Cholestasis

Question 1

Neonatal cholestasis definition…..?

Answer 1

Defined biochemically as prolonged elevation of the serum levels of conjugated bilirubin beyond the first 14 days of life

Question 2

Proposed Subtypes of Intrahepatic Cholestasis

Answer 2

A. Disorders of membrane transport and secretion

B. Disorders of bile acid biosynthesis, conjugation and regulation

C. Disorders of embryogenesis

D. Unclassified (idiopathic “neonatal hepatitis”): mechanism unknown

Question 3

Disorders of membrane transport and secretion…….

Answer 3

1. Disorders of canalicular secretion
   a. Bile acid transport: BSEP deficiency
   i. Persistent, progressive (PFIC type 2)
   ii. Recurrent, benign (BRIC type 2)
   b. Phospholipid transport: MDR3 deficiency (PFIC type 3)
   c. Ion transport: cystic fibrosis (CFTR)
   d. Tight junction defect (TJP2 deficiency)
2. Complex or multiorgan disorders
   a. FIC1 deficiency
   i. Persistent, progressive (PFIC type 1, Byler disease)
   ii. Recurrent, benign (BRIC type 1)
   b. Neonatal sclerosing cholangitis (CLDN1)
   c. Arthrogryposis-renal dysfunction-cholestasis syndrome (VPS33B)

Question 4

Disorders of embryogenesis…….

Answer 4

1. Alagille syndrome (Jagged1 defect, syndromic bile duct paucity)
2. Ductal plate malformation (ARPKD, ADPLD, Caroli disease)

Question 5

Disorders of bile acid biosynthesis, conjugation and regulation

Answer 5

1. Δ4-3-Oxosteroid-5β-reductase deficiency
2. 3β-hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency
3. Oxysterol 7α-hydroxylase deficiency
4. Bile acid-CoA Ligase deficiency
5. BAAT deficiency (familial hypercholanemia)
6. Farnesoid X receptor (FXR) deficiency.

Question 6

The top priority is to recognize conditions that cause cholestasis and for which specific therapy is available …….

Answer 6

sepsis, an endocrinopathy (hypothyroidism, panhypopituitarism), nutritional hepatotoxicity caused by a specific metabolic illness (galactosemia), or other metabolic diseases (tyrosinemia

Question 7

Aagenaes syndrome …….

Answer 7

It is idiopathic familial intrahepatic cholestasis associated with lymphedema of the lower extremities.

Question 8

Zellweger (cerebrohepatorenal) syndrome…..

Answer 8

It is a rare autosomal recessive genetic disorder marked by progressive degeneration of the liver and kidneys.

Question 9

Features of Zellweger (cerebrohepatorenal) syndrome ….

Answer 9

Affected infants have severe, generalized hypotonia and markedly impaired neurologic function with psychomotor retardation.

Patients have an abnormal head shape and unusual facies, hepatomegaly, renal cortical cysts, stippled calcifications of the patellas and greater trochanter, and ocular abnormalities

Question 10

Neonatal iron storage disease (neonatal hemochromatosis, gestational alloimmune liver disease) ………

Answer 10

It is a rapidly progressive disease characterized by increased iron deposition in the liver, heart, and endocrine organs without increased iron stores in the reticuloendothelial system.

Question 11

Most severe form of intrahepatic cholestasis…..?

Answer 11

Progressive familial intrahepatic cholestasis type 1 (PFIC 1) or FIC 1 disease (formerly known as Byler disease)

Question 12

Features of PFIC type 1 …..?

Answer 12

Steatorrhea, pruritus,
vitamin D-deficient rickets,
gradually developing cirrhosis, and
low γ-glutamyl transpeptidase (GGT) levels.

Question 13

Defective gene responsible for PFIC 1 …….?

Answer 13

Mapped on Chromosome 18ql2 and results from defect in the gene for FIC-1 ……..ATP8Bl

Question 14

ATP8B1- FIC1 function…..?

Answer 14

P-type ATPase; aminophospholipid translocase that flips phosphatidylserine and phosphatidylethanolamine from the outer to the inner layer of the canalicular membrane

Question 15

Defective FIC-1 might also result in another form of intrahepatic cholestasis:……….?

