Hospital Medicine

Sideroblastic anemia

Sideroblastic anemia

I. What every physician needs to know.

Overview.

Sideroblastic anemia occurs due to defects in heme synthesis pathway. In addition, defects in iron sulfur pathways or other important pathways in the mitochondria of erythroblasts, which indirectly impair heme production, are responsible for pathogenesis of sideroblastic anemia. A result of these abnormalities is decreased hemoglobin production and abnormal iron metabolism, leading to accumulation of iron in the nucleated immature erythroblasts.

These erythroblasts have iron granule loaded mitochondria, which form rings around the nucleus, and are called ring sideroblasts. The exact mechanisms to explain why ring sideroblasts are produced in this type of anemia versus other types of anemia or disorders with iron overload (for example thalassemia or hemochromatosis) have not been clarified yet.

Sideroblastic anemia can be congenital or acquired with the latter being more common. There is a spectrum of severity on their effect on patient as well from mild life-long anemia to very severe transfusion-dependent anemia. Various types of sideroblastic anemias differ in terms of underlying mechanisms, symptoms and treatment. The unifying feature to all types is a defect in mitochondrial metabolisms related to iron utilization. Another unifying feature is the ring sideroblasts around the nucleus, which are seen on bone marrow examination with Prussian blue stain and are the hallmark of sideroblastic anemia.

Pathogenesis.

Briefly about the pathways disrupted in sideroblastic anemia.

This first step of heme synthesis occurs in mitochondria of the erythroblast. ALA is then transported to cytoplasm for a few more steps to make coproporphyrinogen III. It is then transported back to mitochondria for more steps to eventually reach the final step where iron is inserted into protoporphyrin IX ring by enzyme ferrochetalase, to make heme.

There are two types of ALAS, 1 and 2. Type 2 is more specific to erythrocytes, and its gene is located on the X-chromosome. It is under the influence of erythropoietin. ALAS 2 is a crucial enzyme for the development of red blood cells. ALAS2 is regulated by iron regulatory proteins (IRP1 and IRP 2). These proteins bind and suppress mRNA translation of ALAS 2.

  1. The heme synthesis pathway involves 8 steps. The first step makes ALA (aminolevulinic acid) by combining glycine and succinyl co-enzyme A. In erythrocytes, the enzyme involved in this step is called ALAS 2 (d aminolevulinate synthase). It uses pyridoxal 5’ phosphate, a derivative of pyridoxal (vitamin B6) as a cofactor. This is an important step that is impaired in some types of both congenital and acquired forms.

  2. Iron sulfur clusters are protein complexes that are involved in electron transfer of important mitochondrial and cytosolic pathways. Mutation or inactivation of these proteins can lead to abnormal iron metabolism and accumulation. One mechanism could be through influence on iron regulatory proteins (IRPs).

  3. There are other mitochondrial pathways which are disrupted in some forms of sideroblastic anemia, such as production of certain proteins essential for mitochondrial function. It is less clear how they eventually produce imbalance in iron metabolism and cause anemia.

What causes anemia in sideroblastic anemia?

Increased iron accumulation in mitochondria from abnormal iron metabolism causes formation of reactive oxygen species, and damages forming erythrocytes, usually in later stages of maturation. Thus, even though the bone marrow is hyperplastic and forming effective red cells, many of them are destroyed within the marrow. In addition to this, impaired hemoglobin production, causes reduced number of mature erythrocytes. Resulting anemia is usually microcytic and hypochromic with some exceptions that will be discussed. The degree of ineffective erythropoiesis usually corresponds to anemia severity.

Mechanism of iron overload

Despite the abnormalities in iron utilization in sideroblastic anemia, iron transport to erythroblasts continues since the body senses anemia. Intestinal iron absorption increases which eventually causes both iron accumulation in mitochondria of erythroblasts and possible systemic iron accumulation. It is interesting to note that systemic iron overload occurs only in some forms of sideroblastic anemia, usually when the defects in iron metabolisms involve earlier stages of erythroid pathways. The reasons for this are not entirely clear.

