Jaundice

Front 1

Cholestasis Definition

Back 1

Decrease in bile flow: Impaired secretion by hepatocyte or obstruction of bile flow through intra – or extrahepatic bile ducts

Front 2

Cholestasis Presentation

Back 2

• Substances excreted in bile retained. Most commonly measured conjugated bilirubin (BR) and bile salts – retained to various extents
• Presentation: non specific, routine bloods or fatigue, pruritis and jaundice if severe

Front 3

Bile

Back 3

Bile is a Highly complex water-based medium containing inorganic ions and many classes of organic compounds, the formation of which involves multiple mechanisms and levels of regulation
The transport of solute into the canaliculus by specific transporters creates chemical and osmotic gradients and promotes water flow by a paracellular pathway
Several of these specific transporters have been identified, and their function has been characterized
Defective transporters in some familial cholestatic disorders have been identified..

Front 4

Major hepatocyte transporters that determine bile production and hepatic drug transport

Back 4

Bile acid production
1940- 1991: actively transported in to hepatocyte by Na dependent transporter and then into the cannalicular vi another step??

2013
Sinusoidal membrane: Importers and exporters of bile, (importer (coupled with Na/organic ions),
Canalicular membrane: defect in transporter responsible for syndrome .. Eg MRP2 –Dubin Johnson

Front 5

Solute composition of Bile

Back 5

•Bile acid (41%)
•Electrolytes (31%)
•Phospholipids (17%)
•Proteins (7%)
•Cholesterol (3%)
•Bilirubin (1%)

Front 6

Bile acids
•
Regulates own transport and synthesis via nuclear receptors

Back 6

• Cholestasis can result when there is a defect in the transporter or the regulation of transporter (ie nuclear receptors)

Front 7

Cholestasis is bad..

Back 7

•Hepatocytes must maintain safe intracellular bile acid levels
•Bile acid accumulation – hepatocyte damage
–Increased apoptosis
–Changes in membrane fluidity
–Cell signallling (Fas, PKC, Ca..) … increase in pro-inflammatory cytokine expression

Front 8

Consequences of cholestasis

Back 8

•Mainly effects liver and intestine: widespread secondary effects on most organs
•Increased bile retention in hepatocytes
•Increased serum bile salt
•Reduced bile salt in enterohepatic circulation
•Decreased total bile salt pool size
•Principal sign of cholestasis – jaundice due to elevated serum conjugated BR, and dark urine
•In cholestasis, BR conjugation continues, but excretion is limited in cholestasis.
•How BR regurgitates into serum .. Not clear and likely to depend on underlying disease

Front 9

BR derived from

Back 9

–Hb of senescent erythrocytes (80%)
–Breakdown of haemoproteins in the liver (20%)
–Ineffective erythropoiesis (2—3%)
–Haemoproteins in the extrahepatic tissue such as myoglobin (<1%)

Front 10

Bilirubin Pathway

Back 10

•
Hepatocyte take up BR and conjugate to glucuronide (glucuronyl transferase) and excrete BR diglucuronide in bile into the duodenum
•In terminal ileum and colon, bacteria break down BR conjugate to urobilinogen (80% excreted in faeces). Remaining 20% reabsorbed and excreted in bile and urine (enterohepatic circulation of urobilinogen)
•Functional or anatomical obstruction at any level (from Hb breakdown to uptake by the hepatocellular membrane to excretion in the biliary system can result in jaundice

Front 11

Jaundice

Back 11

•Increased sBR, yellow, due to deposition of bile pigment in sclera, skin and mucus membranes, body fluids and secretions
•Clinical sBR > 40-80 umol/L (2-4 mg/dL)
•Hepatocelllular disease/obstruction
•Genetic defects in uptake and conjugation of BR handling (increased unconjugated BR)
•Increased breakdown of Br (increased unconjugated BR)
–Haemolysis (haemolytic anaemia hereditary or acquired)
–ineffective haemopoiesis, massive transfusion due to decrease lifespan of rbc
–resorption of haematoma, following major trauma

Front 12

Gilbert’s syndrome

Back 12

•Commonest hereditary cause of inc BR (unconjugated), benign disease, minor inborn error of metabolism
• ~5-10% of population
• Due to reduced activity (70-80%) of glucuronlytransferase (UGT1A1) – which also detoxifies some drugs
• Mild jaundice: fasting, exertion, stress, infection
• Reduced risk of coronary heart disease
• DDx Crigler-Najjar sydrome, Dubin Johnson and Rotor sydrome (inc conjugated BR)

