eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Congenital Hepatic Fibrosis

Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H, Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, University of Jordan
Dena Nazer, MD, Medical Director, Child Protection Center, Children's Hospital of Michigan; Assistant Professor, Wayne State University

Updated: Mar 8, 2010

Introduction

Background

Congenital hepatic fibrosis (CHF) is an autosomal recessive disease that primarily affects the hepatobiliary and renal systems. It is characterized by hepatic fibrosis, portal hypertension, and renal cystic disease. Congenital hepatic fibrosis is one of the fibropolycystic diseases, which also include Caroli disease, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD).

Congenital hepatic fibrosis is associated with an impairment of renal functions, usually caused by an ARPKD, which is a severe form of polycystic kidney disease.^{[1 ]}The hepatic manifestations of CHF were first described in 1856.^{[2 ]}In 1961, the term congenital hepatic fibrosis, with its varied clinical manifestations, was recognized.^{[3 ]}

Because of the variable clinical presentations, congenital hepatic fibrosis is believed to represent a broad spectrum of hepatic and renal lesions rather than a single clinical entity. Symptoms, which may be early or late, are mostly related to portal hypertension.

Pathophysiology

Congenital hepatic fibrosis results from a malformation of the ductal plate (the embryological precursor of the biliary system), secondary biliary strictures, and periportal fibrosis.^{[4 ]}This subsequently results in the development of portal hypertension.

The ductal plate is the cylindric layer of cells that surrounds a branch of the portal vein. It is a precursor of the intrahepatic bile ducts. Ductal plates arise around the smaller portal vein branches at a distance from the hilum. Progressive remodeling starts at 12 weeks' gestation. Both interlobular and intralobular bile ductules develop from the ductal plate. The lack of remodeling of the ductal plate results in persistence of an excess of embryonic duct structures. This abnormality has been termed the ductal plate malformation^{[5 ]}and consists of persistence of the ductal plate with an increase in duct elements and an increase in portal fibrous tissue.

The family of fibropolycystic diseases are characterized by varying degrees of persistent bile duct structures, fibrosis, and duct dilatation. They are all developmental anomalies of the duct plate and occurred at various stages of remodeling. Congenital hepatic fibrosis is a ductal plate malformation of the small interlobular bile ducts, whereas Caroli disease involves the large intrahepatic bile ducts.
 
The classic renal lesion associated with congenital hepatic fibrosis is ARPKD, which results in an impairment of renal functions. Its association with ADPKD is also recognized, especially among adults. The relationship of ARPKD to congenital hepatic fibrosis remains a controversial issue. The 2 conditions may actually be one disorder with different clinicopathological presentations.
 
ARPKD is caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene,^{[6 ]}which consists of 86 exons that are variably assembled into numerous alternatively spliced transcripts.^{[7 ]}Most cases of ARPKD and congenital hepatic fibrosis are genetically homogeneous. However, the exact pathogenesis of association between congenital hepatic fibrosis and ADPKD still requires further research and study.

In all cases of congenital hepatic fibrosis–ARPKD, a hepatic lesion of ductal plate malformation of the interlobular bile ducts is found; the difference in its presentation is primarily age dependent. Gradual disappearance of bile duct profiles associated with increased periportal fibrosis results from a progressive destructive cholangiopathy that involves the immature bile duct structures.
 
The hepatic disease progresses to develop portal hypertension associated with splenomegaly and esophageal varices. Congenital hepatic fibrosis is characterized by the intrahepatic form of portal hypertension, which is caused by the intrahepatic obstruction that affects the blood supply to the liver and subsequently leads to the development of cavernous transformations of the portal vein with a rise in portal venous pressure.

Congenital hepatic fibrosis is also associated with cholangitis. The presence of cholangitis or its repeated occurrence may influence the status of the hepatic lesion and the prognosis of the disease. Commonly, the hepatic lesion is associated with renal involvement characterized by cystic tubular dilatations, which affect both the cortical and medullary portions of the kidney. The longer the patient survives, the less characteristic the renal pathology becomes.

