Congenital Hepatic Fibrosis

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. Pathologically, it is defined by its variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts. 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).[1, 2]  ARPKD is reported to be caused by mutations in the PKHD1 gene. More than 300 different mutations in the PKHD1 gene have been described but with no genotype-phenotype correlation.[2]

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 with rather similar kidney manifestations were first described by Bristowe in 1856.[3] In 1961, the term congenital hepatic fibrosis, with its varied clinical manifestations, was recognized by Kerr.[4]

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 an associated portal hypertension.[2, 5]

Congenital hepatic fibrosis results from a malformation of the ductal plate (the embryological precursor of the biliary system), secondary biliary strictures, and periportal fibrosis.[6] This subsequently results in the development of portal hypertension.

The ductal plate is the cylindrical 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[7] 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 clinico-pathological presentations.

ARPKD is caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene,[8] which consists of 86 exons that are variably assembled into numerous alternatively spliced transcripts.[9] 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.[10]

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.

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 from 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.[11]

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.

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.[12]

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.[13]

The following studies are indicated in congenital hepatic fibrosis:

Liver function tests

• Liver enzyme levels are usually within the reference range when uncomplicated by portal hypertension or cholangitis. ^[14]
• 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. Furthermore, thrombocytopenia and splenomegaly may be the only manifestations of the disease.
• 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.

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.[10]

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 periportal 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.

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.

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.[15]

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.

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. Moreover, spontaneous extrahepatic portosystemic shunting has been reported in congenital hepatic fibrosis.[16]

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. 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. 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.[17]

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.[18, 19]

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

• 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

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

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.

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.

Class Summary

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.

Class Summary

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.

Class Summary

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. It may dispose patients with coronary artery disease to cardiac ischemia. This may 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.

Somatostatin (Zecnil)

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

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.

See the list below:

• 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.

See the list below:

• 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.

See the list below:

• 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.

See the list below:

• 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.

See the list below:

• 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.

See the list below:

• 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.