Sideroblastic Anemia

Sideroblastic anemias are a heterogeneous group of bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow disorders characterized by abnormal iron accumulation in the mitochondria of erythroid precursors. The accumulated iron appears as granules in a ringlike distribution around the nucleus, giving rise to the characteristic morphological feature of a ring sideroblast. Sideroblastic anemias may be due to inherited defects in heme synthesis or can be acquired through alcoholism, lead poisoning, medications, or vitamin deficiencies. The anemia is commonly microcytic with low to normal reticulocyte count. Serum iron levels are typically elevated. A bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow examination showing ring sideroblasts establishes the diagnosis. Management involves treating the underlying condition, avoiding causative medication and/or toxins, and phlebotomy in cases of iron overload.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Sideroblastic anemias are a heterogeneous group of bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow disorders characterized by abnormal iron accumulation in the mitochondria of erythroid precursors.

The distribution of the iron is ringlike around the nucleus, manifested by the precursors (ring sideroblasts) in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow.

Epidemiology

  • A rare disease → incidence and prevalence not well characterized
  • Men > women
  • No racial predominance
  • Hereditary forms usually manifest before 30 years of age.
  • Acquired type is often seen at age 65 years or older.

Etiology

Congenital disorders:

  • Syndromic: with accompanying nonhematologic manifestations
  • Nonsyndromic: 
    • Present with anemia, no other clinical manifestations
    • Majority of cases

Acquired:

  • Clonal hematopoietic disorders:
    • Myelodysplastic syndromes Myelodysplastic Syndromes Myelodysplastic syndromes (MDS) are a group of clonal neoplasms with maturation defects characterized by dysplasia, cytopenia, and immature bone marrow precursors. Myelodysplastic syndromes can be idiopathic, or secondary to various injurious exposures such as cytotoxic chemotherapy, ionizing radiation, or environmental toxins. Myelodysplastic Syndromes (MDS)
    • Myeloproliferative neoplasms (MPN)
  • Reversible causes:
    • Alcohol 
    • Vitamin deficiencies (vitamin B6, cofactor for protoporphyrin synthesis)
    • Lead poisoning (inhibits the conversion of protoporphyrins)
    • Medications (isoniazid, chloramphenicol Chloramphenicol Chloramphenicol, the only clinically relevant drug in the amphenicol class, is a potent inhibitor of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Chloramphenicol is a broad-spectrum antibiotic with wide distribution; however, due to its toxicity, its use is limited to severe infections. Chloramphenicol, linezolid)
    • Copper deficiency
    • Zinc poisoning
    • Hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia

Pathophysiology

Heme synthesis

  • Heme:
    • A porphyrin-containing compound, synthesized through an enzymatic pathway that takes place in the mitochondria and cytoplasm
    • Most production occurs in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow.
  • In the mitochondria:
    • Succinyl-CoA + glycine → aminolevulinic acid (ALA) 
    • Reaction is catalyzed by aminolevulinic acid synthase (ALAS2 in the erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes).
    • ALA → exits to the cytoplasm
  • In the cytoplasm: 
    • 2 ALA molecules condense to produce porphobilinogen.
    • Porphobilinogen → uroporphyrinogen III → coproporphyrinogen III 
    • Coproporphyrinogen III is transported back to the mitochondria.
  • In the mitochondria:
    • Coproporphyrinogen III → protoporphyrinogen III, which then is converted to protoporphyrin IX
    • Ferrous iron is inserted into protoporphyrin IX (catalyzed by ferrochelatase), forming heme.
Heme synthesis

Heme synthesis:
Heme synthesis is a process that takes place in the mitochondria and cytoplasm.
In the mitochondria, succinyl-CoA combines with glycine to form aminolevulinic acid (ALA).
This reaction is catalyzed by aminolevulinic acid synthase (ALAS2 in the erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes). The ALA exits to the cytoplasm, where 2 ALA molecules condense to produce porphobilinogen (PB). The subsequent steps lead to the formation of coproporphyrinogen III, which is transported back to the mitochondria. Oxidase facilitates conversion of coproporphyrinogen III to protoporphyrinogen IX, which then is converted to protoporphyrin IX. Ferrous iron is inserted into protoporphyrin IX, forming heme (catalyzed by ferrochelatase).

