Iron deficiency anemia post VSG!!

on 9/21/10 12:41 pm
I'm not sure I agree with your hematologist since Iron is absorbed in the small intestine and not the stomach. I wonder if they're making a big assumption that VSG is like RNY _OR_ possibly basing their comment on the typical for populations of people needing infusions when the problem is as yours is (if it even is).  Were you taking your daily iron 2 hours away from taking calcium as you should?

loose -- (adj)  not tight
lose - (verb)  to rid oneself of

on 9/21/10 1:03 pm - Houston area, TX
I was never taking any iron or other vitamins or minerals.  I don't remember ever being told to.  I have sporadically taken centrum chewables, and just restarted taking a double dose when I got the results of these labs from my PS.

He said that iron is absorbed in the small intestine, but that my stomach is too small to breakdown the iron  to the right form so it is able to be absorbed.  I will question him more about it next time I see him.  I for sure am getting iron infusion this Thursday, and will hopefully be corrected enough for my surgery on October 6th.

on 9/21/10 2:09 pm
If you haven't been taking it then for sure don't assume you can't get to being able to maintain without infusions in the longer term. 
Be careful with double doses--it can cause tummy upsets.  You should be taking a calcium vit D supplement 3x per day and an iron with vit C chewable two hours away from taking your calcium vit D (because it will interfere with absorption).  Now if have another time of day available 2 hours away from vit D and calcium, then you could fit in a second dose.  But I wouldn't double dose at one time.  I chose iron as an amino acid chelate. I think if you do that instead of ferrous sulfate, there really isn't much to have to break down.

loose -- (adj)  not tight
lose - (verb)  to rid oneself of

Andrea U.
on 9/21/10 2:09 pm - Wilson, NC
Iron requires the B vites to absorb and metabolize properly.

In order for B-12 to absorb and metabolize, it requires something called Intrinsic Factor (or IF as it's shortened regularly).  This is cut short in RNY, DS -- and YES in VSG.

So the surgeon is absolutely correct.  But so are you as the iron is, in fact, absorbed in the small intestine.

on 9/21/10 2:24 pm - Houston area, TX
Thanks for chiming in.  I'm going to do a little experiment to see if he's wrong about iron infusions every 3 months forever....

I'm going to supplement the iron and B12 and when we check labs in 3 months or so I will see what has changed.  If I am able to skip the next iron infusion then I will see what the 6 month mark shows when my infusion is completely gone.

on 9/21/10 2:34 pm
Do you have a reference for iron requiring B vits to absorb?  Because I don't think so.

Gastric acid is needed to get heme iron out of food.  That's not the same situation as taking it as a supplement.
loose -- (adj)  not tight
lose - (verb)  to rid oneself of

Andrea U.
on 9/21/10 10:09 pm, edited 9/22/10 12:18 am - Wilson, NC
Seriously?  I mean, seriously?

You've never heard of pernicious anemia?  This is something that MANY RNYers must fight with on a regular basis.  I'm surprised VSGers aren't, either.

Description of Anemia

Anemia occurs when blood does not have enough red blood cells or when the blood does not have enough hemoglobin. Hemoglobin is the oxygen-carrying pigment found in red blood cells. Anemia can be life-threatening.

Although there are over 400 different forms of anemia, this health profile will only address the three most common: iron-deficiency anemia, vitamin B12 anemia and folic acid deficiency.

Anemias can also be caused by such conditions as external bleeding, chronic disease, pregnancy, alcoholism, bleeding disorders, infection and hereditary conditions

Causes and Risk Factors of Anemia

Iron deficiency anemia

Iron deficiency anemia arises from too little iron in the body to make sufficient hemoglobin. There are three (3) causes of iron deficiency anemia:

    1. Loss of iron at a greater rate than normal (blood loss). Blood loss is usually the result of slow, persistent bleeding from inside the body, such as gastritis, peptic ulcers, ulcerative colitis, inflammatory bowel disease, polyps, gastrointestinal tumors (such as stomach or colon cancer), heavy menstrual periods, kidney tumors, bladder tumors, cystitis, prostatitis, and hemorrhoids. Additionally, the frequent use of aspirin, ibuprofen or other non-steroid anti-inflammatory drugs, as well as chronic alcohol abuse, can also cause iron deficiency anemia.