Iron is released from transferrin as Fe3+, and then reduced to Fe2+. It is then transported to cytoplasm, and then to mitochondria of erythroblast. Most of the iron is used for hemoglobin production.

II. Diagnostic Confirmation: Are you sure your patient has sideroblastic anemia?

The diagnostic hallmark is bone marrow examination showing ring sideroblasts.

  1. Anemia is usually variable in severity from mild to severe (hemoglobin ranges from 4-10 mg/dL).

  2. Anemia is usually microcytic and hypochromic due to abnormal hemoglobin production, but sometimes can be dimorphic with normocytic or macrocytic cells, depending on the cause.

  3. Systemic iron overload may or may not be seen depending on the cause.

A. History Part I: Pattern Recognition:

  1. Typical symptoms of anemia, if severe enough, such as fatigue, light-headedness, pallor, decreased cardiac endurance.

  2. If congenital and part of a syndrome, also has other clinical features specific to the syndrome.

  3. Signs of iron overload such as liver or cardiac dysfunction.

B. History Part 2: Prevalence:

Sideroblastic anemia is divided into 2 groups: congenital or acquired, with the latter being more common.

Congenital.

  1. X-linked sideroblastic anemia - due to mutation in ALAS 2 enzyme. It is the most common congenital cause. Mostly affects males, but can also affect women when skewed inactivation of X chromosome occurs with aging. Women usually manifest the anemia later in life. Anemia is variable in severity and more commonly remains stable.

  2. SCL25A38 defects - this is a gene for mitochondrial transporter, likely involved in bringing glycine into mitochondria, which is required for ALA production. This type is inherited in an autosomal recessive pattern and is usually a more severe anemia requiring chronic transfusion support.

  3. Glutaredoxin deficiency - protein involved in iron sulfur biogenesis, which potentially reduces ALAS 2 translation through iron regulatory protein 1 (IPR1).

  4. X-linked sideroblastic anemia with non-progressive cerebellar ataxia - defect in ABCB 7 protein involved in iron sulfur machinery. With the defect, iron remains trapped in mitochondria. Anemia is usually mild and no iron overload is observed.

  5. Pearson marrow pancreas syndrome - severe anemia, neutropenia, thrombocytopenia, exocrine pancreatic insufficiency, lactic acidosis, hepatic and renal problems and failure to thrive as a child. The defects are usually in the structure of mitochondria (DNA deletions thus impairing synthesis of proteins crucial to mitochondrial function of the red cells).

  6. Mitochondrial myopathy sideroblastic anemia - defect in PUS 1 gene involved in mitochondrial tRNA production. Starts in childhood with exercise intolerance, and then progresses to anemia, lactic acidosis and worsening myopathy in adolescence.

  7. Thiamine responsive megaloblastic anemia syndrome or Roger’s Syndrome - mutation in thiamine transporter, where thiamine might be a cofactor in heme synthesis pathway (in generation of succinyl coenzyme A, which together with glycine serves a substrate for ALAS 2). Starts between infant to adolescent age and manifests with anemia, diabetes and sensorineural deafness.

Acquired

Reversible (the most common category, especially with alcohol use):

  1. Alcohol use inhibits heme synthesis in several ways and may cause dietary deficiency in pyridoxine. If sideroblastic anemia is noted in alcoholics, it usually indicates a more severe case of anemia. It is observed in about 1/3 of patients. Interestingly alcohol effects red blood cell production more than white cells.

  2. Chloramphenicol inhibits mitochondrial membrane protein synthesis. Ring sideroblasts usually appear in most patients taking the drug, especially in longer courses and with higher doses. Anemia is moderate to severe.

