Morning Madness

Whether you are in Family Medicine, Internal Medicine, subspecialty clinic, or really in any setting you will encounter anemia. We focused our July 6th morning report on a case of B12 deficiency and reviewed pathophysiology, signs and symptoms, investigations and management, and a few pearls on ‘Choosing Wisely.’ Let’s start with our fictional case – you receive this referral:

“42-year-old African man who has had progressive anemia with a Hb of 103 g/L and an MCV of 110.4. Please assess, thanks.”

The top 5 take-away points from our morning report are summarized below. Before we begin those, we started our talk with an approach to anemia – high yield for any exam situation. Here is the overview:

Credit to former CMRs Dr. Baruch Jakubovic and Dr. Leora Branfield Day for this lovely flow diagram!
  1. Macrocytosis and Macrocytic Anemia

Macrocytosis without anemia can occur and can be normal. For instance, in newborns macrocytosis without anemia is normal, and large erythrocytes can be seen in pregnancy without an obvious etiology. Macrocytosis in itself has to be taken into context with the clinical and laboratory features.

Macrocytic anemia describes abnormally large RBCs in the peripheral blood, and is divided into two categories as above – megaloblastic and non-megaloblastic.

Macrocytic anemia may be related to nutritional deficiencies (B12, folate, drugs), primary bone marrow disorders, and chronic illnesses. In the setting of megaloblastic anemia there is a series of pathophysiologic steps related to ineffective erythropoiesis and defects in DNA synthesis that lead to “megaloblastic” anemia.

There are also a series of drugs that can induce macrocytosis including:

  • Chemotherapeutic agents such as: cyclophosphamide, hydroxyurea, methotrexate, azathioprine, mercaptopurine, cladribine, cytosine arabinoside, 5-FU
  • Antiretroviral agents including: zidovudine, stavudine
  • Hypoglycemic agents: metformin
  • Antimicrobials: trimethoprim-sulfamethoxazole, valacyclovir, pyrimethamine
  • Diuretics: Triamterene
  • Anticovulsant agents: phenytoin, valproic acid, primidine
  • Anti-inflammatories: sulfasalzine
  • Other: nitrous oxide

2. Blood Film Findings of B12 Deficiency

In our case our fictional patient had a Hb of 103 MCV 110.4, Platelets 357, WBC 6.2 with normal differential. Blood film showed hypersegmented neutrophils. B12 was 50 pmol/L, albumin 40, indirect bilirubin 40, LDH 350, INR 1.0, reticulocyte count 130, haptoglobin < 0.1.

The unifying diagnosis is still B12 deficiency. Huh? Well.. there are a variety of abnormalities that can be seen in B12 deficiency summarized here:

  • Hypersegmented neutrophils – 6 nuclei or more
  • Macro-ovalocytes
  • Anisocytosis – RBCs unequal in size
  • Tear drop poikilocytosis – an increase in abnormal RBCs of any shape that make up 10% or more of the total population
  • In severe forms may also see RBC fragments

In our patient’s case, the lab could not process the RBC Folate. Why was that? Well, in 1998, the US Food and Drug Administration and Health Canada mandated the enrichment of all wheat flour with folic acid at an average daily intake of 100 μg. Given that our foods are fortified with folic acid, the prevalence of folate deficiency is very rare, < 1%. Numerous studies have suggested that folate testing should be significantly reduced or discontinued.

3. Signs and Symptoms of B12 Deficiency

The following diagram from the NEJM review linked below summarizes well the clinical signs and symptoms of B12 deficiency. This morning report was named “Morning Madness” after one of the central nervous system-related symptoms of B12 deficiency called “Megaloblastic Madness” which includes depression, mania, irritability, and other neuropsychiatric features.

Figure from this excellent NEJM reference which is worth a read! https://www.nejm.org/doi/pdf/10.1056/NEJMcp1113996
From https://en.wikipedia.org/wiki/Dorsal_column–medial_lemniscus_pathway#/media/File:1417_Ascending_Pathways_of_Spinal_Cord.jpg
Figure from https://courses.lumenlearning.com/ap1x94x1/chapter/the-spinal-cord/

Taking it back to first principles: In one of the most severe manifestations of B12 deficiency called ‘subacute combined degeneration’ where you have spongy degeneration in which there is degeneration of the lateral corticospinal tract and dorsal columns, therefore there is abnormalities in both motor pathways (upper motor neuron) and vibration/proprioception/light touch (given dorsal column involvement). The clinical features that manifest are summarized below and the following Youtube Video includes some important findings to observe: https://www.youtube.com/watch?v=QItIgsq-Ryk

  • Progressive changes from tingling and numbness to weakness
  • Vibration, proprioception, touch diminished
  • + Babinski, +Romberg
  • Spastic paresis/paralysi
  • Gait Initially ataxic (wide based with foot slap), high steppage –> then spastic scissor gait

4. Etiologies of B12 Deficiency

See the image below from NEJM learning module that shares a 6-step pathway on B12 absorption and where the process can go wrong. Deficiencies or defects in any one of these six steps can lead to malabsorption.

