Summary of Anemia

Preparation

Supervision
TABLE OF

SI. No. Topic Page No.

03

02 Some important definitions 05

Normal Hb values for adults
Classification of anemia severity
Clinical presentation of anemia
Primary symptoms of anemia

03 Microcytic Anemia 07

04 Macrocytic Anemia 11

05 Normocytic Anemia 14

06 References 33
INTRODUCTION Summary of Anemia
AND DEFINITIONS

Anemia is strictly defined as a decrease in red blood cell (RBC) mass to a level below normal
values for the tested population, age, gender, and sea level (altitude). In anemia, a decrease in
the number of RBCs that transport oxygen and carbon dioxide impairs the body’s ability for
gas exchange. The decrease may result from blood loss, increased destruction of RBCs
(hemolysis), or decreased production of RBCs.

Similar to fever, anemia is a sign that requires investigation to determine its underlying cause.
However, physicians often overlook mild anemia and its etiology.

There are different classification systems for anemia, but the most popular one is based on mean
corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), as follows:

Microcytic MCV <80 fL

Normocytic MCV = 81–99 fL

Macrocytic MCV >100 fL

Some important definitions

Anemia:
Reduction in one or more RBC parameters (including hemoglobin (Hb),
hematocrit concentration, or RBC count) below normal range for
gender, age, ethnicity, and sea level

Iron deficiency:
Insufficient total body iron stores caused by increased
requirements, decreased intake, increased loss, and/or reduced
absorption,
with normal Hb level

Iron deficiency anemia (IDA):

Anemia due to insufficient body iron stores
The following laboratory findings are typical for
IDA: Microcytic anemia
Hypochromia
Decreased ferriti

03
Summary of Anemia

Normal Hb values for adults

>130 g/L in men
>120 g/L in women
For pregnant women:
>110 g/L in the first or third trimester
>105 g/L in the second trimester

Classification of anemia severity

Mild: Hb >100 g/L
Moderate: Hb 70–100 g/L
Severe: Hb <70 g/L

Clinical presentation of anemia

It varies, depending on
Acuteness of anemia (duration)
Degree of anemia (severity)
Oxygen demand

Primary symptoms of anemia

• Easy fatigability and muscle cramps
Exertional dyspnea
Dyspnea at rest
Signs and symptoms of hyperdynamic
state, such as bounding pulses and
palpitations More severe anemia may lead
to confusion
• Life-threatening complications, such as congestive heart
failure, angina, arrhythmia, and/or myocardial infarction

04
 IMPORTANT POINTS IN THE Summary of Anemia
HISTORY FOR ANEMIA

Table 1: Important points in the history for anemia

Microcytic anemia Macrocytic anemia Normocytic anemia Hemolytic anemia Anemia of

chronic diseases

Family history of Dietary history Blood loss Jaundice, Weight loss

hemoglobinopathies cholelithiasis, and recurrent
Gastro-intestinal Gastro-intestinal dark urine, fever
Gastro-intestinal disorders disorders and
diseases splenectomy Symptoms
Drug history Chronic suggesting an
Blood loss from illnesses Family history of underlying disease,
any site (epistaxis, Jaundice hemoglobinopathies such as cardiac
menorrhagia, Medication or other anemias disease, renal
melena, hematuria, Neurologic history disease, or
hematemesis, manifestations Medication malignancy
blood donation) Dietary history history
Medication history Chronic
Bleeding disorder (cytotoxics) Malabsorption Dietary history infections
and anticoagulant
therapy Gastric surgery Splenomegaly Inflammatory
states
Intestinal surgery Neurological
Dietary history Chronic
manifestations
conditions
Older age
Pregnancy, Renal insufficiency
menstruation, and Pancreatic
abortions insufficiency Lymphoid
malignancy
Gastric surgery
Malabsorption
Intestinal surgery
Connective
Intestinal parasites
tissue diseases
Sprue
Transfusion
Pica or
Recent travel
pagophagia (i.e.,
compulsive
consumption of
ice)

