M.D. / lecturer of internal medicine JAUNDICE DR : RAMY A. SAMY M.D. / lecturer of internal medicine Dr_ramisami@fmed.bu.edu.eg

Jaundice Definition Causes History Investigation-Imaging Clinical Cases

Definition Jaundice is a yellowing of the skin, conjunctiva and mucous membranes caused by hyperbilirubinaemia.

Normal Physiology Bilirubin is from breakdown of hemoglobin Unconjugated bilirubin transported to liver Bound to albumin because insoluble in water Transported into hepatocyte & conjugated With glucuronic acid → now water soluble Secreted into bile In ileum & colon, converted to urobilinogen 10-20% reabsorbed into portal circulation and re-excreted into bile or into urine by kidneys

Pathophysiology Jaundice = bilirubin staining of tissue @ lvl greater than ~2 Mechanisms: ↑ production of bilirubin ↓ hepatocyte transport or conjugation Impaired excretion of bilirubin Impaired delivery of bilirubin into intestine “surgically relevant jaundice” or obstructive jaundice “Cholestasis” refers to the latter two, impaired excretion and obstructive jaundice

What causes jaundice? Category Definition Pre-hepatic Pathology occurs prior to the liver Hepatic Pathology located within the liver Post- hepatic Pathology located after the conjugation of bilirubin in the liver

Prehepatic Jaundice Prehepatic jaundice is caused by increased destruction of erythrocytes either: - mature cells or - precursors (ineffective erythropoiesis). The breakdown of mature cells can be caused by: - haemolysis, or - as a result of the metabolism of blood following internal haemorrhage, e.g. into a soft tissue injury or fracture.

Prehepatic Jaundice Ineffective erythropoiesis occurs in conditions such as: - pernicious anaemia, where the maturation of red cells is impaired, or - thalassaemia, where the structure of haemoglobin is abnormal. Hyperbilirubinaemia in prehepatic jaundice results from the accumulation of unconjugated bilirubin; this is not excreted by the kidney.

Prehepatic Jaundice Jaundice occurs because the conjugating capacity of the liver is saturated, - the capacity of the liver for conjugation is greater than the normal rate of bilirubin production. Increased fluxes of bilirubin through the liver into the gut Greater amounts of urobilinogen are produced, with - increased urobilinogen excretion in urine.

KEY POINTS Prehepatic jaundice is most commonly Caused by haemolytic disease Bilirubin (unconjugated) is not excreted in urine Urinary urobilinogen concentration is increased

Hepatic Jaundice Congenital disorders of bilirubin transport lead to jaundice because of: - defective uptake, reduced conjugation or impaired excretion of bilirubin. Generalized hepatocellular dysfunction may occur in hepatitis and hepatic cirrhosis. Drugs may cause hepatocellular damage, either due to dose-dependent hepatoxicity (e.g. paracetamol).

Hepatic Jaundice The pathogenesis of jaundice in these conditions is complex, - reduced hepatic uptake, - decreased conjugation and, - impaired intracellular transport of bilirubin, all contributing.

Hepatic Jaundice When hyperbilirubinaemia is caused by impaired conjugation of bilirubin; - unconjugated bilirubin, and no increased fluxes of bilirubin through the liver, - bilirubinuria does not occur and - urinary urobilinogen is not increased.

Hepatic Jaundice Serum bilirubin may be unconjugated or conjugated, as glucuronyl transferase and intracellular transport may be defective. If the rate of conjugation exceeds excretory capacity; - conjugated hyperbilirubinaemia will occur and bilirubin may be excreted,in urine, - this is sometimes seen in recovery from acute viral hepatitis.

KEY POINTS Jaundice due to hepatocyte dysfunction may be caused by selective transport defects of generalized cell dysfunction Both conjugated and unconjugated hyperbilrubinaemia may occur in hepatocellular jaundice Bilirubin and excess urobilinogen may be found in urine

Cholestatic Jaundice Cholestatic jaundice results from interference to biliary flow between the sites of secretion by the hepatocyte and drainage into the duodenum. It may be caused by lesions; - within the liver (intrahepatic cholestasis), or in the biliary tree or head of the pancreas (extrahepatic cholestasis); - the term cholestatic is preferable to post-hepatic to describe this pattern of jaundice.

Cholestatic Jaundice Intra- and extra-hepatic cholestasis can be differentiated by; - ultrasound examination or - liver biopsy, but not by liver function tests. Intrahepatic cholestasis may result from generalized hepatocellular dysfunction, such as occurs in; - Hepatitis, - Hepatic cirrhosis Hepatic malignancies may block branches of the biliary tree.