  3. Isoniazid (INH) reacts with pyridoxine, thus inhibiting the first step of heme synthesis. Also may inhibit ALAS 2 activity. Approximately 8% of patients develop anemia, and people with underlying hematologic problems, are more prone to it. It usually develops 1-10 months after starting the therapy and usually manifests as typical, moderate to severe sideroblastic anemia.

  4. Lead toxicity - rare and questionable cause, and most often just leads to microcytic anemia with basophilic stippling.

  5. Pyridoxine deficiency can be due to malnutrition which is quite rare or from discontinuation of multivitamin which contained it. Typically, peripheral neuropathy and dermatitis are more pronounced than anemia.

  6. Copper deficiency - copper has complex role in iron metabolism. It participates in intestinal iron absorption and mobilization from the liver. It is also a part of cytochrome oxidase, an enzyme involved in iron reduction. The deficiency usually occurs in patients who have decreased absorption of copper. Examples include gastric surgery, prolonged parenteral nutrition or enteral feedings without inclusion of copper in the feeds. Decreased intestinal absorption (such as celiac disease or other malabsorptive syndromes) may also be the cause. Lastly, copper chelation has been reported to cause anemia which tends to be severe with hemoglobin levels as low as 5 with normal to slightly-increased mean corpuscular volume (MCV). Iron overload is usually not observed. In addition to sideroblastic changes, patients may develop neutropenia and neurologic abnormalities.

  7. Zinc toxicity – which causes decreasing copper levels.

  8. Other TB drugs such as cycloserine and pyrazinamide - were noted to cause sideroblastic changes in some patients since they also influence pyridoxyl 5’ phosphate synthesis.

  9. Hypothermia - as low temperature may influence mitochondrial functions.

Refractory

The next big group in terms of prevalence after reversible. Refers to myelodysplastic syndrome (MDS) related or clonal sideroblastic anemia (here the abnormal cells grow in clones). The defects are thought to be in heme synthesis pathways, although no clear mutations have been identified. ABCB7 transporter levels were found to be reduced, and so this protein might be involved in pathogenesis.

Unlike in congenital forms of sideroblastic anemia, erythroblasts are effected at all stages of maturation, beginning from stem cells. It usually occurs in the middle age to older population and is often discovered by laboratory abnormalities or symptoms consistent with anemia. Patients may become transfusion dependent and develop iron overload.

  1. Refractory anemia with ring sideroblasts (RARS) - occurs as sole anemia. Often very similar phenotypically to X-linked sideroblastic anemia. Usually runs a benign course and has very low chance of transformation to leukemia.

  2. RCMD-RS - in addition to red cells, involves dysplastic changes in white cells and platelets. This also has a higher incidence of acute leukemia conversions.

  3. RARS-T - a variant of anemia with thrombocytosis, frequently associated with JAK2 mutation, has the best prognosis of all 3 categories.

C. History Part 3: Competing diagnoses that can mimic sideroblastic anemia.

Any anemia can be considered in the differential diagnosis of sideroblastic anemia. The most important types of anemia to consider are the other causes of microcytic anemia, such as thalassemia, iron deficiency or lead poisoning. In addition, different anemias can coexist, for example, a patient with sideroblastic anemia can also be iron deficient. Some types of sideroblastic anemias can have normocytic or macrocytic cells, and therefore, the differential diagnosis should include any cause of anemia that fits the clinical presentation of a patient.

Many different anemias may show similar exam and laboratory findings. Sideroblastic anemia can be guessed based on history, clinical and laboratory presentation, however bone marrow examination is the only study that can accurately distinguish sideroblastic anemia from other types.

D. Physical Examination Findings.

  1. Pallor.

  2. Splenomegaly - usually mild.

  3. Hepatomegaly (with iron overload).

  4. Findings related to cardiac damage in case of iron accumulation, such as arrhythmias, or heart failure, which usually occur late in disease course - rare.

  5. Diabetes (iron overload) – rare.

  6. Hypogonadism (iron overload) – rare.

  7. Physical findings related to specific syndromes as described above.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Diagnostic steps

Start with the usual anemia work-up.

