Macrocytic Anemias

What are the major causes of Megaloblastic anemia?

vitamin B12 deficiency of folic acid deficiency

What are the major causes of nonmegaloblastic anemia?

chronic alcohol intake, hypothyroidism, acute "shift reticulocytosis" after blood loss/hemolysis

Megaloblastic anemia

- defect in DNA synthesis
- unbalanced cell growth/impaired division
- ovalocytosis/elliptocytosis

Clinical presentations for megaloblastic anemia

- occur after H + H decrease
- typical anemia symptoms, dyspeptic, glossitis

What are the peripheral blood findings for megaloblastic anemia?

- pancytopenia

- High MCV (macrocytic)

- marrow erythroid hyperplasia

- hyper segmented neutrophils, tear drop, basophilic, HJ, cabot rings

What values would be increased in megaloblastic anemia?

LDH, indirect bili, serum Fe, ferritin, homocysteine, methylmalonic acid (in B12 def), formiminoglutamic acid (in folate def)

Decreased labs in megaloblastic anemia

vitamin B12 or folic acid

What does the bone marrow look like in patients with megaloblastic anemia?

- hypercellular
- enlarged precursors (esp. erythroid)
- megaloblastosis due to block in DNA synth
- dec M:E ratio (<1:1)

Which of the DNA bases is blocked due to folate/B12 deficiency?

Thymindine (T)

Cobalamin metabolism

- in stomach/small intestine
- dietary B12 released from digested animal proteins

How does cobalamin move through the body?

B12-HC complex > duodenum (separates from haptocorrin) > B12-IF complex > binds receptor cells of small intestine > absorbed binds transcobalamin in plasma

Haptocorrin

transport protein that protects B12 from acid degradation in the stomach

Gastric intrinsic factor

produced by parietal cells of the stomach, B12 can only be absorbed when bound to IF

Transcobalamin

synthesized in the liver, carries 90% of newly absorbed cobalamin (B12)

What is the normal range for B12?

150 - 400 pg/mL (up to 5000 ug)

How long do they B12 stores in your body last after stopping B12 intake?

2-5 years

Dietary cause of B12 deficiency

- very rare in the USA (usu. only vegetarians)
- 5-30 mg/day in average diet
- 5 ug lost per day

How much B12 is stored in the liver?

1/3

How can you see B12 deficiency?

1. impaired DNA synthesis
2. defective fatty acid degeneration (leads to demyelination and neurological disease)

What are causes of B12 deficiency?

malabsorption, biological competition, nutritional deficiency, impaired utilization by tissues (transport proteins/enzyme issue)

What types of biological competition can cause cobalamin deficiency?

intestinal parasites (D. latum) or bacterial overgrowth (Blind loop syndrome)

What can impair the usage of vitamin B12?

transcobalamin deficiency or nitrous oxide inhalation

Pernicious Anemia

- absence of IF (no B12 absorption)
- most common cause of deficiency
- Northern europe (inherited)

What percentage of people older than 60 have undiagnosed PA?

2% (more common in older people)

What antibodies could be present in patients with pernicious anemia?

1. anti-parietal cells (80-90%)
2. anti-IF or IF-B12 complex (60%)

Symptoms of pernicious anemia

- anemia symptoms
- jaundice
- glossitis
- GI symptoms (bad)
- Neuropathy

Gastrectomy

surgical removal of part or all of the the stomach

Malabsorption syndromes

- celiac (atrophy/loss of fx of villi in jejunum)
- surgical resection of the small bowel
- tropical sprue
- inflammatory disease of small intestine (Crohn's)

Blind Loop syndrome

- built up bacteria
- results in diverticulitis
- they take up B12 before it reaches the ileum

What lab findings are present in cobalamin deficiency?

- dec serum B12
- Urinary methylmalonic acid inc > 0.4 mmol/L (earliest detectable marker)
- inc homocysteine
- inc serum IgG if PA

What are the most sensitive indicators of cobalamin deficiency?

MMA and homocysteine

What are examples of foods that provide folic acid?

eggs, milk, leafy vegetables, yeast, liver, fruits

What is the minimum daily dietary requirement of folic acid and where does it come from?

50 ug, small amount made by intestinal flora, rest is dietary

Where is folic acid stored?

liver tissue

What is necessary to convert dUMP to dTMP?

THF bound with methylene

What is needed to convert homocysteine to methionine?

methyl and B12

Causes of folic acid deficiency

- poor intake/increased demand
- liver disease (alcoholism)
- defective absorption (celiac, blind-loop)
- inadequate utilization in the body (chemo)

How long do folate reserves last in the body?

3 months

Where is folic acid deficiency most commonly found?

vegetarians, pregnant women, older pop. w/ poor diet

Lab findings for Folic acid deficiency

- dec serum folate
- inc FIGLU

Non megaloblastic anemia

- unrelated to nutritional deficiency
- ROUND macrocytes
- no hypersegmented neu, leukopenia/thrombo, jaundice, glossitits, or neuropathy

What are conditions that can cause non megaloblastic anemia?

alcoholism, liver disease, hemolytic anemia, hypothyroidism, reticulocytosis