Наследственный сфероцитоз: генетика, проявления и лечение

the hereditary hematologic manifestation of spherocytic disorders

Hereditary spherocytosis (HS) is a congenital hemolytic disorder wherein a genetic mutation coding for a structural membrane protein phenotype causes the red blood cells to be sphere shaped (spherocytosis), rather than the normal biconcave disk shape. This abnormal shape interferes with the cells' ability to flex during blood circulation, and also makes them more prone to rupture under osmotic stress, mechanical stress, or both. Cells with the dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes and results in hemolytic anemia. HS was first described in 1871, and is the most common cause of inherited hemolysis in populations of northern European descent, with an incidence of 1 in 5000 births. The clinical severity of HS varies from mild (symptom free carrier), to moderate (anemic, jaundiced, and with splenomegaly), to severe (hemolytic crisis, in utero hydrops fetalis), because HS is caused by genetic mutations in a multitude of structural membrane proteins and exhibits incomplete penetrance in its expression. Early symptoms include anemia, jaundice, splenomegaly, and fatigue. Acute cases can threaten to cause hypoxia secondary to anemia and acute kernicterus through high blood levels of bilirubin, particularly in newborns. Most cases can be detected soon after birth. Testing for HS is available for the children of affected adults. Occasionally, the disease will go unnoticed until the child is about 4 or 5 years of age. A person may also be a carrier of the disease and show no signs or symptoms of the disease. Late complications may result in the development of pigmented gallstones, which is secondary to the detritus of the broken down blood cells (unconjugated or indirect bilirubin) accumulating within the gallbladder. Also, patients who are heterozygous for a hemochromatosis gene may exhibit iron overload, despite the hemochromatosis genes being recessive. In chronic patients, an infection or other illness can cause an increase in the destruction of red blood cells, resulting in the appearance of acute symptoms, a hemolytic crisis. On a blood smear, Howell Jolly bodies may be seen within red blood cells. Primary treatment for patients with symptomatic HS has been total splenectomy, which eliminates the hemolytic process, allowing normal hemoglobin, reticulocyte and bilirubin levels. The resultant asplenic patient is susceptible to encapsulated bacterial infection, and prevented with vaccination. If other symptoms, such as abdominal pain persist, the removal of the gallbladder may be warranted for symptomatic cholelithiasis.

Hereditary spherocytosis is the heritable hemolytic disorder, affecting 1 in 2,000 people of Northern European ancestry. According to Harrison's Principles of Internal Medicine, the frequency is at least 1 in 5,000 within the United States of America. While HS is most commonly (though not exclusively) found in Northern European and Japanese families, an estimated 25% of cases are due to spontaneous mutations.

Hereditary spherocytosis is caused by a variety of molecular defects in the genes that code for the red blood cell proteins spectrin (alpha and beta), ankyrin, band 3 protein, protein 4.2, and other red blood cell membrane proteins: This leads to both splenomegaly and anemia. Should this process continue unchecked chronically, inappropriate regulation of erythropoeisis leads to extramedullary hematopoiesis.

HS patients present in a vast array of presentations, from being asymptomatic to the extreme situations of splenic rupture, hemolytic crisis, or in utero demise. Asymptomatic HS (mild): 20–30% of patients. Infantile onset HS (moderate): 60–75% of patients. Neonatal or in utero onset HS (severe): <5% of patients. The most common presentation will demonstrate jaundice (due to increased unconjugated bilirubin), anemia (with secondary pallor), and a palpable spleen sometimes with concomitant tenderness (due to splenic congestion and splenomegaly). Its worth noting that a subsection of HS patients will also have incidental black pigmented gallstones (made of calcium bilirubinate consequence of the extravascular hemolysis), and some of these patients will develop cholelithiasis or the potential complex sequelae of this condition, i. e. cholecystitis, choledocholithiasis, etc.

Ultrasound is often used to evaluate the dimensions of the spleen, and also the gallbladder in preparation for functionally curative splenectomy with or without cholecystectomy.

Hemolytic crisis, with more pronounced jaundice due to accelerated hemolysis (may be precipitated by infection). Aplastic crisis with dramatic fall in hemoglobin level and (reticulocyte count) decompensation, usually due to maturation arrest and often associated with megaloblastic changes; may be precipitated by infection, such as influenza, notably with parvovirus B19. Folate deficiency caused by increased bone marrow requirement. Pigmented gallstones occur in approximately half of untreated patients. Increased hemolysis of red blood cells leads to increased bilirubin levels, because bilirubin is a breakdown product of heme. The high levels of bilirubin must be excreted into the bile by the liver, which may cause the formation of a pigmented gallstone, which is composed of calcium bilirubinate. Since these stones contain high levels of calcium carbonates and phosphate, they are radiopaque and are visible on x ray. Hyperglycemia with concomitant low hemoglobin A1C levels. Hemoglobin A1C (glycated hemoglobin) is a test for determining the average blood glucose levels over an extended period of time, and is often used to evaluate glucose control in diabetics. The hemoglobin A1C levels are abnormally low because the life span of the red blood cells is decreased providing less time for the non enzymatic glycosylation of hemoglobin. Thus, even with high overall blood sugar, the A1C will be lower than expected. Iron overload. Leg ulcer. Deep vein thrombosis (DVT). Cardiovascular disease.