The metabolism of bilirubin in humans is summarized in Figure 14.1 and can be divided into three sequential steps: 1 Production of unconjugated bilirubin. Red blood cells are broken down by macrophages (mainly in the spleen), which degrade haemoglobin into iron and unconjugated (water insoluble) bilirubin. The iron is stored inside transferrin proteins. Unconjugated bilirubin travels to the liver bound to albumin. In disease, unconjugated bilirubin can be produced by haemolysis of red cells intravascularly, rather than in the spleen. 2 Conjugation of bilirubin. Liver hepatocytes uptake unconjugated bilirubin and conjugate it to glucuronate, thus making water soluble, conjugated bilirubin. 3 Excretion of bilirubin. Once conjugated, bilirubin is secreted into the bile canaliculi. Conjugated bilirubin flows with bile down the bile ducts and into the duodenum. Inside the bowel, conjugated bilirubin is metabolized by bacteria into colourless products (urobilinogen, stercobilinogen). Some of these can be reabsorbed by the gut and excreted via the kidneys, but the vast majority are oxidized in the gut into coloured pigments (urobilin, stercobilin) which give faeces their brown colour. Consequently, if there is complete obstruction of the bile ducts there will be no flow of conjugated bilirubin into the gut, no conversion into urobilinogen, and therefore not even a trace of urobilinogen in the urine. The terminology is confusing because different people mean different things. If you are going to use this terminology, make sure that you and your colleagues agree on the definitions. Nonetheless, this is what people usually mean: • Prehepatic jaundice: this refers to jaundice caused by an excessive production of bilirubin. Remember that bilirubin is produced by the breakdown of haemoglobin in the blood vessels or the spleen, hence the term prehepatic. • Hepatic jaundice: for some people, this means any jaundice due to pathology in the liver (anatomically), such as points 3, 4, and 5 in Figure 14.1, and can thus include problems with hepatocytes (e.g. hepatitis) or with the bile canaliculi (e.g. primary sclerosing cholangitis, PSC).