05
 DIAGNOSTIC Summary Of Anemia
ALGORITHM FOR ANEMIA
Figure 1: Algorithm for diagnosing anemia

Anemia detected on CBC

Evaluate MCV and look for other "flags" on CBC report

for presence of abnormal RBCs and examine peripheral
smear

Minor population of Minor population of

microcytic RBCs present macrocytic RBCs present

MCV low MCV increased

(<80 fL) (>100 fL)

MCV normal
(80–96 fL)

Other causes, like:

Hemolysis
Iron studies Serum B12 and folate levels Liver disease
Any TIBC Methylmalonate (if needed) Hypothyroidism
Normal to high ferritin Homocysteine (if needed) Drugs
MDs
Pregnancy
Alcohol

High TIBC Requires additonal testing, such as:

(optional/2nd tier) Normal or low TIBC Examination of peripheral smear for abnormal RCBs
Normal or high ferritin Presence of hemolysis (↑LDH, ↑Indirect bilirubin,
Low ferritin ↓haptoglobin) Presence of acute blood loss
Bone marrow suppression
(low reticulocyte responce)
Renal insufficiency (elevated creatininine)
Anemia or Anemia of chronic diseases
chronic disease:
Iron deficiency Infecton,
inflammation,
or malignancy

Iron overload present Teardrop red cells Low B12 Low folate
Siderocytes on perpheral smear Target cells Elevated methylmalonate Normal B12 and methylmalonate
Sideroblasts on bone marrow Splenomeglay Elevated homocysteine Elevated homocysteine
Positive family history

Alpha or beta Folate deficiency:

Sideroblasts anemia: thalassemia: perform B12 deficiency:
Determine cause Determine cause Determine cause
hemoglobin
electrophoresis

MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; CBC, complete blood count; RBC, red blood cell;
LDH, lactate dehydrogenase; TIBC, total iron-binding capacity; MDS, myelodysplasia

06
 MICROCYTIC ANEMIA Summary of Anemia

Figure 2: Algorithm for the management of microcytic anemia

STEP 01 STEP 02 STEP 03 STEP 04

MCV including
Iron studies, <80 fL or MCH <27 pg microcytic
Correct anemia anemia Monitor response
Complete blood count (CBC) serum ferritin and Investigate cause if to replacement
transferrin saturation unknown (unless further therapy
(TSAT) investigation is not in the
Treat disease
patient’s
C-reactive protein (CRP) causing the anemia
Serum ferritin <30 µg/L with CRP <30 mg/L Ferritin 30–99 µg/L, CRP low, and TSAT >20
Serum ferritin 30–99 µg/L with CRP >30 mg/L or TSAT Ferritin ≥100 µg/L, CRP normal or increased, and TSAT >20%
<20%

Manage as iron deficiency anemia

Discuss management with an obstetrician

Iron deficiency anemia

Non-iron deficiency microcytic anemia
a) Start oral iron therapy.
Assess for
b) Start with parenteral iron therapy if there is Acute or chronic inflammatory
History of oral iron intolerance or poor disease Chronic infection
compliance Impaired gastro-intestinal absorption Malignancy
Hemodialysis Liver disease
Major surgery that must take place in <3 Copper deficiency
weeks Symptomatic anemia with hemoglobin Zinc poisoning
<70 g/L Thalassemia
c) Review history and examination for source of chronic Lead poisoning
bleeding.
- Refer to gastroenterologist Check CBCD and LFTs. Refer to a hematologist if
if: Adult male Thalassemia or sideroblastic anemia is suspected
Postmenopausal female Cause of anemia is unknown
Premenopausal female with gastro-intestinal
symptoms or bleeding
- Refer to gynecologist if there
is Post-menopausal
bleeding Menorrhagia

Iron deficiency anemia

Anemia of chronic disease
Check CBC after 4–8 weeks of iron therapy.
If Hb has improved (1–2 g/dL increase): A diagnosis of exclusion; unresponsive to parenteral iron
Check whether Hb has normalized after 2–4 months of iron unless iron deficiency is also present
therapy. Continue iron therapy for another 3 months to replenish
iron stores. If no improvement, consider Treat and monitor the underlying cause.
Switch to intravenous iron therapy

MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; CBCD, complete blood count and differentials;
LFT, liver function test

07
DIAGNOSIS AND TREATMENT OF Summary Of
IDA
Anemia

Introduction
Iron deficiency is the most common nutritional disorder in Saudi Arabia and
worldwide. The diagnosis is confirmed in most cases only by full blood examination
and serum ferritin level (for management summary, see algorithm 2).

