Journal Presentation

Dr. Ummeh Habiba Islam (Punam)

Resident (Phase A)

Department of Hematology

Bangabandhu Sheikh Mujib Medical University

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� Guidelines for the diagnosis and treatment of cobalamin and folate disorders�

Vinod Devalia, Malcom S. Hamilton and Anne M. Molloy

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British Journal of Haematology (BJH)

Volume: 166, Page: 496-513

Published on 18^th June 2014

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Cobalamin Deficiency

Cobalamin Deficiency

• In patients with classical megaloblastic anaemia, the presence of a low serum cobalamin level and objective assessment of response in terms of the rise in haemoglobin concentration clearly outlines the treatment pathway.

Cobalamin Deficiency (Cont)

• The majority of patients do not have a clear-cut picture.

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• Neurological presentation (peripheral neuropathy, sub-acute combined degeneration of the cord) may occur in the absence of haematological changes.

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Cobalamin Deficiency (Cont)

• Early treatment is essential to avoid permanent neurological disability.

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• Low cobalamin levels of uncertain significance may occur with non-specific symptoms & no anemia.

Cobalamin Deficiency (Cont)

• Patients with strong clinical features of cobalamin deficiency may have serum cobalamin levels that lie within the reference range (false normal cobalamin level).

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• As a result, other tests may be used to try and determine an underlying functional or biochemical deficiency.

Cobalamin Deficiency (Cont)

• These are plasma homocysteine, plasma MMA and serum holotranscobalamin.

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• There is currently no ‘gold standard’ test for the diagnosis of cobalamin deficiency.

Cobalamin Deficiency (Cont)

• Patients shows similar clinical features for both cobalamin & folate deficiencies

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• So, assessment of cobalamin and folate status is usually performed concurrently.

Cobalamin Deficiency (Cont)

• In the presence of true cobalamin deficiency, the serum folate is often normal or can be elevated.

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• However, a low serum cobalamin level may be found in the presence of folate deficiency.

Test to confirm cobalamin deficiency

• MCV & PBF
• Serum cobalamin
• Plasma total homocysteine (tHcy)
• Plasma methylmalonic acid (MMA)
• Holotranscobalamin (HoloTC)
• Bone Marrow examination

Recommendations

1. A blood film showing oval macrocytes and hypersegmented neutrophils in the presence of an elevated MCV may alert the clinician to the presence of underlying cobalamin or folate deficiency (Grade 2B).

Recommendations (Cont)

2. Cobalamin and folate assays should be assessed concurrently due to the close relationship in metabolism (Grade 1A).

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3. The writing group recommends adoption of reporting for cobalamin assay results in pmol/l (Grade 2C).

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Recommendations (Cont)

4. A serum cobalamin cut-off level of either 148 pmol/l (200 ng/l) or one derived from a local reference range should be used as evidence of cobalamin deficiency in the presence of a strong clinical suspicion (Grade 2B).

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Recommendations (Cont)

5. The report providing the result of a serum cobalamin assay should include the following:

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a) The interpretation of the result should be considered in relation to the clinical circumstances.

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b) Falsely low serum cobalamin levels may be seen in the presence of folate deficiency or technical issues.

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c) Neurological symptoms due to cobalamin deficiency may occur in the presence of a normal MCV (Grade 1B).

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Recommendations (Cont)

6. Plasma tHcy and/or plasma MMA, depending on availability, may be considered as supplementary tests to determine biochemical cobalamin deficiency in the presence of clinical suspicion of deficiency but an indeterminate serum cobalamin level (Grade 2B).

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a) Although plasma tHcy is a sensitive marker of cobalamin deficiency, plasma MMA is more specific.

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b) Both assays have to be interpreted in relation to renal function.

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Recommendations (Cont)

7. HoloTC is suggested as a suitable assay for assessment of cobalamin status in a routine diagnostic laboratory in the future (Grade 1B).

Test to determine the aetiology of cobalamine deficiency

• Anti-intrinsic factor antibody (Anti-IFAB)
• Gastric anti-parietal cell antibody
• Others-
• Schilling test
• Test to assess cobalamin absorption based on serum HoloTc level
• Endoscopy of Upper GIT

Recommendations

1. All patients with anaemia, neuropathy or glossitis, and suspected of having pernicious anaemia, should be tested for anti-IFAB regardless of cobalamin levels (Grade 1A).

Recommendations (Cont)

2. Patients found to have a low serum cobalamin level in the absence of anaemia and who do not have food malabsorption or other causes of deficiency, should be tested for IFAB to clarify whether they have an early/latent presentation of pernicious anaemia (Grade 2A).

Recommendations (Cont)

3. Anti-GPC antibody testing for diagnosing pernicious anaemia is not recommended (Grade 1A).

Treatment of cobalamin deficiency

• Treatment of cobalamin deficiency with IM hydroxycobalamin
• Treatment of transient hypokalaemia
• Oral cyanocobalamin

Recommendations

1. Treatment of established cobalamin deficiency should follow the schedules in the BNF (Grade 1A).

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2. Initial treatment with oral cobalamin may not be appropriate in pernicious anaemia, but may be considered in maintenance or correction of suboptimal levels in asymptomatic patients (Grade 2C).

