ANEMIA, SIDEROBLASTIC

ANEMIA, SIDEROBLASTIC - Anne C. Nofziger, MD
BASICS
DESCRIPTION
A heterogeneous group of disorders characterized by microcytic, hypochromic anemia, impaired heme biosynthesis causing ineffective erythropoiesis, and ringed sideroblasts in the bone marrow. Severity and course may range from severe progressive to indolent asymptomatic anemia; onset may be congenital or late in life.
GENERAL PREVENTION
Pyridoxine prophylaxis with INH therapy
EPIDEMIOLOGY
• As a group, sideroblastic anemias (SA) are uncommon, and specific incidence/prevalence information is difficult to find.
• Acquired forms more common than hereditary forms (1), usually occur in older adults; present in 25-30% of alcoholics with anemia (2)
• Several hundred X-linked cases described (3) Hereditary forms variably severe, usually manifest in childhood
RISK FACTORS
• Male gender (X-linked SA)
• Family history of hereditary SA
• Chronic alcohol abuse
• Gastric bypass surgery (1 case report) (4)
Genetics
• Usually X-linked
- Defect in aminolevulinic acid synthase (ALAS-2 mutation), the first and rate-limiting enzyme in heme biosynthesis
- With congenital ataxia: hABC7 gene mutations (mitochondrial transport protein)
• Rarely autosomal dominant or recessive; gene(s) unknown
• Mitochondrial cytopathy
- Heterogeneous, involve deletions in mtDNA
- Unpredictable maternal inheritance
• See "Etiology"
PATHOPHYSIOLOGY
• Impaired heme biosynthesis within mitochondria
• Ineffective erythropoiesis
• Increased GI absorption of iron (Fe overload)
• Enhanced apoptosis in bone marrow
• Possibly, reactive oxygen species play a role
ETIOLOGY
Acquired SA
• Reversible
• Drugs and toxins
- Ethanol (SA is a later finding in multifactorial anemia related to alcoholism)
- INH
- Chloramphenicol
- Cycloserine
- Zinc toxicity (Cu deficiency)
• Nutritional deficiencies
- Pyridoxine deficiency
- Copper deficiency
 Post-gastrectomy
 Prolonged parenteral nutrition
 Prolonged zinc supplementation
• Hypothermia
• Acquired idiopathic sideroblastic anemia (AISA)
- Pure sideroblastic anemia (PSA)
 Only the erythroid line affected
- Refractory anemia with ringed sideroblasts (RARS)
 Myelodysplasia, other cell lines also affected
- Associated with hematologic malignancies, myeloproliferative disorders
Hereditary SA
• X-linked
• Autosomal dominant, recessive, maternal inheritance
• Mitochondrial cytopathy
- Wolfram syndrome
- Pearson syndrome
Congenital SA
Disproportionately male, sporadic, mild to severe, kindreds too small to analyze inheritance
ASSOCIATED CONDITIONS
• Alcoholism
• According to mutation, e.g., severe congenital ataxia (hABC7 mutation), pancreatic dysfunction (Pearson syndrome)
• Iron overload or "erythropoeitic hemochromatosis" (2) develops over time in all but reversible and x-linked/ataxia forms.
• Rarely, coexisting iron deficiency masks SA.

DIAGNOSIS
PRE HOSPITAL
Often an incidental finding
SIGNS AND SYMPTOMS
• Moderate to severe anemia
- Fatigue
- Dizziness
- Diminished exercise tolerance
- More symptomatic in older patients with comorbid conditions
• Specific to cause
- Pyridoxine deficiency (peripheral neuropathy, dermatitis)
- Alcoholism
• Manifestations of iron overload
History
• Toxin or drug exposures
• Family history of anemia, especially in men
Physical Exam
• No pathognomonic physical findings
• Mild-moderate hepatosplenomegaly at diagnosis in 1/3-1/2 of patients with AISA (2)
TESTS
Lab
• CBC
- Low MCH
- Low MCHC
- Low MCV (may be normal or high, esp. in myelodysplasia)
- High RDW
- Hgb highly variable
- Siderocytes in peripheral smear (occasional)
- WBC normal; may be reduced if hypersplenism, myelodysplasia
- Platelets normal; may be reduced if hypersplenism, myelodysplasia
- Low reticulocyte count
• Iron studies
- Ferritin increased
- Transferrin saturation increased
- Serum transferrin decreased
- Reticuloendothelial iron increased
• Serum copper, ceruloplasmin, serum zinc if suspected as cause
• Liver enzyme derangements possible depending on cause (EtOH, cirrhosis, Fe overload)
• Molecular studies identify specific mutations causing hereditary SA syndromes
• Myelodysplasia: Morphologic and cytogenetic evaluation required for prognosis
Diagnostic Procedures/Surgery
• Bone marrow examination confirms diagnosis of SA
• Liver biopsy is best; test to assess degree of iron overload.