    2. Poor absorption of iron from the diet. Poor absorption of iron from the diet is usually as a result of surgical removal of part or all of the stomach or celiac sprue (a condition in which the lining of the small intestine is damaged by a protein found in wheat or rye called gluten).

    3. Eating a diet low in iron. This anemia can happen from not eating enough iron-rich foods, such as fruit, whole-grain bread, beans, lean meat and green vegetables.

Vitamin B12 anemia

Vitamin B12 anemia is the result of an impaired ability of the digestive tract to absorb the B12 that is a normal part of the diet. B12 is essential for the production of red blood cells, as well as the maintenance of the nervous system, and is found in food of animal origin such as meat, fish and dairy products. There are four (4) causes.

    1. Failure of the stomach lining to produce intrinsic factor. Intrinsic factor is a chemical produced by the stomach lining and combined with vitamin B12 in the small intestine. Due to an autoimmune disorder (a disorder caused by a person's own immune system attacking the body's organs and tissues), the production of intrinsic factor is blocked.

    2. Rremoval of small intestine where vitamin B12 is absorbed

    3. Crohn’s disease - a chronic inflammatory disease that affects any part of the gastrointestinal tract

    4. Eating a vegan diet which excludes eggs, diary products, meat and fish

Folic acid deficiency

Folic acid deficiency is usually caused by an inadequate intake of folic acid, a vitamin mainly supplied by the fresh green leafy vegetables, mushrooms, lima beans and kidney beans. This disorder is most common in the poor and elderly (due to poor eating habits), in heavy alcohol drinkers, and in persons afflicted with intestinal disorders such as Crohn’s disease or celiac sprue.

Symptoms of Anemia

The symptoms of iron deficiency anemia (if any) are:
    • Paleness
    • Weakness
    • Tiredness
    • Chest pains (in severe cases)
    • Shortness of breath (in severe cases)
    • Heart palpitations (in severe cases)
    • An increased heart rate especially during exertion (in severe cases)
    • Rapid breathing
    • Low blood pressure

The symptoms of vitamin B12 anemia are similar to those of iron deficiency anemia but can also cause:

    • Jaundice
    • Numbness and tingling in the hands and feet
    • Equilibrium difficulties
    • Confusion
    • Personality changes and depression

The symptoms of folic acid deficiency are similar to vitamin B12 anemia.

Symptoms of anemia may also include:

    • Back, maroon or bloody stool
    • Abdominal pain
    • Weight loss
    • Fatigue
    • Chest pain

Diagnosis of Anemia

Anemia is diagnosed from the patient's symptoms and by a blood test that measures the level of hemoglobin in the blood, as well as substances such as folic acid, bilirubin and vitamin B12. Additionally, the size of the red cells provide further clues to the type of anemia.

Other methods of diagnosis may include a bone marrow biopsy, which is the removal of bone marrow for further examination under a microscope.

Bone marrow biopsy is helpful in diagnosing vitamin B12 anemia. Some dietitians suggest that the doctor also check for levels of ferritin in the blood of premenopausal women. Ferritin is a protein that stores iron before the mineral circulates in the bloodstream.

Treatment of Anemia

Iron-deficiency anemia

Treatment will depend upon whether an individual is not getting enough iron in the diet (increase iron intake); not absorbing iron (surgery for celiac sprue, etc.); or losing small amounts over time due to anything from alcoholic gastritis to medication abuse to tumors. The doctor will often recommend iron-rich foods (such as liver, seafood, dried fruits, lima beans, whole grains, green leafy vegetables and blackstrap molasses) or iron pills. In the more severe cases of iron deficiency anemia caused by blood loss, surgery, blood transfusions or hormone injections may be recommended.

Vitamin B12 deficiency

Current treatment of vitamin B12 deficiency consists of a life-long regimen of monthly B-12 injections. Unfortunately, neither diet or iron pills will help, but if diagnosed early a full recovery is promising.

Folic acid deficiency

Treatment is frequently a dietary correction. Main sources of folic acid include meat, poultry, cheese, milk, eggs, liver, green leafy vegetables, raw fruits, lima and kidney beans, and yeast. Folic acid tablets cure the anemia quickly. If intestinal disorders impede folic acid absorption, a supplement may be needed for a time. In rare instances, injections of folic acid are necessary.

Overall treatment considerations

Other therapies for anemia may include oxygen, fluids, fresh frozen plasma, platelet replacement and vasopressors (medication to elevate blood pressure). This will depend upon the underlying cause of the anemia.

