AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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• Introduction
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• Follow-up
• Miscellaneous
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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. CHF is one of the fibropolycystic diseases, which also include Caroli disease, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD).

CHF 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 CHF, with its varied clinical manifestations, was recognized.³

Pathophysiology

CHF 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 malformation⁵ 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. CHF 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 CHF 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 CHF 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 CHF are genetically homogeneous. However, the exact pathogenesis of association between CHF and ADPKD still requires further research and study.

In all cases of CHF-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. CHF 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.

CHF 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

CHF is a rare autosomal recessive disease; the exact incidence and prevalence are not known. Only a few hundred patients with CHF have been reported in the literature. The disease appears in both sporadic (in as many as 56% of cases) and familial patterns.

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 CHF. 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

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

CLINICAL

Section 3 of 11  

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History

The onset of 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 (CHF) 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.
• If renal lesions dominate the clinical picture, the patient may die of renal failure in early infancy.

Physical

• Portal hypertension may be the initial manifestation that leads to the identification of 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 CHF and ARPKD.
• Abdominal pain is rare; when present, it is usually localized to the right upper quadrant.

Causes

• CHF 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 CHF.⁸
• 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 CHF.⁹

DIFFERENTIALS

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Other Problems to Be Considered

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

WORKUP

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Lab Studies

• Liver function tests
• • Liver enzyme levels are usually within the reference range when uncomplicated by portal hypertension or cholangitis.¹⁰
  • 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.

• Ultrasonography
• • This study helps to further support the diagnosis by revealing evidence of a patchy pattern of intense hepatic echogenicity, portal hypertension, splenomegaly, and duplication of the intrahepatic vasculature. 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.
• 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 CHF. Patients with CHF typically have imaging evidence of liver morphologic abnormalities, varices, splenomegaly, renal lesions, and other associated ductal plate abnormalities.¹¹
• 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 CHF 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 CHF, obviating the need for invasive cholangiography.

Procedures

• Endoscopic examination
• • Upper GI endoscopy is often required in the overall evaluation of patients with CHF, 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 CHF 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.
  • CHF 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 Media file 1). 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

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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 CHF complicated by recurrent cholangitis or failure to respond to various medical and surgical therapeutic modalities resulting in progressive hepatic dysfunction.¹²

Consultations

At one stage of the clinical course of CHF, management and follow-up evaluation require consultations with other disciplines, medical and surgical.

• Pediatric nephrologist - Required in most cases because of frequent association of CHF with 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 CHF are usually placed on a regular diet.

Activity

The activity of children with CHF 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

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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.

Drug Category: Antibiotics

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

Drug Category: 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.

Drug Category: 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.

FOLLOW-UP

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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 CHF 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.

In/Out Patient Meds

• No specific medication is available for CHF. 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 centre is recommended to facilitate the consultation and contribution of other services, such as pediatric surgery, vascular surgery, and transplant surgery.

Complications

• Complications in CHF are mainly related to its association with 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 CHF.

Prognosis

• Most patients do well. If bleeding from varices can be controlled and renal failure does not occur, the prognosis in CHF is expected to be favorable.
• As many as 25% of patients may eventually succumb to renal failure.
• Renal involvement in neonates and young infants with CHF carries a poor prognosis, with most of these 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

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Medical/Legal Pitfalls

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

Recognized associations with CHF-ARPKD include the following:

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

Special Concerns

Most neonates and young infants with CHF who have renal involvement die of renal failure within the first year of life. Coexisting renal involvement may remain asymptomatic until early adulthood. CHF 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

The original description of this disease was made by Jacques Caroli (1958).¹³ Caroli disease is characterized by nonobstructive saccular or fusiform dilatation of the intrahepatic bile ducts. The dilatations may involve a part of the liver or the whole liver. Although the classic hepatic fibrosis observed in CHF is not present in Caroli disease, its association with renal involvement is well recognized. Caroli disease is classified into the following 2 types:¹⁴

