EASL guidelines direct genetic cholestatic liver management

The guidelines were created by a panel of experts and rated by level of evidence, strength of recommendation, and degree of consensus, explain Henkjan Verkade (University of Groningen, the Netherlands) and fellow panel members in the Journal of Hepatology.

General recommendations include the early use of next-generation sequencing during diagnostic work-up for patients, especially among adults who are unresponsive to initial therapy or have unusual disease characteristics. Whole-exome or whole-genome sequencing should be repeated at least every 3 years to look for recently discovered variants in patients who do not initially have a genetic alteration identified.

The panel notes that adults with late-onset disease may have a phenotype that occurs due to the interaction of genetic variants with environmental triggers, such as pregnancy or infection, and that the evidence for treatment recommendations is stronger for severe disease than for mild or recurrent symptoms.

The guidelines also focus on the “challenging” management of pruritus. For adults, the panel recommends both conservative strategies, such as use of skin emollients, having short nails, and avoidance of hot baths, and conventional medicines, consisting of first-line fibrates, ursodeoxycholic acid (UDCA), rifampicin and, for patients with PFIC or Alagille syndrome, an ileal bile acid transporter (IBAT) inhibitor. Other pruritus medications may include cholestyramine, the selective serotonin reuptake inhibitor sertraline, the opioid antagonist naltrexone, or the chemical chaperone 4-phenylbutyric acid.

For patients with episodic cholestasis pruritus, molecular adsorbent recirculating system or plasmapheresis may be considered, while chronic cholestatic pruritus may require mechanical or surgical interruption of the enterohepatic circulation (EHC) or liver transplantation.

PFIC guidelines

The guidelines include recommendations for the care of patients with the most common forms of PFIC, namely FIC1 deficiency (ATP8B1 alterations), bile salt export pump deficiency (BSEP; ABCB11 alterations), and multidrug resistance protein 3 deficiency (MDR3; ABCB4 alterations).

For FIC1 deficiency, the expert panel says that the current evidence does not support surgical interruption of the EHC as a routine option for prolonging liver survival. The IBAT inhibitor, odevixibat, may aid pruritus and reduce serum bile acid levels in patients with FIC1 or BSEP deficiency and that long-term data on the impact of the agent on native liver survival “may change the level of evidence,” the authors write. In addition, several reports indicate that surgical EHC interruption or use of an IBAT inhibitor at or after transplantation may be used to treat diarrhea and steatohepatitis.,

For patients with BSEP deficiency, a patient’s management should be guided by their specific genotype, which will predict native liver survival, response to EHC interruption, and risk for hepatocellular carcinoma (HCC). For instance, there is a “strong recommendation” to consider surgical EHC interruption in patients with homozygous p.D482G or p.E297G alterations, which are associated with a good response in terms of liver survival and pruritus, whereas those with a protein-truncating mutation (PPTM) are less likely to respond to surgery and have a high risk for HCC.

The panel also states that there is yet insufficient data to support medical EHC interruption with an IBAT inhibitor to prolong native liver survival in people with BSEP deficiency, but that this drug class may be considered to treat pruritus in patients with a missense mutation prior to transplantation. Long-term results on the ability of odevixibat to delay or prevent liver transplantation are awaited.

HCC screening is recommended every 3–6 months for BSEP deficiency caused by a missense mutation, and every 3 months for biallelic PPTM, although there is not strong evidence to show that this improves long-term survival, the panel continues.

Turning to MDR3 deficiency, the expert panel says that the specific ABCB4 genotype is an indicator of response to UDCA, risk for fibrosis/cirrhosis, native liver survival, and risk for both HCC and cholangiocarcinoma.

The authors recommend that detection of a known pathogenic variant should therefore guide follow-up and screening for fibrosis and malignancy in such patients, as well as the long-term use of UDCA, including in those with evidence of cholestatic liver disease, such as low phospholipid-associated cholelithiasis.

Genetic testing is also recommended for all first-degree relatives of patients with MDR3 deficiency.

The expert panel also provides recommendations for the diagnosis and management of other specific cholestatic liver diagnoses. These include:

• alpha-1 antitrypsin deficiency caused by SERPINA1 mutations, such as the Pi*ZZ genotype
• Alagille syndrome caused by alterations to JAG1 or NOTCH2
• Bile acid synthesis defects caused by multiple mutations including alterations to 3β-HSD, HSD3B7, and AKR1D1.