Table 2: Common causes and risk factors for iron deficiency and IDA in adults

Increased requirements Decreased intake

Pregnancy (2nd/3rd trimester) Low socioeconomic status

Lactation Lack of balanced diet or poor
Rapid growth spurts intake Eating disorder
(infants, children, adolescents) Age >65 years
increased Loss Poor access to iron-rich foods, higher
rates of infectious diseases, and
higher rates of multiparity

Increased loss Decreased absorption

Menstruating females (at least 10% are Upper GI pathology

estimated to have iron deficiency) Chronic gastritis (including
GI bleeding and other chronic Helicobacter pylori gastritis, atrophic
bleeding Colon cancer gastritis) Celiac disease
Gastric/small bowel cancer Crohn’s disease
Hemorrhoids Gastric lymphoma
Peptic ulcer disease Medications that decrease gastric
Inflammatory bowel acidity or bind iron, e.g. antacids/proton
disease Angiodysplasia pump inhibitors
Esophagitis
Gastrectomy or duodenal
Regular blood donation
bypass Bariatric surgery
Post-operative patients
with significant blood loss Chronic renal failure
Hematuria (gross or microscopic)
Intravascular hemolysis
Endurance athletics

08
 Summary of
CLINICAL EVALUATION Anemia
OF IRON DEFICIENCY

Patients with IDA are often asymptomatic, and thorough history and physical examination are
important for identifying the cause of iron deficiency (see Table 1). Further evaluation should be
based on risk factors.

Evaluation of menorrhagia

There is marked variation in menstrual blood loss among women (10–250 mL/menstrual period),
which may result in the overlooking of excessive menstrual losses. Typically, women do not seek
medical attention for menorrhagia unless menstrual flow changes. Patients generally report that
their menses are normal when asked by clinicians.

For better evaluation, ask about the following:

1.Frequency of period
2. Duration of blood loss
3. How many times she changes pads per day
4. Whether the pads get soaked with blood
5. Presence of clots and their sizes

Consider referring to a gynecologist for management of heavy menstruation or bleeding

disorders, for instance, von Willebrand disease.

Diagnosis

Diagnosis of IDA requires laboratory tests to confirm anemia as well as low iron stores.
1.CBC:
a. Low Hb
b. Low MCV and MCH (may be normal in early iron deficiency, or with
coexisting vitamin B12 or folate deficiency)
c. High or normal platelet count

2. Serum iron and total iron-binding capacity (TIBC)

a. Low serum iron and ferritin levels with elevated TIBC levels are typically diagnostic of iron
deficiency.
b. These tests are useful for distinguishing IDA from other microcytic anemias.

. 09
 Anemia
CASE SCENARIOS Clinical Pathway

3. Serum ferritin level

a. ≤30 g/L: IDA
b. 30–99 µg/L: does not exclude iron deficiency (because serum ferritin
will be increased by inflammation, and chronic disease)
i. Increased TIBC, low serum iron, low transferrin saturation, CRP >30 mg/L: IDA
ii. Decreased TIBC, high serum iron, high transferrin saturation, CRP <30 mg/L: not IDA.
Other tests have excluded IDA. (See table 3)
c. ≥100 µg/L: Not IDA (Identify alternative cause(s). Anemia of chronic disease (ACD)
may still be a possibility if transferrin saturation is <20%. Diagnosis of ACD may be
important for directing therapy with intravenous (IV) iron and
erythropoietin-stimulating agents (ESA).

4. To correctly diagnose iron deficiency in the context of multiple comorbidities, such as

inflammation, ferritin threshold of 100 mg/L or even higher values are suggested in
combination with low transferrin saturation (≤20%).

