Disturbance of Pigment Metabolism

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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 PIGMENT1.Melanin 2. Malarial Pigment( Haemazoin) 3. Hematogenous Pigment a. Haemotoidin b. Haemosiderin c. Haemofuscin 4. Lipochromes

EXOGENOUS PIGMENT(1) (2) (3)

Alimentary-a) argyria(Silver) b)Plumbism(Lead) c) Arsenic Respiratory Tract: a)Anthracosis b) Silicosis c) Siderosis(Iron) 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 thedestruction 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 inLeukemia

:Exogenous Dusts:

Pigment:

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 Heme

Fe3+ + CO O2 Heme Oxygenase NADPH + H+

NADP+

BiliverdinBiliverdin Reductase

Bilirubin

Macrophage of the reticuloendothelial systemModified from Ganon, W.F. Review of Medical Physiology, (6th ed.). Physiology,

Blood

The Fate of BilirubinPlasma Hepatic Cell Bile

Alb B

?Alb

B + GST B B :GST+ UDPGA UGT1A1

CB

MRP2

sERAlb = albumin B = bilirubin GST = glutathione-S-transferase UDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubin UGT1A1 = UDP-glucuronosyltransferase 1A1 MRP2 = Multi-drug Resistance Protein 2Adapted from Harrisons 15th Ed. Principles of Internal Medicine, 2001.

Liver

Bilirubin ExcretionCBEnterohepatic circulation

B

Bile

B-glucoronidase

CBbacteria Intestines

B

bacteria Urobilinogen ox Urobilin Stercobilingogen Stercobilin feces

Liver

Bilirubin ExcretionCBEnterohepatic circulation Kidney ox Urobilinogen Bile Urine Urobilin

B

B-glucoronidase

CB

B

bacteria Urobilinogen ox Urobilin Stercobilingogen Stercobilin

bacteria Intestines

feces

Hyperbilirubinemia

Interferences at any one of the points of bilirubin processing described above can lead to a condition known as HYPERBILIRUBINEMIA. HYPERBILIRUBINEMIA.

As the name implies this disease is characterized by abnormally elevated levels of bilirubin in the blood.

SYMPTOMSo 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. 2. 3. 4.

5.

Increased bilirubin production Reduced bilirubin uptake by hepatic cells Disrupted intracellular conjugation Disrupted secretion of bilirubin into bile canaliculi Intra/extraIntra/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 livers 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

Plasma Alb B B + GST B + UDPGA Alb B :GST UGT1A1 CB

e.g. novobiocin, flavopiridolHepatic cell Bile

MRP2

sER

3) DISRUPTED INTRACELLULAR CONJUGATION(unconj. Hyperbilirubinemia)

Neonatal jaundice

occurs in 50% of newborns fetal bilirubin is eliminated by mothers 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) Crigler(CNrecessive allele; mutation-induced loss of conjugating ability in the mutationcritical enzyme glucuronosyltransferase CN-II CNgreatly reduced but detectable glucuronosyltransferase activity due to mutation (predominantly recessive); enzymatic activity can be induced by drugs Gilberts Syndrome glucuronosyl transferase activity reduced to 10-30% of normal; also 10accompanied by defective bilirubin uptake mechanismPlasmaAlb B B + GST B Alb B :GST + UDPGA UGT1A1 CB

Hepatic cell

Bile

MRP2

sER

4) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI(conj. Hyperbilirubinemia) Dubin DubinJohnson 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 bileAlb

PlasmaB B + GST B

Hepatic cell

Bile

+ UDPGA UGT1A1

CB

MRP2

Alb

B :GST

sER

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