Frequency

International

Congenital hepatic fibrosis is a rare autosomal recessive disease; the exact incidence and prevalence are not known. Only a few hundred patients with congenital hepatic fibrosis have been reported in the literature. The disease appears in both sporadic (in as many as 56% of cases) and familial patterns. Congenital hepatic fibrosis–ARPKD is estimated to occur in 1 in 20,000 live births.^{[8 ]}

Mortality/Morbidity

Most neonates and young infants with predominant renal involvement die of renal failure in early infancy. As many as 25% of patients may succumb to renal failure, according to estimates. Cholangitis significantly contributes to morbidity and mortality rates in congenital hepatic fibrosis. When hepatic lesions dominate the clinical expression of the disease, children who are affected may remain asymptomatic until late childhood or even adulthood. Most patients do well. Coexisting renal lesions may also remain asymptomatic until early adulthood.

Sex

No sex predilection is observed.

Age

Congenital hepatic fibrosis may present in the neonatal period, but delayed presentation in late childhood or even adulthood is reported.

Clinical

History

The onset of congenital hepatic fibrosis (CHF) symptoms varies in spectrum and severity. Patients usually develop nonspecific symptoms, making the initial diagnosis difficult. The age at presentation may range form early childhood to the fifth decade of life. However, most cases however are diagnosed during adolescence and early adulthood.

• Congenital hepatic fibrosis has 4 different forms: portal hypertensive (most common), cholangitic, mixed, and latent. Patients in the portal hypertensive group often present with esophageal variceal hemorrhage. Those with the cholangitic form have characteristic cholestasis and recurrent cholangitis. Patients with the latent form present at an older age or are diagnosed as an incidental finding.
• Most patients initially manifest with symptoms and signs of portal hypertension. These include hematemesis and melena.
• When hepatic lesions dominate the clinical expression of the disease, the affected child may remain asymptomatic for years before evidence of hepatic involvement manifests as a sequela of portal hypertension with repeated episodes of GI bleeding of varying severity.
• Rarely, patients may present with abdominal pain localized to the right upper quadrant.
• The presentation of children with congenital hepatic fibrosis–autosomal recessive polycystic kidney disease (ARPKD) also varies, depending on the severity of kidney and liver disease.

Physical

• Portal hypertension may be the initial manifestation that leads to the identification of autosomal dominant polycystic kidney disease (ADPKD).
• Hepatomegaly is present in nearly all patients with predominant involvement of the left lobe. Upon palpation, the liver is firm, and its surface is smooth or finely nodular. The liver edge is sometimes irregular, suggesting cirrhosis.
• In most patients, splenomegaly is associated with evidence of hypersplenism.
• Nephromegaly is a common finding during a physical examination in patients with congenital hepatic fibrosis and ARPKD.
• Abdominal pain is rare; when present, it is usually localized to the right upper quadrant.

Causes

• Congenital hepatic fibrosis is an autosomal recessive disorder.
• No definite cause or causative agent has been identified.
• Transforming growth factor-1 and thrombospondin-1 may play a role in the pathogenesis of liver fibrosis in patients with congenital hepatic fibrosis.^{[9 ]}
• Abundant connective tissue growth factor retained diffusely in heparan sulfate proteoglycan in the fibrous portal tracts or septa may be responsible for nonresolving hepatic fibrosis in congenital hepatic fibrosis.^{[10 ]}

Differential Diagnoses

Caroli Disease
Polycystic Kidney Disease

Other Problems to Be Considered

Other ductal plate malformations (eg, biliary cysts, Caroli Disease, choledochal cyst)

Workup

Laboratory Studies

The following studies are indicated congenital hepatic fibrosis:

• Liver function tests
  • Liver enzyme levels are usually within the reference range when uncomplicated by portal hypertension or cholangitis.^{[11 ]}
  • Serum alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) levels may be elevated.
  • In the presence of cholangitis, serum bilirubin levels, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, WBCs, and the erythrocyte sedimentation rate (ESR) may be elevated.
• Hypersplenism
  • The presence of leukopenia and thrombocytopenia provides evidence of hypersplenism.
  • Splenic pressure is elevated.
• Renal function
  • Renal dysfunction is present in approximately 20% of patients.
  • In the presence of renal involvement, serum urea and serum creatinine levels are elevated, whereas creatinine clearance is decreased.