Adverse effect of Hydroxycobalamine

• It is usually well tolerated
• But it has some side effects eg.
• Itching
• Exanthema
• Chills with fever
• hot flushes
• Nausea
• dizziness
• Rarely
• Anaphylaxis due to hypersensitivity to cobalt or any of the other components of the medication
• Acneiform eruptions

Clinical approach to investigation and treatment of�cobalamin-associated disorders

Folate Deficiency

Folate Deficiency

• Folate is the term encompassing all the different biologically active forms of the vitamin and folic acid is the synthetic form used in supplements, fortified foods and for treatment.

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• Both types are absorbed from the proximal small intestine and almost half of the body folate is found in the liver.

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• The bioavailability of food folates is, on average, about 50% lower than folic acid.

Aetiology of Folate Deficiency

• A low intake/Anorexia
• Poor absorption of folate from GIT
• Acute alcohol consumption
• Normal pregnancy and
• Patients on anticonvulsant therapy (Specially Sodium Valproate)

Effects of Folate Deficiency

• Folate is required for DNA synthesis. So, the earliest signs of deficiency are seen in rapidly proliferating cells eg. in the bone marrow and gastrointestinal tract.

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• Severe folate deficiency can cause
• Pancytopenia
• Megaloblastic anaemia

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Test to diagnose folate deficiency

• Serum folate
• Red cell folate
• Homocysteine (tHcy)

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Recommendations

1. A serum folate level <7 nmol/l (3 lg/l) is indicative of folate deficiency (Grade 1B).

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2. Routine red cell folate testing is not necessary because serum folate alone is sufficient in most cases (Grade 1A).

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3. In the presence of strong clinical suspicion of folate deficiency, despite a normal serum level, a red cell folate assay may be undertaken, having ruled out cobalamin deficiency (Grade 2B).

Recommendations (Cont)

4. Plasma tHcy can be measured to confirm suspected folate deficiency only in special circumstances; a level above 15 lmol/l could be indicative of folate deficiency but must be assessed in relation to local reference ranges (Grade 2B).

Clinical approach to investigation and treatment of�folate associated disorders

Conditions mimicking cobalamin deficiency

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• Isolated clinical folate deficiency are extremely rare

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• Diagnosis of folate deficiency should be made with consideration of a circumstance leading to shortage or malabsorption of multiple nutrients

Clinical approach to investigation and treatment of�folate associated disorders

• The metabolic roles of folate and cobalamin are closely linked, and deficiency of either vitamin can result in the same clinical manifestations

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• a low serum folate may be associated with a low serum cobalamin, in this case treatment is initiated with cobalamin therapy before adding folate therapy.

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• Serum folate is the preferred marker for folate status in cobalamin deficiency because the red cell folate may be lower in the presence of cobalamin deficiency

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Clinical approach to investigation and treatment of�folate associated disorders

Anaemia due to folate deficiency

1. Dietary deficiency

2. Alcoholism

3. Pregnancy

4. Increased requirements

5. Haemodialysis
6. Drug: Specially anticonvulsant (Sodium valproate)

Recommendations

1. Folate status is generally checked in clinical situations similar to those of cobalamin deficiency (Grade 1A).

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2. Consultation of the BNF and Summary of Product Characteristics is recommended for clarifying any suspicion of low serum folate levels associated with prescribed medications.

Treatment of Folate Deficiency

Treatment depends on cause of deficiency

1. Folate deficient megaloblastic anemia: 5mg of folic acid daily for 4 months.

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• In malabsorption: 15 mg/day for 4 months

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• Chronic haemolytic state/Haemodialysis patient: 5mg/day or 5mg/week, depending on the diet & rate of hemolysis.

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• Pregnancy: 200-500 mcg/day upto term

Recommendations

Treatment of folate disorders should follow the schedules in the BNF (Grade 1A).

Take Home Message

1. The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no ‘gold standard’ test to define deficiency.

Take Home Message

2. Serum cobalamin currently remains the first-line test, with additional second-line plasma methylmalonic acid to help clarify uncertainties of underlying biochemical/functional deficiencies.

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Serum holotranscobalamin has the potential as a first-line test, but an indeterminate ‘grey area’ may still exist.

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Take Home Message

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Plasma homocysteine may be helpful as a second-line test, but is less specific than methylmalonic acid.

The availability of these second-line tests is currently limited.

Take Home Message

3. Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established.

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4. In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment.

Take Home Message

5. Treatment of cobalamin deficiency is recommended in line with the British National Formulary. Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue.

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6. Serum folate offers equivalent diagnostic capability to red cell folate and is the first-line test of choice to assess folate