Transcript IRON DEFICIENCY

ANEMIA IN PEDIATRICS
• Anaemia is defined as a low Hb concentration in blood, or less
often, as a low haematocrit, the percentage of blood volume
that consists of red blood cells.
• The Hb and Ht range for assessing iron deficiency are:
Hb (g/dL)
Ht (%)
• Children 6 months - 5 years
11
33
• Children 5 - 11 years
11,5
34
• Children 12 - 13 years
12,0
36
• Normal levels of RBCs at birth range from 5.1 to
5.3 million/mm3 for term newborns and 4.6 to
5.3 million/mm3 for premature neonates.
• Because of active in utero erythropoiesis, the
reticulocyte count at birth is 3 to 7% in full-term
babies and 8 to 10% in premature babies. This
declines to 0 to 1% by the first week of age,
reflecting diminished erythropoiesis.
• The life span of adult erythrocytes is 120 days.
RBCs in term neonate will survive between 60
and 90 days. Erythrocytes from premature
neonates have considerably shorter life spans,
ranging from 35 to 50 days
• Mean Cell Volume. Early embryonic RBCs are
large; diameters range from 20 to 25 µm with a
mean cell volume (MCV) of 180 femtoliters (fl) or
µm3. Cell size decreases gradually during
development reaching 130 fl at midgestation and
115 fl at term. MCV at 1 year of age is 82 fl.
• The mean corpuscular hemoglobin concentration
(MCHC) is fairly constant from birth through
adulthood.It averages 34 pg in full-term cord
blood, 35 pg on the first day of life, and 33
picograms (pg) at 1 week of age. Premature
neonates, however, have higher MCHCs; values
range from 40 pg at 28 weeks to 38 pg at 34
weeks
RBC and Hemoglobin Physiology
• RBCs, erythrocytes, play role in the support of tissue
metabolism. They contain hemoglobin, which
transports oxygen to and removes carbon dioxide from
tissues.
• RBC production involves a series of maturational steps,
beginning with a pluripotent cell that differentiates into
erythroid As the cells undergo maturational changes,
they lose their nuclei and acquire hemoglobin.
• Once RBCs have achieved their normal life span, usually
about 120 days, they become sequestered and
destroyed in the spleen. Liberated iron is then recycled
for use by the marrow in further RBC production
• . Hemoglobin is a molecule composed of two globulin
chains and four heme groups. It has been described as
the respiratory protein of the RBC, related to its
important role in the transport of oxygen and carbon
dioxide.
• Hemoglobin is able to bind reversibly with oxygen,
which allows it to be released to the tissues when
needed. Carbon dioxide is then picked up by unbound
hemoglobin for transport to the lungs and excretion.
The fetus is able to produce a unique type of
hemoglobin, fetal hemoglobin (HgF), which more
efficiently binds and releases oxygen within the
relatively hypoxic intrauterine environment.
• Anemia refers to RBC mass, amount of
hemoglobin, and/or volume of packed RBCs less
than normal.
• Clinically, this is determined either as a
hematocrit (% of RBCs per spun whole blood
sample) or hemoglobin (directly measured
concentration) greater than 2 standard deviations
below the normal mean for age.
• For children between 6 months and 2 years of
age, this represents a hemoglobin <11 grams/dl
or hematocrit < 33%.
• Hemoglobin is considered a more sensitive
indicator of anemia than hematocrit, as it is not
affected by variations in RBC size within the
specimen; however, both are commonly utilized
in clinical practice.
• WHO data show that 40% of the world's
population suffer from anaemia. The World
Health Organization calls iron deficiency the most
common anemia (Centers for Disease Control) as
it is estimated to affect approximately 2 billion
people worldwide.
• The groups with the highest prevalence in
pediatric age are: infants and children of 0-2
years, 48%; school children, 40%; adolescents,
30-55%; and preschool children, 25%.
• Anaemia occurs at a late stage of iron deficiency,
after stores are depleted. The prevalence of iron
deficiency, which is usually detected by low
serum ferritin concentrations, is estimated to be
from 2.0 to 2.5 times the prevalence of anaemia.
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Sources of iron
The sources of iron are:
Birth - 6 months
Breast milk alone
Iron-fortified formula from birth 6 months to 1 year
Infant formulas based on cow's milk contain 1.0 to 1.5 mg
of iron per litre; soy-based formula and iron-fortified
formula based on cow's milk contain 12 to 13 mg of iron
per litre. The availability of iron from soy-based formulas
appears to be lower than that from milk-based products.
Iron-fortified formula ( supplementing with formula or if no
breastfeeding) The iron source of fortified formulas is
ferrous sulfate, which is significantly more available than
the iron used in infant cereals.
Iron-fortified infant cereals
Iron-enriched breakfast cereals and breads
Meats (poultry ) , yolk egg
Fish
• One litre of human milk contains only 0.3 to 0.5 mg of
iron. About 50% of the iron is absorbed, in contrast to a
much smaller proportion from other foods.
• Term infants who are breast-fed exclusively for the first
6 months may not be at risk for iron depletion or for
the development of iron deficiency. However, if solid
foods are given they may compromise the
bioavailability of iron from human milk.
• Although some term infants who are exclusively breastfed may remain iron-sufficient until 9 months of age, a
source of dietary iron is recommended starting at 6
months (or earlier if solid foods are introduced into the
diet) to reduce the risk of iron deficiency.
Etiology
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Low iron diet
Inadequate absorption of dietary iron
Growth spurt
Blood loss
• At high risk for iron deficiency are preterm infants
and infants from a low socioeconomic
background, low birth weight, perinatal bleeding,
a low hemoglobin concentration at birth, chronic
hypoxia,
• frequent infections, early intake of cow's milk or
solid food, or both, excessive tea intake, low
vitamin C or meat intake, breast-feeding for more
than 6 months without supplemental iron, intake
of infant formula not fortified with iron for more
than 4 months without other foods.
