Download megaloblastic anemia (1).

BY
DR. Hayam Hebah
Associate Professor of Internal Medicine
AL Maarefa College
Objectives:
 Background
 Causes
 B12
 Folic acid
 Management.
BACKGROUND:
Megaloblastosis describes a heterogeneous
group of disorders that share common morphologic
characteristics: large cells with an arrest in nuclear
maturation. Nuclear maturation is immature relative
to cytoplasmic maturity. Cells seen in bone marrow
aspirates and in peripheral smears have been called
megaloblasts.
 Megaloblastic changes are most apparent in rapidly
dividing cells such as blood cells and gastrointestinal
cells.
PATHOPHYSIOLOGY:
 The common feature in megaloblastosis is a defect in
DNA synthesis in rapidly dividing cells. To a lesser
extent, RNA and protein synthesis are impaired.
 B12 helps to synthesize thiamine, thus deficiency
leads to problems with DNA replication
Causes of Megaloblastic
Anemia
B12 deficiency
Folate deficiency
Pernicious anemia
OTHER CAUSES OF
MEGALOBLASTOSIS:
*Medications(antimetabolite drugs as azathioprine)
*Direct interference of DNA synthesis by:
-- HIV infections
--myelodysplastic disorders.
*Liver disease with inadequate cholesterol esterification
*Alcohol abuse independent of folate (MCV 100-105)
*Post-splenectomy
VITAMIN B12 AND FOLIC ACID-PHYSIOLOGIC
CONSIDERATIONS
Vitamin B12
meat, fish
Sources
yeast
Daily requirement
Body stores
Folic acid
green vegetables,
2-5 ug
50-100 ug
3-5 mg (liver)
10-12mg (liver)
Places of absorption
ileum
duodenum
and proxymal
segment of small
intestine
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Vitamin B12 (cobalamin)
 The primary sources of cobalamin (Clb), a cobalt-
containing vitamin, are meat, fish, and dairy products
and not vegetables and fruit.
 Cobalamin is the only water-soluble vitamin stored in
the body. About 3 mg of cobalamin are stored, of
which 1 mg is stored in the liver. Hence, it takes 3-5
years to develop a vitamin B-12 deficiency after a total
gastrectomy. In contrast, significant amounts of folate
are not stored. Clinical evidence of folate deficiency
can occur within a month after folate intake is stopped
B12 Metabolism
 Bind to cobalophilin (cobalamine binding protein)
in saliva and gastric secretion
 Bind to IF (from parietal cell) in the duodenum
 Cbl-IF complex bind to receptor (cubilin) at distal
ileum for mucosal absorption
 1% B12 can be absorbed without IF (megadose of
B12 for IF deficiency )
MEGALOBLASTIC ANEMIAS
Causes of Vit.B12 deficiency(1)
1. Malabsorption
a) Inadequate production of intrinsic factor
- pernicious anemia (autoimmune destruction of gastric
parietal cells)
- gastrectomy, partial or total
b) Inadequate releasing vit. B12 from food
- (partial gastrectomy, atrophic gastritis and achlorhydria
(mainly in elderly patients),
- chronic pancreatic insufficiency (the alkaline environment
in the small intestine is insufficient for release of cobalamin
from R-proteins and binding to intrinsic factor)
c) Terminal ileum disease (sprue, celiac disease, ilea resection,
Crohn
disease, Imerslund syndrome)
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Causes of Vit.B12 deficiency(2(
d) Competition for intestinal B12 :
- bacterial overgrowth: jejunal diverticula, intestinal stasis
and
obstruction due to strictures, blind-loop syndrome
- Fish tapeworm Diphyllobothrium latum , found in Canada,
Alaska, and the Baltic Sea.
2-Inadequate intake
Dietary cobalamin deficiency rarely causes megaloblastic anemia,
except in vegetarians
3. Inadequate utilisation
Drugs: PAS, Neomycin, Colchicin, Nitrous oxide
 in the Zollinger-Ellison syndrome, the acid
environment also prevents binding of cobalamin to
intrinsic factor.
 Disorders of the terminal ileum can result in
cobalamin deficiency. Because the terminal ileum is
the site of uptake of cobalamin-IF complexes, tropical
sprue, inflammatory bowel disease, lymphoma, and
ileal resection can lead to cobalamin deficiency.
