Macrocytic Anemias Flashcards
What is this describing:
- Deficiency of either folate or cobalamin (B12) with or without other cytopenias, caused by megalobastic hematopoiesis that results from defective DNA synthesis
macrocytic anemias
Pertaining to macrocytic anemias:
- RBCs are unusually (…)
- (…) synthesis is defective
- Due to deficiencies in (…) or (…)
- (…) processes occur at a normal rate which results in unequal grown of the (…) and (…)
- large
- DNA
- vitamin B12 or folate
- RNA processes; nucleus and cytoplasm
What are co-enzymes for nuclear maturation and the DNA synthesis pathway?
vitamin B12 or folate
- The most common causes of macrocytic anemias are (…) and (…)
- What is the MCV in macrocytic anemia?
- vitamin B12 and folate
- MCV > 100 fL
- What labs can you order for macrocytic anemias?
- If all tests are normal, what can you get?
- peripheral smear and retic count; serum vitamin B12, folate, RBC folate levels, methylmalonic acid (MMA) and homocysteine levels; TSH
- bone marrow biopsy
- What is the earliest manifestation of megaloblastosis in peripheral blood?
- What is diagnosed if more than 5% of polymorphonuclear leukocytes have 5 lobes or if 1% have six lobes on the smear?
- What does this strongly suggest?
- increase in MCV with macro-ovalocytes
- nuclear hypersegmentation of neutrophils
- megaloblastosis, especially in association with macro-ovalocytosis
- Neutrophil hypersegmentation is not sensitive for the diagnosis of (…) and (…) is absent in nearly 50% of cases
- There may be associated (…) shaped erythrocytes and (…) with leukopenia and thrombocytopenia
- mild cobalamin deficiency; macrocytosis
- teardrop shaped; anisocytosis
What is the differential diagnosis for megaloblastic macrocytic anemia? (things you need to rule out first)
- vitamine B12 deficiency
- folic acid deficiency
- drug-induced
What is the differential diagnosis for non-megaloblastic macrocytic anemia?
- excess alcohol consumption
- chronic liver disease
- hypothyroidism
- aplastic anemia
- paraproteinemia (multiple myeloma)
- pregnancy
- pure red cell aplasia
- What type of vitamin is vitamin B12?
- How is it excreted?
- What is it bound to?
- What is the name of the B12 found in your blood?
- water soluble vitamin
- urine
- plasma proteins
- cyanocobalamin
- How do mammals get vitamin B12?
- Where is it stored?
- What is the role of vitamin B12?
- What does vitamin B12 act as a coenzyme for?
- outside source such as diet/supplements because the body cannot synthesize it
- liver
- helps synthesize nucleotides, DNA, RNA, and proteins
- 2 different reactions in the body
- Vitamin B12 plays a role in (…) of erythroid nucleus
- Lack of vitamin B12 leads to (…) which is low RBC count specifically due to impaired synthesis of (…)
- The serum concentration of B12 will be less than (…), the normal levels are (…)
- DNA synthesis
- macrocytic anemia; RBC DNA
- 200; 200-900
What are some main causes of B12 deficiency?
- gastric bypass (surgery)
- bowel diseases (crohns)
- B12 cannot be absorbed until it reaches the end of the (…)
- To protect it from being deactivated by enzymes, (…) is made to protect B12 until absorption
- If a person is deficient in B12, they can lose (…) in nerves which can lead to neurological problems
- small bowel
- intrinsic factor
- myelin sheaths
What are extensive possible causes of a cobalamin(B12) deficiency?
- nutritional B12 deficiency (insufficient cobalamin intake)
- abnormal intragastric events (inadequate breakdown)
- loss/atrophy of gastric oxyntic mucosa (deficient intrinsic factor)
What patients may have a nutritional cobalamin deficiency?
- vegetarians
- poverty-imposed-near vegetarians
- breast-fed infants of mothers with pernicious anemia
What patients may have a cobalamin deficiency due to abnormal intragastric events?
patients with:
- atrophic gastritis
- hypochlorhydria (low acid)
- proton pump inhibitors
- H2 blockers
What patients may have a cobalamin deficiency due to deficient intrinstic factor molecules?
patients with:
- total or partial gastrectomy
- adult and juvenile pernicious anemia
- caustic destruction (lye)
What are some other causes of cobalamin deficiencies?