Anemia is usually microcytic with low MCV and hypochromic (low mean corpuscular hemoglobin [MCH]). The degree of microcytosis and hypochromia parallel the severity of anemia. Red cell distribution width (RDW) is increased as there are variable sizes of cells. Often at times you may see dimorphic cells, different in sizes - micro and macrocytic or normocytic (especially in females with X-linked sideroblastic anemia, MDS and alcohol use).

  1. Complete blood count with differential will show variable severity of anemia, with usually normal leukocytes and platelets. However the latter 2 cell lines may be abnormal if hypersplenism is present, in some subtypes of MDS, drug or alcohol toxicity. The smear shows many microcytic and hypochromic cells. Some dysmorphic cells can also be seen. Occasionally Pappenheimer bodies, which are iron inclusions, can be seen as well (see Figure 1, Figure 2).

  2. Reticulocyte count is low because of impaired erythroblast maturation.

  3. Epogen level is usually elevated as a response to anemia.

  4. Iron studies usually show elevated iron, transferrin saturation and ferritin levels with low transferrin levels. However, iron deficiency may coexist, especially in young menstruating women.

  5. Bilirubin level may be slightly elevated due to destruction of ineffective erythroblasts.

Figure 1.

Peripheral smear - top panel shows some hypochromic cells and bottom panel shows a smear from another. patient with multiple hypochromic, microcytic and misshapen cells.

Figure 2.

Peripheral smear - shows hypochromic and microcytic cells. The arrow points towards a cell with iron containing inclusions, called Pappenheimer bodies.

At this point, would need to confirm the suspected diagnosis with bone marrow biopsy, which is the only way to accurately diagnose the disease.

Bone marrow examination - shows crowded hyperplastic marrow with ineffective erythrocytes and ring sideroblasts, that are mostly seen in the later non-dividing stages of erythroblasts differentiation (except MDS where they are seen in all stages). The official definition of ring sideroblast is when the erythroblasts have at least 5 granules, which cover at least 1/3 of the nucleus rim. Bone marrow biopsy will also help in diagnosis of MDS, if sideroblastic anemia is related to it (see Figure 3, Figure 4, Figure 5).

Figure 3.

Top panel shows bone marrow smear stained with Prussian blue stain. Arrows point towards iron positive granules around the nucleus. Bottom panel shows electron micrograph picture.

Figure 4.

Patient with X-linked sideroblastic anemia. (A) Peripheral blood smear with many hypochromic and microcytic cells. (B) Bone marrow smear with erythroid hyperplasia and abnormal erythroblasts. (C) Bone marrow smear showing erythroblasts with defective hemoglobinization (left) and erythroblasts containing multiple Pappenheimer bodies (right) (D) Bone marrow smear – ring erythroblasts which are ring sideroblasts with at least five positive granules disposed in a ring surrounding a third or more of the circumference of the nucleus.

Figure 5.

Patient with refractory anemia with ring sideroblasts (RARS). (A). Peripheral blood smear shows dimorphic red cells with macrocytic and hypochromic microcytic red cells. (B) Bone marrow smear shows erythroid hyperplasia with megaloblastoid features. Upper right, a late erythroblast with defective hemoglobinization; lower right, an early erythroblast with vacuolated cytoplasm and a late erythroblast with Pappenheimer bodies. (C) Bone marrow smear stained by Perls’ reaction shows several ring sideroblasts. (D) Bone marrow smear - mitochondrial ferritin in granules surrounding the nucleus.

As a note - often it is possible to see blue iron granules scattered around the cytoplasm on bone marrow examination. This is a normal finding and represents endosomes filled with ferritin loaded with unutilized iron. Ring sideroblasts, on the other hand, are never a normal finding. The iron in them is stored in mitochondrial ferritin.