Answer 15

Benign recurrent intrahepatic cholestasis (BRIC) type I.

The disease is characterized by recurrent bouts of cholestasis, jaundice, and severe pruritus.

The episodes vary from few episodes per year to 1 episode per decade but can profoundly affect the quality of life

Question 16

GGT levels in BRIC type 1 ……?

Answer 16

BRIC type I have normal serum cholesterol and GGT levels.

Question 17

PFIC type 2 (BSEP deficiency) is results from…..?

Answer 17

Mapped to chromosome 2q24 and is similar to PFIC 1.

The disease results from defects in the canalicular adenosine triphosphate -dependent bile acid transporter BSEP (ABCB11)

Question 18

Features of PFIC type 2 ……?

Answer 18

The progressive liver disease results from accumulation of bile acids secondary to reduction in canalicular bile acid secretion.

Mutation in ABC11 is also described in another disorder, BRIC type 2, characterized by recurrent bouts of cholestasis

Question 19

PFIC type 3 (MDR3 disease) features……..

Answer 19

The disease results from defects in a canalicular phospholipids flippase, MDR3 (ABCB4), which results in deficient translocation of phosphatidylcholine across the canalicular membrane.

Mothers who are heterozygous for this gene can develop intrahepatic cholestasis during pregnancy

Question 20

GGT levels in PFIC type 3…..?

Answer 20

In contrast to PFIC I and PFIC 2, patients with PFIC type 3 (MDR3 disease) have high levels of GGT.

Question 21

What is Familial hypercholanemia. ……..?

Answer 21

It is characterized by an elevated serum bile acid concentration, pruritus, failure to thrive, and coagulopathy.

Familial hypercholanemia is a complex genetic trait associated with mutation of bile acid coenzyme A (CoA), amino acid N-acyltransferase (encoded by bile acid transporter [BAAT]) as well as mutations in tight junction protein 2 (encoded by TJP 2, also known as ZO-2)

Question 22

Alagille syndrome…..?

Answer 22

Alagille syndrome (arteriohepatic dysplasia) is the most common syndrome with intrahepatic bile duct paucity.

Bile duct paucity (often erroneously called intrahepatic biliary atresia) designates an absence or marked reduction in the number of interlobular bile ducts in the portal triads, with normal-size branches of portal vein and hepatic arteriole

Question 23

Biopsy in alagille syndrome….?

Answer 23

Biopsy in early life often reveals an inflammatory process involving the bile ducts

Subsequent biopsy specimens then show subsidence of the inflammation, with residual reduction in the number and diameter of bile ducts.

Analogous to the disappearing bile duct syndrome noted in adults with immune-mediated disorders.

Serial assessment of hepatic histology often suggests progressive destruction of bile ducts.

Question 24

Clinical manifestations of Alagille syndrome…..?

Answer 24

Unusual facial characteristics (broad forehead; deep-set, widely spaced eyes; long, straight nose; and an underdeveloped mandible)

ocular abnormalities posterior embryotoxon, microcornea, optic disk drusen, shallow anterior chamber),

cardiovascular abnormalities (usually peripheral pulmonic stenosis, sometimes tetralogy of Fallot, pulmonary atresia, ventricular septal defect, atrial septal defect, aortic coarctation),

vertebral defects (butterfly vertebrae, fused vertebrae, spina bifida occulta, rib anomalies), and 
tubule interstitial nephropathy

Question 25

Other features of Alagille Syndrome …

Answer 25

short stature, pancreatic insufficiency, vasculopathy (Moyamoya syndrome, stroke), and defective spermatogenesis can reflect or produce nutritional deficiency.

Question 26

Clinical features of Alagille syndrome….?

Answer 26

Patients with Alagille syndrome are likely to have pruritus, xanthomas with markedly elevated serum cholesterol levels, and neurologic complications of vitamin E deficiency if untreated

Question 27

Gene responsible for Alagille syndrome….?

Answer 27

Mutations in human Jagged l gene (JAG1), which encodes a ligand for the notch receptor, are linked to ~90% of patients with Alagille syndrome.

Alagille syndrome type 2 is due to mutations in NOTCH2

Question 28

Complications of Alagille syndrome……?

Answer 28

Cardiac , reanal, end stage liver disease..

Hepatocellular carcinoma