Imaging Studies

Characteristic imaging features are generally present and increased recognition of these findings may obviate the need for routine liver biopsy while preserving diagnostic accuracy. Imaging is used in both initial diagnosis and follow-up of patients. However, the hepatobiliary imaging findings of congenital hepatic fibrosis may not be detected until later. The combination of conventional and high-resolution ultrasonography with magnetic resonance cholangiography allows the definition of the extent of liver and renal disease without requiring ionizing radiation and contrast agents.^{[8 ]}

• Ultrasonography
  • This study helps to further support the diagnosis by revealing evidence of a patchy pattern of intense hepatic echogenicity, portal hypertension, splenomegaly, and intrahepatic and extrahepatic biliary cysts and dilatations. It is the first-line modality used in the diagnostic process because of its lack of radiation and its capability of detecting renal and liver abnormalities.
  • Ultrasonographic evaluation should include Doppler flow studies to assess the patency of the portal vasculature.
  • Evidence of nephromegaly and increased echogenicity with polycystic changes add further support to the diagnosis of congenital hepatic fibrosis (CHF)-ARPKD.
  • Ultrasonography of liver and kidneys are also indicated as part of preparation for liver and renal biopsies.
  • Color Doppler ultrasonography assists in evaluating the portal venous system. It shows the direction of portal blood flow and varicose venous collaterals.
• CT scanning: CT scanning of the abdomen is occasionally indicated as part of the imaging studies for further evaluation of hepatic and renal involvement in congenital hepatic fibrosis. CT scanning can demonstrate the abnormal shape and size of the liver. It can also show the peroportal thickening, varices, and splenomegaly. In patients with renal insufficiency, contrast medium is not administered, limiting the study.
• Intravenous pyelography
  • Intravenous pyelography (IVP) findings may be abnormal, revealing nephromegaly and alternation of radiodense and radiolucent streaks radiating from the medulla to the cortex.
  • This study is not mandatory for the diagnosis of congenital hepatic fibrosis with potential renal involvement.
• Splenoportography
  • This study may reveal an abnormality of the intrahepatic portal venous system characterized by duplication of the venous channels.
  • Naturally occurring splenorenal or gastrorenal shunts with increasing collateral formation may also be observed.
• Angiography
  • This test further reveals the details of the vascular anatomy and its patency, as well as the extent of the variceal formation.
  • Transhepatic cholangiography is a safe and direct means of identifying cholangitis.
• MRI and magnetic resonance cholangiopancreatography: Magnetic resonance cholangiopancreatography (MRCP) is described as a sensitive method for detecting biliary abnormalities, even when ultrasonographic findings are normal. It may reveal the unusual distribution of the biliary tree with mild dilatation peripherally and poor visibility centrally. MRI can reveal portal hypertension and periportal fibrosis and may help in the preoperative planning of the affected children with the cholangitic form of congenital hepatic fibrosis, obviating the need for invasive cholangiography.

Procedures

• Endoscopic examination
  • Upper GI endoscopy is often required in the overall evaluation of patients with congenital hepatic fibrosis, especially in the presence of anemia and/or a history of hematemesis or melena.
  • Endoscopy is helpful to confirm or rule out the presence of varices, erosions, or ulceration.
  • In bleeding varices, the procedure is followed by sclerotherapy or band ligation.
• Liver biopsy
  • The diagnosis of congenital hepatic fibrosis depends on histological liver biopsy findings, preferably obtained through minilaparotomy (wedge liver biopsy) to ensure examination of a sufficient number of portal tracts to support the diagnosis.
  • A percutaneous liver biopsy may produce sufficient tissue to confirm the diagnosis; findings may reveal the histological changes in the portal tracts. Remember that the pathological lesions may not be uniform throughout the liver; therefore, the percutaneous liver biopsy may prove inadequate to support the diagnosis. Furthermore, cases with one-lobe involvement have been reported.
  • Congenital hepatic fibrosis is characterized by fibrous enlargement of the portal tracts, which contain variable numbers of abnormally shaped bile ducts.

Histologic Findings

• Liver histology, as revealed through the biopsy, reveals extensive hepatic fibrosis. The widened fibrous bands in the portal tract contain an increased number of ectatic and dysplastic branches of the interlobular bile ducts. The irregularly shaped proliferating bile ducts are lined by normal cuboidal epithelium.
• The hepatic lobules are usually normal. See the image below.
• 
  

  

  Histopathology of liver biopsy in congenital hepatic fibrosis, which shows a widened portal tract with bands of fibrous tissue that separate areas of normal hepatic parenchyma. Note the multiple irregularly shaped narrow and elongated bile ducts and the absent lobular and portal inflammation.

