Folate deficiency differential diagnosis: Difference between revisions

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==Differential Diagnosis==
==Differential Diagnosis==
* Folate deficiency must be differentiated from other diseases associated with the Macrocytic anemia such as [[Vitamin B12 deficiency]], [[Alcoholic liver disease]], [[Hypothyroidism]], [[Myelodysplastic syndrome|Myelodysplasia]] and  [[Aplastic anemia]]
* Folate deficiency must be differentiated from other diseases associated with the Macrocytic anemia such as [[Vitamin B12 deficiency]], [[Alcoholic liver disease]], [[Hypothyroidism]], [[Myelodysplastic syndrome|Myelodysplasia]] and  [[Aplastic anemia]]<ref name="pmid10386505">{{cite journal| author=Snow CF| title=Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. | journal=Arch Intern Med | year= 1999 | volume= 159 | issue= 12 | pages= 1289-98 | pmid=10386505 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10386505  }}</ref><ref name="NagaoHirokawa2017">{{cite journal|last1=Nagao|first1=Takayo|last2=Hirokawa|first2=Makoto|title=Diagnosis and treatment of macrocytic anemias in adults|journal=Journal of General and Family Medicine|volume=18|issue=5|year=2017|pages=200–204|issn=21897948|doi=10.1002/jgf2.31}}</ref>
* Folate and Vitamin B12 deficiencies are the two most important causes of '''Megaloblastic macrocytic anemia''' associated with impaired DNA synthesis and megaloblastic changes like hypersegmented neutrophils and glossitis. History and physical examination, vitamin B<sub>12</sub> level, reticulocyte count, and a peripheral smear are helpful in delineating the underlying cause of megaloblastosis. A measurement of methylmalonic acid in the blood or urine, can provide an indirect method for partially differentiating Vitamin B<sub><small>12</small></sub> and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency while it is raised in Vitamin B12 (cobalamin) deficiency. Direct measurement of blood cobalamin and folate is the gold standard to differentiate between the two causes.
* Vitamin B12 deficiency must be ruled out, and treated if present, before giving folic acid to a patient with megaloblastic anemia, since administration of folic acid may worsen neurologic complications of untreated vitamin B12 deficiency.


=== Differentiating Folate deficiency from other Diseases: ===
=== Differentiating Folate deficiency from other Diseases: ===
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|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.
|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.
|
|
* Stool exam reveals characteristic eggs of the fish tapeworm
* Identification of the operculated eggs in the stool
* Serum vitamin B12 levels are low.
* Polymerase chain reaction (PCR)
* Serum folate is normal.
* Megaloblastic anemia with low vitamin B12 level
|}
 
==Differentiating Macrocytic Anemia from Other Diseases==
 
'''''To review the differential diagnosis of anemia, click [[Anemia#Differentiating Anemia from Other Diseases|here]].''''' 
 
