence of cholelithiasis. The usual age of presentation is in the second decade and it is twice as common in females as in males. Common presenting symptoms are right upper quadrant or epigastric pain, nausea, vomiting, fatty-food intolerance, constipation and weight loss. The diagnosis is suggested if there is a gallbladder ejection fraction of <35% as assessed either by cholecystokinin stimulated hepatobiliary scintigraphy (CCKs-HBS), ultrasonography after a fatty meal or
PAEDIATRICS AND CHILD HEALTH 20:1
Acute severe distension and inflammation of the gallbladder without gallstones or any other biliary tract disease is called acute acalculous cholecystitis. It is a rare disease in children and most cases of acute acalculous cholecystitis reported in children are associated with systemic infection such as typhoid fever, scarlet fever, measles, or AIDS. This condition has also been associated with systemic vasculitis such as Kawasaki’s disease and periarteritis nodosa. Shock, sepsis, total parenteral nutrition,
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prolonged fasting, intravenous narcotics and multiple transfusions have also been implicated in gallbladder ischemia and biliary stasis, two probable pathogenic mechanisms for acute acalculous cholecystitis. Clinical features include fever, vomiting, abdominal pain, localized tenderness and palpable gallbladder. Laboratory tests reveal leukocytosis, raised acute phase reactants, hyperbiliruminemia and mild hyperamylasemia. An enlarged, thickwalled, distended gallbladder without calculi is found on ultrasonography. Many patients improve with conservative management in the form of antibiotics, intravenous fluids and bowel rest. However, cholecystectomy or cholecystostomy is indicated if there is progressive clinical deterioration, persistent tender mass and/or increasing gallbladder distension on ultrasound.
bleeding. Liver histology shows biliary features but is not diagnostic of PSC. The characteristic ‘‘onion skin’’ fibrosis around bile ducts is uncommonly seen. The gold standard for diagnosis of PSC is ERCP, however, though MRCP has an increasing role. The prognosis of PSC in children is guarded. The clinical course is variable but usually progressive. The treatment of PSC is unsatisfactory. There is no definite role for immunosuppressive therapy except in those cases where a component of autoimmune hepatitis is present. Ursodeoxycholic acid (UDCA) therapy in a limited number of children has shown some improvement in clinical and biochemical abnormalities. Some patients may benefit from percutaneous or endoscopic balloon dilatation of a focal stricture but surgery should be avoided. Eventually a significant proportion of cases will need liver transplantation due to end stage liver disease but recurrence of PSC in the transplanted liver has been reported.
Sclerosing cholangitis
Benign biliary stricture
Sclerosing cholangitis is a rare progressive disease of the biliary tract characterized by inflammation and fibrosis of intra and extra hepatic bile ducts, eventually leading to biliary cirrhosis. There are four different types of sclerosing cholangitis; 1. Neonatal sclerosing cholangitis. 2. Autoimmune sclerosing cholangitis. 3. Sclerosing cholangitis associated with systemic diseases such as Langerhans cell histiocytosis, immunodeficiencies, cystic fibrosis, psoriasis and sickle-cell anemia. 4. Primary sclerosing cholangitis (PSC).
Strictures in the extrahepatic bile ducts in children are rare. They are usually associated with cholelithiasis, choledocholithiasis, operative or non-operative trauma, PSC, chronic pancreatitis etc. However, a localized, benign, inflammatory, nontraumatic stricture of extrahepatic bile duct in children is a rare cause of obstructive jaundice. There are only a few published case series of this condition in the literature. Bowles et al. reported a series of seven cases, all of whom presented with obstructive jaundice beyond infancy (age ranged from 15 months to 15 years). Cholangiogram (percutaneous or endoscopic) showed a localized stricture in the extrahepatic bile ducts (mainly common hepatic ducts and upper common bile ducts). They had characteristic histological features of ulceration of biliary epithelium, mural fibrosis and chronic inflammation. The outcome of these cases after biliary reconstruction was reported to be good. A
Neonatal sclerosing cholangitis Neonatal sclerosing cholangitis presents in the first two weeks of life with jaundice which resolves between 4-6 months and one year of age. Despite that, these children eventually develop cirrhosis diagnosed between 1 to 10 years of age. A history of parenteral consanguinity has been reported in 40% of cases. Liver histology is indistinguishable from biliary atresia but cholangiography demonstrates patency of the bile ducts, with characteristic changes of sclerosing cholangitis. These children may be treated with UDCA with variable results. However, eventually they require liver transplantation for end-stage liver disease.