Once the diagnosis of sideroblastic anemia is made, will need to perform other tests to find the etiology:

  1. May check red blood cell protoporphyrin levels. They will be normal or low in X-linked sideroblastic anemia and SLC25A38 deficiency as the defect is in early step of heme pathway, thus not forming enough porphyrins. They will be high in X-linked sideroblastic anemia with ataxia since the defect is not in heme synthesis pathway. It is also elevated in acquired forms related to MDS.

  2. Genetic testing if no acquired cause is found and genetic defect is suspected.

  3. Copper or zinc levels if copper deficiency or zinc toxicity is suspected.

  4. Ethanol level - to confirm alcohol toxicity.

  5. If diagnosis of MDS type sideroblastic anemia is suspected, bone marrow performed would aid in the diagnosis.

With any of the causes found, may need to perform tests to look for complications of the disease:

  1. Iron studies to look for iron overload.

  2. Liver biopsy may be considered if iron overload is suspected. It may show iron deposition or evidence of cirrhosis. Usually the degree of iron overload does not correlate with anemia but is related more to the degree of marrow hyperplasia and the duration of the problem, being more severe in congenital forms. Also, occasionally patients have coinheritance of hemochromatosis gene, which makes the problem worse.

  3. Look for diabetes or glucose intolerance related to iron overload.

  4. Cardiac monitoring to look for arrhythmias or signs of heart failure if iron overload present.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiography is not helpful for the diagnosis of sideroblastic anemia itself. It could be helpful in looking for complications of the disease, such as iron overload in the liver or the heart. Finding of splenomegaly on radiography may also help narrow the diagnosis.

III. Default Management.

Goals of management are to control anemia and prevent organ damage from iron overload.

Treatment of anemia.

Pyridoxine supplementation will also be helpful when patients are receiving INH to prevent anemia development (in addition to preventing neurotoxicity). Supplementation ranges from 10-50mg/day depending on risk factors. However, once symptoms develop, patients will likely need higher doses of 200mg/day.

  1. Transfusion - depending on the severity of anemia. For mild forms, may only need observation. In children, it is important to maintain adequate hemoglobin levels to ensure appropriate growth and development.

  2. Pyridoxine supplementation - should be attempted (as pyridoxine is a cofactor for ALAS 2 in hemoglobin synthesis pathways). Some forms of sideroblastic anemia are responsive to it. For example, in X-linked sideroblastic anemia at least 2/3 of the patients respond well to treatment (if the defect in enzyme ALAS 2 is in the sites of pyridoxine binding, then supplementation will help correct the anemia. If the defect is in other sites that are involved in enzyme folding, etc, then pyridoxine will not be helpful).

  3. Cessation of offending agents (such as alcohol or drugs) usually resolves the anemia.

  4. In patients with MDS related sideroblastic anemia, erythropoietin and G-CSF for synergy were found to be helpful (especially if epogen levels were not elevated). G-CSF also inhibits apoptosis of red cells in the marrow. That combination reduced the need for transfusions but have not affected survival. In these patients, chemotherapeutic agents were tried, but were not as effective.

  5. Copper supplementation in copper deficiency usually helps reverse the anemia. 2mg of PO or IV copper a day is the average dose and usually corrects the abnormality in about 2 months. Sometimes higher doses and for longer periods of time are required.

  6. Thiamine supplementation in thiamine responsive megaloblastic anemia usually improves anemia and diabetes. This becomes less effective with aging.

  7. Phlebotomy or iron chelation have been shown to improve anemia in some cases. The explanation to this maybe that reduced iron levels decrease reactive oxygen species formation and the oxidative damage to the cells. It also helps improve pyridoxine responsiveness.

  8. Folic acid can be given to compensate for increased erythropoiesis.

Treatment of iron overload.

  1. Need to monitor for iron overload even without transfusions as iron overload occurs as a result of anemia itself in some types of sideroblastic anemia.

  2. If patients are chronically transfusion dependent, there is even more risk of iron overload.

  3. Interventions usually start it if ferritin levels are above 500-1000, or patient has received more than 10 transfusions.