 Blind loop syndrome can result in cobalamin
deficiency. Bacterial colonization can occur in
intestines deformed by strictures, surgical blind loops,
scleroderma, inflammatory bowel disease, or
amyloidosis. Bacteria then compete with the host for
cobalamin.
 A partial list of medications that can cause cobalamin
deficiency includes:
1. purine analogs (6-mercaptopurine, 6-thioguanine,
acyclovir),
2. pyrimidine analogues (5-fluorouracil, 5-azacytidine,
zidovudine),
3. ribonucleotide reductase inhibitors (hydroxyurea,
cytarabine arabinoside)
4. drugs that affect cobalamin metabolism (p aminosalicylic acid, phenformin, metformin).
Causes of B12 Deficiency
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Gastrectomy/Bariatric surgery
Ileal resection or bypass
Ileal disease (TB, lymphoma, amyloid, post-radiation, Crohn’s)
Enteropathies (protein losing, chronic diarrhea, celiac sprue
Fish tapeworm (Diphyllobothrium latum) infection
Bacterial overgrowth
HIV infection
Chronic alcoholism
Sjogren’s syndrome
Pancreatic Exocrine Insufficiency
Strict vegan diet
Inherited
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Trans-Cbl II or IF deficiency
decreased uptake of IF-Cbl (juvenile megaloblastic anemia) - also presents with proteinuria
Homocysteinuria, severe abnormalities of methionone synthesis, abnormal lysosomal exporter
 Decreased absorption from medication
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Neomycin
Metformin up to 10-25%
PPI
Nitric oxide (inhibits methionine synthase)
Pernicious Anemia
 Autoantibody to Intrinsic Factor detectable in
<70%
 Highly specific, but insensitive
 2 types of anti-IF antibody
 Blocks attachment of Cbl to IF
 Blocks attachment of Cbl-IF complex
 to ileal receptors
 Chronic atrophic gastritis
 Autoantibody against parietal cells (H-K-ATPase)
though pathology indicates destruction by CD4+ T cells
 Increased risk of gastric cancer (carcinoid and
intestinal- type)
 Folate is found in vegetables, fruits, and animal protein
 Physiological folate absorption and transport is receptor
mediated. There is no equivalent of IF to stabilize and
transport ingested folate. Uptake occurs in the jejunum and
throughout the small intestine
 Storage is limited, and folate deficiency develops about 3-4
weeks after the cessation of folate intake
 The daily requirement for adults is about 0.4 mg/d.
Causes of folate deficiency:
 Low folate food content and overcooking are
causes for folate deficiency, especially in elderly
persons.
 Increased demand can result in deficiency as in
hemolysis, pregnancy, lactation, rapid growth,
hyperalimentation, renal dialysis, psoriasis, and
exfoliative dermatitis.
 Intestinal disorders that impede folate absorption
include tropical sprue, nontropical sprue (celiac
disease or gluten sensitivity), amyloidosis, and
inflammatory bowel disease.
Medications include:
 phenytoin
 metformin
 phenobarbital
 dihydrofolate reductase inhibitors (trimethoprim,
pyrimethamine)
 methotrexate
 sulfonamides
 valproic acid.
History findings to help identify
folate deficiency are as follows
 Poor nutrition, alternative diets, and excessive heating and
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dilution of foods
Chronic alcoholism
Conditions that interfere with folate absorption, including
inflammatory bowel disease, sprue or gluten sensitivity, and
amyloidosis
Conditions that increase folate consumption, such as pregnancy,
lactation, hemolytic anemia, hyperthyroidism, and exfoliative
dermatitis
Hyperalimentation and hemodialysis
Medications that affect folate (see the list in Etiology)
Hereditary disorder: A lifelong history of megaloblastosis or
folate deficiency would suggest a hereditary disorder as the
cause.
MEGALOBLASTIC ANEMIAS
clinical features
1- Asymptomatic for years
2-Symptoms of anemia(weakness and cardiopulmonary impairement)
3- Symptoms associated with vit. B12 or Folic acid deficiency
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neurologic manifestations (exclusivly in wit. B12 deficiency)
- megaloblastic madness or psychosis,
- subacute, combined degeneration of the spinal cord
( proprioceptive and vibratory sensation), spinal ataxia with
unsteady gait and abnormal balance.
