Sideroblastic anemia

Sideroblastic anemia

A Ring Sideroblast visualized by Prussian blue stain
Classification and external resources
Specialty	hematology
ICD-10	D64.0-D64.3
ICD-9-CM	285.0
OMIM	301310 206000 300751
DiseasesDB	12110
MeSH	D000756

Sideroblastic anemia or sideroachrestic anemia is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes).^[1] In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need to transport oxygen efficiently. The disorder may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome,^[2] which can evolve into hematological malignancies (especially acute myelogenous leukemia).

Sideroblasts (sidero- + -blast) are atypical, abnormal nucleated erythroblasts (precursors to mature red blood cells) with granules of iron accumulated in the mitochondria surrounding the nucleus.^[3] Normally, sideroblasts are present in the bone marrow, and enter the circulation after maturing into a normal erythrocyte.

Ring sideroblasts are named so because iron-laden mitochondria form a ring around the nucleus. To count a cell as a ring sideroblast, the ring must encircle a third or more of the nucleus and contain five or more iron granules, according to the 2008 WHO classification of the tumors of the hematopoietic and lymphoid tissues.^[4]

The WHO International Working Group on Morphology of MDS (IWGM-MDS) defined three types of sideroblasts:

Type 1 sideroblasts: fewer than 5 siderotic granules in the cytoplasm
Type 2 sideroblasts: 5 or more siderotic granules, but not in a perinuclear distribution
Type 3 or ring sideroblasts: 5 or more granules in a perinuclear position, surrounding the nucleus or encompassing at least one third of the nuclear circumference.

Classification

Sideroblastic anemia is typically divided into subtypes based on its cause.

Hereditary or congenital sideroblastic anemia may be X-linked^[5] or autosomal.

OMIM	Name	Gene
300751	X-linked sideroblastic anemia (XLSA)	ALAS2
301310	sideroblastic anemia with spinocerebellar ataxia (ASAT)	ABCB7
205950	pyridoxine-refractory autosomal recessive sideroblastic anemia	SLC25A38
206000	pyridoxine-responsive sideroblastic anemia	(vitamin B6 deficiency; pyridoxal phosphate required for heme synthesis)

GLRX5 has also been implicated.^[6]

Acquired, or secondary, sideroblastic anemia develops after birth and is divided according to its cause.

Symptoms

Symptoms of sideroblastic anemia include skin paleness, fatigue, dizziness, and enlarged spleen and liver. Heart disease, liver damage, and kidney failure can result from iron buildup in these organs.^[7]

Causes

Causes of sideroblastic anemia can be categorized into three groups: congenital sideroblastic anemia, acquired clonal sideroblastic anemia, and acquired reversible sideroblastic anemia. All cases involve dysfunctional heme synthesis or processing. This leads to granular deposition of iron in the mitochondria that form a ring around the nucleus of the developing red blood cell. Congenital forms often present with normocytic or microcytic anemia while acquired forms of sideroblastic anemia are often normocytic or macrocytic.

Congenital sideroblastic anemia
- X-linked sideroblastic anemia: This is the most common congenital cause of sideroblastic anemia and involves a defect in ALAS2,^[8] which is involved in the first step of heme synthesis. Although X-linked, approximately one third of patients are women due to skewed X-inactivation.
- Autosomal recessive sideroblastic anemia involves mutations in the SLC25A38 gene. The function of this protein is not fully understood, but it is involved in mitochondrial transport of glycine. Glycine is a substrate for ALAS2 and necessary for heme synthesis. The autosomal recessive form is typically severe in presentation.
- Genetic syndromes: Rarely, sideroblastic anemia may be part of a congenital syndrome and present with associated findings, such as ataxia, myopathy, and pancreatic insufficiency.
Acquired clonal sideroblastic anemia
- Clonal sideroblastic anemias fall under the broader category of myelodysplastic syndromes (MDS). Three forms exist and include refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), and refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS). These anemias are associated with increased risk for leukemic evolution.
Acquired reversible sideroblastic anemia
- Causes include excessive alcohol use (the most common cause of sideroblastic anemia), pyridoxine deficiency, lead poisoning, and copper deficiency. Excess zinc^[9] can indirectly cause sideroblastic anemia by decreasing absorption and increasing excretion of copper. Antimicrobials that may lead to sideroblastic anemia include isoniazid, chloramphenicol, cycloserine, and linezolid.^[10]

Diagnosis

Bone marrow aspirate: ring sideroblasts

Ringed sideroblasts are seen in the bone marrow.

