Elsevier

Clinics in Liver Disease

Volume 10, Issue 1, February 2006, Pages 27-53
Clinics in Liver Disease

Whatever Happened to “Neonatal Hepatitis”?

https://doi.org/10.1016/j.cld.2005.10.008Get rights and content

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Sporadic and familial forms of idiopathic neonatal hepatitis

In analysis, it seemed that some cases of idiopathic neonatal hepatitis apparently arose spontaneously, whereas others recurred in families. This observation led to the speculation that two fairly distinct subsets of idiopathic neonatal hepatitis existed, sporadic neonatal hepatitis and familial neonatal hepatitis. In the late 1980s a clear understanding of hepatobiliary physiology in early life and the phenomenon of physiologic cholestasis caused by immaturity of bile secretion emerged [2], [3]

Dissecting the components of familial neonatal hepatitis

Progress in proving the hypothesis that familial neonatal hepatitis is caused by inborn errors in hepatic metabolic or excretory function (altered membrane transport, bile acid biosynthesis, or organelle dysfunction) was slow at first. The initial description of organelle dysfunction presenting as cholestasis came in 1969 with discovery of homozygous α1-antitrypsin deficiency–associated cirrhosis [11]. In this disorder, defective storage and intracellular processing of the mutant PiZZ protein

Subtypes of inherited forms of intrahepatic cholestasis

There are multiple clearly identifiable forms of genetic intrahepatic cholestasis, each with varying clinical features and with a high degree of variability in presentation and prognosis. The nature of this heterogeneous subset of intrahepatic cholestatic diseases is being clarified rapidly: they are caused by specific defects in canalicular transport (bile acid or phospholipid) or in bile acid synthesis or by abnormal embryogenesis. The entities have differing prognostic implications. Certain

The biological basis of familial (genetic) forms of neonatal hepatitis

The many theories advanced to explain jaundice without obstruction have long stood as clear evidence of the need of precise information regarding the formation and excretion of the bile.

A. R. Rich, Bulletin of the Johns Hopkins Hospital 1930;47:338.

It has long been postulated that specific inborn molecular defects in the complex structure and function of the bile canaliculus and hepatic excretory systems could lead to cholestasis.

The canalicular membrane

As shown in Table 1, a major mechanism of several inherited forms of intrahepatic cholestasis is altered canalicular transport of either bile acids or phospholipids. The bile canaliculus is surrounded by the apical plasma membrane domains of adjacent hepatocytes (Fig. 2). The composition of the canalicular membrane is distinct from the basolateral membrane. It is enriched in cholesterol and sphingomyelin and in ATP-binding cassette (ABC) transporters that function as export pumps for bile acids

Bile salt export pump deficiency (progressive familial intrahepatic cholestasis type 2): altered bile acid transport

The discovery of BSEP deficiency (also known as PFIC type 2) emerged from genetic analysis that determined locus heterogeneity among patients who had PFIC. The gene mutated in patients who have PFIC2 is ABCB11, which codes for BSEP; the chromosomal locus is 2q24. BSEP, an ABC transporter found only in the hepatocyte canalicular membrane, is the major canalicular transport protein responsible for transporting bile acid out of the hepatocyte. Mutations of the BSEP gene lead to deficiency of

Multi-drug resistance protein 3 deficiency (progressive familial intrahepatic cholestasis type 3): altered phospholipid transport

MDR3/Mdr2 (ABCB4/Abcb4) is a phospholipid translocase that flips phosphatidylcholine from the inner to the outer layer of the canalicular membrane [12], [13], [26]. The gene is localized on chromosome 7q21. Normally, the potential damaging detergent effect of bile acids on the bile duct epithelium is abrogated by the formation of mixed micelles with transported phospholipid [15]. Mutations of the MDR3 gene lead to altered phospholipid transport into the canaliculus and thus the formation of

Altered ion transport—cystic fibrosis (cystic fibrosis transmembrane conductance regulator)

Although not typically considered a cholestatic disorder, cystic fibrosis is included here as a prototype of inherited ductular secretory insufficiency. The well-known basis for the clinical manifestations of cystic fibrosis is mutations in cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent chloride channel that regulates epithelial surface fluid secretion. CFTR is present in cholangiocytes but not in hepatocytes [33], [34]. In theory, deranged cholangiocyte ion

Familial intrahepatic cholestasis-1 gene deficiency (progressive familial intrahepatic cholestasis type 1)

The FIC1 gene (ATP8B1), located on chromosome 18q21-22, has been identified as the gene involved in several related autosomal recessive forms of intrahepatic cholestasis—PFIC type 1, Byler's disease, Greenland familial cholestasis, and BRIC type 1 [35], [36], [37]. This spectrum of disease caused by this gene defect should now be termed “FIC1 deficiency” [10]. The mechanisms by which mutations in FIC1 cause intrahepatic cholestasis are unknown but are the subject of several recent studies. Chen

Disorders of bile acid biosynthesis and conjugation

Bile acids play a major role in the generation of bile flow. Inborn errors in bile acid biosynthesis, which are now recognized as important causes of neonatal cholestasis, lead to absence of normal trophic or choleretic primary bile acids and accumulation of primitive (hepatotoxic) metabolites. Serum levels of the primary bile acids are typically normal or low in affected patients [10], [50], [51]. Hepatobiliary injury is caused by the hepatotoxicity of intermediate metabolites and the absence

Disorders of embryogenesis

Altered embryogenesis is the basis for several discrete disorders, including Alagille syndrome (Jagged 1 defect, syndromic bile duct paucity) and various forms of ductal plate malformation (autosomal dominant polycystic liver disease [ADPLD], autosomal recessive polycystic kidney disease [ARPKD], and Caroli's disease).