•Premature infants have a lower level of body iron at
birth, approximately 64 mg in infants weighting 1 kg
•The rapid rate of postnatal growth lead to a higher
requirement for dietary iron than in term infants of 2.0
to 2.5 mg/kg daily to prevent late anemia.
•10% of the iron in a mixed diet is absorbed
•the recommended iron intake is approximately 7 mg/d
for term infants aged 5 to 12 months, 6 mg/d for toddlers
aged 1 to 3 years and 8 mg/d for children aged 4 to 12
years.
• There are some factors that interfere absorbtion of iron:
• High Gastric pH: hemigastrectomy, vagotomy, pernicious
anemia , histamine H2 receptor blockers, calcium-based
antacids
• Disruption of Intestinal Structure: hemigastrectomy,
segments of bowel which are sometimes removed
surgically, disrupting iron absorption, volvulus or
intusseception, vagotomy, pernicious anemia,
• Inhibitors: phylates, tannins, soil clay, laundry starch, iron
overload, cobalt, lead, strontium
• Some factors are facilitating iron absorbtion: bioavailability
(heme > Fe2+> Fe3+ ), ascorbate, citrate, amino acids, iron
deficiency
• As regarding growth spurt iron need for infants
is1.0 mg/1,000 kcal of dietary energy; for
adolescent girls, 0.8 (half of their iron
requirement is needed to replace iron losses in
menstruation ); adolescent boys need 0.6
mg/1,000 kcal.
• Some absorbtion problems can interfere iron. A
major cause of anaemia is infection with malaria
or other parasites. Plasmodium falciparum is the
primary cause of severe malaria in regions of the
world where malaria is endemic Sprue, both of
the tropical and non-tropical variety (celiac
disease), can also interfere with iron absorption.
Degeneration of the intestinal lining cells along
with chronic inflammation causes profound
malabsorption.
Blood loss
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DIGESTIVE
Meckel's diverticulum (persistent omphalomesenteric duct)
Colonic arteriovenous malformations
Arteriovenous malformations (the Osler-Weber-Rendu
syndrome.)
Ulcer disease are associated with Helicobacter pylori
infection
Gastric hiatal hernia
Erosive esophogitis
Milk-induced enteropathy (whole cow's milk contains
proteins that often irritate the lining of the gastrointestinal
tract in infants )
Parasites :the world's leading cause of gastrointestinal
blood loss is parasitic infestation. Hookworm infection is
caused primarily by Necator americanus or Ancylostoma
duodenal Trichuris trichiura. Growth retardation, in
addition to iron deficiency, occurs with heavy infestations.
URINARY
• Berger's disease, which produces relapsing
episodes of gross or microscopic hematuria
occurs most commonly in older children and
young adults. Diffuse mesangial proliferation or
focal and segmental glomerulonephritis with
mesangial deposits of IgA is the most common
renal pathology related to iron deficiency. Sickle
cell trait occasionally develop gross hematuria.
Hemoglobinuria classically is ascribed to
paroxysmal nocturnal hemoglobinuria.
PULMONARY
• Hemoptysis, chronic pulmonary infection with
bronchiectasis,idiopathic pulmonary
hemosiderosis, a condition characterized by
recurrent pulmonary hemorrhage along with
pulmonary fibrosis and right heart strain.
Clinical symptoms
• Palor of skin and mucosa
• The microcytic, hypochromic anemia impairs tissue oxygen
delivery, producing weakness, loss of apetite, fatigue, palpitations,
and light-headedness.
• Iron deficiency include poor weight gain, anorexia, blood in stools,
malabsorption, irritability, decreased attention span, exercise
intolerance and decreased physical activity.
• Regarding the psychomotor development when iron deficiency
progresses to anemia, performance on developmental tests is
adversely affected for up to at least 3 months despite correction of
the anemia with iron therapy. Among infants with severe or chronic
iron deficiency, some of these abnormalities may persist indefinitely
despite adequate iron therapy. The relation between iron deficiency
and behavioural development is nowadays well known.
• Iron deficiency produces significant gastrointestinal
tract abnormalities. Some patients develop angular
stomatitis and glossitis with painful swelling of the
tongue. The flattened, atrophic lingual papillae makes
the tongue smooth and shiny. A rare complication of
iron deficiency is the Plummer-Vinson syndrome with
the formation of a postcrycoid oesophageal web.
• Long-standing, severe iron deficiency affects the cells
that generate the finger nails producing koilonychia.
The "spoon-shaped" changes featured in many text
books are rare.
• Pica occurs variably in patients with iron deficiency. The
precise pathophysiology of the syndrome is unknown.
Patients consume unusually laundry starch, ice, and soil
clay, have abnormalities including massive hepatosplenomegaly, poor wound-healing, and a bleeding
diathesis; initially had simple iron deficiency associated
with pica, including geophagia. The soil contained
compounds that bound both iron and zinc. The secondary
zinc deficiency caused the hepatomegaly. Both clay and
starch can bind iron in the gastrointestinal tract,
exacerbating the deficiency.
• Impaired immune function is reported in subjects who are
iron deficient, and there are reports that these patients are
prone to infection
• Splenomegaly may occur with severe, persistent, untreated
iron deficiency anemia and is evident in up to 15% of
affected children.
• A systolic murmur can be heard because of the low blood
viscosity and increased circulation speed of the blood
Laboratory tests
• Iron deficiency anemia lowers the number of circulating red cells (a
feature of all anemias).
• Hb is low, the red cells are microcytic (usually less than 80 fl in size) and
hypochromic. Iron deficiency alters red cell size uneven.( anyzocytosis).
• Mean red cell volume or mean corpuscular volume (MCV) is reduced.The
range of variation in red cell size expressed as the RDW or red cell
distribution width is high.