  4. One can use phlebotomy or chelation therapy.

  5. Phlebotomy must be used with care and may be contraindicated in patients with heart failure.

  6. For chelation, there are several options:

    • Deferoxamine is used as IV therapy, 40mg/kg a day, which can be given over 12-24 hours. Vitamin C is often given as well at 200mg daily to help iron removal.

    • Oral chelators - deferasirox: 20-30mg/kg a day.

    • Deferiprone - used in Europe, but can be obtained by special request.

Other considerations.

  1. Severe refractory cases of anemia may require bone marrow transplant, usually at younger ages.

  2. Splenectomy is contraindicated as treatment because there have been reports of adverse outcomes.

A. Immediate management.

No immediate management unless life-threatening anemia.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Mostly done as outpatient:

  • Monitor complete blood count (CBC) to ensure stable hemoglobin.

  • Monitor iron studies, and make sure ferritin level is below 500.

D. Long-term management.

  1. In pyridoxine responsive cases: pyridoxine supplementation of 50-100mg a day.

  2. Chronic transfusions.

  3. Iron chelation.

  4. Management of underlying conditions.

E. Common Pitfalls and Side-Effects of Management.

Deferoxamine.

  • May develop local chemical reaction and occasional hypersensitivity (in which case desensitization may be attempted).

  • Auditory and visual toxicity are rare, especially if there is no overdose. Need to perform ophthalmologic exams.

  • There is an increased risk of mucormycosis and Yersinia infections.

IV. Management with Co-Morbidities.

N/A

V. Transitions of Care.

B. Anticipated Length of Stay.

Sideroblastic anemia, unless severe or noted with other problems such as iron overload syndrome, alcohol toxicity or MDS complications, is usually not the primary cause for hospital stay.

1. When should clinic follow up be arranged and with whom?

Hematology clinic.

If patient had acute problems as an inpatient related to the disease, then a sooner follow-up will be necessary to monitor hemoglobin levels within 1 week.

2. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

  1. CBC.

  2. Iron studies.

F. Prognosis and Patient Counseling.

  1. In congenital forms, the anemia usually remains stable. There are few exceptions:

    • In women with X-linked sideroblastic anemia, the X chromosome with normal allele may become inactivated with aging, thus making higher expression of the mutant allele (this is called skewing).

    • New pyridoxine deficiency or change in metabolism with age, may worsen pyridoxine responsive anemia.

  2. In forms of anemia in which systemic iron overload develops, the symptoms of iron overload become worse with aging.

  3. In children with severe congenital forms, one needs to look for development and growth delay.

  4. In MDS forms of sideroblastic anemia, conversion to acute leukemia is possible, especially in the RCMD-RS form, where all types of hematopoietic lines are affected.

What’s the evidence?

Maguire, A, Hellier, K, Hammans, S, May, A. "X-linked cerebellar ataxia and sideroblastic anaemia associated with missense mutation in ABC7 gene predicting V411L". British Journal of Haematology. vol. 115. 2001. pp. 910.

"Sideroblastic anemias". British Journal of Haematology. vol. 116. 2002. pp. 733.

Camaschella, C. "Hereditary sideroblastic anemias: pathophysiology, diagnosis and treatment". Seminars in Hematology. vol. 46. 2009. pp. 371-377.

Camaschella, C. "Recent advances in the understanding of inherited sideroblastic anaemia". British Journal of Haematology. vol. 143. 2008. pp. 27-38.

Harigae, H, Furuyama, K. "Hereditary sideroblastic anemia: pathophysiology and gene mutations". International Journal of Hematology. vol. 92. 2010. pp. 425-431.

Cazzola, M, Invernizzi, R. "Ring sideroblasts and sideroblastic anemias". Haematological. vol. 96. 2011. pp. 789-792.

Kobayashi, Y, Hatta, Y. "Copper deficiency anaemia". British Journal of Haematology. vol. 164. 2014. pp. 161.

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