Pigments ( REWORK) Flashcards
explain the main laboratory indicators of pigment metabolism include ?
- Serum bilirubin:
a) total, its content is normally 8.5 - 20.5 µmol / l;
b) conjugated (direct) - 1.2 - 5.3 μmol / l (about 25% of the total);
c) unconjugated (indirect) - 1.7–17.1 μmol / l (up to 75% of the total). - Stercobilin is determined in feces in the amount of 40 - 280 mg / day.
- Urobilin (in the urine) - 0 - 6 mg / day.
Normally, urine does not detect urobilinogen. Its appearance indicates damage to the liver parenchyma,
impaired formation of dipyrrole compounds, and may precede the staining of tissues in yellow
(jaundice)
-An increase in the level of total bilirubin in the blood to a level above 20.5 μmol / l is called
hyperbilirubinemia. Hyperbilirubinemia may be associated with increased bilirubin formation, liver
damage, disrupting conjugation and excretion of bilirubin, as well as impaired biliary tract patency. If the
content of bilirubin in the blood exceeds 30 - 35 µmol / l, this is accompanied by a jaundice staining of
the skin.
DIFFERENTIAL DIAGNOSTICS OF JAUNDICE , df , types
-Jaundice is a syndrome that develops due to the accumulation in the blood of an excess amount
of bilirubin. In clinical practice, this syndrome is diagnosed by icteric staining of the skin,mucous membranes and sclera.
-There are three main types of jaundice: pre-hepatic, intra-hepatic and post-hepatic jaundice is isolated.
PRE-HEPATIC JAUNDICE , df , types
-df :Pre-hepatic jaundice is caused by an increased breakdown of red blood cells as a result of hemolysis and the accelerated formation of bilirubin. The main causes of pre-hepatic jaundice
are hereditary and acquired hemolytic anemia. Conventionally, all hemolytic anemia (pre-hepatic jaundice) can be divided into the following groups : .
I. Hereditary hemolytic anemia.
1. Hemoglobinopathies (violation of the structure or synthesis of hemoglobin).
2. Membranopathies (changes in the structure of proteins or membrane lipids).
3. Enzymopathies (violation of the activity of erythrocyte enzymes).
II. Acquired hemolytic anemia.
-1. Isoimmune:
a) hemolytic disease of the newborn;
b) post-transfusion hemolytic anemia.
-2. Autoimmune hemolytic anemia (AIHA).
A. AIGA with thermal antibodies:
a) idiopathic;
b) secondary or symptomatic (against the background of viral or mycoplasmal
infections, lymphosarcoma, chronic lymphocytic leukemia and other malignant diseases,
c) due to medication.
B. Autoimmune hemolytic anemia with cold antibodies:
a) cold hemagglutinin disease (idiopathic and secondary);
b) paroxysmal cold hemoglobinuria.
-3. Associated with changes in the structure of membrane proteins due to mutation (paroxysmal
night hemoglobinuria).
-4. In case of mechanical damage to the erythrocyte membrane:
a) in the presence of prosthetic heart valves;
b) marching hemoglobinuria;
c) hemolytic uremic syndrome;
d) Disseminated intravascular coagulation (DIC) syndrome;
e) anemia in splenomegaly.
-5. In case of poisoning with hemolytic poisons.
-6. Parasitic anemia (malaria).
-7. Vitamin E deficiency in newborns
what is df of Hemoglobinopathy
-Normal hemoglobin (Hb) molecule consists of four subunits, each of which is represented by a polypeptide chain associated with one heme molecule. Polypeptide chains are usually denoted by
Greek letters: α, β, γ, δ, etc.
explain Sickle cell anemia , df ,heterozygous ,Homozygotes ,Laboratory signs
-DF :where one of the peptide chains of amino acids is
replaced by another. Sickle cell anemia is a common anomaly in this group. Its occurrence is associated with the formation of Hb S, which in the 6th position of the β-chain glutamic acid is replaced by valine. This leads to a sharp decrease in the solubility of the reduced (deoxygenated) form of Hb (s). when the partial pressure of oxygen in the blood decreases, Hb (s) aggregates into reticular crystals (tanatoids) and deforms the normal form of the erythrocyte. The resulting sickle-shaped red blood cells (drepanocytes) form sludge in the lumen of small vessels, which leads to their hemolysis, activation of the blood coagulation system and vascular microthrombosi
-In people heterozygous for Hb S, clinical signs of the disease may be absent, but there is a tendency to hemolysis of red blood cells and thrombosis of blood vessels on the background of
hypoxia when climbing to high altitudes, operations, infectious diseases, heavy physical work
-Homozygotes suffer from chronic hemolytic anemia, which has a more severe course and high mortality in childhood. With hypoxia, stress, infections, physical activity, they have hemolytic crises. Often they end with microthrombosis and the development of heart attacks of the kidneys, lungs, brain, the emergence of significant pain, osteomyelitis, fractures and trophic ulcers of the limbs. Repeated heart attacks of the spleen lead to” autosplenectomy
-Laboratory signs:
1. Normochromic anemia (reduction of hemoglobin to 50 - 100 g/l).
2. Poikilocytosis (up to 10 – 15% of red blood cells in smears have sickleform.)
3. Basophilic inclusions in red blood cells.
4. Reticulocytosis up to 10 – 20%.
5. Erythrocyte sedimentation rate is normal or reduced.
6. Leukocytosis.
7. Thrombocytosis.
8. In serum - increase of indirect bilirubin fraction, in urine and feces – urobilin sterkobilina and.
9. In electrophoresis of hemoglobin, HBS is detected.
explain Hemoglobinopathies Hb M , df , Laboratory diagnostics:
-DF :Is a group of hemoglobinopathies occurs during the replacement of the histidine involved in binding the iron atom, the other amino acid. As a result, it is difficult to restore iron from Fe3+ to Fe2+ by the enzyme methemoglobin reductase. This leads to the loss of hemoglobin ability to bind oxygen and its transport and a significant increase in the content of
methemoglobin in the blood.
- For homozygotes, the disease is fatal.
-In heterozygotes, a mixture of hemoglobin and methemoglobin is found in the blood. The main clinical sign is cyanosis
-In healthy individuals, methemoglobinemia can develop when poisoned with nitrites, nitrates, aniline, sulfanilamide preparations and bromides.
-Laboratory diagnostics:
1. Increase of methemoglobin content up to 15% or more (normally above 0.1-0.3%).
2. In electrophoresis of hemoglobin, HB M is detected.
explain thalassemia , DF, types , Laboratory values
-DF:Thalassemia - a group of hereditary diseases, which are based on a violation of the synthesis of globin chains. The Greek letter before the onset of the disease indicates the synthesis of which chain is violated: α-, β-thalassemia, etc.
A normal cell contains 4 genes controlling the synthesis of the α-chain and 2 genes responsible for the
synthesis of the β-chain. The severity of clinical and laboratory manifestations depends on the number of mutated genes.
-α-Thalassemia. Violation of α-chain synthesis leads to a decrease in the formation of all types of physiological hemoglobins — HbA1, HbA2, and HbF.
-Homozygous α-thalassemia form - mutation of all four genes involved in the synthesis of the α-chain is
incompatible with life. Pregnancy usually ends in miscarriage. In non-viable newborns, cerebral dropsy is
detected, and in the blood, Barts Hb (4 γ) with a small amount of HbH (4 β).
-The heterozygous form of α-thalassemia usually occurs as mild chronic hemolytic anemia, since, along
with abnormal HbH in patients, a reduced amount of physiological hemoglobins — HbA1, HbA2, and HbF — is present in the blood.
-β-Thalassemia occurs much more frequently. The disease is associated with impaired synthesis of the β-
chains of globin, which are part of HbA1. As a result, the ratio of normal hemoglobin fractions changes with an increase in the proportion of HbA2 and HbF. An excess of α-chains readily binds to SH-groups of the erythrocyte cell membrane, damages it and leads to hemolysis.
-Inheritance of the β-thalassemia gene from both parents leads to a homozygous state of β-thalassemia (thalassemia major or Coule’s disease). In this case, by the end of the first year of life, a clinic of severe hemolytic anemia occurs. Yellowness and paleness of the skin along with hepatosplenomegaly is detected
-Heterozygous β-thalassemia occurs in the form of mild chronic hemolytic anemia, often detected by chance.
-Laboratory values:
1. Hypochromic anemia of varying severity.
2. Microcytosis of erythrocytes.
3. In blood smears - target erythrocytes (codocytes).
4. Increasing the number of reticulocytes.
5. Increasing osmotic resistance of erythrocytes.
6. Increase in indirect bilirubin.
7. Increased serum iron levels.
It is often necessary to conduct a differential diagnosis of thalassemia with other hypochromic anemias, especially with iron deficiency anemia.
explain Membranopathy (anemia of Minkowski - Chauffard)
-Hereditary microspheresis (anemia of Minkowski - Chauffard) is transmitted by autosomal dominant inheritance.
