Sore mouth and anemia.

Pernicious anemia has long been of interest to the medical profession since  the clinical presentation of a sore, beefy red, smooth tongue, and some digital numbness and tingling that occasionally progressed to spasticity and ataxia. By the end of the 19th century, patients with these clinical manifestations were shown to have atrophy of the gastric mucosa and absence of acid in the gastric juice as well as an anemia characterized by large, oval erythrocytes. The term “pernicious anemia” crept into common medical parlance for designating patients with this striking constellation of clinical and laboratory findings. Survival in untreated patients was from 1-3 years hence the name pernicious. Observations on the bone marrow showed ineffective red cell formation which could be improved by a diet rich in liver and a rise in the reticulocyte count was seen soon after starting the diet. The diagnosis depended on the finding of large volume RBCs or megalocytes in the blood and megaloblasts in the bone marrow and sometimes blood. In 1934, the Nobel Prize in Physiology or Medicine was bestowed on Minot, Murphy, and Whipple “in recognition of their discoveries respecting liver therapy in anaemias.” Castle further did work on the the extrinsic factor in liver that cured these patients interacted with an intrinsic factor normally present within the stomach. He put his own gastric juice (after eating a burger!!) into the patients he was working on. A prompt rise in the reticulocytes ensued in 5 days. Just a reminder that we have Vit B12 stored in the liver to last us for 1-3 years. After a gastrectomy, when insufficient intrinsic factor is being secreted, it takes that long for a person to develop pernicious anemia.

Pernicious anemia is but one of a host of diseases that arises because of the interplay between nature and nurture.

  • Genetics. The distribution of certain HLA polymorphisms is substantially skewed in persons with chronic atrophic gastritis as well as those with autoimmune thyroiditis.
  • Autoimmunity. Atrophic gastritis is strongly associated with autoimmune thyroiditis, a combination designated as the autoimmune polyglandular syndrome type 3B. In addition, atrophic gastritis is often encountered with other autoimmune disorders such as type 1 diabetes, vitiligo, Addison’s disease (chronic primary adrenal insufficiency), and Graves’ disease (hyperthyroidism).
  • Food cobalamin malabsorption is a term used to describe vitamin B12 deficiency despite normal dietary levels of vitamin B12 in food. This is also called pernicious anemia. (Think adult onset coeliac disease, atrophic gastritis; gastric surgery; chronic H. pylori infection; achlorhydria from chronic use of antacids, H2 receptor blockers, or proton pump inhibitors; chronic excess alcohol use; pancreatic insufficiency; or antibiotic use with intestinal bacterial overgrowth.)

It is manifested as:

  • a macrocytic anemia
  • associated disturbances of the gastrointestinal tract
  • frequently disturbance of the nervous system.
  • Untreated, the disease progresses over a period generally of about three years to a fatal termination. Under adequate treatment the blood becomes essentially normal, digestive symptoms vanish and manifestations referable to the nervous system are completely arrested.
  • The disease occurs particularly in the fourth and fifth decades of life, although rare cases have been reported before the age of thirty. It is most common in blue-eyed persons of northern European stock, but typical cases have occurred in essentially every race, including the Negro.
  • A familial tendency is common.
  • The onset of the disease is usually insidious, and all too frequently gastrointestinal, neurologic or cardiac symptoms precede the development of obvious anemia by many months.
  • Every patient of middle age or over who complains of indigestion, flatulence, anorexia, “gall-bladder attacks,” diarrhea or soreness of the tongue should have the diagnosis of pernicious anemia excluded. A “beefy,” “inflamed” or pale, smooth tongue, although found in other deficiency disorders, should always arouse the suspicion of pernicious anemia.
  • Any patient with persistent paresthesias of the hands or feet together with anemia should be considered to have pernicious anemia until proved otherwise. The numbness and tingling of the extremities in pernicious anemia differ from those encountered in many other severe anemias and in circulatory disturbances in being relatively constant over long periods. Other manifestations of the neural changes of pernicious anemia may suggest “neuritis,” tabes dorsalis, fallen arches or “rheumatism.”
  • Gross diminution of ability to perceive the vibration of a tuning fork held in contact with the tibia is an almost constant finding in the presence of the neural lesion of pernicious anemia. Reflex changes vary from complete absence to extreme hyperactivity associated with clonus, depending on whether the lesion is predominantly in the posterior or lateral columns of the spinal cord. In the former, ataxia and a positive Romberg sign occur, and in the latter, spasticity and the sign of Babinski. Any combination of signs in the posterior and lateral columns may be seen. Sphincter disturbances are common in advanced cases.
  • In the absence of well marked abnormalities of the blood, lumbar puncture may be necessary to exclude syphilis of the central nervous system, spinal-cord tumors, lesions of the cauda equina and prolapsed intervertebral disk.

Blood Picture

The blood picture in well developed pernicious anemia is typical of diminished productivity of the bone marrow with decreased numbers of white blood cells and blood platelets, as well as of red blood cells. The red-cell count is usually below 2,500,000. The mean corpuscular volume of the red blood cells is large (110 to 160 cubic microns). Some increase in size is prone to occur before there is any out-spoken reduction of the red-cell count. The mean corpuscular hemoglobin concentration is 32 per cent or more, and the color index almost always is above 1. The plasma pigments are usually increased, with an elevation in the indirect van den Bergh reaction. Red cell survival is reduced.