FURTHER READING Bruch SW, Ein SH, Rocchi C, Kim PCW. The management of nonpigmented gallstones in children. J Pediatr Surg 2000; 35: 729e32. Bowles MJ, Salisbury JR, Howard ER. Localized, benign, nontraumatic strictures of the extrahepatic biliary tree in children. Surgery 2001; 130: 55e9. Debray D, Pariente D, Urvoas E, Hadchouel M, Bernard O. Sclerosing cholangitis in children. J Pediatr 1994; 124: 49e56. Debray D, Pariente D, Gauthier F, Myara A, Bernard O. Cholelithiasis in infancy: A study of 40 cases. J Pediatr 1993; 122: 385e91. Gamba PG, Zancan L, Muraca M, Vilei MT, Talenti E, Guglielmi M. Is there a place of medical treatment in children with gallstones? J Pediatr Surg 1997; 32: 476e8. Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001; 33: 544e53. Haricharan RN, Proklova LV, Aprahamian CJ, et al. Laparoscopic cholecystectomy for biliary dyskinesia in children provides durable symptom relief. J Pediatr Surg 2008; 43: 1060e4. Matos C, Avni EF, Van Gansbeke D, Pardou A, Struyven J. Total parenteral nutrition (TPN) and gallbladder diseases in neonates, sonographic assessment. J Ultrasound Med 1987; 6: 243e8. Mah D, Wales P, Njere I, Kortan P, Masiakos P, Kim CW. Management of suspected common bile duct stones in children: role of selective
Autoimmune sclerosing cholangitis There is some debate regarding this condition. King’s College Hospital, London, reported a significant proportion (50%) of their autoimmune hepatitis patients who had characteristic features of sclerosing cholangitis on cholangiography. They labelled this group ‘‘autoimmune sclerosing cholangitis’’. Interestingly these children responded satisfactorily to the same immunosuppressive treatment as that used for autoimmune hepatitis. This condition has been infrequently identified in other series of sclerosing cholangitis in children. Primary sclerosing cholangitis Almost one third of all cases of sclerosing cholangitis in children are due to PSC. PSC is commonly associated with IBD, mainly ulcerative colitis. In the majority, liver disease is suspected by the incidental finding of hepato-and/or splenomegaly during consultation for non-specific symptoms. Increased GGT and alkaline phosphatase is almost universal. Over time, patients develop symptoms of progressive liver disease in the form of pruritus, jaundice, portal hypertension with ascites and variceal
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SYMPOSIUM: HEPATOLOGY
intraoperative cholangiogram and endoscopic retrograde cholangiopancreatogarphy. J Pediatr Surg 2004; 39: 808e12. Millar AJW. Surgical disorders of the liver and bile ducts and portal hypertension. In: Kelly D, ed. Disease of the liver and biliary system in children. 3rd ed. UK: Wiley-Blackwell Publication; 2008. p. 433e74. Nelson RS, Kolts R, Park R, Heikenen J. A comparison of cholecystectomy and observation in children with biliary dyskinesia. J Pediatr Surg 2006; 41: 1894e8. Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet J Rare Dis 2007; 2: 29. doi:10.1186/1750-1172-2-29. PMid:17562004. St-Vil D, Yazbeck S, Luks FI, Hancock BJ, Filiatrault D, Youssef S. Cholelithiasis in newborns and infants. J Pediatr Surg 1992; 27: 1305e7. Webb DK, Darby JS, Dunn DT, Terry SI, Serjeant GR. Gallstones in Jamaican children with homozygous sickle-cell disease. Arch Dis Child 1989; 64: 693e6.
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Wesdorp I, Bosman D, de Graaff A, Aronson D, van der Blij F, Taminiau J. Clinical presentations and predisposing factors of cholelithiasis and sludge in children. J Pediatr Gastroenterol Nutr 2000; 31: 411e7.
Practice points C
C C
C
12
Gallstone disease is uncommon in children but more cases are being diagnosed due to increasing use of ultrasonography Gallstones in infants most often resolve spontaneously Gallstones in a setting of hemolytic disease develop after 5 years of age and require prophylactic cholecystectomy Asymptomatic gallstones or gallstones with atypical symptoms may be observed as the natural history is benign
Ó 2009 Elsevier Ltd. All rights reserved.
