Familial intrahepatic cholestasis (also called hereditary intrahepatic cholestasis) is defined in the MONDO ontology as intrahepatic cholestasis caused by an inherited modification of the individual's genome. The packet lists four related subtypes: intrahepatic cholestasis of pregnancy types 1 and 3, progressive familial intrahepatic cholestasis, and benign recurrent intrahepatic cholestasis. Because this is a broad grouping, the detailed clinical material in this packet comes from a single GeneReviews chapter that covers one genetically defined form of the condition, and does not necessarily describe every subtype. No genes, OMIM entries, inheritance patterns or onset categories are populated at the umbrella level.

No HPO phenotype annotations are recorded for this umbrella condition in the packet. The GeneReviews chapter on the one form it covers describes a spectrum from severe to mild. Severe disease is described as infantile-onset cholestasis, with affected children typically presenting in the first year of life, often with severe itching (pruritus) and jaundice. Related findings listed there include clinically significant diarrhea, failure to thrive, bleeding from vitamin K deficiency, enlarged liver and spleen, and pale stools. Poor growth and malabsorption can appear before age three months. In infants, irritability may be an early sign of itching.

Mild-to-moderate disease, sometimes called benign recurrent intrahepatic cholestasis, is described as intermittent episodes of cholestasis, itching and jaundice without bile duct obstruction outside the liver. Episodes may last weeks to months, and symptom-free intervals may last months to years. Triggers are described as variable or unknown. GeneReviews notes that "benign" refers to the absence of progressive liver disease but may be a misnomer, since quality of life and other manifestations can be affected, and some individuals who first have episodic disease later develop progressive liver disease. Sensorineural hearing loss is listed as common in both severe and milder forms. Severity can differ between family members who share the same variants and can change over time, with mild childhood disease in some cases progressing to severe disease in adulthood.

The packet lists no genes, OMIM entries or molecular mechanism for the umbrella condition, so the genetic basis of the full group is not described here. The MONDO definition states that the condition is caused by an inherited modification of the genome. For the one form covered by the GeneReviews chapter, the chapter states that it is inherited in an autosomal recessive manner. It states that parents of an affected child are presumed carriers, and that a sibling of an affected individual has a 25% chance of being affected, 50% of being a carrier and 25% of inheriting neither variant when both parents are carriers. This inheritance information is attributed to that form only and has not been certified for the other subtypes.

GeneReviews reports that disease severity generally correlates with variant type: variants expected to severely impair the protein, such as nonsense and frameshift variants and large deletions, are more often found in severe disease, while missense variants are more common in milder disease. It notes that some variants are associated with the Old Amish kindred and with Greenland familial cholestasis and that carriers may be at increased risk of transient neonatal cholestasis and intrahepatic cholestasis of pregnancy. GeneReviews also states that the prevalence of the form it covers is unknown. It reports an estimated collective prevalence of 1 in 50,000 to 1 in 100,000 births for progressive familial intrahepatic cholestasis disorders with high GGT, and carrier frequencies of 0.16 and 0.23 in two East Greenland localities.

The GeneReviews chapter states that no consensus clinical diagnostic criteria have been published for the form it covers, and describes suggestive findings rather than definitive criteria. These include cholestasis with conjugated hyperbilirubinemia or elevated bile acids alongside normal or low serum gamma-glutamyltranspeptidase (GGT), described as "low-GGT cholestasis". In severe disease, serum cholesterol is usually not elevated and total bile acids are often markedly elevated. In milder disease, bile acids are described as markedly elevated during symptomatic periods and normal between episodes. Sweat chloride may be elevated, and liver imaging findings are variable.

The chapter's differential diagnosis section lists other inherited cholestatic liver disorders with low or normal GGT and distinguishes them from the much more common cholestatic disorders with elevated GGT. The chapter's evaluation table lists assessments by a hepatologist, audiology, and evaluation of itching, growth and nutrition. This packet does not list newborn screening information or certified diagnostic methods for the umbrella condition.

This packet contains no FDA-approved treatment records for familial intrahepatic cholestasis, and treatment coverage for the full group is not certified here. The following describes only what the GeneReviews chapter on the single covered form reports. For severe disease, it states that pharmacotherapy for cholestasis is ineffective and that surgical interruption of the enterohepatic circulation (partial or total external or internal diversion, or ileal exclusion) is the primary surgical therapy, which can relieve itching and may slow or reverse progression to hepatic fibrosis. Liver transplantation is described as considered when disease progresses to decompensated cirrhosis. For milder disease, nasobiliary drainage and extracorporeal liver support are described as possibly hastening the end of an episode.

For itching, the chapter reports that agents such as ursodeoxycholic acid, cholestyramine, rifampin and several others are relatively ineffective in severe disease and do not alter progression, but may be efficacious in milder disease. It refers to recently FDA-approved ileal bile acid transporter inhibitors and states that real-world experience is still needed. Other described measures include medium-chain triglyceride-based formulas for growth failure and fat-soluble vitamin supplementation. The chapter also states that oral contraceptive therapy can induce or exacerbate episodes of cholestasis.

The packet records no natural-history data for the umbrella condition. The GeneReviews chapter on the covered form describes severe disease as infantile-onset cholestasis that progresses to cirrhosis, hepatic failure and death, with onset in the first year of life and progression to cirrhosis by the end of the first decade described as typical, though variability is noted between and within families. In truly mild disease, chronic liver damage is described as not developing, although fibrosis has been found on biopsy in some people clinically diagnosed with mild disease. The chapter also states that clinical findings can shift over time from episodic to persistent cholestasis. Outcomes for the other subtypes are not certified in this packet.

The packet lists clinical trial records from ClinicalTrials.gov, several of which concern progressive familial intrahepatic cholestasis specifically. Recruiting studies include the Mirum-sponsored long-term safety and outcomes study of LivmArli in the United States (NCT06193928) and a European Union study in Alagille syndrome or progressive familial intrahepatic cholestasis (NCT07290257, listed as Phase 4). Ipsen sponsors studies of odevixibat in South Korea (NCT07185919) and China (NCT07588880) and an external-control outcomes study (NCT07497724, active, not recruiting). Other listed studies include a Takeda database study of maralixibat (NCT07293897), a Groningen prospective treatment analysis (NCT06778174), a Canadian pediatric cholestasis registry (NCT07411716), and an Italian study of genetic drivers of adult-onset cholestatic liver disease (NCT07317193). Listing of a trial does not indicate that an intervention is effective. The GeneReviews chapter also reports that cystic fibrosis transmembrane conductance regulator corrector compounds improved trafficking of a mutated protein in cell culture, and that ileal bile acid transporter inhibitors reduced bile acid levels and itching in children in reported studies. Trial statuses are as listed in the packet.