Anemia

Reporter: FM R1 余明謙

Supervisor: Dr 陳信儒
Anemia definitions
• World Health Organization (WHO):
 Male: Hb <13 g/dL

 Female: Hb <12 g/dL

• 家庭醫師臨床手冊 :

 Male: Hb <13.5 g/dL, HCT<41%

 Female: Hb <12 g/dL, HCT<36%

Normal hematologic parameters in adults
Clinical manifestation
• Fatigue
• Weakness
• Exertional dyspnea

• Exercise intolerance

• Palpitation
• Headache

• Dizziness

• Pica ( in IDA)

• Restless legs syndrome( in IDA)

Physical Examinations
HEENT

Chest - Pale conjunctivae,  face

- Sternum bone pain - Atrophic glossitis
(tenderness) - angular cheilitis
- Dyspnea Heart
- Palpitation
- Heart murmur
Abdomen
Skin and Extremities
- Pallor - hepatosplenomegaly
- Dry or rough skin
- Koilonychia(spoon
nails)
- Alopecia(rare, in
severe case)
- ecchymosis
Diagnostic approach
Diagnostic approach

1. Evaluation based on clinical presentation

2. Evaluation based on CBC/RETIC count

3. Evaluation based on MCV

Diagnostic approach- clinical presentation
• Known underlying medical conditions and
medications that cause anemia

• Family history of a specific type of anemia

• Causes of acquired anemia

 Bleeding (heavy menses, melena, hematemesis,
hematuria, hemoptysis, large ecchymoses)
 Dietary practices (eg, vegan diet lacks vitamin B12)

 Infections

 Travel (eg, acquired parasitic infections)

• Chronicity of the anemia

• Symptoms or conditions that would suggest hemolysis

 Dark urine
 Jaundice

 Anemia with certain food or drug exposures

(fava beans, oxidant drugs)

• Symptoms or findings that suggest kidney or liver disease

or hypersplenism
Diagnostic approach

1. Evaluation based on clinical presentation

2. Evaluation based on CBC/RETIC count

3. Evaluation based on MCV

Diagnostic approach- Laboratory test

initial evaluation of unexplained anemia:

• CBC with RBC indices
• Reticulocyte count : Reflects the ability of the bone marrow
to produce RBCs and can be used to categorize possible
causes of anemia

• Chemistry panel : Should include assessments of kidney and

liver function

• Hemolysis labs – Lactate dehydrogenase (LDH) ,

bilirubin(indirect) , and haptoglobin , if the clinical history
suggests hemolytic anemia and/or the reticulocyte count is
increased
Reticulocyte count

• Absolute reticulocyte count (millions of cells/microL)

= Reticulocytes (%) × RBC count (millions of cells/microL)
• Corrected reticulocyte count (%)
= Reticulocytes (%) × (observed patient HCT [percent] ÷ 45 [percent])
or
= Reticulocytes (%) × (observed patient hemoglobin [g/dL] ÷ 15 [g/dL])

• Reticulocyte production index (no units)

= Corrected reticulocyte count (%) ÷ maturation correction factor*
(days)
maturation factors : Hct: 45% = 1, 35% = 1.5, 25% = 2, 20% = 2.5

• RI >2% → adequate marrow response;

• RI <2% → hypoproliferation
Reticulocyte count
• Decreased – Anemia with a decreased (or inappropriately
low) reticulocyte count may be due to:
 Deficiency of iron, vitamin B12, folate, or copper
 Medications that suppress the bone marrow
 Primary bone marrow disorders including myelodysplastic
syndrome (MDS), myelofibrosis, or leukemia
 Very recent bleeding (within five to seven days, before bone
marrow compensation has occurred)

• Increased – Anemia with an increased reticulocyte count

may be due to:
 Hemolysis
 Repletion of deficient iron, vitamin B12, folate, or
copper (early phase of recovery)
 Recovery from bleeding
Diagnostic approach