  
  
• Cholestasis is observed in association with cholangitis. Other findings include portal vein branch hypoplasia and degeneration of the bile duct epithelium. Hypoplasia of the portal vein branches in association with supernumerous hepatic artery branches is also observed.

Treatment

Medical Care

• Medical therapy is provided mainly in the presence of cholangitis. Results of the liver biopsy and culture determine medical therapy in congenital hepatic fibrosis (CHF).
• Portal hypertension with secondary esophageal varices also requires treatment.
  • Some episodes of variceal bleeding may spontaneously resolve. However, persistent hemorrhage that lasts longer than 12 hours or requires blood transfusion warrants the consideration of medical therapy, surgical therapy, or both.
  • Acute management includes intravenous fluid administration, nasogastric tube placement, and, once the patient is stable, an endoscopy.
  • An initial pharmacologic approach with vasopressin, somatostatin, or other vasoconstricting medications is preferred in pediatrics. Each is discussed more thoroughly in the Medication section.
  • In cases of uncontrolled hemorrhage, one may resort to other interventions, including endoscopic sclerotherapy or band ligation, transjugular intrahepatic portosystemic shunting, or surgical shunting.

Surgical Care

Portosystemic shunt surgery is the treatment of choice for these patients because the risk of postoperative hepatic encephalopathy is low. Patients also have a patent portal vein and preserved liver function. External or internal drainage may be required to resolve the refractory hepatobiliary infection.

• Sclerotherapy is indicated for the treatment of acute hemorrhage from esophageal varices and as a primary therapy for management of recurrent or chronic variceal bleeding. Prophylactic use of sclerotherapy is still controversial.
  • Relative contraindications to the procedure include uncorrectable severe coagulopathy, fever, or compromise of respiratory status.
  • Complications of sclerotherapy include ulcers, strictures, rebleeding, perforations, and bacteremia.
• A Sengstaken-Blakemore tube may be required in some patients to control massive life-threatening bleeding. However, its current use is very much limited to patients who fail to respond to endoscopic sclerotherapy and in whom band ligation is not possible.
• Endoscopic variceal ligation is an effective and safe method for early variceal obliteration in children. It is effective in controlling active bleeding and preventing recurrences. However, its benefit over sclerotherapy has not been uniformly established.
• Types of surgical shunt include nonselective total portosystemic shunts, nonselective partial portosystemic shunts that maintain some antegrade blood flow to the liver, and selective portosystemic shunts, which decompress the gastroesophageal junction and the spleen through the splenic vein to the left renal vein.
• Transjugular intrahepatic portosystemic shunts are considered for patients not amenable to sclerotherapy. It is particularly valuable in treating patients with refractory bleeding before liver transplantation.
• Early shunt surgery with splenorenal or portacaval shunting may be required if repeated endoscopic sclerotherapy fails to arrest the variceal bleeding. Select the type of shunt carefully so that renal or hepatic transplantation remains a future option, with minimal limitations and complications. Both the portacaval H-graft shunt and the distal splenorenal shunt are appropriate options.
• Liver transplantation is also considered in the management of congenital hepatic fibrosis complicated by recurrent cholangitis or failure to respond to various medical and surgical therapeutic modalities resulting in progressive hepatic dysfunction.^{[12 ]}

Consultations

• Pediatric nephrologist - Required in most cases because of frequent association of congenital hepatic fibrosis with autosomal recessive polycystic kidney disease (ARPKD)
• Pediatric surgeon - Required for biliary drainage procedure and wedge liver biopsy
• Invasive radiologist - Required for imaging studies, angiography, and splenic portography
• Vascular surgeon - Required for evaluation of the case with regard to type and timing of shunt surgery
• Transplant surgeon - Required for liver transplantation, renal transplantation, or both

Diet

• Patients with congenital hepatic fibrosis are usually placed on a regular diet.

Activity

• The activity of children with congenital hepatic fibrosis is not restricted, except in late stages of severe hepatic involvement with progressive bleeding varices, severe renal impairment, and shortly after liver or kidney transplantation.

