by notes of doctor Claudio Italiano
They represent a heterogeneous group of
erythrocyte pathologies both from the morphological and pathogenetic point of
view. Where there is malaria, there is thalassemia, in the sense that the
subjects affected by thalassemia did not make malaria and, for this reason, they
survived, they reproduced and spread the affection. The term "hemoglobinopathy"
indicates the congenital and hereditary conditions characterized by an abnormal
synthesis of the globin component of hemoglobin. The synthesis of hemoglobin (Hb)
is under the control of specific genes, called "structural loci" that have the
task of synthesizing the amino acid sequence of each of the four polypeptide
chains alpha, beta, gamma, delta, while "regulatory loci" exert a quantitative
control on protein synthesis.
The
pathogenesis of hemoglobinopathies depends on the following factors:
1. synthesis of structurally abnormal polypeptide chains (hemoglobinosis) by
substitution or loss of one or, rarely, more than one of the amino acids that
make up the globin chain;
2. deficient synthesis of one or more types of normal globin chain (alpha, beta,
alpha-beta, typical of the thalassemia);
3. synthesis of tetramers consisting of 4 β polypeptide chains all of the same
type (composed of structurally normal or pathological globins); these tend to
precipitate or aggregate within the cell giving rise to pathological and
unstable tetrameters.
4. Hereditary persistence of fetal hemoglobin (HbF).
The transmission of the pathological gene occurs according to the laws of
autosomal recessive or dominant inheritance. The structurally abnormal Hb known
to date are over 200; many of them are observable in single family or ethnic
groups, but some (such as thalassemia and sickle cell disease) are present in
millions of people prevalently in Mediterranean ethnic groups, Central Africa,
India and Middle Eastern regions.
It is a heterogeneous group of hemoglobinopathies due to a diminished or absent
synthesis of one or more globin chains that enter the normal HB constitution.
The name of beta-, alpha-thalassemia indicates precisely the type of chains in
which synthesis is lacking. There are also mixed forms (alpha-beta thalassemia)
or forms characterized by the hereditary persistence of fetal hemoglobin. During
beta thalassemia, free alpha chains tend to precipitate within the erythroid
cell, or sometimes aggregate to form abnormal, insoluble tetrameters that cause
cellular pain and intramedullary death. In alpha thalassemia, the excess of beta
chains induces the same alterations of beta thalassemia; unlike what happens
during beta thalassemia, in the alpha thalassemia the excess beta chains are
more soluble so that tetrameters 4 are formed that allow the red blood cell to
complete the maturation process (albeit in the presence of a component
ineffective erythropoiesis variable). Therefore, thalassemia anemia is due both
to ineffective erythropoiesis and to chronic hyperemolysis (following the
intraerythrocytic precipitation of anomalous tetrameters); the result is a
marked and progressive medullary erythroid hyperplasia involving the bone marrow
and other hemopoietic tissues with consequent skeletal changes. The red blood
cells show an osmotic hyper-existence associated with an abnormal fragility in
the face of mechanical insults in the passage in the circle; at the level of the
viscera capillaries a reduction of their survival results. This last
characteristic is not proper, however, of the entire erythrocyte population; in
fact, two populations are generally distinguishable: one with a short life span,
the other with a normal life; the former is characterized by an excess of Hb F
while the latter for a scarce or absent amount of FibF.
Erythroblastic hyperplasia is spread to the whole marrow (including the yellow
one) but also in extra-medullary (heterotopic), and is sustained by an
erythropoietinal stimulus secondary to hyperemolysis that intervening since the
neonatal era induces tissue expansion erythropoietic also outside the normal
bone lacunae. A large proportion of erythroblasts and newly formed bone marrow
erythrocytes undergo intramedullary premature destruction (ineffective
erythropoiesis) for the aforementioned reasons.
The thalassemias in general and in particular the beta thalassemias represent
the most widespread hemoglobinopathies in the world, with endemic areas in the
Mediterranean basin (in Italy they are frequent in the area of the Delta
Padano, in Sardinia, Sicily, Puglia, Calabria and Campania), Africa , India, and
the Middle East. The alpha-thalassemia, much rarer among the Mediterranean races,
is instead widespread in the Middle-East Or: you and among the African blacks of
America.
Also called M. di Cooley, it represents a serious form of thalassemia with a fatal outcome due to the alteration of the homozygous state of the beta-globin gene. In rt: include different pathological conditions: according to the type of globin alteration. There is a β ° variant, characterized by failure to synthesize the β globin chain, and a β + variant, characterized by reduced synthesis of the globin chain. In both cases the genetic alterations are heterogeneous since there can be "non-sense" point mutations (able to determine the arrest of mRNA transcription) at various levels of the sequenz; gene (introns, exons, promoter genes). Depending on the type of gene abnormalities, clinical pictures of different severity can be observed.
Example of a patient with "orientalis facies" of cooleyans.
In general, the electrophoresis of hemoglobin; highlights a high percentage of
Hb F (1 ~ -90%), a higher than normal (4-6%) c Hb A2 and a reduced percentage of
Hb A.