1. Evaluation based on clinical presentation

2. Evaluation based on CBC/RETIC count

3. Evaluation based on MCV

Evaluation based on MCV
Microcytic Anemia - Cause
Hereditary disorders
• Defects of globin synthesis
Thalassemia
• Defects of iron metabolism
Sideroblastic anemia
Iron refractory iron deficiency anemia (IRIDA)*
Atransferrinemia*
Acquired disorders
Iron deficiency anemia
Anemia of chronic disease/anemia of inflammation (ACD/AI)
=> Normocytic anemia is more common
lead poisoning
Copper deficiency (some cases)*
Zinc toxicity*
Myelodysplastic syndrome (MDS) with acquired thalassemia*
Microcytic Anemia- Evaluation

• All patients : serum iron, (TIBC)/transferrin, serum ferritin, with calculated

transferrin saturation (TSAT)
 Iron studies will identify iron deficiency (the most likely diagnosis for
microcytic anemia) and ACD/AI in most cases.
• Individuals with normal iron studies :
 Hemoglobin quantitation to identify beta thalassemia or other hemoglobinopathy
 Globin gene studies may be needed to diagnose alpha thalassemia
• Individuals with normal hemoglobin:
 Basophilic stippling suggests possible lead poisoning
 The diagnosis of sideroblastic anemia requires bone marrow examination.
Iron deficiency anemia
• Clinical findings :
 symptoms of anemia, pica, and restless legs syndrome
 The examination may be normal or show pallor, alopecia, dry
skin, atrophic glossitis, angular cheilitis, or koilonychia (spoon
nails) 
• Prevalence : Iron deficiency affects >12 percent of the world's
population, especially women, children, and individuals living in
under-resourced and middle-income countries

• Causes :
 Major causes include blood loss and reduced absorption (celiac
disease, Helicobacter pylori, gastritis, bariatric surgery)
 Less common causes include erythropoiesis-stimulating agents
(ESAs), urinary or pulmonary hemosiderosis, or rare inherited
disorders.
Iron deficiency anemia
• Stages
Iron deficiency anemia
• Diagnosis • Serum ferritin level <30 ng/mL is
confirmatory
• The optimal threshold for TSAT has
not been established. Confidence in
the diagnosis of iron deficiency is
very high if TSAT is <10% (<19% if
concomitant inflammation); some
experts use a threshold of <16%

• Response to iron administration

may be helpful in confirming the
diagnosis.
Iron deficiency anemia
• Causes
Management and predictors of early mortality in elderly patients
with iron deficiency anemia: a prospective study of 111 patients

腸胃道出血 !

腸胃道癌症 !

非腸胃道癌症 !
Iron deficiency anemia
• Evaluation for the cause 
 Dietary history
 Menstrual/pregnancy/lactation history for females
 History of GI blood loss, melena, hematemesis, hematuria
 History of other GI symptoms that might suggest celiac disease,
autoimmune gastritis, or H. pylori infection
 History of multiple blood donations
 Use of NSAIDS or anticoagulants
 Personal or family history of bleeding diathesis, celiac disease, colon
cancer, or other gastrointestinal disorders
 Review of the results of prior gastrointestinal evaluations (eg,
routine colon cancer screening)
 Testing the stool for occult blood in adults 50 years of age or older

• Who needs a GI work-up?

Iron deficiency anemia
• Who needs a GI work-up?
• In asymptomatic postmenopausal women and men with iron
deficiency anemia, the AGA recommends bidirectional
endoscopy over no endoscopy
Strength of recommendation: strong
• In asymptomatic premenopausal women with iron deficiency
anemia, the AGA suggests bidirectional endoscopy over iron
replacement therapy only
Strength of recommendation: conditional

• In patients with iron deficiency anemia without other

identifiable etiology after bidirectional endoscopy, the AGA
suggests noninvasive testing for Helicobacter pylori
Strength of recommendation: conditional

AGA Clinical Practice Guidelines on the

Gastrointestinal Evaluation of Iron Deficiency Anemia
Iron deficiency anemia
• Treatment

*Oral iron should be continued

for 3 months after the iron
deficiency has been corrected
so that stores are replenished!
Oral versus IV iron
• Most patients are treated with oral iron because it is generally
effective, readily available, inexpensive, and safe
• However, up to 70 percent of patients for whom oral iron is
prescribed report gastrointestinal side effects
• Prefer IV iron if
 Lack of response to, intolerance, or inability to adhere to oral iron
 Surgery planned with the next two months
 Late 2nd trimester or 3rd trimister of pregnancy
 Inflammatory bowel disease
 Gastrectomy or bariatric surgery
 Dialysis
Monitor
• There are NO standard recommendations for follow-up