Prevention of Anemia

Consumption of a healthy diet including iron-containing foods and those with B-complex vitamins is essential to developing and maintaining a satisfactory blood count.

Questions To Ask Your Doctor About Anemia

What tests need to be done to diagnose the condition and to determine the cause?

What type of anemia is it?

What is the cause of the anemia?

How serious is this type of anemia?

Has any permanent damage been done?

What treatment will you be recommending?

Will you be prescribing any medications?

What are the side effects?

Will treatment need to be continued for life?

This is a TECHNICAL medical document as it's written by doctors (a heme) FOR doctors.

eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Pernicious Anemia

Author: Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
Contributor Information and Disclosures

Updated: Aug 26, 2009



Pernicious anemia (see images below) is a chronic illness caused by impaired absorption of vitamin B-12 because of a lack of intrinsic factor (IF) in gastric secretions.

Peripheral smear of blood from a patient with per...

Peripheral smear of blood from a patient with pernicious anemia. Macrocytes are observed, and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leucocyte is present.

Bone marrow aspirate from a patient with untreate...

Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.

Pernicious anemia occurs as a relatively common adult form of anemia that is associated with gastric atrophy and a loss of IF production and as a rare congenital autosomal recessive form in which IF production is lacking without gastric atrophy.

The disease was named pernicious anemia because it was fatal before treatment became available, first as liver therapy and, subsequently, as purified vitamin B-12. The term pernicious is no longer appropriate, but it is retained for historical reasons.

While the term pernicious anemia is reserved for patients with vitamin B-12 deficiency due to a lack of production of IF in the stomach, vitamin B-12 absorption is complex and other causes of vitamin B-12 deficiency exist and are described briefly in this article.


Classic pernicious anemia is caused by the failure of gastric parietal cells to produce sufficient IF to permit the absorption of adequate quantities of dietary vitamin B-12. Other disorders that interfere with the absorption and metabolism of vitamin B-12 can produce cobalamin (Cbl) deficiency, with the development of a macrocytic anemia and neurological complications.

Cbl is an organometallic substance containing a corrin ring, a centrally located cobalt atom, and various axial ligands. See the image below.

Pernicious anemia. The structure of cyanocobalami...

Pernicious anemia. The structure of cyanocobalamin is depicted. The cyanide (Cn) is in green. Other forms of cobalamin (Cbl) include hydroxocobalamin (OHCbl), methylcobalamin (MeCbl), and deoxyadenosylcobalamin (AdoCbl). In these forms, the beta-group is substituted for Cn. The corrin ring with a central cobalt atom is shown in red and the benzimidazole unit in blue. The corrin ring has 4 pyrroles, which bind to the cobalt atom. The fifth substituent is a derivative of dimethylbenzimidazole. The sixth substituent can be Cn, CC3, hydroxycorticosteroid (OH), or deoxyadenosyl.

The cobalt atom can be in a +1, +2, or +3 oxidation state. In hydroxocobalamin, it is in the +3 state. The cobalt atom is reduced in a nicotinamide adenine dinucleotide (NADH)–dependent reaction to yield the active coenzyme. It catalyzes 2 types of reactions, which involve either rearrangements (conversion of l methylmalonyl coenzyme A [CoA] to succinyl CoA) or methylation (synthesis of methionine).

The basic structure known as vitamin B-12 is solely synthesized by microorganisms, but most animals are capable of converting vitamin B-12 into the 2 coenzyme forms, adenosylcobalamin and methylcobalamin. The former is required for conversion of L- methylmalonic acid to succinyl coenzyme A (CoA), and the latter acts as a methyltransferase for conversion of homocysteine to methionine. When either Cbl or folate is deficient, thymidine synthase function is impaired. This leads to megaloblastic changes in all rapidly dividing cells because DNA synthesis is diminished. In erythroid precursors, macrocytosis and ineffective erythropoiesis occur.

Dietary Cbl is acquired mostly from meat and milk and is absorbed in a series of steps, which require proteolytic release from foodstuffs and binding to a gastric protein secreted by parietal cells that is known as IF. Subsequently, recognition of the IF-Cbl complex by specialized ileal receptors must occur for transport into the portal circulation to be bound by transcobalamin II (TC II), which serves as the plasma transporter.