-The pathogenesis of the disease is not completely clear. It is assumed that one of the reasons is the disruption of the structure of microfilaments of the spectrin membrane protein, leading to increased permeability of the erythrocyte membrane for sodium ions and the accumulation of water in them. Red blood cells acquire a spherical shape, which reduces their ability to deform when passing through the sinuses of the spleen, and increase the time of this passage. Normal erythrocytes pass the splenic
sinuses in 10–15 s, and in hereditary spherocytosis in 4–5 min.
-Laboratory values:
1. Reducing the number of Hb.
2. Increase in reticulocytes.
3. Microcytosis of erythrocytes (average diameter of erythrocytes is 6 microns, normal - 7.2 - 7.5 microns).
4. Spherocytosis.
5. The decrease in osmotic resistance of erythrocytes:
normal - the minimum hemolysis in 0.48 - 0.46% p-re sodium chloride, maximum - at 0.34 - 0.32%; with hereditary microspherocytosis - minimal hemolysis - 0.7 - 0.6% p-re,
maximum - at 0.46 - 0.48%.6. Increase in indirect serum bilirubin.
7. Enhancement of urobilin and stercobilin.
8. Irritation of the erythroid sprout of the bone marrow, the ratio
Leiko: Erythro approaches 1: 1, in norm - 3: 1.
explain Membranopathy ( elliptocytosis, or ovalocytosis)
-Hereditary elliptocytosis, or ovalocytosis, is considered another disease resulting from abnormalities of
the membrane protein of spectrin. Inherited by autosomal dominant type. The elliptocytosis gene is linked to the rhesus system genes. Most carriers of the pathological gene have no clinical manifestations.
If symptoms are present, they are similar to manifestations of microspherocytosis. However, in the study of blood smear elliptocytosis is detected.
explain Membranopathy (acanthocytic hemolytic anemia or a-β-lipoproteinemia)
-This group includes acanthocytic hemolytic anemia or a-β-lipoproteinemia. In this pathology, changes in
the composition of phospholipids and fatty acids of the erythrocyte membrane are observed. The
contour of erythrocytes becomes serrated (acanthocytes), the cells resemble in appearance the leaves
of the acanthus plant, from which the name originated. Osmotic resistance of erythrocytes is within the
normal range.
-In the blood plasma of patients, the content of triglycerides approaches zero, the content of cholesterol
and the transport forms of both types of lipids are significantly reduced. Marked anemia, retinitis,
ataxia, hyporeflexia, nystagmus, tremor.
-Laboratory values:
1. Reduction of plasma triglycerides down to zero.
2. Significant lowering of cholesterol.
3. Reduction of the transport forms of lipids (CM, LDL, VLDL).
4. Anemia.
explain Membranopathy (paroxysmal nocturnal hemoglobinuria)
-paroxysmal nocturnal hemoglobinuria: The disease results from the acquired somatic mutation of the PIG-A gene of hematopoietic cells.
-This gene is responsible for the synthesis of glycosyl-phosphatidyl-inositol “anchor” (GPI), which fixes a
number of molecules on the membranes of blood cells. Violation of GPI synthesis in patients with paroxysmal nocturnal hemoglobinuria (PNH) results in the absence of a number of proteins on the membrane surface, which normally have this component.
Thus, a decrease in the expression of inhibitors of the complement-dependent lysis of CD55, CD59 on erythrocytes leads to intravascular hemolysis. The destruction of red blood cells is significantly enhanced by intercurrent infections, taking
certain medications, hypercoagulation syndrome, blood transfusion, as well as at night, against the
background of a physiological decrease in pH.
explain Enzymopathies
-These include a number of hereditary hemolytic anemias caused by a deficiency of erythrocyte enzymes.
The development of the disease can lead to disruption of the enzymes: the pentose phosphate pathway
for the conversion of carbohydrates (glucose-6-phosphate dehydrogenase); glycolysis (pyruvate kinase);
glutathione metabolism (synthetase, reductase, peroxidase); ATPase, adenylate cyclase; porphyrin
synthesis.
-The lack of enzyme activity leads to disruption of the vital functions of the cell due to energy starvation,
ionic imbalance, inhibition of oxidation-reduction reactions, etc. As a result, the erythrocyte becomes
more sensitive to the effects of various alimentary, drug and infectious factors. Among enzymopathies,
the most common is glucose-6-phosphate dehydrogenase deficiency, inherited by the X-linked recessive
type
-The first manifestations in most patients are provoked by any external influences: taking certain
medications (antimalarial drugs, sulfonamides), viral diseases, eating certain foods (mushrooms,
legumes).
According to the severity of the course, 5 classes of disease are distinguished:
1) almost complete loss of enzyme activity (manifested as chronic hemolytic anemia);
2) residual enzyme activity - up to 10% of the norm (clinical symptoms appear only after provocation);
3) enzyme activity - 10-60% of the norm;
4) normal or slightly reduced enzyme activity (60 - 100% of normal);
5) enzyme activity - 2 times higher than normal.
