Differentials
Folic acid (vitamin B9) deficiency
SIGNS / SYMPTOMS
Generally does not present with neurologic symptoms. Rare in the present era of folic acid fortification in the US.
INVESTIGATIONS
Serum folate levels are low.
Be aware that low serum folate can result in falsely low vitamin B12 levels.
Treat with folic acid and retest.
Myelodysplastic syndrome (MDS)
SIGNS / SYMPTOMS
Presents with macrocytic anemia and is difficult to differentiate from vitamin B12 deficiency initially.
MDS is a group of disorders characterized by a clonal chromosomal abnormality, ineffective and dysplastic hematopoiesis resulting in ≥1 cytopenias, and a varying predilection to develop acute myeloid leukemia.
These disorders can arise primarily without any precipitating event or may be related to previous treatment with either chemotherapy or radiation.
INVESTIGATIONS
CBC in MDS shows normochromic or macrocytic red cells; about 40% of patients have neutropenia, and >30% have thrombocytopenia. Morphologic abnormalities include oval macrocytic red cells and granulocytes with the pseudo-Pelger-Huet anomaly (hypogranular and hypolobulated granulocytes).
Bone marrow histopathology in MDS demonstrates dysplasia in a proportion of undifferentiated myeloblasts.
Prussian blue iron staining of bone marrow aspirate can show ringed sideroblasts (abnormal erythroid precursor cells that have granules around the nucleus).
Alcoholic liver disease
SIGNS / SYMPTOMS
May present with macrocytic anemia and nutritional deficiencies. History should reveal alcohol use.
INVESTIGATIONS
Elevated liver enzymes.
Liver biopsy histopathology shows fatty change, inflammation, and variable amounts of fibrosis leading to cirrhosis in severe, chronic alcoholic liver disease.
Hypothyroidism
SIGNS / SYMPTOMS
May present with macrocytic anemia.
May show signs of muscle and joint pain, weakness in the extremities, and fatigue; delayed relaxation of deep tendon reflexes strongly suggests hypothyroidism.
INVESTIGATIONS
Elevated thyroid-stimulating hormone, decreased T3 and T4, and elevated creatine kinase.
Peripheral neuropathy
SIGNS / SYMPTOMS
Compression neuropathies, and neuropathies due to diabetes or thyroid disease, may be difficult to differentiate from neurologic symptoms of vitamin B12 deficiency.
INVESTIGATIONS
Nerve conduction studies and electromyogram are helpful in confirming and characterizing neuropathy; that is, demyelinating, axonal, polyneuropathy, mononeuropathy multiplex, radiculopathy, or plexopathy.
Treatment with vitamin B12 may improve symptoms, but neuropathy may be irreversible.
Diabetic neuropathy
SIGNS / SYMPTOMS
Paresthesia is a common feature and may occur in the extremities as a result of neuropathy in those with prolonged undiagnosed diabetes. Other types of neuropathy may be present in diabetes, including autonomic neuropathy.
INVESTIGATIONS
Elevated fasting glucose or HbA1c.
Antiglutamic acid decarboxylase antibodies, islet cell antibodies, and insulin autoantibodies are present in 85% of patients with type 1 diabetes at the time of diagnosis, but may disappear within a few years.
Drug-induced macrocytosis
SIGNS / SYMPTOMS
Macrocytosis due to certain medications, including hydroxyurea, methotrexate, zidovudine, azathioprine, capecitabine, and cladribine.
INVESTIGATIONS
Usually a clinical diagnosis. Serum drug levels may confirm the association.
Dementia
SIGNS / SYMPTOMS
Characterized by cognitive (memory) changes, psychiatric symptoms, personality changes, problem behaviors, and changes in day-to-day functioning.
May be due to multiple different factors that are clinically indistinguishable from vitamin B12 deficiency.
INVESTIGATIONS
A mental state exam or neuropsychiatric testing should be conducted if the diagnosis is uncertain.
Vitamin B12 testing is normal.
Depression
SIGNS / SYMPTOMS
Characterized by persistent low mood causing varying levels of social, cognitive, occupational, and physical dysfunction.[78]
INVESTIGATIONS
Vitamin B12 testing is normal.
