Basics
Description
- Congenital hepatic fibrosis (CHF) is an inherited, noncirrhotic liver disease.
- Prominent clinical features include the following:
- Portal hypertension
- Increased risk of ascending cholangitis
- Liver biopsy shows the classic lesion of ductal plate malformation.
- Majority of patients with CHF have associated autosomal recessive polycystic kidney disease (ARPKD). However, several other genetic diseases also result in CHF.
Epidemiology
- The incidence of ARPKD is 1/20,000-1/40,000 live births.
- Carrier frequency of PKHD1 mutation in the general population is ~1:70.
Risk Factors
Genetics
- Inheritance is autosomal recessive in most families, but X-linked and autosomal dominant patterns are also seen.
- Penetrance is 100% but marked intrafamilial variation in severity is observed.
- PKHD1, the ARPKD/CHF disease gene, is located on chromosome 6p12.
- The gene is large, consisting of at least 86 exons extending over 469 kb of genomic DNA.
- It is expressed at high levels in fetal and adult kidneys and at lower levels in the liver and pancreas.
- More than 300 mutations of the PKHD1 gene have been reported with variable rates of progression of hepatic/renal disease, even with the same PKHD1 mutation, indicating the presence of modifier genes.
- Mutations of the PKHD1 gene include frameshift, nonsense, and out-of-frame splicing alterations that are consistent with a loss of function mechanism.
- The presence of 2 truncating mutations leads to the most severe phenotype, associated with death in the neonatal period.
- The PKHD1 gene product is a protein called polyductin or fibrocystin.
- Transmembrane protein
- Located mostly on the primary cilia and apical surface of renal tubular cells and cholangiocytes
- It complexes with polycystin 1 and polycystin 2, the mutated proteins in autosomal dominant polycystic kidney disease (ADPKD).
- Together, the complex is thought to function as mechanotransducer, detecting the shear force from urine and bile flow. Further studies will be needed to identify the biologic function of polyductin and to determine how mutations of the protein cause disease.
Pathophysiology
- Ductal plate malformation is a characteristic histologic lesion of the liver, implying a disturbance of the normal development of the bile ducts.
- Hallmarks include the following:
- Irregularly shaped, dilated, proliferating bile ducts, often described as staghorn shaped
- Noninflammatory periportal fibrosis
- Normal appearance of hepatocytes and lobular architecture
- The primary defect in ARPKD may be linked to ciliary dysfunction.
- The ciliary structure is abnormal in ARPKD renal tubule cells and cholangiocytes.
- Developmental abnormalities involve the liver and kidneys and, less commonly, the vasculature and the heart.
- Portal hypertension is thought to result from the fibrosis in the portal tracts as well as, in some patients, from portal vein abnormalities.
Commonly Associated Conditions
- Portal hypertension leading to varices and hypersplenism
- Hepatomegaly
- Systemic hypertension
- Renal dysfunction
- Cholangitis
- Conditions associated with the finding of ductal plate malformation/CHF:
- ARPKD; most frequent association
- ADPKD, rare
- Caroli syndrome (CHF and intrahepatic bile duct dilation)
- Juvenile nephronophthisis
- Congenital disorder of glycosylation type 1b (phosphomannose isomerase deficiency)
- Congenital malformation syndromes
- Meckel Gruber syndrome
- Joubert syndrome
- Jeune syndrome
- Bardet-Biedl syndrome
Diagnosis
History
- Severely affected patients are usually diagnosed in utero or shortly after birth due to massively enlarged cystic kidneys.
- Prenatal renal dysfunction may result in pulmonary hypoplasia.
- Older patients may present with systemic hypertension or signs of portal hypertension and esophageal variceal bleeding.
- Patients may present with fever and jaundice (cholangitis) or, rarely, with signs of liver failure.
Physical Exam
- Firm, enlarged liver with a prominent left lobe
- Splenomegaly
- Kidneys may be palpable on abdominal exam.
Diagnostic Tests & Interpretation
Lab
- Thrombocytopenia and leukopenia are associated with hypersplenism.
- Liver enzymes and bilirubin are typically normal; transaminases may be mildly elevated in some patients.
- Usually, hepatic synthetic function (albumin, prothrombin time) is normal.
- May see elevated blood urea nitrogen and creatinine with renal involvement
- Genetic testing is available and consultation is recommended.
Imaging
- Complete abdominal ultrasound with Doppler
- Increased hepatic echogenicity
- Splenomegaly
- Evidence of portal hypertension, portal vein patency, and decreased flow variability
- Cystic kidneys
- Magnetic resonance cholangiopancreatography (MRCP) can further characterize the biliary system in Caroli syndrome.