The Bone Marrow.

The bone marrow is red, extends into the long bone cavity and consists of sheets of proliferating immature red cells which mature rapidly when intrinsic factor and vitamin B12 are administered. White cell and platelet progenitors are crowded out. Vitamin B12 was discovered in 1947 and was found to be the extrinsic factor in food specially liver which together with intrinsic factor from the stomach,”cured” pernicious anemia.

Folic Acid.

The introduction of synthetic pteroylglutamic acid in the treatment of pernicious anemia was at first considered a major therapeutic advance that would permit patients to be maintained without the necessity of receiving liver extract by injection. However, before many months went by, it became apparent not only that pteroylglutamic acid failed to protect the nervous system against the progression of subacute combined degeneration of the spinal cord but also, in a number of cases, that fulminating neurologic relapse seemed to be related to its administration. Folate is also called vitamin B9. The terms “folate” and “folic acid” are sometimes used interchangeably; however, the vitamin is found in nature as a folate, while folic acid is the synthetic form used therapeutically and is an oxidized, water-soluble form that does not exist in nature. Dietary folates are also called folate polyglutamates. Dietary folate is found in plant-based foods and fortified grains.

Folinic acid (leucovorin, N5-formyl-tetrahydofolate [THF], 5-formylTHF) and 5-methyltetrahydrofolate (5-MTHF) are naturally occurring forms of reduced folate. Folinic acid is typically used to prevent toxicities of methotrexate and to potentiate cytotoxicity of fluorouracil (FU) in chemotherapy regimens for colon cancer. This is because folinic acid is rapidly converted to the metabolically active form of folate required in cells (tetrahydrofolate) without the need for dihydrofolate reductase, which is inhibited by methotrexate. Folic acid, folinic acid, and 5-MTHF are all effective in treating folate deficiency.

Homocysteine and methylmalonic acid. If a step in the formation of recycling of folate is blocked homocysteine and methylmalonic acid (MMA) form as metabolic intermediates that accumulate. Homocysteine is elevated in both vitamin B12 and folate deficiencies, whereas MMA is only elevated in vitamin B12 deficiency.

So what can be measured in addition vitamin B12 levels in blood or folate levels in serum or RBCs? Homocysteine or MMA levels.

Vitamin B12.

Dr. Karl Folkers announced the chemical nature of one fraction of the vitamin B12 molecule to be 5,6-dimethyl benzimidazole. Riboflavin, a matter of interest in view of the fact that a diet rich in riboflavin appears to favor bacterial synthesis of vitamin B12 in the gastrointestinal tract. It is the parent compound from which B12 is derived. The endogenous forms include cobalamin and holotranscobalamin, which represent the active fraction of plasma cobalamin. The supplemental forms used to treat vitamin B12 deficiency include cyanocobalamin, which contains a cyanide (CN) group introduced during chemical synthesis, and hydroxocobalamin.

Megaloblastic versus macrocytic anemia 

Both vitamin B12 and folate deficiencies cause megaloblastic anemia. When the process of nucleic acid metabolism is impaired, nuclear-cytoplasmic synchrony is disrupted, the number of red cell divisions in the bone marrow are reduced, and nuclear abnormalities in both myeloid and erythroid precursors occur. Megaloblastic anemia is a term that refers to anemia in which nuclear material persists in RBCs and their precursors.. Therefore, the term should be confined to nucleated red blood cell (RBC) precursors when used to describe red blood cell morphology. Macrocytic anemia is purely a morphologic term that describes large RBCs in the peripheral blood and includes all anemias with a high mean corpuscular volume (MCV). Megaloblastic anemia is a specific subtype of macrocytic anemia.

Gastrointestinal symptoms — 

Vitamin B12 deficiency can cause glossitis (including pain, swelling, tenderness, and loss of papillae of the tongue), and folate deficiency can cause oral ulcers. This occurs because cells in the gastrointestinal tract divide rapidly and are thus sensitive to the lack of nucleic acids that occurs when these vitamins are deficient. Other individuals may have gastrointestinal symptoms related to the underlying condition that caused the deficiency, such as pain or diarrhea related to inflammatory bowel disease, celiac disease, or other malabsorptive states.

Treatment of B12 and folate deficiency.

When is treatment an emergency?

  • Symptomatic anemia or neurologic or neuropsychiatric findings, to prevent irreversible neurologic deficits.
  • Pregnancy, as the developing fetus may be affected.
  • Neonates and infants

Route of administration. Vitamin B12, formulations are available for intramuscular/deep subcutaneous injection and oral , sublingual, and nasal administration: the underlined forms will need to have intrinsic factor added or be given in large doses. For folic acid, formulations are available for intravenous, intramuscular, and subcutaneous use, as well as oral ingestion.

Duration of therapy — The duration of therapy depends on whether the initial cause of the deficiency persists. Lifelong replacement is necessary for individuals with a condition that is not reversed (eg, gastric bypass surgery, autoantibodies to intrinsic factor [pernicious anemia]). If the cause of the deficiency can be treated or eliminated (eg, excessively restrictive diet, drug-induced deficiency, reversible cause of malabsorption), supplementation can be discontinued after the deficiency is corrected.

Ref: H. Franklin Bunn, M.D.

February 20, 2014
N Engl J Med 2014; 370:773-776
DOI: 10.1056/NEJMcibr1315544

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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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