The anemia is moderate to severe and dimorphic. Microscopic viewing of the red blood cells will reveal marked unequal cell size and abnormal cell shape. Basophilic stippling is marked and target cells are common. Pappenheimer bodies are present in the red blood cells. The mean cell volume is commonly decreased (i.e., a microcytic anemia), but MCV may also be normal or even high. The RDW is increased with the red blood cell histogram shifted to the left. Leukocytes and platelets are normal. Bone marrow shows erythroid hyperplasia with a maturation arrest.

In excess of 40% of the developing erythrocytes are ringed sideroblasts. Serum iron, percentage saturation and ferritin are increased. The total iron-binding capacity of the cells is normal to decreased. Stainable marrow hemosiderin is increased.

Laboratory findings

Serum Iron: High
Increased ferritin levels
Normal total iron-binding capacity
High transferrin saturation
Hematocrit of about 20-30%
The mean corpuscular volume or MCV is usually normal or low for congenital causes of sideroblastic anemia but normal or high for acquired forms.
With lead poisoning, see coarse basophilic stippling of red blood cells on peripheral blood smear
Specific test: Prussian blue stain of RBC in marrow shows ringed sideroblasts. Prussian blue staining involves a non-enzymatic reaction of ferrous iron with ferrocyanide forming ferric-ferrocyanide, which is blue in color. A counterstain may be used to provide better visualization.

Treatment

Occasionally, the anemia is so severe that support with transfusion is required. These patients usually do not respond to erythropoietin therapy.^[11] Some cases have been reported that the anemia is reversed or heme level is improved through use of moderate to high doses of pyrodoxine (Vitamin B₆). In severe cases of SBA, bone marrow transplant is also an option with limited information about the success rate. Some cases are listed on MedLine and various other medical sites. In the case of isoniazid-induced sideroblastic anemia, the addition of B₆ is sufficient to correct the anemia. Desferrioxamine, a chelating agent, is used to treat iron overload from transfusions. Therapeutic phlebotomy can be used to manage iron overload.^[12] Bone marrow transplant (BMT) can be considered in severe cases.

Course and prognosis

Sideroblastic anemias are often described as responsive or non-responsive in terms of increased hemoglobin levels to pharmacological doses of vitamin B₆.

1- Congenital: 80% are responsive, though the anemia does not completely resolve.

2- Acquired clonal: 40% are responsive, but the response may be minimal.

3- Acquired reversible: 60% are responsive, but course depends on treatment of the underlying cause.

Severe refractory sideroblastic anemias requiring regular transfusions and/or that undergo leukemic transformation (5-10%) significantly reduce life expectancy.

