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Conditions

Intrahepatic cholestasis

Intrahepatic cholestasis is a reduced biliary-tree bile flow without an anatomical obstruction. There are different types and subtypes. Monogenic diseases contribute to the minority of cases.

Overview

Intrahepatic cholestasis is the slowing or stalling of bile flow without any anatomical obstruction within the biliary tree; bile that stays within the liver can lead to progressive injury. There are different types. Progressive familial intrahepatic cholestasis (PFIC) is a disorder where there is a deficiency of the proteins needed for normal bile flow, with different genes associated to its different subtypes. Other genetic causes include: benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy, Alagille syndrome or low-phospholipid associated cholelithiasis syndrome.

Clinical features

In adults, acute presentations of intrahepatic cholestasis are due to drug-induced liver injury, sepsis and viral hepatitis. Chronic cholestatic liver diseases are primary biliary and primary sclerosing cholangitis. Cholestasis can be a paraneoplastic manifestation of lymphoma or cancer. In paediatrics, obstructive pathologies, such as biliary atresia, present in infancy. Infectious and metabolic aetiologies can present with cholestasis. Monogenic diseases, such as those described below, contribute to the minority.

PFIC 1

  • This subtype can also known as Baylor disease.
  • Neonatal:
    • jaundice appears in the first month.
  • Childhood:
    • severe itching in the first year;
    • end-stage liver disease develops before adulthood;
    • extrahepatic features include:
      • short stature;
      • watery diarrhoea;
      • pancreatitis; and
      • sensorineural deafness.
  • Serum bile acid levels are high and gamma-glutamyl transpeptidase (GGT) levels low.
  • It is common to have a fat-soluble vitamin deficiency.

PFIC 2

  • Neonatal:
    • severe itching develops in the first year of life.
  • Childhood:
    • liver failure within the first few years of life; and
    • GGT levels are normal.
  • Adulthood:
    • symptoms and signs are related to liver disease only, though these are generally more severe; and
    • patients are at increased risk of developing hepatocellular carcinoma.

PFIC 3

  • Can present during infancy, childhood and even into young adulthood. When it presents later, the patient may already have cirrhosis and portal hypertension.
  • Itching is milder.
  • A high GGT level distinguishes it from PFIC 1, PFIC 2 and BRIC.
  • Gallstones and intrahepatic duct stones are common.
  • Increased risk of hepatocellular carcinoma and cholangiocarcinoma has been reported.
  • One-third of adults presenting with unexplained cholestasis have pathogenic variants in the coding region of at least one ABCB4 allele. ABCB4 variants are also associated with acute recurrent biliary pancreatitis, biliary cirrhosis and fibrosing cholestatic liver disease in adults, with or without biliary symptoms.
  • Women who are carriers of an ABCB4 variant may develop itching and jaundice during pregnancy.

PFIC 4

  • Neonatal (all identified within the first 3 months of life):
    • normal serum GGT levels;
    • raised bile acid levels;
  • In a 2014 case review by Sambrotta and others, out of the patients studied:
    • nine of 12 required liver transplantation;
    • one died at 13 months; and
    • two others had portal hypertension by 5–7 years of age.

PFIC 5

  • Cholestasis with low GGT progresses rapidly to liver failure.

BRIC

  • BRIC is characterised by episodes of intrahepatic cholestasis.
  • The age at which it first presents ranges from infancy (2 months) to late adulthood (47 years).
  • Frequency, duration and severity can vary widely. Episodes may occur from several a year to once in a decade. Severity and frequency of episodes decreases with age.
  • During the attacks, the patient presents with the following, all of which can resolve completely:
    • itching;
    • jaundice;
    • anorexia;
    • maldigestion; and
    • weight loss.
  • Pancreatitis is a known extrahepatic manifestation in BRIC caused by the ATP8B1 variants, but not in BRIC patients with variants in the ABCB11 gene.
  • Cholelithiasis has been described in patients with the ABCB11 variant, but not in those with variants in the ATP8B1 gene.

Low phospholipid-associated cholestasis (LPAC) syndrome

  • LPAC is characterised by:
    • cholelithiasis before 40 years of age;
    • recurrence after cholecystectomy; and
    • intrahepatic hyperechogenic foci compatible with sludge or microlithiasis.
  • Many patients have a family history of cholelithiasis in first-degree relatives or a history of intrahepatic cholestasis of pregnancy.
  • Affected individuals are at increased risk for hepatobiliary malignancy.

Alagille syndrome

  • Alagille syndrome is characterised by:
    • paucity of interlobular bile ducts;
    • chronic cholestasis; and
    • often with severe liver disease.
  • Most patients have the following associated anomalies:
    • cardiac anomalies (such as peripheral pulmonic stenosis);
    • butterfly vertebrae;
    • posterior embryotoxon;
    • dysmorphic facies;
    • impaired growth/developmental delay;
    • kidney disease; and
    • pancreatic insufficiency.

Genomics

PFIC 1

PFIC 1 is caused by pathogenic variants in the ATP8B1 gene (at genomic location 18q21–22) encoding the FIC1 protein, expressed at the canalicular membrane of hepatocytes, disrupting bile acid secretion.

PFIC 2

PFIC 2 is an autosomal recessive disorder caused by pathogenic variants in ABCB11 which encodes the bile salt export pump. This pump is an ATP-dependent transporter of bile acids from the hepatocytes into the bile canaliculus.