• membranes of iron deficient red cells are abnormally rigid. This rigidity
could contribute to poikilocytic changes, seen particularly with severe iron
deficiency. These small, stiff, misshapen cells are cleared by the
reticuloendothelial system, contributing to the low-grade hemolysis that
often accompanies iron deficiency.reticulocyte count can be under 1% or
normal ( 2%-4% ).
• Unexplained thrombocytosis occurs frequently with platelet counts in the
range of 500,000 to 700,000 cells /fl.
• In bone marrow aspirate sideroblasts are under 10%, and
iron stores are low, there is an absence of stainable iron.
• The quantity of the iron-carrying protein, transferrin, in the
circulation increases over baseline by 50% to 100%. The
quantity of iron on transferrin can fall by as much as 90%.
Consequently the transferrin saturation frequently declines
from its usual 30% to under 10%.
• Ferritin is the cellular storage protein for iron and is low.
The plasma ferritin value often falls to under 10% of its
baseline level with significant iron deficiency. Total ironbinding capacity (TIBC) is raised.
• Free erythrocyte protoporphyrin (FEP) has concentrations
elevate when serum iron is insufficient for RBC production.
• Testing stool for the presence of hemoglobin is useful in
establishing gastrointestinal bleeding as the etiology of iron
deficiency anemia. To detect blood loss, the patient can be
placed on a strict vegetarian diet for 3-5 days and the stool
can be tested for hemoglobin using a benzidine method.
Positive diagnosis
• The diagnosis of iron deficiency is often
prompted by historical features and aided by
specific clinical and laboratory data.
Differential diagnosis
• Chronic inflammation ( ex in rheumatoid arthritis ),
perturb the plasma values of iron, transferrin, and
ferritin. Body iron stores revealed by serum ferritin
level are elevated
• Lead poisoning : chronic lead poisoning may produce a
mild microcytosis, persons live in old houses, lead
concentration is high in blood and urines.
• Thalasemia: in peripherial smear anemia target cells
usually are present, and anisocytosis and poikilocytosis
are marked, there are intraerythrocytic crystals
,bilirubin is raised, family history and clinical aspect of
the child is particular in beta thalassemia. Hemoglobin
electrophoresis should also be considered to rule out
the presence of inherited hemoglobinopathies.
• Sideroblastic anemia
Treatment
• The profilaxy of infant’s iron deficiency begins in mother’s
pregnancy. The WHO recommends that all pregnant
women be supplemented with 60 mg iron daily, in a pill
that also usually contains 400 mg folic acid.
• For low born weight infants the global recommendation is
to supply them with supplemental iron drops starting at 2
months of age. For developing countries the
recommendation is to provide 12.5 mg of elemental iron
plus 50 mg folic acid per day from age 6 months to age 12
months in regions where the anaemia prevalence is <40%,
and from age 6 to 24 months where the prevalence of
anaemia is > 40%.
• Supplements are provided for school children. Together
with iron, vitamin B6, folic acid, vitamin C and vitamin A
supplements are provided.
• When Hb is under the value of 7gm/dl, a transfusion with red packed cells
is necessary. Whole blood is a less used alternative, because of anafilactic
reactions of plasma proteins, immunological antigens of lymphocytes and
risk of infections. RED PACKED CELLS
Treatment with iron salts
• Dose of elemental iron is 6-8 mg/kg/day divided in 3-4 or once daily dose
before meals.
• Therapy is continued until fully Hb normalization; than 6-8 weeks of
additional iron therapy is necessary to complete body iron stores.
• Although ferrous sulphate is often recommended to treat iron deficiency,
frequent problems with the drug including gastrointestinal discomfort
appear. Ferrous gluconate, produces fewer problems, and is preferable as
the initial treatment of iron deficiency. Ascorbic acid supplementation
enhances iron absorption. Polysaccharide-iron complex, is a good
replacement form of iron that differs from the iron salts. Most patients
tolerate this form of iron better than the iron salts, even though the 150
mg of elemental iron per tablet is substantially greater than that provided
by iron salts (50 to 70 mg per tablet)
• Parenteral iron is available either as iron dextran or iron saccharide
(commonly ferric polymaltose). There can be side effects as anaphylaxis.
• Parenteral, im or iv is indicated when oral iron
is poorly tolerated or gastrointestinal iron
absorption is compromised Intramuscular
injection of iron-dextran can be painful, and
leakage into the subcutaneous tissue
produces long-standing skin discoloration
hages.
• Can also cause fever, artralgia,dyspnea,
myalgia.
• Peak reticulocytosis occurs after about 7-10 days, Hb
is restored together with red blood cell number and
hematocrit, and complete correction of the anemia
can take 3 to 4 weeks, The hematocrit rises
sufficiently in a week or two to provide symptomatic
relief for most patients, serum iron, transferrin
recoveres and at the end ferritin reaches normality.
• Human erythropoietin was one of the first agents
used to correct the anemia of end-stage renal disease
this hormone has provided new insight into the
kinetic relationship between iron and erythropoietin
in red cell production. The shifting states of storage
iron contribute to the inconsistency with which
erythropoietin corrects the anemia of renal failure
and premature newborn anemia.
Follow up
• The hematocrit or hemoglobin should be reevaluated in 1 month. Approximately 6
months following therapy, the hemoglobin or
hematocrit should be assessed to document
success of treatment and replenishment of
iron stores. Severe anemia (hemoglobin < 8
g/dl) and anemia that fails to respond to
adequate iron supplementation will require
more intensive investigation to confirm the
diagnosis and offer appropriate management.
MEGALOBLASTIC ANEMIA
Definition
• The term megaloblastic anemia (MA) is used
to describe a macrocytic anemia that is
associated with a characteristic change-the
megaloblastic change in the erythroid
precursors in the bone marrow.
