History

Fact Explanation
Generalised weakness, malaise and fatigue Absorption of vitamin B-12 is dependent on the intrinsic factor(IF), which is secreted by gastric parietal cells. IF and vitamin B12 complex get absorbed by the receptors in the ileum. In patients with pernicious anaemia, gastric parietal cells are not producing this intrinsic factor(IF) in adequate amounts due to gastric atrophy, [4] leading to malabsorption and deficiency of vitamin B12.
Shortness of breath on exertion Pernicious anaemia can present with features of heart failure. [5]
Low grade fever, weight loss May be the presenting features on certain occasions. [4]
Paresthesia in the hands and feet, sensory loss, and distal weakness This is due to subacute combined degeneration of the cord. [2] As cobalamin is required for the conversion of methylmalonyl CoA to succinyl CoA, lack of cobalamin causes accumulation of methylmalonyl CoA, leading to reduction in myelin synthesis. Impaired DNA synthesis also can contributes to this decreased myelin production. [3]
Burning or soreness of the tongue with impaired taste There will be loss of papillae, [4] and reddish tongue making burning sensation and difficulty in swallowing.
Anorexia, nausea, vomiting, heartburnand dyspepsia Non specific gastrointestinal symptoms, [5] that are associated with pernicious anemia.
Vegetarian diet Inadequate dietary intake of vitamin B12 will aggravate the deficiency. [2]
History of ileal resection, inflammatory bowel disease, lymphoma, amyloidosis, gastrectomy, use of histamine 2 [H2] blockers etc These conditions can lead to vitamin B12 deficiency [2] and further aggravate the condition.
Other autoimmune diseases Pernicious anaemia is known to have an autoimmune basis and is associated with thyroid disorders, type 1 diabetes mellitus, ulcerative colitis, vitiligo and addison disease. [4]
Gastric carcinoma There is increased incidence of gastric carcinoma in this group. [4]
References
  1. LEVER EG, ELWES RD, WILLIAMS A, REYNOLDS EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry [online] 1986 Oct, 49(10):1203-1207 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1029058
  2. CABRERIZO-GARCíA JOSé LUIS, SEBASTIáN-ROYO MARIANO, MONTES NEREA, ZALBA-ETAYO BEGOñA. Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency. Sao Paulo Med. J. [online] 2012 December, 130(4):259-262 [viewed 09 July 2014] Available from: doi:10.1590/S1516-31802012000400010
  3. HEMMER B, GLOCKER F X, SCHUMACHER M, DEUSCHL G, LUCKING C H. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. Journal of Neurology, Neurosurgery & Psychiatry [online] 1998 December, 65(6):822-827 [viewed 09 July 2014] Available from: doi:10.1136/jnnp.65.6.822
  4. CAREY J, HACK E. Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient BMJ Case Rep [online] :bcr0120125576 [viewed 09 July 2014] Available from: doi:10.1136/bcr.01.2012.5576
  5. SEMPLE CG, WILLIAMSON JM. Pernicious anaemia in a young man presenting with dyspepsia Postgrad Med J [online] 1982 Jul, 58(681):439-440 [viewed 17 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2426502

Examination

Fact Explanation
Pallor Due to the anaemia. [2,3]
Dyspnoea Due to the anaemia. [3] As there is low haemoglobin in the blood leading to hypoxia, that can trigger carotid chemoreceptors result in rapid breaths. Worsening of heart failure can also be a cause for dyspnoea.
Tachycardia, peripheral oedema, elevated jugular venous pressure, hepatomegallt, bibasal fine crepitations Features of congestive heart failure [3] are seen in severe disease especially in patients with a history of cardiac lesions.
Angular stomatitis , glossitis [3] Tongue may be painful and erythematous with atrophy of the dorsal aspect. [3]
Vitiligo [3] Autoimmune disorders are associated with pernicious anaemia with a genetic predisposition. [3] (Human leukocyte antigen (HLA) types A2, A3, and B7 are associated)
Koilonoychia There can be coexistent iron deficiency as reduction of the chloride secretion [4] by the stomach affects the solubilization of ferric iron in the diet.
Bilateral lower limb weakness, sosticity, clonus, bilateral extensor plantar response and loss of vibration and proprioception Pyramidal and dorsal column signs are seen due to subacute combined degeneration of the cord. [1,2]
Absent knee and ankle reflexes Due to peripheral neuropathy. [1,2]
Altered mental state, poor concentration, poor memory, depressed level of consciousness Due to associated psychiatric manifestations. [1,2] They can even develop conditions like dementia. [3]
References
  1. LEVER EG, ELWES RD, WILLIAMS A, REYNOLDS EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry [online] 1986 Oct, 49(10):1203-1207 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1029058
  2. CABRERIZO-GARCíA JOSé LUIS, SEBASTIáN-ROYO MARIANO, MONTES NEREA, ZALBA-ETAYO BEGOñA. Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency. Sao Paulo Med. J. [online] 2012 December, 130(4):259-262 [viewed 09 July 2014] Available from: doi:10.1590/S1516-31802012000400010
  3. CAREY J, HACK E. Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient BMJ Case Rep [online] :bcr0120125576 [viewed 09 July 2014] Available from: doi:10.1136/bcr.01.2012.5576
  4. STURGIS CC. Remarks on the Differential Diagnosis and Treatment of Pernicious Anemia Bull N Y Acad Med [online] 1938 Dec, 14(12):715-724 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1911327