Acquired biliary diseases in children
exact prevalence of gallstones in children is not known. European studies in pediatric patients estimated an overall prevalence of 0.13% to 0.2% for gallstone disease in children up to 19 years of age. In Japan, the prevalence of gallstone disease is reported to be less than 0.13% of children. In a recent study, however, the prevalence of gallstones among obese children and adolescents was shown to be quite high (2% of 493 children). Studies on cholelithiasis in children have shown a bimodal distribution, with a small peak in infancy and a steady rising incidence from early adolescence onward. Boys and girls are similarly affected in early childhood, but as in adults, a clear female preponderance emerges during adolescence. A unique subset is those with chronic hemolytic disease. Interestingly in this condition cholelithiasis is not seen commonly before the age of 5 and thereafter the incidence increases progressively with age. In sickle-cell disease the prevalence of pigment gallstones is 10% to 15% in children under 10 years of age and it increases to 40% in those aged 10e18 years. In hereditary spherocytosis the prevalence of gallstones is 10% to 20% and in thalassemia the figure is 10% to 15%.
Ujjal Poddar Winita Hardikar
Abstract Acquired biliary diseases are far less common in children than in adults and include gallstones, acalculous cholecystitis, biliary dyskinesia, primary sclerosing cholangitis (PSC) and benign biliary strictures. Gallstones have been increasingly diagnosed in children in recent years mainly due to increasing use of ultrasonography. The etiologies of cholelithiasis are hemolytic (20%e50%), other known etiology (30%e40%) such as total parenteral nutrition, ileal disease, congenital biliary diseases and idiopathic (20%). Spontaneous resolution of gallstones is frequent in infants and hence a period of observation is recommended even for choledocholithiasis. Children with gallstones can present with typical biliary symptoms (50%), nonspecific symptoms (25%), be asymptomatic (20%) or complicated (5%e10%). Cholecystectomy is useful in children with typical biliary symptoms but is not recommended in those with nonspecific symptoms. Prophylactic cholecystectomy is recommended in children with hemolytic disorders. Biliary dyskinesia is characterized by biliary colic without the presence of gallstones. Management is controversial. In PSC immunosuppressive therapy helps children with PSC with autoimmune hepatitis features.
Pathogenesis Gallstones are either cholesterol gallstones (pure and mixed) or pigment stones (black or brown). Cholesterol supersaturation of bile with stasis predisposes to cholesterol gallstone formation. Mixed cholesterol gallstones are the commonest stones in adults and in adolescent girls. However, pigment stones are more common in children. Black pigment stones are formed due to supersaturation of bile with calcium bilirubinate and are seen in hemolytic disorders and in association with total parenteral nutrition. Brown pigment stones are associated with infection and biliary stasis and form more often in the bile ducts than in the gallbladder. Biliary sludge is composed of mucin, calcium bilirubinate and cholesterol crystals. It is commonly associated with prolonged fasting, total parenteral nutrition, pregnancy, sickle-cell disease, treatment with ceftriaxone or octreotide. The natural history of biliary sludge is variable; it may disappear spontaneously or may progress to gallstone development. Persistent sludge may give rise to biliary complications (such as obstruction or infection). Etiologically cholelithiasis (Table 1) in children can be divided into three groups; hemolytic, other known etiology and idiopathic. Almost 20% to 50% of all gallstones in children are due to hemolytic diseases such as sickle-cell disease, hereditary spherocytosis and thalassaemia. In around 30% to 40% of cases, gallstones are due to another known etiology such as total parenteral nutrition, prolonged fasting, ileal disease or ileal resection, frusemide therapy, congenital biliary diseases such as choledochal cyst, chronic liver disease and progressive familial intrahepatic cholestasis (PFIC). Around 20% of cases are idiopathic. As in adults, gallstones in adolescent girls are more often idiopathic.
Keywords acalculous cholecystitis; biliary dyskinesia; cholelithiasis; LPAC; sclerosing cholangitis
Overall biliary diseases are far less common in children than in adults and those that do occur are usually congenital such as biliary atresia and Alagille Syndrome. Among the acquired biliary diseases, gallstones, acalculous cholecystitis, biliary dyskinesia, primary sclerosing cholangitis and benign biliary strictures will be discussed.