Pernicious anemia (PA)
SIGNS / SYMPTOMS
Patients present with symptoms of anemia and vitamin B12 deficiency. They may also have fever and complain of gastric pain or discomfort. Common features include tiredness, dyspnea, paresthesias, sore red tongue, diarrhea, and mild jaundice.
INVESTIGATIONS
Once vitamin B12 deficiency is confirmed, testing for anti-intrinsic factor antibody (anti-IFAB) can determine whether PA is the cause. It is only 50% sensitive, but highly specific for PA.[2] Testing for anti-IFAB should be done before initiating vitamin B12 replacement therapy because high vitamin B12 levels may lead to false positive results.[70][71]
Antiparietal cell (APC) antibody can, in conjunction with other tests, help to determine whether PA is the cause. It is highly sensitive (85%), but has low specificity for PA. APC antibodies may be elevated in atrophic gastritis.[2]
Once a patient is given intrinsic factor and vitamin B12 level is normal, gastrin levels will normalize.
Crohn disease
SIGNS / SYMPTOMS
Crohn disease can affect any part of the gastrointestinal tract, and symptoms may be extremely variable.
Increased risk for B12 deficiency occurs with ileectomy >20 cm.[47]
INVESTIGATIONS
The classic findings on histologic exam include involvement of all layers of the bowel wall by granulomas, ulcerations, and acute and chronic inflammation.
Celiac disease
SIGNS / SYMPTOMS
Patients present with unexplained gastrointestinal symptoms, chronic diarrhea, unexplained iron deficiency anemia, vitamin D deficiency, or a skin rash consistent with dermatitis herpetiformis.
Other situations include failure to thrive, short stature, recurrent severe aphthous stomatitis, recurrent spontaneous abortion, and infertility.
INVESTIGATIONS
Immunoglobulin A antigliadin and antiendomysial antibodies.
Small-bowel histology is the most specific and sensitive test, showing villous atrophy and mucosal inflammation with hyperplastic changes to crypts.
Iron deficiency anemia is the most common clinical presentation in adults.
Folate (and less commonly vitamin B12) deficiency may lead to macrocytic anemia.
Peptic ulcer disease from Helicobacter pylori infection
SIGNS / SYMPTOMS
H pylori is a gram-negative, microaerophile bacterium that inhabits the stomach and duodenum. It causes a chronic low-level atrophic gastritis and is strongly linked to the development of duodenal and gastric ulcers and stomach cancer.
Over 80% of people infected with the bacterium are asymptomatic.
INVESTIGATIONS
The carbon urea breath test is positive.
The most reliable method for detecting H pylori infection is endoscopic biopsy. Histopathology shows gastric atrophy, inflammation, and bacterial organisms on special stains.
Chronic pancreatitis
SIGNS / SYMPTOMS
History of gallstone disease or alcohol misuse.
Characterized by recurrent or persistent abdominal pain and progressive injury to the pancreas and surrounding structures, resulting in scarring and loss of function.
INVESTIGATIONS
Ultrasound or CT imaging of the abdomen may reveal fibrosis and calcification of the pancreas.
Evaluation of pancreatic enzymes is the most sensitive and specific test for diagnosing mild to moderate pancreatic insufficiency or chronic pancreatitis, but it is available in only a few centers. Pancreatic juice is collected with a gastroduodenal tube during exogenous hormone stimulation with cholecystokinin and/or secretin.
Helps differentiate pancreatic from nonpancreatic types of malabsorption.
Small-intestinal bacterial overgrowth
SIGNS / SYMPTOMS
History may show conditions that alter intestinal anatomy, motility, and gastric acid secretion. These include use of proton-pump inhibitors and anatomic disturbances in the bowel, including fistulae, diverticula, and blind loops created after surgery.
INVESTIGATIONS
The definitive investigation requires culture of jejunal fluid that grows >10⁵ bacteria/mL.
Hydrogen breath testing may show malabsorption but is not very sensitive or specific for bacterial overgrowth.
A trial of treatment with antibiotics for 1 week may give the diagnosis.
