Hereditary spherocytosisD58.0

Oskar Minkowski, 1900

Hereditary spherocytosis (HS) is a heterogeneous group of disorders of erythrocytes. The common denominator is structural membrane defects leading to a disorder of erythrocyte deformability. The clinical spectrum of hereditary spherocytosis ranges from severe courses with transfusion requirements in childhood to asymptomatic patients with an incidental diagnosis in old age on the occasion of a laboratory examination for other indications. Anemia, icterus, usually elevated indirect bilirubin, splenomegaly; family history: usually positive. The very variable clinical expression is due to the different mutations in membrane protein genes leading to different functional effects.

Hereditary spherocytosis is by far the most common congenital hemolytic anemia in individuals with a northern or central European background, but is one of the rare disorders. The prevalence is estimated to be about 1:2,500 - 5,000 in Germany, an exact analysis is not available.

The cause are different mutations in the genes for α-spectrin, β-spectrin, ankyrin-1, band 3 or protein 4.2. In about 75% of affected patients, the disease is inherited in an autosomal dominant manner. In the remaining patients, recessive inheritance or new mutations are present.

The mutations lead to a loss of cohesion between the membrane skeleton and the lipid layer. The surface and deformability of erythrocytes is progressively reduced. One of the consequences is accelerated degradation of dysfunctional erythrocytes in the spleen. The erythrocytes formed in the bone marrow initially still have a normal biconcave shape. They undergo a loss of their membrane portions in the course of passage through the spleen du the rest of the RES. As a result, the cells become spherical. The spectrum of mutations in the affected genes is diverse: splicing, skipping, missense, nonsense, deletion, frameshift, polymorphisms. Many genetic aberrations are 'private', i.e. specific to the affected family. The clinical picture of HS within a family is often very similar.

There is no single test that can detect all forms of hereditary spherocytosis and reliably differentiate them from other forms of membrane-related hemolytic anemia. Therefore, testing with two test methods is recommended. The combination of AGLT and EMA test can achieve a sensitivity of up to 100%. The examination of osmotic resistance with hypotonic salt solutions has a significantly lower sensitivity than AGLT and EMA test.

Acidified Glycerol Lysis Time (AGLT)

The AGLT test measures the time to 50% hemolysis of a blood sample in a hypotonic saline/glycerol solution. Determination of hemolysis time with the Acidified Glycerol Lysis Time (AGLT) has high specificity, with sensitivity ranging from 80 to 95%. The test must be performed within hours after blood collection or on samples sent by express mail (refrigerated depending on the season)! It may also be positive in patients with acquired hemolytic anemia, chronic renal failure or myelodysplastic syndrome.

Flow cytometry (eosin-5-maleimide test)

The flow cytometric method (EMA test) was introduced in 2000 [23]. It is based on the decreased binding of the fluorescent dye eosin-5-maleimide in pat. with hereditary spherocytosis compared to normal subjects. Sensitivity is 90 - 95%, specificity is 95 - 99%. The result is only valid with a maximum delay of 48 hours between blood collection and test performance. In hereditary pyropoikilocytosis, the fluorescent dye is bound even less than in hereditary spherocytosis; in stomatocytosis, binding is increased [17]. Also, in pat. with congenital dyserythropoietic anemia type II (CDA type II), the binding of eosin-5-maleimide may be decreased.

Gene - Analysis: Molecular genetic diagnostics identifies the specific genetic defect It is reserved for special cases due to the numerous target genes with the heterogeneity of possible mutations as well as the considerable costs associated with it, in which a therapeutic consequence results from the diagnostics.

Hiniwes: In all diagnostic procedures there are false positive and / or false negative results. Therefore, in persons without a positive family history, the diagnosis should generally not be based on one method, e.g., osmotic resistance only or EMA only or biochemical membrane diagnostics only. At least 2 different methods should be used as screening. Also, future, diagnostic tests will have to be compared in their specificity and sensitivity with these laboratory methods.

There is no causal therapy for the genetic defect. The most effective symptomatic therapy is splenectomy. In symptomatic cholelithiasis, cholecystectomy is indicated.

Splenectomy: Splenectomy often leads to elimination of anemia and regression of elevated hemolysis parameters. On the other hand, the changes in the smear usually become more obvious than before. The indication for splenectomy is usually given in childhood, but if possible, it is not performed before school age [2]. However, it must also be considered in adulthood depending on the clinical findings [16, 26]. Splenectomy is also an option in adults with extramedullary hematopoiesis. Whether extramedullary hematopoiesis subsequently regresses is an open question.

If hemolysis persists after splenectomy, the diagnosis must be questioned again, secondary spleens must be searched for and removed if necessary. The indication for splenectomy depends on the clinical severity. The risk of splenectomy lies in the operation and the lifelong increased rate of severe infections, especially by pneumococci with a mortality of 0.1 - 0.4 %. This risk is reduced by near-complete rather than complete splenectomy, so the former procedure should be preferred.

1. Bianchi P et al. (2011) Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study on 150 patients grouped according to the molecular and clinical characteristics. Haematologica 97:516-523.
2. Giraldi S et al (2003) Leg ulcer in hereditary spherocytosis. Pediatr Dermatol 20:427-428.
3. Guizetti L (2016) Total versus partial splenectomy in pediatric hereditary spherocytosis: A systematic review and meta-analysis. Pediatr Blood Cancer 63:1713-1722.
4. Krajewski PK et al. (2021) Pyoderma gangrenosum in a splenectomy incision in a patient with haemolytic anemia due to hereditary spherocytosis: a case report and literature review. Acta Derm Venereol 101:adv00599.
5. Minkowski O (1990) Hereditary affection presenting as chronic jaundice with urobilinuria, splenomegaly and renal siderosis. Verh Dtsch Kongr Inn Med 18: 316-319.
6. Perrotta S et al (2018) Hereditary spherocytosis. Lancet 372:1411-1426
7. Rabhi S et al (2011) Hereditary spherocytosis with leg ulcers healing after splenectomy. South Med J 104:150-152.
8. S1 guideline hereditary spherocytosis 2016, 025-018. https://www.awmf.org/uploads/tx_szleitlinien/025-018l-s1_hereditaere-sphaerozytose_2016-12
9. Kwon HI et al (2016) Pyoderma gangrenosum in a patient with hereditary spherocytosis. Int J Low Extrem Wounds15:92-95.
10. Mohandas N (2018) Inherited hemolytic anemia: a possessive beginner's guide. Hematology Am Soc Hematol Educ Program 377-381.
11. Vanscheidt W et al (1990) Leg ulcers in a patient with spherocytosis: a clinicopathological report. Dermatologica 181:56-59.