- disorders of ileal mucosa/intrinsic factor-cobalamin receptors (IF-cobalamin not bound to IF-cobalamin receptors)
- diminished or absent cubam receptors (ileal bypass, resection, fistula)
- drug effects
What are intrinsic factor-cobalamin receptors also known as?
cubam receptors
What can cause a decrease or total absence of cubam receptors?
- ileal bypass
- resection
- fistula
What drugs can cause cobalamin deficiency?
- metformin
- cholestyramine
- colchicine
- neomycin
- How long may it take for a patient with a B12 deficiency to show symptoms?
- Why this long?
- Humans don’t have to take in that much B12 because we can (…) so there is a baseline
- 3-5 years
- it is stored for that long in our liver
- recycle it
What does the aborption process of B12 require?
- a dysfunction in any of these can lead to what?
- intact stomach intrinsic factor
- pancreatic sufficiency
- functioning terminal ileum
can lead to malabsorption
What is the most common cause of macrocytic anemias and is a megaloblastic anemia caused by autoimmune gastritis that impairs intrinsic factor, which is required for vitamin B12 uptake from the gut?
pernicious anemia
What can these lead to:
- gastric mucosa attacked by autoimmune disease and destroyed parietal cells that secrete intrinsic factor
- atrophy of gastric mucosa, disordered ileac mucoa
pernicious anemia
- Pernicious anemia may be a (…) or (…) disorder
- (…) can be formed against instrinsic factor
- congenital or autoimmune
- autoantibodies
What conditions increase the risk of pernicious anemia?
- past infection with Helicobacter pylori
- gastrectomy
- proton-pump inhibitors
In pernicious anemia, gastric galnds in the atrophic mucosa are sparse and consist mainly of (…) cells; the mucosa is densely infiltrated by (…)
- mucus-secreting cells
- lymphocytes
- The majority of patients with pernicious anemia are (…)
- Pernicious anemia is more prevalent in which populations?
- asymptomatic
- elderly, infants, vegetarians, pregnant and breastfeeding women
What percent of the elderly over age 70 have pernicious anemia and are vitamin B12 deficient?
about 6%
Pertaining to risk factors of pernicious anemia:
- There is a heritable component of pernicious anemia; it is deemed congenital if abscence occurs without (…)
- Patients have a higher risk of developing this anemia with a (…) of it
- There is also a strong association of pernicious anemia with (…) and (…) disease
- gastric atrophy
- family history
- autoimmune disorders and thyroid disease
What autoimmune disorders are associated with pernicious anemia?
- Addison’s disease
- type I diabetes
- vitiligo
What are other factors that increase a patients risk of pernicious anemia?
- gastrectomy, gastric stapling, gastric bypass procedures
- vegetarianism (especially strict vegans)
- pharmacologic agents (nitric oxide, metformin, phenformin, colchicine)
Perinicious anemia is often unrecognizable in (…) decause of its subtle, slow onset and presentation
older adults
What are some anemia symptoms of pernicious anemia?
- general weakness/fatigue/light headedness
- shortness of breath
- heart palpitations
- pale skin
- diarrhea, constipation, loss of appetite
- swollen, red tongue and/or bleeding gums
What are some neurologic symptoms that can occur with prolonged B12 deficiency?
- paresthesia, numbness, muscle weakness, proprioceptive problems
- degeneration of spinal cord
- vision loss/changes
- depression, memory loss, changes in behavior
- problems concentrating
Being deficient in folic acid presents differently that B12 deficiency as it does not affect or cause what?
does not affect nerve fibers or cause neurological symptoms
What may a peripheral smear of pernicious anemia show?
- hypersegmented neutrophils (> 6)
- anisocytosis, poikilocytosis
- macro-ovalocytosis may be present
What may a bone marrow aspiration/biopsy in a patient with pernicious anemia show?
(this is not common do to)
- megaloblastric erythroid precursor
- cells with nuclear cytoplasmic dissociation
- What will serum cobalamin levels be in a patient with pernicious anemia?
- How will serum LDH and indirect bilirubin be affected (if hemolysis is present)?
- When doing gastric secretion evals and intrinsic factor antibody assay in a patient with pernicious anemia, what will the results be?
- What other tests can be done, are highly sensitive but very expensive?
- How will these tests be affected in cobalamin deficiency?
