Transcript Iron Deficiency & Clinical Sequelae, Diagnosis

Iron Deficiency: Clinical Sequelae
and Diagnosis
Photis Beris, MD
Professor of Clinical Haematology
Department of Internal Medicine
Geneva University Hospital
Geneva, Switzerland
Iron Deficiency—Definitions
Successive Stages of Iron Deficiency
• Iron-deficient erythropoiesis, or functional
iron deficiency
• Depletion of iron stores
• Iron-deficiency anaemia
Grosbois B, et al. Bull Acad Natl Med. 2005;189:1649.
Iron Deficiency—Prevalence
World’s most common nutritional deficiency
• 2% in adult men (≤ 69 years old)
• 4% in adult men ≥ 70 years old*
• 10% in Caucasian, non-Hispanic women
• 19% in African-American women
*Value for 1994
CDC. MMWR. 2002;51:899.
Main Causes of Anaemia
Others
9%
Haemolysis
17.5%
Iron Deficiency
29%
Acute
Bleeding
17.5%
Chronic Disease
27%
Beris P, Tobler A. Schweiz Rundsch Med Prax. 1997;86:1684.
Reprinted from Lambert JF, et al. In C Beaumont, P Beris, Y Beuzard, C Brugnara, eds. Disorders of iron
homeostasis, erythrocytes, erythropoiesis. Forum service editore, Genoa, Italy, 2006 page 73 figure 1, by
permission of European School of Haemotology.
Iron Deficiency—Aetiology
• Increased demand for iron and/or
haematopoiesis
• Iron loss
• Decreased iron intake or absorption
Adamson JW. In: Kasper DL, ed. Harrison’s Principles Of Internal Medicine. 16th ed. New York:
McGraw-Hill; 2005.
Iron Deficiency—Increased Demand for Iron
and/or Haematopoiesis
• Infancy and adolescence1,2
• Pregnancy and lactation1,2
– Low socioeconomic status and poverty greatly
increase the prevalence of iron deficiency in
this category of populations3
• In patients receiving erythropoietin therapy
(= functional iron deficiency)2
1. Adamson JW. In: Kasper DL, ed. Harrison’s Principles Of Internal Medicine. 16th ed. New York:
McGraw-Hill; 2005.
2. Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed. 2005.
3. CDC. MMWR. 2002;51:899.
Iron Deficiency—Iron loss
• In physiologic conditions
– Menstruation
• In pathologic conditions
– Surgery, delivery
– Haemoglobinuria,haemoptysis
– Gastrointestinal tract pathology
• In therapeutic procedures
– Phlebotomy
• In blood donation
Adamson JW. In: Kasper DL, ed. Harrison’s Principles Of Internal Medicine. 16th ed. New York:
McGraw-Hill; 2005: Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed. 2005.
Iron Deficiency—Decreased Iron Intake
or Absorption
• Vegetarians or malnutrition (low-cost diet)1
• Malabsorption syndromes
– Sprue, UHC, and Crohn’s disease2
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•
•
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After gastric and intestinal surgery3
Intestinal parasitosis (ankylostomiasis)3
Helicobacter pylori infection2
Autoimmune atrophic gastritis2
1. CDC. MMWR. 1998;47(RR-3);1-36.
2. Annabale B, et al. Am J Med. 2001;111:439.
3. Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed. 2005.
Iron Deficiency
Clinical Manifestations (I)
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Fatigue
Decreased exercise tolerance
Tachycardia
Dermatologic manifestations
Decreased intellectual performance
Dysphagia
Depression, increased incidence of infections
Restless legs syndrome
Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed. 2005.
Trost LB, et al. J Am Acad Dermatol. 2006;54:824.
Iron Deficiency
Clinical Manifestations (II)
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Skin and conjuctival pallor
Koilonychia
Angular cheilosis
Burning tongue
Glossitis
Hair loss (alopecia areata)
Top figure accessed from: www.nature.com/bdj/v194/n12/images/4810265f1, with permission from Nature
Publishing Group.
Bottom figure accessed from: www.dentistry.leeds.ac.uk/biochem/lectures/nutrition.org. Modern Nutrition
in Health & Disease. 9th ed. Editors: Shils, Olsen, Shike & Ross. Williams & Williams, pub.
Iron Deficiency
Diagnosis
Laboratory tests for:
• Iron depletion in the body
• Iron-deficient erythropoiesis (functional
iron deficiency)
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis.
Forum service editore: Genoa, Italy; 2006.
Diagnosis of Iron Depletion in
the Body—Haematology
Peripheral
blood smear of
a patient with
severe iron
deficient
anaemia. Note
the important
microcytosis
(compare red
blood cells with
lymphocyte) as
well as
hypochromia,
target cells, and
poikilocytosis.
Graphic courtesy of Dr. P. Beris.
Diagnosis of Iron Depletion in
the Body—Haematology
Hypochromic, microcytic anaemia usually with high platelets
Differential diagnosis of microcytosis
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Iron deficiency
Thalassaemia syndromes
Haemoglobinopathies (E,C,CS, Lepore…)
Anaemia of chronic diseases
Familial sideroblastic anaemia
Miscellaneous (lead intoxication…)
Hoffman, ed. Hematology: Basic Principles and Practice, 4th ed. 2005.
Diagnosis of Iron Depletion in
the Body—Clinical Chemistry
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Serum iron
Transferrin (iron binding capacity)
Transferrin saturation
These parameters are modified by inflammation and by
fasting state. They are thus of limited value.
Serum ferritin, soluble transferrin receptors (sTfR) and
sTfR/log ferritin are excellent tools for screening iron stores
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis.
Forum service editore: Genoa, Italy; 2006.
Serum Levels That Differentiate ACD
from IDA
ACD
IDA
Both
Conditions
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Transferrin
 To normal