Front 13

Genetic disorders

Back 13

Front 14

Cholestasis
- hepatocellular vs Obstructive
- Chronic vs acute

Back 14

Classified into hepatocellular (impairment of bile formation) and obstructive (impedance of bile flow anywhere distal to the bile canaliculi)
Chronic if > 6 m duration
Patients can present as asymptomatic work up (ALP >1.5 x and GGT > 3x increase, later elevated s conjugated BR)
Isolated GGT non specific (from enzyme induction due to alcohol or drugs)
Isolated ALP can occur in cholestatic liver disease (eg, progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis defects), but also from rapid bone growth in kids, bone disease (Pagets) or pregnancy

Front 15

Hepatocellular cholestasis

Back 15

•Drugs, TPN, sepsis, congestive hepatopathy
•Alcoholic or non-alcoholic steatohepatitis
•Genetic disorders: e.g. Wilson’s disease, BRIC, PFIC, ABCB4 deficiency
•Viral hepatitis
•Cirrhosis
•Cholestasis of pregnancy
•Malignant infiltration: haematologic, metastates
•Paraneoplastic: e.g., Hodgkin disease, renal carcinoma
•Amyloidosis, sarcoidosis,storage diseases, erythropoietic protoporphyria, nodular regenerative hyperplasia
•Vascular disorders: Budd–Chiari, veno-occlusive disease

Front 16

Cholangiocellular cholestasis..

Back 16

Cholangiocellular (cells pertaining to the bile duct)

Primary biliary cirrhosis
Primary (secondary) sclerosing cholangitis
Autoimmune hepatitis
Drug-induced cholangitis
Sarcoidosis
ABCB4 deficiency
CF
Hepatitis C, B, E), AIDS
2. Fibrous obliterative cholangitis
Primary sclerosing cholangitis
Secondary sclerosing cholangitis
IgG4-associated cholangitis
Sarcoidosis
3. Other cholangitis (unusual)
Malignant cholangitis
Lymphoma (Hodgkin or non-Hodgkin)
Systemic mastocytosis
Langerhans cell histiocytosis
Neutrophilic cholangitis: neutrophilic dermatosis
4. Ductal plate malformations
Biliary hamartomas (von Meyenburg complexes)
Caroli syndrome
Congenital hepatic fibrosis

Front 17

Drug induced cholestasis

Back 17

Acute drug-induced cholestatic injury represents one of three major forms of drug-induced liver injury (DILI) and has been defined by an international consensus panel by an isolated elevation of serum alkaline phosphatase (AP) >2 ULN or an alanine aminotransferase (ALT)/AP ratio (both elevated above ULN) <2.
Several hundred drugs, herbal remedies, and illegal compounds have been reported to trigger drug-induced cholestatic injury.
Adverse liver reactions are predictable and dose dependent only in a very few cases, whereas the vast majority is caused by unpredictable idiosyncratic or hypersensitive mechanisms.
Both environmental and genetic factors may determine susceptibility.
Genetically determined variations of hepatobiliary transporter and biotransformation enzyme expression and function may be important risk factors for an individual’s susceptibility to cholestasis under conditions of xenobiotic stress by drugs.

Front 18

Drug induced cholestasis
- DRUGS

Back 18

•Intrahepatic
–Acute
•Cholestasis without hepatitis rare (oestrogen and anabolic steroids)
•Cholestasis with hepatitis (isoniazid, tricyclic antidepressents, cabamezapine, metformin, augmentin, atorvastatin)
•Cholestasis with bile duct injury (flucloxacillin, pioglitazone)
–Chronic
•Mild, non specific bile duct injury (ductopenia)
•VBDA (azathioprine, ciprofloxicin, erythromycin, methyltestosterone, tetracycline)
•PSC like (intralesional: eg iodine, alcohol, hypertonic saline)

•Extrahepatic
–Cholelithiasis
–PSC like

Front 19

Childhood intrahepatic cholestasis

Back 19

•Metabolic disease
–with biliary tract involvement: alpha 1-antitrypsin deficiency, storage disease, cystic fibrosis
–without biliary tract involvement: galactosemia, tyrosinemia, fatty aacid oxidation defects, lipid and glycogen storage disorders, peroxisomal disorders
–defects in biliary function
•Disorders of bile acid biosynthesis and conjugation
•Disorders of canalicular secretion (PFIC)
•Paucity of bile ducts
–syndromic: Alagille syndrome (Jagged 1 defect
–non-syndromic
•Ductal plate malformations
•Infections: bacterial, viral
•Toxic: parenteral nutrition, drugs
•Idiopathic neonatal hepatitis
•Cirrhosis