The Cbl-TC II complex binds to cell surfaces and is endocytosed. The transcobalamin (TC) is degraded within a lysozyme, and the Cbl is released into the cytoplasm. An enzyme-mediated reduction of the cobalt occurs with either cytoplasmic methylation to form methylcobalamin or mitochondrial adenosylation to form adenosylcobalamin. Defects of these steps produce manifestations of Cbl dysfunction. Most defects become manifest in infancy and early childhood and result in impaired development, mental retardation, and a macrocytic anemia. Certain defects cause methylmalonic aciduria and homocystinuria. See the image below.

Pernicious anemia. Inherited disorders of cobalam...

Pernicious anemia. Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters correspond to the sites at which abnormalities have been identified, as follows: (1) absence of intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II (TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl E and G), and (f) lysosomal Cbl efflux (Cbl F).

Pernicious anemia probably is an autoimmune disorder with a genetic predisposition. Pernicious anemia is more common than is expected in families of patients with pernicious anemia, and the disease is associated with human leucocyte antigen (HLA) types A2, A3, and B7 and type A blood group.

Antiparietal cell antibodies occur in 90% of patients with pernicious anemia but in only 5% of healthy adults. Similarly, binding and blocking antibodies to IF are found in most patients with pernicious anemia. A greater association than anticipated exists between pernicious anemia and other autoimmune diseases, whi*****lude thyroid disorders, type I diabetes mellitus, ulcerative colitis, Addison disease, infertility, and acquired agammaglobulinemia. An association between pernicious anemia and Helicobacter pylori infections has been postulated but not clearly proven.

Cbl deficiency may result from dietary insufficiency of vitamin B-12; disorders of the stomach, small bowel, and pancreas; certain infections; and abnormalities of transport, metabolism, and utilization (see the summary of causes of Cbl deficiency below). Deficiency may be observed in strict vegetarians.1 Breastfed infants of vegetarian mothers also are affected. Severely affected infants of vegetarian mothers who do not have overt Cbl deficiency have been reported. Meat and milk are the main source of dietary Cbl. Because body stores of Cbl usually exceed 1000 mcg and the daily requirement is about 1 mcg, strict adherence to a vegetarian diet for more than 5 years usually is required to produce findings of Cbl deficiency.

Classic pernicious anemia produces Cbl deficiency due to failure of the stomach to secrete IF. See the image below.

Pernicious anemia. Cobalamin (Cbl) is freed from ...

Pernicious anemia. Cobalamin (Cbl) is freed from meat in the acidic milieu of the stomach where it binds R factors in competition with intrinsic factor (IF). Cbl is freed from R factors in the duodenum by proteolytic digestion of the R factors by pancreatic enzymes. The IF-Cbl complex transits to the ileum where it is bound to ileal receptors. The IF-Cbl enters the ileal absorptive cell, and the Cbl is released and enters the plasma. In the plasma, the Cbl is bound to transcobalamin II (TC II), which delivers the complex to nonintestinal cells. In these cells, Cbl is freed from the transport protein.

In adults, pernicious anemia is associated with severe gastric atrophy and achlorhydria, which are irreversible. Coexistent iron deficiency is common because achlorhydria prevents solubilization of dietary ferric iron from foodstuffs. Autoimmune phenomena and thyroid disease frequently are observed. Patients with pernicious anemia have a 2- to 3-fold increased incidence of gastric carcinoma.

Summary of causes of Cbl deficiency

  • Inadequate dietary intake (ie, vegetarian diet)
  • Atrophy or loss of gastric mucosa (eg, pernicious anemia, gastrectomy, ingestion of caustic material, hypochlorhydria, histamine 2 [H2] blockers)
  • Functionally abnormal IF
  • Inadequate proteolysis of dietary Cbl
  • Insufficient pancreatic protease (eg, chronic pancreatitis, Zollinger-Ellison syndrome)
  • Bacterial overgrowth in intestine (eg, blind loop, diverticula)
  • Disorders of ileal mucosa (eg, resection, ileitis, sprue, lymphoma, amyloidosis, absent IF-Cbl receptor, Imerslünd-Grasbeck syndrome, Zollinger-Ellison syndrome, TCII deficiency, use of certain drugs)
  • Disorders of plasma transport of cobalamin (eg, TCII deficiency, R binder deficiency)
  • Dysfunctional uptake and use of cobalamin by cells (eg, defects in cellular deoxyadenosylcobalamin [AdoCbl] and methylcobalamin [MeCbl] synthesis)


United States

The adult form of pernicious anemia is most prevalent among individuals of either Celtic (ie, English, Irish, Scottish) or Scandinavian origin. In these groups, 10-20 cases per 100,000 people occur per year. Pernicious anemia is reported less commonly in people of other racial backgrounds. Although the disease was once believed to be rare in Native American people and uncommon in black people, recent observations suggest that the incidence was underestimated.