Medication

No specific medical therapy is available for congenital hepatic fibrosis (CHF). The child's condition is usually stable, with liver enzyme levels within the reference range.

Antibiotics

Antibiotic therapy is indicated for acute and recurrent cholangitis and is based essentially on the results of culture.

Sulfamethoxazole and trimethoprim (Bactrim, Septra, Cotrim)

Reported to be an effective therapy in cholangitis that complicates CHF. Efficacy is attributed to high concentration in bile and hepatic parenchyma. Also has good in vitro activity against Enterobacteriaceae.

Dosing

Adult

IV: 15-20 mg/kg/d (based on trimethoprim component) IV divided q12h
PO: 160/800 mg (ie, 1 double-strength tab) PO bid

Pediatric

8-20 mg/kg/d (based on the trimethoprim component) IV divided q12h for about 2 wk; followed by PO treatment for up to 3 mo

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; megaloblastic anemia caused by folate deficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use in pregnancy near term because of risk of kernicterus; discontinue at first appearance of rash or sign of adverse reaction; obtain CBC counts frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, patients with chronic alcoholism, elderly patients, patients receiving anticonvulsant therapy, or patients with malabsorption syndrome); hemolysis may occur in G-6-PD deficiency; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); administer fluids to prevent crystalluria and stone formation

Choleretic agents

These agents enhance bile salt–dependent biliary flow. These may prove to be a valuable addition to therapy in repeated and refractory cholangitis.

Ursodiol (Actigall, Urso)

Also called ursodeoxycholic acid. Has been shown to promote bile flow in cholestatic conditions associated with a patent extrahepatic biliary system.

Dosing

Adult

13-15 mg/kg/d PO divided bid/qid

Pediatric

10-20 mg/kg/d PO divided tid/qid

Interactions

Antacids, charcoal, cholestyramine, and colestipol interfere with absorption

Contraindications

Documented hypersensitivity; extrahepatic biliary tree obstruction

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in chronic liver disease, peptic ulcer, or inflammatory bowel disease; GI effects (eg, nausea, vomiting, diarrhea, constipation); dermatologic effects (eg, rash); monitor hepatic enzymes

Vasoconstrictors

These agents are used in medical management of portal hypertension. They reduce portal pressure through vasoconstriction of the mesenteric arterioles and reduce inflow to the portal venous system and portosystemic collaterals.

Vasopressin (Pitressin)

Decreases portal pressure in portal hypertension through vasoconstriction of the splanchnic arterioles thus controlling hemorrhage. Coronary artery disease is a notable undesirable effect. May dispose patients with coronary artery disease to cardiac ischemia. This can be prevented with concurrent use of nitrates.
Has vasopressor and ADH activity. Increases water resorption at distal renal tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout vascular bed of renal tubular epithelium.
Glypressin, triglycyl lysine vasopressin, can also be used in a dose of up to 2 mg IV q6h.

Dosing

Adult

0.1-0.5 U/min IV and titrate dose prn
After bleeding stops, continue at same dose for 12 h and taper off over 24-48 h

Pediatric

Initial dose: 0.002-0.005 U/kg/min IV, titrate dose prn, not to exceed 0.01 U/kg/min
After bleeding stops, continue at same dose for 12 h and taper off over 24-48 h

Interactions

Lithium, epinephrine, demeclocycline, heparin, and alcohol may decrease effects; chlorpropamide, urea, fludrocortisone, and carbamazepine may potentiate effects

Contraindications

Documented hypersensitivity; coronary artery disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in cardiovascular disease, seizure disorders, nitrogen retention, asthma, or migraine; excessive doses may result in hyponatremia

Somatostatin (Zecnil)

Not available in United States. Diminishes blood flow to portal system because of vasoconstriction, thus decreasing variceal bleeding. Has similar effects as vasopressin but does not cause coronary vasoconstriction.

