Cystic Diseases of the Biliary Tract and Liver

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Chapter 357 Cystic Diseases of the Biliary Tract and Liver

Cystic lesions of liver may be initially recognized during infancy and childhood (see Table 357-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). Hepatic fibrosis can also occur as part of an underlying developmental defect (see Table 357-2 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). Cystic renal disease is usually associated and often determines the clinical presentation and prognosis. Virtually all proteins encoded by genes mutated in combined cystic diseases of the liver and kidney are at least partially localized to primary cilia in renal tubular cells and cholangiocytes.

Table 357-1 RENAL DISORDERS ASSOCIATED WITH FIBROPOLYCYSTIC LIVER DISEASES

FIBROPOLYCYSTIC LIVER DISEASE	ASSOCIATED RENAL DISORDER
Congenital hepatic fibrosis (CHF)	Autosomal-recessive polycystic kidney disease* Autosomal-dominant polycystic kidney disease Cystic renal dysplasia Nephronophthisis None
Caroli’s syndrome (CS)	Autosomal-recessive polycystic kidney disease* Autosomal-dominant polycystic kidney disease None
Caroli’s disease	Autosomal-recessive polycystic kidney disease
Von Meyenburg complexes (isolated)	?
Von Meyenburg complexes with CHF or CS	Autosomal-recessive polycystic kidney disease
Von Meyenburg complexes with polycystic liver disease	Autosomal-dominant polycystic kidney disease
Polycystic liver disease	Autosomal-dominant polycystic kidney disease* ? None

* Most common associated disorders.

From Suchy FJ, Sokol RJ, Balistreri WF, editors: Liver disease in children, ed 3, New York, 2007, Cambridge University Press, p 27.

Table 357-2 SYNDROMES ASSOCIATED WITH CONGENITAL HEPATIC FIBROSIS

SYNDROME	FEATURES
Jeune synrome	Asphyxiating thoracic dystrophy, with cystic renal tubular dysplasia and congenital hepatic fibrosis (15q13)
Joubert’s syndrome	Oculo-encephalo-hepato-renal (AH11, HPHP1)
COACH syndrome	Cerebellar vermis hypoplasia, oligophrenia, congintal ataxia, ocular coloboma, and hepatic fibrosis
Meckel syndrome type 1	Cystic renal dysplasia abnormal bile duct development with fibrosis, posterior encephalocele, and polydactyly (13q13, 17a21, 8q24)
Carbohydrate-deficient glycoprotein syndrome type 1b	Phosphomannose isomerise 1 deficiency (PMI)
Ivemark syndrome type 2	Autosomal-recessive renal-hepatic-pancreatic dysplasia
Miscellaneous syndromes	Intestinal lymphangiectasia, enterocolotis cystic Short rib (Beemer-Langer) syndrome Osteochondrodysplasia

From Suchy FJ, Sokol RJ, Balistreri WF, editors: Liver disease in children, ed 3, New York, 2007, Cambridge University Press, p 931.

Choledochal Cysts

Choledochal cysts are congenital dilatations of the common bile duct that can cause progressive biliary obstruction and biliary cirrhosis. Cylindrical (fusiform) and spherical (saccular) cysts of the extrahepatic ducts are the most common types. Segmental or diffuse dilatation can be observed. A diverticulum of the common bile duct or dilatation of the intraduodenal portion of the common duct (choledochocele) is a variant. Cystic dilatation of the intrahepatic bile ducts may be associated with a choledochal cyst or Caroli disease.

The pathogenesis of choledochal cysts remains uncertain. Some reports have suggested that junction of the common bile duct and the pancreatic duct before their entry into the sphincter of Oddi might allow reflux of pancreatic enzymes into the common bile duct, causing inflammation, localized weakness, and dilatation of the duct. Other possibilities are that choledochal cysts represent malformations of the common duct or that they occur as part of the spectrum of an infectious disease that includes neonatal hepatitis and biliary atresia. Consistent with this theory, reovirus RNA has been detected in liver and biliary tissues of some infants with choledochal cysts.

