ANEMIA

Roll number 26-30

IRON DEFICIENCY ANEMIA
IRON METABOLISM
A. DISTRIBUTION OF IRON :-
● The total body iron content (3-4 g) is divided into functional and storage compartments .Iron
in the body is extensively recycled between the functional and storage pools.
● Functional - constitutes about 80% of the total iron pool. Mainly constituted by
Hemoglobin(2.5g) ; also includes Myoglobin and iron containing enzymes
(catalase,cytochromes,peroxidases)
● Storage - about 15-20% of the total body iron is bound to protein and stored in the body in 2
forms Ferritin and Hemosiderin.
● Ferritin is a protein-iron complex (apoferritin + iron) found in all tissues but particularly
in liver, spleen, bone marrow, and skeletal muscles. Very small amounts of ferritin
circulate in the serum, the value normally being 15-300 ug/L. Serum ferritin levels reflect
the iron stores and are a sensitive indicator of the amount of iron in the body.
● Hemosiderin is an aggregate of iron and protein which is found in the reticuloendothelial
cells of bone marrow, spleen, and liver. It is formed when iron is in excess (amorphous
iron deposition).
B. IRON ABSORPTION :-
Site of absorption: Iron is absorbed from the duodenum and proximal jejunum.

Iron balance is maintained mainly by regulating the dietary absorption of iron (by the synthesis
of apoferritin within mucosal cells).

Daily requirements: The recommended dietary allowance 10-15 mg. The daily requirement in
adult males is 5-10 mg/day and in females 20 mg/day.

Dietary sources: The diet contains iron either in the form of heme contained in animal products
and/or nonheme iron in vegetables. Of 10-50 mg in the diet, only 10-15% is normally absorbed.

C. TRANSPORT OF IRON :-
Transferrin: Iron is transported in plasma by the iron transport protein transferrin, which is
synthesized in the liver. normalorivicion of plasma transferrin is to deliver iron to erythroid
precursors for the synthesis of hemoglobin.
C. TRANSPORT OF IRON :-(CONTD.)
● Lactoferrin: It binds iron in milk (has an antimicrobial effect)
● Haptoglobin: It binds hemoglobin in the plasma.

D. IRON EXCRETION/LOSS :-
Iron metabolism is unique as it is very efficiently utilized and reutilized by the body. There
is no physiological regulated mechanism for iron excretion and 1-2 mg/day is lost by
shedding of epithelial cells of Gl tract, skin epithelial cells (by sweat), and renal tubules
and by menstruation, pregnancy, multiple births, lactation, and bleeding.

E. REGULATION OF IRON BALANCE :-

Iron is essential for cellular metabolism; at the same time, excess of it is highly toxic.
Therefore, the total body iron stores must be properly regulated. Iron balance is mainly
achieved by regulating the absorption of iron in the diet. As body stores decrease, the
absorption of iron rises and vice versa.
HEPCIDIN

It is synthesized in the liver and is the central (key) regulator of iron homeostasis and it controls
intestinal iron absorption, plasma iron concentrations, tissue iron distribution, and storage.

Ferroportin is the cellular iron exporter which exports iron into plasma:-

• from absorptive enterocytes,

• from macrophages that recycle the iron of senescent erythrocytes, and

• from hepatocytes that store iron.

• The major mechanism of hepcidin is the regulation of transmembrane iron transport. Hepcidin
binds to ferroportin and forms hepcidin-ferroportin complex. This complex is degraded in the
lysosomes and thus degrades its receptor ferroportin. By this mechanism, hepcidin reduces
resorption of iron in the intestine and inhibits iron transfer from the enterocyte to plasma (thereby
reduces concentration of iron in plasma).

• When hepcidin levels rise, it lowers iron absorption in the intestine, iron gets stored (locked)
within enterocytes forming mucosal ferritin, and iron is shed with the cells. It also lowers iron
release from hepatocytes and macrophages (through degradation of ferroportin) leading to
decreased serum iron.
IRON DEFICIENCY ANEMIA
Anemia caused by insufficient iron in the body to produce
hemoglobin.
CAUSES OF IDA :-
A. Decreased iron intake ;-
● Milk fed infants
● Elderly with poor diet
● Low socio-economic sections

A. Decreased absorption of iron ;-

● Total/partial gastrectomy
● Sprue , other causes of intestinal steatorrhea and chronic diarrhea
● Phytates, Tannates, Carbonate, Oxalates, Phosphates in diet
C. Increased demand for iron ;-

● Rapid growth in infancy or adolescence

● Pregnancy and lactation

D. Increased iron loss ;-

Chronic blood loss due to bleeding from the:

● Gastrointestinal tract (peptic ulcers, gastric or colonic carcinoma. hemorrhoids,

hookworm infestation, schistosomiasis, or NSAIDS.
● Urinary tract (renal or bladder tumors)
● Genital tract (menorrhagia, uterine cancer)
Stages of Iron Deficiency
Stage I: Negative iron balance is characterized by decreased bone
marrow iron stores.
• Stage 2: Iron-deficient erythropoiesis-erythropoiesis is impaired
when serum iron falls to <50 mcg/dL.

