Macrocytic Anaemias

Question 1

What is macrocytic anaemia?

Answer 1

Macrocytic anaemia is a condition in which your body has overly large red blood cells and not enough normal red blood cells.

Question 2

Types of macrocytic anaemia

Answer 2

Megaloblastic

Nonmegaloblastic

Question 3

Megaloblastic macrocytic anaemia

Answer 3

Most macrocytic anaemias are also megaloblastic. Megaloblastic anaemia is a result of errors in RBC DNA production. Leads to incorrect DNA production
Possible causes include:
Vitamin B-12 deficiency
folate deficiency
some medications, such as chemotherapy drugs like hydroxyurea, antiseizure medications, and antiretroviral drugs used for people with HIV

Question 4

Nonmegaloblastic macrocytic anaemia

Answer 4

Nonmegaloblastic forms of macrocytic anaemia may be caused by a variety of factors. 
These can include:
Alcohol		
Pregnancy	
Drugs	–chemotherapy (anti-folates,anti-purines) and 	anti-HIV	drugs	
Liver disease	
Raised reticulocyte count	
Hypothyroidism	
Myelodysplasia, including	acquired sideroblastic anaemia
Aplastic anemia and red cell aplasia
Hypoxia	
Myeloma and other paraproteinaemias

Question 5

How does vitamin B12 deficiency present?

Answer 5

Classically presents with megaloblastic anaemia.

But can also present with peripheral neuropathy and neuropsychiatric complaints.

Question 6

Typical patients with vitamin B12 deficiency?

Answer 6

Older people.
People with chronic malabsorption,
Patients with Hx of gastric resection or bypass.
People taking metformin and PPI.

Question 7

Causes of vitamin B12 deficiency?

Answer 7

Decreased dietary intake (vegan, poor diet, pregnancy)
Diminished gastric breakdown of vitamin B12 from food.
Malabsorption from the GUT (Crohn’s disease, coeliac disease, bacterial overgrowth substances, surgery, pernicious anaemia, fish tapeworm, ileal resection)

Question 8

Signs & Symptoms of vitamin B12 deficiency?

Answer 8

Fatigue
Pre-hepatic jaundice 
Pallor in conjunctiva, nails and lips. 
Glossitis 
Stomatitis (angular cheilosis- inflammation of the corners of the mouth) 
Ataxia 
Paraesthesias 
Neuropathy- peripheral, optic and dementia (early diagnosis is key in halting the progression of neuropathy)

Question 9

Risk factors of vitamin B12 deficiency

Answer 9

Age > 65 years 
Hx of gastric surgery 
Vegan 
Chronic GI illnesses (IBD)
Use of known causative medications

Question 10

Tests and investigations for vitamin B12 deficiency?

Answer 10

FBC- elevated MCV, low haematocrit
Blood film
Serum vitamin B12
Consider-
Methylmalonic acid (elevated)- a marker for vitamin B12 deficiency.
Homocysteine (elevated)- a marker for vitamin B12 deficiency.
Holotranscobalamin
IF antibody -positive if pernicious anaemia is the cause

Question 11

Differentials for vitamin B12 deficiency

Answer 11

Folic acid deficiency 
Myelodysplastic syndrome
Alcoholic liver disease
Hypothyroidism 
Peripheral neuropathy 
Dementia 
Depression 
Pernicious anaemia 
Crohn's disease 
Coeliac disease 
HIV

Question 12

Vitamin B12 absorption in the body

Answer 12

The stomach and salivary glands are critical to the absorption of B12.
 Transcobalamin I (TCN1), also known variously as haptocorrin, R-factor, and R-protein, is a glycoprotein produced by the salivary glands of the mouth. 
It primarily serves to protect cobalamin (Vitamin B12) from acid degradation in the stomach by producing a Haptocorrin-Vitamin B12 complex. 
Once the complex has travelled to the more neutral duodenum, pancreatic proteases degrade haptocorrin, releasing free cobalamin (i.e. free B12), which now binds to intrinsic factor (IF) for absorption by the enterocytes of the terminal ileum.

Question 13

How is IF critical to the absorption of B12?

Answer 13

IF is critical to the absorption of B12 and this is secreted by the stomach parietal cells. IF is a glycoprotein, with a molecular weight of 45 kDa.
In the duodenum, the free vitamin B12 binds to IF to create a vitamin B12-IF complex. This complex then travels through the small bowel and reaches the terminal ileum, which has on its surface specialized receptors called cubilin receptors.
These identify the B12-IF complexes and take them up into the circulation via endocytosis-mediated absorption.
Lack of IF results in pernicious anaemia.

Question 14

Management of B12 deficiency?