Approximately 75% of cases appear during childhood. The infant typically presents with cholestatic jaundice; severe liver dysfunction including ascites and coagulopathy can rapidly evolve if biliary obstruction is not relieved. An abdominal mass is rarely palpable. In an older child, the classic triad of abdominal pain, jaundice, and mass occurs in <33% of patients. Features of acute cholangitis (fever, right upper quadrant [RUQ] tenderness, jaundice, leukocytosis) may be present. The diagnosis is made by ultrasonography; choledochal cysts have been identified prenatally using this technique. Magnetic resonance cholangiography is useful in the preoperative assessment of choledochal cyst anatomy.

The treatment of choice is primary excision of the cyst and a Roux-en-Y choledochojejunostomy. Simple drainage into the small bowel is less satisfactory owing to a risk of development of carcinoma in the residual cystic tissue. The postoperative course can be complicated by recurrent cholangitis or stricture at the anastomotic site.

Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) manifests predominantly in childhood (Chapter 515.2). Bilateral enlargement of the kidneys is caused by a generalized dilatation of the collecting tubules. The disorder is invariably associated with congenital hepatic fibrosis and various degrees of biliary ductal ectasia that are discussed in detail later.

The gene for ARPKD encodes a protein that is called fibrocystin, which is localized to cilia on the apical domain of renal collecting cells and cholangiocytes. The primary defect in ARPKD may be ciliary dysfunction related to the abnormality in this protein. In ARPKD, the cysts arise as ectatic expansions of the collecting tubules and bile ducts that remain in continuity with their structures of origin.

ARPKD normally occurs in early life, often shortly after birth, and is generally more severe than ADPKD. Patients with ARPKD can die in the perinatal period owing to renal failure or lung dysgenesis. The kidneys in these patients are usually markedly enlarged and dysfunctional. Respiratory failure can result from compression of the chest by grossly enlarged kidneys, from fluid retention, or from concomitant pulmonary hypoplasia (Chapter 515.2). The clinical pathologic findings within a family tend to breed true, although there has been some variability in the severity of the disease and the time for presentation within the same family. In patients surviving infancy because of a milder renal phenotype, liver disease may be a prominent part of the disorder. The liver disease in ARPKD is related to congenital malformation of the liver with varying degrees of periportal fibrosis, bile ductular hyperplasia, ectasia, and dysgenesis. This can manifest clinically as cystic dilation of the intrahepatic biliary tree with or without congenital hepatic fibrosis (Caroli’s syndrome or Caroli’s disease). CHF and Caroli’s syndrome likely result from an abnormality in remodeling of the embryonic ductal plate of the liver. Ductal plate malformation (DPM) refers to the persistence of excess embryonic bile duct structures in the portal tracts.

Variable abnormalities of bile ducts (irregular dilatation, proliferation, cysts) and portal fibrosis can also be associated with Meckel syndrome, trisomy 17-18, tuberous sclerosis, and asphyxiating thoracic dystrophy (see Table 357-2).

Cystic Dilatation of the Intrahepatic Bile Ducts (Caroli Disease and Syndrome)

Congenital saccular dilatation can affect several segments of the intrahepatic bile ducts; the dilated ducts are lined by cuboidal epithelium and are in continuity with the main duct system, which is usually normal. Caroli actually described 2 variants: Caroli disease, characterized by ectasias of the intrahepatic bile ducts without other abnormalities, and Caroli syndrome, in which congenital ductal dilatation is associated with features of congenital hepatic fibrosis and the renal lesion of autosomal recessive polycystic renal disease. Caroli syndrome is more common, but both varieties can occur in the same family and are inherited in an autosomal recessive fashion. Choledochal cysts have also been associated with Caroli disease. There is a marked predisposition to ascending cholangitis and calculus formation within the abnormal bile ducts.

Affected patients usually experience symptoms of acute cholangitis as children or young adults. Fever, abdominal pain, mild jaundice, and pruritus occur, and a slightly enlarged, tender liver is palpable. Elevated alkaline phosphatase (ALP) activity, direct-reacting bilirubin levels, and leukocytosis may be observed during episodes of acute infection. In patients with Caroli syndrome, clinical features may be due to a combination of recurring bouts of cholangitis reflecting the intrahepatic ductal abnormalities and portal hypertensive bleeding resulting from hepatic fibrosis. Ultrasonography shows the dilated intrahepatic ducts, but definitive diagnosis and extent of disease must be determined by percutaneous transhepatic, endoscopic, or magnetic resonance cholangiography.

