A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters
Identifieur interne : 004A23 ( Pmc/Corpus ); précédent : 004A22; suivant : 004A24A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters
Auteurs : Syed Amer ; Amtul HajiraSource :
- Gastroenterology Research [ 1918-2805 ] ; 2014.
Abstract
Progressive familial intrahepatic cholestasis or PFIC is a general term used to describe a group of genetic disorders involving the hepatocanalicular transporters. These diseases are characterized by persistent cholestasis, pruritus and jaundice. Type I PFIC is characterized by defect in the gene that codes for aminophospholipid translocase protein and maintains canalicular membrane stability. Types 2 and 3 are caused by defect in genes that code for bile acid transporter and a phospholipid translocase, respectively. This review summarizes the genetics, clinical features, diagnosis and treatment of the three types of PFIC.
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DOI: 10.14740/gr609e
PubMed: 27785268
PubMed Central: 5051073
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters</title><author><name sortKey="Amer, Syed" sort="Amer, Syed" uniqKey="Amer S" first="Syed" last="Amer">Syed Amer</name><affiliation><nlm:aff id="Aa">Department of Internal Medicine, Mayo Clinic, Phoenix, AZ 85054, USA</nlm:aff></affiliation></author><author><name sortKey="Hajira, Amtul" sort="Hajira, Amtul" uniqKey="Hajira A" first="Amtul" last="Hajira">Amtul Hajira</name><affiliation><nlm:aff id="Ab">Department of Family Medicine, Carle Foundation Hospital, Urbana, IL 61801, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27785268</idno><idno type="pmc">5051073</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051073</idno><idno type="RBID">PMC:5051073</idno><idno type="doi">10.14740/gr609e</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">004A23</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004A23</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters</title><author><name sortKey="Amer, Syed" sort="Amer, Syed" uniqKey="Amer S" first="Syed" last="Amer">Syed Amer</name><affiliation><nlm:aff id="Aa">Department of Internal Medicine, Mayo Clinic, Phoenix, AZ 85054, USA</nlm:aff></affiliation></author><author><name sortKey="Hajira, Amtul" sort="Hajira, Amtul" uniqKey="Hajira A" first="Amtul" last="Hajira">Amtul Hajira</name><affiliation><nlm:aff id="Ab">Department of Family Medicine, Carle Foundation Hospital, Urbana, IL 61801, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Gastroenterology Research</title><idno type="ISSN">1918-2805</idno><idno type="eISSN">1918-2813</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Progressive familial intrahepatic cholestasis or PFIC is a general term used to describe a group of genetic disorders involving the hepatocanalicular transporters. These diseases are characterized by persistent cholestasis, pruritus and jaundice. Type I PFIC is characterized by defect in the gene that codes for aminophospholipid translocase protein and maintains canalicular membrane stability. Types 2 and 3 are caused by defect in genes that code for bile acid transporter and a phospholipid translocase, respectively. This review summarizes the genetics, clinical features, diagnosis and treatment of the three types of PFIC.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Davit Spraul, A" uniqKey="Davit Spraul A">A Davit-Spraul</name></author><author><name sortKey="Gonzales, E" uniqKey="Gonzales E">E Gonzales</name></author><author><name sortKey="Baussan, C" uniqKey="Baussan C">C Baussan</name></author><author><name sortKey="Jacquemin, E" uniqKey="Jacquemin E">E Jacquemin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kullak Ublick, Ga" uniqKey="Kullak Ublick G">GA Kullak-Ublick</name></author><author><name sortKey="Beuers, U" uniqKey="Beuers U">U Beuers</name></author><author><name sortKey="Paumgartner, G" uniqKey="Paumgartner G">G Paumgartner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hori, T" uniqKey="Hori T">T Hori</name></author><author><name sortKey="Nguyen, Jh" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Gastroenterology Res</journal-id><journal-id journal-id-type="iso-abbrev">Gastroenterology Res</journal-id><journal-id journal-id-type="publisher-id">Elmer Press</journal-id><journal-title-group><journal-title>Gastroenterology Research</journal-title></journal-title-group><issn pub-type="ppub">1918-2805</issn><issn pub-type="epub">1918-2813</issn><publisher><publisher-name>Elmer Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27785268</article-id><article-id pub-id-type="pmc">5051073</article-id><article-id pub-id-type="doi">10.14740/gr609e</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters</article-title><alt-title alt-title-type="short">Progressive Familial Intrahepatic Cholestasis</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Amer</surname><given-names>Syed</given-names></name><xref ref-type="aff" rid="Aa">a</xref><xref ref-type="corresp" rid="CORc">c</xref></contrib><contrib