{|
! rowspan="3" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Disease
! rowspan="3" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Genetics
! colspan="5" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Clinical manifestation
! colspan="12" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Lab findings
|-
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |History
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Symptoms
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Signs
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hemolysis
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Intrinsic/Extrinsic
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hb concentration
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |MCV
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |RDW
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Reticulocytosis
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Haptoglobin levels
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hepcidin
! colspan="5" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Iron studies
! rowspan="2" style="background: #4479BA; color: #FFFFFF; text-align: center;" |Specific finding on blood smear
|-
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Serum iron
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Serum Tfr level
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Transferrin or TIBC
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Ferritin
! style="background: #4479BA; color: #FFFFFF; text-align: center;" | Transferrin saturation
|-
! align="center" style="background:#DCDCDC;" |[[Folate deficiency]]<ref name="pmid25663227">{{cite journal |vauthors=Koike H, Takahashi M, Ohyama K, Hashimoto R, Kawagashira Y, Iijima M, Katsuno M, Doi H, Tanaka F, Sobue G |title=Clinicopathologic features of folate-deficiency neuropathy |journal=Neurology |volume=84 |issue=10 |pages=1026–33 |date=March 2015 |pmid=25663227 |doi=10.1212/WNL.0000000000001343 |url=}}</ref>
| align="left" style="background:#F5F5F5;" |
* Impaired [[DNA]] synthesis
| align="left" style="background:#F5F5F5;" |
* [[Long-term effects of alcohol|Alcohol consumption]]
* History of using drugs like [[methotrexate]], [[trimethoprim]], and [[phenytoin]]
* Low socioeconomic groups with poor nutrition
* Older people
* [[Pregnancy|Pregnant]] and [[lactating]] women
| align="left" style="background:#F5F5F5;" |
* No neurological symptoms vs [[Vitamin B12 deficiency|B12 deficiency]]
* [[Odinophagia|Odynophagia]]
* [[Stomatitis|Angular stomatitis]]
| align="left" style="background:#F5F5F5;" |
* [[Glossitis]]
* Signs of [[Congestive heart failure|heart failure]]
* [[Anencephaly]] and [[spina bifida]]
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Anisochromic
| align="center" style="background:#F5F5F5;" |[[Macrocytic anemia|Macrocytic]]
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="left" style="background:#F5F5F5;" |
* [[Macrocytosis|RBC macrocytosis]]
* [[Neutrophil|Hypersegmented neutrophils]]
* [[Pancytopenia]] in severe cases
*
|-
! align="center" style="background:#DCDCDC;" |[[Vitamin B12 deficiency]]<ref name="pmid25189324">{{cite journal |vauthors=Hunt A, Harrington D, Robinson S |title=Vitamin B12 deficiency |journal=BMJ |volume=349 |issue= |pages=g5226 |date=September 2014 |pmid=25189324 |doi= |url=}}</ref>
| align="left" style="background:#F5F5F5;" |
* Impaired [[DNA synthesis]]
| align="left" style="background:#F5F5F5;" |
* [[Pernicious anemia]]
* [[Crohn's disease]]
* [[Gastrectomy]]
* [[Vegan|Veganism]]
* [[Diphyllobothrium|Diphyllobothrium latum]] infection
| align="left" style="background:#F5F5F5;" |
* [[Psychosis]]
* [[Insomnia]]
* [[Depression]]
* Cognitive slowing
* [[Restless leg syndrome]]
| align="left" style="background:#F5F5F5;" |
* Neurological deficit
* [[Myelopathy]]
* [[Memory loss]] with reduced attention span
* [[Nystagmus]]
* Positive [[Romberg test|romberg sign]]
* Positive [[Lhermitte's sign]]
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Anisochromic
| align="center" style="background:#F5F5F5;" |[[Macrocytic anemia|Macrocytic]]
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="left" style="background:#F5F5F5;" |
* [[Senile]] [[neutrophil]]
* [[Anisocytosis]]
* [[Ovalocytosis|Ovalocytes]]
|-
! align="center" style="background:#DCDCDC;" |[[Orotic aciduria]]<ref name="pmid25757096">{{cite journal |vauthors=Grohmann K, Lauffer H, Lauenstein P, Hoffmann GF, Seidlitz G |title=Hereditary orotic aciduria with epilepsy and without megaloblastic anemia |journal=Neuropediatrics |volume=46 |issue=2 |pages=123–5 |date=April 2015 |pmid=25757096 |doi=10.1055/s-0035-1547341 |url=}}</ref>
| align="left" style="background:#F5F5F5;" |
* [[Autosomal recessive]]
* Deficiency of enzyme [[Uridine monophosphate synthetase|UMPS]]
| align="left" style="background:#F5F5F5;" |
* Episodic [[Nausea and vomiting|vomiting]]
* [[Rhabdomyolysis]]
| align="left" style="background:#F5F5F5;" |
* [[Coma]]
* [[Gastrointestinal tract|Gastrointestinal]] manifestation
| align="left" style="background:#F5F5F5;" |
* Neurological manifestation
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Anisochromic
| align="center" style="background:#F5F5F5;" |[[Macrocytic anemia|Macrocytic]]
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |NA
|-
! align="center" style="background:#DCDCDC;" |[[Fanconi anemia]]<ref name="pmid25455269">{{cite journal |vauthors=Alter BP |title=Fanconi anemia and the development of leukemia |journal=Best Pract Res Clin Haematol |volume=27 |issue=3-4 |pages=214–21 |date=2014 |pmid=25455269 |pmc=4254647 |doi=10.1016/j.beha.2014.10.002 |url=}}</ref>
| align="left" style="background:#F5F5F5;" |
* [[Autosomal recessive]]
* [[X-linked recessive]]
| align="left" style="background:#F5F5F5;" |
* History of [[anemia]] at age 16
| align="left" style="background:#F5F5F5;" |
* [[Hypopigmentation]]
* [[Café au lait spot|Cafe-au-lait patches]]
* Radial ray anomaly
| align="left" style="background:#F5F5F5;" |
* Significant for bilateral short thumbs
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Anisochromic
| align="center" style="background:#F5F5F5;" |[[Macrocytic anemia|Macrocytic]]
