Overview 

Vitamins are important micronutrients required in small amounts for the proper functioning of the metabolic pathways to support cell function.¹ Vitamin B12, also known as cobalamin, is a water-soluble vitamin required by animals that is used as a cofactor for the synthesis of DNA, fatty acids, and amino acids. Pernicious anaemia (PA) is an autoimmune condition caused by the destruction (atrophy) of gastric parietal cells and the absence of intrinsic factor (IF). Intrinsic factor is essential for vitamin B12 absorption, and PA is caused by a deficiency of vitamin B12. The affected individual may present with constitutional, neurological, psychiatric, otolaryngologic, cardiopulmonary and gastrointestinal symptoms. If left untreated, it may affect quality of life and can cause gastric cancer. Thus, proper diagnosis and treatment should be carried out as early as possible.³

Pathophysiology of PA

It is important to know the physiological process involved in PA. Food from the mouth travels through the oesophagus,  known as the ‘food pipe’. It then moves to the stomach, where the food undergoes mechanical and chemical digestion, then to the small intestine, where the nutrients get absorbed, before moving to the large intestine. 

Vitamin B12 is found mostly in meat, egg and dairy products, and its deficiency is therefore notably seen in vegetarians and vegans. The primary mechanism of PA is due to the decreased synthesis of IF.  The stomach is made of 4 parts: cardiac, fundus, body and pylorus, and they secrete many enzymes and mucus. The lining of the body is composed of cells like parietal cells, chief cells and enteroendocrine cells. The parietal cells produce hydrochloric acid and IF. IF binds with vitamin B12, and as a complex, they are then absorbed in the small intestine and transported to the bloodstream with the help of transport mechanisms by binding with transcobalamin. However, it is possible for the autoimmune system to destroy IF-producing cells, causing a deficiency or decreased production of IF.³

Figure 1 - Illustration showing the gastric mucosa and gastric gland  

Clinical manifestation

Individuals with PA may present with a wide variety of symptoms, such as constitutional, neurological, psychiatric, otolaryngologic, cardiopulmonary, and gastrointestinal symptoms. Constitutional symptoms that affect the entire body include weight loss, anorexia, fatigue, and lethargy. Neurological problems include difficulty concentrating, imbalance, headache, confusion, paraesthesia, and numbness. Psychiatric problems include emotional lability, depression, and psychosis. Two of the most important symptoms are dysgeusia/hypogeusia (altered or reduced taste), and glossitis (sore, inflamed tongue. Cardiopulmonary symptoms include dyspnoea, palpitations, an increased cardiac output, and an increased heart rate. Digestive problems include loss of appetite, loose motion, and indigestion.⁴

Fatigue 

Vitamin B12 impairs the production of red blood cells (RBCs), impacting their function to transport oxygen to various parts of the body. Fatigue is commonly experienced if there is decreased oxygen availability, and can vary from mild to severe, and can be persistent.

Pallor 

Pallor describes the paleness of the skin and mucous membrane. It is usually a result of decreased red blood cell count (anaemia). Vitamin B12 is essential for the formation and function of RBCs. In individuals with European ancestry, the combination of pallor with jaundice caused by haemolysis can make the skin appear a peculiar lemon-yellow colour.³

Glossitis 

Glossitis is the most important feature of PA. It presents as a smooth red appearance of the tongue and can also be painful. The taste buds of the tongue, known as papillae or filiform papillae, are lost, resulting in a smooth appearance called atrophic glossitis. Redness is also observed due to patchy or diffuse erythematous lesions (caused by increased blood flow), resulting in the description of a ‘beefy red’ tongue being observed. This is also called Moeller's glossitis or Hunter's glossitis. Patients may complain of glossodynia (a hot feeling on the tongue and mouth) and lingual paraesthesia.⁵

Neurological symptoms

Peripheral neuropathy is an early neurological symptom of pernicious anaemia. Examination shows a decrease in sensitivity to light touch, pinprick, burning extremities, unsteady gait, ataxia and vibration. Optic nerve degeneration (atrophy) may lead to loss of vision. The classic neurologic manifestation is the combined sclerosis of the spinal cord. Patients may also display psychological symptoms that range from a change in personality to psychosis.⁵

Diagnostic consideration

• Peripheral blood smear: PA causes a macrocytic type of anaemia where the red blood cells are larger in size, which can be observed with a  peripheral blood smear
• Complete blood count: enables the measurement of haematocrit, total ferritin (iron) levels, and cobalamin (vitamin B12) levels
• Serological tests: valuable for evaluation of antibodies against parietal cells and IF
• Bone marrow biopsy: tests for blood disorders
• Endoscopy with biopsies: assess the stomach lining
• Schilling test: used to find out the absorption capacity of vitamin B12 by measuring the radioactive vitamin B12 in urine³

Treatment and prognosis 

Lifelong treatment is needed for confirmed PA patients. This usually begins with intramuscular injections with hydroxocobalamin, which are then later switched to oral vitamin B12 supplements. A proper diet should be followed, especially for vegetarians. Prognosis is good in most patients as supplements are readily available. In some cases, if left untreated, PA may lead to gastric cancer.³

Commonly asked questions

What is megaloblastic anaemia?

It is a specific type of anaemia in which there is a deficiency of vitamin B12 and/or folic acid, which causes the bone marrow to produce unusually large, structurally abnormal and immature red blood cells (megaloblasts).

What are the main causes of vitamin B12 deficiency?

Vitamin B12 deficiency can be caused by inadequate food intake, a deficiency of IF due to autoimmune disease (PA), gastric surgery (in which a part of the stomach is removed), and achlorhydria, wherein the low production of hydrochloric acid affects the absorption of the vitamin.

Why is vitamin B12 deficiency called pernicious anaemia?

The word pernicious means ‘deadly’. In the past, treatment was not available, but now they are accessible and readily available, resulting in a good disease prognosis.

Why can PA be dangerous?

PA mainly affects the red blood cells and nerves; hence, nerve sensation can be lost in severe cases.

Why is pernicious anaemia macrocytic?

Cells need RNA and DNA to make protein, grow, and divide into new cells. The difference between RNA and DNA is that RNA has uracil, whereas DNA has thymine. Thymine is methylated uracil. To divide, blood cells need to transfer a methyl group to uracil to make thymine. This methyl group is carried by the vitamin folic acid, which then receives the methyl group from another vitamin carrier, vitamin B12. Therefore, in the absence of these vitamins, blood cells can enlarge but not divide, resulting in macrocytosis.

Summary  

PA is usually caused by a deficiency in IF, which is produced by the parietal cells of the stomach. It is an autoimmune condition that can cause various symptoms such as pallor, jaundice, anaemia, neurological problems, glossitis, fatigue, palpitation and weakness. Macrocytic anaemia can also be seen in peripheral blood smears. Whilst the Schilling test is one of the most important diagnostic tests, peripheral blood smears are often assessed for macrocytic anaemia. Treatment should not be delayed as it may cause gastric cancer in some individuals.