References

↑ Caudill JS, Imran H, Porcher JC, Steensma DP (October 2008). "Congenital sideroblastic anemia associated with germline polymorphisms reducing expression of FECH". Haematologica. 93 (10): 1582–4. doi:10.3324/haematol.12597. PMID 18698088.
↑ Sideroblastic Anemias: Anemias Caused by Deficient Erythropoiesis at Merck Manual of Diagnosis and Therapy Professional Edition
↑ "Sideroblast" at Dorland's Medical Dictionary
↑ Mufti, GJ; Bennett, JM; Goasguen, J; Bain, BJ; Baumann, I; Brunning, R; Cazzola, M; Fenaux, P; Germing, U; Hellström-Lindberg, E; Jinnai, I; Manabe, A; Matsuda, A; Niemeyer, CM; Sanz, G; Tomonaga, M; Vallespi, T; Yoshimi, A; International Working Group on Morphology of Myelodysplastic, Syndrome (Nov 2008). "Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts.". Haematologica. 93 (11): 1712–7. doi:10.3324/haematol.13405. PMID 18838480.
↑ X-linked sideroblastic anemia at NLM Genetics Home Reference
↑ Camaschella C (September 2008). "Recent advances in the understanding of inherited sideroblastic anaemia". Br. J. Haematol. 143 (1): 27–38. doi:10.1111/j.1365-2141.2008.07290.x. PMID 18637800.
↑ Genetics Home Reference: Genetic Conditions > X-linked sideroblastic anemia Reviewed October 2006. Retrieved on 5 Mars, 2009
↑ Aivado M, Gattermann N, Rong A, et al. (2006). "X-linked sideroblastic anemia associated with a novel ALAS2 mutation and unfortunate skewed X-chromosome inactivation patterns". Blood Cells Mol. Dis. 37 (1): 40–5. doi:10.1016/j.bcmd.2006.04.003. PMID 16735131.
↑ Forman, W.B. (1990). "Zinc abuse: an unsuspected cause of sideroblastic anemia". West J Med. 152: 190–2. PMC 1002314. PMID 2400417.
↑ Saini, N; Jacobson, JO; Jha, S; Saini, V; Weinger, R (April 2012). "The perils of not digging deep enough--uncovering a rare cause of acquired anemia.". American journal of hematology. 87 (4): 413–6. doi:10.1002/ajh.22235. PMID 22120958.
↑ Papadakis, Maxine A.; Tierney, Lawrence M.; McPhee, Stephen J. (2005). "Sideroblastic Anemia". Current Medical Diagnosis & Treatment, 2006. McGraw-Hill Medical. ISBN 0-07-145410-1.
↑ Peto, T. E. A., Pippard, M. J., Weatherall, D. J. Iron overload in mild sideroblastic anaemias" Lancet 321: 375-378, 1983. Note: Originally Volume I.

External links

Diseases of red blood cells (D50–69,74, 280–287)

↑

Polycythemia	Polycythemia vera

↓

Anemia

Nutritional

Micro-: Iron-deficiency anemia
- Plummer–Vinson syndrome

Macro-: Megaloblastic anemia
- Pernicious anemia

Hemolytic
(mostly normo-)

Hereditary	enzymopathy: G6PD glycolysis PK TI HK hemoglobinopathy: Thalassemia alpha beta delta Sickle-cell disease/trait HPFH membrane: Hereditary spherocytosis Minkowski–Chauffard syndrome Hereditary elliptocytosis Southeast Asian ovalocytosis Hereditary stomatocytosis

Acquired	Autoimmune WAHA CAD PCH membrane PNH MAHA TM HUS Drug-induced autoimmune Drug-induced nonautoimmune Hemolytic disease of the newborn

Aplastic
(mostly normo-)

Blood tests

MCV
MCHC
- Normochromic
- Hypochromic

Other

Myeloid hematological malignancy/leukemia histology (ICD-O 9590–9989, C81–C96, 200–208)

CFU-GM/
and other granulocytes

CFU-GM

Myelocyte

AML:	Acute myeloblastic leukemia M0 M1 M2 APL/M3

MP	Chronic neutrophilic leukemia

Monocyte

AML	AMoL/M5 Myeloid dendritic cell leukemia

CML	Philadelphia chromosome Accelerated phase chronic myelogenous leukemia

Myelomonocyte

AML	M4

MD-MP	Juvenile myelomonocytic leukemia Chronic myelomonocytic leukemia

Other

Histiocytosis

CFU-Baso

AML	Acute basophilic

CFU-Eos

AML	Acute eosinophilic

MP	Chronic eosinophilic leukemia/Hypereosinophilic syndrome

MEP

CFU-Meg

AML	AMKL/M7

MP	Essential thrombocytosis

CFU-E

AML	Erythroleukemia/M6

MP	Polycythemia vera

MD	Refractory anemia Refractory anemia with excess of blasts Chromosome 5q deletion syndrome Sideroblastic anemia Paroxysmal nocturnal hemoglobinuria Refractory cytopenia with multilineage dysplasia