Historically, pernicious anemia was believed to occur predominantly in people of northern European descent. During recent years, it has become apparent that occurrence of pernicious anemia in all racial and ethnic groups is more common than was previously recognized. Chan et al presented a longitudinal study of Chinese patients.2

In the period betwee***** to 2007, the investigators recruited 199 intrinsic factor antibody (IFA)-positive and 168 IFA-negative patients. At baseline the 2 groups had similar characteristics, except the IFA-positive group had more severe hematologic findings and more thyrogastric immune features, whereas the IFA-negative patients included more who had type 2 diabetes mellitus and gastrointestinal disease or gastrointestinal surgery.2

Despite a good hematologic response to therapy, both groups had an unsatisfactory neurologic response, and newly diagnosed hypothyroidism was found during follow-up. In addition, newly diagnosed cancers were also found (24 IFA-positive, 7 IFA-negative patients), of which 20% were gastric cancer.2  Of the IFA-positive patients with a cancer, mean survival was 64 months; of those without a cancer, it was 129 months (P <0.001). Mortality was 31% in this group, in which cancer-related deaths were 37%.2 Of the IFA-negative patients with a cancer, mean survival was 36 months; of those without a cancer, it was 126 months (P <0.001). Mortality was 21% in this group, of which cancer-related deaths were 14%.

Chan et al concluded that although Chinese patients treated for pernicious anemia have a good survival period, the risk of gastric carcinomas is increased. Furthermore, IFA-positive patients had a higher risk of developing all types of cancers and cancer-related deaths than IFA-negative patients.2


The disease is called pernicious anemia because it was fatal prior to the discovery that it was a nutritional disorder. The megaloblastic appearance of cells led many to speculate that it was a neoplastic disease. The response of patients to liver therapy suggested that a nutritional deficiency was responsible for the disorder. This became obvious in clinical trials once vitamin B-12 was isolated. Presently, patients on appropriate treatment have a normal lifespan.


While the disease originally was believed to be restricted primarily to whites of Scandinavian and Celtic origin, recent evidence shows that it occurs in all races.


A female predominance has been reported in England, Scandinavia, and among persons of African descent (1.5:1). However, data in the United States show an equal sex distribution.


Adult pernicious anemia usually occurs in people aged 40-70 years.3 Among white people, the mean age of onset is 60 years, whereas it occurs at a younger age in black people (mean age of 50 y), with a bimodal distribution caused by increased occurrence in young black females. Congenital pernicious anemia is usually manifested in children younger than 2 years.



The onset of pernicious anemia usually is insidious and vague. The classic triad of weakness, sore tongue, and paresthesias may be elicited but usually is not the chief symptom complex. Usually, medical attention is sought because of symptoms suggestive of cardiac, renal, genitourinary, gastrointestinal, infectious, mental, or neurological disorders, and the patient is found to be anemic with macrocytic cellular indices.
  • General findings: Weight loss of 10-15 pounds occurs in about 50% of patients and probably is due to anorexia, which is observed in most patients. Low-grade fever occurs in one third of newly diagnosed patients and promptly disappears with treatment.
  • Anemia: The anemia often is well tolerated in pernicious anemia, and many patients are ambulatory with hematocrit levels in the mid teens. However, the cardiac output is usually increased with hematocrits less than 20%, and the heart rate accelerates. Congestive heart failure and coronary insufficiency can occur, most particularly in patients with preexisting heart disease.
  • Gastrointestinal findings: Approximately 50% of patients have a smooth tongue with loss of papillae. This is usually most marked along the edges of the tongue. The tongue may be painful and beefy red. Occasionally, red patches are observed on the edges of the dorsum of the tongue. Patients may report burning or soreness, most particularly on the anterior one third of the tongue. These symptoms may be associated with changes in taste and loss of appetite.
    • Patients may report either constipation or having several semisolid bowel movements daily. This has been attributed to megaloblastic changes of the cells of the intestinal mucosa.
    • Nonspecific gastrointestinal symptoms are not unusual and include anorexia, nausea, vomiting, heartburn, pyrosis, flatulence, and a sense of fullness. Rarely, patients present with severe abdominal pain associated with abdominal rigidity; this has been attributed to spinal cord pathology.
  • Nervous system: Neurological symptoms can be elicited in most patients with pernicious anemia, and the most common symptoms are paresthesias, weakness, clumsiness, and an unsteady gait. The 2 latter symptoms become worse in a dark room because they reflect the loss of proprioception in a patient who is unable to rely upon vision for compensation. These neurological symptoms are due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex.
    • Neurological symptoms and findings may be present in the absence of anemia; this is more common in patients taking folic acid or on a high-folate diet.
    • Patients who are older may present with symptoms suggesting senile dementia or Alzheimer disease; memory loss, irritability, and personality changes are commonplace. Megaloblastic madness is less common and can be manifested by delusions, hallucinations, outbursts, and paranoid schizophrenic ideation. Identifying the cause is important because significant reversal of these symptoms and findings can occur with vitamin B-12 administration.
  • Genitourinary system: Urinary retention and impaired micturition may occur because of spinal cord damage. This can predispose patients to urinary tract infections.