• See "Pathological Findings"
Pathological Findings
• Bone marrow examination is the key diagnostic modality (1)[C]
- Normoblastic erythroid hyperplasia
- Perls' Prussian blue iron stain: Ringed sideroblasts, >10% of erythroblasts with increased number of abnormally large granules ringing the nucleus
- Electron microscopy: Iron-overloaded mitochondria within erythroblasts
- Iron-laden macrophages
• Liver biopsy
- Iron deposition as in hereditary hemachromatosis
- Micronodular cirrhosis by 3rd or 4th decade
DIFFERENTIAL DIAGNOSIS
• Thalassemias
• Iron deficiency anemia
• Anemia of chronic disease
• Myelodysplastic syndromes
• Lead toxicity with anemia
TREATMENT
GENERAL MEASURES
Treatment is largely supportive
• Pyridoxine supplementation improves symptoms in responsive cases (1)[B]
• Eliminate toxins, causative drugs
• Periodic transfusion: Maintain acceptable hemoglobin to alleviate symptoms and allow normal growth and development (children) (1)[B]
• Prevent end-organ damage from severe iron overload (1)[B]
- Phlebotomy preferred modality if anemia is mild or moderate
- Iron chelation in patients with more severe anemia, or requiring more transfusions
Diet
Address relevant nutritional deficiencies
Activity
As tolerated
SPECIAL THERAPY
Allogeneic stem cell transplantation has been successful in a few cases in younger patients with myelodysplastic syndromes.
IV Fluids
RBC transfusion when necessary
MEDICATION (DRUGS)
First Line
• Trial of pyridoxine is indicated because it has few drawbacks and is very beneficial in responsive cases (1)[B]
- Pyridoxine 50-100 mg PO daily
- Maintenance: Minimum dose to maintain acceptable hgb.
- Supplement folate to compensate for increased erythropoiesis if effective
- Response likely if SA caused by alcohol abuse, pyridoxine antagonists, or some forms of hereditary x-linked SA.
• Chelation therapy for iron overload (1)[B]
• Deferoxamine 40 mg/kg/d in continuous 12-24-hour daily infusions
- Limit ascorbate intake to 200 mg/d
- Auditory/visual toxicity very rare
• Defirasirox is a new oral once-daily iron chelator
- No long-term safety data
- Main complications skin rash, GI upset
• Goal of therapy is to maintain serum ferritin 500 ug/L
Second Line
• Myelodysplasia: PSA and RARS
• Treatment considerations as above, though no expected response to pyridoxine
• Some respond to combination of erythropoeitin (EPO) and granulocyte colony-stimulating factor (G-CSF) (1)[C]
• Chemotherapeutic agents may have a role.
SURGERY
• Splenectomy is contraindicated due to frequent postoperative thromboembolic complications (2)[B].
FOLLOW-UP
DISPOSITION
Admission Criteria
Generally managed in outpatient settings except for treatment of complications such as CHF, dysrhythmias.
Issues for Referral
• Hematology consultation is helpful for diagnosis and management, particularly if no reversible cause identified.
• Genetic counseling is important for patients with heritable cause of SA.
PROGNOSIS
• 75% of x-linked SA with ALAS-2 mutations are pyridoxine responsive (2)
• Prognosis better if iron overload prevented
• Aquired Idiopathic SA:
- RARS: 1- and 5-year cumulative risk of acute leukemia are 20% and 38%, respectively (1)
- When only the erythroid line is affected (PSA), course as in age-matched controls, transformation to leukemia not observed. (2)
- If SA follows treatment for malignancy, leukemic transformation is common.
COMPLICATIONS
• Iron overload causing organ damage
- Cardiac arrhythmia or CHF
- Hepatic dysfunction
• Transfusion complications
PATIENT MONITORING
• Yearly ferritin and transferrin saturation to monitor for Fe overload
• Follow response to treatment: Reticulocytosis within 2 weeks, improved hgb within 1-2 months of response to pyridoxine, and correction of nutritional deficiency or withdrawal of reversible cause.
REFERENCES
1. Alcindor T, Bridges KR. Sideroblastic anaemias. Br J Haematol. 2002;116:733-743.
2. Bottomley SS. Sideroblastic anemias. In: Greer JP, Foerster J, Lukens J, et al., eds. Wintrobe's Clinical Hematology, 11th ed. Philadelphia: Lippincott, Williams and Wilkins; 2004.
3. http://ghr.nlm.nih.gov/ghr/ accessed February 2006
4. Almhanna K, Khan P, Schaldenbrand M, Momin F. Sideroblastic anemia after bariatric surgery. Am J Hematol. 2006;81(2):155-156.
ADDITIONAL READING
• See http://www.genetests.org for counseling information on specific heritable SA syndromes and availability of testing.
• http://ghr.nlm.nih.gov/condition=xlinkedsideroblasticanemia