Image by Lecturio.

Pathogenesis

Defects in heme synthesis:

  • X-linked sideroblastic anemia (XLSA):
    • Mutations in ALAS2 gene, which encodes aminolevulinic acid synthase, the rate-limiting enzyme in heme synthesis
    • Frequently (> 50% of cases) responsive to B6 supplementation
  • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancesideroblastic anemia:
    • SLC25A38 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: impaired glycine transporter into mitochondria 
    • FECH mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: impaired ferrochelatase
  • Acquired:
    • Isoniazid (INH): causes ALAS2 impairment
    • Alcohol

Defects in iron-sulfur cluster (ISC) biogenesis:

  • ISCs are involved in multiple biological functions including electron transport, iron regulation, and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair.
  • Dysfunction in ISC transfer in and out of mitochondria disables erythropoiesis Erythropoiesis Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes.
  • Seen in mutations such as:
    • ABCB7: associated with ataxia (syndromic)
    • HSPA9
    • GLRX5

Defects in mitochondrial protein synthesis:

  • Congenital etiologies affect multifunctional proteins, so these are associated with systemic signs (syndromic) such as:
    • Pearson marrow- pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas syndrome
    • Myopathy, lactic acidosis, and sideroblastic anemia (MLASA)
    • TRNT1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (immunodeficiency, recurrent fevers, developmental delay) 
  • Acquired:
    • Chloramphenicol
    • Linezolid

Dysfunction in erythropoiesis Erythropoiesis Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes:

  • RBCs unable to mature
  • Leads to cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death in the marrow (intramedullary hemolysis)
  • ↑ Inappropriate iron absorption → iron overload
  • Seen in:
    • XLSA
    • SLC25A38 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
    • MDS/MPN

Clinical Presentation

Clinical presentation varies depending on the underlying disease.

General features of anemia:

  • Growth retardation in children 
  • Fatigue and muscle weakness
  • Hypothermia Hypothermia Hypothermia can be defined as a drop in the core body temperature below 35°C (95°F) and is classified into mild, moderate, severe, and profound forms based on the degree of temperature decrease. Hypothermia
  • Photosensitivity

Patients with vitamin B6 deficiency may have:

  • Peripheral neuropathy
  • Ataxia
  • Dermatitis
  • Glossitis

Patients with lead poisoning may have:

  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Dental lead lines
  • Peripheral neuropathy (adults)
  • Ataxia
  • Encephalopathy
  • Mental and growth retardation (children)

Others:

  • Pink-stained urine from porphyrins
  • Those with syndromic sideroblastic anemias will have other nonhematologic manifestations.

Diagnosis

Medical history

  • Family history of anemia
  • Presence of concurrent clinical features (in syndromic forms)
  • Possibilities of copper deficiency:
    • History of gastrointestinal surgery 
    • Enteral or parenteral nutrition without copper 
    • Excessive zinc intake 
  • Alcohol use
  • History of exposure to lead
  • Medications 
  • Long-term dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis

Laboratory findings

  • Complete blood count:
    • Microcytosis (MCV < 80)
    • ↑ RBC distribution width (RDW)
    • Clinical significance: In children, neither microcytic anemia with no iron deficiency nor thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia is suggestive of XLSA.
  • Normal to low reticulocyte count
  • Iron studies:
    • ↑ Serum iron 
    • ↑ Ferritin levels
    • Normal or ↓ total iron-binding capacity (TIBC)
    • ↑ Transferrin saturation
  • Abnormal peripheral blood smear:
    • Anisocytosis, poikilocytosis
    • Siderocytes: hypochromic erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes with basophilic granules staining positive for iron
  • Diagnosis is based on bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow aspirate (in Prussian blue-stained smear): ring sideroblasts
Ring sideroblasts

