Bilirubin Met

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Heme Degradation & Hyperbilirubinemias

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Bahan ajar

Transcript of Bilirubin Met

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Heme Degradation & Hyperbilirubinemias

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FATE OF RED BLOOD CELLS

Life span in blood stream is 60-120 days Senescent RBCs are phagocytosed and/or lysed

Normally, lysis occurs extravascularly in the reticuloendothelial system subsequent to RBC phagocytosis

Lysis can also occur intravascularly (in blood stream)

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Extravascular Pathway for RBC Destruction

(Liver, Bone marrow, & Spleen)

Hemoglobin

Globin

Amino acids

Amino acid pool

Heme Bilirubin

Fe2+

Excreted

Phagocytosis & Lysis

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Handling of Free (Intravascular) HemoglobinPurposes: 1. Scavenge iron

2. Prevent major iron losses3. Complex free heme (very toxic)

• Haptoglobin: hemoglobin-haptoglobin complex is readily metabolized in the liver and spleen forming an iron-globin complex and bilirubin. Prevents loss of iron in urine.

• Hemopexin: binds free heme. The heme-hemopexin complex is taken up by the liver and the iron is stored bound to ferritin.

• Methemalbumin: complex of oxidized heme and albumin.

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DEGRADATION OF HEME TO BILIRUBIN

P450 cytochrome

75% is derived from RBCs

In normal adults this results in a daily load of 250-300 mg of bilirubin

Normal plasma concentrations are less then 1 mg/dL

Hydrophobic – transported by albumin to the liver for further metabolism prior to its excretion

“unconjugated” bilirubin

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NORMAL BILIRUBIN METABOLISM

Uptake of bilirubin by the liver is mediated by a carrier protein (receptor)

Uptake may be competitively inhibited by other organic anions

On the smooth ER, bilirubin is conjugated with glucoronic acid, xylose, or ribose

Glucoronic acid is the major conjugate - catalyzed by UDP glucuronyl tranferase

“Conjugated” bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi

Converted to stercobilinogen (urobilinogen) (colorless) by bacteria in the gut

Oxidized to stercobilin which is colored

Excreted in feces

Some stercobilin may be re-adsorbed by the gut and re-excreted by either the liver or kidney

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HYPERBILIRUBINEMIA Increased plasma concentrations of bilirubin (> 3 mg/dL) occurs when there is an imbalance between its production and excretion Recognized clinically as jaundice

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Prehepatic (hemolytic) jaundice• Results from excess

production of bilirubin (beyond the livers ability to conjugate it) following hemolysis

• Excess RBC lysis is commonly the result of autoimmune disease; hemolytic disease of the newborn (Rh- or ABO- incompatibility); structurally abnormal RBCs (Sickle cell disease); or breakdown of extravasated blood

• High plasma concentrations of unconjugated bilirubin (normal concentration ~0.5 mg/dL)

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Intrahepatic jaundice• Impaired uptake,

conjugation, or secretion of bilirubin

• Reflects a generalized liver (hepatocyte) dysfunction

• In this case, hyperbilirubinemia is usually accompanied by other abnormalities in biochemical markers of liver function

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Posthepatic jaundice• Caused by an obstruction of

the biliary tree

• Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma

• Characterized by pale colored stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin)

• In a complete obstruction, urobilin is absent from the urine

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Diagnoses of Jaundice

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Causes of Hyperbilirubinemia