Front 20

Jaundice in pregnancy

Back 20

•Hyperemesis gravidarum:
–jaundice seen occasionally
•Intrahepatic cholestasis of pregnancy:
–3rd trimester, pruritis and occasional jaundice
- this is a benign cause but need to DDx from fatty liver because that can be fatal
•Acute fatty liver of pregnancy:
–3rd trimester, jaundice, nausea or abdominal pain and encephalopathy
–Fatal unless delivered
•Preclampsia:
–liver involvement (~10%) with severe form of haemolysis, increased liver tests low platelets (HELLP)
–requires prompt delivery

Front 21

Cholestasis due to obstruction

Back 21

•Obstruction or paucity of small bile ducts can result in functional obstruction of the entire biliary system
•Physical obstruction of the extrahepatic biliary system:
–Choledocholithiasis
–Bile duct diseases
–Extrinsic Compression

Front 22

Choledocholithiasis

Back 22

Front 23

Bile duct disease

Back 23

Front 24

Extrinsic compression

Back 24

Front 25

Jaundice: evaluation and management

Back 25

Front 26

History

Back 26

•
History: Age, sex, overseas travel, occupation, contacts, sexual history, onset of symptoms, other symptoms, family history, alcohol, hepatotoxin, IVDU, transfusion, symptoms of viral prodrome, fevers, pain
In particular…
•Drug + herbals (esp < 6 wks) and occupational history
•Fever + rigors or right upper quadrant abdominal pain ?? cholangitis due to obstructive diseases (particularly choledocholithiasis); fever and pain (alcoholic and viral hepatitis)
•Previous biliary surgery, increases likelihood of obstruction
•Family history
•Special conditions: (e.g., pregnancy, childhood, liver transplantation, HIV-infection)

MAINLY
- drugs and Family Hx

Front 27

Physical examination

Back 27

•Failure to thrive: due to fat malabsorption
•Scleral icterus +/- cutaneous jaundice
•Physical evidence of scratching / pruritis (severe bile acid retention)
•Xanthomas: small white papules or plaques, trunk, diaper area, areas of friction
•Fever, bruising, tenderness, palpable mass, palpable gallbladder (Courvoisier’s sign), abdominal scar
•Features of portal hypertension or chronic liver disease (splenomegaly, prominent abdominal veins, spider naevi, gynaecomastia), hyperpigmentation of HFE, Kayser-Fleischer rings in Wilsons disease

Front 28

General labs

Back 28

- FBC, EUC (platelets tend to be lower in liver failure) and glucose low as well
•Liver function tests:
–Hepatitis: high ALT and AST (viral hepatitis), AST 10xULN and > ALT suggests alcoholic liver disease, acute Wilsons disease
–Cholestatic: non jaundice-ALP and GGT high, normal BR (abscess, metastasis)
–Cholestatic: high Br, ALP, GGT, intra or extrahepatic disease
•Prothrombin time (INR)
–measures activity of coagulation factors (I, II, V, VII, X) synthesised by liver
–Prolonged INR due to reduced synthesis or Vit K deficiency
–Vit K absorption requires intact enterohepatic circulation of bile salts and is reduced with biliary obstruction (corrected by parenteral Vit K)

Front 29

Cholestasis: Labs

Back 29

•Increased serum
–bilirubin
–bile salt
–alkaline phosphatase
–5'-nucleotidase
–gamma-glutamyl transferase (GGT) levels
–total cholesterol level (high-density lipoprotein (HDL) level is within the reference range or low)
–lipoprotein-X levels
–Autoimmune markers (ANA, AMA, Ig G4)
•Qualitative serum and urine bile acids by mass spectroscopy to dx genetically determined errors in bile acid synthesis

Front 30

Percutaneous transhepatic cholangiogram (PTC)

Back 30

PTC showing abrupt ending of the common bile duct

Front 31

Histology

Back 31

•
Liver biopsy can be diagnostic but can also be non specific and requires expertise in interpretation
•Many histologic findings are disease specific..
•Features of hepatocellular cholestasis: presence of bile within hepatocytes and canalicular spaces, in association with generalized cholate injury
•Obstructive cholestasis: bile plugging of the interlobular bile ducts, portal expansion, and bile duct proliferation in association with centrilobular cholate injury
•These changes can lead to disruption of cell membranes, inflammation, fibrosis and eventually to cirrhosis