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Teddy was diagnosed with PFIC 

Teddy was diagnosed with PFIC

Teddy’s fur is scratched and her abdomen is swollen. Her eyes are tired and jaundiced. Her ability to learn and grow is suffering. Teddy has progressive familial intrahepatic cholestasis (PFIC); more specifically, she has PFIC2.

Like with every patient with chronic cholestatic liver disease, PFIC has impaired Teddy’s quality of life and robbed her of her childhood.1 Teddy shouldn’t have to bear it any longer.

That’s why Mirum is speaking up. We’re dedicated to raising awareness and addressing the impact cholestatic liver disease can have on patients like Teddy. In support of this commitment, we are doing our part to conduct research and help patients reclaim their childhoods.

What Is PFIC?

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare, life-threatening autosomal recessive disorders related to functional deficiencies in the hepatocyte transporters that result in the accumulation of toxic bile acids. PFIC consists of 3 main subtypes: PFIC1, PFIC2, and PFIC3, though recent scientific advancements have uncovered a growing list of subtypes that continue to expand our understanding of PFIC. PFIC2, also known as bile salt export pump (BSEP) deficiency, is the most common type.1-6

For more information about cholestatic liver disease, visit these Resources.

The 3 main subtypes of PFIC are caused by defects in transporters required for bile secretion.1

More specifically, PFIC1 is caused by mutations in the ATP8B1 gene, also called familial intrahepatic cholestasis 1 (FIC1); PFIC2 is caused by mutations in the ABCB11 gene, also called BSEP; and PFIC3 is caused by mutations in the ABCB4 gene, also called multidrug resistance class III (MDR3).1,2

PFIC affects males and females equally, and has been reported from all geographical areas around the world.1

The estimated incidence of PFIC is 1 per 50,000 to 100,000 births. However, the exact prevalence is unknown.1

PFIC accounts for 10% to 15% of cases of1:

  • Neonatal cholestasis
  • Children requiring liver transplant

PFIC2 is generally the most common subtype among patients diagnosed with PFIC via genetic testing4:

PFIC
PFIC1
PFIC1
PFIC2
PFIC2
PFIC3
PFIC3

Mirum is proud to sponsor free genetic testing through Travere Therapeutics to help with early diagnosis.

There are 3 main types of PFIC—Types 1, 2, and 3—based on the genetic defect involved in bile transport1:

Age at presentation
Infancy
End-stage liver disease (ESLD)
First decade
Course of disease
Moderately severe
Pruritus
Severe
Extrahepatic manifestations
Present
Risk of liver tumor development
No
Risk of cholesterol stone disease
Absent
Serum ALT
Mild elevation
Serum AFP
Normal
Serum GGT
Normal
Serum bile acids*
Raised ++
Primary bile acids
Low (3-8 mM)
Phospholipids
Normal
Liver histology
Bland cholestasis, mild lobular fibrosis
Electron microscopy
Granular bile

Adapted from Srivastava et al. 2014.

*Raised + signifies low/mild elevation, Raised ++ signifies medium/moderate elevation, and Raised +++ signifies high/severe elevation.

Age at presentation
Neonatal period/early infancy
End-stage liver disease (ESLD)
Rapid, first few years of life
Course of disease
Very severe
Pruritus
Very severe
Extrahepatic manifestations
Absent
Risk of liver tumor development
High
Risk of cholesterol stone disease
Increased
Serum ALT
Moderate elevation
Serum AFP
Raised
Serum GGT
Normal
Serum bile acids*
Raised +++
Primary bile acids
Very low (<1 mM)
Phospholipids
Normal
Liver histology
Cholestasis, giant cell hepatitis, hepatocellular necrosis, portal fibrosis
Electron microscopy
Amorphous bile

Adapted from Srivastava et al. 2014.

*Raised + signifies low/mild elevation, Raised ++ signifies medium/moderate elevation, and Raised +++ signifies high/severe elevation.