Cholangitis and sepsis are treated with appropriate antibiotics. Calculi can require surgery. Partial hepatectomy may be curative in rare cases in which disease is confined to a single lobe. The prognosis is otherwise guarded, largely owing to difficulties in controlling cholangitis and biliary lithiasis and to a significant risk for developing cholangiocarcinoma. Liver transplantation may be required.

Congenital Hepatic Fibrosis

Congenital hepatic fibrosis is usually associated with ARPKD and is characterized pathologically by diffuse periportal and perilobular fibrosis in broad bands that contain distorted bile duct–like structures and that often compress or incorporate central or sublobular veins (see Table 357-2). Irregularly shaped islands of liver parenchyma contain normal-appearing hepatocytes. Caroli disease and choledochal cysts have been associated. Most patients have renal disease, mostly autosomal recessive polycystic renal disease and rarely nephronophthisis. Congenital hepatic fibrosis also occurs as part of the COACH syndrome (cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis). Congenital hepatic fibrosis has been described in children with a congenital disorder of glycosylation caused by mutations in the gene encoding phosphomannose isomerase (Chapter 81.6).

The disorder usually has its clinical onset in childhood, with hepatosplenomegaly or with bleeding secondary to portal hypertension. Cholangitis can occur in patients who have associated abnormalities of bile ducts. Hepatocellular function is well preserved. Serum aminotransferase activities and bilirubin levels are usually normal; serum ALP activity may be slightly elevated. The serum albumin level and prothrombin time are normal. Liver biopsy is usually required for diagnosis.

Treatment of this disorder should focus on control of bleeding from esophageal varices. Infrequent mild bleeding episodes may be managed by endoscopic sclerotherapy or band ligation of the varices. After more-severe hemorrhage, portacaval anastomosis can relieve portal hypertension. The prognosis may be greatly improved by a shunting procedure, but survival in some patients may be limited by renal failure.

Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) (Chapter 515.3), a common inherited disease, affects 1/1,000 live births. It is characterized by progressive renal cyst development and cyst enlargement and an array of extrarenal manifestations. There is a high degree of intrafamilial and interfamilial variability in the clinical expression of the disease.

ADPKD is caused by mutation in 1 of 2 genes, PKD1 or PKD2, which account for 85-90% and 10-15% of cases, respectively. The proteins encoded by these genes, polycystin-1 and polycystin-2, are expressed in renal tubule cells and in cholangiocytes. Polycystin-1 functions as a mechanosensor in cilia, detecting the movement of fluid through tubules and transmitting the signal through polycystin-2, which acts as a calcium channel.

Multiple hepatic lesions have been associated with ADPKD and include the ductal plate malformation with cystic communicating duct elements, dilated and apparently noncommunicating cysts, and biliary microhamartomas (the von Meyenburg complexes). Segmental dilatation of the intrahepatic ducts (Caroli disease) and congenital hepatic fibrosis have been reported rarely. Approximately 50% of patients with renal failure have demonstrable hepatic cysts that are derived from but not in continuity with the biliary tract. The hepatic cysts increase with age but are extremely uncommon before the age of 16 yr. Hepatic cystogenesis appears to be influenced by estrogens. Although the frequency of cysts is similar in boys and girls, the development of large hepatic cysts is mainly a complication in girls. Hepatic cysts are often asymptomatic but can cause pain and are occasionally complicated by hemorrhage, infection, jaundice from bile duct compression, portal hypertension with variceal bleeding, or hepatic venous outflow obstruction from mechanical compression of hepatic veins, resulting in tender hepatomegaly and exudative ascites. Cholangiocarcinoma can occur. Selected patients with severe symptomatic polycystic liver disease and favorable anatomy benefit from liver resection or fenestration.

Subarachnoid hemorrhage can result from the associated cerebral arterial aneurysms.