contrib-type="author"><name><surname>Hajira</surname><given-names>Amtul</given-names></name><xref ref-type="aff" rid="Ab">b</xref></contrib></contrib-group><aff id="Aa"><label>a</label>Department of Internal Medicine, Mayo Clinic, Phoenix, AZ 85054, USA</aff><aff id="Ab"><label>b</label>Department of Family Medicine, Carle Foundation Hospital, Urbana, IL 61801, USA</aff><author-notes><corresp id="CORc"><label>c</label>Corresponding author: Syed Amer, Department of Medicine, Mayo Clinic Hospital, Phoenix, AZ 85054, USA. Email: <email>drsyedamer1@gmail.com</email></corresp></author-notes><pub-date pub-type="ppub"><month>4</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>02</day><month>5</month><year>2014</year></pub-date><volume>7</volume><issue>2</issue><fpage>39</fpage><lpage>43</lpage><history><date date-type="accepted"><day>24</day><month>4</month><year>2014</year></date></history><permissions><copyright-statement>Copyright 2014, Amer et al.</copyright-statement><copyright-year>2014</copyright-year><license license-type="open access" xlink:href="http://creativecommons.org/licenses/by/2.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>Progressive familial intrahepatic cholestasis or PFIC is a general term used to describe a group of genetic disorders involving the hepatocanalicular transporters. These diseases are characterized by persistent cholestasis, pruritus and jaundice. Type I PFIC is characterized by defect in the gene that codes for aminophospholipid translocase protein and maintains canalicular membrane stability. Types 2 and 3 are caused by defect in genes that code for bile acid transporter and a phospholipid translocase, respectively. This review summarizes the genetics, clinical features, diagnosis and treatment of the three types of PFIC.</p></abstract><kwd-group><kwd>Progressive familial intrahepatic Cholestasis</kwd><kwd>Cholestasis</kwd><kwd>Hepatocanalicular transporters</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare, genetic autosomal recessive disorders, resulting from defects in the mechanisms involved in bile formation with typical clinical, biochemical and histological features. These patients typically present with intrahepatic cholestasis in infancy or childhood. The course of the disease involves portal hypertension, liver failure, cirrhosis, hepatocellular carcinoma along with several extra hepatic manifestations. Three types of PFIC have been described: 1) PFIC type 1, caused by mutations in ATP8B1 gene (also called FIC1); 2) PFIC type 2, caused by mutations in ABCB11 gene (also called BSEP) and 3) PFIC type 3, caused by mutations in ABCB4 gene (also called MDR3). Each mutation is related to the hepatocellular transport system genes involved in bile formation [<xref rid="R01" ref-type="bibr">1</xref>, <xref rid="R02" ref-type="bibr">2</xref>]. Cholestasis is a major clinical sign in all three types [<xref rid="R03" ref-type="bibr">3</xref>].</p><p><xref ref-type="table" rid="T1">Table 1</xref> summarizes the typical features of the three types of PFIC.</p><table-wrap id="T1" orientation="portrait" position="float"><label>Table 1</label><caption><title>Characteristic Features of the Three Types of Progressive Familial Intrahepatic Cholestasis</title></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">PFIC 1</th><th align="left" rowspan="1" colspan="1">PFIC 2</th><th align="left" rowspan="1" colspan="1">PFIC 3</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">Inheritance</td><td align="left" valign="top" rowspan="1" colspan="1">Autosomal recessive</td><td align="left" valign="top" rowspan="1" colspan="1">Autosomal recessive</td><td align="left" valign="top" rowspan="1" colspan="1">Autosomal recessive</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Age of onset</td><td align="left" valign="top" rowspan="1" colspan="1">Neonates</td><td align="left" valign="top" rowspan="1" colspan="1">Neonates</td><td align="left" valign="top" rowspan="1" colspan="1">1 month - 20 years</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Gene</td><td align="left" valign="top" rowspan="1" colspan="1">ATP8B1/F1C1</td><td align="left" valign="top" rowspan="1" colspan="1">ABCB11/BSEP</td><td align="left" valign="top" rowspan="1" colspan="1">ABCB4/MDR3</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Chromosome</td><td align="left" valign="top" rowspan="1" colspan="1">18q21-q22</td><td align="left" valign="top" rowspan="1" colspan="1">2q24</td><td align="left" valign="top" rowspan="1" colspan="1">7q21</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Function of hereditary defect</td><td align="left" valign="top" rowspan="1" colspan="1">Aminophospholipid translocase</td><td align="left" valign="top" rowspan="1" colspan="1">Bile acid secretion</td><td align="left" valign="top" rowspan="1" colspan="1">Phosphatidylcholine secretion</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Cholestasis</td><td align="left" valign="top" rowspan="1" colspan="1">Chronic</td><td align="left" valign="top" rowspan="1" colspan="1">Chronic</td><td