PFIC 3

PFIC 3 is caused by biallelic pathogenic variants in the ABCB4 gene, which encodes multidrug resistance protein 3 (also known as P-glycoprotein).

PFIC 4

Protein-truncating variants in the TJP2 gene are shown to cause failure of protein localisation, with disruption of tight-junction structure leading to severe cholestatic liver disease.

PFIC 5

PFIC 5 is caused by pathogenic variants of the NR1H4 gene, which encodes the farnesoid X receptor. This protein is an important regulator of bile acid cholestasis.

BRIC

Where BRIC is caused by monoallelic pathogenic variants in the ATP8B1 and ABCB11 genes, it is called BRIC1 and BRIC2, respectively.

Monoallelic ABCB11 variants predispose the patient to drug-induced cholestasis, intrahepatic cholestasis of pregnancy, low phospholipid-associated cholelithiasis (LPAC), transient neonatal cholestasis and fibrosing cholestatic liver disease in adults.

LPAC syndrome

LPAC syndrome is caused by heterozygous variants in ABCB4. These variants can reduce biliary phospholipid concentration, resulting in increased risk for cholesterol stones, microlithiasis or sludge.

Alagille syndrome

Alagille syndrome is an autosomal dominant condition usually caused by pathogenic variants in the JAG1 gene or, occasionally, by NOTCH2 variants.

Diagnosis

Genomic testing for cholestatic liver disease without a clear cause is recommended in any of the following instances:

  • neonatal conjugated hyperbilirubinaemia where multifactorial and infective causes have been excluded;
  • unexplained cholestasis developing below 18 years of age (it may be appropriate to test individuals presenting over 18 years old under R171 Cholestasis in the National Genomic Test Directory, following expert review);
  • persistence of unexplained cholestasis beyond 3 months or recurrence of otherwise unexplained cholestasis, including those with a suspected precipitating drug; or
  • cholestasis of pregnancy onset in the second trimester or serum bile acids >42μmol/mL in the third trimester.

Testing may occasionally be appropriate outside these criteria following discussion at the national gastro-hepatology genomics multidisciplinary team meeting.

A gene panel test is available for the many different genetic causes of cholestasis. For more information about genomic testing for cholestasis, see Presentation: Patient with unexplained intrahepatic cholestasis [link to T1].

Inheritance and genomic counselling

The heritability of intrahepatic cholestasis can vary and is described below. For LPAC and BRIC, which are not covered in this section, research is ongoing.

PFIC

All together, PFIC 1, PFIC 2 and PFIC 3 are estimated to occur in 1 in 50,000 to 1 in 100,000 births. These subtypes are inherited in an autosomal recessive pattern. If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

  • 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Genotyping should be used to confirm the diagnosis of PFIC in affected children. Heterozygosity of parents for the variants found in affected patients confirms the recessive inheritance of the disease.

Prenatal diagnosis can be proposed if a pathogenic variant has been identified in each parent. Molecular antenatal diagnosis of PFIC 1–3 subtypes is reliable. Research is ongoing to characterise inherited PFIC 4 and PFIC 5 subtypes.

Note that there are variabilities in manifestations (see Clinical features) even between variants of the same gene.

Alagille syndrome

Alagille syndrome occurs in 1 in 30,000 to 1 in 70,000 births. It is inherited in an autosomal dominant pattern.

  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Incomplete penetrance can occur when not everyone who has the variant develops the disease.

Molecular antenatal diagnosis of Alagille syndrome is reliable.

Management

Given the complexities, children with suspected PFIC should be referred to/discussed with a specialist paediatric liver unit. Recently, a national multidisciplinary team (MDT) meeting has been initiated: the National Genetic Cholestasis MDT.

There will be some variation in medical and surgical management of the different causes of cholestasis. For most patients, it will be important to ensure they have appropriate fat-soluble vitamin supplementation and good nutritional management.

Symptomatic management of pruritus (itch) will be broadly similar across all causes of cholestasis. Instituting simple measures can help manage pruritus and minimise damage from excoriation (scratch mark). This can include skin emollients, short nails, using soap substitutes, distraction from itch and well-ventilated cool rooms.

Medical measures will usually be needed as well. There could be differences in approach between paediatric and adult populations, but treatments that may be considered include:

  • ursodeoxycholic acid;
  • cholestyramine;
  • fibrates, such as bexafibrate or fenofibrate);
  • ileal bile acid transporter (IBAT) inhibitors, such as maralixibat or odevixibat (when genetic aetiology is confirmed);
  • rifampicin;
  • selective serotonin reuptake inhibitor (SSRI), such as sertraline;
  • opioid antagonist, such as naltrexone; and
  • chaperones, such as 4-phenylbutyrate.

For many of these conditions, surgical intervention may ultimately be required. This may include biliary diversion – where pruritus is refractory to medical management, part of the bile flow can be diverted to an external fistula – and liver transplant. Transplant is an important option for those with end-stage liver disease as a result of the conditions mentioned above or for some patients with intractable pruritus unresponsive to other measures.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 28/02/2025
  • Next review due: 28/02/2027
  • Authors: Dr Robert A D Scott
  • Reviewers: Professor Guruprasad P Aithal, Dr Laura Kelly