Health Care Professional Site | Testing + Diagnosis

Diagnostic Tools

There are various investigations that aid in diagnosing progressive familial intrahepatic cholestasis (PFIC), identifying its classification into types 1, 2, or 3, and differentiating it from other causes of cholestasis.

These include¹:

Genetic testing
Gold standard for diagnosis
Involves DNA sequencing of the 27 coding exons and their splice junctions
Learn more about genetic testing

Liver function tests
Differ in 3 types of PFIC
Poor synthetic functions (low serum albumin and uncorrectable coagulopathy) are seen in patients with advanced disease
Liver biopsy
Shows canalicular type of cholestasis, biliary plugs, and lobular disarray

Bile analysis
Rarely, duodenal aspiration or gallbladder puncture may be performed to obtain bile

Radiology
Ultrasonography is the ﬁrst test, which is essentially normal except for the presence of cholelithiasis in some cases of PFIC2 or PFIC3
Cholangiography helps in excluding sclerosing cholangitis in patients with high gamma-glutamyl transferase (GGT) cholestasis

Immunohistochemistry
Shows mild or absent canalicular staining with multidrug resistance class III (MDR3) and bile salt export pump (BSEP) antibodies in PFIC3 and PFIC2, respectively
Normal immunostaining does not preclude the diagnosis of PFIC
Standardized antibodies for immunohistochemistry for PFIC1 are not yet available
Electron microscopy
Bile in PFIC1 is coarse and granular
Bile in PFIC2 is amorphous

Genetic Testing

Historically, diagnosis of progressive familial intrahepatic cholestasis (PFIC) has been based on a combination of clinical and laboratory or biochemical approaches. More recently, however, genetic testing has become the gold standard.² In fact, genetic testing is the only reliable way to distinguish between PFIC1 and PFIC2.³

Genetic testing involves DNA sequencing of the 27 coding exons and their splice junctions. A resequencing chip that is dedicated to look for genetic syndromes of cholestasis has been developed and may facilitate diagnosis.¹

Given that no phenotypic features can exclude PFIC1 or PFIC2 in a patient with normal GGT PFIC, immunohistochemistry with BSEP staining followed by genetic analysis is recommended. In patients with negative BSEP staining, one should ﬁrst test for ABCB11, whereas in patients with normal BSEP staining, ATB8B1 mutation should be looked for.¹

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

Current Management Strategies

For patients with progressive familial intrahepatic cholestasis (PFIC), more pharmacologic treatment options are needed that relieve symptoms or prevent disease progression.² In 2021, an ileal bile acid transport inhibitor was approved to treat the pruritus associated with PFIC.⁵

Symptom Management
Surgical Options + Transplant

Management of PFIC currently includes nutritional support—adequate calories, supplementation of fat-soluble vitamins, and medium chain triglycerides—and the use of medications to help relieve pruritus.^1,4 In 2021, an ileal bile acid transport inhibitor was approved to treat the pruritus associated with PFIC.⁵

In patients with PFIC 2, the heightened risk of progression to end-stage liver disease (ESLD) means there is a limited time for intervention.^2,6.7

Partial external biliary diversion (PEBD) has been a main alternative to liver transplant for patients with PFIC.⁸

Liver transplant is typically viewed as an option when medical treatment and/or surgical biliary diversion has failed, and/or patients have a poor quality of life due to refractory pruritus.⁹

While liver transplant addresses cholestatic liver disease and its manifestations, there are transplant-related considerations, including rejection, post-transplant hepatic steatosis and recurrence of disease, and lifelong antirejection medication.^6,10

BSEP=bile salt export pump; ESLD=end-stage liver disease; GGT=gamma-glutamyl transferase; MDR3=multidrug resistance class III; PEBD=partial external biliary diversion; 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. 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 3. 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 4. Gunaydin M, Bozkurter Cil AT. Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment. Hepat Med. 2018;10:95-104. doi:10.2147/HMER.S137209 5. Bylvay Prescribing Information. Albireo Pharma, Inc. 6. van der Woerd WL, Houwen RH, van de Graaf SF. Current and future therapies for inherited cholestatic liver diseases. World J Gastroenterol. 2017;23(5):763-775. doi:10.3748/wjg.v23.i5.763 7. van Wessel DBE, Thompson RJ, Gonzales E, et al. Genotype correlates with the natural history of severe bile salt export pump deficiency. J Hepatol. 2020;73(1):84-93. doi:10.1016/j.jhep.2020.02.007 8. Wassman S, Pfister ED, Kuebler JF, et al. Quality of life in patients with progressive familial intrahepatic cholestasis: no difference between post-liver transplantation and post-partial external biliary diversion. J Pediatr Gastroenterol Nutr. 2018;67(5):643-648. doi:10.1097/MPG.0000000000002118 9. Mehl A, Bohorquez H, Serrano M-S, Galliano G, Reichman TW. Liver transplantation and the management of progressive familial intrahepatic cholestasis in children. World J Transplant. 2016;6(2):278-290. doi:10.5500/wjt.v6.i2.278 10. Kamath BM, Stein P, Houwen RHJ, Verkade HJ. Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis. Liver Int. 2020;40(8):1812-1822. doi:10.1111/liv.14553

Testing + Diagnosis

Diagnostic Tools

Genetic testing

Liver function tests

Liver biopsy

Bile analysis

Radiology

Immunohistochemistry

Electron microscopy

Genetic Testing

Current Management Strategies