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="left" style="background:#F5F5F5;" |
* Nl appearing [[White blood cells|WBC]], [[Red blood cell|RBC]] and [[Platelet|Platelets]]
* But the number is greatly reduced
|-
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Disease
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Genetics
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |History
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Symptoms
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Signs
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hemolysis
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Intrinsic/Extrinsic
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hb concentration
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |MCV
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |RDW
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Reticulocytosis
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Haptoglobin levels
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hepcidin
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Serum iron
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Serum Tfr level
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |IBC
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Ferritin
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Transferrin saturation
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Specific finding on blood smear
|-
! align="center" style="background:#DCDCDC;" |[[Diamond-Blackfan anemia]]<ref name="pmid24665981">{{cite journal |vauthors=Vlachos A, Blanc L, Lipton JM |title=Diamond Blackfan anemia: a model for the translational approach to understanding human disease |journal=Expert Rev Hematol |volume=7 |issue=3 |pages=359–72 |date=June 2014 |pmid=24665981 |doi=10.1586/17474086.2014.897923 |url=}}</ref>
| align="left" style="background:#F5F5F5;" |Mutations in:
* ''RPL5''
* ''RPL11''
* ''RPL35A''
* ''RPS7''
* ''RPS10''
* ''RPS17''
* ''RPS19''
* ''RPS24''
* ''RPS26''
| align="left" style="background:#F5F5F5;" |
* Associated with [[myelodysplastic syndrome]]
* Increased risk of [[AML]]
| align="left" style="background:#F5F5F5;" |
* [[Pale skin]]
* Sleepiness
* [[Murmur|Heart murmurs]]
| align="left" style="background:#F5F5F5;" |
* Triphalangeal  thumbs
* [[Short stature]]
* [[Microcephaly]]
* [[Hypertelorism]]
* [[Ptosis]]
* [[Micrognathia]]
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Anisochromic
| align="center" style="background:#F5F5F5;" |[[Macrocytic anemia|Macrocytic]]
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |NA
|-
! align="center" style="background:#DCDCDC;" |[[Hepato-biliary diseases|Liver disease]]<ref name="pmid23953338">{{cite journal |vauthors=Marks PW |title=Hematologic manifestations of liver disease |journal=Semin. Hematol. |volume=50 |issue=3 |pages=216–21 |date=July 2013 |pmid=23953338 |doi=10.1053/j.seminhematol.2013.06.003 |url=}}</ref>
| align="center" style="background:#F5F5F5;" |−
| align="left" style="background:#F5F5F5;" |
* [[Hepatitis]]
* Binge drinking
* Gall bladder disease
| align="left" style="background:#F5F5F5;" |
* [[Jaundice]]
* [[Abdominal pain]]
* [[Itchy skin]]
| align="left" style="background:#F5F5F5;" |
* [[Ascites]]
* Right upper quadrant pain
* [[Hepatomegaly]]
* [[Edema|Swelling]] in the legs
* [[Ankle swelling]]
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Anisochromic
| align="center" style="background:#F5F5F5;" |[[Macrocytic anemia|Macrocytic]]
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="left" style="background:#F5F5F5;" |
* [[Macrocyte|Round macrocytes]]
* [[Macrocyte|Target macrocytes]]
|-
! align="center" style="background:#DCDCDC;" |[[Alcoholism]]<ref name="pmid24588059">{{cite journal |vauthors=Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K |title=Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men |journal=Alcohol. Clin. Exp. Res. |volume=38 |issue=5 |pages=1237–46 |date=May 2014 |pmid=24588059 |doi=10.1111/acer.12372 |url=}}</ref>
| align="center" style="background:#F5F5F5;" |−
| align="left" style="background:#F5F5F5;" |
* History of increased [[Effects of alcohol on the body|alcohol intake]]
* [[Folic acid deficiency]]
| align="left" style="background:#F5F5F5;" |
* [[Memory impairment]]
* [[Nausea]]
* [[Sweating]]
| align="left" style="background:#F5F5F5;" |
* Truncal [[obesity]]
* [[Asterixis]]
* [[Encephalopathy]]
* [[Spider angiomas]]
* [[Hematemesis]]
* [[Gynecomastia]]
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |−
| align="center" style="background:#F5F5F5;" |Anisochromic
| align="center" style="background:#F5F5F5;" |[[Macrocytic anemia|Macrocytic]]
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |Nl
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↓
| align="center" style="background:#F5F5F5;" |↑
| align="center" style="background:#F5F5F5;" |↑
| align="left" style="background:#F5F5F5;" |
* [[Macrocyte|Oval macrocytes]]
* [[Neutrophil|Hypersegmented neutrophils]]
|-
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Disease
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Genetics
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |History
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Symptoms
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Signs
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hemolysis
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Intrinsic/Extrinsic
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hb concentration
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |MCV
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |RDW
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Reticulocytosis
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Haptoglobin levels
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Hepcidin
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Serum iron
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Serum Tfr level
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |IBC
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Ferritin
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Transferrin saturation
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Specific finding on blood smear
|}
|}