Dosing

Adult

250 mcg IV bolus initially, followed by a 250 mcg/h IV

Pediatric

Not established, limited data suggest 15-25 mcg IV bolus initially, followed by 15-25 mcg/h IV for up to 48 h

Interactions

Epinephrine, demeclocycline, and thyroid hormone supplementation may decrease effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate or cause gall bladder disease; alters balance in counter-regulatory hormones and may cause hypothyroidism and cardiac conduction defects; monitor blood glucose and adjust infusion rate accordingly

Propranolol (Inderal)

Beta-blocker that lowers heart rate, myocardial contractility, cardiac output, and portal hypertension, thus reducing the risk of bleeding. Additionally, prevents increases in portal pressure (hepatic venous pressure gradient) during physical exertion.
Both propranolol and nadolol, beta-blockers, are effective in preventing first bleeding and reducing the mortality rate associated with bleeding.

Dosing

Adult

20 mg PO bid initially; may titrate upward by increments of 10 mg/d q3-4d according to heart rate (heart rate should be decreased by about 25%, but not <55 bpm)

Pediatric

0.5-1 mg/kg/d PO divided q6-8h initially; may gradually titrate upward q4-7d to desired effect

Interactions

Epinephrine, demeclocycline, and thyroid hormone supplementation may decrease effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate or cause gall bladder disease; alters balance in counter-regulatory hormones and may cause hypothyroidism and cardiac conduction defects

Follow-up

Further Inpatient Care

• Recurrent episodes of GI bleeding, recurrent cholangitis, and the extent of renal impairment largely influence the course of the disease.
• Congenital hepatic fibrosis (CHF) is also associated with varied clinical conditions that require consultations, resulting in further inpatient care and management (see Consultations).
• With severe bleeding varices, the child may require admission to the intensive care unit.

Further Outpatient Care

• Patients with congenital hepatic fibrosis are usually seen regularly at pediatric gastroenterology, hepatology, and nephrology clinics.
• In complicated cases, other disciplines are involved for regular follow-up assessment, including pediatric infectious disease, vascular surgery, and transplant surgery.

Inpatient & Outpatient Medications

• No specific medication is available for congenital hepatic fibrosis.
• Medication therapy is usually directed at treatment of complications, such as recurrent cholangitis, sepsis, or renal impairment.

Transfer

• A pediatric gastroenterologist or hepatologist usually provides follow-up care to the child with CHF, in collaboration with a pediatric nephrologist in cases with renal involvement (eg, ARPKD).
• Transfer to other services is indicated only in the presence of complications, especially cholangitis, and particularly with recurrent cholangitis that does not adequately respond to medical management.
• In complicated cases, transfer to a tertiary care center is recommended to facilitate the consultation and contribution of other services, such as pediatric surgery, vascular surgery, and transplant surgery.

Complications

• Complications in congenital hepatic fibrosis are mainly related to its association with autosomal recessive polycystic kidney disease (ARPKD), resulting in renal impairment, bleeding varices, and recurrent cholangitis.
• Recognition of cholangitis and prevention of its recurrence by appropriate surgical procedures are important. Transhepatic cholangiography is a safe and direct means of identifying this entity.
• Cholangiocarcinoma and amyloidosis have been reported as late sequelae of congenital hepatic fibrosis.

Prognosis

• Most patients do well. If bleeding from varices can be controlled and renal failure does not occur, the prognosis in congenital hepatic fibrosis is expected to be favorable. Respiratory insufficiency in the first month of life and renal insufficiency are primary determinant factors of mortality.
• As many as 25% of patients may eventually succumb to renal failure.
• Renal involvement in neonates and young infants with congenital hepatic fibrosis carries a worse prognosis, with most patients dying of renal failure within the first year of life.
• Other major causes of death include sepsis with ascending cholangitis and hepatic failure.

Miscellaneous

Medicolegal Pitfalls

The lack of awareness of congenital hepatic fibrosis (CHF) often leads to its misdiagnosis as cirrhosis.

Recognized associations with congenital hepatic fibrosis–autosomal recessive polycystic kidney disease (ARPKD) include the following:

• Congenital heart disease
• Pulmonary hypertension
• Intestinal lymphangiectasia
• Caroli syndrome
• Pulmonary fibrosis
• Cerebellar vermis hypoplasia
• Congenital ataxia
• Pancreatic fibrosis

Syndromes associated with congenital hepatic fibrosis include the following:

• Jeune syndrome
• Joubert syndrome
• COACH syndrome
• Ivemark syndrome
• Meckel syndrome 

Special Concerns

Most neonates and young infants with congenital hepatic fibrosis who have renal involvement die of renal failure within the first year of life. Coexisting renal involvement may remain asymptomatic until early adulthood. congenital hepatic fibrosis with predominant hepatic involvement may remain undiagnosed for years because of left lobe involvement and normal liver function test results. Percutaneous liver biopsy may fail to reveal the classic histological changes in CHF.