Differential Diagnoses

Fact Explanation
Folate defficiency All the clinical features would be same as in the B12 deficiency. Blood film also shows macrocytosis. [1] Differentiation may be possible with the serum levels of B12 and folate.
Aplastic anaemia Aplastic anaemia can present with fever, recurrent infections, bleeding manifestations and features of anaemia. They will also have macrocytosis [1] and pancytopenia on investigations.
Bone Marrow Failure Bone marrow failure affects all the three blood cell lineages, and presents with the same features as in aplastic anemia. Fanconi anemia is one such example with progressive bone-marrow failure. [3] Myelodysplasia, lymphocytic and myeloid leukaemia are other malignancies result in bone marrow failure.
Anaemia due to other causes Microcytic anaemia can be seen in iron deficiency, chronic diseases, thalassemia etc. Iron deficiency patients may have low serum iron levels. Increased total iron binding capacity and reduced transferrin saturation in the blood. Red cell distribution width is increased in iron deficiency where as it is normal in thalassemia. [4] Haemolytic anaemia patients may have jaundice, dark urine. Investigations will reveal increased unconjugated bilirubin levels, spherocytes on blood film and increased osmotic fragility in hereditary spherocytosis.
Macrocytosis Liver disease, alcoholism, pregnancy, lymphoma, use of drugs like oral contraceptive pills, phenytoin, zidovudine, trimethoprim , chronic diseases [2] and hypothyroidism are some other conditions, that can give rise to macrocytosis. [1]
References
  1. STURGIS CC. Remarks on the Differential Diagnosis and Treatment of Pernicious Anemia Bull N Y Acad Med [online] 1938 Dec, 14(12):715-724 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1911327
  2. TENNANKORE KARTHIK K, SOROKA STEVEN D, WEST KENNETH A, KIBERD BRYCE A. Macrocytosis may be associated with mortality in chronic hemodialysis patients: a prospective study. Array [online] 2011 December [viewed 09 July 2014] Available from: doi:10.1186/1471-2369-12-19
  3. PARIKH S, BESSLER M. Recent insights into inherited bone marrow failure syndromes. Curr Opin Pediatr [online] 2012 Feb, 24(1):23-32 [viewed 09 July 2014] Available from: doi:10.1097/MOP.0b013e32834eca77
  4. HTET MK, DILLON D, AKIB A, UTOMO B, FAHMIDA U, THURNHAM DI. Microcytic anaemia predominates in adolescent school girls in the delta region of Myanmar. Asia Pac J Clin Nutr [online] 2012, 21(3):411-5 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22705432

Investigations - for Diagnosis

Fact Explanation
Full blood count Haemoglobin, red blood cell concentration and pack cell volume are reduced. Mean corpuscular haemoglobin (MCH) and Mean corpuscular haemoglobin concentration (MCHC) are reduced. Mean corpuscular volume is increased. [2,3]
Blood picture shows Blood picture shows megaloblastic, macrocytic anaemia [3,6] (macrocytosis is size of the red blood cell more than 96 cubic microns [5] ) with abnormal red cells, hypersegmented neutrophils and absent blast cells. [4] Erythropoiesis become inefficient as DNA synthesis is impaired due to lack of vitamin B12.
Reticulocyte count Reticulocyte count may be reduced due to ineffective erythropoiesis. [4]
Bone marrow biopsy Megaloblastic cells are seen. [1,6] Also important to exclude other causes for pancytopenia which can present in severe disease.
Serum vitamin B12 and folate levels Serum vitamin B12 is diminished with normal serum folate levels. [1,2] It is important to look at the folate level as folate deficiency also can presents with macrocytic megaloblastic anaemia. [4]
Antiparietal cell antibodies, antibodies to intrinsic factor May be positive. [4]
Lactic dehydrogenase Lactic dehydrogenase level is increased due to ineffective erythropoiesis. [2]
Methylmalonic acid and homocysteine levels As these are metabolites of cobalamin, the levels go up when there is deficiency of vitamin B12. [2]
References
  1. LEVER EG, ELWES RD, WILLIAMS A, REYNOLDS EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry [online] 1986 Oct, 49(10):1203-1207 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1029058
  2. CABRERIZO-GARCíA JOSé LUIS, SEBASTIáN-ROYO MARIANO, MONTES NEREA, ZALBA-ETAYO BEGOñA. Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency. Sao Paulo Med. J. [online] 2012 December, 130(4):259-262 [viewed 09 July 2014] Available from: doi:10.1590/S1516-31802012000400010
  3. TIAN C. Hyperintense signal on spinal cord diffusion-weighted imaging in a patient with subacute combined degeneration. Neurol India [online] 2011 May-Jun, 59(3):429-31 [viewed 09 July 2014] Available from: doi:10.4103/0028-3886.82764
  4. CAREY J, HACK E. Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient BMJ Case Rep [online] :bcr0120125576 [viewed 09 July 2014] Available from: doi:10.1136/bcr.01.2012.5576
  5. STURGIS CC. Remarks on the Differential Diagnosis and Treatment of Pernicious Anemia Bull N Y Acad Med [online] 1938 Dec, 14(12):715-724 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1911327
  6. STABLER SALLY P.. Vitamin B Deficiency . N Engl J Med [online] 2013 January, 368(2):149-160 [viewed 10 July 2014] Available from: doi:10.1056/NEJMcp1113996