-Peripheral neuropathy (numbness, pain, tingling, and
burning in a patient’s hands and feet in glove and stocking
distribution).
•
gastrointestinal compraints (vit.B12 and folic acid deficiency)
- loss of appetite
- glossitis (red, sore, smooth tongue)
- diarrhea or constipation
-
weight loss
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c/p: signs:
 Patients may have a lemon-yellow complexion (combined
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anemia and increased indirect bilirubin from
intramedullary hemolysis)
Anemia signs(tachycardia , dyspnea)
Glossitis ( with loss of papilla)
Dermatologic signs include hyperpigmentation of the skin
and abnormal pigmentation of hair due to increased
melanin synthesis
Mental changes of psychosis
Peripheral neuropathy
SCD of cord and abnormal gait.
Blindness due to optic atrophy may occur.
signs of the cause.
Signs suggestive of the cause:
 Abdominal scars may suggest a blind loop syndrome due to
gastric surgery or a lack of ileal absorption of cobalamin in a
patient who had an ileal resection.
 Patients with nontropical and tropical sprue may have signs of
malabsorption, such as weight loss, abdominal distention,
diarrhea, and steatorrhea. These patients often have metabolic
bone disease or bleeding resulting from to deficiencies in
vitamin K–dependent factors.
 Patients who have megaloblastosis as a result of HIV infection or
myelodysplastic syndromes usually have signs of these disorders.
 Children with inborn errors associated with folate and
cobalamin deficiencies may have signs of these hereditary
disorders .
Subacute combined degeneration
of the cord
Degeneration and demyelination of
the dorsal (posterior) and lateral
spinal columns.
Whom should you test for B12 or Folate deficiency?
 MCV >100 with or without anemia
 Hypersegmented neutrophils
 Pancytopenia of uncertain cause
 Unexplained neurologic s/s
 Alcoholics
 Malnourished, particularly the elderly
 Vegans if no history of supplementation
 Diabetics on metformin with new onset neuropathy
Lab work out:
 Reticulocyte counts are inappropriately low, representing
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lack of production of RBCs due to massive intramedullary
hemolysis
LDH is usually markedly increased
Peripheral smear morphology:
Macroovalocytes
Single and multiple Howell-Jolly bodies, nuclear fragment,
may be seen in RBCs. Cabot rings, remnants of mitotic
spindles, may also be present in RBCs.
Nucleated RBCs and megaloblasts
hypersegmented neutrophils
pancytopenia
Cabot rings in RBCs
Hypersegmented PMN
Megaloblastic anemia
Megaloblastic BM
Bone marrow aspiration
 Bone marrow aspiration is usually not needed to make
the diagnosis of vitamin B-12 deficiency. However, it
can help rule out myelodysplasia and assess iron
stores.
 The bone marrow is hypercellular with erythroid
hyperplasia
 Giant bands, neutrophil precursers, can be present.
Megakaryocytes may be large and hyperlobulated .
Primary Tests for B-12 and Folate
Deficiencies
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Serum B-12 (cobalamin)
Reference range: 200-900 pg/mL
Borderline: 180-250 pg/mL
Associated with anemia and neuropathy: < 180 mg/L
Diagnostic of B-12 deficiency: < 150 mg/L
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Serum folate
Reference range: 2.5-20 ng/mL
5 ng/mL
Folate deficiency likely (overlap with normal): < 2.5 ng/mL
 RBC folate:
Lab tests to confirm and distinguish B-12 and folate
deficiencies
B12 deficiency
Folate deficiency
homocysteine
↑
↑
MMA
↑
↔
Intrinsic factor (IF) blocking and parietal cell and antibodies
IF antibodies, type 1 and type 2, occur in 50% of patients with pernicious anemia
Parietal cell antibody occurs in 90% of patients.
with pernicious anemia. Both tests are non
Specific.
(Schilling test) not done now.
Other
needed
tests:
 Baseline iron studies and serum ferritin should be
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obtained since they may predict the need for iron
therapy since iron stores can be consumed during
cobalamin or folate therapy.
