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1

Cholestasis

Impairment in bile flow
From:
Defects in intrahepatic production
Transmembrane transport
Mechanical obstruction

2

Cholestasis - Manifestations

Retention of bile components
Elevated serum bile acids - Pruritis
Hyperbilirubinemia - Jaundice
Hypercholesterolemia - Xanthomas
Impaired copper excretion - fibrosis
Neonatal cholestasis > 2 weeks affects 1 in 2500 births

3

Cholestasis Consequences - Impaired Bile Salt Excretion

Fat Malabsorption - Nutritional Impairment
Fat Soluble Vitamin Deficiency

4

Cholestasis Consequences - Hepatocellular Injury

Progressive fibrosis, evolving to cirrhosis
Portal hypertension
Loss of hepatic synthetic function

5

Most common cause of neonatal cholestasis, but least understood

Idiopathic Neonatal Hepatitis

6

Idiopathic Neonatal Hepatitis

30 - 40% of neonatal cholestasis
Jaundice in the first week of life
33% FTT or fulminant course
Hepatomegaly +/- Splenomegaly
Acholic stool possible

7

Two forms of Idiopathic Neonatal Hepatitis

Sporadic (60 - 70% full recovery)
Familial (20 - 30% recovery, 10 - 15% cirrhosis)

8

Idiopathic Neonatal Hepatitis - Pathology

Severe diffuse hepatocellular disease
Marked infiltration by inflammatory cells
Focal hepatocellular necrosis
GIANT CELL HEPATITIS

Not present:
Bile ductular proliferation
Bile duct paucity

9

Biliary Atresia

Uncommon
No familiar pattern
Icteric by first week
Acholic stools

10

Biliary Atresia - Associated abnormalities

Polysplenia
Heterotaxia
Intra-abdominal vascular abnormalities

11

Biliary Atresia - Cause

Unknown
Can be induced via infectious agents (Reovirus III, CMV)

12

Biliary Atresia - Investigations

Abdominal ultrasound (to rule out biliary obstruction like a choledochal cyst)
HIDA scan with phenobarb x 5D (good for ruling out)
Liver biopsy
Intra-op cholangiogram

13

If you give phenobarb to a pediatric patient, what are the two ways they can go about bile absorption?

Bile acid dependent (main/only pathway in adults)
Bile acid independent (about 10% of the pathway in kids, can induce this pathway with phenobarb)

14

Biliary Atresia - Pathology

Infantile obstructive cholangiopathy
Bile ductular proliferation
Portal expansion with edema +/- fibrosis
Bile plugs
Intact lobular architecture
Giant cells may be present

15

Biliary Atresia - Treatment

Kasai hepatic porto-enterostomy
Performed in the first few months of life (

16

Alagille Syndrome

Autosomal Dominant
Arteriohepatic dysplasia
Variable penetrance
JAG 1 (notch ligand) mutation (>90%)
Chromosome 20p12
Intrahepatic interlobular bile duct paucity

17

Alagille syndrome - Abnormalities

Face - Broad forehead, underdeveloped mandible, straight nose (95%)
Ocular - Posterior embryotoxon - finding in the eye, doesn't change vision(88%)
Cardiovascular - Peripheral Pulmonic Stenosis or Tetralogy of Fallot (85%)
Vertebral - Butterfly vertebrae (87%)
Minor abnormalities - Renal disease, short stature, pancreatic insufficiency

18

Alagille's Syndrome - Prognosis

Prolonged survival good (80% without OLT)
Pruritus
Xanthoma - Lipoprotein X
Neurologic complications (Vitamin E deficiency)
Defective spermatogenesis
Growth retardation
CNS anyeurisms

19

Progressive Familial Intrahepatic Cholestasis (PFIC)

Byler's-like syndrome
Autosomal Recessive

PFIC-1 defect in P-type ATPase gene (ATP8B1)
FIC-1 gene localized to chromosome 18q21
Defect in biliary canalicular membrane phospholipid transport

PFIC-2 - defective bile salt export pump (BSEP) - You can stain for this on biopsy now!!

Normal GGTP (it's a transport defect!)