Table 3: Tests to differentiate causes of microcytosis

Tests to differentiate causes of microcytosis

Test Causes of Microcytosis

Lead
poisoning/
Sideroblastic
IDA Thalassemia ACD anemia

Normal to Normal to
Serum ferritin Decreased Increased increased increased

Decreased Normal to Normal to Normal to

Serum iron increased decreased increased

TIBC Increased Normal Decreased Normal

Normal to
Transferrin Decreased Normal to slightly Normal to
saturation increased decreased increased

‫خ‬TIBC, total iron-binding capacity; IDA, iron deficiency anemia; ACD, anemia of chronic disease

10
MACROCYTIC ANEMIA Summary of
Anemia

Figure 3: Algorithm for the management of macrocytic anemia

STEP 01 STEP 02 STEP 03 STEP 04

* MCV
Check >100
folate and fL or MCH >32 pg;
Treatrefer to hematologist
anemia Monitor response
vitamin B12 levels and investigate to replacement
CBC and PBS the underlying
Urea, creatinine, therapy
eGFR LFTs cause
Treat
underlying
Low folate and/or low vitamin B12 level Normal renal function,
FOLATE AND/OR VITAMIN B12 DEFICIENCY folate, and vitamin B12 levels
*** Seek urgent advice from a hematologist if there are
neurological symptoms secondary to folate or vitamin
B12 deficiency or if patient is pregnant

MACROCYTIC ANEMIA
OF UNKNOWN CAUSE
FOLATE DEFICIENCY VITAMIN B12 DEFICIENCY Investigate for possible cause:
a. Start oral folic acid 5 mg daily. a. Hydroxocobalamin • Liver disease
If vitamin B12 deficiency co-exists, intramuscular injections: Alcohol misuse
start vitamin B12 injections at the 1 mg on alternate days for 2 Hypothyroidism
same time to avoid neurological weeks, then 1 mg every 3 months Drugs, e.g. cytotoxics
complications for life
Refer to a
b. Assess for cause: poor b. Investigate for possible cause, e.g. hematologist if
diet, liver disease, alcohol Malabsorption myelodysplasia or
misuse, gastro-intestinal Gastrectomy myeloma is suspected
surgery, recent pregnancy, Terminal ileum or if the cause is still unknown.
chronic inflammatory disease disease or resection
(e.g., Crohn’s disease or
tuberculosis), malignancy, and
drug therapy (e.g., anticonvulsants)

NON-VITAMIN B12/FOLATE
DEFICIENCY MACROCYTIC
FOLATE DEFICIENCY VITAMIN B12 DEFICIENCY ANEMIA
Monitor Hb and reticulocyte count
Monitor Hb and reticulocyte count Monitor Hb
After 10 days: for response Treat and monitor
After 10 days: for response
After 8 weeks: check if Hb cause if identified
After 8 weeks: check if Hb
has returned to normal range
has returned to normal range
After 4 months: treatment
course completed

MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; CBC, complete blood count; LFT, liver function test;
Hb, hemoglobin; eGFR, estimated glomerular filtration rate; PBS, peripheral blood smear.

11
GUIDELINES AND Summary Of Anemia
TREATMENT

GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF COBALAMIN (VIT

Introduction
Vitamin B12 and folate levels should always be assessed together due to their close metabolic
relationship. Low intake or poor absorption of folate leads to low serum folate level, whereas
vitamin B12 deficiency can be due to poor intake of animal products (e.g., vegan diet),
low absorption due to various reasons (including low gastric acidity, anti-parietal cell or
anti-intrinsic factor antibody (anti-IFAB), pancreatic insufficiency, and diseases of the
terminal ilium), and exposure to nitrous oxide (for management summary, see algorithm
3).

Folate
Sources: green vegetables, nuts, and
liver Can be synthesized by gut bacteria
Store are depleted after 3 months of restriction
Absorbed in the duodenum and proximal
jejunum

Vitamin B12
Sources: meat and dairy products, but not plants
Stores are depleted after 3 years of restriction
Absorbed in the terminal ilium after binding to
intrinsic factor from the stomach to form a complex

Normal Values for Adults

Serum B12: 180–914 ng/L
Serum folate: 2–20 µg/L
RBC folate: 31.7–115.5
nmol/L

Differential Diagnoses of Macrocytosis (MCV >100 fL)

Alcohol and/or liver disease (especially if macrocytosis is accompanied
by thrombocytopenia and anemia is mild or absent)
Vitamin B12/folate deficiency
Hypothyroidism