The finding of severe anemia in an adult patient whose constitutional symptoms are relatively mild and in whom weight loss is not a major symptom should arouse suspicion of pernicious anemia.

  • Typically, patients with pernicious anemia are described as having a stereotypic appearance.
    • Patients have a lemon-yellow waxy pallor with premature whitening of the hair.
    • They appear flabby, with a bulky frame that is generally incongruent with the severe anemia and weakness.
    • While this characterization is useful in patients of northern European descent, it is less helpful among patients of other ethnic groups who develop Cbl deficiency.
  • Low-grade fever and mild icterus are commonplace but are usually mild and easily missed.
  • A beefy, red, smooth tongue may be observed.
  • In patients with dark complexions, blotchy skin pigmentation may be observed.
  • Tachycardia often is present and may be accompanied by flow murmurs.
  • Abnormal mentation and deterioration of vision and hearing may be observed.
  • With severe anemia, dyspnea, tachypnea, and evidence of congestive heart failure may be present.
  • Retinal hemorrhages and exudates may accompany severe anemia.
  • The liver may be enlarged in association with congestive heart failure.
  • A splenic tip is palpable in about 20% of patients.
  • A careful neurological assessment is important. In all megaloblastic disorders, hematological and epithelial manifestations occur, but only Cbl deficiency causes neurological deficits. Neurological findings may occur in the absence of anemia and epithelial manifestations of pernicious anemia, making it more difficult to identify the etiology. If left untreated, they can become irreversible.
    • Central nervous system: Suspect pernicious anemia in all patients with recent loss of mental capacities. Somnolence, dementia, psychotic depression, and frank psychosis may be observed, which can be reversed or improved by treatment with Cbl. Perversion of taste and smell and visual disturbances, which can progress to optic atrophy, can likewise result from central nervous system Cbl deficiency.
    • Combined system disease: A history of either paresthesias in the fingers and toes or difficulty with gait and balance should prompt a careful neurological examination. Loss of position sense in the second toe and loss of vibratory sense for a 256-Hz but not a 128-Hz tuning fork are the earliest signs of posterolateral column disease. If untreated, this can progress to spastic ataxia from demyelinization of the dorsal and lateral columns of the spinal cord.


An increased incidence of pernicious anemia in families suggests a hereditary component to the disease. Patients with pernicious anemia have an increased incidence of autoimmune disorders and thyroid disease, suggesting that an immunological component to the disease exists. Children who develop Cbl deficiency usually have a hereditary disorder, and the etiology of their Cbl deficiency is different from the etiology observed in classic pernicious anemia.

Congenital pernicious anemia is a hereditary disorder in which an absence of IF occurs without gastric atrophy. Other gastric disorders that cause Cbl deficiency are gastrectomy, gastric stapling, and bypass procedures for obesity and extensive infiltrative disease of the gastric mucosa. Usually, these disorders are associated with a decreased ability to mobilize Cbl from food rather than a malabsorption of Cbl. Thus, a patient with these disorders may exhibit a normal finding on Schilling test (stage I).