Causes of megaloblastic anemia
• There are many causes of megaloblastic anemia, but the most common
source in children occurs from a vitamin deficiency of folic acid or vitamin
B-12. Other sources of megaloblastic anemia include the following:
• Digestive diseases
These include celiac disease, chronic infectious enteritis, and
enteroenteric fistulas. Pernicious anemia is a type of megaloblastic anemia
caused by an inability to absorb Vitamin B-12 due to a lack of intrinsic
factor in gastric (stomach) secretions. which factor enables the absorption
of Vitamin B-12.
• malabsorption
Inherited congenital folate malabsorption, a genetic disease; condition
requires early intensive treatment to prevent long term problems such as
mental retardation.
• Infection (intestinal parasites, bacterial overgrowth)
• Medication-induced folic acid deficiency
Certain medications, specifically ones that prevent seizures, such as
phenytoin, primidone, and phenobarbital, can impair the absorption of
folic acid. The deficiency can usually be treated with a dietary supplement.
Folic acid is a B vitamin required for the production of normal red blood
cells. Folic acid is present in foods such as green vegetables, liver, and yeast.
It is also produced synthetically and added to many food items.
Foods that are rich in folic acid include the following:
• orange juice
• lentils
• oranges
• wheat germ
• romaine lettuce
• chick peas (garbanzo beans)
• spinach
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Foods that are rich in folic acid and
• liver
vitamin B12 include the following:
• rice
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• barley
eggs
• sprouts
• meat
• wheat germ
• poultry
• soy beans
• milk
• green, leafy vegetables
• shellfish
• beans
• fortified cereals
• peanuts
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• broccoli
• asparagus
• peas
• Nutritional megaloblastic anemia in children occurs
commonly among under-nourished or malnourished
societies of tropical and subtropical countries. The
commonest age is 3-18 months with maximum number
of cases being in 9-12 months(1). These children are
generally exclusively breast-fed by mothers who are
undernourished and have poor blood levels of folate
and cobalamin
• Intrinsic factor is a protein the body uses to absorb
vitamin B12. When gastric secretions do not have
enough intrinsic factor, vitamin B12 is not adequately
absorbed, resulting in pernicious anemia. Absence of
intrinsic factor itself is the most common cause of
Vitamin B12 deficiency. Intrinsic factor is produced by
cells within the stomach
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Clinics
• The onset of the disease is slow and may span decades.
• pallor
• Developmental retardation or regression is an important finding. These
children are normally apathetic, not interested in surroundings and have
hypotomia.
• Hyperpigmentation of knukles, terminal phalanges, dorsum of hand etc is
seen.
• Tremors are described in 5-15% cases-the infantile tremor syndrome of
megaloblastic anemia, hypotonia, developmental regression and tremors.
Some of the cases of MA may clinically mimic cases of acute leukemia and
aplastic anemia as hepatosplenomegaly (due to extramedullary hemopoiesis)
of varying severity and cutaneous and other bleeding manifestations are
described in 25-30% cases.abnormal paleness or lack of color of the skin
• decreased appetite
• irritability
• lack of energy or tiring easily (fatigue)
• diarrhea
• difficulty walking
• numbness or tingling in hands and feet
• smooth and tender tongue
• weak muscles
Laboratory tests
• Diagnosis of MA is suggested by presence of macrocytosis. Presence of
hypersegmented neutrophils also supports the diagnosis. Some cases may
have circulating red cell precursors showing megaloblastic changes.
Reticulocyte count is usually decreased. MCV is found to be increased (>90
fl.) What is more striking on peripheral blood examination is presence of
• thrombocytopenia, leucopenia and neutropenia. Thrombocytopenia is
described in 50-80% cases with many of them having precariously low
platelet counts. Neutropenia has been reported in 20-50% cases. Thus
many cases (upto 50% in some cases) of MA may have pancytopenia - a
finding which might lead to misdiagnosis of aplastic anemia (or acute
leukemia if hepatosplenomegaly is also present). In some series on
pancytopenia it has been observed that MA is more frequent etiological
diagnosis than aplastic anemia or leukemia. The diagnosis of MA is
confirmed on bone marrow examination that shows trilineal hyperplasia
with megaloblastic change typically in the erythroid precursors.
• Reduced serum levels of B12 and folate will make the etiological diagnosis.
It has been shown that serum and urinary methylmalonic acid (MMA) are
increased in B12 deficiency and not in folate deficiency states.
• The Schilling test is performed to detect
vitamin B12 absorption. In the Schilling test,
vitamin B12 levels are measured in the urine
after the ingestion of radioactive vitamin B12.
With normal absorption, the ileum (portion of
the small intestine) absorbs more vitamin B12
than the body needs and excretes the excess
into the urine. With impaired absorption,
however, little or no vitamin B12 is excreted
into the urine.
Treatment
• Daily dose of 1mg of folic acid is more than adequate
though larger doses are safe.
• The dose schedule if B12 therapeutic response can be
obtained with a dose of 0.2 µg/kg for 2 days, but usually a
1000 µg dose is recommended which may be continued for
the first 7 days. In our experience and other studies, use of
this high dose has resulted in hyperexitability and tremors
in some patients. Smaller dose i.e. 100-250 µg by initially
given daily for a week and then less frequently
• reticulocytosis. appear, fall in MCV by 5-10 fl over 1-2
weeks,
platelet count and neutrophil count tend to improve
quickly, some patients may develop thrombocytosis
APLASTIC ANEMIAS
• ETIOLOGY
Inherited Bone Marrow Syndromes Associated with Pancytopenia,
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Fanconi's Anemia
Dyskeratosis Congenita
Shwachman-Diamond Syndrome
Cartilage-Hair Hypoplasia
Pearson's Syndrome
Down Syndrome
Familial Marrow Dysfunction
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Inherited Bone Marrow Failure Syndromes Associated with Isolated
Cytopenia,
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Diamond-Blackfan Anemia
Congenital Dyserythropoietic Anemia
Severe Congenital Neutropenia
Inherited Thrombocytopenia
Amegakaryocytic Thrombocytopenia,
Thrombocytopenia with Absent Radii,
ETIOLOGY
• Aquired:
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* Imune
* Nonimune :
radiations
drugs- Chloramphenicol, phenylbutazone, and gold
benzene exposure, chemicals
infectious causes such as hepatitis viruses, Ebstein-Barr virus
(EBV), HIV, parvovirus, and mycobacterial infections
• Among the acquired cytopenias paroxysmal nocturnal
hemoglobinuria (PNH) is relatively rare;however, it can pose
formidable management problems. Since its first recognition as a
disease, PNH has been correctly classified as a hemolyticanemia;
however, the frequent co-existence of other cytopenias has hinted
strongly at a more complex pathogenesis.
