Internal Medicine Correlations and Clinical Scenarios (CCS) USMLE Step 3

CASE 3: Vitamin B₁₂ Deficiency (Alcoholism, Peripheral Neuropathy)

Setting: office

CC: “I have numbness and tingling in my feet.”

HPI: A 78-year-old man comes to your office with several weeks of progressive weakness and fatigue. He easily tires when exerting himself. Over the last 1 to 2 weeks, he has developed a “tingling” in his feet that he describes as a “pins and needles” sensation.

PMHX:

Alcoholism

Hypertension

Diabetes

Medications:

Enalapril

Metformin

PE:

General: tired older man

Cardiovascular: 2/6 murmur at apex radiating to axilla

Chest: clear

Neurological: decreased sensation symmetrically over the lower extremities bilaterally; normal position and vibratory sensation

How can you tell the difference between peripheral neuropathy from alcohol, diabetes, or vitamin B₁₂ deficiency by symptoms alone?

a. Duration

b. Intensity

c. Location

d. Impossible to tell

Answer d. Impossible to tell

Peripheral neuropathy is indistinguishable based on the etiology. All etiologies cause bilateral symptoms, which are more noticed in the feet, slowly progressive, and defined as “pins and needles” sensations. The precise mechanism of the damage to myelin in vitamin B₁₂ deficiency is not precise. Diabetes and alcohol can also cause deficits of position and vibratory sense.

All peripheral neuropathy is from damaged myelin.

Discuss the patient’s alcohol use with him. Use the CAGE questions:

Are you trying to Cut down the amount of alcohol you use?

Does it make you Annoyed when asked about your drinking?

Do you feel Guilty after drinking?

Do you start your day with an Eye opener in the morning?

Initial Orders:

CBC

Basic metabolic panel (CHEM-7)

Calcium and magnesium levels

Glycosylated hemoglobin (HbA₁c)

Vitamin B₁₂ and folate levels

Although the most accurate test of peripheral neuropathy is the electrodiagnostic test (i.e., nerve conduction studies), this test should not be done routinely for either diabetes or vitamin B₁₂ deficiency. It should be a clinical diagnosis.

The precise mechanism of myelin damage in vitamin B₁₂ deficiency is not clear.

You advance the clock 1 week.

CBC Results:

Hematocrit: 28%

MCV: 118 fL

WBCs: 2800/μL

Platelets: 120,000/μL

Vitamin B₁₂ level: borderline low

Folate: normal

Calcium, magnesium: normal

Glucose: 185 mg/dL

HbA₁c: 8.5%

Vitamin B₁₂ is essential for methyl transfer in DNA production (Figure 2-1).

Figure 2-1. Role of cobalamin (vitamin B₁₂) and folic acid in nucleic acid and myelin metabolism. Lack of either cobalamin or folic acid retards DNA synthesis (A) and lack of cobalamin leads to loss of folic acid, which cannot be held intracellularly unless polyglutamated. Lack of cobalamin also leads to abnormal myelin synthesis, probably via a deficiency in methionine production (B). CH₃, methylium cation; CoA, coenzyme A; ?, possible. (Reproduced with permission from Chandrasoma P, Taylor CR. Concise Pathology, 3rd ed. New York: McGraw-Hill; 1998.)

Vitamin B₁₂ deficiency can cause pancytopenia or anemia alone.

What is the goal of glucose in a diabetic?

a. It depends on whether it is type 1 or 2 diabetes.

b. The goal is between 80 and 110 mg/dL.

c. The goal is HbA₁c <6.5%.

d. The goal is HbA₁c <7%.

e. The goal is HbA₁c <10%.

Answer d. The goal is HbA₁c <7%.

You should add medications until the HbA₁c is <7%. The initial diagnosis of diabetes is a HbA₁c >6.5%.

With a HbA₁c >7%, you should add a second oral hypoglycemic. Which second agent to add is not clear. Metformin is first. As a second, you can add a sulfonylurea, rosiglitazone, nateglinide (or repaglinide), or a dipeptidyl peptidase IV (DPP-IV) inhibitor such as sitagliptin, saxagliptin, or linagliptin.