Pancreatic insufficiency can produce Cbl deficiency. Nonspecific R binders chelate Cbl in the stomach, making it unavailable for binding to IF. Pancreatic proteases degrade the R binders and release the Cbl so that it can bind IF. The Cbl-IF complex is formed so that it can bind ileal receptors that enable uptake by absorptive cells. Thus, patients with chronic pancreatitis may have impaired absorption of Cbl.

Cbl deficiency is reported in the Zollinger-Ellison syndrome. The mechanism is believed to be due to the acidic pH of the distal small intestine such that the Cbl-IF complex cannot effectively bind the ileal receptors.

Disorders of the ileum cause Cbl deficiency due to loss of the ileal receptors for the Cbl-IF complex. Thus, surgical loss of the ileum or diseases such as tropical sprue, regional enteritis, ulcerative colitis, and ileal lymphoma interfere with Cbl absorption.

Genetic defects of the ileal receptors for IF (ie, Imerslünd-Grasbeck syndrome) and hereditary transcobalamin I (TC I) deficiency produce Cbl deficiency from birth and are usually discovered early in life.

Many drugs impair Cbl uptake in the ileum but rarely are a cause of symptomatic vitamin B-12 deficiency because they are not taken long enough to deplete body stores of Cbl (eg, nitrous oxide, cholestyramine, para -aminosalicylic acid, neomycin, metformin, phenformin, colchicine).

The clinical manifestations of inherited defects of Cbl transport and metabolism are usually observed in infancy and childhood. Thus, they are discussed only briefly in this article.

Three hereditary disorders affect absorption and transport of Cbl, and another 7 alter cellular use and coenzyme production. See the image below.

Pernicious anemia. Inherited disorders of cobalam...

Pernicious anemia. Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters correspond to the sites at which abnormalities have been identified, as follows: (1) absence of intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II (TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl E and G), and (f) lysosomal Cbl efflux (Cbl F).

  • The 3 disorders of absorption and transport are TC II deficiency and deficiencies of either IF or IF receptors. These defects produce developmental delay and a megaloblastic anemia, which can be alleviated with pharmacological doses of Cbl. Serum Cbl values are decreased in the IF abnormalities but may be within the reference range in TC II deficiency.
  • The abnormalities of cellular use can be detected by the presence or absence of methylmalonic aciduria and homocystinuria. The presence of only methylmalonic aciduria indicates a block in conversion of methylmalonic CoA to succinyl CoA and results in either a genetic deficit in the methylmalonyl CoA mutase that catalyzes the reaction or a defect in synthesis of its CoA Cbl (Cbl A and Cbl B).
  • The presence of only homocystinuria results either from poor binding of Cbl to methionine synthase (Cbl E) or from producing methylcobalamin from Cbl and S adenosylmethionine (Cbl G). This results in a reduction in methionine synthesis, with pronounced homocystinemia and homocystinuria.
  • Methylmalonic aciduria and homocystinuria occur when the metabolic defect impairs reduction of Cbl III to Cbl II (Cbl C, Cbl D, Cbl F). This reaction is essential for formation of both methylmalonic acid and homocystinuria.
  • Early detection of these rare disorders is important because most patients respond favorably to large doses of Cbl. However, some of these disorders are less responsive than others, and delayed diagnosis and treatment are less efficacious.

Abnormalities in the intestinal lumen may produce Cbl deficiency. Individuals with blind intestinal loops, stricture, and large diverticula may develop bacterial overgrowth, which sequesters dietary Cbl for their metabolic needs. Tapeworm infestation with Diphyllobothrium latum occurs from eating poorly cooked lake fish that are infected and causes Cbl deficiency because the parasites have a high requirement for Cbl.

Differential Diagnoses

Achlorhydria Hyperthyroidism
Alcoholic Fatty Liver Hypothyroidism
Alcoholic Hepatitis Immune Thrombocytopenic Purpura
Anemia Iron Deficiency Anemia
Aplastic Anemia Macrocytosis
Bone Marrow Failure Malabsorption
Celiac Sprue Megaloblastic Anemia
Cirrhosis Myeloproliferative Disease
Folic Acid Deficiency Neutropenia
Gastric Cancer Schizophrenia
Gastritis, Atrophic Sprue, Tropical
Hemolytic Anemia Zollinger-Ellison Syndrome
Hyperbilirubinemia, Unconjugated  

Other Problems to Be Considered

Alcoholic cirrhosis
Alzheimer disease
Cestode infection
Neurologic disorders


Laboratory Studies

Peripheral blood: The peripheral blood usually shows a macrocytic anemia with a mild leukopenia and thrombocytopenia. The mean cell volume (MCV) and mean cell hemoglobin (MCH) are increased, with a mean corpuscular hemoglobin concentration (MCHC) within the reference range. The leukopenia and thrombocytopenia usually parallel the severity of the anemia. See the images below.