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In most patients, an autoimmune mechanism has been inferred
from positive responses to nontransplant therapies and laboratory
data. Cytotoxic T cell attack, with production of type I cytokines,
leads to hematopoietic stem cell destruction and ultimately
pancytopenia.
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The antigen that incites disease is unknown in aplastic anemia.
• Inherited bone marrow failure syndromes
(IBMFSs) are genetic disorders characterized
by inadequate blood cell production
• Bone marrow failure usually presents in
childhood, with petechiae, bruising, and
hemorrhages due to thrombocytopenia; pallor
and fatigue from anemia; and infections due
to neutropenia
• Inherited bone marrow failure syndromes (IBMFS) are
genetic disorders characterized by inadequate blood
cell production. Bone marrow failure (BMF) may be
manifested as an isolated cytopenia (pure red cell
aplasia, neutropenia, or thrombocytopenia) or as
pancytopenia and the clinical picture of aplastic
anemia.
• Other organ systems are often affected by these
genetic abnormalities and result in birth defects or
clinical disease in nonhematopoietic organs. Birth
defects and extrahematopoietic manifestations are
often characteristic and may be noticed before the
onset of BMF.
• BMF may be present at birth (congenital BMF) or
develop later in life
• Fanconi's anemia is an autosomal recessive and Xlinked disorder characterized by progressive bone
marrow failure, congenital abnormalities, and a
predisposition for malignancies.
• Cells from FA patients exhibit spontaneous
chromosomal instability and a characteristic
hypersensitivity to DNA interstrand cross-linking
agents.
• The incidence of FA is estimated to be approximately 3
per million with a carrier frequency of 1 in 300.
• The clinical manifestations of FA are heterogeneous
(variable penetrance and expressivity)
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Specific Types of Anomalies in Fanconi's Anemia SKIN
Generalized hyperpigmentation on the trunk, neck, and
intertriginous areas; café au lait spots; hypopigmented
areas
BODY
Short stature, delicate features, small size, underweight
UPPER LIMBS
Thumbs: absent or hypoplastic; supernumerary, bifid,
or duplicated; rudimentary; short triphalangeal,
tubular, stiff, hyperextensible
Radii: absent or hypoplastic (only with abnormal
thumbs); absent or weak pulse
Hands: clinodactyly; hypoplastic thenar eminence; six
fingers; absent first metacarpal; enlarged, abnormal
fingers; short fingers, transverse crease
Ulnae: dysplastic
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GONADS
Males: hypogenitalia, undescended testes, hypospadias, abnormal
genitalia, absent testis, atrophic testes, azoospermia, phimosis,
abnormal urethra, micropenis, delayed development
Females: hypogenitalia; bicornuate uterus; abnormal genitalia;
aplasia of the uterus and vagina; atresia of the uterus, vagina, and
ovary
OTHER SKELETAL ANOMALIES
Head and face: microcephaly, hydrocephalus, micrognathia, peculiar
face, bird-like face, flat head, frontal bossing, scaphocephaly, sloped
forehead, choanal atresia, dental abnormalities
Neck: Sprengel's deformity; short, low hairline; webbed
Spine: spina bifida (thoracic, lumbar, cervical, occult sacral),
scoliosis, abnormal ribs, sacrococcygeal sinus, vertebral anomalies,
extra vertebrae
EYES
Small eyes, strabismus, epicanthal folds, hypertelorism, ptosis,
cataracts, astigmatism, blindness,, nystagmus, proptosis, small iris
EARS
Deafness (usually conductive); abnormal shape; atresia; dysplasia;
low-set, large or small; infections; abnormal middle ear; absent
drum; canal stenosis
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KIDNEYS
Ectopic or pelvic; abnormal, horseshoe, hypoplastic, or dysplastic; absent;
hydronephrosis or hydroureter; infections; duplicated; rotated; reflux; hyperplasia; no
function; abnormal artery
GASTROINTESTINAL SYSTEM
High-arched palate, atresia (esophagus, duodenum, jejunum), imperforate anus,
tracheoesophageal fistula, Meckel's diverticulum, umbilical hernia, hypoplastic uvula,
abnormal biliary ducts, megacolon, abdominal diastasis, Budd-Chiari syndrome
LOWER LIMBS
Feet: toe syndactyly, abnormal toes, flatfeet, short toes, clubfeet, six toes,
supernumerary toe
Legs: congenital hip dislocation, Perthes' disease, coxa vara, abnormal femur, thigh
osteoma, abnormal legs
CARDIOPULMONARY SYSTEM
Patent ductus arteriosus, ventricular septal defect, abnormal heart, peripheral
pulmonic stenosis, aortic stenosis, coarctation, absent lung lobes, vascular
malformation, aortic atheromas, atrial septal defect, tetralogy of Fallot, pseudotruncus,
hypoplastic aorta, abnormal pulmonary drainage, double aortic arch, cardiac myopathy
OTHER ANOMALIES
Slow development, hyperreflexia, Bell's palsy, central nervous system arterial
malformation, stenosis of the internal carotid artery, small pituitary gland, absent
corpus callosum
Hematologic Abnormalities
• The first hematologic abnormalities in
individuals with FA are detected at a median
age of 7 years. The majority of FA patients
already have pancytopenia at the time of
diagnosis (53%). By the age of 40, the
cumulative incidence of hematologic
abnormalities is 90% to 98%
• In rare cases, thrombocytopenia may be
present at birth and progress to pancytopenia
in the neonatal period or infancy
• Bone marrow examination generally shows
reduced cellularity
• FA HAS a predisposition for cancer, including
leukemia and solid tumors
• The risk of solid tumors and leukemia (AML)
developing increases with age
Diagnosis
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The most widely used diagnostic test for FA
is hypersensitivity to the clastogenic
(chromosome-breaking) effect of
diepoxybutane (DEB) or mitomycin C (MMC).