From NEJM learning module – https://www.nejm.org/doi/full/10.1056/NEJMimc1700838
CategoryExamples
StomachPernicious anemia (North European/African American increased) – autoimmune gastritis –> think about screening/assessing for concomitant T1DM, Vitiligo
Roux-en-Y gastrectomy
Bariatric Surgery
Gastritis
Small BowelMalabsorption
Ileal resection/bypass
IBD Bacterial overgrowth
Fish tapeworm (Diphyllobothrium latum)
Drugs (block/inhibit absorption)Metformin PPI/anti-histamines
Reduced IntakeVegan diet, vegetarian diet
Credit to former CMRs Dr. Baruch Jakubovic and Dr. Leora Branfield Day

Wondering what tests you want to order next and how to interpret the findings? See below!

TestFinding/Result
CBCMacrocytic anemia (especially if MCV > 110), may see pancytopenia if severe
Blood filmMegaloblasts, hypersegmented neutrophils, anisocytosis, tear drop poikilocytosis and RBC fragments if severe
Serum B12/cobalamin levels> 221 pmol/L – Normal result, deficiency unlikely
148 to 221 pmol/L – Borderline result, deficiency possible (then may send for MMA or homocysteine levels)
< 148 pmol/L – Deficient
Methylmalonic acid and homocysteine levelsIncreased (theses levels will be elevated prior to fall in cobalamin)
Anti-parietal cell and ant—intrinsic factor antibodiesPositive in the setting of pernicious anemia For instance if the patient consumes B12 but is B12 deficient (+/- OGD)
Adapted from former CMRs Dr. Baruch Jakubovic and Dr. Leora Branfield Day, Other references: UpToDate

In the absence of vitamin B12, serum levels of methylmalonic acid rise. MMA is usually converted via methylmalonyl-CoA mutase with vitamin B12 as a cofactor to succinyl CoA to enter the Krebs cycle. Without B12 as a cofactor, levels of MMA rise.

5. Management of B12 Deficiency

Route of AdministrationFrequency/Dose of Administration
Injected Vitamin B12 (severe anemia, neurologic symptoms, malabsorption)If severe abnormalities, should receive injections of 1000 ug at least several times per week for 1-2 weeks, then weekly until clear improvement is shown Maintenance therapy if response as expected – 1000 mcg monthly (cyanocobalamin) or q2 months (hydroxycobalamin)
Oral Vitamin B12Normal absorption – oral dosing is effective at 1000 mcg orally once per day Impaired absorption – 1000 to 2000 mcg daily

With parenteral therapy, we can expect an increase in reticulocyte count in 1 week and correction of megaloblastic anemia in in 6-8 weeks. Neurologic symptoms may worsen transiently and then subside weeks-months. The degree and duration of neurologic symptoms prior to treatment influence the amount of recovery.

A Word on Choosing Wisely

Silverstein WK et al (2019) published in JAMA on a retrospective cohort study and looked at B12 results and administration.

They defined inappropriate administration as:

(1) IM B12 administration following a documented normal B12 level (≥221 pmol/L) which occurred in 25.5% of cases

(2) no documented B12 testing in the 12 months prior to supplementation which occurred in 38.2% of cases.

43.1% of 56,128 people without a B12 level documented in the year preceding their first B12 prescription had ever had one measured, and 35.3% of these 24,175 persons had marginally deficient B12 levels.

Based on this paper, most parenteral B12 in Ontario was prescribed to individuals without evidence of deficiency in the 12 months prior to their prescription. Choosing Wisely guidance has suggested that first line therapy should focus on oral B12 supplementation rather than parenteral (in patients with low vitamin B12 without the severe features that we discussed above).

Helpful Resources

I suggest checking out the following papers if you want to read more as well as the NEJM article and learning module on this topic:

I hope you found this useful! Thanks for your participation in Morning Report on July 6th! Please email any questions or feedback to cmr@wchospital.ca.

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