Pigment metabolism

1. Pigment metabolism

2.

Bilirubin metabolism
1.
2.
3.
4.
5.
6.
7.
8.
9.
Hemoglobin is broken down into heme and globin in the spleen and, to a lesser
extent, in the bone marrow.
Macrophages break down heme into unconjugated bilirubin. Bound to albumin,
unconjugated bilirubin is transported in the bloodstream and taken up by the liver.
Bilirubin is conjugated in the liver and excreted into the bile.
To be secreted, conjugated bilirubin enters the blood and reaches the
hepatocytes, directly connecting to the bile canaliculi. At this stage, conjugated
bilirubin is detected in the blood.
Bilirubin enters the intestine with the bile. Intestinal bacteria convert bilirubin into
urobilinogen.
Most urobilinogen is converted to stercobilinogen and then to stercobilin.
Stercobilin is excreted in the feces, giving it its characteristic brown color.
A smaller portion of urobilinogen is reabsorbed via two different pathways:
→ Most of it undergoes hepatobiliary recirculation, while the remainder is filtered by
the kidneys.
→ Or: The remainder is excreted by the kidneys. In the urine, urobilinogen is oxidized
to urobilin, which is responsible for the characteristic yellow color.

3.

4. The main laboratory parameters of pigment metabolism include:

1) Serum bilirubin:
a) total, its normal content is 8.5 – 20.5 μmol/L;
b) direct – 1.2 – 5.3 μmol/L (about 25% of total);
c) indirect – 1.7 – 17.1 μmol/L (up to 75% of total).
2) Stercobilin is determined in feces in the amount of 40 –
280 mg/day.
3) Urobilin (in urine) – 0 – 6 mg/day.

5.

Jaundice is a syndrome that develops due to the
accumulation of excess bilirubin in the blood. In clinical
practice, this syndrome is diagnosed by the yellow
discoloration of the skin, mucous membranes, and
sclera.
According to the mechanism of occurrence, the
following types of jaundice are distinguished:
Prehepatic
(hemolytic)
Hepatic
Subhepatic
(obstructive,
mechanical)

6.

Prehepatic
Hepatic
Indirect bilirubin (in
blood)
Direct bilirubin (in
blood)
Urobilin (in urine)
/
Stercobilin (in feces)
/
Subhepatic

7. Prehepatic jaundice

Prehepatic jaundice is caused by increased breakdown of erythrocytes due to hemolysis and
accelerated formation of bilirubin.
Classification:
I. Hereditary hemolytic anemias.
1) Hemoglobinopathies (disorder of hemoglobin structure or synthesis)
2) Membranopathies (alteration in membrane protein or lipid structure)
3) Enzymopathies (impairment of erythrocyte enzyme activity)
II. Acquired hemolytic anemias
1) Isoimmune
2) Autoimmune hemolytic anemias (AIHA)
3) Associated with altered membrane protein structure due to mutation (paroxysmal nocturnal
hemoglobinuria)
4) Due to mechanical damage to the erythrocyte membrane
5) Due to poisoning with hemolytic poisons
6) Parasitic anemias (malaria)
7) Vitamin E deficiency in newborns

8. Physiological types of hemoglobin

Hb P – n in the first 12 weeks of human embryonic development
Hb F – 60-80% at birth, 1% in adults
HbA1 – 96-98% in adults
HbA2 – 2-4% in adults
HbA3 – in the elderly (about 10%)

9. Hemoglobinopathies

Among hemoglobinopathies, the following groups are distinguished:
Defects caused by the replacement of one amino acid residue in the globin
peptide chain (sickle cell anemia, hemoglobinopathies Hb M)
Defects caused by impaired synthesis of globin chains (thalassemias)