Zollinger-Ellison syndrome
SIGNS / SYMPTOMS
A condition caused by a gastrin-secreting tumor that causes hypersecretion of gastric acid leading to ulcer disease. It most commonly presents with abdominal pain, diarrhea, and gastroesophageal reflux. Less common presentations include weight loss, gastrointestinal bleeding, nausea, and vomiting.
INVESTIGATIONS
Elevated level of fasting serum gastrin in the absence of achlorhydria, and either a positive secretion test or histologically demonstrated neuroendocrine tumor.
Tropical sprue
SIGNS / SYMPTOMS
Believed to be initiated or sustained by an undefined infection.
Presents with symptoms and signs of malabsorption, stomach pain, diarrhea, and bloating.
The relapse rate is substantial in treated patients who remain in, or return to, endemic areas in the tropics.
INVESTIGATIONS
Endoscopy and small bowel biopsy reveals progressive villus atrophy in the small intestine similar to celiac disease.
Therapeutic trial with tetracyclines for 6 months normalizes mucosal structure in the small intestine.
Fish tapeworm (Diphyllobothrium latum)
SIGNS / SYMPTOMS
Fish tapeworm is native to Scandinavia, western Russia, and the Baltic states. Now present in North America, especially the Pacific Northwest.
Infection arises following eating raw fish or fish products.
Patients present with symptoms of malnutrition including anemia.
INVESTIGATIONS
Fish tapeworm eggs appear in the feces 5 to 6 weeks after infection, and fecal exam may confirm the diagnosis.
HIV infection
SIGNS / SYMPTOMS
Malnutrition is common in HIV disease, particularly in resource-poor areas. A cycle of opportunistic infection causing loss of weight and poor appetite, together with diarrhea and malabsorption, contributes to malnutrition.
INVESTIGATIONS
Enzyme-linked immunosorbent assay (ELISA) testing should be ordered when HIV testing is indicated. False-negatives may occur during window period immediately after infection and before antibodies to HIV have developed. A positive result should be confirmed with a Western blot or second ELISA. The window period can be reduced to 2-4 weeks by using fourth-generation tests that detect IgM and IgG antibodies to HIV and p24 antigen.[79] CDC: HIV - laboratory tests Opens in new window
Alpha-thalassemia
SIGNS / SYMPTOMS
An inherited autosomal recessive blood disease.
Vitamin B12 requirement is increased in alpha-thalassemia; vitamin B12 deficiency may be the presenting feature. Patients present with anemia, hepatosplenomegaly, leg ulcers, and bone pain. This disease is more common in Mediterranean countries, Asia, the Middle East, and South America.
INVESTIGATIONS
CBC and peripheral smear show microcytosis, erythrocytosis, hypochromia, and mild anemia.
A diagnosis can be made by a combination of family studies and the ruling out of both iron deficiency anemia and beta-thalassemia trait.
A definitive diagnosis can be made by DNA sequencing of the alpha-globin chain.
Multiple sclerosis
SIGNS / SYMPTOMS
Neurologic manifestations of vitamin B12 deficiency can mimic clinical symptoms of multiple sclerosis. However, in almost all cases of multiple sclerosis there are also brain lesions.
Variable presentation: multiple episodes separated by space (i.e., neurologic symptoms result from lesions in different central nervous system sites) and time. Symptoms include progressive limb weakness, gait difficulty, ataxia, loss of balance, and paroxysmal vertigo.
INVESTIGATIONS
Brain MRI typically shows areas of demyelination.
Cerebrospinal fluid (CSF) exam shows elevated IgG and oligoclonal banding.
Syphilis (tabes dorsalis)
SIGNS / SYMPTOMS
History of syphilis infection or sexually transmitted infection.
Neurologic symptoms of tabes dorsalis and subacute combined spinal degeneration may be similar.
INVESTIGATIONS
The Venereal Disease Research Laboratory (VDRL) reaction test alone cannot always be depended on in differential diagnosis.
CSF exam is required to diagnose neurosyphilis.
CSF VDRL reactivity test is specific but not sensitive for neurosyphilis.
CSF fluorescent treponemal antibody absorption reactivity test is sensitive but not specific for neurosyphilis.
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