• Stage 3: Iron deficiency anemia-microcytosis and then hypochromia

develop. Eventually iron deficiency affects tissues resulting in
symptoms and signs.
CLINICAL FEATURES
Clinical features of iron deficiency anemia include the usual symptoms and
signs of anemia.
Characteristic signs of advanced iron deficiency include:
• Cheilosis (fissures at the corners of the mouth)/ angular stomatitis
• Atrophic glossitis
• Brittle fingernails, platonychia, and koilonychia (spooning of the fingernails)
brittle hair
• Blue-tinged sclera, alopecia
•Pica - the unusual craving for substances that have a ‘crunching’ sound with
no nutritional value like chalk or clay
• Restless leg syndrome - in about 25% of the patients
DIAGNOSIS
A. To confirm Iron deficiency
● Hemoglobin and hematocrit (PCV): Decreased
● Red cell indices:

MCV: <80 fL; MCH: <25 pg; MCHC: <27 g/dL.

RDW: Increased, > 15%. Earliest sign of iron deficiency

● Peripheral smear: Microcytic hypochromic RBCs. Severe anemia —tear drop cells, target cells
and pencil/cigar-shaped cells with anisocytosis and poikilocytosis with reactive
thrombocytosis in a few cases
● Reticulocyte count: Low for degree of anemia
● Bone marrow: Moderate erythroid hyperplasia and micronormoblastic maturation
● Absence of bone marrow iron: "Gold standard" test, demonstrated by negative Prussian blue
reaction
● Hepcidin: Decreased
B. To determine the cause of Iron Deficiency ;

● Stool: Examine for occult blood and hookworm infestation

● Endoscopy: This includes upper gastrointestinal endoscopy,
sigmoidoscopy, and colonoscopy
● Urine: Examine for bleeding and for parasites such as
schistosomiasis
● Investigations for malabsorption
Management
a. Treatment of the underlying cause
b. Iron therapy

1. ORAL IRON THERAPY

Most patients can be treated with oral iron preparations.

a. Iron preparations and dose: Oral iron dose is a6mg/kg/day, Commonly

used and best are ferrous sulfate ,ferrous gluconate, ferrous fumarate and
others.
b. Alternate-day dosing appears to result in equivalent or better iron
absorption than daily dosing, usually with fewer adverse effects.
 C. Side effects: Few patients may develop metallic taste, nausea,
dyspepsia, constipation, black tarry stools, or diarrhea. These can be
reduced by taking iron tablets with food or reducing the dose or by using
preparation with less iron (e.g., ferrous gluconate) or a controlled-release
preparation or a liquid preparation.

D. Duration of oral iron therapy: Iron should be given to correct the

Hb level to normal range and usually occurs within 4-6 weeks. If it does
not occur, it may be due to failure of response to therapy.

2. PARENTERAL IRON THERAPY

Should only be used when a definite diagnosis of IDA is made, otherwise may
lead to iron overload and it’s adverse effects.
INDICATIONS ;
a. Intolerance to oral therapy
b. Severe malabsorption
c. Chronic GI tract disease which may worsen with oral iron

Calculation of total iron dose required :

Iron dose in mg = Body weight (kg) x 2.3 x (normal Hb— patient's hemoglobin,
g/dL) + 500 or 1,000 mg (to provide body iron stores).

Route of administration: Parenteral iron can be given by slow intravenous

infusion or by intramuscular injection.

Types of parenteral iron preparations: These include iron-sorbitol, iron-dextran

(imferon), and preparations with much lower rates of adverse effects such as iron
sucrose or sodium ferric gluconate, ferric carboxymaltose, and iron isomaltoside.
Side effects/toxicity of parenteral iron preparations :

• Pain and swelling at the site of injection/infusion

• Anaphylactic reactions: Fever, generalized urticarial rash,

lymphadenopathy, splenomegaly, and arthralgias
• Hemochromatosis
B12 and Folate deficiency anemia
Megaloblastic anemia
This results from a deficiency of vitamin B₁₂ or folic acid, or from
disturbances in folic acid metabolism. Folate is an important substrate of,
and vitamin B12, a co-factor for, the generation of the essential amino acid
methionine from homocysteine. This reaction produces tetrahydrofolate,
which is converted to thymidine monophosphate for incorporation into
DNA. Deficiency of either vitamin B₁₂ or folate will therefore produce high
plasma levels of homocysteine and impaired DNA synthesis.