Cholelithiasis (Gallstone disease) in children Epidemiology Little is known about the epidemiology of cholelithiasis in children. Cholelithiasis and choledocholithiasis were considered to be uncommon in infants and children but have been increasingly diagnosed in recent years. This phenomenon may be attributed to better medical imaging (especially ultrasonography) and its usage in investigating children with unexplained abdominal pain and/or a genuine increase in the incidence of cholelithiasis. The
Ujjal Poddar MD DM Gastroenterology Fellow Department of Paediatric Gastroenterology & Nutrition, Royal Children Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
Total parenteral nutrition and cholelithiasis Total parenteral nutrition (TPN) impairs enterohepatic circulation and cholecystokinin induced gallbladder contraction resulting in biliary stasis, sludge and stones. The longer the duration of TPN therapy, the higher the risk of developing cholelithiasis. The risk of developing gallstones in children on prolonged TPN therapy is increased if there is concomitant ileal resection or disease. In
Winita Hardikar MBBS PhD FRACP is Head of Hepatology, Department of Paediatric Gastroenterology & Nutrition, Royal Children Hospital, Flemington Road, Parkville, Victoria 3052, Australia.
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SYMPOSIUM: HEPATOLOGY
Etiology of gallstones in children Type of gallstones
Proportion of all gallstones in children
Etiology
1. 2.
Hemolytic Non-hemolytic
20% 40% to 50%
3.
Idiopathic
30e40%
Sickle-cell disease, hereditary spherocytosis, thalassemia major TPN, prolonged fasting, ileal disease (like Crohn’s disease) or resection, prematurity, frusemide therapy, cardiopulmonary bypass, congenital biliary malformations, PFIC, chronic liver disease, cystic fibrosis, OCP, teenage pregnancy No predisposing factor
TPN: total parenteral nutrition, PFIC: progressive familial intrahepatic cholestasis, OCP: oral contraceptive pills.
Table 1
a study of 21 children on prolonged TPN (more than 3 months) Roslyn et al. have shown that 43% of children developed gallstones but this figure was 64% in children with ileal resection or disease. Sludge develops more rapidly in neonates than in adults after a mean time of TPN infusion in neonates of 10 days, as compared with more than 6 weeks in adults. In a prospective study of 41 neonates, Matos et al. have shown that gallbladder sludge appeared in 18 (44%) of those infants who had received TPN infusion for a mean period of 10 days. In 12 infants, the sludge cleared within one week of resuming enteral feeding but two of the remaining infants went on to develop asymptomatic gallstones. Spontaneous resolution occurred in one of these two infants by 6 months while the calculi persisted in the other baby.
phosphatidylcholine, bile becomes supersaturated with cholesterol and predisposes to gallstone formation. This condition is more frequent in females than in males (3:1). Apart from a family history of cholesterol gallstones amongst first degree relatives, intrahepatic hyperechoic foci (cholesterol crystal deposits in intrahepatic bile ducts) are a characteristic sign of the LPAC syndrome. The typical biliary symptoms experienced by these patients are probably due to cholesterol crystal deposits and bile duct inflammation as symptoms recur in more than half of the cases after cholecystectomy. Ursodeoxycholic acid (UDCA) appears to relieve biliary symptoms long before the dissolution of intrahepatic stones. Clinical presentation According to the age of presentation, children can be divided into three groups; infants (0 to 2 years), children (2 to 14 years) and adolescents (14 to 18 years) (Table 2).
Low phospholipid associated cholelithiasis (LPAC) Gallstones in the adolescent age group with a strong family history of gallstones under the age of 40 years, intrahepatic cholestasis of pregnancy or a cholestatic reaction to oral contraception should raise the suspicion of a rare condition called low phospholipid associated cholelithiasis (LPAC). The underlying cause is a mutation in MDR3, a gene which encodes the ABCB4 transporter. This protein is responsible for the translocation of phosphatidylcholine across the canalicular membrane of hepatocytes which then solubilises cholesterol in bile. In the absence of
Cholelithiasis in infancy Cholelithiasis is uncommon in infants but more and more cases are reported in recent years mainly due to increasing use of ultrasonography (US). Gallstones have even been detected in the fetus. Gallstones in infancy are usually asymptomatic but occasionally can present with cholestatic jaundice, transient acholic stools, sepsis and abdominal pain.
Clinical presentations of gallstones in children Age group
Proportion of all gallstones in children
Clinical presentations
1.
Infants
10%
2.
Children
40%
3.