align="left" valign="top" rowspan="1" colspan="1">Chronic</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Pruritus</td><td align="left" valign="top" rowspan="1" colspan="1">Severe</td><td align="left" valign="top" rowspan="1" colspan="1">Severe</td><td align="left" valign="top" rowspan="1" colspan="1">Moderate</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Serum GGT</td><td align="left" valign="top" rowspan="1" colspan="1">Normal</td><td align="left" valign="top" rowspan="1" colspan="1">Normal</td><td align="left" valign="top" rowspan="1" colspan="1">High</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Serum ALT</td><td align="left" valign="top" rowspan="1" colspan="1">Mildly elevated</td><td align="left" valign="top" rowspan="1" colspan="1">> 5 × normal</td><td align="left" valign="top" rowspan="1" colspan="1">> 5 × normal</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Serum AFP</td><td align="left" valign="top" rowspan="1" colspan="1">Normal</td><td align="left" valign="top" rowspan="1" colspan="1">elevated</td><td align="left" valign="top" rowspan="1" colspan="1">Normal</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Serum primary bile acid (PBA) concentration</td><td align="left" valign="top" rowspan="1" colspan="1">Very high</td><td align="left" valign="top" rowspan="1" colspan="1">Very high</td><td align="left" valign="top" rowspan="1" colspan="1">High</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Lipoprotein X</td><td align="left" valign="top" rowspan="1" colspan="1">Present</td><td align="left" valign="top" rowspan="1" colspan="1">Present</td><td align="left" valign="top" rowspan="1" colspan="1">Absent</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Albumin</td><td align="left" valign="top" rowspan="1" colspan="1">Low</td><td align="left" valign="top" rowspan="1" colspan="1">Usually normal</td><td align="left" valign="top" rowspan="1" colspan="1">Normal</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Hepatocyte location</td><td align="left" valign="top" rowspan="1" colspan="1">Canalicular membrane</td><td align="left" valign="top" rowspan="1" colspan="1">Canalicular membrane</td><td align="left" valign="top" rowspan="1" colspan="1">Canalicular membrane</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Other sites of expression</td><td align="left" valign="top" rowspan="1" colspan="1">CholangiocytesPancreasIntestines</td><td align="left" valign="top" rowspan="1" colspan="1">None</td><td align="left" valign="top" rowspan="1" colspan="1">None</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Functional defect</td><td align="left" valign="top" rowspan="1" colspan="1">ATP dependent aminophospholipid transport</td><td align="left" valign="top" rowspan="1" colspan="1">ATP dependent bile acid transport in bile</td><td align="left" valign="top" rowspan="1" colspan="1">ATP dependent phosphatidylcholine translocation in bile</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Liver biopsy</td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Histology</td><td align="left" valign="top" rowspan="1" colspan="1">Minimal giant cell transformation, intracanalicular cholestasis, no ductal proliferation, minimal inflammation Late fibrosis</td><td align="left" valign="top" rowspan="1" colspan="1">Giant cell transformation, intracanalicular cholestasis, no ductular proliferation, moderate inflammation, fibrosis</td><td align="left" valign="top" rowspan="1" colspan="1">Giant cell transformation, intracanalicular cholestatis, ductular proliferation, moderate inflammation, marked fibrosis</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Electron microscopy</td><td align="left" valign="top" rowspan="1" colspan="1">Coarsely granular bile Loss of microvilli, swollen microvilli</td><td align="left" valign="top" rowspan="1" colspan="1">Amorphous filamentous bile Loss of microvilli</td><td align="left" valign="top" rowspan="1" colspan="1">Presence of cholesterol crystals Loss of microvilli</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Immunohistochemistry</td><td align="left" valign="top" rowspan="1" colspan="1">BSEP positive</td><td align="left" valign="top" rowspan="1" colspan="1">BSEP negative</td><td align="left" valign="top" rowspan="1" colspan="1">BSEP positive</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1">MDR3 positive</td><td align="left" valign="top" rowspan="1" colspan="1">MDR3 positive</td><td align="left" valign="top" rowspan="1" colspan="1">MDR3 negative</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1">GGT negative</td><td align="left" valign="top" rowspan="1" colspan="1">GGT negative to weakly positive</td><td align="left" valign="top" rowspan="1" colspan="1">GGT positive</td></tr></tbody></table><table-wrap-foot><fn id="nt101"><p>BSEP: bile salt export protein; MDR3: multidrug resistance protein; GGTL: gamma glutamyl transpeptidase; ALT: alkaline tranferase; AFP: alpha fetoprotein.