Radiographic imaging of the upper and lower GIT may
be useful for detecting abnormalities that could cause
a blind loop syndrome
Other tests that may be considered include :
With cobalamin deficiency, evaluate and rule out
autoimmune disorders, Zollinger-Ellison syndrome,
pancreatic insufficiency, fish tapeworm infestation,
Crohn disease, or ileal scarring.
With folate deficiency, evaluate evidence for
malnutrition and alcoholism, sprue, chronic
hemolysis, and exfoliative dermatitis.
Megaloblastic anemia
THERAPY:
 Transfusion therapy should be restricted to patients
with severe, uncompensated, and life-threatening
anemia.
 Cobalamin Therapy
 Cobalamin (1000 µg) should be given intramuscularly
daily for 2 weeks, then weekly until the hematocrit
value is normal, and then monthly for life. Oral
cobalamin (1000-2000 µg) also can be administered.
Note the following:
 Oral cobalamin is indicated in patients with hemophilia to avoid
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intramuscular injections and bleeding.
Intramuscular cobalamin and not oral cobalamin should be used
to treat patients with cobalamin-related neurological disorders.
One advantage of parenteral over oral cobalamin is that all
abnormalities in cobalamin absorption are bypassed.
It may be practical to initially administer parenteral cobalamin
and then to continue treatment with oral cobalamin. Oral
cobalamin is less expensive and is better tolerated by patients.
Patients who have undergone either a total or partial
gastrectomy should be started on replacement therapy after the
surgery to prevent the development of megaloblastosis
Folate Therapy
 Folate (3-5 mg) should be administered orally.
 Folate should be administered prophylactically during
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pregnancy, lactation, and the perinatal period.
Folate is also indicated in patients with chronic hemolytic
anemias, psoriasis and exfoliative dermatitis, and during
extensive renal dialysis.
Folate therapy has been recommended in patients with
hyperhomocysteinemia who are at risk for thromboembolic
complication
Fortification of foods and folic acid supplements have been
recommended to reduce the risk of pancreatic, cervical,
and colon cancers.
Folic acid supplements are indicated in end-stage renal
disease. Folate supplementation is indicated in elderly
persons
Folate Deficiency Treatment
 Oral folate 1mg daily for 4 months or until hematologic
recovery
 Rule out B12 deficiency prior to treament as folic
acid will not prevent progression of neurologic
manifestations of B12 deficiency
 Repeat testing for B12 deficiency may be reasonable
for those on long-term folic acid therapy if
hematologic (macrocytosis or ↑LDH) or neurologic
sx persist
Warning
 Folate therapy should not be instituted in a patient
with megaloblastic anemia if cobalamin deficiency has
not been definitively ruled out. The danger is that folic
acid will improve the anemia but not the neurological
complications of cobalamin deficiency, and the
neurological disorder will worsen. Both cobalamin and
folate should be initiated if cobalamin deficiency has
not been ruled out
Treatment of Other Related
Conditions
 Blind loop syndrome should be treated with antibiotics.
 Patients with transcobalamin II (TCII) deficiency may
require higher doses of cobalamin.
 Tropical sprue should be treated with both cobalamin and
folate.
 Acute megaloblastic anemias due to nitrous oxide exposure
can be treated with folate and cobalamin.
 Fish tapeworm infection, pancreatitis, Zollinger-Ellison
syndrome, and inborn errors should be treated with
appropriate measures.
diet
 Patients should have diets rich with folic acid.
Examples of such foods include asparagus, broccoli,
spinach, lettuce, lemons, bananas, melons, liver, and
mushrooms.
 To prevent loss of folate, foods should not be cooked
excessively and should not be diluted in large amounts
of water.
 To prevent cobalamin deficiency, vegetarians should
include dairy products and eggs in their meals
Prognosis
 The prognosis is favorable if the etiology of
megaloblastosis has been identified and appropriate
treatment has been instituted. However, patients are at
risk for hypokalemia and anemia-related cardiac
complications during therapy for cobalamin
deficiency.
 Folate deficiency during pregnancy can lead to neural
tube defects and other developmental disorders in the
fetus. However, folate in prenatal vitamins given
during pregnancy has reduced these morbidities