Adolescents
50%
1. Symptomatic: Cholestatic jaundice, transient acholic stools, abdominal pain, and sepsis 2. Asymptomatic: incidental detection. 1. Typical biliary symptoms (40%e50%): right upper quadrant or epigastric pain with or without nausea, vomiting and fat intolerance 2. Non-specific abdominal pain (20%e30%) 3. Acute abdomen (5%e10%): due to acute cholecystitis, pancreatitis or cholangitis 4. Asymptomatic (20%) Same as in children but right upper quadrant pain and fatty food intolerance are more common in adolescents than in children
Table 2
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In symptomatic infants, gallstones are more often associated with stones in the common bile duct (CBD) than stones in the gallbladder alone. In a series of 13 cases of cholelithiasis in infants, St-Vil et al. have reported that 11 were asymptomatic and detected by US done for unrelated problems. In another series of 40 cases of cholelithiasis in infancy, Debray et al. have shown that 6 had isolated gallstones and were asymptomatic whereas 34 had bile duct obstruction and all were symptomatic.
Bruch SW et al. followed 41 children with non-specific or no symptoms for 21 months. Of these, 50% remained or became asymptomatic, 32% experienced definite improvement in symptoms, 18% had continued symptoms but none had any biliary complications. Wesdorp et al. have substantiated this observation in their study of 82 children with cholelithiasis who were followed up for a mean period of 4.6 years. The suggested treatment algorithm for gallstones in children is given in Figure 1. Children with gallstones should be divided into two groups. Those with typical symptoms (right upper quadrant or epigastric pain, nausea, vomiting and fatty food intolerance) should have their gallbladders removed. Asymptomatic children or children with nonspecific symptoms can undergo safe follow up. These children will require observation into adulthood to determine their lifetime risk of developing symptoms. In recent years, laparoscopic cholecystectomy has become the treatment of choice in the surgical management of children with cholelithiasis. It has the advantage of being less invasive with lower morbidity and mortality and shorter hospital stay over conventional open cholecystectomy. The role of dissolution therapy in the management of gallstones in children remains to be defined. The only study of UDCA therapy for gallstones in children by Gamba et al. has shown disappointing results. Of 15 children with radiolucent stones (<10 mm) and a functional gallbladder treated for one year, stones disappeared completely in only two cases but returned later in both. Extracorporeal shock-wave lithotripsy for gallstones in children has been successful in a single case report.
Cholelithiasis in children Children with gallstones can present with acute abdominal pain due to cholecystitis, cholangitis or pancreatitis. However, an acute presentation is uncommon (5% to 10% of cases only). Most commonly, children with cholelithiasis present with typical right upper quadrant pain (50%) or non-specific abdominal symptoms (25%) including poorly localized abdominal pain and nausea. Around 20% of cases are asymptomatic (incidentally detected stones). Gallstones in children are more often (60%) symptomatic than in adults (20%). The type of symptoms depend on the age of presentation, older children (6 years or more) often localize pain in the right upper quadrant whereas younger children (5 years or less) tend to present with nonspecific symptoms. Fatty food intolerance, a typical symptoms of gallstone disease in adults, tends to be reported by older children. Cholelithiasis in adolescents In this age group, the symptoms are similar to those generally found in adults. Patients are more often girls who are overweight and have a positive family history. Fatty food intolerance, biliary colic and acute or chronic cholecystitis are usual presenting features of symptomatic patients.
The approach to cholelithiasis in infancy is different as spontaneous resolution has been reported in a significant proportion of cases (cholelithiasis almost 50% and choledocholithiasis 30%). Spontaneous resolution within 6 months is more common with idiopathic gallstones than in patients with known predisposing factors. Based on limited information, it can be recommended that asymptomatic infants with idiopathic cholelithiasis be observed for spontaneous resolution. Even for choledocholithiasis an observation period of one to two weeks is recommended before active therapy as there is a chance of spontaneous resolution. Cholecystectomy is indicated for symptomatic cholelithiasis, asymptomatic cholelithiasis persisting beyond 12 months and radiopaque calculi.