Transferrin
saturation
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

Normal to 

 To normal
Normal

Normal to 
sTfR/log ferritin
Low (<1)
High (>2)
High (>2)
Cytokine levels

Normal

Variable
Iron
Ferritin
sTfR
Iron Deficiency—Diagnosis
• Bone marrow examination for stainable
iron was regarded in the past as the gold
standard for diagnosing iron deficiency
• No longer recommended for routine
evaluation
– High inter- and intra-observer variability in
evaluation
– Discomfort associated with procedure
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis.
Forum service editore: Genoa, Italy; 2006.
Iron Deficiency—Diagnosis
Microphotograph
of bone marrow
staining for iron.
Iron is stained
blue and it is
mainly in the
macrophages
(lower left)
Graphic courtesy of Dr. P. Beris.
Iron Deficiency—Diagnosis
• Patients with IDA and a high risk of
underlying disease (eg, men of all ages
and postmenopausal women) should be
evaluated endoscopically for occult
bleeding1
• Video capsule endoscopy (VCE) should
be considered in suspected small-bowel
malignancy2
1. S Killip, et al. Am Fam Physician. 2007;75:671.
2. Urbain D, et al. Endoscopy. 2006;38:408.
Screening for Iron Deficiency
• The US Preventive Services Task Force
recommends screening only for pregnant
women
• There is insufficient evidence to support
routine screening in other asymptomatic
persons
S Killip, et al. Am Fam Physician. 2007;75:671.
Iron-Deficient Erythropoiesis
(Functional Iron Deficiency)—Diagnosis
• Normal or increased ferritin
• Laboratory signs of iron-deficient
erythropoiesis
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Serum iron <60 μg/dL
Transferrin saturation <20%
Hypochromic RBC >5%
Reticulocyte Hb content (CHr) <29 pg
Soluble transferrin receptor > 7 mg/L
Beguin Y, et al. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis.
Forum service editore: Genoa, Italy; 2006.
Main Conditions Characterized by
Functional Iron Deficiency
• EPO-stimulated red cell production
(anaemia of chronic kidney disease)
• Insufficient mobilization of iron from
macrophages (anaemia in rheumatoid
arthritis and in cancer)
Beguin Y, et al. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis.
Forum service editore: Genoa, Italy; 2006.
Refractory Iron Deficiency Anaemia
• In recent years, Helicobacter pylori has
been implicated in several studies as a
cause of iron deficiency anaemia (IDA)
refractory to oral iron treatment, with a
favorable response to H. pylori eradication
• Another nonbleeding gastrointestinal
condition that may result in IDA refractory
to oral iron treatment is coeliac disease
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis.
Forum service editore: Genoa, Italy; 2006.
Refractory Iron Deficiency Anaemia
Autoimmune atrophic gastritis or atrophic
body gastritis has been associated with
chronic idiopathic iron deficiency with no
evidence of gastrointestinal blood loss
and thus is another cause that leads to
refractory IDA
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis.
Forum service editore: Genoa, Italy; 2006.
Recommendations for the Diagnostic
Work-Up of Refractory IDA
Screening for coeliac disease, autoimmune type A
atrophic gastritis and for H. pylori should be performed
in the following populations
• Males and postmenopausal females with IDA and
negative endoscopic and radiologic studies
• Fertile females and children/adolescents refractory
to oral iron treatment
Hershko C. In: Beaumont C, et al, eds. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis.
Forum service editore: Genoa, Italy; 2006.
Algorithm for Investigation of Microcytic Anaemia
RBC count ↓
RBC count normal or↑
CRP ↑
CRP normal
Ferritin < 50
Ferritin 50-150
sTfR/logFerr
≥1.55
Ferritin <20
Ferritin normal
BM examination
Ring sideroblasts?
Ferritin >150
sTfR/logFerr
<1.55
Anaemia of
chronic disease
Aetiology?
Hb analysis
HbA2 ↑ or HbF ↑
Familial sideroblastic anaemia
Iron def anaemia
Ferritin normal
Consider H.
pylori infection
No response to ttt
Consider Hb analysis
Normal pattern
Family studies,
chromosome 16
deletion search
β-thalassaemia
α-thalassaemia
Reprinted from Lambert JF, et al. In C Beaumont, P Beris, Y Beuzard, C Brugnara, eds. Disorders of iron
homeostasis, erythrocytes, erythropoiesis. Forum service editore, Genoa, Italy, 2006 page 73 figure 1, by
permission of European School of Haemotology.
IDA—Conclusions
• Iron deficiency causes not only anaemia but also
extraerythroid symptoms
• Diagnosis of iron deficiency may be difficult in
the presence of a concommitant inflammatory
state
• Patients should be assessed for functional iron
deficiency when erythropoietin is used to correct
anaemia
• IDA refractory to oral iron treatment is a new
entity justifying a particular diagnostic work-up