Peripheral smear of blood from a patient with per...

Peripheral smear of blood from a patient with pernicious anemia. Macrocytes are observed, and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leucocyte is present.

Bone marrow aspirate from a patient with untreate...

Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.

The peripheral smear shows oval macrocytes, hypersegmented granulocytes, and anisopoikilocytosis. In severe anemia, red blood cell inclusions may include Howell-Jolly bodies, Cabot rings, and punctate basophilia. The macrocytosis can be obscured by the coexistence of iron deficiency, thalassemia minor, or inflammatory disease.

Serum: The indirect bilirubin may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin. The serum lactic dehydrogenase usually is markedly increased. Increased values for other red blood cells, enzymes, and serum iron saturation also are observed. The serum potassium, cholesterol, and skeletal alkaline phosphatase often are decreased.

Gastric secretions: Total gastric secretions are decreased to about 10% of the reference range. Most patients with pernicious anemia are achlorhydric, even with histamine stimulation. IF is either absent or markedly decreased.

Serum Cbl levels: The serum Cbl is low in patients with pernicious anemia; however, it may be within the reference range in certain patients with other forms of Cbl deficiency. These include some inborn areas of Cbl deficiency, TC II deficiency, and Cbl deficiency due to nitrous oxide.

  • Conversely, serum Cbl levels may be low in patients who are pregnant, have TC I deficiency, have severe folic acid deficiency, and following large doses of ascorbic acid.
  • Screening of individuals who are older has shown that 10-20% have low serum Cbl levels, and half of these patients have increased levels of homocysteine and methylmalonic acid, indicating a tissue Cbl deficiency.

Methylmalonic acid and homocysteine (see Table 1): Elevated serum methylmalonic acid and homocysteine levels are found in patients with pernicious anemia. They probably are the most reliable test for Cbl deficiency in patients who do not have a congenital metabolism disorder. In the absence of an inborn error of methylmalonic acid metabolism, methylmalonic aciduria is a sign of Cbl deficiency.

Table 1. Serum Methylmalonic Acid and Homocysteine Values Used in Differentiating Between Cbl and Folic Acid Deficiency

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Patient Condition Methylmalonic Acid Homocysteine
Healthy Normal Normal
Vitamin B-12 deficiency Elevated Elevated
Folate deficiency Normal Elevated
Patient Condition Methylmalonic Acid Homocysteine
Healthy Normal Normal
Vitamin B-12 deficiency Elevated Elevated
Folate deficiency Normal Elevated

Schilling test (see Table 2): The Schilling test measures Cbl absorption by increasing urine radioactivity after an oral dose of radioactive Cbl. The test is useful in demonstrating that the anemia is caused by an absence of IF and is not secondary to other causes of Cbl deficiency. Likewise, it is helpful because it is used to identify patients with classic pernicious anemia, even after they have been treated with vitamin B-12.

Table 2. Schilling Test Results

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Patient Condition Stage I
Stage II
Intrinsic Factor
Stage III
Stage IV
Pancreatic Extract
Healthy Normal
Pernicious anemia Low Normal
Bacterial overgrowth Low Low Normal
on 9/22/10 4:23 am - Houston area, TX
Thanks for the great articles, Andrea!
on 9/22/10 12:37 am - Mexico
On September 21, 2010 at 9:34 PM Pacific Time, Jesse_James wrote:
Do you have a reference for iron requiring B vits to absorb?  Because I don't think so.

Gastric acid is needed to get heme iron out of food.  That's not the same situation as taking it as a supplement.
Oh my goodness, yes it does! Less than 1% of us will not make enough IF to absorb B vites and without B vites we will become anemic.

For those who fall into less than 1% we need to take B12 via another route such as SL or IM.

Previously Midwesterngirl

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on 9/22/10 1:13 am
It worries me that your surgeon never told you to supplement your B12.  This is from the National Institutes of Health.

                                   Flying Spagetti Monster

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