212 spring 2005 heme degradation

8/6/2019 212 Spring 2005 Heme Degradation

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Heme Degradation & Hyperbilirubinemias

Beth A. BouchardBIOC 212: Biochemistry of Human DiseaseSpring 2005


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FATE OF RED BLOOD CELLS

y Life span in blood stream is 60-120 days

y Senescent RBCs are phagocytosed and/orlysed

yNormally, lysis occurs extravascularly in thereticuloendothelial system subsequent to RBCphagocytosis

y Lysis can also occur intravascularly (in bloodstream)


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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) Hemoglobin

Purposes: 1. Scavenge iron

2. Prevent major iron losses

3. Complex free heme (very toxic)

Haptoglobin: hemoglobin-haptoglobin complex is readilymetabolized in the liver and spleen forming an iron-globincomplex 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 toferritin.

Methemalbumin: complex of oxidized heme and albumin.


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DEGRADATION OF HEME TO BILIRUBIN

P450 cytochrome

y 75% is derived from RBCs

y In normal adults thisresults in a daily load of

250-300 mg of bilirubin

y Normal plasmaconcentrations are less then1 mg/dL

y Hydrophobic transportedby albumin to the liver forfurther metabolism prior toits excretion

unconjugated bilirubin


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NORMAL BILIRUBINMETABOLISM

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

y Uptake may be competitively inhibited by

other organic anions

y On the smooth ER, bilirubin is conjugated withglucoronic acid, xylose, or ribose

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

yConjugated bilirubin is water soluble and issecreted by the hepatocytes into the biliarycanaliculi

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

y Oxidized to stercobilin which is colored

y Excreted in feces

y Some stercobilin may be re-adsorbed by thegut and re-excreted by either the liver or

kidney


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HYPERBILIRUBINEMIA

y Increased plasma concentrations of bilirubin (> 3 mg/dL) occurs whenthere is an imbalance between its production and excretiony Recognized clinically as jaundice


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Prehepatic (hemolytic) jaundice

Results from excessproduction of bilirubin (beyondthe livers ability to conjugateit) following hemolysis

Excess RBC lysis is commonlythe result of autoimmunedisease; hemolytic disease ofthe newborn (Rh- or ABO-incompatibility); structurallyabnormal RBCs (Sickle celldisease); or breakdown of

extravasated blood

High plasma concentrations ofunconjugated bilirubin (normalconcentration ~0.5 mg/dL)


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Intrahepatic jaundice

Impaired uptake,conjugation, or secretionof bilirubin

Reflects a generalized

liver (hepatocyte)dysfunction

In this case,hyperbilirubinemia isusually accompanied byother abnormalities inbiochemical markers ofliver function


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Posthepatic jaundice

Caused by an obstruction ofthe biliary tree

Plasma bilirubin is conjugated,and other biliary metabolites,such as bile acids accumulate inthe plasma

Characterized by pale coloredstools (absence of fecalbilirubin or urobilin), and dark

urine (increased conjugatedbilirubin)

In a complete obstruction,urobilin is absent from theurine


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Diagnoses of Jaundice


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Neonatal Jaundice Common, particularly in premature infants

Transient (resolves in the first 10 days)

Due to immaturity of the enzymes involved in bilirubin conjugation

High levels of unconjugated bilirubin are toxic to the newborn due to its

hydrophobicity it can cross the blood-brain barrier and cause a type ofmental retardation known as kernicterus

If bilirubin levels are judged to be too high, then phototherapy with UVlight is used to convert it to a water soluble, non-toxic form

If necessary, exchange blood transfusion is used to remove excess bilirubin

Phenobarbital is oftentimes administered to Mom prior to an induced laborof a premature infant crosses the placenta and induces the synthesis ofUDP glucuronyl transferase

Jaundice within the first 24 hrs of life or which takes longer then 10 daysto resolve is usually pathological and needs to be further investigated


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Causes of Hyperbilirubinemia


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y

Benign liver disorder

y of the affected individuals inherited it

y Characterized by mild, fluctuating increases in

unconjugated bilirubin caused by decreased abilityof the liver to conjugate bilirubin oftencorrelated with fasting or illness

y Males more frequently affected then females

yOnset of symptoms in teens, early 20s or 30s

y Can be treated with small doses of phenobarbital

to stimulate UDP glucuronyl transferase activity

Gilberts Syndrome


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y Autosomal recessive

y Extremely rare < 200 cases worldwide gene frequency is < 1:1000

y High incidence in the plain people of Pennsylvania (Amish andMennonites)

y Characterized by a complete absence or marked reduction inbilirubin conjugation

y Present with a severe unconjugated hyperbilirubinemia thatusually presents at birth

y Afflicted individuals are at a high risk for kernicterus

y Condition is fatal when the enzyme is completely absent

y Treated by phototherapy (10-12 hrs/day) and liver transplant by

age 5

Crigler-Najjar Syndrome


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y Characterized by impaired biliarysecretion of conjugated bilirubin

y Present with a conjugatedhyperbilirubinemia that is usually mild

Dubin-Johnson and Rotors Syndromes


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Regulation of iron metabolism

212 spring 2005 heme degradation

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