- < 200 pg/mL (low sensitivity)
- elevated LDH and indirect bilirubin
- pernicious anemia; intrinsic factor absent or decreased
- serum homocysteine and methylmalonic acid (MMA)
- both will be elevated
How will serum homocysteine and methylmalonic acid (MMA) be affected in a cobalamin deficiency vs folate deficiency?
- both will be elevated in cobalamin deficiency
- only homocysteine will be elevated in folate deficiency
- What is the normal methylmalonic acid (MMA) level?
- What is the normal total homocysteine levels?
- 70-270 nM
- 5-14 uM
If both methylmalonic acid and total homocysteine are elevated, what is the diagnosis?
- cobalamin deficiency confirmed
- folate deficiency still possible
(combined cobalamin + folate deficiency possible)
If methylmalonic acid is normal but total homocysteine is elevated, what is the diagnosis?
- folate deficiency likely
- < 5% may have cobalamin deficiency
If both methylmalonic acid and total homocysteine are normal, what is the diagnosis relating to cobalamin/folate deficiencies?
both cobalamin and folate deficiencies are excluded
What is the treatment for pernicious anemia in severely decompensated patients (emergent)?
- transfusion post blood draw
- vitamin replacement
What is the treatment for individuals with an established cobalamin deficiency?
- replace B12 rapidly at 1 mg/day IM or SQ (1st week), 1 mg twice weekly (2nd week), 1 mg/week (3rd-6th week), 1 mg/month (for life)
- pernicious anemia - lifelong 1 mg/month
(treatment the same no matter the cause)
What is the treatment for individuals with a mild cobalamin deficiency?
oral cobalamin (sublingual) 2 mg/day for 3 months, then monthly maintenance or 2 mg/day orally
(food intake will reduce absorption of oral by 50%)
What is the treatment for a patient with a subclinical deficiency of B12? How does this patient typically present?
- patient asymptomatic w/ mildly abnormal values for many months but sometimes returns to normal
- no treatment and level monitoring
- monitor and treat when levels are abnormal
- empiric treatment 1-2 mg/day orally while monitoring levels every 6-12 months
Neurological signs and symptoms of cobalamin deficiency are reversible if treated within (…)
6 months
- Folate is an essential vitamin for (…) and (…) synthesis
- Where does absorption of folate occur?
- Is folate dependent on any other facilitating factors?
- Folate deficiencies are common in which individuals?
- What is a folate deficiency associated with in the fetus?
- RNA and DNA synthesis
- upper small intestion
- no
- alcoholics, chronic malnourishment
- neural tube defects
- Folic acid is required for (…) and (…) synthesis, however, it must come from (…) sources
- Daily needs of folic acid are dependent on what?
- The degree of absorption depends on its (…)
- About (…) of folate naturally occurring in food is bioavailable
- Folate is (…) in fruits and veggies, but boiling veggies destroys (…)% of folate content
- (…)% of folic acid supplementation is bioavailable when consumed with food
- DNA and RNA; exogenous
- age and other co-morbidities
- source
- half
- endogenous; 95%
- 85%
Where is folate stored?
How is it excreted?
- fat tissue and the liver
- urine and bile
Pertaining to folate deficiency:
- can lead to (…) anemia
- can lead to (…) defects in utero
- will result in impairment in (…) and accumulation of (…)
- is associated with (…) levels of homocysteine with chronic deficiency
- is associated with an increased risk for (…) and (…)
- megaloblastic anemia
- neural tube defects
- cell division; toxic metabolites
- elevated levels
- ischemic heart disease and stroke
What are some causes of folate deficiencies?
(longer list)
- nutritional causes
- decreased dietary intake d/t poverty/famine, institutionalization, debilitating disease, feeding infants w/ goats milk
- decreased dietary intake with increased requirements (pregnancy/lactation)
- pregnancy, lactation, prematurity, hyperemesis gravidarum, infancy
- folate antagonists
- drugs
What can lead to folate deficiency?
- deficieny folic acid consumption
- previous diagnosis of hemolytic anemia
- alcoholism
- medications
What is the RDA of folic acid consumption for:
- adult men and non-pregnant women
- pregnant women
- lactating women
- children between 9-18 years old
- 400 ug
- 600 ug
- 500 ug
- 300-400 ug
Why can alcoholism lead to a folate deficiency?
- hyperactive alcohol dehydrogenase can catabolize folate prior to its absorption in the gut
What medications can cause folate deficiency?
