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