Diagnosis The most universally used and the most accurate diagnostic aid in detecting the presence of gallstones is ultrasonography. Gallstones are usually mobile, single or multiple and characteristically cast an acoustic shadow. Biliary sludge though appearing echogenic on ultrasound, does not cast an acoustic shadow. A stone, as small as 1.5 mm, can be detected by ultrasonography. The sensitivity and specificity of ultrasonography exceeds 95% for gallbladder cholelithiasis, but this figure is only 50%e75% for choledocholithiasis. In children 20% to 50% gallstones are radiopaque. Cholescintigraphy, with technetium 99 m labeled diisopropyl iminodiacetic acid (DISIDA), is the most accurate method of diagnosing acute cholecystitis. Nonvisulization of the gallbladder in an otherwise patent biliary system suggests acute cholecystitis. Magnetic resonance cholangiopancreatography (MRCP) is being used increasingly to investigate complicated gallstone disease. Endoscopic retrograde cholangiopancreatography (ERCP) offers the additional advantage of therapeutic intervention in common bile duct stones.
Management of cholelithiasis in hemolytic disease: In this group of children, screening with US is recommended at around 5 years of age. Screening is also recommended before splenectomy as both splenectomy and cholecystectomy can be combined in presence of gallstones and it confers a survival benefit over splenectomy alone in hereditary spherocytosis. However, there is no advantage of doing cholecystectomy during splenectomy if there are no gallstones as these patients are not at an increased risk of cholelithiasis after splenectomy. In sickle-cell disease, prophylactic cholecystectomy is recommended even for asymptomatic gallstones as it is difficult to differentiate an acute abdominal crisis from acute cholecystitis, and the morbidity and mortality of emergency cholecystectomy in this setting is much higher than in elective cholecystectomy. To avoid sickling during the perioperative period it is recommended that hemoglobin S be
Management Management of gallstones depends on the symptoms and age of the patient. Symptomatic gallstones need cholecystectomy and same is true for complicated gallstones but there is no consensus about the management of asymptomatic gallstones in children. In a prospective study of children with non-pigmented gallstones,
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Management algorithm for gallstones in children Gallstones in infants
Gallstones in children
Symptomatic
Asymptomatic
Observe for 1–2 weeks
Non-calcified
Stone passed spontaneously
No improvement
No treatment
Symptomatic
Asymptomatic
Gallstones in haemolytic disease
Symptomatic
Asymptomatic
Calcified
Observe for 12 months
± splenectomy
Observation
Persistence beyond 12 months
Cholecystectomy
Figure 1
decreased to at least 30% and total hemoglobin be increased to at least 11 g/dL. During the operation and recovery period, hypotension, dehydration, hypoxia, hypothermia and acidosis should be prevented.
computed tomography after a Lipomul challenge. Pediatricians have reported BD as a cause of chronic abdominal pain in children since the mid-1990s and several authors have reported the benefit of cholecystectomy in relieving symptoms in BD. As a result BD has become the commonest indication of cholecystectomy in the United States. Laparoscopic cholecystectomy has been shown to completely resolve symptoms in nearly 80% to 90% of adult patients with biliary dyskinesia but the results in children are not so encouraging. Haricharan et al. have shown complete relief or marked improvement of symptoms after short term follow up following laparoscopic cholecystectomy in 87% of 23 children with BD but on long term follow-up (median 2.7 years) this figure decreased to 67%. Similarly Vegunta et al. in a study of 62 children with BD have shown a good response (85%) to LC in the short term, but more than half of the patients have residual or recurrent symptoms at long term follow up. In another study, Nelson et al. have followed up two groups of children with BD for two years. One group (n ¼ 35) after LC and the other group (n ¼ 20) without cholecystectomy. At the end of two years, improvement of symptoms was similar in both groups (74% in the cholecystectomy group and 75% in the non-operative group). Hence, the utility of laparoscopic cholecystectomy for the treatment of biliary dyskinesia is controversial at best.
Choledocholithiasis Most often common bile duct (CBD) stones are associated with gallstones except in hemolytic conditions where these may be primary stones. Overall CBD stones are uncommon in children (only 10% of all gallstones), but infants have a higher incidence. Clinical presentation of CBD stones comprises jaundice, cholangitis, and gallstone pancreatitis. A CBD stone should also be suspected in a patient with gallstones with hyperbilirubinemia (total bilirubin >1.3 mg/dL) and/or a dilated CBD on US (>6 mm). The most appropriate method of investigation and management of CBD stones seems to be laparoscopic cholecystectomy (LC) with intraoperative cholangiogram (IOC) followed by ERCP. In a study of 48 cases of suspected CBD stones, Mah et al. have compared preoperative ERCP followed by LC with LC þ IOC followed by ERCP. The diagnostic yield of ERCP in detecting CBD stone was just 23% with the former approach compared with 100% with the latter approach.