Post transplant sometimes you end up with bile salty diarrhea

20

Choledocal Cyst

Congenital biliary dilatation
Common bile duct affected
Cyst wall - fibrous tissue lacking epithelium
Malignant potential - Merits resection

Early

21

Choledocal Cyst - Type 1

50 - 80%
Diffuse fusiform dilatation of the common bile duct

22

Choledocal Cyst - Type 2

Diverticulum of common bile duct

23

Choledocal Cyst - Type 3

Within the duodenal wall

24

Choledocal Cyst - Type 4

Type 1 (diffuse fusiform dilatation) with intrahepatic duct cyst

25

Choledocal Cyst - Diagnosis

Abdominal ultrasound

26

Caroli's Disease

Cystic dilatation of intrahepatic ducts
Not familial
75% male
Usually present in childhood or early adult life
Abdominal pain, hepatomegaly, gram (-) sepsis

27

Caroli's Disease - Diagnosis

Ultrasound, CT scan, ERCP, PTC
Common bile duct normal, multiple saccular dilatations of intrahepatic ducts, can be unilateral
Cholangiocarcinoma risk - 7% of patients

28

Caroli's Disease - Treatment

Stenting, suppressive antibiotics, pain meidcation

29

Gestational Alloimmune Liver Disease

Formerly known as neonatal hemochromatosis

Hepatic failure (at birth!) and iron deposition
Onset is intrauterine
Anti-human C5B-9 complex - Transplacental IgG
Activates fetal complement cascade
Target protein not identified

30

Gestational Alloimmune Liver Disease - Treatment

IVIG and exchange transfusion
Liver transplant if medical treatment fails

Subsequent pregnancies treated with IVIG beginning at 18 weeks gestation (90% recurrence)

31

Infectious Hepatitis - Pathogens

Toxoplasmosis
Rubella
CMV
Herpes
Syphillis
Coxsackie
Echovirus (11, 14, 19)
Adenovirus
Parvovirus B19
EBV (unusual)

32

Alpha-1 Antitrypsin Deficiency

AAT serine protease inhibitor (PI)
Accumulation of abnormal protein in ER
PI phenotyping - defined by isoelectric focusing of plasma
Gene on chromosome 14 with over 100 known mutations
Most common allele causing liver disease is Z
Transplant for severe liver disease / cirrhosis - 65%
Risk of COPD with panlobular emphysema

33

Alpha-1 Antitrypsin Deficiency - Path

PAS+ Globules that resist diastase treatment

34

Parenteral Nutrition-Associated Liver Disease

Formerly TPN Cholestasis
Range from mildly elevated LFTs and Fatty Liver to Frank Cirrhosis
Cholestasis - Worse with time and lack of enteral stimulation
Etiology unknown - Toxic bile acid metabolites, bacterial toxins, glucose concentration, free oxygen radicals from peroxidation of lipids

35

Parenteral Nutrition-Associated Liver Disease - Treatment

Feed, Cycle or stop TPN
Reduce lipids
Bowel in circuit
STEP
Ursodiol
Bowel decontamination

36

Parenteral Nutrition-Associated Liver Disease - Biopsy

Indistinguishable from Biliary Atresia

Bile plugs
Ductular abnormalities

37

Tyrosinemia

Autosomal Recessive
Lack fumaryl acetoacetate hydrolase (FAH)
Metabolites toxic to liver and kidney (RTA)
Neurologic impairment can occur
Painful crises, mimicking porphyria
HCC occur in >40% of cases

38

Tyrosinemia - Diagnosis

Elevated urinary succinyl acetone

39

Tyrosinemia - Treatment

NTBC/Orfadin
Specific inhibitor of tyrosine metabolism

40

Tyronsinemia - Cure

Transplant

41

Galactosemia

Autosomal recessive
Lacking galactose-1-phosphate-uridyl transferase
Diffuse hepatocellular fatty change

42

Galactosemia - Infant signs

Feeding problems, cataracts, vomiting, jaundice, diarrhea, ascites, HM, sepsis

43

Galactosemia - Diagnosis

+ Urine reducing substance, G1PUT levels

44

Galactosemia - Treatment

Withdrawal of dietary milk and milk products

45

Cholestasis - Overall management

Nutritional support (vitamin supplementation)
Alleviate pruritus (Choleretic agents)
Monitor growth, clinical and biochemical parameters
Optimize psychosocial development
Assess quality of live
Gauge success, search for complications
Disease specific therapy - diet, surgical palliation, medications
Liver transplant