12
GUIDELINES AND Summary Of Anemia
TREATMENT

Hemolytic anemia
Myelodysplasia

12
GUIDELINES AND Summary Of Anemia
TREATMENT

Drugs, especially anti-metabolites that interfere with DNA synthesis and cell
division; for example, hydroxycarbamide, azathioprine, methotrexate, trimethoprim,
and zidovudine and other nucleoside reverse transcriptase inhibitor treatments for
human immunodeficiency virus infection
Aplastic anemia or other causes of bone marrow stress

Indications for evaluating vitamin B12 and folate Levels

1.Hematological
Either isolated macrocytosis or macrocytic anemia
Megaloblastic anemia
Pancytopenia (especially if MCV >120 fL)
Unexplained anemia

2. Neurological or psychiatric
Peripheral neuropathy
Cognitive changes, e.g. dementia
Optic neuritis

3. Gastro-intestinal
Possible malabsorptive processes
Angular cheilosis or sore, beefy red
tongue Post-gastric and bariatric surgery

Diagnostic workup

1.Clinical evaluation for cobalamin and folate deficiency

Thorough history and physical examination to help identify the cause

2. Full blood picture

Low Hb
MCV >100 fL or MCH >32 pg (may be normal initially, or with coexisting iron deficiency)
3. Serum

13
GUIDELINES AND Summary Of Anemia
TREATMENT

cobalamin assay n
Currently, it is g
the standard /
initial routine m
diagnostic test. L
It is done with a )
widely
available, low- i
cost, automated s
method.
The World i
Health n
Organization d
(WHO) i
recommende c
d levels <150 a
pmol/L (203 t
pg/mL) for i
the diagnosis v
of B12 e
deficiency.
o
4. Serum folate
f
Serum
folate
f
concentr
o
ation
l
reflects
a
recent
t
folate
e
status
and
d
intake.
e
Serum
f
folate
i
level <10
c
nmol/L
i
(4
e

13
GUIDELINES AND Summary Of Anemia
TREATMENT

ncy.
1.Anti-intrinsic factor
5. Red cell folate antibodies (anti-IFABs)
Red cell folate If positive, the test has
level helps a high positive
predictive value.
assess the
(95%; i.e., high
tissue folate
specificity) for
status during pernicious anemia.
the lifetime of Negative IFAB assay
red cells and is does not, however,
therefore rule out pernicious
anemia (hereafter
regarded as an
referred to as Ab-Neg
indicator of PA).
longer-term
folate status 2. Gastric anti-parietal
when cell antibodies
compared with This assay has low
specificity for
serum folate
pernicious anemia,
assay. despite being positive
The in 80% of cases.
WHO
recomm 3. Thyroid function tests
ended and anti-thyroid
antibodies
red cell
folate 4. Test for celiac disease
<340 Tissue
nmol/L transglutaminase-IgA
(151 assay (tTG-IgA)
ng/mL)
5. Tests for generalized
for the malabsorption (if
diagnosi symptoms are
s of suggestive)
folate These include serum
deficien calcium, vitamin D,
folate, and ferritin
cy. levels. We recommend
that
Investigation of the fecal tests, such as
fecal fats and elastase,
cause of cobalamin deficiency
13
GUIDELINES AND Summary Of Anemia
TREATMENT

should only be requested by a

gastroenterologist.RMOCYTIC
ANEMIA

Figure 4: Algorithm for the management of normocytic anemia

STEP 01 STEP 02 STEP 03 STEP 04

MCV 80–100 fL, MCH 27–32 pg normocytic anemia
Iron studies, including ferritin and Treat anemia Monitor response
TSAT Check folate and vitamin B12 and investigate to replacement
Check CBC and other
tests for evidence of levels Urea, creatinine, eGFR the underlying therapy
hemolysis Reticulocyte count, cause
LDH, haptoglobin, and Treat underlying
Normal renal
causing function,
of anemia (if
Low folate and/or low vitamin B12 level
folate, and vitamin B12 levels
FOLATE AND/OR VITAMIN B12 DEFICIENCY
*** Seek urgent advice from a hematologist if there are
neurological symptoms secondary to folate or vitamin
B12 deficiency or if patient is pregnant

