Jaundice Overview

Introduction

Jaundice refers to yellow staining of the skin, sclera and mucous membranes by bilirubin, a yellow-orange bile pigment

Normal bilirubin metabolism and bile formation

Bilirubin is produced mainly from the breakdown of mature red blood cells in the Kuppfer cell of the liver and reticuloendothelial system. 15% comes from the breakdown of other haem proteins (e.g. myoglobin, cytochrome).

The bilirubin is initially unconjugated and water-insoluble. Therefore, it cannot pass into urine. Unconjugated bilirubin is attached to albumin and transported to the liver.

Unconjugated bilirubin is taken up by hepatocytes at the sinusoidal membrane. There, it becomes conjugated to glucuronic acid. This conjugated bilirubin is water-soluble and is excreted into bile. The liver secretes 1-2 litres of bile daily, which consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated bilirubin.  Most of the bile is reabsorbed and reused.

In the fasting state, 50% of bile is diverted to the gallbladder and the remainder into the gut. In the gallbladder, 80-90% of water and electrolytes are reabsorbed (although bile salts and cholesterol are impermeable).

Bile enters the intestine. At the terminal ileum, bilirubin is metabolised by colonic bacteria to form stercobilinogen/urobilinogen. This can then be:

• Reabsorbed into blood (90%), here it then goes to:
  1. Liver: to be re-excreted into bile (via enterohepatic circulation)
  2. Kidneys: to be converted to urobilin and excreted
• Excreted in stool (10%). This gives stool its brown colour

Causes of jaundice

Jaundice can be divided into several types:

• Pre-hepatic (unconjugated): haemolysis or hyperbilirubinaemia
• Hepatic/hepatocellular
• Obstructive/cholestatic: can be intrahepatic or extrahepatic causes

Pre-hepatic

Either by haemolysis or congenital hyperbilirubinaemias. It is characterised an isolated raise in bilirubin levels.

Haemolysis leads to an increased production of bilirubin. The resulting jaundice is mild as normal liver function can excrete a bilirubin level 6 times greater than normal before unconjugated bilirubin accumulates in blood. The unconjugated bilirubin does not pass into urine as it is water-insoluble; however, urinary urobilinogen is increased and may be detected in urine tests. Investigations would show features of haemolysis (e.g. raised LDH, increased reticulocytes).

Congenital hyperbilirubinaemias can be conjugated or unconjugated. Gilbert’s syndrome is by far the commonest hyperbilirubinaemia, which is an autosomal dominant condition that produces an isolated increase in bilirubin; it is asymptomatic and requires no treatment. Another cause of congenital unconjugated hyperbilirubinaemia is Criggler-Najjar syndrome and presents in childhood.

Investigations: raised unconjugated bilirubin. There is raised urinary excretion of urobilinogen. Blood tests for haemolysis should also be ordered.

Hepatic

Results from the inability of the liver to transport bbilirubin into bile. This impairment can occur at any point between the uptake of unconjugated bilirubin and transport of conjugated bilirubin into the canaliculi. In addition, swelling of cells and oedema can cause obstruction of the biliary canaliculi.

Jaunice due to liver injury typically increases alanine transaminase (ALT) more than alkaline phosphatase (ALP). Causes may be acute or chronic. Acute jaundice with an ALT level >1000 is highly suggestive of an infectious cause, hepatic ischaemia or drug-induced damage.

Causes include:

• Alcoholic liver disease
• Non-alcoholic fatty liver disease
• Viral hepatitis and other viruses e.g. CMV, EBV
• Autoimmune hepatitis
• Drugs e.g. paracetamol
• Inherited conditions e.g. Wilsons’s disease, haemochromatosis, alpha₁-antitrypsin deficiency

Investigations: Raised conjugated bilirubin. ALT is raised more than ALP.

Obstructive/Cholestatic

Results from obstruction of bile flow into the intestines. Therefore, it presents with pale stools (steatorrhoea; due to absence of stercobilin) and dark urine (increased excretion of urobilin). Pruritus and malabsorption are also important clinical presentations of obstructive jaundice.

It can be:

1. Extrahepatic: large duct obstruction of bile flow at any point in the biliary tract distal to the bile canaliculi. Includes:
   1. Gallstones
   2. Tumour e.g. head of pancreas, cholangiocarcinoma
   3. Primary sclerosing cholangitis
   4. Choledocholithiasis
2. Intrahepatic: failure of bile secretion. Includes:
   1. Primary biliary cirrhosis
   2. Viral hepatitis
   3. Alcohol
   4. Chronic right heart failure
   5. Intrahepatic cholestasis of pregnancy
   6. Hepatic infiltration e.g. amyloidosis

Investigations: Raised conjugated bilirubin. ALP is raised more than ALT. Abdominal ultrasound scans would show dilated bile ducts in extrahepatic cholestasis.

Clinical features to consider

Hepatitis: right upper quadrant discomfort

Obstructive jaundice: steatorrhoea, dark urine, pruritus

Infection: fever, diarrhoea

Malignancy: weight loss, fever, night sweats

Hemochromatosis: bronzed skin, signs of diabetes

Investigations

First-line investigations

Blood tests:

• FBC and reticulocyte count
• LFT: check bilirubin, ALT and ALP.
  • Bilirubin is raised in jaundice.
  • ALT is raised in hepatocyte damage.
  • ALP is raised in obstructive causes of jaundice. It is non-specific and also raised in bone disease and pregnancy. It should be interpreted alongside GGT (cholestasis increases ALP and GGT).
• GGT: non-specific marker of liver disease. It is a good guide to alcohol intake. It is also raised in cholestasis. A rise in ALP with no rise in GGT suggests that cholestasis is not the cause of raised ALP.
• Clotting studies: measure of hepatic synthetic function
• Viral screen – hepatis A-E, CMV, EBV
• Autoimmune antibodies – ANA, AMA, ANCA
• Immunoglobulin levels – IgG, IgM

Urine dipstick: urobilinogen in raised in prehepatic causes.

Abdominal ultrasound scan: check for biliary obstruction and structural lesions

Pregnancy test

Further investigations

Blood tests:

• Haemolysis screen
• Caeruloplasmin levels (reduced in Wilson’s disease)
• Ferritin levels (increased in haemochromatosis)
• Alpha₁-antitrypsin levels

Magnetic resonance cholangiopancreatography (MRCP)/Endoscopic retrograde cholangiopancreatography (ERCP): if considering cholestatic causes.

Liver biopsy: used to assist in the diagnosis of hepatic disease