Hereditary spherocytosis (Minkowski-Schoffar disease)

Hereditary spherocytosis (Minkowski-Chauffard disease) is a hemolytic anemia based on structural or functional disorders of membrane proteins, occurring with intracellular hemolysis.

The German therapist O. Minkowski (1900) was the first to describe familial hemolytic anemia; M.A. Chauffard (1907), a French therapist, discovered a decrease in the resistance of erythrocytes and the associated increase in hemolysis in patients.

The disease is widespread, with an incidence of 1:5,000 in the population. It is transmitted in an autosomal dominant manner; about 25% of cases are sporadic, caused by the emergence of a new mutation.

It is more common among residents of Northern Europe, where the prevalence of the disease is 1 in 5000 population.

Autosomal dominant inheritance occurs in approximately 75% of cases. The severity of anemia and degree of spherocytosis may vary among family members. In 25% of cases, there is no family history. In some patients, changes in laboratory parameters are minimal, which suggests an autosomal recessive inheritance pattern, while other cases are the result of spontaneous mutations.

How does Minkowski-Chauffard disease develop?

Associated with a hereditary defect of the erythrocyte membrane in the form of a deficiency of certain structural proteins (spectrins, ankyrins, actins). These proteins serve to maintain the biconcave shape of erythrocytes and at the same time allow them to deform when passing through narrow capillaries. There is an isolated partial deficiency of spectrin, a combined deficiency of spectrin and ankyrin (30-60% of cases), a partial deficiency of band 3 protein (15-40% of cases), a deficiency of protein 4.2 and other, less significant proteins. Deficiency of these proteins leads to destabilization of the lipid structure of the erythrocyte membrane, and the functioning of the sodium-potassium pump of the membrane is disrupted. The permeability of the erythrocyte for sodium ions increases. Entering the cell, sodium pulls water along with it. Swelling, the erythrocyte acquires a spherical shape - the most energetically advantageous. In this case, it decreases in diameter, but its thickness increases. Such an erythrocyte, due to the altered structure of the membrane, is not capable of transformation when passing through small intersinusoidal spaces of the spleen, where the concentration of glucose and cholesterol is reduced, which contributes to even greater swelling of the erythrocyte. This passage is accompanied by the detachment of lipid structures. The erythrocyte becomes increasingly defective and small. Such an erythrocyte is perceived by the macrophages of the spleen as foreign, captured and destroyed. Thus, intracellular hemolysis occurs. The lifespan of erythrocytes is sharply reduced (to 12-14 days) due to their severe wear, since more energy is required to remove sodium ions from the cell, which enter the cell in excess. Compensatory erythrouoiesis in the bone marrow increases. As a result of hemolysis, the amount of indirect bilirubin in the blood increases, but there is no sharp increase, since the liver significantly increases its functional activity: it increases the formation of direct bilirubin, as a result of which its concentration in bile and content in the bile ducts increases. In this case, bilirubin stones are often formed in the gallbladder and ducts - cholelithiasis develops. As a consequence, mechanical jaundice may appear: the amount of stercobilinogen and the content of urobilin increase. After the age of 10, gallstones are found in half of patients who have not undergone splenectomy.

Pathogenesis of hereditary spherocytosis (Minkowski-Chauffard disease)

Symptoms of Minkowski-Chauffard disease

The severity and diversity of the clinical picture are determined by the type of structural protein missing from the erythrocyte membrane (deficiency of the α-chain of spectrin is inherited in an autosomal dominant manner and is mild, while deficiency of the beta-chain causes a severe disease inherited in an autosomal recessive manner). In half of the cases, hereditary spherocytosis manifests itself already in the neonatal period, imitating the picture of hemolytic disease of the newborn or prolonged conjugation hyperbilirubinemia. The clinical picture of a hemolytic crisis consists of a triad of symptoms: pallor, jaundice, splenomegaly. Crises can be provoked by infectious diseases, taking a number of medications, but can also be spontaneous. In the intercrisis period, patients do not complain, but their enlarged spleen is always palpable. The more severe the disease, the more pronounced are certain fendtypic features, namely: tower skull, gothic palate, wide nasal bridge, large spaces between teeth. These changes in bone tissue are associated with compensatory hyperplasia of the bone marrow (erythroid germ), and, as a consequence, osteoporosis of flat bones. Depending on the severity of hereditary spherocytosis, the degree of expression of clinical symptoms may vary. Sometimes jaundice may be the only symptom for which the patient consults a doctor. It is to these individuals that the famous expression of M.A. Chauffard applies: "They are more jaundiced than sick." Along with the typical classical signs of the disease, there are forms of hereditary spherocytosis, when hemolytic anemia can be so well compensated that the patient learns about the disease only after the appropriate examination.