• Caroli disease: Caroli disease is unassociated with CHF and is a rare variety. Originally described by Caroli, this form is characterized by segmental saccular and communicating intrahepatic bile duct ectasia and is frequently associated with cholangitis and stone formation without fibrosis.
• Caroli syndrome: Caroli syndrome is more common and is associated with CHF. Bile duct dilatation is less prominent in this form. Esophageal varices, portal hypertension, and liver failure are recognized complications. Both types are associated with renal abnormalities consistent with 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  

As in CHF, 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. Recognized associations of Caroli disease include choledochal cysts, medullary sponge kidney,¹⁵ and ARPKD.

Caroli disease is being diagnosed more frequently because of improved diagnostic facilities.¹⁶ 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 CHF 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

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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.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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3. Kerr DN, Harrison CV, Sherlock S, Walker RM. Congenital hepatic fibrosis. Q J Med. Jan 1961;30:91-117. [Medline].
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5. Desmet VJ. Congenital diseases of intrahepatic bile ducts: variations on the theme "ductal plate malformation". Hepatology. Oct 1992;16(4):1069-83. [Medline].
6. Harris PC, Rossetti S. Molecular genetics of autosomal recessive polycystic kidney disease. Mol Genet Metab. Feb 2004;81(2):75-85. [Medline].
7. Losekoot M, Haarloo C, Ruivenkamp C, et al. Analysis of missense variants in the PKHD1-gene in patients with autosomal recessive polycystic kidney disease (ARPKD). Hum Genet. Nov 2005;118(2):185-206. [Medline].
8. El-Youssef M, Mu Y, Huang L, et al. Increased expression of transforming growth factor-beta1 and thrombospondin-1 in congenital hepatic fibrosis: possible role of the hepatic stellate cell. J Pediatr Gastroenterol Nutr. Apr 1999;28(4):386-92. [Medline].
9. Ozaki S, Sato Y, Yasoshima M, et al. Diffuse expression of heparan sulfate proteoglycan and connective tissue growth factor in fibrous septa with many mast cells relate to unresolving hepatic fibrosis of congenital hepatic fibrosis. Liver Int. Aug 2005;25(4):817-28. [Medline].
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12. Arikan C, Ozgenc F, Akman SA, et al. Impact of liver transplantation on renal function of patients with congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease. Pediatr Transplant. Dec 2004;8(6):558-60. [Medline].
13. Miller WJ, Sechtin AG, Campbell WL, Pieters PC. Imaging findings in Caroli's disease. AJR Am J Roentgenol. Aug 1995;165(2):333-7. [Medline].
14. Ananthakrishnan AN, Saeian K. Caroli's disease: identification and treatment strategy. Curr Gastroenterol Rep. Apr 2007;9(2):151-5. [Medline].
15. Braga AC, Calheno A, Rocha H, Lourenco-Gomes J. Caroli's disease with congenital hepatic fibrosis and medullary sponge kidney. J Pediatr Gastroenterol Nutr. Nov 1994;19(4):464-7. [Medline].
16. Dagli U, Atalay F, Sasmaz N, et al. Caroli's disease: 1977-1995 experiences. Eur J Gastroenterol Hepatol. Feb 1998;10(2):109-12. [Medline].
17. Gocmen R, Akhan O, Talim B. Congenital absence of the portal vein associated with congenital hepatic fibrosis. Pediatr Radiol. Sep 2007;37(9):920-4. [Medline].
18. McEvoy CF, Suchy FJ. Biliary tract disease in children. Pediatr Clin North Am. Feb 1996;43(1):75-98. [Medline].
19. Suchy FJ. Liver disease in children. In: Mosby Yearbook. St Louis, MO: Mosby Year Book Inc; 1994.
20. Yonem O, Ozkayar N, Balkanci F, et al. Is congenital hepatic fibrosis a pure liver disease?. Am J Gastroenterol. Jun 2006;101(6):1253-9. [Medline].

Article Last Updated: Mar 31, 2008