Progressive familial intrahepatic cholestasis (PFIC ...



Progressive familial intrahepatic cholestasis

• Autosomal recessive inherited disorder of childhood characterized by cholestasis of hepatocellular origin.

• Often presents in the neonatal period or the first year of life and leads to death from liver failure at ages ranging from infancy to adolescence.

• Cholangiograms show normal extra- and intrahepatic bile ducts.

• Recent molecular and genetic studies have allowed the identification of genes responsible for three types of PFIC.

PFIC TYPE 1 (BYLER'S DISEASE)

• Was originally described in Amish kindred, the Byler family.

• Patients with phenotypic findings resembling those of PFIC1 but unrelated to the original Byler family are considered to have Byler syndrome.

• Genetic defect

• A locus for PFIC1 has been mapped to 18q21-q22 in the original Byler pedigree.

• Same as that for benign recurrent intrahepatic cholestasis (BRIC).

• Byler's disease is caused by a defect of a gene, FIC1.

• This gene encodes a P-type ATPase which may be involved in the transport of aminophospholipids from the outer to the inner leaflet of various cellular membranes.

• Five mutations have been identified; one deletion, one skipped exon, and three missense mutations.

• The FIC1 gene is expressed in various organs, including the liver, pancreas, kidney, and small intestine().

• Pathogenesis

• The function of FIC1 is not yet known, but it is postulated that the defect of the FIC1 gene ( impair the membrane distribution of aminophospholipids( indirectly disturbing the biliary secretion of bile acids.

• Being highly expressed in the small intestine could explain the chronic watery diarrhea present in a few children with PFIC1.

• Clinically

• Initially characterized by bouts of jaundice which resolve spontaneously.

• Jaundice becomes permanent later in the course of the disease with severe pruritus.

• Chronic watery diarrhea present in a few children with PFIC1 which does not resolve after liver transplantation.

• Fibrosis progresses to irregular cirrhosis and leads to death from liver failure within the first decade and rarely after adolescence.

• Biochemically

• Conjugated hyperbilirubinemia.

• Normal serum (γGTP) activity and cholesterol level.

• High concentrations of serum primary bile acids.

• Low biliary primary bile acid concentration mainly affecting chenodeoxycholic acid.

• Liver histology

• In the first months of life shows:

o Canalicular cholestasis.

o Minimal giant cell transformation.

o Slight lobular and portal fibrosis.

o Absence of a true ductular proliferation.

PFIC TYPE 2

• Genetic defect

• A gene locus for PFIC2 has been mapped to 2q24 in Middle Eastern patients in whom the PFIC1 locus was excluded.

• This gene codes for the transporter, called the sister of P-glycoprotein (SPGP) which represents a canalicular bile salt export pump (BSEP).

• Pathogenesis

• Defect in canalicular bile salt export pump ( ↓canalicular excretion of bile acids ( accumulation of bile acids inside the hepatocyte ( severe hepatocellular damage.

• Clinically

• Initial presentation and evolution seem to be severer, with permanent jaundice from the onset and the rapid appearance of liver failure.

• Severe pruritus.

• Fibrosis progresses rapidly to irregular cirrhosis and leads to liver failure within the first years of life.

• Biochemically

• Conjugated hyperbilirubinemia.

• Normal serum γGTP activity and cholesterol level.

• High concentration of serum primary bile acids.

• Low biliary primary bile acid concentration.

• Liver histology

• Initial liver histology shows:

o Same as type 1 +

o Liver architecture is more perturbed.

PFIC TYPE 3

• Genetic defect

• Genetic defect in the MDR3 gene, which is located on 7q21 which encodes for the normal formation of phospholipid in bile.

• Pathogenesis

• In the absence of biliary phospholipids( toxic effect of bile acids on bile canaliculi and the biliary epithelium.

• Biliary phospholipids normally protect ductular epithelial cells from the toxicity of bile acids by forming mixed micelles.

• Clinically

• Patients with PFIC3 usually present later in life.

• Higher risk of portal hypertension and gastrointestinal bleeding, and end in liver failure at a later age.

• Mild and variable pruritus.

• Nonsuppurative cholangitis.

• In family having an affected child heterozygous women had experienced typical recurrent episodes of intrahepatic cholestasis of pregnancy.

• It is likely that the heterozygous state for a MDR3 gene defect represents a genetic predisposition in these families because cholestasis was not present in every pregnancy in these women.

• Biochemically

• Conjugated hyperbilirubinemia.

• High serum γGTP activity.

• Moderately raised concentrations of serum primary bile acids.

• Normal concentration of biliary primary bile acids.

• Liver histology

o Portal fibrosis.

o Ductular proliferation.

o Inflammatory infiltrate in the early stages despite patency of intra- and extrahepatic bile ducts.

o Biliary cirrhosis.

• Genomic DNA analysis, cDNA analysis and immunohistochemistry can identify MDR3 gene defect.

TREATMENT

o Ursodeoxycholic acid (UDCA).

o Partial external biliary diversion.

o Liver transplantation.

• Therapy with UDCA and partial external biliary diversion should be considered in the initial therapeutic management of children with PFIC.

• It could prevent evolution towards cirrhosis and therefore avoid, at least in the short term, the need for liver transplantation in some children.

• Ursodeoxycholic acid (UDCA)

• Effective in all types of PFIC for resolving or improving liver tests and improving the clinical status of a proportion of children.