Symptoms of hereditary spherocytosis (Minkowski-Chauffard disease)

Complications of Minkowski-Chauffard disease

The most common complication of hereditary spherocytosis is the development of cholelithiasis due to bilirubin metabolism disorder. Often, the development of mechanical jaundice in cholelithiasis is mistaken for a hemolytic crisis. In the presence of stones in the gallbladder, cholecystectomy is indicated together with splenectomy. Performing only cholecystectomy is inappropriate, since ongoing hemolysis will sooner or later lead to the formation of stones in the bile ducts.

Formation of trophic ulcers is a rather rare complication that occurs in children. Ulcers occur due to the destruction of red blood cells, which results in thrombosis of blood vessels and development of ischemia.

Very rarely, so-called aregenerative or aplastic crises occur, when increased hemolysis is not accompanied by increased erythropoiesis for several days. As a result, reticulocytes disappear from the blood, anemia rapidly increases, and the level of indirect bilirubin falls. Currently, the leading etiologic role in this complication is given to parvovirus (B 19).

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How to recognize hereditary spherocytosis?

The diagnosis of this disease is quite simple. The following signs make the diagnosis of hereditary spherocytosis undoubted: jaundice, deformation of the facial skull, enlarged spleen, spherocytosis of erythrocytes, their reduced osmotic resistance, high reticulocytosis. A thorough collection of anamnesis plays a great role in establishing the correct diagnosis. As a rule, similar symptoms can be found in one of the patient's parents, although their severity may be different (for example, periodic icterus of the sclera). In rare cases, the parents are completely healthy. Diagnostic difficulties are often due to cholelithiasis, which usually accompanies hereditary microspherocytosis (due to the formation of bilirubin stones in the ducts and gallbladder). Indirect bilirubinemia, characteristic of hemolysis, is replaced by direct bilirubinemia in cholelithiasis - mechanical jaundice occurs. Pain in the gallbladder area, some enlargement of the liver are common signs in hereditary microspherocytosis. Often, for many years, patients are mistakenly considered to have a disease of the biliary tract or liver. One of the reasons for the misdiagnosis in this case is the lack of information about reticulocytes.

Laboratory diagnostics includes a number of studies.

Clinical blood test - normochromic hyperregenerative anemia, microspherocytosis of erythrocytes are determined. During the crisis, there may be neutrophilic leukocytosis with a shift to the left. An increase in ESR is characteristic.

Biochemical analysis of blood reveals an increase in indirect bilirubin, serum iron, and LDH.

It is necessary to study the osmotic resistance of erythrocytes in sodium chloride solutions of various concentrations. In hereditary spherocytosis, a decrease in the minimum osmotic resistance is noted, when hemolysis of the least resistant erythrocytes begins already at a sodium chloride concentration of 0.6-0.7% (the norm is 0.44-0.48%). Maximum resistance can be increased (the norm is 0.28-0.3%). Among patients with hereditary spherocytosis, there are individuals who, despite obvious changes in the morphology of erythrocytes, under normal conditions, have normal osmotic resistance of erythrocytes. In these cases, it is necessary to study it after a preliminary 24-hour incubation of erythrocytes.

Morphological features of erythrocytes in hereditary spherocytosis include a spherical shape (spherocytes), a decrease in diameter (the average diameter of an erythrocyte is <6.4 μm), and an increase in thickness (2.5-3 μm with a norm of 1.9-2.1 μm) with a usually normal average volume of erythrocytes. In this regard, in most cells, no central clearing is visible, since the erythrocyte changes from biconcave to spherical.