</p></fn></table-wrap-foot></table-wrap></sec><sec><title>PFIC Type 1</title><sec id="s1a"><title>Genetics</title><p>PFIC1, an autosomal recessive disease is caused by the mutation in ATP8B1 gene, which encodes a P-type ATPase, located on human chromosome 18. It is found in several tissues such a small intestine, bladder, stomach, liver and pancreas. It is localized on the apical membrane of epithelial cells, including the canalicular membrane of hepatocytes [<xref rid="R04" ref-type="bibr">4</xref>, <xref rid="R05" ref-type="bibr">5</xref>]. ATP8B1 is hypothesized to be an aminophospholipid flippase, translocating phospholipids such as phosphatidylserine from outer to the inner leaflet of plasma membrane [<xref rid="R06" ref-type="bibr">6</xref>]. Deficiency of ATP8B1 in the hepatocyte may result in loss of asymmetric distribution of the phospholipids in the canalicular membrane, thus reducing membrane stability and function of transmembrane transporters like ABCB11, impairing bile salt transport and decreasing hepatocyte resistance to bile salts, ultimately leading to reduced transport of bile salts in liver and gut resulting in cholestasis and watery diarrhea.</p></sec><sec id="s1b"><title>Clinical features</title><p>In newborns afflicted with type 1 PFIC is characterized by recurrent episodes of intrahepatic cholestasis, intractable pruritus, diarrhea and failure to thrive in first several months of life. It is generally progressive leading to cirrhosis and eventually liver failure in the first decade of life. Other features include short stature, diarrhea, hepatosplenomegaly, malabsorption and occasionally hearing loss.</p></sec><sec id="s1c"><title>Diagnosis</title><p>The diagnostic features include elevated serum bile salts, normal serum GGT, electron microscopy showing coarse granular bile and light microscopy showing bland cholestasis. Genetic testing is the only reliable way to distinguish between PFIC 1 and PFIC 2.</p></sec><sec id="s1d"><title>Treatment</title><p>Pharmacological treatment includes ursodeoxycholic acid (UDCA) to promote biliary flow [<xref rid="R07" ref-type="bibr">7</xref>], but its effect on disease progression is uncertain. Rifampin (accelerates hepatic detoxification and excretion of bilirubin and bile salts) and cholestyramine (a hydrophilic, water insoluble anion exchange resin that binds bile salts, preventing their reabsorption in enterohepatic circulation) ease pruritus. These patients may also need supplements of fat soluble vitamins.</p><p>Partial biliary diversion may be beneficial in some patients, significantly decreasing their symptoms [<xref rid="R08" ref-type="bibr">8</xref>]. It may even delay or interrupt hepatocyte injury if performed early in the course of the disease. Liver transplantation is the most effective form of treatment especially in those with progressive disease or established cirrhosis, usually within the first decade of life.</p></sec></sec><sec id="s2"><title>PFIC Type 2</title><sec id="s2a"><title>Genetics</title><p>PFIC 2, an autosomal recessive disease is caused by mutation in ABCB11 gene on chromosome 2q24, which encodes the canalicular bile salt export protein (BSEP), a liver specific adenosine triphosphate (ATP)-binding cassette transporter [<xref rid="R9" ref-type="bibr">9</xref>, <xref rid="R10" ref-type="bibr">10</xref>]. BSEP is a major exporter of primary bile acids against extreme concentration gradients. There are many mutations that have been identified, but the most common mutations are the missense mutations E297G and D482G. Defective BSEP can lead to impaired bile salt secretion, accumulation of bile salts in hepatocytes and subsequent hepatocellular injury, apoptosis or necrosis. Missense mutations cause less severe disease, whereas the risk of hepatobiliary malignancy is increased with trunacating mutations.</p></sec><sec id="s2b"><title>Clinical features</title><p>Patients usually present with cholestatic jaundice in neonatal period. Pruritus is usually the dominant feature. Clinical features and disease progression may be more severe in PFIC 2 than in PFIC 1. Other features may include growth failure, deficiency of fat soluble vitamins. These patients are at considerable risk of hepatobiliary malignancy, hepatocellular carcinoma or cholangiocarcinoma , thus close surveillance is important in these patients [<xref rid="R11" ref-type="bibr">11</xref>].</p></sec><sec id="s2c"><title>Diagnosis</title><p>Diagnostic features include elevated bile salts, normal serum GGT, electron microscopy showing amorphous or filamentous bile. Light microscopy shows nonspecific giant cell hepatitis. Immunohistochemical staining for canalicular BSEP is negative in majority of patients.</p></sec><sec id="s2d"><title>Treatment</title><p>Patients with PFIC 2 have poor response to ursodeoxycholic acid. Partial external biliary diversion (PBED) (it interrupts the enterohepatic circulation by partially diverting bile from the gallbladder through a loop of jejunum connecting the gallbladder to abdominal skin) may be useful and if performed early enough may delay or interrupt hepatic injury. Histological changes may show some improvement.