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Progressive Familial Intrahepatic Cholestasis Workup

  • Author: Melissa Kennedy, MD; Chief Editor: Carmen Cuffari, MD  more...
 
Updated: Nov 19, 2015
 

Laboratory Studies

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  • Serum bilirubin levels are elevated in virtually all patients with progressive familial intrahepatic cholestasis (PFIC).
  • Serum direct or conjugated bilirubin levels are elevated in virtually all patients.
  • Total serum bile salt concentration is elevated 10-fold to 20-fold in virtually all patients.
  • Qualitative serum and urine bile acids by mass spectroscopy are used to exclude genetically determined errors in bile acid synthesis.
  • Total serum cholesterol level is within reference ranges; high-density lipoprotein (HDL) level is normal or low.
  • Serum alkaline phosphatase is elevated in virtually all patients.
  • Serum 5'-nucleotidase is elevated in virtually all patients.
  • Serum gamma-glutamyl transferase (GGT) levels are within reference ranges or low in PFIC1 and PFIC2; patients may have GGT levels of more than 100 IU/L while receiving microsomal inducers (eg, phenobarbital). These levels are elevated (ie, usually 3-fold to 10-fold) in patients with PFIC3.
  • Fecal fat is elevated in virtually all patients.
  • Genetic testing: A DNA resequencing array has been developed that includes the genes associated with PFIC types 1, 2, and 3.[9]
  • Serum AFP
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Imaging Studies

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  • Ultrasonography of the liver and gall bladder is useful in determining biliary tract anatomy and differentiating from extrahepatic causes of cholestasis.
  • Cholangiography may be necessary to exclude extrahepatic biliary obstruction.
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Other Tests

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  • Sampling bile from the duodenum or directly from the biliary tract for analysis of phospholipid content can be useful in making the diagnosis of PFIC3.
  • Histologic evaluation of the liver architecture can be helpful as described below. Further immunohistochemical staining of liver specimen for BSEP and MDR3 can be diagnostic and help differentiate between the types of PFIC.
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Procedures

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  • Liver biopsy
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Histologic Findings

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  • In patients with PFIC1 and PFIC2, hepatocellular and canalicular cholestasis with pseudoacinar transformation are the most uniform histologic findings. Hepatocellular injury manifests as giant cell formation and ballooned hepatocytes (see following images).
    Progressive familial intrahepatic cholestasis (PFIProgressive familial intrahepatic cholestasis (PFIC), typical findings. Ballooned hepatocytes from cholate injury, scattered giant cells, cholestasis, and lacy fibrosis extending from central veins to portal areas.
    Ballooned hepatocytes with cholestasis and some giBallooned hepatocytes with cholestasis and some giant cell transformation. Note the sinusoidal lacy fibrosis.
  • Giant cells are prominent during infancy in 57% of patients and may regress with increasing age. Bile duct damage leads to their loss and ductal paucity in 70% of older patients. The degenerating biliary epithelium shows apoptotic changes, consisting of small hyperchromatic nuclei, attenuated cytoplasm, and loss of duct lumina. Inflammation is absent.
  • The typical progression of fibrosis starts early (ie, 76% of patients have some fibrosis by age 2 y) and may appear initially as pericentral sclerosis, portal fibrosis, or sometimes both. Portal-to-central bridging then develops in association with lacy lobular fibrosis and eventually leads to cirrhosis. Proliferating bile ductules develop at the edge of the portal tracts in patients with significant fibrosis. The progression rate of the fibrosis widely varies but loosely correlates to clinical disease severity. Mallory hyaline and hepatocellular carcinoma may occur with very advanced disease.
  • Examination with electron microscopy shows subtle differences between PFIC1 and PFIC2. Samples from patients with PFIC1 show the retention of coarsely granular bile (so-called Byler bile) in canalicular spaces.
  • In PFIC3, liver biopsy reveals expanded portal areas with proliferation of interlobular bile ducts plugged with bile. As in PFIC1 and PFIC2, progressive fibrosis, nodularity, and cirrhosis will develop.
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Contributor Information and Disclosures
Author

Melissa Kennedy, MD Attending Physician, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia

Melissa Kennedy, MD is a member of the following medical societies: American Academy of Pediatrics, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Nothing to disclose.

Coauthor(s)

Joshua R Friedman, MD, PhD Adjunct Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania

Joshua R Friedman, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Study of Liver Diseases, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Received salary from Johnson & Johnson for employment.

Amanda Brooke Muir, MD Resident Physician, Department of Pediatrics, Children’s Hospital of Philadelphia

Amanda Brooke Muir, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Stefano Guandalini, MD Founder and Medical Director, Celiac Disease Center, Chief, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Chicago Medical Center; Professor, Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Division of the Biological Sciences, The Pritzker School of Medicine

Stefano Guandalini, MD is a member of the following medical societies: American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, European Society for Paediatric Gastroenterology, Hepatology & Nutrition, North American Society for the Study of Celiac Disease

Disclosure: Received consulting fee from AbbVie for consulting.

Chief Editor

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Royal College of Physicians and Surgeons of Canada

Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching.

Additional Contributors

Hisham Nazer, MB, BCh, FRCP, , DTM&H Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, University of Jordan Faculty of Medicine, Jordan

Hisham Nazer, MB, BCh, FRCP, , DTM&H is a member of the following medical societies: American Association for Physician Leadership, Royal College of Paediatrics and Child Health, Royal College of Surgeons in Ireland, Royal Society of Tropical Medicine and Hygiene, Royal College of Physicians and Surgeons of the United Kingdom

Disclosure: Nothing to disclose.

References
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Progressive familial intrahepatic cholestasis (PFIC), typical findings. Ballooned hepatocytes from cholate injury, scattered giant cells, cholestasis, and lacy fibrosis extending from central veins to portal areas.
Ballooned hepatocytes with cholestasis and some giant cell transformation. Note the sinusoidal lacy fibrosis.
Table 1.
GeneProteinProposed



Pathophysiology



GGTClinical considerations
ATP8B1FIC 1 (ATP8B1)Increased phospholipid membrane instability leads to decreased bile acid transportLowExtrahepatic manifestations: diarrhea, pancreatitis, hearing loss
ABCB11BPEPMutation in bile acid export pump (BSEP) leads to cholestasisLowIncreased risk of hepatobiliary malignancies
ABCB4MDR3Decreased phospholipid concentration in bile leads to destabilized micelles within ductules causing inflammation/destruction and eventually cholestasisHighOnset of cholestasis tends to be later in life
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