McCune-Albright syndrome

McCune-Albright syndrome is a sporadic disorder characterized by the triad of polyostotic fibrous dysplasia, café au lait skin pigmentation, and peripheral precocious puberty in girls. Lumbroso and colleagues [66] reported that McCune-Albright syndrome is actually quite heterogeneous and is caused by postzygotic activating mutations of arginine 201 in the guanine-nucleotide–binding protein alpha subunit, leading to a mosaic distribution of cells bearing constitutively active adenylate cyclase.

New Insights into metabolic disease

In addition to the remarkable progress in understanding the molecular basis of inherited forms of intrahepatic cholestasis, recent studies have also identified new forms of metabolic liver disease manifest as neonatal cholestasis. Other studies have defined the mechanism of these disorders and defined new treatment options. A few of these recent advances are discussed briefly here.

Evaluation

With the insight into the clinical phenotype and the genotype–phenotype correlations, it is now possible to evaluate more precisely the neonate who presents with conjugated hyperbilirubinemia [10]. A logical, sequential evaluation scheme is recommended. First, cholestasis must be promptly recognized. All infants who have persistent jaundice (>14 days of life) should be evaluated for cholestasis [75]. Second, testing should be performed for the specific treatable causes of neonatal cholestasis,

Treatment

The therapeutic goals for patients who have cholestasis caused by any of the disorders discussed here are similar: to alleviate symptoms and improve quality of life as much as possible (pruritus being the predominant complaint), to maintain nutritional health through the administration of medium-chain triglyceride-containing formulas and fat-soluble vitamin supplementation, and to retard the rate of progression to fibrosis and cirrhosis. Current therapeutic approaches are largely empiric and

The future

Despite the recent remarkable developments in the understanding of the pathophysiology of intrahepatic cholestasis and the wide range of genes that has been identified as the molecular basis for many previously enigmatic cholestatic diseases of children, much more work needs to be done. There exists a small percentage of patients who have idiopathic neonatal hepatitis in whom no genetic defect has been detected. Given the multifaceted aspects of these disorders, it is likely that several

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References (83)

  • J.F. Lucena et al.

    A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis

    Gastroenterology

    (2003)
  • E. Jacquemin et al.

    The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood

    Gastroenterology

    (2001)
  • O. Rosmorduc et al.

    ABCB4 gene mutation-associated cholelithiasis in adults

    Gastroenterology

    (2003)
  • J.J. Smit et al.

    Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease

    Cell

    (1993)
  • C.M. Van Nieuwkerk et al.

    Effects of ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene

    Gastroenterology

    (1996)
  • P. Durie et al.

    Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic fibrosis transmembrane regulator knockout murine model

    Am J Pathol

    (2004)
  • L.W. Klomp et al.

    A missense mutation in FIC1 is associated with Greenland familial cholestasis

    Hepatology

    (2000)
  • F. Chen et al.

    Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity

    Gastroenterology

    (2004)
  • R.J. Clayton et al.

    Byler disease: fatal familial intrahepatic cholestasis in an Amish kindred

    J Pediatr

    (1965)
  • L.N. Bull et al.

    Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC1] and Byler syndrome): evidence for heterogeneity

    Hepatology

    (1997)
  • A.C. Kurbegov et al.

    Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile

    Gastroenterology

    (2003)
  • L. Baala et al.

    Homozygosity mapping of a locus for a novel syndromic ichthyosis to chromosome 3q27-q28

    J Invest Derm

    (2002)
  • S. Hadj-Rabia et al.

    Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight junction disease

    Gastroenterology

    (2004)
  • L.N. Bull et al.

    Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q

    Am J Hum Genet

    (2000)
  • M. Fruhwirth et al.

    Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome

    J Pediatr

    (2003)
  • W.F. Balistreri

    Inborn errors of bile acid biosynthesis and transport—novel forms of metabolic liver disease

    Gastroenterol Clin North Am

    (1999)
  • E. Gonzales et al.

    SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase deficiency: evidence for primary genetic defect

    J Hepatol

    (2004)
  • D. Alagille et al.

    Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases

    J Pediatr

    (1987)
  • P. Chagnon et al.

    A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis

    Am J Hum Genet

    (2002)
  • M.J. Phillips et al.

    Abnormalities in villin gene expression and canalicular microvillus structure in progressive cholestatic liver disease of childhood

    Lancet

    (2003)
  • P.F. Whitington et al.

    High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis

    Lancet

    (2004)
  • G. Paumgartner et al.

    Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease

    Clin Liver Dis

    (2004)
  • H.U. Marschall et al.

    Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans

    Gastroenterology

    (2005)
  • J.L. Boyer

    Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease?

    Gastroenterology

    (2005)
  • P. Lykavieris et al.

    Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation

    J Hepatol

    (2003)
  • H. Egawa et al.

    Intractable diarrhea after liver transplantation for Byler's disease: successful treatment with bile adsorptive resin

    Liver Transpl

    (2002)
  • N. Balasubramaniyan et al.

    Multiple mechanisms of ontogenic regulation of nuclear hormone receptors during rat liver development

    Am J Physiol Gastrointest Liver Physiol

    (2005)
  • E. Jacquemin et al.

    Transient neonatal cholestasis: origin and outcome

    J Pediatr

    (1998)
  • D. Herzog et al.

    Transient cholestasis in newborn infants with perinatal asphyxia

    Can J Gastroenterol

    (2003)
  • A. Brucato et al.

    Neonatal lupus

    Clin Rev Allergy Immunol

    (2002)
  • L.A. Lee et al.

    Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry

    Pediatrics

    (2002)
  • Cited by (0)

    Dr. Balistreri has received funding from Digestive Care, Inc., Giliad Sciences, Inc., and Hoffman LaRoche.

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