10. Sickle cell anemia

Etiology: replacement of glutamic acid with valine in the β-chain of Hb
Pathogenesis: hypoxia -> hemoglobin formation -> hemoglobin crystallization ->
formation of drepanocytes -> microthromboses -> heart attacks, strokes, kidney
and retinal damage
Laboratory parameters:
1) Normochromic anemia (decrease in hemoglobin to 50 - 100 g/L)
2) Poikilocytosis (10 - 15% of erythrocytes in smears have a sickle shape)
3) Basophilic inclusions in erythrocytes
4) Reticulocytosis up to 10 - 20%
5) ESR normal or decreased
6) Leukocytosis
7) Thrombocytosis
8) In serum - increase in the indirect fraction of bilirubin, in urine and feces - urobilin
and stercobilin
9) Hemoglobin electrophoresis reveals Hb S

11. Thalassemias

α-Thalassemia. Impaired synthesis of the α-chain leads to reduced formation of all
types of physiological hemoglobins - HbA1, HbA2 and HbF.
Pathological types are formed: HbH (4 β-chains) and Hb Barts (4γ-chains) - easily
destroyed and poorly carry O2.
In homozygotes, Hb Barts - intrauterine fetal death.
In heterozygotes, HbH - chronic hemolytic anemia.
β-thalassemia - impaired synthesis of β-chains of Hb. (HbA1↓, HbA2↑, HbF↑)
δ-thalassemia - impaired synthesis of β and δ chains of Hb. (HbA1↓, HbA2↓, HbF↑)
Laboratory diagnostics:
1) hypochromic anemia with reticulocytosis
2) poikilocytosis, codocytes, microcytes
3) ↑ indirect bilirubin, uro- and stercobilin
4) HbH and Hb Barts on electrophoresis

12. Membranopathies

Membranopathies associated with impaired structure of
erythrocyte membrane proteins
Membranopathies associated with impaired structure of
erythrocyte membrane lipids

13. Hereditary spherocytosis (Minkowski–Chauffard anemia)

Etiopathogenesis: – abnormality of spectrin protein in the erythrocyte
membrane -> increased membrane permeability to Na ions and water ->
macrospherocytes "get stuck" in the spleen -> microspherocytes ->
reduced lifespan to 10-12 days -> hemolysis
Laboratory diagnostics:
1) anemia with reticulocytosis
2) anisocytosis, poikilocytosis, microcytosis, spherocytosis
3) ↑ indirect bilirubin, uro- and stercobilin
4) decreased osmotic resistance of erythrocytes

14. Paroxysmal nocturnal hemoglobinuria

Cause – absence of inhibitors of complement-dependent lysis (CD55,
CD59 receptors) on the erythrocyte membrane.
Pathogenesis: ↓pH -> activation of the complement system ->
destruction of Er, tr, lec.
Laboratory diagnostics:
1) anemia with reticulocytosis, thrombocytopenia, leukopenia
2) ↑ indirect bilirubin, uro- and stercobilin
3) hemoglobinuria
4) positive Ham test (hemolysis of patient's erythrocytes in acidified
human serum)

15. Enzymopathies

Enzymopathies can be caused by deficiency of:
enzymes of the pentose phosphate pathway
enzymes of glycolysis
enzymes of glutathione metabolism
ATPase, adenylate cyclase
enzymes of porphyrin synthesis.
5 classes:
1) Complete loss of enzyme activity
2) Enzyme activity less than 10% of normal
3) Enzyme activity from 10% to 60%
4) Enzyme activity from 60% to 100%
5) Enzyme activity twice the normal level

16. Deficiency of glucose-6-phosphate dehydrogenase

Inherited in an X-linked recessive manner.
Deficiency of glucose-6-phosphate dehydrogenase leads to reduced formation of
NADPH, which is involved in the reduction of glutathione. Normally, the latter
provides protection of the erythrocyte membrane from the effects of oxidants.
First manifestations can be triggered by medication intake, viral diseases,
consumption of mushrooms, legumes.
Laboratory parameters:
1. Normochromic macrocytic anemia
2. Reticulocytosis
3. Normal or increased osmotic resistance of erythrocytes
4. Hyperbilirubinemia (due to the indirect fraction)
5. Increased content of stercobilin in feces, urobilin in urine
6. Detection of Heinz bodies in erythrocytes in smears (fragments of the erythrocyte
membrane damaged by oxidants)
7. Decreased activity of erythrocyte enzymes

17.