The end result is cells with arrested nuclear maturation, but normal
cytoplasmic development: so-called nucleocytoplasmic asynchrony. All
proliferating cells will exhibit megaloblastosis.
The mature red cells are large and oval,
and sometimes contain nuclear
remnants. Nuclear changes are seen in
the immature granulocyte precursors
and a characteristic appearance is that
of 'giant' metamyelocytes with a large
'sausage-shaped' nucleus. The mature
neutrophils show hypersegmentation of
their nuclei, with cells having six or
more nuclear lobes.
Vitamin B12 deficiency
ABSORPTION
In the stomach, gastric enzymes release vitamin B12
from food and at gastric plas pH it binds to a carrier
protein termed R protein. The gastric parietal cells
produce intrinsic factor, a vitamin B12 binding protein
that optimally binds vitamin B12 at pH 8. As gastric
emptying occurs, pancreatic secretion raises the pH
and vitamin B12 released from the diet switches from
the R protein to intrinsic factor. Bile also contains
vitamin B12 that is available for reabsorption in the
intestine. The vitamin B12 intrinsic factor complex
binds to specific receptors in the terminal ileum, and
vitamin B12 is actively transported by the enterocytes
to plasma, where it binds to transcobalamin II, a
transport protein produced by the liver, which carries
it to the tissues for utilisation.
CAUSES OF VITAMIN B12 DEFICIENCY
● Dietary deficiency- This occurs only in strict vegans, but the onset of
clinical features can occur at any age between 10 and 80 years. Less strict
vegetarians often have slightly low vitamin B12 levels, but are not tissue
vitamin B12 deficient.
● Gastric pathology- Release of vitamin B₁₂ from food requires normal gastric
acid and enzyme secretion and this is impaired by hypochlorhydria in older
patients or following gastric surgery.
● Pernicious anaemia- This is an organ-specific autoimmune disorder in
which the gastric mucosa is atrophic, with loss of parietal cells causing
intrinsic factor deficiency. In the absence of intrinsic factor, less than 1%
of dietary vitamin B₁, is absorbed.
● Small bowel pathology - One-third of patients with pancreatic exocrine
insufficiency fail to transfer dietary vitamin B₁₂ from R protein to intrinsic
Signs
and
sympto
ms
FOLATE DEFICIENCY
FOLATE ABSORBTION

Folates are produced by plants and bacteria; hence dietary leafy vege-
tables (spinach, broccoli, lettuce), fruits (bananas, melons) and animal
protein (liver, kidney) are a rich source. Most dietary folate is present as
polyglutamates; these are converted to monoglutamate in the upper
small bowel and actively transported into plasma. Plasma folate is
loosely bound to plasma proteins such as albumin and there is an
enterohepatic circulation. Total body stores of folate are small and
deficiency can occur in a matter of weeks.
Management of megaloblastic anaemia

If a patient with a severe megaloblastic anaemia is very ill and

treatment must be started before vitamin B12 and red cell folate
results are available, that treatment should always include both
folic acid and vitamin B12The use of folic acid alone in the
presence of vitamin B12 deficiency may result in worsening of
neurological features.

Rarely, if severe angina or heart failure is present, transfusion

can be used. The cardiovascular system is adapted to the
chronic anaemia present in megaloblastosis and the volume
load imposed by transfusion may result in decompensation and
severe cardiac failure. In such circumstances, exchange
transfusion or slow administration of 1U of red cells with diuretic
Vitamin B12 deficiency
Vitamin B12 deficiency is treated with hydroxycobalamin.
● In cases of actively malabsorption, 1000 µg IM for 6 doses 2 or 3
days apart, followed by maintenance therapy of 1000 µg every 3
months for life, is recommended.
● In the presence of neurological involvement, a dose of 1000 µg on
alternate days until there is no further improvement, followed by
maintenance as above, is recommended.
● In dietary deficiency oral B₁₂ replacement will suffice.
● The reticulocyte count will peak by the 5th-10th day after starting
replacement therapy. The haemoglobin will rise by 10 g/L every
week until normalised.
● A sensory neuropathy may take 6-12 months to correct; long-
standing neurological damage may not improve.
Folate deficiency

● Oral folic acid (5 mg daily for 3 weeks) will treat acute

deficiency and 5 mg once weekly is adequate maintenance
therapy. Prophylactic folic acid in pregnancy prevents
megaloblastosis in women at risk and reduces the risk of
fetal neural tube defects. Prophylactic supplementation is
also given in chronic haematological disease associated
with reduced red cell lifespan (e.g. haemolytic anaemias).
ANEMIA OF CHRONIC DISEASE
INTRODUCTION

The anemia of chronic disease (ACD), also termed

the anemia of chronic inflammation, is associated
with many chronic diseases (infectious,
inflammatory, neoplastic disease, severe trauma,
heart disease, diabetes mellitus, etc.). Though
ACD occurs in chronic diseases, it can begin
acutely during virtually any infection or
inflammation.
 PATHOPHYSIOLOGY
Reticuloendothelial cells retain
iron from senescent RBCs,
Three pathophysiologic
mechanisms have been making iron unavailable for Hb
identified in ACD synthesis.