• Once normal, the Hb concentration and red cell indices

should be monitored periodically
 every 3 month for 1year  one additional CBC
obtained 12 months later
 no further follow-up is necessary if the patient is
asymptomatic and hematocrit level remains normal

• 若成年患者經半年的鐵劑治療仍不見 Hb 改善，要高度懷疑
IRIDA(iron-refractory iron-deficiency anemia) ，此時會建議
病人 至血液專科醫師門診追蹤
Thalassemia
Thalassemia
• Prevalence : 體染色體隱性遺傳，台灣 :5% 為 α 海洋性貧血帶因
者， 1.1% 為 β 海洋性貧血帶因者
• Clinical findings :
• from asymptomatic carrier to profound anemia and associated
abnormalities(hemolysis, extramedullary hematopoiesis, and iron
overload)
• Alpha thalassemia findings are present at birth; beta thalassemia
findings develop at 6 to 12 months
• Laboratory
• Diagnosis 

• The diagnosis is best confirmed by genetic testing

• Hemoglobin analysis(electrophoresis):
電泳只能檢查 B 型 (Hb A2 ; Hb F)
• 婚後孕前健檢
Evaluation based on MCV
Causes and mechanisms of macrocytosis
Abnormalities of DNA metabolism (Megaloblastic)
Vitamin B12 (cobalamin) deficiency
Folate deficiency
Drugs : Antiretroviral therapies for HIV infection (eg, zidovudine), Azathioprine or 6-mercaptopurine,
Capecitabine, Cladribine, Cytosine arabinoside, Hydroxyurea,Imatinib, sunitinib, Methotrexate
Shift to immature or stressed red cells
Reticulocytosis (Ex: hemolytic anemia)
Action of erythropoietin - skip macrocytes, stress erythrocytosis
Aplastic anemia/Fanconi anemia
Pure red cell aplasia
Primary bone marrow disorders
Myelodysplastic syndromes
Congenital dyserythropoietic anemias
Some sideroblastic anemias
Large granular lymphocyte (LGL) leukemia
Lipid abnormalities (Membrane changes)
Liver disease
Hypothyroidism
Mechanism unknown
Alcohol abuse
Multiple myeloma and other plasma cell disorders
Copper dificiency
Evaluation of macrocytic anemia
• All individuals 
 Serum vitamin B12 level should be measured in all patients

 All individuals who are nutritionally compromised or who

have had gastric surgery should also have serum folate
measured

• 但是在現在臺灣營養過剩的社會，怎麼會缺乏葉酸和維
他命 B12 呢？其中原因一定要探討，最常見如下：
1. 以前接受過胃切除手術：缺少胃分泌產生的內生性因
子 (intrinsic factor) ，維他命 B12 要和內生性因子結合，
才能被腸道吸收，缺乏內生性因子，維他命 B12 就無法
被腸道吸收
2. 萎縮性胃炎
3. 全素食者
Evaluation of macrocytic anemia
• Individuals with normal vitamin B12 and folate
 Thyroid stimulating hormone (TSH) should be checked

 Alcohol use should be assessed. The MCV typically is not

>105 fL in alcohol-induced macrocytosis
 liver synthetic tests should be measured. The MCV in liver
disease typically is not >105 fL.
 Serum copper level should be checked, especially if
neutropenia and/or neuropathy are present or if the history
reveals zinc ingestion or other risk factors
 If the blood smear shows evidence of dysplasia such as
bilobed or immature neutrophils or binucleate RBCs, or
other cytopenias
=> refer to a hematologist for bone marrow and/or
molecular (DNA) studies
EVALUATION BASED ON MCV
Normocytic Anemia(the most frequently encountered
type)