.Macrocytosis is defined as a MCV (mean corpuscular volume) greater than 100 fL. It can be divided into megaloblastic and non-megaloblastic types. Following are the causes of '''Non-megaloblastic anemia''' i.e. MCV >100 fL without DNA replication problems and megaloblastic changes.
*[[Alcoholism]] : This is a result of dietary lack, a weak antifolate action and a direct toxic effect of alcohol on the bone marrow.
*[[Hypothyroidism]] : Macrocytosis is found in up to 55% patients with hypothyroidism and may result from the insufficiency of the [[thyroid]] hormones themselves and also due to 20 times increased risk of [[pernicious anemia]] in people with hypothyroidism
*[[Aplastic anemia]] : Mild [[macrocytosis]] can be observed in association with stress erythropoiesis and elevated [[fetal hemoglobin]] levels in aplastic anemia.
*[[Reticulocytosis]] : Commonly due to hemolysis or a recent history of blood loss. This is due to increased hematopoeisis and rapid release of immature RBCs from the bone marrow to replace the blood loss.
*[[Liver diseases|Liver disease]]  : Liver enzymes play an important role in the process of normal erythropoiesis and liver dysfunction can lead to defective erythropoiesis.
*[[Myeloproliferative neoplasm|Myeloproliferative diseas]] and [[Myelodysplastic syndrome|Myelodysplastic syndromes]] : due to bone marrow dysfunction
*Chronic exposure to benzene and drugs like [[Fluorouracil|5- Fluorouracil.]]
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 07:06, 7 May 2020

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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

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
Serum iron Serum Tfr level Transferrin or TIBC Ferritin Transferrin saturation
Folate deficiency[3]
  • Impaired DNA synthesis
Anisochromic Macrocytic Nl Nl
Vitamin B12 deficiency[4] Anisochromic Macrocytic Nl Nl
Orotic aciduria[5]
  • Neurological manifestation
Anisochromic Macrocytic Nl Nl NA
Fanconi anemia[6]
  • Significant for bilateral short thumbs
Anisochromic Macrocytic Nl Nl
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
Anisochromic Macrocytic Nl Nl Nl NA
Liver disease[8]
  • Hepatitis
  • Binge drinking
  • Gall bladder disease
Anisochromic Macrocytic Nl Nl
Alcoholism[9] Anisochromic Macrocytic Nl Nl
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

  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.
  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.
  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.
  4. Hunt A, Harrington D, Robinson S (September 2014). "Vitamin B12 deficiency". BMJ. 349: g5226. PMID 25189324.
  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.
  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.
  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.
  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.
  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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