Investigations - Fitness for Management

Fact Explanation
Full blood count There can be severe pancytopenia (reduction of all three cell lines: white blood cells, platelets and red blood cells)in severe anaemia. [1]
References
  1. CABRERIZO-GARCíA JOSé LUIS, SEBASTIáN-ROYO MARIANO, MONTES NEREA, ZALBA-ETAYO BEGOñA. Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency. Sao Paulo Med. J. [online] 2012 December, 130(4):259-262 [viewed 09 July 2014] Available from: doi:10.1590/S1516-31802012000400010

Investigations - Followup

Fact Explanation
Full blood count Hemoglobin levels usually return to normal range within 3 months of treatment. [6] Increase in red cell count depends on dose of vitamin B12 and initial count of red blood cells at presentation. [5] There is slight increase in count within 5 days and gradually increase between day 5-10, with a peak around day 15. Remission is considered when there is red cell count of 4, 500, 000 or more per cubic millimeter. [5] Mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV) should come to the normal range with the treatment. [1] MCV peaks around day 5. [5]
Reticulocyte count Reticulocyte count responds very fast for the treatment. [3] This usually improves after 3-6 days of treatment. [4] It starts to rise around day 2-3 and peak around day 5-6. [5]
Serum vitamin B12 level This is usually reduced in B12 deficiency [7] and gradually come up with the treatment.
Daily lactate dehydrogenase Is checked daily in the initial stages of treatment. [3]
Somatosensory evoked potentials Tibial nerve somatosensory evoked potentials can be remain abnormal even after long term treatment of subacute combined degeneration of the cord. [2]
References
  1. CABRERIZO-GARCíA JOSé LUIS, SEBASTIáN-ROYO MARIANO, MONTES NEREA, ZALBA-ETAYO BEGOñA. Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency. Sao Paulo Med. J. [online] 2012 December, 130(4):259-262 [viewed 09 July 2014] Available from: doi:10.1590/S1516-31802012000400010
  2. HEMMER B, GLOCKER F X, SCHUMACHER M, DEUSCHL G, LUCKING C H. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. Journal of Neurology, Neurosurgery & Psychiatry [online] 1998 December, 65(6):822-827 [viewed 09 July 2014] Available from: doi:10.1136/jnnp.65.6.822
  3. CAREY J, HACK E. Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient BMJ Case Rep [online] :bcr0120125576 [viewed 09 July 2014] Available from: doi:10.1136/bcr.01.2012.5576
  4. STURGIS CC. Remarks on the Differential Diagnosis and Treatment of Pernicious Anemia Bull N Y Acad Med [online] 1938 Dec, 14(12):715-724 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1911327
  5. UNGLEY CC. Vitamin B12 in Pernicious Anaemia Br Med J [online] 1949 Dec 17, 2(4641):1370-1377 [viewed 10 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2051842
  6. SONG IC, LEE HJ, KIM HJ, BAE SB, LEE KT, YANG YJ, PARK SY, CHO DY, KIM NY, CHO IS, JO DY. A Multicenter Retrospective Analysis of the Clinical Features of Pernicious Anemia in a Korean Population J Korean Med Sci [online] 2013 Feb, 28(2):200-204 [viewed 10 July 2014] Available from: doi:10.3346/jkms.2013.28.2.200
  7. LEVER EG, ELWES RD, WILLIAMS A, REYNOLDS EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry [online] 1986 Oct, 49(10):1203-1207 [viewed 09 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1029058