Biliary dyskinesia Acute acalculous cholecystitis in children
Biliary dyskinesia (BD) is characterized by symptomatic biliary colic without evidence of cholelithiasis. The usual age of presentation is in the second decade and it is twice as common in females as in males. Common presenting symptoms are right upper quadrant or epigastric pain, nausea, vomiting, fatty-food intolerance, constipation and weight loss. The diagnosis is suggested if there is a gallbladder ejection fraction of <35% as assessed either by cholecystokinin stimulated hepatobiliary scintigraphy (CCKs-HBS), ultrasonography after a fatty meal or
PAEDIATRICS AND CHILD HEALTH 20:1
Acute severe distension and inflammation of the gallbladder without gallstones or any other biliary tract disease is called acute acalculous cholecystitis. It is a rare disease in children and most cases of acute acalculous cholecystitis reported in children are associated with systemic infection such as typhoid fever, scarlet fever, measles, or AIDS. This condition has also been associated with systemic vasculitis such as Kawasaki’s disease and periarteritis nodosa. Shock, sepsis, total parenteral nutrition,
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prolonged fasting, intravenous narcotics and multiple transfusions have also been implicated in gallbladder ischemia and biliary stasis, two probable pathogenic mechanisms for acute acalculous cholecystitis. Clinical features include fever, vomiting, abdominal pain, localized tenderness and palpable gallbladder. Laboratory tests reveal leukocytosis, raised acute phase reactants, hyperbiliruminemia and mild hyperamylasemia. An enlarged, thickwalled, distended gallbladder without calculi is found on ultrasonography. Many patients improve with conservative management in the form of antibiotics, intravenous fluids and bowel rest. However, cholecystectomy or cholecystostomy is indicated if there is progressive clinical deterioration, persistent tender mass and/or increasing gallbladder distension on ultrasound.
bleeding. Liver histology shows biliary features but is not diagnostic of PSC. The characteristic ‘‘onion skin’’ fibrosis around bile ducts is uncommonly seen. The gold standard for diagnosis of PSC is ERCP, however, though MRCP has an increasing role. The prognosis of PSC in children is guarded. The clinical course is variable but usually progressive. The treatment of PSC is unsatisfactory. There is no definite role for immunosuppressive therapy except in those cases where a component of autoimmune hepatitis is present. Ursodeoxycholic acid (UDCA) therapy in a limited number of children has shown some improvement in clinical and biochemical abnormalities. Some patients may benefit from percutaneous or endoscopic balloon dilatation of a focal stricture but surgery should be avoided. Eventually a significant proportion of cases will need liver transplantation due to end stage liver disease but recurrence of PSC in the transplanted liver has been reported.
Sclerosing cholangitis
Benign biliary stricture
Sclerosing cholangitis is a rare progressive disease of the biliary tract characterized by inflammation and fibrosis of intra and extra hepatic bile ducts, eventually leading to biliary cirrhosis. There are four different types of sclerosing cholangitis; 1. Neonatal sclerosing cholangitis. 2. Autoimmune sclerosing cholangitis. 3. Sclerosing cholangitis associated with systemic diseases such as Langerhans cell histiocytosis, immunodeficiencies, cystic fibrosis, psoriasis and sickle-cell anemia. 4. Primary sclerosing cholangitis (PSC).
Strictures in the extrahepatic bile ducts in children are rare. They are usually associated with cholelithiasis, choledocholithiasis, operative or non-operative trauma, PSC, chronic pancreatitis etc. However, a localized, benign, inflammatory, nontraumatic stricture of extrahepatic bile duct in children is a rare cause of obstructive jaundice. There are only a few published case series of this condition in the literature. Bowles et al. reported a series of seven cases, all of whom presented with obstructive jaundice beyond infancy (age ranged from 15 months to 15 years). Cholangiogram (percutaneous or endoscopic) showed a localized stricture in the extrahepatic bile ducts (mainly common hepatic ducts and upper common bile ducts). They had characteristic histological features of ulceration of biliary epithelium, mural fibrosis and chronic inflammation. The outcome of these cases after biliary reconstruction was reported to be good. A
Neonatal sclerosing cholangitis Neonatal sclerosing cholangitis presents in the first two weeks of life with jaundice which resolves between 4-6 months and one year of age. Despite that, these children eventually develop cirrhosis diagnosed between 1 to 10 years of age. A history of parenteral consanguinity has been reported in 40% of cases. Liver histology is indistinguishable from biliary atresia but cholangiography demonstrates patency of the bile ducts, with characteristic changes of sclerosing cholangitis. These children may be treated with UDCA with variable results. However, eventually they require liver transplantation for end-stage liver disease.