Age at presentation
Late infancy (≈30%) to early adulthood
End-stage liver disease (ESLD)
1st to 2nd decade of life
Course of disease
Insidious
Pruritus
Moderate
Extrahepatic manifestations
Absent
Risk of liver tumor development
Mild increase
Risk of cholesterol stone disease
Increased
Serum ALT
Mild elevation
Serum AFP
Normal
Serum GGT
Elevated
Serum bile acids*
Raised +
Primary bile acids
Normal
Phospholipids
Low
Liver histology
Bile ductular proliferation, inflammatory infiltrate, biliary fibrosis
Electron microscopy
—

Adapted from Srivastava et al. 2014.

*Raised + signifies low/mild elevation, Raised ++ signifies medium/moderate elevation, and Raised +++ signifies high/severe elevation.

For more information about cholestatic liver disease, visit these Resources.

Signs +
Symptoms

Progressive familial intrahepatic cholestasis (PFIC) predominantly affects children, and symptoms of PFIC1 and PFIC2 generally appear by 3 months of age, with a tendency for earlier appearance in patients with PFIC2. Patients with PFIC3 sometimes do not present with symptoms until after 2 to 3 years.4

Patients with PFIC typically present with intrahepatic cholestasis in infancy or childhood, although exact clinical manifestation differs among PFIC subtypes and multiple symptoms may be reported at presentation.2,4

Cholestatic pruritus has been identified as the most debilitating symptom of PFIC.1 In fact, based on the Whitington scale, pruritus was reported to be “Often Severe” in 76% to 80% of patients (grade 3 or higher).4 This bothersome pruritus often leads to cutaneous mutilation, loss of sleep, irritability, poor attention, and impaired school performance in children with PFIC.1

PFIC is associated with a range of potentially fatal complications of liver disease, including portal hypertension, liver failure, cirrhosis, and hepatocellular carcinoma (PFIC2), as well as extrahepatic manifestations (PFIC1).4

Additional signs and symptoms in PFIC may include1,4:

Jaundice
Jaundice
Growth deficiencies
Growth deficiencies
Failure to thrive
Failure to thrive
Diminished quality of life
Diminished quality of life

Extrahepatic manifestations include1,4,7:

  • Pale stools
  • Diarrhea
  • Pancreatitis
  • Sensorineural hearing loss
  • Splenomegaly
The path to a PFIC diagnosis 
can feel challenging See the diagnostic tools
PFIC is generally caused by 
a defect in bile secretion1 Learn about the mechanism behind each subtype
AFP=alpha-fetoprotein; ALT=alanine aminotransferase; BSEP=bile salt export pump; ESLD=end-stage liver disease; FIC1=familial intrahepatic cholestasis 1; GGT=gamma-glutamyl transferase; MDR3=multidrug resistance class III; PFIC=progressive familial intrahepatic cholestasis.
References: 1. Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4(1):25-36. doi:10.1016/j.jceh.2013.10.005 2. Amer S, Hajira A. A comprehensive review of progressive familial intrahepatic cholestasis (PFIC): genetic disorders of hepatocanalicular transporters. Gastroenterol Res. 2014;7(2):39-43. doi:10.14740/gr609e 3. Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2012;36(suppl 1):S26-S35. doi:10.1016/S2210-7401(12)70018-9 4. Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ. Systematic review of progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2019;43(1):20-36. doi:10.1016/j.clinre.2018.07.010 5. Henkel SAF, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol. 2019;11(5):450-463. doi:10.4254/wjh.v11.i5.450 6. Goldberg A, Mack CL. Inherited cholestatic diseases in the era of personalized medicine. Clin Liver Dis (Hoboken). 2020;15(3):105-109. doi:10.1002/cld.872 7. Gunaydin M, Bozkurter Cil AT. Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment. Hepat Med. 2018;10:95-104. doi:10.2147/HMER.S137209