What test should be done to confirm the presence of vitamin B₁₂ deficiency?

a. Methylmalonic acid level

b. Anti-intrinsic factor/antiparietal cell antibodies

c. Schilling test

d. Homocysteine level

Answer a. Methylmalonic acid level

Methylmalonic acid levels build up in vitamin B₁₂ deficiency. Homocysteine level increases in both vitamin B₁₂ and folate deficiency. Vitamin B₁₂ deficiency can have a low normal level in 10% to 20% of patients routinely. Anti-intrinsic factor, antiparietal cell antibodies, and the Schilling test are not used to discover whether there is a vitamin B₁₂ deficiency. They are used to identify the etiology of the deficiency.

Orders:

Second oral hypoglycemic agent

Methylmalonic acid level

Dilated eye examination

Advance the clock to get the results of the methylmalonic acid (MMA) level, which turns out to be elevated. The point of doing the anti-intrinsic factor and antiparietal cell antibody tests is to determine the etiology of the vitamin B₁₂ deficiency, which is particularly important in this case.

Both antibodies are negative.

What is the most likely cause of the vitamin B₁₂ deficiency?

a. Blind loop syndrome

b. Pernicious anemia

c. Metformin use

d. Angiotensin-converting enzyme (ACE) inhibitor use

e. Dietary deficiency

Answer c. Metformin use

Metformin decreases intestinal absorption of vitamin B₁₂ in 10% to 30% of patients.

Metformin causes decreased ileal absorption of vitamin B₁₂. Calcium supplementation corrects it.

What is the difference between megaloblastic and macrocytic anemia?

a. MCV

b. Vitamin B₁₂ etiology

c. Folate deficiency etiology

d. Hypersegmented neutrophils

Answer d. Hypersegmented neutrophils

Macrocytic just means an MCV >100 fL. Vitamin B₁₂ and folate deficiency both cause macrocytosis and megaloblastosis. They are indistinguishable based on hematologic findings (Figure 2-2).

Figure 2-2. Peripheral blood smear from a patient with vitamin B₁₂ deficiency showing oval macrocytes (A) and hypersegmented neutrophil (B). (Reproduced with permission from Lichtman MA, et al. Lichtman’s Atlas of Hematology. 2007, www.accessmedicine.com.)

Folate is not needed for myelin formation.

Vitamin B₁₂ is given orally. Two weeks later, laboratory test results show an elevated lactate dehydrogenase (LDH) and indirect bilirubin. The smear still shows hypersegmented neutrophils.

Why did the hematologic picture not improve?

a. Vitamin B₁₂ is malabsorbed and needs to be given by injection.

b. It needs more time to recover.

c. Diabetes prevents cell formation until it is corrected.

Answer a. Vitamin B₁₂ is malabsorbed and needs to be given by injection.

Whether the malabsorption is caused by calcium-dependent ileal malabsorption or pernicious anemia, you need to give vitamin B₁₂ by intramuscular injection. Step 3 does not test dosing, but does test route of administration. The LDH and indirect bilirubin are elevated because there is an “ineffective erythropoiesis.” Cells are made in the marrow, but destroyed just after production.

Reticulocyte count is low in vitamin B₁₂ deficiency from early cell destruction.

Expect a hypercellular bone marrow in vitamin B₁₂ deficiency.

Intramuscular vitamin B₁₂ is given. Reticulocytes are expected to be produced in 2 to 3 days.

What should you test for immediately after replacement?

a. Potassium level

b. Calcium level

c. LDH and bilirubin

d. Hematocrit

Answer a. Potassium level

The potassium level can suddenly drop after giving vitamin B₁₂. Changes in LDH and bilirubin are of no clinical significance. You have to wait 1 to 2 weeks to see a meaningful change in hematocrit. Potassium is “packaged up” into an enormous number of new cells. If rapid cell breakdown causes hyperkalemia, then vitamin B₁₂ replacement is one of the only things in which rapid cell formation can cause low potassium.

Potassium is 95% intracellular.

Neuropathy can improve if it is minor and of short duration.