Pernicious Anaemia (PA)

1. MEGALOBLASTIC ANAEMIA

• Result from interference in DNA synthesis
• Megaloblastic anemia – caused by interference with DNA synthesis, due to deficiency of cobalamin or folic acid
• Pernicious anaemia – megalobalstic anemia due to autoimmune chronic gastritis with destruction of parietal cells

Pathophysiology of megaloblastic anemia

Folic acid

• Required for transfer of methyl groups in many chemical reactions
• Abundant in vegetables, fruits, cereals, dairy
• Absorbed in jejunum
• Daily requirement – 50μg (pregnant – 400μg)
• Primarily stored in the liver
• Deficiency in pregnancy can cause NTDs in fetus

Causes of folate deficiency

• Inadequate diet – ↓fresh fruit+veg; alcoholism
• Malabsorption – celiac disease, SI resection, IBD
• Rare causes – hemodialysis, antifolate drugs, increased requirements (preg, chr hemolytic anemia)

Treatment

• Oral folate supplements – [400-1000μg daily]
• B12 levels need to be normal as folic acid may exacerbate neural degeneration

Vitamin B₁₂

• Sources – meat, eggs, milk, cheese
• Daily requirement – 1μg
• Most cases of B₁₂ deficiency are due to malabsorption

Steps in cobalamin absorption

• B₁₂ is digested off food protein by pepsin and gastric acid
• The released B₁₂ is then bound to R proteins produced in salivary glands, which block binding of IF
• Panc enzymes release B₁₂ from R proteins, allowing IF to bind
• The B₁₂-IF complex is absorbed in the terminal ileum
• After uptake by the enterocytes of the terminal ileum, the B₁₂-IF complex degrades and transcobalamin II binds B₁₂ to circulate it in the blood and transport it to tissues

2. PERNICIOUS ANEMIA

• MCC of cobalamin deficieny

Etiology/epidemiology

• MC in Scandinavians, British and Irish
• Familial predisposition
• Strong association between PA and other AI disorders e.g. Grave’s and Hashimoto’s, Addisons, vitiligo etc.

Pathophysiology

• PA is an autoimmune chronic gastritis, resulting in destruction of parietal cells and loss of IF production
• Types of antibodies in the serum of a patient with PA
  • Anti-parietal cell antibodies
  • Anti-IF antibodies

Clinical Features

• Fatigue, lethargy, dyspnoea, faintness, palpitations, yellow tinge to skin
• Glossitis, oral ulceration
• Neurological symptoms
  • paraesthesia, numbness, cognitive changes, visual disturbances
  • Most advanced cases – hyperreflexia, clonus, Romberg + Babinski
• Demyelination of dorsal and lateral columns of spinal cord, peripheral neuropathy
  • Symmetrical impairment of pain, temp, touch sensations; legs involved more commonly
  • Triad – absent knee/ankle jerk (LMN), extensor palmaris (UMN)

Lab diagnosis

• Key finding – hypersegmented neutrophils (earliest blood finding)
• Increased serum LDH and BR due to marked intramedullary hemolysis
• Bone marrow – hypercellular, increased erythroid precursors
  • Megaloblasts are large erythroid precursors with an immature (open) nucleus
• Biochemistry (table)
  • Increased MMA (methylmalonic acid) is very sensitive for B₁₂ deficiency, increase homocysteine

• Schilling test – standard method to diagnose PA once B₁₂ deficiency is confirmed
  • Radiolabelled B₁₂ is given orally and a large dose of B₁₂ is given i.m. Urine collected for 24hrs
  • Amount of radioactivity in urine indicates how much B₁₂ was absorbed oraly
  • Recovery of <6% B₁₂ in urine indicates malabsorption
  • If initial value is ABNORMAL, then IF is given together with radiolabelled B₁₂
  • Increase in the amount of B₁₂ absorbed during this stage indicates PA
• Serum analysis – anti-parietal cell Abs; anti-IF Abs
• Other causes of B12 deficiency – metformin, coeliac disease, crohns

Treatment

• Parenteral therapy
• Hydroxycobalamin [1mg x 3 weeks, then 1mg every 3 months] – checks levels on day 3/5/7
• Rapid response to therapy
  • Reticulocytosis in 2 days, Hb rises after 1 week, hypersegmented neutrophils disappear in 2 wks, BM shows disappearance of megaloblasts within few days