• Actions:

• Increases the hepatocyte excretion of endogenous bile acids.

• Limits their return to the liver by inhibiting their intestinal reabsorption.

• Induce stimulation of canalicular exocytosis.

• Modulation of biliary bile acid composition in favor of hydrophilic bile acids which might diminish cellular injury.

• Partial external biliary diversion

• Can provide effective relief from pruritus and reversal of liver disease in children with normal γGTP-PFIC (PFIC1 and PFIC2).

• Biliary diversion would reduce the size of bile acid pool and possibly reduce preload for defective transport mechanisms (

o ↓hepatocellular concentrations of bile acids.

o Reverse cellular membrane injury.

o Recover canalicular mechanisms for bile formation.

DD

[pic]

Causes of hyperbilirubinemia in childhood

1. Increased bilirubin production

a. Increase in the release of heme from red blood cells

i. Hemolysis due to Rh incompatibility, ABO incompatibility.

ii. Increased fragility of erythrocytes in congenital spherocytosis, hereditary elliptocytosis, , or red blood cell enzyme defects (G6PD; pyruvate kinase, PK)

iii. Enclosed hematomas.

2. Decreased bilirubin uptake into hepatocyte:

a. Hypothyroidism or gestational hormones that may inhibit the uptake of bilirubin across the hepatocyte membrane.

b. Hypoalbuminemia, generalized hypoproteinemia.

3. Abnormalities of intracellular binding or storage of bilirubin within hepatocytes:

a. Deficiencies or alteration in glutathione S-transferase (GST), the primary intracellular binding protein for bilirubin

b. Rotor syndrome represents deficient intracellular storage of bilirubin and is characterized by:

i. direct and indirect hyperbilirubinemia without hemolysis

ii. No alterations in liver enzymes or liver histology.

4. Inefficient conjugation of bilirubin within the hepatocyte.

a. Decrease in BGT activity is seen in Gilbert's syndrome, resulting in benign elevations in serum bilirubin levels, especially during stresses such as viral illnesses

b. Crigler-Najjar syndrome characterized by absence of BGT leading to severe hyperbilirubinemia with associated neurologic effects secondary to kernicterus

c. Neonatal hemochromatosis, alpha-1 antitrypsin deficiency, Wolman's disease, NiemannPick disease and cystic fibrosis can cause hyperbilirubinemia in the neonatal period, presumably secondary to hepatocyte damage

5. Alterations in the secretion of bilirubin through the canalicular membrane into the biliary tract: bilirubin diglucuronide is excreted into the canaliculus by an undescribed carrier protein.

a. Alterations in this protein are thought to be the cause of Dubin-Johnson syndrome.

i. No associated morbidity or mortality.

ii. Elevated levels of conjugated and unconjugated serum bilirubin.

iii. Hyperbilirubinemia is accentuated during pregnancy or with use of oral contraceptives.

iv. Autosomal recessive disorder.

v. Increase in urinary coproporphyrin 1 level.

vi. Liver biopsy shows a characteristic melanin-like pigment deposited in liver cells but is otherwise histologically normal

6. Structural abnormalities of the biliary tree can prevent drainage of bile from the canaliculus into the intestine, causing accumulation of bile and reflux of bilirubin into the systemic circulation:

a. Extrahepatic biliary atresia characterized by

i. inflammation and fibrosis of the extrahepatic biliary tract ( partial or complete obliteration of the extrahepatic bile ducts

ii. Presents between 2 and 6 weeks of age as cholestasis.

iii. Liver biopsy shows fibrosis and bile duct proliferation

iv. May be syndromic (< 15% of cases) associated with cardiac anomalies, polysplenism, and malrotation or situs inversus, or non-syndromic (majority of cases), etiology unknown

b. Intrahepatic cholestasis

i. Histological finding of bile duct paucity, defined as a reduced ratio of interlobular bile ducts to portal tracts (normal = 0.9-1.8; paucity 30 mg/dL are associated with development of encephalopathy.

• Cholestasis

• Malnutrition secondary to fat malabsorption can lead to failure to thrive and fat-soluble vitamin deficiencies

• Intractable pruritus

• Xanthomatosis secondary to alterations in cholesterol metabolism 9 Treatment

Lymphedema-cholestasis syndrome or Aagenaes syndrome

• Intrahepatic cholestasis associated with lymphedema of the lower extremities.

• Serum γ-GTP levels are inappropriately low.

• Episodic cholestasis with patient normal in-between..

Zellweger (cerebrohepatorenal) syndrome

• Autosomal recessive genetic disorder marked by degeneration of the liver and kidneys.

• Fatal within 6–12 mo.

• Severe, generalized hypotonia and markedly impaired neurologic function.

Niemann-Pick disease type C

• Cholestasis + disproportionate splenomegaly.

• Mildly delayed motor development and persistent splenomegaly with or without hepatomegaly

• Defective cellular cholesterol esterification in cultured skin fibroblasts.

Neonatal iron storage disease

• Increased iron deposition in the liver, heart, and endocrine organs without increased iron stores in the reticuloendothelial system.

• Multiorgan failure and shortened survival.

• The diagnosis is confirmed by buccal mucosal biopsy or MRI demonstrating extrahepatic siderosis.

|BRIC |Unknown but most likely a regulatory |Recurrent attacks of severe cholestasis, pruritus, jaundice, steatorrhea, and|

| |defect of bile salt secretion |weight loss. Normal liver function in intervals between the attacks |

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download