Clinical manifestations in the last three cases may be absent.
-Laboratory values:
1. Normochromic macrocytic anemia.
2. Reticulocytosis.
3. Normal or increased osmotic resistance of erythrocytes.
4. Hyperbilirubinemia (due to the indirect fraction).
5. The increase in the content of stercobilin in feces, urobilin in the urine.
6. When staining blood smears with crystal violet - detection of Heinz bodies in erythrocytes (fragments
of erythrocyte membrane damaged by oxidants).
7. Reduction of the activity of erythrocyte enzymes.
explain Hepatic Jaundice
-This group of jaundice is associated with damage to the hepatocytes and biliary capillaries. Depending
on the mechanism of the pathological process in the hepatocyte, three types of hepatic jaundice are distinguished: hepatocellular, cholestatic, and fermentopathic.
-Hepatic jaundice occurs due to impaired permeability and integrity of the hepatocyte membranes and
the release of direct bilirubin into the sinusoids, and then into the bloodstream. Clinically, it manifests
itself as a bright jaundiced skin color, a uniform enlargement of the liver, often with splenomegaly, signs of hepatocellular failure
-Laboratory values:
1. Increased activity of ALT and AsAT; increasing content
serum iron (signs of cytolysis of hepatocytes).
2. Increased thymol test; hypergamma globulinemia
(signs of mesenchymal inflammatory syndrome).
3. Increase in total bilirubin with a predominance of the direct fraction;
bilirubinuria; an increase in urobilinoids in the urine due to urobilinogen (pigment metabolism).
-Laboratory values:
Raising:
- level of bilirubin due to direct fraction;
- enzyme activities - cholestasis markers: alkaline phosphatase,γ-glutamyltransferase, 5-nucleotidase, leucine aminopeptidase;
- bile acids;
- cholesterol and β-lipoproteins
explain Hepatic Jaundice ( Gilbert’s syndrome)
–associated with impaired transport of bilirubin to the hepatocyte-
-Gilbert’s syndrome, caused by a genetically determined decrease in the activity of the enzyme UDP-glucuronyltransferase (UGT) to less than 30% of the norm. Glucuronyltransferase
conjugates various toxic substances to the hepatocyte with glucuronic acid and has 5 isoenzymes.
Among them, the isoenzyme UHT 1A is considered to be responsible for the conjugation of indirect
bilirubin.
-Clinically, Gilbert’s syndrome manifests itself when, in addition to the deficiency of UGT1A, the patient
has at least one of the following congenital defects:
1) insufficiency of the enzyme bilirubintranslokazy, contributing to the capture of indirect bilirubin from the blood and its transport to the hepatocyte;
2) deficiency of Y- and Z-protein-ligandins, contributing to the transfer of indirect bilirubin in the
endoplasmic reticulum of hepatocytes, where conjugation is carried out.
-NB! The disease is inherited in an autosomal dominant manner. For the first time it usually manifests itself after viral infections, stress, fasting, considerable physical exertion, drinking alcohol
-Laboratory values:
-increase of indirect bilirubin in the blood (periodically, usually not more than 90-100 micromol / L;
- decrease in urobilin in urine and stercobilin in feces;
- it is possible to increase the level of AST and ALT in the cytolysis of hepatocytes;
- immunohistochemical study of liver biopsy with
polyclonal antibodies to UGT 1A.
explain Hepatic Jaundice ( Crigler - Nayar Type I and type 2 syndrome)
-NB! : impaired conjugation of bilirubin
- Crigler - Nayar Type I syndrome, which is characterized by complete loss of glucuronyltransferase activity. Inherited by an autosomal recessive type, considered a potentially lethal mutation.
The disease manifests itself from the first days of a child’s life, characterized by a sharp increase in the
level of indirect bilirubin (15-50 times higher than normal), its penetration through the BBB, deposition
in the subcortical nuclei of the brain and the development of deadly bilirubin encephalopathy (nuclear jaundice). The child dies during the first year of life
———————
-Crigler-Nayar Type II syndrome is inherited by an autosomal dominant type and is characterized by
incomplete loss of glucuronyltransferase activity. The level of indirect bilirubin in the blood is increased
by no more than 5 to 20 times compared with the norm.
3. Lucius-Driscoll syndrome (transient familial hyperbilirubinemia of the newborn) is associated with the
presence of inhibitors of conjugation of maternal bilirubin in the blood serum of a child. In some cases, the factor inhibiting the activity of glucuronyltransferase is contained in the mother’s milk