The hemoglobin content in erythrocytes remains within the physiological norm or slightly higher. The color index is close to 1.0. The Price-Jones erythrocytometric curve is stretched, shifted to the left.

Bone marrow puncture is not mandatory. It is performed only in unclear cases. The myelogram should show compensatory irritation of the erythroid hematopoietic line.

To conduct differential diagnostics with immune hemolytic anemias, it is necessary to perform the Coombs test. In hereditary spherocytosis, it is negative.

Electrophoresis of erythrocyte membrane proteins in combination with quantitative determination of proteins allows for a definitive and reliable confirmation of the diagnosis of hereditary spherocytosis.

Differential diagnosis

Spherocytosis of erythrocytes and other signs of hemolysis (jaundice, enlarged spleen, reticulocytosis) are also found in autoimmune hemolytic anemias. However, unlike hereditary microspherocytosis, the latter do not have changes in the skull bones or signs of hereditary microspherocytosis in either parent; at the first clinical manifestations of autoimmune hemolysis, there is no significant enlargement of the spleen or pain in the gallbladder, but anisocytosis and poikilocytosis of erythrocytes are more pronounced than in microspherocytosis. In doubtful cases, it is necessary to conduct the Coombs test, which is positive (direct test) in most cases of autoimmune hemolytic anemia and negative in hereditary microspherocytosis.

Diagnosis of hereditary spherocytosis (Minkowski-Chauffard disease)

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Treatment of Minkowski-Chauffard disease

Treatment during a hemolytic crisis consists of replacement therapy with red blood cells when hemoglobin drops below 70 g/l. In some cases, infusion therapy is required for detoxification purposes. With high bilirubin levels, treatment with albumin is indicated. During the non-crisis period, treatment with choleretic drugs should be carried out. In the case of a severe course of the disease in combination with a delay in physical development, accompanied by frequent crises requiring constant replacement therapy, splenectomy is indicated. In addition, the indication for splenectomy is the development of hypersplenism. Splenectomy does not cure this pathology, but after removal of the spleen, the main platform for the destruction of red blood cells disappears and their lifespan is extended. As a rule, hemolytic crises do not recur in children with a removed spleen. There are also negative aspects of splenectomy. Removal of the spleen has a negative effect on the immunological reactivity of the child's body, there is a decrease in the phagocytic activity of leukocytes, and susceptibility to parasitic, fungal and viral infections increases. It is believed that removal of the spleen leads to the development of hyposplenism syndrome, which manifests itself in a decrease in vitality, mental lability and decreased ability to work. Potential risk factors for splenectomy are technical difficulties during surgery in patients with large organ sizes, the development of bleeding during and after surgery, as well as infectious and septic complications. There are cases of fatal bacterial infections in the late postoperative period in children who underwent splenectomy at the age of under 5 years. This is why splenectomy at the age of under 5 years is not recommended. Preparation for splenectomy includes the introduction of pneumococcal and meningococcal vaccines 2 weeks before surgery, glucocorticoids, and IVIG. During the next 2 years, monthly administration of bicillin-5 is indicated. In recent years, laparoscopic splenectomy has been widely performed, which has significantly fewer surgical and postoperative complications, leaves a minimal cosmetic defect, and allows to reduce the patient's stay in hospital. An alternative to splenectomy can be considered endovascular occlusion of the spleen - the introduction of substances into the splenic artery that cause its spasm and subsequently lead to the development of splenic infarction. 2-5% of tissue after organ occlusion retains blood supply due to collaterals. This maintains the body's immunological reactivity, which is important for pediatric practice. This operation has a minimum number of complications. Abroad, proximal embolization of the spleen is most often used a few days before splenectomy to reduce the risk of complications after surgery.

How is hereditary spherocytosis (Minkowski-Chauffard disease) treated?

Exodus

In mild cases of the disease, as well as in case of timely splenectomy, the outcome is favorable. The course of hereditary spherocytosis is undulating. Following the development of the crisis, clinical and laboratory indicators improve and remission occurs, which can last from several weeks to several years.