Management of pernicious anaemia

This condition predominantly affects the elderly. By Dr Anicee Danaee and Dr Deepti Radia.

Blood film showing ovalomacrocytes (large oval red cells) and hypersegmented neutrophils (Photograph: SPL)
Blood film showing ovalomacrocytes (large oval red cells) and hypersegmented neutrophils (Photograph: SPL)

Pernicious anaemia (PA) occurs when there is vitamin B12 (cobalamin) malabsorption due to a severe lack of intrinsic factor (IF), usually secondary to gastric atrophy.

PA predominantly affects the elderly with no ethnic variance. The incidence in the UK is 120/100,000. The majority of patients are over the age of 60, but 10 per cent are younger than 40 years. It is common in northern Europe with a slight female preponderance (male to female ratio is 1:1.6).

PA is thought to be immune mediated as demonstrated by the presence of IF, parietal cells and gastric receptor antibodies.

Cobalamin absorption is mediated by gastric IF, produced from gastric parietal cells in the body and fundus of the stomach. IF binding to cobalamin makes it resistant to enzymatic digestion allowing it to pass through the ileum, the predominant site for active absorption of cobalamin.

Signs and symptoms
PA has a slow and insidious onset. Adult daily requirement of cobalamin is approximately 1-3 micrograms and an average western diet contains 5-30 micrograms, so that body stores are usually sufficient for three to four years.

Most cobalamin is found in foods of animal origin. Many asymptomatic patients are diagnosed while being investigated for macrocytosis. Low B12 can precede anaemia by months and up to 25 per cent of patients with PA will have mild or no anaemia. Symptomatic patients at diagnosis usually have anaemia or neurological manifestations.

Anaemia causes fatigue, headaches, changes in concentration and memory or neurological symptoms.

Neurological symptoms include paraesthesia, unsteadiness, peripheral neuropathy, involvement of the posterior and lateral columns, which can progress to demyelination and eventual neuronal death. These rare symptoms may be reversible with treatment and it is vital to recognise them early.

Diagnosis and investigation
The diagnosis of PA requires the presence of anaemia, macrocytosis, low vitamin B12 levels, atrophic body gastritis, low IF and the presence of positive IF antibodies. Other causes of macrocytosis and B12 deficiency should be excluded.

Macrocytic anaemia is easily demonstrable on a FBC. A blood film may show ovalocytes and hypersegmented neutrophils. Demonstrating true cobalamin deficiency is slightly more complicated.

Acceptable lower limits for serum B12 vary and range from 150-300 picograms/ml or 200-350 picograms/ml. An additional complicating factor is 'subclinical deficiency'. There is a subgroup of patients with biochemically low cobalamin levels but no clinical evidence nor haematological parameters supporting low B12 levels. In this instance, methylmalonic acid (MMA) and homocysteine (HC) levels are used to assist diagnosis.

Levels of both MMA and HC have been shown to be raised in the absence of sufficient vitamin B12. MMA is a more accurate reflection of the body's functional B12 stores.

IF antibodies
Historically, Schilling's test was used to demonstrate reduced levels of IF but this method is no longer available.

The presence of IF antibodies and parietal cell antibodies are used as serological markers of PA. There are two types of IF antibodies (I and II), the presence of which are considered to be diagnostic of PA.

These antibodies have a 50 per cent sensitivity and >95 per cent specificity. Parietal cell antibodies are found in 90 per cent of patients with PA but are not specific and can be found in other autoimmune conditions.

Atrophic body gastritis can be confirmed histologically, as well as serologically, by demonstrating elevated fasting gastrin levels and low pepsinogen level, but this procedure is outdated.

Treatment
The anaemia of cobalamin deficiency is usually well tolerated. An initial 1,000 microgram intramuscular hydroxocobalamin injection is usually enough to correct the anaemia and replenish stores.

The first objective marker of response is a reticulocytosis within a week of commencing treatment. Iron studies are recommended as iron deficiency is often masked by low B12 levels. It may also be useful at week one to measure MMA as it should have normalised and a failure to do so would indicate an alternative diagnosis.

Both anaemia and macrocytosis should have fully resolved by week eight. Neurological improvement should commence after the first week but can take up to three months. However, up to 6 per cent of patients with neurological symptoms will have residual disability.

A typical treatment regimen is six injections in the initial four to six weeks followed by three-monthly injections. Oral doses deliver less cobalamin per dose with variable absorption, but large doses of oral hydroxocobalamin can maintain cobalamin levels in patients once they have had their loading injections.

Some younger patients have found this a suitable method of replacement. An annual B12/MMA level is recommended.

Diagnosis of PA
  • Macrocytic anaemia.
  • Low serum B12 +/raised MMA levels.
  • Presence of IF and parietal cell antibodies.
  • Atrophic body gastritis: based on histology and raised serum gastrin and low pepsinogen levels.

 

Complications
PA is associated with an increased risk of gastric adenocarcinoma and gastric carcinoid type-I. Around 4 per cent of patients develop gastric carcinoids and the annual risk of gastric cancer in patients with PA is between 0.1-0.5 per cent. There are no specific guidelines relating to the frequency of endoscopic and histological surveillance in these patients.

One study suggests endoscopy for patients soon after their initial diagnosis and from then only the subgroup of patients with GI symptoms and/or preneoplastic lesions should undergo endoscopic surveillance. Another study suggests three yearly endoscopy for patients under the age of 60. All these studies suggest an initial endoscopy at diagnosis.

The frequency of further endoscopy will be multifactorial and partly dependent on the gastroenterology department. It is also important to follow-up periodic screening for iron deficiency and thyroid disease.

TEST YOUR KNOWLEDGE

Question 1: An 83-year-old gentleman presents to your practice with gradual worsening SOB and lethargy. His medication includes levothyroxine and simvastatin.

Blood test results:

  • Hb 9.5g/dl
  • MCV 105 fl (normal range 80-100fl)
  • B12 90 nanogram/ml (normal range 145-1000ng/ml)
  • MMA 500 mmol/l (normal range 73-271nmol/l)
  • Negative intrinsic factor
  • Negative parietal cell antibodies.

Is this:

    1. Definitive pernicious anaemia
    2. Most likely pernicious anaemia
    3. Not pernicious anaemia

      Question 2: What is your immediate management?

      a. Referral to haematology
      b. Admission to A&E
      c. Single lM dose of hydroxocobalamin
      d. Commence oral cobalamin

      Question 3: If a patient has a low B12 level, high MMA level, positive gastric parietal antibodies and negative intrinsic factor antibodies - how often would you test for intrinsic factor antibodies?

      a. Repeat until positive result
      b. Once only
      c. Twice to confirm assay result.

      CLICK HERE TO VIEW THE ANWSERS

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      • - Find more articles about haematology and questions on pernicious anaemia at the haematology resource centre gponline.com/haematology

      • Dr Danaee is a specialist registrar in haematology and Dr Radia is a consultant haematologist, Guy's and St Thomas' NHS Foundation Trust

      Resources
      1. Lahner E, Annibale B. Pernicious anemia: New insights from a gasteroenterological point of view. World J Gastroenterol 2009; 15 (41): 5121-8.

      2. R Carmel. How I treat cobalamin (Vitamin B12) deficiency. Blood 2008; 112: 2214-21.

      3. Hoffbrand V, Catovsky D, Tuddenham E. Postgraduate Haematology. March 2005.

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