Reticulocyte count
RBC size/
MCV Low or normal* Increased
•Bleeding (acute)
•Iron deficiency (early)
• Anemia of chronic
disease/inflammation •Bleeding (with bone
•Bone marrow suppression marrow recovery)
Normocytic (cancer, aplastic anemia, •Hemolysis
MCV 80 to 100 fL infection) •Bone marrow recovery
•Chronic renal insufficiency (eg, after infection, vitamin
•Hypothyroidism B12 or folate replacement,
•Hypopituitarism and/or iron replacement)
•Excess alcohol
•Copper deficiency/zinc
poisoning
Etiology
• early microcytic or macrocytic anemia
• mixture of microcytic and macrocytic anemias
• Increased red blood cell loss or destruction
 Acute blood loss  Hemolytic disorders  Hypersplenism
• Decreased red blood cell production
• Primary causes
 Marrow hypoplasia or aplasia  Pure red blood cell aplasia
 Myeloproliferative diseases  Myelopathies

• Secondary causes
 Anemia of chronic disease*  Chronic renal failure  Liver disease
 Endocrine deficiency states  Sideroblastic anemias  Cancer
• Overexpansion of plasma volume
 Pregnancy  Overhydration
Evaluation
• Reticulocyte count and chemistry panel
All individuals with normocytic anemia of unknown cause
• Iron studies and hemolysis labs 
If the reticulocyte count and chemistry panel are unrevealing,
determine serum iron concentration, serum TIBC/transferrin,
serum ferritin and transferrin saturation (TSAT), in order to
diagnose iron deficiency or ACD/AI
If iron stores are normal, evaluate for hemolysis
• Additional tests 
consider conditions listed above including cancer, endocrine
disorders, blood loss, and nutrient deficiencies.
 Normocytic anemia with eGFR <45 and no other identified cause is
most probably the anemia of chronic kidney disease
 Evaluation for disorders common in older adults is generally
reasonable, including monoclonal gammopathies, clonal cytopenias,
androgen deficiency (in men), and bone marrow evaluation
Anemia of chronic disease/anemia of inflammation(ACD/AI)

• Anemia of chronic disease is the most common normocytic

anemia and the second most common form of anemia
worldwide (after iron deficiency anemia)

• The typical patient with ACD/AI has a known underlying

chronic condition with an inflammatory component

• The anemia is typically normochromic, normocytic,

hypoproliferative (associated with a low or inappropriately
low reticulocyte count), and mild to moderate in degree 
Anemia of chronic disease/anemia of inflammation(ACD/AI)

• Mechanism
Anemia of chronic disease/anemia of inflammation(ACD/AI)
• Lab findings
Anemia of chronic disease/anemia of inflammation(ACD/AI)
Causes of ACD/AI 
• Congestive heart failure
• COPD and pulmonary arterial hypertension
• Hematologic malignancies and other cancers
• Infection
 Complicated urinary tract, skin, or skin structure infections
 Endocarditis/ Osteomyelitis/Pneumonia/Septicemia
 Other systemic bacterial, parasitic, viral, and fungal infections
 HIV infection
 Tuberculosis
• Autoimmune and inflammatory diseases
 Castleman disease
 Inflammatory bowel disease
 Rheumatoid arthritis
 Sarcoidosis
 SLE
 Vasculitis
Anemia of chronic disease/anemia of inflammation(ACD/AI)
Making the diagnosis 
• The diagnosis is generally made based on the pattern of
findings consistent with ACD/AI and exclusion of other
types of anemia
• ACD/AI is most likely when all (or most) of the following are present 
 Normochromic, normocytic anemia (HB generally between 10 and
12 g/dL)
 Low reticulocyte count (or inappropriately low for the degree of
anemia)
 Low serum iron (generally <60 mcg/dL)
 Normal to low serum transferrin (generally <300 mcg/dL)
 Low transferrin saturation (TSAT; generally <20 percent)
 Normal to increased serum ferritin (>100 mcg/L)
 Elevated CRP (generally >5 mg/L)
• Tests to exclude other causes of anemia 

 Hemolysis – Haptoglobin, lactate dehydrogenase (LDH),

and/or bilirubin

 Decreased kidney function – Serum creatinine and

estimated glomerular filtration rate (eGFR)
 Liver disease – Serum transaminases

 Vitamin/mineral deficiencies(Copper/Folate/Iron/Vitamin
B12/Vitamin D)

 Endocrine disorders – Hormone levels (eg, thyroid-

stimulating hormone [TSH] or cortisol)

 Malignancy – Age-appropriate cancer screening

Anemia of the elderly
Summary
Reference

• Up-todate

• AAFP

• 家庭醫師臨床手冊