• The increased spontaneous chromosomal
instability of FA cells leads to distinctive
chromosomal breaks, gaps, and various
chromatid interchanges, which were
previously used as a cellular marker for FA.
Clinical Management
• Once the diagnosis is confirmed, the family should be
referred to a clinical geneticist for counseling and
careful examination of family members.
• Genetic testing or chromosome breakage analysis
should be offered to all family members.
• Early diagnosis is important for correct management
of hematologic complications, diagnosis and
appropriate treatment of coexisting congenital
abnormalities and associated endocrinopathies, and
identification of affected but asymptomatic family
members and unaffected family members
• Initially, in the absence of hematologic abnormalities
or clinical and laboratory signs of mild BMF, monitoring
of peripheral blood values and yearly examination of
bone marrow might be sufficient (see also elsewhere
• Androgens and hematopoietic growth factors transiently improve BMF in
about 50% to 60% of FA patients.
• Side effects of androgen therapy include masculinization, acne,
hyperactivity, growth spurt followed by premature closure of the
epiphyseal growth plates, liver enzyme abnormalities, hepatic adenomas,
and a risk for hepatic adenocarcinomas
• Frequent monitoring of liver function and liver ultra-sound scans.
Hematopoietic growth factors (granulocyte colony-stimulating factor [GCSF]or granulocyte-macrophage colony-stimulating factor [GM-CSF]may
transiently improve neutrophil counts and, in rare FA patients, also
hemoglobin levels and platelet numbers.
• The use of hematopoietic growth factors in patients with clonal
cytogenetic abnormalities is controversial because of the potential risk of
inducing or promoting leukemia.
• Red cell transfusion therapy and iron chelation (after multiple red cell
transfusions) are frequently used in symptomatic FA patients. Platelet
transfusions may be indicated in thrombocytopenic patients with bleeding
or before surgical procedures.
• HSCT from an HLA-matched sibling donor is accepted as the best
treatment to cure BMF in FA patients and to prevent progression to MDS
and AML
• The prognosis for FA patients without HLA-matched siblings after HSCT
with unrelated donors is less favorable. Extensive malformations, a
positive recipient cytomegalovirus serology, the use of androgens before
transplantation, and female donors were associated with a worse
outcome
• Treatment
• Supportive care for patients with symptomatic anemia includes
transfusions of packed red blood cells that have been
leukodepleted. Thrombocytopenia istreated with platelets units;
single-donor platelets are preferred to reduce the frequency of
antibody formation
• Aplastic anemia can be effectively treated by either stem cell
transplantation or immuno-suppression.
• Hematopoietic stem cell transplantation HSCT (bone marrow, cord
blood, or peripheral blood stem cells) may cure aplastic anemia
• Immunosuppressive therapy using antithymocyte globulin,
cyclosporine, and danazol with or without human granulocyte
colony-stimulating factor and high dose cyclophosphamide.
• Other types of imunosupressive therapy and stem cell stimulation.:
• Oxymetholone (Anadrol-50) -- Anabolic and androgenic derivative
of testosterone
• 2-4 mg/kg/day; Nandrolone decanoate (Deca-Durabolin);
Prednisone : 1-2 mg/kg 4 weeks
•
• Dyskeratosis congenita (DC) rare
inherited bone marrow failure (BMF) syndrome
with X-linked, autosomal dominant, and
autosomal recessive inheritance.
• Classically, BMF in DC patients is associated with
the mucocutaneous triad, including abnormal
pigmentation, dystrophic nails, and mucosal
leukoplakia.
• About 85% of patients with classic DC are initially
found to have cytopenia of one or more lineages,
and pancytopenia develops in more than 95% of
patients by 40 years of age. Complications of
BMF, such as hemorrhage or opportunistic
infection, represent the major cause of death in
patients with DC.
• DC is a cancer predisposition syndrome
Laboratory finding
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PERIPHERAL BLOOD
Cytopenia of one or more lineages (80%)
Initial manifestation highly variable
Macrocytosis with or without anemia
Thrombocytopenia
Neutropenia
Pancytopenia
Low number of circulating progenitor cells
Elevated hemoglobin F
Elevated von Willebrand factor
• BONE MARROW EXAMINATION
• Hypocellular bone marrow affecting all three
lineages
• Increased number of mast cells
• Dyserythropoiesis
• Hypocellular myelodysplastic syndrome
• Myelodysplastic syndrome/acute myeloid
leukemia
Diamond-Blackfan Anemia
• Diamond-Blackfan anemia (DBA) is a pure red cell
aplasia with autosomal dominant inheritance
that is usually seen in early infancy. DBA is
associated with a reduction or absence of
erythroid precursors in bone marrow, variable
congenital anomalies, and a predisposition to
malignancy. DBA red cells characteristically have
increased adenosine deaminase activity.
