HEME DEGRADATION & RELATED DISORDERS & HYPERBILIRUBINEMIA

LEARNING OBJECTIVES
To state the normal turnover of erythrocytes List the sites of erythrocyte and hemoglobin degradation State the fates of protein and prosthetic part of hemoglobin List the requirements for heme degradation Explain the working of heme oxygenase system Justify that bilirubin is conjugated in the liver Explain the transport of bilirubin through blood elate the levels of bilirubin with the discoloration of tissues

Explain the excretion of bile pigments through the body elate various types of hyperbilirubinemia with altered heme and bilirubin metabolic processes

Heme Degradatio & Bi!ir"#i Meta#o!i$m Erythrocyte turnover: 1 2 108 per hour 6 grams of hemoglobin released in one day Sites: eticuloendothelial system !iver Spleen "one #arro$ %ates: &lobin )ron *orphyrin e+uirements: En,yme -eme ./ygenase System 'egraded )ron pool 'egraded (mino acids reused eused

#olecular o/ygen educing agent 0itamin "1 23iacin4 derivative 3('*- 5 -5

-eme ./ygenase System: -emin enters in the system -emin is reduced to -eme using 3('*-5-5 #olecular o/ygen is added %e52 is o/idi,ed to %e51 ./ygen is added again )ron released 6. is formed 7etrapyrrol opens "iliverdin released

"ile *igments: Biliverdin - blue green pigment (reduced to bilirubin4 Bilirubin - yellow pigment -ighly hydrophobic 6ombines $ith albumin in the blood stream "ilirubin #etabolism: 18 9pta:e by liver by facilitated transport 28 6on;ugation $ith glucuronic acid in E to ma:e it $ater soluble by the help of 9'* glucuronic acid and &lucuronyl transferase 18 (ctive secretion of con;ugated bilirubin into bile "ilirubin E/cretion: 7hrough terminal )lium and !arge intestine &lucuronide removed "acterial flora reduce it to colorless urobilinogen ./idi,ed urobilin and stercobilin give feces their color 7here is Enterohepatic circulation 9rine color is due to the presence of urobilin

-yperbilirubinemia: E/cessive bilirubin in blood 2 < 1 mg = dl 4 >aundice i8e8 yello$ discoloration of s:in and sclera 2 < 2 mg = dl 4 o -emolytic o -epatic o *ost hepatic #ostly 9n?con;ugated 6on;ugated #ostly 6on;ugated

Ta#!e o% diag o$ti& te$t$ Pre()e*ati& Ja" di&e !ormal " #ncreased !ormal !ormal " #ncreased !ormal " #ncreased !ormal !ormal #ncreased !ormal (lanine transferase and (spartate transferase levels $onjugated )ilirubin in %rine !ot 'resent #ncreased He*ati& Ja" di&e Po$t()e*ati& Ja" di&e

'" &tio te$t

Total bilirubin

#ncreased

$onjugated bilirubin

#ncreased

%nconjugated bilirubin

#ncreased

!ormal

%robilinogen

&ecreased " !egative &ark 'ale

%rine $olor Stool $olor (lkaline phosphatase levels

'resent

6auses of -yperbilirubinemia:

*rehepatic 2hemolytic4 ;aundice : @ @ esults from e/cess production of bilirubin 2beyond the livers ability to con;ugate it4 follo$ing hemolysis E/cess "6 lysis is commonly the result of autoimmune diseaseA hemolytic disease of the ne$born 2 h? or (".? incompatibility4A structurally abnormal "6s 2Sic:le cell disease4A or brea:do$n of e/travasated blood @ -igh plasma concentrations of uncon;ugated bilirubin 2normal concentration B08C mg=d!4

)ntrahepatic ;aundice : @ @ @ )mpaired upta:eD con;ugationD or secretion of bilirubin eflects a generali,ed liver 2hepatocyte4 dysfunction )n this caseD hyperbilirubinemia is usually accompanied by other abnormalities in biochemical mar:ers of liver function

*osthepatic ;aundice : @ @ @ @ 6aused by an obstruction of the biliary tree *lasma bilirubin is con;ugatedD and other biliary metabolitesD such as bile acids accumulate in the plasma 6haracteri,ed by pale colored stools 2absence of fecal bilirubin or urobilin4D and dar: urine 2increased con;ugated bilirubin4 )n a complete obstructionD urobilin is absent from the urine

Gilberts Syndrome : "enign liver disorder E of the affected individuals inherit it8

 6haracteri,ed by mildD fluctuating increases in uncon;ugated bilirubin caused by decreased ability of the liver to con;ugate bilirubin often correlated $ith fasting or illness #ales more fre+uently affected then females .nset of symptoms in teensD early 20Fs or 10Fs 6an be treated $ith small doses of phenobarbital to stimulate 9'* glucuronyl transferase activity8 Crigler-Najjar Syndrome : (utosomal recessive E/tremely rare G 200 cases $orld$ide gene fre+uency is G 1:1000 6haracteri,ed by a complete absence or mar:ed reduction in bilirubin con;ugation *resent $ith a severe uncon;ugated hyperbilirubinemia that usually presents at birth (fflicted individuals are at a high ris: for :ernicterus 6ondition is fatal $hen the en,yme is completely absent 7reated by phototherapy 210?12 hrs=day4 and liver transplant by age C

Dubin-Jo nson and !otors Syndromes : 6haracteri,ed by impaired biliary secretion of con;ugated bilirubin8 *resent $ith a con;ugated hyperbilirubinemia that is usually mild8 "#$N% &'(