Answer 14

Patients with severe haematological or neurological symptoms of vitamin B12 deficiency require immediate treatment with an intensive regimen of cyanocobalamin or hydroxocobalamin over 1 month, followed by ongoing maintenance doses.

Question 15

What is folate deficiency?

Answer 15

Normal folate stores only last 2-3 months.
Diagnosis is confirmed by the presence of low serum folate.
Vitamin B12 deficiency must be ruled out before initiating folic acid therapy.

Question 16

Signs & symptoms of folate deficiency

Answer 16

Similar to B12 deficiency but often only sensory peripheral neuropathy.

Question 17

Causes of folate deficiency

Answer 17

Nutritional- poor diet, chronic alcohol intake
Surgical- coeliac disease, jejunal resection
Physiological- pregnancy, prematurity
Disease states- chronic haemolysis, severe skin disease
Iatrogenic- methotrexate, anticonvulsants, dialysis
NB: Deficiency in pregnancy is associated with an increased incidence of NTDs in babies.

Question 18

What is aplastic anaemia?

Answer 18

A rare disease in which the haematopoietic stem cells of the bone marrow are damaged.
This causes a deficiency of all 3 blood cell types (pancytopenia)- anaemia, leukopenia and thrombocytopenia.

Question 19

Causes of aplastic anaemia

Answer 19

Exposure- radiation, chemicals (benzene), drugs (phenytoin, quinine, chloramphenicol, carbamazepine)
Infection- acute renal hepatitis, parvovirus B19, autoimmune disorders.

Question 20

Diagnosis of aplastic anaemia

Answer 20

FBC 
Reticulocyte count 
Bone marrow biopsy: 
Normal bone marrow has 30-70% blood stem cells, but in aplastic anaemia, these cells are mostly gone and replaced by fat.
Cytogenic analyses.

Question 21

Management of aplastic anaemia

Answer 21

Immunosuppressive drugs typically either anti-lymphocyte globulin combined with corticosteroids and ciclosporin.
Haematopoietic stem cell transplantation is also used especially for patients under 30 years of age.

Question 22

What is red cell aplasia?

Answer 22

Anaemia affecting erythroblasts.

Question 23

Types of red cell aplasia

Answer 23

Acquired Pure Red Cell Aplasia
Transient or Acute Self-limited PRCA
Inherited or Congenital Pure Red Cell Aplasia (Diamond-Blackfan Anaemia)

Question 24

What is acquired red cell aplasia?

Answer 24

This is a very rare condition and usually affects adults.
It is characterized by an absence of red cell precursors (reticulocytes) in the marrow and a low red blood cell count.
The amounts of white blood cells and platelet remain normal.

Question 25

What is transient or acute self-limited PRCA?

Answer 25

This is the most common type of PRCA. It is identical to acquired PRCA except that, at some point, it simply goes away.
Transient PRCA is usually triggered by a virus or drug. In most cases, when the virus clears, or the responsible drugs are eliminated, the PRCA will disappear.
This is most dangerous to patients who already have chronic hemolytic anaemia.
Patients with otherwise normal functioning bone marrow may even recover without having known they had it.

Question 26

What is inherited PRCA?

Answer 26

Diamond-Blackfan anaemia is a genetic condition usually diagnosed during the first two years of life.
About half of the patients also have physical malformations or mental retardation.
Only several hundred cases have been reported worldwide. The severity of the disease varies by patient.

Question 27

Causes of red cell aplasia

Answer 27

Infections- HIV, herpes, parvovirus B19, hepatitis
Lymphoproliferative- T-cell large granular lymphocytic leukaemia
Drugs- Mycophenolate, EPO
Congenital- Diamond-Blackfan anaemia, autosomal dominantly inherited defects in ribosomal proteins.

Question 28

Treatment of PRCA

Answer 28

The treatment goal is to restore red blood cell production and to treat any underlying disorder. The most common treatments are:
Blood Transfusions to increase red blood cell levels. Patients who don’t respond to other treatments may need to rely on transfusions on an ongoing basis.

Corticosteroids, like prednisolone, are often the initial treatment for PRCA. Unfortunately, the large doses that are often required can have severe side effects. For that reason, corticosteroid medications are rarely used alone as a treatment.

Immunosuppressive therapy may be used if the underlying cause of the PRCA is immunological and the patient hasn’t responded to corticosteroids. Drug therapies include cyclophosphamide, cyclosporine, azathioprine with or without corticosteroids, and anti-thymocyte globulin. In some cases, rituximab may be effective.
PRCA caused by viruses (especially B19 parvovirus) is treated with immunoglobulin infusions.
Thymoma-associated PCRA has to be treated with surgical removal of the thymoma. There is a significant relapse rate after immunosuppressive therapy, but treatments can be repeated.