• DBA is a rare disease with a frequency of 2 to 7
per million live births and has no ethnic or gender
predilection
• Head, face, palate Hypertelorism, cleft palate,
high-arched palate, microcephaly, micrognathia,
microtia, low-set ears, low hairline, epicanthus,
ptosis, flat broad nasal bridge
• Upper limb Triphalangeal, duplex or bifid,
hypoplastic thumb; flat thenar eminence;
syndactyly; absent radial artery
• Renal, urogenital Absent kidney, horseshoe
kidney, hypospadias
• Cardiopulmonary Ventricular septal defect, atrial
septal defect, coarctation of the aorta, complex
cardiac anomalies
• Congenital glaucoma, strabismus, congenital
cataract
• Anemia, macrocytosis, reticulocytopenia, and
absent or decreased numbers of erythroid
progenitor cells in bone marrow are the major
diagnostic criteria for DBA. In 13% to 20% of
individuals, anemia may be present at birth
• Elevated levels of red cell adenosine deaminase
(ADA), a critical enzyme in the purine salvage
pathway, are characteristic of DBA erythropoiesis
and may be found in 80% to 89% of patients
TREATMENT
• Glucocorticoid Therapy
• Steroids and red cell transfusions are the main forms of therapy.
Prednisone (or prednisolone) therapy is usually initiated at a dosage
of 2 mg/kg/day. For glucocorticoid responders, the prednisone
dosage is slowly tapered until the patient is taking an alternate-day
dosage that maintains a reasonable hemoglobin level. Many
patients remain on small, alternate-day doses of steroids for years.
70% - 80% of patients with DBA are initially steroid responsive, but
only 60% to 70% achieve transfusion independence
• Iron chelation should begin as soon as patients have increased iron
stores (ferritin >1500 mg/dL
• Subcutaneous infusion of deferoxamine is the standard chelation
therapy in patients with DBA. The recently developed oral iron
chelators deferiprone, a bidentate and deferasirox, a tridentate may
eventually supplant deferoxamine as the standard of iron chelation
therapy
HEMOLYTIC ANEMIAS
Hemolytic anemias = reduced red-cell life
span
Classification of Hemolytic anemias
I. Red cell abnormality (Intracorpuscular factors)
A. Hereditary
1. Membrane defect (spherocytosis, elliptocytosis)
2. Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD)
deficiency, Pyruvate kinase (PK) deficiency)
3. Hemoglobinopathies (unstable hemoglobins,
thalassemias, sickle cell anemia )
B. Acquired
1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria
(PNH)
II. Extracorpuscular factors
A. Immune hemolytic anemias
1. Autoimmune hemolytic anemia
- caused by warm-reactive antibodies
- caused by cold-reactive antibodies
2. Transfusion of incompatible blood
B. Nonimmune hemolytic anemias
1. Chemicals
2. Bacterial infections, parasitic infections (malaria), venons
3. Hemolysis due to physical trauma
- hemolytic - uremic syndrome (HUS)
- thrombotic thrombocytopenic purpura (TTP)
- prosthetic heart valves
4. Hypersplenism
DISORDERS OF RED CELL
MEMBRANE
Hereditary Spherocytosis
• Definition;incidence
• Most common hereditary hemolytic anemia with dominant
autosomal trait among people of Northern European origin.
• Phisiopathology
• This disorder is caused by a defective gene. The defect
results in an abnormal red cell membrane so that the
affected cells have a smaller surface area for their volume
than normal red blood cells and resulting in cytoskeleton
instability. The cells are less resistant to stresses and
rupture easily.
• Four abnormalities in red cell membrane
proteins include :
• spectrin deficiency
• combined spectrin and ankyrin deficiency
• band 3 deficiency
• protein 4.2 defects
Clinical signs
• There can be a marked heterogeneity of clinical
features, ranging from an asymptomatic condition to
fulminant hemolytic anemia. A family history of HS is
present.
• Jaundice ; most prominent in newborns
• Pallor
• Shortness of breath
• Fatigue
• Weakness
• Irritability
• Enlarged spleen.
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Lab tests
Elevated reticulocyte count.
Blood smear shows spherocytes, anisocytosis
Complete blood count shows anemia. Peripheral smear:
Howell-Jolly bodies may be present
Osmotic fragility and incubated fragility test (hemolysis of
HS cells may be complete at a solute concentration that
causes little or no lysis of normal cells),
Coombs' test - direct is negative.
Coombs' test - indirect is negative.
Elevated bilirubin ( indirect )
Elevated LDH.
• Treatment; complications
• Red blood cells are transfused to patients whenever Hb drops under
7gm/dl or clinical status is deteriorated. Aplastic crises (severe
decrease in red blood cell production) caused by a viral infection, is
due to imbalance distruction - RBC production
• Splenectomy usually is curative. Fatal sepsis caused by capsulated
organisms (eg, Streptococcus pneumoniae, Haemophilus influenzae)
is a complication in children who had a splenectomy. Bilirubin
gallstones are found in approximately 50% of patients. Splenectomy
for children with HS should be performed when the child is older
than 6 years. Before having a splenectomy, anyone with HS should
have the pneumococcal vaccine.
• Folic acid, an important cofactor for enzymes used in production of
RBCs is given at a dose of 1 mg/day
• Prognosis
• The prognosis (outlook) after splenectomy is for a normal life and a
normal life expectancy.
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THALASSEMIAS
• Classification
• Thalassemias are genetic disorders of
hemoglobin (Hb) synthesis. Their clinical severity
varies widely, ranging from mild to severe forms.
Alpha thalassemia affects the alpha-globin genes.
Beta thalassemia affects one or both of the betaglobin genes.
• In beta thalassemia minor (beta thalassemia trait
or heterozygous carrier-type), one of the betaglobin genes is defective. In beta thalassemia
major (homozygous beta thalassemia), the
production of beta-globin chains is low because
both beta-globin genes are mutated.
