This accumulation depletes the other types of folate required for purine and thymidylate synthesis, which are required for the synthesis of DNA. Inhibition of DNA replication in maturing red blood cells results in the formation of large, fragile megaloblastic erythrocytes. The neurological aspects of the disease are thought to arise from the accumulation of methylmalonyl- CoA due to the requirement of B12 as a cofactor to the enzyme methylmalonyl-CoA mutase. Diagnosis
Pernicious anemia is thought mainly to be an autoimmune disorder that attacks the gastric parietal cells that produce intrinsic factor resulting in impaired absorption of B12. However, pernicious anemia may also have a genetic component, potentially running in families. Pernicious anemia may be suspected when a blood smear shows large, brittle, immature, erythrocytes, known as megaloblasts. To make a diagnosis a full blood count, and blood smear, with the following tests included is needed:
A complete blood count and blood smear evaluates the mean corpuscular volume (MCV) and the mean corpuscular hemoglobin concentration (MCHC) to demonstrate  megaloblastic anemia. PA is identified with a high MCV (macrocytic anemia) and a normal MCHC (normochromic anemia). Ovalocytes are also typically seen on the blood smear, and a pathognomonic feature of megaloblastic anemias (which include PA and others) is hypersegmented neutrophils. Vitamin B12 serum levels are used to detect its deficiency, but do not distinguish its causes. Vitamin B12 levels can be falsely high or low and data for sensitivity and specificity vary widely.
Anemia may present with a number of further common symptoms, including hair thinning and loss, early greying of the hair, mouth ulcers, bleeding gums, angular cheilitis, a look of exhaustion with pale and dehydrated or cracked lips and dark circles around the eyes, as well as brittle nails.In more severe or prolonged cases of pernicious anemia, nerve cell damage may occur, which can lead to more severe symptoms, including sense loss, difficulty in proprioception, neuropathic pain, unsteady walking (ataxia), poor balance, loss of sensation in the feet, muscle weakness, blurred vision (either due to retinopathy or optic neuropathy), impaired urination, fertility problems, decreased sense of taste and smell, decreased level of consciousness, changes in reflexes, memory loss, mood swings, depression, irritability, slurred speech, cognitive impairment, confusion, anxiety, clumsiness, psychosis, and, in more severe cases, dementia. Anemia may also lead to cardiac murmurs and/or altered blood pressure (low or high). The deficiency may also present with thyroid disorders. In severe cases, the anemia may cause congestive heart failure. A complication of severe chronic PA is subacute combined degeneration of spinal cord, which leads to distal sensory loss (posterior column), absent ankle reflex, increased knee reflex response, and extensor plantar response. Other than anemia, hematological symptoms may include cytopenias, intramedullary hemolysis, and pseudothrombotic microangiopathy. Vitamin B12 deficiency, which is reversible, is occasionally confused with acute myeloid leukemia, which is an irreversible autoimmune condition presenting with some of the same hematological symptoms, including hypercellular bone marrow with blastic differentiation and hypersegmented neutrophils.