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.

Jaundice

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

Jaundice

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

Category Definition

Pre-hepaticPathology occurs prior to the liver

Hepatic Pathology located within the liver

Post-hepatic

Pathology located after the conjugation of bilirubin in the liver

What causes jaundice?

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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.

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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.

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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.

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KEY POINTS

Prehepatic jaundice is most commonly Caused by haemolytic disease

Bilirubin (unconjugated) is not excreted in urine

Urinary urobilinogen concentration is increased

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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).

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Hepatic Jaundice

• The pathogenesis of jaundice in these conditions is complex,

- reduced hepatic uptake,

- decreased conjugation and,

- impaired intracellular transport

of bilirubin, all contributing.

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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.

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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.

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KEY POINTS

Jaundice due to hepatocyte dysfunction may be caused by selective transport defects

of generalized cell dysfunction

Both conjugated and unconjugated hyperbilrubinaemiamay occur in hepatocellular jaundice

Bilirubin and excess urobilinogen may be found in urine

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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.

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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.

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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.

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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.

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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

– 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

Jaundice

Broad Differential Diagnosis↑production ↓transport or

↓conjugationImpaired excretion

Biliary obstruction

↑ Unconjugate ↑ Unconjugate ↑ Conjugated ↑ Conjugated

Hemolysis Gilbert’s Rotor’s CH/CBD stone

Transfusions Crigler-Najarr DubinJohnson Stricture

Sepsis Cirrhosis Cirrhosis Chronic pancreatitis

Burns Hepatitis Hepatitis PSC

Hgb-opathies Drug inhibition Amyloidosis

Pregnancy

Jaundice

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

Jaundice

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

Jaundice

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

Jaundice

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

Jaundice

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

Diagnosis

Laboratory Tests

Bilirubin level in serum (total and direct)

Aminotransferase Alkaline

phosphatase U/A for bilirubin and

urobilogen

Complete blood count

Prothrombin time Other laboratory

tests pertinent to history

Coombs test Electrophoresis of

hemoglobin Viral hepatitis panel

Treatment

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

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Summary in liver function tests in the differential diagnosis of jaundice

Test Prehepatic Hepatic Cholestatic

Serum bilirubin Uncojugated MixedConjugated

Urine bilirubin Absent//PresentPresent 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