Folate deficiency differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Folate deficiency must be differentiated from other diseases associated with the Macrocytic anemia such as Vitamin B12 deficiency, Alcoholic liver disease, Hypothyroidism, Myelodysplasia and Aplastic anemia.

Differential Diagnosis

Folate deficiency must be differentiated from other diseases associated with the Macrocytic anemia such as Vitamin B12 deficiency, Alcoholic liver disease, Hypothyroidism, Myelodysplasia and Aplastic anemia^[1]^[2]

Differentiating Folate deficiency from other Diseases:

CONDITIONS	SIGNS/SYMPTOMS	INVESTIGATIONS
Vitamin B12 deficiency	Associated with neurologic and neuropsychiatric symptoms. e.g. decreased vibration sense, peripheral neuropathy, gait abnormalities.	Serum vitamin B12 levels are low. Both homocysteine and methylmalonic acid are elevated.
Alcoholic liver disease	Nutritional deficiencies and macrocytic anemia may be the presenting features. History reveals alcohol abuse.	Elevated liver enzymes e.g. ALT and AST Liver biopsy shows fatty liver or cirrhosis.
Hypothyroidism	Associated with constipation, weight gain, cold intolerance, hoarse voice, bradycardia, dry skin, delayed tendon reflexes.	Elevated TSH, low T4, and low T3. Serum folate level is normal. Homocysteine is often elevated
Myelodysplastic syndrome	Gradual-onset fatigue often present. Patients may have splenomegaly.	Macrocytic anemia may be associated with neutropenia and thrombocytopenia. Peripheral smear may suggestive of large, hypogranular platelets; hypogranulated, hyposegmented neutrophils with Dohle bodies; and circulating myeloblasts. Bone marrow findings include dyserythropoiesis; hypogranulated, hyposegmented granulocytic precursors; increased myeloblasts; and megakaryocytes showing fewer or disorganized nuclei. Ringed sideroblasts can also be seen Cytogenetic analysis and fluorescence in-situ hybridization can identify specific chromosomal abnormalities.
Aplastic anemia	Hx of recent viral illness, chemical exposure, or drug use. Bleeding and symptoms of infection are usually present. Ecchymosis and signs of infection may be present.	Macrocytic anemia, neutropenia, thrombocytopenia, and reticulocytopenia are present. Bone marrow aspirate and biopsy show decreased cellularity and paucity of all 3 lineage precursor cells.
Drug-induced macrocytosis	Hx of intake of certain drugs, such as DNA synthesis-inhibiting drugs, immunosuppressive drugs, anticonvulsants, and antiviral medications.	Serum folate level is normal.
Diphyllobothriasis	Associated with abdominal discomfort, diarrhea, vomiting, weakness, weight loss, and occasionally acute abdominal pain due to intestinal obstruction, cholangitis, or cholecystitis. Other features are megaloblastic anemia and neurologic abnormalities secondary to vitamin B12 (cobalamin) deficiency.	Identification of the operculated eggs in the stool Polymerase chain reaction (PCR) Megaloblastic anemia with low vitamin B12 level

Differentiating Macrocytic Anemia from Other Diseases

To review the differential diagnosis of anemia, click here.

Disease	Genetics	Clinical manifestation					Lab findings
		History	Symptoms	Signs	Hemolysis	Intrinsic/Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Iron studies					Specific finding on blood smear
		History	Symptoms	Signs	Hemolysis	Intrinsic/Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	Transferrin or TIBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Folate deficiency^[3]	Impaired DNA synthesis	Alcohol consumption History of using drugs like methotrexate, trimethoprim, and phenytoin Low socioeconomic groups with poor nutrition Older people Pregnant and lactating women	No neurological symptoms vs B12 deficiency Odynophagia Angular stomatitis	Glossitis Signs of heart failure Anencephaly and spina bifida	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	RBC macrocytosis Hypersegmented neutrophils Pancytopenia in severe cases
Vitamin B12 deficiency^[4]	Impaired DNA synthesis	Pernicious anemia Crohn’s disease Gastrectomy Veganism Diphyllobothrium latum infection	Psychosis Insomnia Depression Cognitive slowing Restless leg syndrome	Neurological deficit Myelopathy Memory loss with reduced attention span Nystagmus Positive romberg sign Positive Lhermitte’s sign	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	Senile neutrophil Anisocytosis Ovalocytes
Orotic aciduria^[5]	Autosomal recessive Deficiency of enzyme UMPS	Episodic vomiting Rhabdomyolysis	Coma Gastrointestinal manifestation	Neurological manifestation	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Fanconi anemia^[6]	Autosomal recessive X-linked recessive	History of anemia at age 16	Hypopigmentation Cafe-au-lait patches Radial ray anomaly	Significant for bilateral short thumbs	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	Nl appearing WBC, RBC and Platelets But the number is greatly reduced
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Diamond-Blackfan anemia^[7]	Mutations in: RPL5 RPL11 RPL35A RPS7 RPS10 RPS17 RPS19 RPS24 RPS26	Associated with myelodysplastic syndrome Increased risk of AML	Pale skin Sleepiness Heart murmurs	Triphalangeal thumbs Short stature Microcephaly Hypertelorism Ptosis Micrognathia	−	−	Anisochromic	Macrocytic	Nl	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Liver disease^[8]	−	Hepatitis Binge drinking Gall bladder disease	Jaundice Abdominal pain Itchy skin	Ascites Right upper quadrant pain Hepatomegaly Swelling in the legs Ankle swelling	−	−	Anisochromic	Macrocytic	↑	↑	Nl	Nl	↑	↑	↓	↑	↑	Round macrocytes Target macrocytes
Alcoholism^[9]	−	History of increased alcohol intake Folic acid deficiency	Memory impairment Nausea Sweating	Truncal obesity Asterixis Encephalopathy Spider angiomas Hematemesis Gynecomastia	−	−	Anisochromic	Macrocytic	↑	↑	Nl	Nl	↑	↑	↓	↑	↑	Oval macrocytes Hypersegmented neutrophils
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear

References

↑ Snow CF (1999). “Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician”. Arch Intern Med. 159 (12): 1289–98. PMID 10386505.
↑ Nagao, Takayo; Hirokawa, Makoto (2017). “Diagnosis and treatment of macrocytic anemias in adults”. Journal of General and Family Medicine. 18 (5): 200–204. doi:10.1002/jgf2.31. ISSN 2189-7948.
↑ Koike H, Takahashi M, Ohyama K, Hashimoto R, Kawagashira Y, Iijima M, Katsuno M, Doi H, Tanaka F, Sobue G (March 2015). “Clinicopathologic features of folate-deficiency neuropathy”. Neurology. 84 (10): 1026–33. doi:10.1212/WNL.0000000000001343. PMID 25663227.
↑ Hunt A, Harrington D, Robinson S (September 2014). “Vitamin B12 deficiency”. BMJ. 349: g5226. PMID 25189324.
↑ Grohmann K, Lauffer H, Lauenstein P, Hoffmann GF, Seidlitz G (April 2015). “Hereditary orotic aciduria with epilepsy and without megaloblastic anemia”. Neuropediatrics. 46 (2): 123–5. doi:10.1055/s-0035-1547341. PMID 25757096.
↑ Alter BP (2014). “Fanconi anemia and the development of leukemia”. Best Pract Res Clin Haematol. 27 (3–4): 214–21. doi:10.1016/j.beha.2014.10.002. PMC 4254647. PMID 25455269.
↑ Vlachos A, Blanc L, Lipton JM (June 2014). “Diamond Blackfan anemia: a model for the translational approach to understanding human disease”. Expert Rev Hematol. 7 (3): 359–72. doi:10.1586/17474086.2014.897923. PMID 24665981.
↑ Marks PW (July 2013). “Hematologic manifestations of liver disease”. Semin. Hematol. 50 (3): 216–21. doi:10.1053/j.seminhematol.2013.06.003. PMID 23953338.
↑ Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K (May 2014). “Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men”. Alcohol. Clin. Exp. Res. 38 (5): 1237–46. doi:10.1111/acer.12372. PMID 24588059.

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[pmid10386505-1] Snow CF (1999). “Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician”. Arch Intern Med. 159 (12): 1289–98. PMID 10386505.

[NagaoHirokawa2017-2] Nagao, Takayo; Hirokawa, Makoto (2017). “Diagnosis and treatment of macrocytic anemias in adults”. Journal of General and Family Medicine. 18 (5): 200–204. doi:10.1002/jgf2.31. ISSN 2189-7948.

[pmid25663227-3] Koike H, Takahashi M, Ohyama K, Hashimoto R, Kawagashira Y, Iijima M, Katsuno M, Doi H, Tanaka F, Sobue G (March 2015). “Clinicopathologic features of folate-deficiency neuropathy”. Neurology. 84 (10): 1026–33. doi:10.1212/WNL.0000000000001343. PMID 25663227.

[pmid25189324-4] Hunt A, Harrington D, Robinson S (September 2014). “Vitamin B12 deficiency”. BMJ. 349: g5226. PMID 25189324.

[pmid25757096-5] Grohmann K, Lauffer H, Lauenstein P, Hoffmann GF, Seidlitz G (April 2015). “Hereditary orotic aciduria with epilepsy and without megaloblastic anemia”. Neuropediatrics. 46 (2): 123–5. doi:10.1055/s-0035-1547341. PMID 25757096.

[pmid25455269-6] Alter BP (2014). “Fanconi anemia and the development of leukemia”. Best Pract Res Clin Haematol. 27 (3–4): 214–21. doi:10.1016/j.beha.2014.10.002. PMC 4254647. PMID 25455269.

[pmid24665981-7] Vlachos A, Blanc L, Lipton JM (June 2014). “Diamond Blackfan anemia: a model for the translational approach to understanding human disease”. Expert Rev Hematol. 7 (3): 359–72. doi:10.1586/17474086.2014.897923. PMID 24665981.

[pmid23953338-8] Marks PW (July 2013). “Hematologic manifestations of liver disease”. Semin. Hematol. 50 (3): 216–21. doi:10.1053/j.seminhematol.2013.06.003. PMID 23953338.

[pmid24588059-9] Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K (May 2014). “Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men”. Alcohol. Clin. Exp. Res. 38 (5): 1237–46. doi:10.1111/acer.12372. PMID 24588059.

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