Investigations - Screening/Staging

Fact Explanation
Magnetic Resonance Imaging Sub acute combined degeneration of the cord result in bilateral highintense signal within the dorsal columns giving the appearance of "inverted V sign on MRI, specially in cervical and thoracic regions. [1] This high intense signals are due to myelin oedema due to the intramyelin accumulation of free water. [2]
Electroneurogram This shows, slowing of sensory conduction or somatosensory evoked potentials. [1]
Free thyroxine (T4) and TSH levels, antithyroglobulin and antithyroid peroxidase antibodies There can be autoimmune hypothyroidism associated with pernicious anaemia. [3]
Fasting blood sugar Can be associated with diabetes type 1 and 2 mellitus. [3]
References
  1. CABRERIZO-GARCíA JOSé LUIS, SEBASTIáN-ROYO MARIANO, MONTES NEREA, ZALBA-ETAYO BEGOñA. Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency. Sao Paulo Med. J. [online] 2012 December, 130(4):259-262 [viewed 09 July 2014] Available from: doi:10.1590/S1516-31802012000400010
  2. TIAN C. Hyperintense signal on spinal cord diffusion-weighted imaging in a patient with subacute combined degeneration. Neurol India [online] 2011 May-Jun, 59(3):429-31 [viewed 09 July 2014] Available from: doi:10.4103/0028-3886.82764
  3. CAREY J, HACK E. Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient BMJ Case Rep [online] :bcr0120125576 [viewed 09 July 2014] Available from: doi:10.1136/bcr.01.2012.5576

Management - General Measures

Fact Explanation
Blood transfusion If the patient is hemodynamically unstable or if there is evidence of bleeding, they need red blood cell and platelet transfusion. [2]
Supportive management As they can develop complications such as subacute combined degeneration of cord, [1] they need assistance and support on certain occasions.
Dietary advice Strict vegetarians have a high risk of B12 deficiency. They should be advised regarding their dietary habits and lifetime B12 supplementation. [3]
Follow up Patients with pernicious anemia need lifelong treatment with vitamin B12 and development of complications and response to therapy should be monitored. [1]
References
  1. TIAN C. Hyperintense signal on spinal cord diffusion-weighted imaging in a patient with subacute combined degeneration. Neurol India [online] 2011 May-Jun, 59(3):429-31 [viewed 09 July 2014] Available from: doi:10.4103/0028-3886.82764
  2. CAREY J, HACK E. Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient BMJ Case Rep [online] :bcr0120125576 [viewed 09 July 2014] Available from: doi:10.1136/bcr.01.2012.5576
  3. CABRERIZO-GARCíA JOSé LUIS, SEBASTIáN-ROYO MARIANO, MONTES NEREA, ZALBA-ETAYO BEGOñA. Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency. Sao Paulo Med. J. [online] 2012 December, 130(4):259-262 [viewed 09 July 2014] Available from: doi:10.1590/S1516-31802012000400010

Management - Specific Treatments

Fact Explanation
Treatment with vitamin B12 Vitamin B12 treatment is given as intramuscular injections at a dose of 1,000 mcg/day for a week, then 1,000 mcg/week for a month and, later 1,000 mcg/month for life. Intramuscular injections bypass the ileal absorption and thus need for intrinsic factor produced by parietal cells. [1] Oral B12 complex (0.5 mg) , B6 (250 mg) and B1 (250 mg) twice a day can also be given, as there are evidence to suggest that very small amount of vitamin B12 is absorbed without IF. But this gives only a transient response. [1]
Management of complcations One of the main complications of this disease is subacute combined degeneration of the cord. Treatment would be the same B12 therapy, but most will have residual symptoms such as sensory disturbances and gait disturbance. [2]
Management of associated autoimmune diseases As there is an association with hypothyroidism and diabetes mellitus, it should be detected and treated as appropriately. [3]
References
  1. CABRERIZO-GARCíA JOSé LUIS, SEBASTIáN-ROYO MARIANO, MONTES NEREA, ZALBA-ETAYO BEGOñA. Subacute combined spinal cord degeneration and pancytopenia secondary to severe vitamin B12 deficiency. Sao Paulo Med. J. [online] 2012 December, 130(4):259-262 [viewed 09 July 2014] Available from: doi:10.1590/S1516-31802012000400010
  2. HEMMER B, GLOCKER F X, SCHUMACHER M, DEUSCHL G, LUCKING C H. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. Journal of Neurology, Neurosurgery & Psychiatry [online] 1998 December, 65(6):822-827 [viewed 09 July 2014] Available from: doi:10.1136/jnnp.65.6.822
  3. CAREY J, HACK E. Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient BMJ Case Rep [online] :bcr0120125576 [viewed 09 July 2014] Available from: doi:10.1136/bcr.01.2012.5576