- folate antagonists: phenytoin, methotrexate, TMP-SMX, sulfasalazine
- triamterene, pyrimethamine, barbiturates
- Symptoms of anemia manifests within (…) of folate deficiency and dominates the overall clinical picture
- What are some general symptoms of anemia in this case?
- 4-6 months
- weakness, pallor, dizziness, fatigue
What are some more specific symptoms specific to folate deficiency (hematologic/mouth)?
hematologic:
- pancytopenia w/ megaloblastic bone marrow
mouth:
- sore/swollen/red tongue or dysphagia (glossitis)
- mouth ulcers
- angular cheilosis
What are some gastrointestinal manifestations of folate deficiency?
- megaloblastosis w or w/o malabsorption
- vomiting, abdominal pain, diarrhea especially after meals
- anorexia or marked weight loss
What are some dermatologic manifestarions of folate deficiency?
- acquired hyperpigmentation of skin on palms and soles
- overall gross pallor
- premature graying
What are some other manifestations of folate deficiency?
(2)
- infertility
- psychiatric: flat affect
- When a patient comes in with macrocytic anemia (suspected folate deficiency), what should done first?
- After determining folate deficiency, what can be ordered?
- What reflects changes in folate intake?
- What test should be ordered next?
- What makes this test unreliable?
- rule out cobalamin (B12) deficiency by obtaining serum cobalamin level
- serum folate level
- serume folate
- RBC folate level
- RBC transfusions
- What is the normal range of serum cobalamin?
- Folate treatment will not be effective on neurological symptoms if (…) is the cause
- What levels alone are not enough to diagnose a folate deficiency as 2-5% of the population are naturally deficient and considered normal?
- What test is only useful in ruling out folate deficiency ( > 5 ng/mL is the target to r/o)
- What test level reflects folate storage levels?
- If this test is low, then it is (…)
- 200-900 pg/mL
- cobalamin
- serum folate
- serum folate
- RBC folate levels
- diagnostic of folate deficiency
What is the pattern for work-ups when determining folate deficiency?
- serum cobalamin
- serum folate
- RBC folate level
- serum homocysteine, methylmalonic acid
- peripheral smear
- What will be elevated in both folate deficiency and B12 deficiency?
- What is only elevated in B12 deficiency only?
- If this is not elevated, then it is most likely (…)
- serum homocysteine level
- serum methylmalonic acid (MMA)
- folate deficiency
What will be seen on a peripheral smear for a patient with folate deficiency?
- hypersegmented neutrophils and oval macrocytes
- howell-jolly bodies (nuclear remnants) are typical
What is pathognomonic for folate deficiency if seen on a peripheral smear?
hypersegmented neutrophils and oval macrocytes
- What tests help guide diagnosis and treatment of folate deficiency?
- What tests are the most diagnostic for folate deficiency?
- folate and cobalamin levels
- serum homocystein and methylmalonic acid levels
What is the dialy requirement of folate that is usually met by balanced diet?
50-100 mg/dL
What is the treatment for acute and chronic folate deficiency?
- 1 mg/day or IV until complete hematologic recovery documented
** adequate absorption despite intestinal malabsorption
What are some other methods of treating folate deficiencies?
- increase folate through dietary changes
- supplemental dietary folic acid during pregnancy
What are some foods that you can obtain folate through? What should you avoid?
- leafy green veggies, fruits, eggs, poultry, pork, fortified cereals
- avoid alcohol and antagonists
What should be given during pregnancy that can reduce incidence of neural tube defects in babies is mom is folate deficient?
supplemental dietary folic acid
- Folate deficiencies will not manifest with (…)
- Be sure to ask patients if they have had (…)
- neurologic symptoms such as neuropathy
- peripheral neuropathy
You can narrow down your diagnosis of folate deficiency anemia by considering what?
- alcoholics
- pregnancy
- gluten-free diet
- methotrexate use (antagonist)
What are some causes of megaloblastic anemia not responding to therapy with cobalamin or folate?
- wrong diagnosis
- combined folate and cobalamin deficiencies treated with only one vitamin
- associated iron deficiency
- associated hemoglobinopathy (sickle cell, thalassemia)
- associated ACD
- associated hypothyroidism
What is this showing? What is this associated with?
- hypersegmentation
- pernicious anemia (possibly folate deficiency)
What is this showing? What is this associated wtih?
- hypersegmentation with oval macrocytes
- folate deficiency
What is this showing? These are typically seen on a peripheral smear associated with what?
- howell-jolly bodies
- folate deficiency
