DISTURBANCE OF PIGMENT METABOLISM
Pigments:
Pigment are the heterogeneous group of colored substance, some of which are normal constituents of cells ( Melanin), while other are abnormal and collected in cells only under certain circumstances.
Pathological pigmentation means deposition of coloured substances on skin, mucosa, & internal organs in abnormal amounts or at abnormal sites.
Pigment metabolism 1. Naturally occuring but in excess 2. Diminished in the normal amount of
pigment of a part 3. Presence of normally occuring
pigment in unusual situation 4. Presence of Pigment of abnormal
composition & foreign to body.
Pigment can be divided in two:
(1) Endogenous Pigment(Produce in the body)
(2) Exogenous Pigment(Introduced in to the body without)
ENDOGENOUS PIGMENT 1.Melanin 2. Malarial Pigment( Haemazoin) 3. Hematogenous Pigment
a. Haemotoidin
b. Haemosiderin
c. Haemofuscin 4. Lipochromes
EXOGENOUS PIGMENT(1) Alimentary-a) argyria(Silver) b)Plumbism(Lead) c)
Arsenic
(2) Respiratory Tract: a)Anthracosis b) Silicosis c) Siderosis(Iron)
(3) Skin: a) Tattooing
Melanin
Haematogenous Pigment: Haemosiderin:
Demonstrated by Prussian Blue reaction Excessive deposition of haemosiderin in tissue called as
Haemosiderosis Causes of Haemosiderosis.
Localized- Trauma, Hematoma, Infarct, Purpura.
Generalized: Hemolytic Anemia, Incompatible blood transfusion
Sites:
Localized : Pigment accumulate within macrophages.
Generalized: Accumulates within cells of liver, spleen, BM.
Mechanism: Pigment Haemosiderin is produced by the destruction of red blood cells with liberation of hemoglobin & splitting of Iron.
The hepatocytes and Kupffer cells here are full of granular brown deposits of hemosiderin from accumulation of excess iron in the liver. The term "hemosiderosis" is used to denote a relatively benign accumulation of iron. The term "hemochromatosis" is used when organ dysfunction occurs. The iron accumulation may lead to a micronodular cirrhosis
Malarial Pigment(Haemazoin) Haemazoin: Formed by malarial parasite. Appears as brownish black coarse granules Negative Prussian Blue reaction This is brownish black in color & does not give the iron
reaction. It is formed by the malaria parasite from hemoglobin of red cells. In very heavy infection the pigment may be seen free in capillaries of internal organs. In chronic infection, it is stored by reticular endothelial cell in different organs. In very heavy malarial infection also in chronic cases, the affected organs like spleen, liver, kidney, brain intestine & Bone marrow become discolored, slaty gray.
Other conditions Haemochromatosis: Genetic defect caused by
Pigmentary cirrhosis of liver, portal Hypertention or Ascitis
Haematin Pigment: It is Hb derived Pigmentation It is a golden Brown granular found within macrophage Prussian Blue Negative because Iron is bound in to
organic complex with protein. Causes- Hemolytic crisis in hemolytic anemia
Porphyrin: Normally Present in Hb, myoglobin, cytochromes. It is caused by Pigmentation of Skin, Bones, Teeth.
Bile Pigment
Hemochromatosis
Porphyrin
Lipopigment: - Lipochromes , Lipofuschin, ceroids
- Sites: Myocardial Fibers, Liver Cells, epithelial cells of prostate, seminal vesicle, & Nerve cells.
- When deposited in Heart called as “BROWN ATROPHY OF HEART”
- Lipofuscin is PAS positive, Acid fast.
The yellow-brown granular pigment seen in the hepatocytes here is lipochrome (lipofuscin) which accumulates over time in cells (particularly liver and heart) as a result of "wear and tear" with aging.
BROWN ATROPHY OF HEART
Chloroma which is a green pigment in Leukemia
:Exogenous Pigment: Dusts: e.g. Anthracosis, Pneumoconiosis Argyria: Prolonged use of silver nitrate as
tropical application- deposited in skin, mucous membrane, in bone marrow or in dermis
Tatoo Pigment: Using colored metallic organic dyes like india ink, indigo, carmine, lead
Bilirubin
What is Bilirubin?
Is a bile pigment Is lipid soluble
Is a product of heme metabolism
Heme Metabolism
Hemoglobin – 80%
Myoglobin
Cytochrome P450s
Hemoproteins
Macrophage of the reticuloendothelial system
HemeHeme
Oxygenase
BiliverdinBiliverdin Reductase
Bilirubin
Blood
O2
Fe3+ + CO
NADPH + H+
NADP+
Modified from Ganon, W.F. Review of Medical Physiology, (6th ed.).