There is thus a failure to

1. Shortened RBC survival due to
compensate for the anemia
unknown mechanisms
with increased RBC production.
2. Impaired erythropoiesis due to Macrophage-derived cytokines
decrease in both erythropoietin (e.g. IL-1, TNF, interferon)
(EPO) production and marrow contribute to the decrease in
responsiveness to EPO EPO production and the
impaired iron metabolism.
3. Impaired intracellular iron
metabolism.
CLINICAL FEATURES

Most patients have mild anemia that produces no

symptoms.
Signs and symptoms of underlying disease may be
present.
INVESTIGATIONS

● Normochromic normocytic anemia

● Reticulocyte count, leukocyte count and
reticulocyte count normal
● Serum iron concentration and transferrin level
are low
● Percent saturation of transferrin is normal
TREATMENT

● Correction of underlying disorder

● Iron supplements
● Severe anemia = Administer recombinant
human erythropoietin
Alpha Thalassemia
Alpha thalassemia results from deletions or mutations in the HBA1 and HBA2 genes, which encode the alpha-globin subunits of hemoglobin. It is classified based on the number of affected alpha-globin genes:

1. Alpha Thalassemia Major (Hemoglobin Bart’s Hydrops Fetalis Syndrome):

• Genotype: Deletion or inactivation of all four alpha-globin genes .

2. Hemoglobin H Disease:

• Genotype: Deletion or inactivation of three alpha-globin genes.

3. Alpha Thalassemia Trait (Alpha Thalassemia Minor):

• Genotype: Deletion or inactivation of two alpha-globin genes, either in cis (same chromosome: –/αα) or trans (opposite chromosomes: -α/-α).

4. Silent Carrier:

• Genotype: Deletion or inactivation of one alpha-globin gene (-α/αα).

Haemolytic Anemia
Hemolytic anemia is a condition in which red blood cells are destroyed
and removed from the bloodstream before their normal lifespan is over.
This premature destruction of red blood cells leads to a shortage of red
blood cells, causing symptoms such as fatigue, weakness, pallor,
shortness of breath, and jaundice.
Reduced RBC —-> reduced Hb—-> hypoxia to tissues —-> reticulocyte
index>2.5(hyper proliferation)
SITE OF HEMOLYSIS
Intravascular hemolysis Extravascular hemolysis

RBCs destroyed within the blood. RBCS destroyed in the

Hemoglobinemia + reticuloendothelial system (spleen)
Hemoglobinuria + Reticulocytosis + (mcv is higher).
Hemosiderinuria + (due to modification of proximal Iron overload from heme. (Serum
tubular cells). Ferritin levels increased)

Dark/ high colored urine. unconjugated hyper bilirubinemia/ jaundice from

Elevated LDH. protoporphyrin.
urobilinogen + in urine.
Splenomegaly +.

Decreased haptoglobin levels (Released Hb binds Low haptoglobin levels (but lower in intravascular
to haptoglobin) hemolysis)

INVESTIGATIONS— LDH,HAPTOGLOBIN LEVELS,UROBILINOGEN,

S.BILIRUBIN
CAUSES
Antibody mediated RBC DESTRUCTION
IgG Antibody mediated.(warm mediation ) monoclonal Igm Antibody mediated( cold
mediation)

more common Less common

Females » males. Optimal Temperature for preferential Binding : 4°C
• moderate splenomegaly. C0° - 4°C).
• Polychromasia/ Spherocytes/ Fragmented RBCS/ • Primary/ idiopathic : Cold agglutinin disease
• Splenic macrophages → Have receptors for Fc (CAD).
portion of IgG antibody → IgG Antibodies Trapped On exposure to cold → compliment activation (C3b)
by splenic macrophages → subacute presentation. → mostly Intravascular + Partly Extravascular →
• Optimal Temperature for preferential binding 37°C. Precipitates in peripheries → Presents like
Acrocyanosis and Raynaud's phenomenon.

Treatment-Ist line: Oral Steroids 1mg/Kg → 4weeks Relapse:

Low dose Rituximab 100mg/mª → weekly Hb at presentation very low → Indicator of relapse
Splenectomy.
• Unwilling for Splenectomy → High dose Rituximab
Treatment
1. Stabilisation
2. Blood transfusion- PRCBs can be given to elevate Hb instantly.
3. Treat underlying cause.- steroids - antibiotics- discontinue drugs of
lysis
4. Manage complications- iron chelation and hydration with fluid
correction
5. Supportive care - folic acid supplements - pain killers