Ring sideroblasts

Image: “Ringed sideroblasts” by S. Bhimji, MD. License: CC BY 4.0

Differentiating sideroblastic anemia from other microcytic anemias

Table: Differentiating sideroblastic anemia from other microcytic anemias (MCV < 80)
CBC finding Diagnosis Iron level Features or historical setting
Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview with MCV < 80 Sideroblastic anemia ↑ Iron level Alcoholic, MDS
Iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Iron Deficiency Anemia ↓ Iron level Blood loss
Thalassemia Normal iron level Variant dependent (asymptomatic to severe anemia)
MDS: myelodysplastic syndromes

Additional tests

  • If indicated based on history:
    • Copper and ceruloplasmin levels
    • Lead level
  • Genetic testing:
    • Necessary to establish a specific diagnosis
    • Performed on leukocytes from the peripheral blood

Management

Goals

  • Prevent organ damage from subsequent iron overload. 
  • Control symptoms associated with anemia.

Treatment options

Treatment options depend on the etiology and include:

  • Drug induced: withdrawal of the medication
  • Alcohol or toxin induced: alcohol abstinence, removal of the toxic agents
  • Treatment of underlying condition, i.e., MDS/MPN 
  • In the case of INH intake: Co-administration of B6 is required.
  • For XLSA: vitamin B6 (pyridoxine) supplements 
  • For thiamine-responsive megaloblastic anemia Megaloblastic anemia Megaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies. Megaloblastic Anemia: vitamin B1 
  • For symptomatic anemia: transfusion if indicated
  • Iron overload: phlebotomy, iron chelation
  • For some inherited sideroblastic anemias: possible allogeneic hematopoietic stem cell transplantation

Clinical Relevance

  • Lead poisoning: lead inhibits ferrochelatase and ALA dehydratase ( enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in the heme synthesis pathway), resulting in decreased heme synthesis. Features include gastrointestinal symptoms and neurological manifestations. Laboratory findings include anemia, erythrocyte basophilic stippling in peripheral smear, and ringed sideroblasts in bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow. Diagnosis is by lead level measurement.
  • Myelodysplastic syndrome: a group of malignant myeloid stem cell disorders characterized by dysplastic and ineffective bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow myeloid line cell production and an increased risk of transformation to acute leukemia. Myelodysplastic syndrome usually presents in older patients, greater than 60 years of age. The syndrome manifests as thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, anemia, and neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia with dysfunctional granulocytes, despite a hypercellular bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow.
  • Vitamin B6 deficiency: caused by pyridoxine-inactivating drugs (e.g., isoniazid), protein-energy undernutrition, malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion, alcoholism, or excessive loss due to hemodialysis. Deficiency can cause peripheral neuropathy, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, seborrheic dermatitis Seborrheic dermatitis Seborrheic dermatitis is a common chronic, relapsing skin disorder that presents as erythematous plaques with greasy, yellow scales in susceptible areas (scalp, face, and trunk). Seborrheic dermatitis has a biphasic incidence, occurring in two peaks: first in infants, then in adolescence and early adulthood. Seborrheic Dermatitis, glossitis, cheilosis, and sideroblastic anemia.

References

  1. Ashorobi D, Chhabra A. (2020). Sideroblastic Anemia. StatPearls: StatPearls Publishing. Retrieved April 6, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK538287/
  2. Bottomley SS. (2021). Sideroblastic anemias: Diagnosis and management. UpToDate. Retrieved April 6, 2021, from https://www.uptodate.com/contents/sideroblastic-anemias-diagnosis-and-management
  3. Bottomley SS. (2021). Causes and pathophysiology of the sideroblastic anemias. UpToDate. Retrieved April 6, 2021, from https://www.uptodate.com/contents/causes-and-pathophysiology-of-the-sideroblastic-anemias
  4. Ducamp S, Fleming MD. (2019). The molecular genetics of sideroblastic anemia. https://pubmed.ncbi.nlm.nih.gov/30401706/
  5. Sticco KL, Yarrarapu, SNS, Al Obaidi NM. (2021) Refractory Anemia With Ring Sideroblasts. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Retrieved April 6, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK537073/

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