FURTHER READING Bruch SW, Ein SH, Rocchi C, Kim PCW. The management of nonpigmented gallstones in children. J Pediatr Surg 2000; 35: 729e32. Bowles MJ, Salisbury JR, Howard ER. Localized, benign, nontraumatic strictures of the extrahepatic biliary tree in children. Surgery 2001; 130: 55e9. Debray D, Pariente D, Urvoas E, Hadchouel M, Bernard O. Sclerosing cholangitis in children. J Pediatr 1994; 124: 49e56. Debray D, Pariente D, Gauthier F, Myara A, Bernard O. Cholelithiasis in infancy: A study of 40 cases. J Pediatr 1993; 122: 385e91. Gamba PG, Zancan L, Muraca M, Vilei MT, Talenti E, Guglielmi M. Is there a place of medical treatment in children with gallstones? J Pediatr Surg 1997; 32: 476e8. Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001; 33: 544e53. Haricharan RN, Proklova LV, Aprahamian CJ, et al. Laparoscopic cholecystectomy for biliary dyskinesia in children provides durable symptom relief. J Pediatr Surg 2008; 43: 1060e4. Matos C, Avni EF, Van Gansbeke D, Pardou A, Struyven J. Total parenteral nutrition (TPN) and gallbladder diseases in neonates, sonographic assessment. J Ultrasound Med 1987; 6: 243e8. Mah D, Wales P, Njere I, Kortan P, Masiakos P, Kim CW. Management of suspected common bile duct stones in children: role of selective
Autoimmune sclerosing cholangitis There is some debate regarding this condition. King’s College Hospital, London, reported a significant proportion (50%) of their autoimmune hepatitis patients who had characteristic features of sclerosing cholangitis on cholangiography. They labelled this group ‘‘autoimmune sclerosing cholangitis’’. Interestingly these children responded satisfactorily to the same immunosuppressive treatment as that used for autoimmune hepatitis. This condition has been infrequently identified in other series of sclerosing cholangitis in children. Primary sclerosing cholangitis Almost one third of all cases of sclerosing cholangitis in children are due to PSC. PSC is commonly associated with IBD, mainly ulcerative colitis. In the majority, liver disease is suspected by the incidental finding of hepato-and/or splenomegaly during consultation for non-specific symptoms. Increased GGT and alkaline phosphatase is almost universal. Over time, patients develop symptoms of progressive liver disease in the form of pruritus, jaundice, portal hypertension with ascites and variceal
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intraoperative cholangiogram and endoscopic retrograde cholangiopancreatogarphy. J Pediatr Surg 2004; 39: 808e12. Millar AJW. Surgical disorders of the liver and bile ducts and portal hypertension. In: Kelly D, ed. Disease of the liver and biliary system in children. 3rd ed. UK: Wiley-Blackwell Publication; 2008. p. 433e74. Nelson RS, Kolts R, Park R, Heikenen J. A comparison of cholecystectomy and observation in children with biliary dyskinesia. J Pediatr Surg 2006; 41: 1894e8. Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet J Rare Dis 2007; 2: 29. doi:10.1186/1750-1172-2-29. PMid:17562004. St-Vil D, Yazbeck S, Luks FI, Hancock BJ, Filiatrault D, Youssef S. Cholelithiasis in newborns and infants. J Pediatr Surg 1992; 27: 1305e7. Webb DK, Darby JS, Dunn DT, Terry SI, Serjeant GR. Gallstones in Jamaican children with homozygous sickle-cell disease. Arch Dis Child 1989; 64: 693e6.
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Wesdorp I, Bosman D, de Graaff A, Aronson D, van der Blij F, Taminiau J. Clinical presentations and predisposing factors of cholelithiasis and sludge in children. J Pediatr Gastroenterol Nutr 2000; 31: 411e7.
Practice points C
C C
C
12
Gallstone disease is uncommon in children but more cases are being diagnosed due to increasing use of ultrasonography Gallstones in infants most often resolve spontaneously Gallstones in a setting of hemolytic disease develop after 5 years of age and require prophylactic cholecystectomy Asymptomatic gallstones or gallstones with atypical symptoms may be observed as the natural history is benign
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