In the peripheral blood there is a marked reduction in the number of GR (often
less than: 2,000,000 / uL), Hb value β-7 g / 100 dL), MCH (16-20 pg); while the
MCHC is only modestly reduced; anisopoichilocytosis is very pronounced in the
presence of frequent target cells, ellipsocytes, schistocytes and hams with the
most bizarre forms; there are also polychromatophile hematics or basophilic
punctuation or with bodies of Jolly, erythroblasts in various maturational
attitudes (mostly orthochromatic or polychrome-strands, often with a picnotic
nucleus); peripheral erythroblastosis can reach very high values (up to
100,000 / pL); discreet increase in reticulocytes (up to 5-15%); the automatic
meters reveal a marked microcitosis and a reduction of the MCHC; the RDW value
has generally increased. Rare leukocytosis (up to 50,000 / uL) with circulating
myeloblasts and myelocytes, even if electronic counters often reveal a false
leukocytosis (secondary to the presence of erythroblasts in the circulation,
which are misinterpreted as leukocytes). The values of indirect bilirubinemia
(up to 4 mg / 100 ml) and sideremia have increased as well as the transferrin
saturation index.
The bone marrow has a marked erythroid hyperplasia with the presence of
proherritroblasts and giant erythroblasts (megaloblasts); the more mature forms
sometimes have a diameter below the norm (micro-thromboblasts). In most
erythroblasts, the excess of alpha chains, which do not find the corresponding
beta chains to form the tetramers, gives rise to intra-cytoplasmatic
precipitates with consequent ineffective erythropoiesis. The clinical picture is
therefore characterized by the signs of hyperemolysis, ineffective
erythropoiesis, hepatic damage that evolves towards pigmentary cirrhosis
secondary to hemochromatosis), cardiac suffering leading to congestive
cardiocirculatory failure, skeletal changes of a clinical-radiological order (characteristic
the "microcytememic facies" of Mongoloid appearance and the "brush skull"); from
the delay of bodily development in the child.
4. The severity of the clinical picture depends on the period of onset of the
disease; a) that of the infant, with a very high percentage of FTbF in the red
blood cells and death in the first years of life; b) the chronic one of the
second and third childhood, typical, with an inauspicious outcome in the
adolescent age; c) the "mild" adult, with a slower increase and the possibility
of survival until about 30-40 years.
The natural history of the disease has been profoundly changed in recent years
as a result of current therapies that have made it possible to significantly
extend the lives of these patients and in some cases even to cure them. The
therapy is + rasa on a constant transfusion regimen and at an early start (first
years of life) which aims to maintain constant hemoglobin values around 10 g /
day. The second therapeutic treatment is based on a correct iron chelation
therapy that eliminates or at least attenuates the polyorganic pathologies
secondary to siderochromatosis. Useful for the purposes of parenchymal control (liver,
kidney and myocardium), b) to systemic hemose-derosis of variable but often
imposing entity, especially in the longest surviving subjects and who have
received repeated blood transfusions in the course of the disease , c)
splenomegaly, and c) osteomidullary lesions.
Example of a patient with "orientalis facies" of cooleyans.
The spleen is always and very enlarged (often> 1 Kg), and of increased
consistency; the capsule is somewhat thickened. When cut, the pulp is
hyperplastic, dark red in color and well restrained, while the lymphatic
follicles are mostly poorly visible, etologically next to the hypertrophy of the
follicles and the congestion of the breasts, there is hyperplasia of the
monocyte-macrophage cells of the cords of Billroth (sometimes with figures of
erythrophagocytosis) and of the lining cells of the breasts, and hyper-rlasia of
the reticular fibers, more marked "in the advanced stages of the disease.The
hemosiderine deposit is generally modest, except in cases that are immediately
repeated transfusions Extensive outbreaks of hematopoiesis, with a predominantly
erythropoietic imprint, are found mainly in the infant's premei and severe forms,
finally the presence in the pulp of large histiocytes, with abundant cytoplasm,
eosinophilus, granulosis, intensely PAS positive and partly also positive These
tesaurosic cells, of similgaucherian appearance, besides being constantly
present in greater or lesser abundance in the spleen (and in the bone marrow),
they differ, due to histochemical and ultrastructural features, from similar but
not identical tesaurotic cells, described under other conditions, such as
Gaucher's disease, chronic myeloid leukemia, purple idiopathic
thrombocytophenics and the so-called "blue histiocyte syndrome". The exact
nature of the material accumulated in the thalassemic tesaurosis cells is still
under study, but seems to be predominantly sialoglycoproteins.