CFU-Mast

Mastocytoma	Mast cell leukemia Mast cell sarcoma Systemic mastocytosis

Mastocytosis:	Diffuse cutaneous mastocytosis Erythrodermic mastocytosis Adult type of generalized eruption of cutaneous mastocytosis Urticaria pigmentosa Mast cell sarcoma Solitary mastocytoma

Systemic mastocytosis	Xanthelasmoidal mastocytosis

Multiple/unknown

AML	Acute panmyelosis with myelofibrosis Myeloid sarcoma

MP	Myelofibrosis Acute biphenotypic leukaemia

Sex linkage: X-linked disorders

X-linked recessive

Immune	Chronic granulomatous disease (CYBB) Wiskott–Aldrich syndrome X-linked severe combined immunodeficiency X-linked agammaglobulinemia Hyper-IgM syndrome type 1 IPEX X-linked lymphoproliferative disease Properdin deficiency

Hematologic	Haemophilia A Haemophilia B X-linked sideroblastic anemia

Endocrine	Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy KAL1 Kallmann syndrome X-linked adrenal hypoplasia congenita

Metabolic	Amino acid: Ornithine transcarbamylase deficiency Oculocerebrorenal syndrome Dyslipidemia: Adrenoleukodystrophy Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency Pyruvate dehydrogenase deficiency Danon disease/glycogen storage disease Type IIb Lipid storage disorder: Fabry's disease Mucopolysaccharidosis: Hunter syndrome Purine-pyrimidine metabolism: Lesch–Nyhan syndrome Mineral: Menkes disease/Occipital horn syndrome

Nervous system	X-linked mental retardation: Coffin–Lowry syndrome MASA syndrome Alpha-thalassemia mental retardation syndrome Siderius X-linked mental retardation syndrome Eye disorders: Color blindness (red and green, but not blue) Ocular albinism (1) Norrie disease Choroideremia Other: Charcot–Marie–Tooth disease (CMTX2-3) Pelizaeus–Merzbacher disease SMAX2

Skin and related tissue	Dyskeratosis congenita Hypohidrotic ectodermal dysplasia (EDA) X-linked ichthyosis X-linked endothelial corneal dystrophy

Neuromuscular	Becker's muscular dystrophy/Duchenne Centronuclear myopathy (MTM1) Conradi–Hünermann syndrome Emery–Dreifuss muscular dystrophy 1

Urologic	Alport syndrome Dent's disease X-linked nephrogenic diabetes insipidus

Bone/tooth	AMELX Amelogenesis imperfecta

No primary system	Barth syndrome McLeod syndrome Smith–Fineman–Myers syndrome Simpson–Golabi–Behmel syndrome Mohr–Tranebjærg syndrome Nasodigitoacoustic syndrome

X-linked dominant

X-linked hypophosphatemia Focal dermal hypoplasia Fragile X syndrome Aicardi syndrome Incontinentia pigmenti Rett syndrome CHILD syndrome Lujan–Fryns syndrome Orofaciodigital syndrome 1 Craniofrontonasal dysplasia

Genetic disorder, membrane: ABC-transporter disorders

ABCA	ABCA1 (Tangier disease) ABCA3 (Surfactant metabolism dysfunction 3) ABCA4 (Stargardt disease 1, Retinitis pigmentosa 19) ABCA12 (Harlequin-type ichthyosis, Lamellar ichthyosis 2)

ABCB	ABCB4 (Progressive familial intrahepatic cholestasis 3) ABCB7 (ASAT) ABCB11 (Progressive familial intrahepatic cholestasis 2)

ABCC	ABCC2 (Dubin–Johnson syndrome) ABCC6 (Pseudoxanthoma elasticum) ABCC7 (Cystic fibrosis) ABCC8 (HHF1, TNDM2) ABCC9 (Dilated cardiomyopathy 1O)

ABCD	ABCD1 (Adrenoleukodystrophy, Adrenomyeloneuropathy)

ABCG	ABCG5 (Sitosterolemia) ABCG8 (Gallbladder disease 4, Sitosterolemia)

see also ABC transporters

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