thumbJaundice is typically caused<unk> y an underlying pathological process that occurs at some point along the normal physiological pathway of heme metabolism. A deeper understanding of the anatomical flow of normal heme metabolism is essential to appreciate the importance of prehepatic, hepatic, and posthepatic categories. Thus, an anatomical approach to heme metabolism precedes a discussion of the pathophysiology of jaundice. Normal heme metabolism Prehepatic metabolism When red<unk> lood cells complete their lifespan of about 120 days, or if they are damaged, they rupture as they pass through the reticuloendothelial system, and cell contents including hemoglobin are released into circulation. Macrophages phagocytose free hemoglobin and split it into heme and globin. Two reactions then take place with the heme molecule. The first oxidation reaction is catalyzed<unk> y the microsomal enzyme heme oxygenase and results in<unk> iliverdin (green color pigment), iron, and carbon monoxide. The next step is the reduction of<unk> iliverdin to a yellow color tetrapyrrole pigment called<unk> ilirubin<unk> y cytosolic enzyme<unk> iliverdin reductase. This<unk> ilirubin is "unconjugated", "free", or "indirect"<unk> ilirubin. Around 4 mg of<unk> ilirubin per kg of<unk> lood are produced each day. The majority of this<unk> ilirubin comes from the<unk> reakdown of heme from expired red<unk> lood cells in the process just described. Roughly 20% comes from other heme sources, however, including ineffective erythropoiesis, and the<unk> reakdown of other heme-containing proteins, such as muscle myoglobin and cytochromes. The unconjugated<unk> ilirubin then travels to the liver through the<unk> loodstream.<unk> ecause this<unk> ilirubin is not soluble, it is transported through the<unk> lood<unk> ound to serum albumin. Hepatic metabolism Once unconjugated<unk> ilirubin arrives in the liver, liver enzyme UDP-glucuronyl transferase conjugates<unk> ilirubin + glucuronic acid →<unk> ilirubin diglucuronide (conjugated<unk> ilirubin).<unk> ilirubin that has<unk> een conjugated<unk> y the liver is water-soluble and excreted into the gallbladder. Posthepatic metabolism<unk> ilirubin enters the intestinal tract via<unk> ile. In the intestinal tract,<unk> ilirubin is converted into urobilinogen<unk> y symbiotic intestinal<unk> acteria. Most urobilinogen is converted into stercobilinogen and further oxidized into stercobilin. Stercobilin is excreted via feces, giving stool its characteristic<unk> rown coloration. A small portion of urobilinogen is reabsorbed<unk> ack into the gastrointestinal cells. Most reabsorbed urobilinogen undergoes hepatobiliary recirculation. A smaller portion of reabsorbed urobilinogen is filtered into the kidneys. In the urine, urobilinogen is converted to urobilin, which gives urine its characteristic yellow color. Abnormalities in heme metabolism and excretion One way to understand jaundice pathophysiology is to organize it into disorders that cause increased<unk> ilirubin production (abnormal heme metabolism) or decreased<unk> ilirubin excretion (abnormal heme excretion). Prehepatic pathophysiology Prehepatic jaundice is attributed to a pathological increase in<unk> ilirubin production. The pathophysiology is quite simple; an increased rate of erythrocyte hemolysis → increased<unk> ilirubin production → increased deposition of<unk> ilirubin in mucosal tissue → appearance of yellow hue. Hepatic pathophysiology Hepatic jaundice (hepatocellular jaundice) is due to significant damage to liver function → hepatic cell death and necrosis occur → impaired<unk> ilirubin transport across hepatocytes.<unk> ilirubin transport across hepatocytes may<unk> e impaired at any point<unk> etween hepatocellular uptake of unconjugated<unk> ilirubin and hepatocellular transport of conjugated<unk> ilirubin into the gallbladder. In addition, subsequent cellular edema due to inflammation causes mechanical obstruction of intrahepatic<unk> iliary tract. Most commonly, interferences in all three major steps of<unk> ilirubin metabolism — uptake, conjugation, and excretion — usually occur in hepatocellular jaundice. Thus, an abnormal rise in<unk> oth unconjugated and conjugated<unk> ilirubin will<unk> e present.<unk> ecause excretion (the rate-limiting step) is usually impaired to the greatest extent, conjugated hyperbilirubinemia predominates. The unconjugated<unk> ilirubin still enters the liver cells and<unk> ecomes conjugated in the usual way. This conjugated<unk> ilirubin is then returned to the<unk> lood, probably<unk> y rupture of the congested<unk> ile canaliculi and direct emptying of the<unk> ile into the lymph leaving the liver. Thus, most of the<unk> ilirubin in the plasma<unk> ecomes the conjugated type rather than the unconjugated type, and this conjugated<unk> ilirubin, which did not go to intestine to<unk> ecome urobilinogen, gives the urine the dark color. Posthepatic pathophysiology Posthepatic jaundice (obstructive jaundice) is due to a<unk> lockage of<unk> ile excretion from the<unk> iliary tract → increased conjugated<unk> ilirubin and<unk> ile salts. In complete obstruction of the<unk> ile duct, conjugated<unk> ilirubin cannot access the intestinal tract → no further<unk> ilirubin conversion to urobilinogen → no stercobilin or urobilin. Instead, excess conjugated<unk> ilirubin is filtered into the urine without urobilinogen in obstructive jaundice. Conjugated<unk> ilirubin in urine <unk> ilirubinuria) gives urine an abnormally dark<unk> rown color. Thus, the presence of pale stool (stercobilin absent from feces) and dark urine (conjugated<unk> ilirubin present in urine) suggest an obstructive cause of jaundice.<unk> ecause these associated signs are also positive in many hepatic jaundice conditions, they cannot<unk> e a reliable clinical feature to distinguish obstruction versus hepatocellular jaundice causes.
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