Diagnostic Procedures/Other
- Liver biopsy
- Characteristic histology of ductal plate malformation
- If cholangitis is suspected clinically, send specimen for bacterial culture.
Differential Diagnosis
Varies with presentation. Usually, differential diagnosis is that of early cirrhosis or idiopathic portal hypertension.
Treatment
Medication
Choleretic agents, including ursodeoxycholic acid, are used in bile stasis.
Additional Treatment
General Measures
- Monitor growth, weight gain, nutritional status, and for vitamin A, D, E, K malabsorption.
- Suspected cholangitis should be managed with blood culture, antibiotics to cover gram-negative rods, and +/- liver biopsy. Some patients with chronic cholangitis may require antibiotic prophylaxis.
- Endoscopic variceal banding and/or sclerotherapy provide prevention and treatment of esophageal variceal hemorrhage in many cases.
- Activity
- No contact sports if splenomegaly is present.
- Spleen guard may be used to protect against injury from abdominal trauma.
Surgery/Other Procedures
- Portosystemic shunting may be needed but should be considered in the context of kidney function given ammonia disposal occurs renally.
- Liver transplant may be indicated for chronic cholangitis, recurrent bleeding, or progressive hepatic disease.
- Children who require transplantation should be considered for combined liver and renal transplantation.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Acute upper GI tract bleeding or melena requires urgent EGD for bleeding control, frequent Hgb/Hct checks, blood cultures, IV proton pump inhibitor, antibiotics, and possible need for octreotide drip in the ICU setting.
- Platelet count is the best predictor of pulmonary hypertension severity; an acute drop could indicate hepatorenal syndrome.
- Morbidity and mortality occurs mainly from variceal bleeding and cholangitis.
- Systemic hypertension and kidney function must be monitored.
- Early referral to a hepatologist, nephrologist, and transplant center is indicated in neonatal disease.
Diet
No restrictions are needed unless secondary to renal disease.
Prognosis
- Substantial variability in severity and progression of clinical manifestation exists.
- Bleeding from varices is a major cause of morbidity and mortality.
- Ascending cholangitis with resultant sepsis is a major cause of morbidity and mortality.
- Those presenting during childhood have better prognosis compared to those presenting within the neonatal period.
- Need for eventual liver +/- kidney transplantation needs to be considered.
Complications
- Portal hypertension with hypersplenism and variceal bleeding (chronic, common)
- Cholangitis: acute and recurrent, significant cause of morbidity in Caroli syndrome
- Renal and/or hepatic failure
- Associated vascular anomalies in the liver and brain
- Increased risk of hepatocellular or cholangiocarcinoma in adulthood; screening in pediatric population is not warranted.
- Systemic hypertension owing to renal involvement
Additional Reading
- Badano JL, Mitsuma N, Beales PL, et al. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125-148. [View Abstract]
- Buscher R, Buscher AK, Weber S, et al. Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney related phenotypes. Pediatr Nephrol. 2014;29(10):1915-1925. [View Abstract]
- Gunay-Aygun M, Avner ED, Bacallao RL, et al. Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: summary statement of a first National Institutes of Health/Office of Rare Diseases conference. J Pediatr. 2006;149(2):159-164. [View Abstract]
- Gunay-Aygun M, Font-Montgomery E, Lukose L, et al. Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease. Gastroenterology. 2013;144(1):112-121. [View Abstract]
- Harris PC, Rossetti S. Molecular genetics of autosomal recessive polycystic kidney disease. Mol Genet Metab. 2004;81(2):75-85. [View Abstract]
- Rawat D, Kelly DA, Milford DV, et al. Phenotypic variation and long-term outcomes in children with congenital hepatic fibrosis. J Pediatr Gastroenterol Nutr. 2013;57(2):161-166. [View Abstract]
Codes
ICD09
- 777.8 Other specified perinatal disorders of digestive system
- 572.3 Portal hypertension
- 576.1 Cholangitis
ICD10
- P78.89 Other specified perinatal digestive system disorders
- K76.6 Portal hypertension
- K83.0 Cholangitis
SNOMED
- 79607001 Congenital hepatic fibrosis (disorder)
- 34742003 Portal hypertension (disorder)
- 26918003 Ascending cholangitis (disorder)
FAQ
- Q: Will other children of mine be affected?
- A: Maybe. The inheritance pattern is autosomal recessive, with the possibility of an affected sibling being 1:4.
- Q: Is my child at increased risk if he contracts viral hepatitis?
- A: Yes. The underlying liver disease places these patients at increased risk. They should be immunized against hepatitis A and B.
- Q: If my child has a fever, does she need to be seen by her doctor?
- A: Yes. Patients with CHF who have fever without an obvious source should be evaluated for possible cholangitis, at least by obtaining a blood culture and liver enzymes.