• Pathophisiology
• The severe imbalance of globin chain synthesis results in
ineffective erythropoiesis and severe microcytic
hypochromic anemia .The excess unpaired alpha-globin
chains aggregate and form precipitates that damage red cell
membranes, resulting in intravascular hemolysis. Premature
destruction of erythroid precursors leads to intramedullary
death and ineffective erythropoiesis. The profound anemia
typically is associated with erythroid hyperplasia and
extramedullary hematopoiesis. Gamma chain are increased,
resulting in an elevated level of Hb F. The symptoms of
thalassemia intermedia reflect ineffective erythropoiesis,
which leads to anemia, medullary expansion, and
extramedullary hematopoiesis. Iron overload is a potential
complication of thalassemia.
• Frequency
• This condition appears to be common in the Mediterranean
basin, northern Africa, the Indian subcontinent.
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Clinics
• Thalassemia minor usually presents as an asymptomatic
mild microcytic anemia and is detected through routine
blood tests. Thalassemia major is a severe anemia that
presents during the first few months after birth.
• Thalassemia minor (beta thalassemia trait) usually is
asymptomatic, and it typically is identified during routine
blood count evaluation.
• Thalassemia major (homozygous beta thalassemia) is
detected during the first few months of life, when the
patient's level of fetal Hb decreases.
• General pallor and pale conjunctivae and fingernails
indicate anemia but are not specific for hemolytic anemias
• Jaundice
• In moderately severe cases, patients or their family
members may observe slight
pallor, slight yellowish
discoloration of the sclerae, or enlarged abdomen.
• Abnormal facies with prominent facial bones and dental
malocclusions. The skull and other bones may be deformed
secondary to erythroid hyperplasia with intramedullary
expansion and cortical bone thinning.
• Modifications of liver, gall bladder, and spleen.
Hepatomegaly related to significant extramedullary
hematopoiesis is observed. Patients who have received
blood transfusions may have hepatomegaly or chronic
hepatitis due to iron overload; transfusion-associated viral
hepatitis resulting in cirrhosis or portal hypertension also
may be seen. The gall bladder may contain bilirubin stones
formed as a result of the patient's life-long hemolytic state.
• Bronze skin color and diabetes result from
hemochromatosis due to multiple transfusions or
erroneously administered iron therapy
• Splenomegaly typically is observed as part of the
extramedullary hematopoiesis or as a hypertrophic
response related to the extravascular hemolysis.
• Skin ulceration
• Iron overload cause endocrine dysfunction,
especially affecting the pancreas, testes, and
thyroid. The heart is a major organ that is
affected by iron overload and anemia. Cardiac
dysfunction in patients with thalassemia
major includes conduction system defects,
decreased myocardial function, and fibrosis.
Some patients also develop pericarditis.
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Differential diagnosis
Red cell membrane disorders
Anemia of chronic disease
Lead poisoning
Sideroblastic anemia
Other microcytic anemia:
Complications
• The severe anemia resulting from this disease, if
untreated, can result in high-output cardiac failure
• Increased iron deposition results in secondary iron
overload. This overload causes clinical problems :
endocrine dysfunction, liver dysfunction, cardiac
dysfunction
• The gall bladder may contain bilirubin stones formed as
a result of hemolytic state
Treatment
• The goal of long-term hypertransfusional support
is to maintain the patient's Hb at 9-10 g/dL.
Patients receiving transfusion therapy also
require iron chelation with desferrioxamine,
deferasirox.
• Allogeneic hematopoietic transplantation may be
curative in some patients with thalassemia major.
• Patients with thalassemia minor rarely require
splenectomy, although the development of
bilirubin stones can require cholecistectomy.
Glucose-6-Phosphate
Dehydrogenase Deficiency
• The G6PD enzyme catalyzes an oxidationreduction reaction transferring electrons from
one molecule to another;the G6PD enzyme
functions in catalyzing the oxidation of
glucose-6-phosphate to 6-phosphogluconate,
while concomitantly reducing nicotinamide
adenine dinucleotide phosphate (NADP+ to
NADPH).
• Incidence
• Highest prevalence rates are found in tropical Africa Middle East,
tropical and subtropical Asia, Mediterranean areas.
• These include neonatal jaundice, abdominal and/or back pain,
dizziness, headache, dyspnea (irregular breathing), and palpitations.
• Clinics
• Phisycal signs include neonatal jaundice, abdominal and/or back
pain, dizziness, headache, dyspnea (irregular breathing), and
palpitations.
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• Neonatal jaundice is a common condition in all newborns, but when
it persists, G6PD deficiency is suspected. Neonatal jaundice is a
yellowish coloration of eyes, skin, and mucous membranes caused
by deposition of bile salts in these tissues. This is a direct result of
insufficient activity of the G6PD enzyme in the liver. In some cases,
the neonatal jaundice is severe enough to cause death or
permanent neurologic damage. Kernicterus is a rare complication.
• Hemolytic anemia is another condition which
may cause problems for G6PD deficient
individuals,back pain,abdominal pain, jaundice
and splenomegaly may be present during a crisis.
An anemic response can be induced in affected
individuals by certain oxidative drugs, fava beans
or infections. Most common drugs that can
trigger haemolytic crisis are: acetophenetidin
(phenacetin), amidopyrine (aminopyrine),aspirin,
pyramidone, methylene blue,nalidixic acid,
quinine, vitamin K (water soluble), cotrimoxazole,
nitrofurantoin,
• Sulfacetamide; infections that can precipitate a
hemolytic episode are viral hepatitis, pneumonia,
and salmonella infections.
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Laboratory tests
Level of enzyme activity of G6PD is low
CBC count ( red blood cells can present Heinz bodies) with
reticulocyte count to determine the level of anemia
Indirect bilirubinemia occurs
Serum haptoglobin levels are decreased
Abdominal ultrasound may be useful in assessing for
splenomegaly and gallstones.
Treatment
Infants with prolonged neonatal jaundice are placed under
special lights, called bili-lights, which alleviate the jaundice or
require exchange transfusional procedures
Identification and discontinuation of the precipitating agent is
critical. Individuals are treated with oxygen and bed rest,
which may afford symptomatic relief.
Avoid oxidant drugs. Most patients do not need treatment.