Cholestatic Disorders Flashcards
Cholestasis Definition and complications
Cholestasis = impaired bile flow.
- Complications in the liver: build up of bile in hepatocytes leads to apoptosis and fibrosis and cirrhosis.
- Complications in the intestine: lack of bile in intestine leads to decreased fat absorption (diarrhea and malnutrition), and decreased vitamin absorption (ADEK deficiencies).
Enterohepatic circulation of bile acids
- Bile is secreted into the duodenum, reabsorbed in distal ileum, each bile acid circulates 8-10 times a day. This is an efficient process.
Causes of neonatal cholestasis
- BA (41%)
- Idiopathic (13%)
- Preterm (10%)
- PFIC (10%)
Anatomic causes of cholestasis:
- Extrahepatic bile ducts and gallbladder:
- Intrahepatic bile ducts:
- Hepatocytes:
Extrahepatic causes of neonatal cholestasis include
- BA
- Choledochal cyst
- Neonatal SC
Intrahepatic causes of neonatal cholestasis include:
- Bile duct paucity (Alagille syndrome: JAG1 and Notch 2); non-syndromic
- Ductal plate malformation: Congenital hepatic fibrosis, ARPKD, Caroli disease.
- Cystic fibrosis.
Hepatocellular causes of neonatal cholestasis include
- Indeterminate
- Infectious
- PFIC
- Metabolic/storage disease, bile acid synthesis defects, mitochondrial and peroxisomal disease, alpha-1-antitrypsin deficiency.
Miscellaneous causes of neonatal cholestasis include:
- Endocrine (panhypopit, hypothyroidism)
- GALD
-TPN associated cholestasis - Drug toxicity.
Abbreviations:
- PFIC: Progressive Familial Intrahepatic Cholestasis.
- BRIC: Benign Recurrent Intrahepatic Cholestasis.
- BASD: Bile Acid Synthesis Defect
PFIC Genes
- PFIC 1: deficiency in gene ATP8B1 (protein FIC1) deficiency: affects bile acids.
- PFIC 2: deficiency in gene ABCB11 (protein BSEP) deficiency: affects bile acids. (PFIC light)
- PFIC 3: deficiency in ABCB4 (protein MDR3) deficiency: affects phospholipids.
Decreased transporter gene function causes cholestasis (Can be worsened by inflammation, immaturity, drug-induced, pregnancy).
Solute Composition of BIle
- Phospholipids (17%)
- Bile acids (41%)
- Bilirubin: 1%.
- Electrolytes: 31%
- Cholesterol: 3%.
PFIC 2 (ABCB11 Deficiency)
- Biopsies: giant cells, disordered cellular architecture.
- low/normal GGT.
- PFIC 2 is a deficiency of bile acid transport.
Why make a diagnosis?
BSEP deficiency untreated: increased likelihood of liver cancer.
Bile Acid Synthesis Defects
- Cholestatic presentation: +/- liver failure.
- elevated ALT, D Bili, INR
- Low serum GGT and Bile Acid levels.
- Decreased vitamin absorption (ADEK deficiencies)
- Liver damage from intracellular accumulation of toxic BA intermediates.
- Early recognition is key to survival.
- Diagnosis: urine BA analysis (absent primary bile acids) or genetic testing
- FDA approved therapy for cholic acid.
- Glycocholic acid for BA CONJUGATION defects.
Mechanisms of low GGT cholestasis
- retention of bile acids within hepatocyte. If bile acids cannot get into bile ducts, then bile acid cannot damage cholangiocytes (GGT is on apical membrane of cholangiocytes).
Mechanisms of high GGT cholestasis
retention of bile acids within hepatocytes.
presence of bile acids within bile ducts, damages cholangiocyte lining and leads to release of GGT.
PFIC 3 (ABCB4)
- ## High GGT.
PFIC Chart
Alagille Syndrome
- 1 in 30,000
- Clinical diagnosis: 3/7 criteria: Liver, heart, bone, kidney, facies, vascular, eye.
- Gene: JAG1, NOTCH2
- triangle face, posterior embryotoxon, absent bile ducts, butterfly vertebrae, peripheral pulmonic stenosis, 15% prevalence of intracranial hemorrhage, other vasculopathies.
Biliary Atresia
- Bile duct proliferation
- Portal fibrosis
- bile duct plugs
- rapid progression of fibrosis to cirrhosis.
- the later a Kasai is performed, the less likely a patient will keep their native liver beyond infancy.
Biliary Atresia
- Fibro-obliterative disease
- Asplenia/polysplenia
- situs abnormalities
- Cardiac abnormalities
- More prevalent in Asia.