Caroli disease and Caroli syndrome

The original description of this disease was made by Jacques Caroli (1958). Two variable clinical entities are recognized:

• Caroli disease: Caroli disease is not associated with congenital hepatic fibrosis and is a rare variety. Originally described by Caroli, this form is characterized by a congenital dilatation of the segmental saccular and communicating intrahepatic bile ducts. No renal autosomal recessive polycystic kidney disease (ARPKD) lesions are associated. However, choledochal cysts may be present. The mode of inheritance is controversial, with some observations suggesting a hereditary nature.
• Caroli syndrome: Caroli syndrome is more common and is associated with congenital hepatic fibrosis. Bile duct dilatation is less prominent in this form. Esophageal varices, portal hypertension, and liver failure are recognized complications. Caroli syndrome has an autosomal recessive inheritance pattern and is associated with the kidney lesions of ARPKD.

The major clinical feature is recurrent cholangitis, which may be complicated by intrahepatic calculi and hepatic abscess formation. Patients usually present with fever and abdominal pain, with or without jaundice. Hepatosplenomegaly is commonly detected upon physical examination. Complications include amyloidosis and cholangiocarcinoma.

As in congenital hepatic fibrosis, the disease may be segmental and limited to one lobe, usually the left lobe of the liver. Moreover, renal involvement with cortical cysts and features of medullary sponge kidneys occur in as many as 25% of cases. Caroli disease is being diagnosed more frequently because of improved diagnostic facilities.^{[13 ]}Diagnosis is usually made through endoscopic or percutaneous cholangiography; more recently, MRCP has emerged as the diagnostic modality of choice.

The presence of saccular dilatation in the bile duct results in stagnation of bile, bile sludge formation, and superinfection, usually in the form of repeated cholangitis.

Therapy in Caroli disease is similar to that for congenital hepatic fibrosis with cholangitis. Antibiotic therapy may be sufficient, but measures to obtain sufficient biliary drainage and to relieve symptoms must be implemented. Overall management depends on the clinical features, history of recurrence, results of culture, and severity of hepatic and renal involvement. Ursodeoxycholic acid has been proposed as an adjuvant treatment in patients with lithiasis. In severe cases, lobectomy of the affected lobe may be required. Liver transplantation is considered in patients with recurrent cholangitis and extensive bilateral involvement.

Multimedia

Media file 1: Histopathology of liver biopsy in congenital hepatic fibrosis, which shows a widened portal tract with bands of fibrous tissue that separate areas of normal hepatic parenchyma. Note the multiple irregularly shaped narrow and elongated bile ducts and the absent lobular and portal inflammation.

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Keywords

congenital hepatic fibrosis, CHF, ductal plate malformation, autosomal recessive polycystic kidney disease, Caroli disease, autosomal dominant polycystic kidney disease, cholangitis, hematemesis, cholestasis, hepatomegaly, cirrhosis, symptoms

Contributor Information and Disclosures

Author

Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H, Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, University of Jordan
Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H is a member of the following medical societies: Royal College of Paediatrics and Child Health, Royal College of Physicians, Royal College of Surgeons in Ireland, Royal College of Surgeons of Edinburgh, and Royal Society of Tropical Medicine and Hygiene
Disclosure: Nothing to disclose.

Coauthor(s)

Dena Nazer, MD, Medical Director, Child Protection Center, Children's Hospital of Michigan; Assistant Professor, Wayne State University
Dena Nazer, MD is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, American Professional Society on the Abuse of Children, and Helfer Society
Disclosure: Nothing to disclose.

Medical Editor

Chris A Liacouras, MD, Director of Pediatric Endoscopy, Department of Pediatrics, Division of Gastroenterology and Nutrition, Associate Professor, Children's Hospital of Philadelphia and University of Pennsylvania
Chris A Liacouras, MD is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor; Johnson & Johnson, Inc. Grant/research funds Independent contractor

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

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