The Fate of Bilirubin…
Alb = albumin B = bilirubin GST = glutathione-S-transferaseUDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubinUGT1A1 = UDP-glucuronosyltransferase 1A1MRP2 = Multi-drug Resistance Protein 2
Adapted from Harrison’s 15th Ed. “Principles of Internal Medicine”, 2001.
MRP2
B+ GST CB
Plasma Hepatic Cell Bile
AlbB
Alb
?:GSTB
sER
B + UDPGA UGT1A1
Bilirubin Excretion
Intestines
Liver
B CB
CB BUrobilinogen
B-glucoronidase bacteria
bacteria
Bile
Enterohepatic circulation
ox Urobilin
Stercobilin
Stercobilingogen
feces
Bilirubin Excretion
Intestines
Liver
B CB
CB BUrobilinogen
B-glucoronidase bacteria
bacteria
BileEnterohepatic circulation
KidneyUrobilin
ox
Urobilinogen
Urobilin
Stercobilin
Stercobilingogen
feces
Urine
ox
Hyperbilirubinemia
Interferences at any one of the points of bilirubin processing described above can lead to a condition known as HYPERBILIRUBINEMIA.
As the name implies this disease is characterized by abnormally elevated levels of bilirubin in the blood.
SYMPTOMS
o Yellowing of the skin, scleras (white of the eye), and mucous membranes (jaundice)
o Detectable when total plasma bilirubin levels exceed 2mg/100mL
AHHH!!! I have symptoms of hyperbilirubinemia!!!
Causes:
1. Increased bilirubin production
2. Reduced bilirubin uptake by hepatic cells
3. Disrupted intracellular conjugation
4. Disrupted secretion of bilirubin into bile canaliculi
5. Intra/extra-hepatic bile duct obstruction
Lead to increases in free (unconj.) bilirubin
Result in rise in conj. bilirubin levels
1) INCREASED BILIRUBIN PRODUCTION(unconj. Hyperbilirubinemia)
Hemolysis Increased destruction of RBCs
eg sickle cell anemia, thalassemia Drastic increase in the amount of bilirubin produced Unconj. bilirubin levels rise due to liver’s inability to
catch up to the increased rate of RBC destruction Prolonged hemolysis may lead to precipitation of
bilirubin salts in the gall bladder and biliary network result in formation of gallstones and conditions such as
cholecystitis and biliary obstruction
Other Degradation of Hb originating from areas of tissue
infarctions and hematomas Ineffective erythropoiesis
2) DECREASED HEPATIC UPTAKE(unconj. Hyperbilirubinemia)
Several drugs have been reported to inhibit bilirubin uptake by the liver
e.g. novobiocin, flavopiridol
Bile
MRP2
B + GST
CB
Plasma Hepatic cell
Alb B
Alb :GSTB
sER
B + UDPGA UGT1A1
3) DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia)
Neonatal jaundice occurs in 50% of newborns fetal bilirubin is eliminated by mother’s liver causes:
hepatic mechanisms are not fully developed resulting in decreased ability to conjugate bilirubin
rate of bilirubin production is increased due to shorter lifespan of RBCs
Acquired disorders hepatitis, cirrhosis impaired liver function
3) DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia)
Crigler-Najjar Syndrome, Type I (CN-I)
recessive allele; mutation-induced loss of conjugating ability in the critical enzyme glucuronosyltransferase CN-II
greatly reduced but detectable glucuronosyltransferase activity due to mutation (predominantly recessive); enzymatic activity can be induced by drugs
Gilbert’s Syndrome glucuronosyl transferase activity reduced to 10-30% of normal;
also accompanied by defective bilirubin uptake mechanism
Bile
MRP2
B + GST
CB
Plasma Hepatic cellAlb
B
Alb :GSTB
sER
B + UDPGAUGT1A1
4) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI(conj. Hyperbilirubinemia)
Dubin–Johnson Syndrome mild conj. hyperbilirubinemia, but can increase with concurrent
illness, pregnancy, and use of oral contraceptives; otherwise asymptomatic
Inability of hepatocytes to secrete CB after it has formed Due to mutation in the MRP2 gene (autosomal recessive trait)
Rotor Syndrome Autosomal recessive condition characterized by increased total
bilirubin levels due to a rise in CB Caused by a defect in transport of bilirubin into bile
Bile
MRP2
B + GST
CB
Plasma Hepatic cellAlb
B
Alb :GSTB
sER
B + UDPGAUGT1A1
5) INTRA/EXTRA-HEPATIC BILE DUCT OBSTRUCTION
Intra-hepaticObstruction of bile canaliculi, bile ductules or hepatic ducts
Extra-hepaticObstruction of cystic duct or common bile duct
Cholecystitis
Obstruction causes backup and reabsorption of CB which
results in increased blood levels of CB
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