Macrocytic anemia of
unknown cause
Folate deficiency Vitamin B12 deficiency Investigate for possible cause:
a. Start oral folic acid 5 mg daily. a. Hydroxocobalamin • Liver disease
If vitamin B12 deficiency co-exists, intramuscular injections: Alcohol misuse
start vitamin B12 injections at the 1 mg on alternate days for 2 Hypothyroidism
same time to avoid neurological weeks, then 1 mg every 3 months Drugs, e.g. cytotoxics
complications for life
Refer to a
b. Assess for cause: poor b. Investigate for possible cause, e.g. hematologist if
diet, liver disease, alcohol Malabsorption myelodysplasia or
misuse, gastro-intestinal Gastrectomy myeloma is suspected
surgery, recent pregnancy, Terminal ileum or if the cause is still unknown
chronic inflammatory disease disease or resection
(e.g., Crohn’s disease or
tuberculosis), malignancy, and
drug therapy (e.g., anticonvulsants)

Non-vitamin B12/folate
deficiency macrocytic
Folate deficiency Vitamin B12 deficiency anemia
Monitor Hb and reticulocyte count Monitor Hb and reticulocyte count Monitor Hb.
After 10 days: for response Treat and monitor
After 10 days: for response
After 8 weeks: check if Hb cause if identified
After 8 weeks: check if Hb
has returned to normal range has returned to normal range
After 4 months: treatment
course completed

MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; CBCD, complete blood count and differentials;
LFT, liver function test; TSAT, transferrin saturation; Hb, hemoglobin; eGFR, estimated glomerular filtration rate;
LDH; lactate dehydrogenase; IDA, iron deficiency anemia; ESA, erythropoietin-stimulating agents

13
 Summary Of Anemia
MANAGEMENT

Management of normocytic normochromic anemia

The possible etiologies of normocytic normochromic anemia are classified into three:
1. Blood loss
2. Hemolysis
3. Decreased production of RBCs

In most anemias, one of these causes is the dominant factor, although, more than a
single cause may play determining roles in certain anemias. For example, pernicious
anemia
may be attributed to the decreased production of erythrocytes, but hemolysis also contributes
significantly to its severity.

Investigations

Complete blood count and differentials

Peripheral blood smear
Renal function test
Liver function test (LFT)
LDH
Reticulocyte count
Serum ferritin
Serum vitamin B12 and folate levels
ESR and CRP

Patients should also have thorough

Evaluation for blood loss (see microcytic anemia)
Evaluation for hemolysis
Evaluation for decreased RBC production

Treatment of normocytic normochromic anemia

Treatment is individualized and depends on the etiology.

For combined deficiency (IDA, folate, and/or B12), treat IDA and macrocytic anemia as above.
For hemolytic anemia, refer to a hematologist.
For anemia of chronic kidney disease, refer to a
nephrologist. If decrease production is suspected, refer to a

16
 Summary Of Anemia
MANAGEMENT

hematologist.

16
 Summary Of Anemia
REFERENCES

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Blood 2017; 129:940–49.

02 Actt.albertadoctors.org. 2018. Iron deficiency anemia: Clinical practice guideline. [online] Available at:
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04 Camaschella C. Iron deficiency. Blood 2019; 133:30–9.

05 Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood 2008; 112:2214–21.

06 Devalia V, Hamilton MS, Mollo AM. British Committee for Standards in Haematology. Guidelines for the diagnosis and
treatment of cobalamin and folate disorders. British Journal of Haematology 2014; 166:496–513.

07 Docplayer.net. 2020. [online] Available at: <http://docplayer.net/> [Accessed 9 December 2020].

08 Emedicine.medscape.com. 2020. [online] Available at: <https://emedicine.medscape.com/> [Accessed 9 December 2020].

09 Fletcher A, Holding S. Guidelines for the investigation and management of Vitamin B12 and folate
deficiency, Approved by HERPC: January 2015.

10 Gov.bc.ca. 2013. Cobalamin (vitamin B12) deficiency - investigation & management. [online] Available at:
<https://www2.gov.bc.ca/assets/gov/health/practitioner-pro/bc-guidelines/cobalamin.pdf> [Accessed 9 December 2020].

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