Cholestatic Jaundice Some drugs may cause intrahepatic cholestasis such as: - anabolic steroids, and - phenothiazines Extrahepatic obstruction may be due to tumours in: - major branches of the biliary tract, - head of pancreas. Gallstones may obstruct biliary flow.

Cholestatic Jaundice Jaundice is due to impaired excretion and accumulation of conjugated bilirubin which can be filtered by the kidney and appear in urine. If obstruction is complete bilirubin does not reach the gut, therefore urobilinogen: - is not produced, and - is absent in urine. Under such circumstances the stools are pale.

KEY POINTS Cholestasis may be caused by lesions within or outside the liver Jaundice is due to conjugated bilirubin Bilirubin is found in urine

Obstructive Jaundice Common Infrequent Rare Common bile duct stones Carcinoma of the head of pancreas Malignant lymph nodes at the porta hepatis Infrequent Ampullary carcinoma Pancreatitis Liver secondaries Rare Benign strictures - iatrogenic, trauma Recurrent cholangitis Mirrizi's syndrome Sclerosing cholangitis Cholangiocarcinoma Bilary atresia Choledochal cysts

Broad Differential Diagnosis ↑production ↓transport or ↓conjugation Impaired excretion Biliary obstruction ↑ Unconjugate ↑ Conjugated Hemolysis Gilbert’s Rotor’s CH/CBD stone Transfusions Crigler-Najarr DubinJohnson Stricture Sepsis Cirrhosis Chronic pancreatitis Burns Hepatitis PSC Hgb-opathies Drug inhibition Amyloidosis Pregnancy

DDx: Unconjugated bilirubinemia ↑production Extravascular hemolysis Extravasation of blood into tissues Intravascular hemolysis Errors in production of red blood cells Impaired hepatic bilirubin uptake(trnsport) CHF Portosystemic shunts Drug inhibition: rifampin, probenecid

DDx: Unconjugated bilirubinemia Impaired bilirubin conjugation Gilbert’s disease Crigler-Najarr syndrome Neonatal jaundice (this is physiologic) Hyperthyroidism Estrogens Liver diseases chronic hepatitis, cirrhosis, Wilson’s disease

DDx: Conjugated Bilirubinemia Intrahepatic cholestasis/impaired excretion Hepatitis (viral, alcoholic, and non-alcoholic) Any cause of hepatocellular injury Primary biliary cirrhosis or end-stage liver dz Sepsis and hypoperfusion states TPN Pregnancy Infiltrative dz: TB, amyloid, sarcoid, lymphoma Drugs/toxins i.e. chlorpromazine, arsenic Post-op patient or post-organ transplantation Hepatic crisis in sickle cell disease

DDx: Obstructive Jaundice Obstructive Jaundice– extrahepatic cholestasis Choledocholithiasis (CBD or CHD stone) Cancer (peri-ampullary or cholangioCA) Strictures after invasive procedures Acute and chronic pancreatitis Primary sclerosing cholangitis (PSC) Parasitic infections Ascaris lumbricoides, liver flukes

Diagnosis History Physical examination Blood tests - laboratory Ultrasonography CT MRI Liver biopsy ERCP Endoscopic ultrasound Diagnosis

Laboratory Tests Bilirubin level in serum (total and direct) Complete blood count Prothrombin time Other laboratory tests pertinent to history Coombs test Electrophoresis of hemoglobin Viral hepatitis panel Bilirubin level in serum (total and direct) Aminotransferase Alkaline phosphatase U/A for bilirubin and urobilogen

Treatment Treatment requires a precise diagnosis of the specific cause and should be directed to the specific problem

Summary in liver function tests in the differential diagnosis of jaundice Test Prehepatic Hepatic Cholestatic Serum bilirubin Uncojugated Mixed Conjugated Urine bilirubin Absent//Present Present Present Urine Urobilinogen Increased Increased Decreased ALT & AST Normal Marked Slight increase increase ALP Normal Slight Marked increase increase

Clinical Case 1 50 year old female Acute, severe pain in RUQ Nausea and vomiting Calls GP – pethidine pain relief Next few days notices dark urine and pale stools Her husband comments she has a pale yellow tinge

Emergency admission What investigations would you do ? What results would you expect?

Abdominal Ultrasound showing multiple gallstones in gallbladder

US shows stone in Common Bile Duct

MRCP showing stone in Common Bile Duct

ERCP showing stone in Common Bile Duct

Case 1 Obstructive jaundice due to gallstone in common bile duct Blood tests show high bilirubin and high alkaline phosphatase Urine contains bilirubin Treatment includes ERCP to remove stone and then plan Cholecystectomy

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