</p><p>Liver transplantation is usually successful in this group of patients although recurrence after transplantation has been reported [<xref rid="R12" ref-type="bibr">12</xref>]. This can be resolved with aggressive immunosuppressive therapy.</p></sec></sec><sec id="s3"><title>PFIC Type 3</title><sec id="s3a"><title>Genetics</title><p>PFIC 3, an autosomal recessive disease is caused by mutations in ABCB4, which encodes the multidrug resistance-3 gene (MDR3), an ATP-binding cassette transporter. It is located on chromosome 7q21. It acts as a phospholipid translocator involved in biliary phospholipid (phosphatiylcholine) excretion. It is mainly expressed in the hepatocyte canalicular membrane. ABCB4 defects cause impaired excretion of phophatidycholine, which is an important component in formation of mixed micelles, which protect the membrane of cells facing biliary tree from the detergent activity of bile salts. Functional deficiency of ABCB4 causes the detergent action of bile salts to solubilize the cell membrane of the biliary epithelium inducing inflammation and cell death.</p><p>Several different types of mutation have been identified and those with missense mutation have less severe phenotype, with later onset of disease, slower progression and better response to treatment than those with trunacating mutations.</p><p>Heterozygous mutations in ABCB4 gene can cause conditions such as intrahepatic cholestasis of pregnancy, cholesterol gall stone formation, drug induced cholestasis and adult biliary cirrhosis [<xref rid="R13" ref-type="bibr">13</xref>].</p></sec><sec id="s3b"><title>Clinical features</title><p>Patients with ABCB4 deficiency usually have jaundice, pale stools, hepatosplenomegaly or pruritus. Age at onset varies from infancy to adulthood. Adolescent and young adult patients are more likely to have cirrhotic symptoms owing to portal hypertension. No association with malignancy has been described in PFIC 3 patients [<xref rid="R14" ref-type="bibr">14</xref>].</p></sec><sec id="s3c"><title>Diagnosis</title><p>The diagnostic features include elevated serum bile salts, elevated serum GGT, electron microscopy showing presence of cholesterol crystals and loss of microvilli, light microscopy showing ductular proliferation and inflammatory infiltrate in early stages, portal and peri-portal fibrosis, cirrhosis and cholestasis which are seen in the later stages.</p></sec><sec id="s3d"><title>Treatment</title><p>UDCA is useful in almost half of the patients. It is more likely to work in those who have an MDR3 missense mutation as they have some residual protein activity. Those who do not respond to UDCA treatment are likely to have a truncated protein. In these patients, liver transplantation is the primary treatment.</p><p><xref ref-type="table" rid="T2">Table 2</xref> lists the differential diagnosis of the three types of PFIC that an astute clinical should be mindful of.</p><table-wrap id="T2" orientation="portrait" position="float"><label>Table 2</label><caption><title>Differential Diagnosis of PFIC</title></caption><table frame="hsides" rules="groups"><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">A) Disorders of bile acid synthesis biosynthesis and conjugation</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> i) 3-oxo-4-steroid 5-reductase deficiency</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> ii) 3 -hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> iii) Oxysterol 7-hydroxylase deficiency</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> iv) Bile acid-CoA: amino-acid N-acyltransferase deficiency (familial hypercholanemia)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">B) Disorders of embryogenesis</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> i) Alagille syndrome (jagged 1 defect, syndromic bile duct paucity)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> ii) Ductal plate malformation (autosomal recessive polycystic kidney disease, autosomal dominant polycystic liver disease, Caroli’s disease)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">C) Trafficking and canalicular targeting defects</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> i) Arthrogryposis, renal dysfunction, cholestasis</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">D) Tight, junction defects</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> i) Neonatal ichthyosis sclerosing cholangitis</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> ii) Familial Amish hypercholanemia</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">E) Miscellaneous</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> i) Aagenaes syndrome ( hereditary cholestasis with lymphedema)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"> ii) North American Indian Childhood Cirrhosis</td></tr></tbody></table></table-wrap></sec></sec><sec id="s4"><title>Conclusion</title><p>The review aims to summarize the genetics, clinical features, diagnostic and therapeutic strategies for the three types of PFIC. 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