18. HEPATIC JAUNDICE

19. Hepatocellular jaundice

Occurs due to impaired permeability and integrity of hepatocyte membranes and
the release of direct bilirubin into the sinusoids, and then into the bloodstream.
Clinically, this is manifested by bright yellow discoloration of the skin, uniform
enlargement of the liver, often with splenomegaly, and signs of hepatocellular
insufficiency.
It can be observed in acute viral hepatitis, infectious mononucleosis, toxic, druginduced, alcoholic liver damage, as well as in cirrhosis and hepatocellular
carcinoma.
Laboratory parameters:
1. Increased activity of ALT and AST; increased serum iron levels (signs of hepatocyte
cytolysis)
2. Increased thymol test values; hypergammaglobulinemia (signs of mesenchymalinflammatory syndrome)
3. Increase in total bilirubin with a predominance of the direct fraction; bilirubinuria;
increase in urobilinoids in urine due to urobilinogen (impaired pigment metabolism)

20. Cholestatic jaundice

The basis is a violation of the excretion of bile from hepatocytes or intrahepatic
bile ducts, associated with a violation of the formation of the bile micelle.
It is observed in drug-induced hepatitis due to the use of aminazine, anabolic
steroids, androgens, sulfonamides, the cholestatic form of viral hepatitis, toxic
and alcoholic liver damage.
A vivid clinical manifestation is skin itching.
Laboratory parameters:
Increase in:
- bilirubin level due to the direct fraction
- activity of enzymes - markers of cholestasis: alkaline phosphatase, γglutamyltransferase, 5-nucleotidase, leucine aminopeptidase
- bile acids
- cholesterol and β-lipoproteins

21. Enzymopathic jaundice

Impaired
uptake
of bilirubin
from the blood
by the
hepatocyte
Gilbert
syndrome
↑ indirect
bilirubin
↓urobilin
↓stercobilin
Impairment
of bilirubin
conjugation
CriglerNajjar
syndrome
LuceyDriscoll
syndrome
↑ indirect bilirubin
↓urobilin
↓stercobilin
Impairment
of excretion
of conjugated
bilirubin into
the bile ducts
DubinJohnson
syndrome
Rotor
syndrome
↑ indirect bilirubin
↓urobilin
↓stercobilin
Impairment
of all stages
of bilirubin
detoxification
Hepatitis; liver cirrhosis;
drug-induced or
alcoholic liver damage;
infectious
mononucleosis;
hepatocellular
carcinoma
↑ indirect and direct
bilirubin

22. SUBHEPATIC JAUNDICES

Occurs due to obstruction of bile outflow from the bile ducts due to
blockage, compression, or stricture of the biliary tract.
Most common causes:
- obstruction of the hepatic or common bile duct by stones, tumors,
parasites
- obstruction of the ampulla of Vater by stones, tumors, parasites
- cysts, tumors, chronic inflammation of the pancreas
- postoperative stricture of the common bile duct
- anomalies of the biliary tract development
- significant enlargement of lymph nodes in the porta hepatis
(lymphogranulomatosis)

23.

Obstruction of bile flow leads to increased pressure in the upstream bile
ducts. Hepatocytes become overloaded with bile, which then enters
the lymph and blood.
As jaundice intensifies, the skin takes on a greenish tint, and itching
appears.
Beer-colored urine is excreted (due to the penetration of direct bilirubin
into it) and feces become discolored.
Laboratory parameters:
- increase in the direct fraction of bilirubin and bile acids
- bilirubinuria
- increased activity of alkaline phosphatase, gamma-glutamyl transferase
- elevated levels of cholesterol, β-lipoproteins
- significant decrease in stercobilin and urobilin
All of the above is characteristic of cholestasis syndrome. When cytolysis
is added, an increase in ALT and AST is detected.