The liver, enlarged and increased in consistency, with frequent fatty degeneration, often has a rusty complexion due to the intense hemosisosis, and it is not rare, in
subjects late to death, aspects that are similar or frankly cirrhotic, for which the responsibility can not be excluded. of blood transfusion as a vehicle for
virus-hepatitis infection. Histologically, next to the centrilobular steatosis, there is the intense hemosiderosis of both Kupffer cells, hypertrophic and more
numerous than in general, and of the hepatic cells especially of the lobular periphery; often there is more or less noteworthy sclerosis up to the
similacriric pictures. You can observe conspicuous erythroblastic foci.The lymph nodes are often modally hypertrophic, may present hemosiderosis, especially
those located in the hepatic hile. The bone marrow is intensely hyperplastic with bright red complexion in all sites, with the usual disappearance of the
adipose marrow. The hyperplasia concerns above all the red series and consists
in a clear increase of the erythroblasts, especially the more immature ones and
the basophilous forms (ineffective erythropoiesis). Hyperplasia of histiocytic
cells, diffuse or in islets, coexists with frequent aspects of
erythrophagocytosis and storage in the cytoplasm of positive PAS material.
Constants and characteristics are the skeletal lesions, which reach their
maximum expression in the second and third infancy and in the rare forms of the
adult. There are phenomena of diffuse osteoporosis, but more pronounced at the
level of the spongy-shaped skeletal parts, and of bone neoformation of
periosteal origin, so that the bones involved increase in thickness also
considerably. Moreover, at the level of the thickened skullcap (but sometimes
also of long bones), the tendency of newly formed bone trabeculae to assume an
orientation perpendicular to the bone surface is singular. This results in the
classic radiological appearance of the "brush skull", characteristic (though not
exclusive) of M. di Cooley. These high bone ratios of the hyperostotic-porotic
type are, among other things, responsible, through the thickening of the bones
of the face and in particular of the zygomatic bones, of the "facies
orientaloide" of the cooleyans. The heart, especially in cases of long duration,
is hypertrophic in photos due to the increase in volume of the muscle fibers due
to the anoxic state; more or less serious phenomena of fatty degeneration of
interstitial sclerosis and hemosiderosis coexist; there are also cases of
serious siderochromatosis of the myocardium with a lethal outcome if not treated
appropriately
The pancreas, often thickened and rusty, presents an intense hemosiderosis of
the acinar tissue (with inconstant and mostly modest participation of the
insular cells) and a modest thickening of the interlobular connective tissue. In
other organs, a haemosuria, sometimes conspicuous, is found histologically in
the glandular epithelia of the adrenal (cortical), thyroid, parathyroid and
pituitary gland, and often also in the lining and glandular epithelia of the
stomach and intestine, as well as in the histiocytic cells of each organ and
tissue, with overall aspects sometimes apparently superimposable to those of the
hemacromatosis (or siderochromatosis) essential. Striated muscles are free from
hemosiderinic deposits. It is probable that somatic and also sexual
hypoevolutism, especially in males, depends on lesions of the endocrine glands;
apart from hemosiderosis, these are however usually exempt from significant
changes. The exitus generally occurs for diseases related to siderochromatosis,
cardiocirculatory insufficiency, cardiovascular accidents.
It is the heterozygous form of beta-thalassemia major and exists in various
clinical forms. The asymptomatic form is called "thalassemia minor" and
represents the condition of healthy carrier. The thalassemia minor appears in
people heterozygous for genes that produce minimum or nil quantities of α or β
globin chains. Since this condition is asymptomatic, the resulting microcitosis,
which lasts for life, can remain misunderstood or be confused with an iron
deficiency; therefore it is not rare for minor thalassemia to be diagnosed
during old age. Other anemias caused by the presence of abnormal Hb are usually
diagnosed in younger people, because they are symptomatic or because the patient
has a more pronounced anemia.
The thalassemia minor causes microcitosis with or without mild anemia. In
general, reticulocyte counts are normal and serum, TIBC and ferritinemia are
also normal. In β-thalassemia, electrophoresis of Hb may reveal an increase in
minor Hb, especially fetal Hb or Hb A2; in α-thalassemia, hemoglobin
electrophoresis may be normal. No thalassemia is required for thalassemia minor,
and martial therapy is contraindicated because it can cause iron overload.
it is a type of thalassemia that involves the genes that code for Hb A and Hb A2 hemoglobin. The disease is characterized by compromising the production of one, two, three or even all four α-chains of hemoglobin, which directly correlates with the clinical severity of the disease. There are two gene loci for the α chains, which become four in the diploid cells, two of maternal origin and two of paternal origin. The clinical severity of alpha thalassemia is inversely proportional to the number of α chains; the more they will miss, the clinical manifestations will be worse. The condition is called HbH disease. There are two types of hemoglobin in the blood, both unstable: tetramer γ4 (Hb Bart) and tetramer β4 (HbH). Both are characterized by a high affinity for oxygen, greater than that of normal hemoglobin, which causes a reduced oxygenation of the tissues. There is a marked hypochromic microcytic anemia with the presence of "target cells" and "Heinz bodies" (formed by the precipitation of HbH) on microscopic examination of the peripheral blood smear. The disease is usually diagnosed in infancy or during adolescence, as a result of the detection of anemia and splenomegaly in routine tests.