Michelle Srour

Case Report: Vitamin B-12

Hyperhomocysteinemia, Deep Vein Thrombosis and Vitamin B12

Deficiency in a Metformin-treated Diabetic Patient
Hsuan-Yu Lin,1 Chih-Yuan Chung,1 Cheng-Shyong Chang,1 Ming-Lun Wang,1 Jen-Shiou Lin,2
Ming-Ching Shen1,3*

Abstract
Vitamin B12 deficiency may be induced by long-term use of metformin, which may in turn lead to
hyperhomocysteinemia. Thus, hyperhomocysteinemia may increase the risk of vascular thrombosis in
diabetic patients, when metformin is used and a homozygous methylenetetrahydrofolate reductase
(MTHFR) C677T mutation is present. We report a 65-year-old Taiwanese diabetic woman who was
treated with metformin for 6 years and who had suffered from swelling of the left lower extremity for 3
months. Ascending venography confirmed the diagnosis of proximal deep vein thrombosis, while
hyperhomocysteinemia, megaloblastic anemia caused by vitamin B12 deficiency, and a homozygous
C677T mutation of the MTHFR gene were also found. She had no identifiable venous thrombotic risk
factors other than hyperhomocysteinemia, which seemed to be caused by both MTHFR C677T
homozygous mutation and vitamin B12 deficiency. With the substitution of insulin injection for
metformin, short-term supplement of vitamin B12, and anticoagulant therapy for the deep vein
thrombosis, her anemia and hyperhomocysteinemia recovered rapidly. The deep vein thrombosis also
responded well. Our findings highly suggested the role of metformin in causing vitamin B12 deficiency,
which may serve as an additional risk factor for venous thrombosis in diabetic patients. Our report also
highlights the need to check vitamin B12 levels during metformin treatment. [J Formos Med Assoc
2007;106(9):774778]

The Link between Metformin, Vitamin B-12 deficiency and Deep Vein
Thrombosis

A 65 year old, Taiwanese woman was admitted due to swelling of her left thigh and
calf for 3 months. She had a pale appearance.
She has type 2 diabetes and has been controlling it with metformin for the past 6
years, thus her HbA1c was at 5.8%.
A venography (an x-ray tests that involves injecting x-ray contrast material, dye,
into the vein to show blood flow) done on her lower left extremity demonstrated:
-Intraluminal filing defect at the left popliteal vein
-Intramural thrombosis (a clot with the endocardial lining on a cardiac
chamber OR blood vessel)
-Occlusion of the superficial femoral vein (blockage or closing of the blood
vessel
-Non opacification of the left external iliac vein, slight opacification in the left
internal iliac vein
*All results of the test are consistent with deep vein thrombosis in her left leg*

Lab Results- Elevated D-dimer value (a blood test measuring a substance released when a
blood clot breaks up)
Decreased level of Vitamin B-12
Macrocytic anemia- a large abnormal RBC
Increased level of fasting homocysteine
Increased lactate dehydrogenase
MTHFR C67TT homozygous gene mutation
 Results/ Discussion

Deep vein thrombosis may be associated with many risk factors however the only
significant prothrombotic risk identified was hyperhomocysteinemia.

Hyperhomocysteinemia may be caused by a variety of factors consistent with this

patient, including:
Vitamin B12 deficiency
Common in older patients
Patients with MTHFR C677T homozygous gene mutation and B12 deficiency
Thrombosis, which is common in the Taiwanese population

Vitamin B12 supplementation given to the patient resulted in, normalized levels of
both homocysteine and megaloblastic anemia.
- Vitamin B12 deficiency is associated with megaloblastic, macrocytic anemia
along with increased levels of homocysteine. Thus this may conclude that the B12
deficiency among the patient is what may have caused the high levels of
homocysteine.
-The study further demonstrates that the patient did not have pernicious
anemia (an autoimmune disorder that attacks the stomach lining which may impair
B12 absorption) because there was no evidence of atrophic gastritis or antiparietal
cell antibodies.

Metformin
An association between metformin medication and vitamin B12 deficiency has
previously been reported, and evidence shows that 10-30% of patients taking
metformin may develop a deficiency.
Metformin may have an effect on calcium- dependent actions on the
membrane. Absorption of vitamin B12 occurs when the B12 binds to the intrinsic
factor receptors in the ileum, which is calcium dependent. Therefore, if metformin
alters or blocks calcium dependent actions, we cannot absorb vitamin B12 efficiently.
In addition, metformin may also lead to bacterial overgrowth. This may lead to
binding of the bacteria to vitamin B12 thus impairing its absorption.
Therefore the medication was stopped and the patient was injected with
insulin as a substitute, to check her vitamin B12 storage while controlling her
hyperglycemia.

Anticoagulant therapy was given to treat the deep vein thromboses; signs and
symptoms resided.

Conclusion

In conclusion, the long term use of metformin caused the patient, with a MTHFR
homozygous C677T mutation, to become vitamin B12 deficient. The deficiency led to
many side effects including increased levels of homocysteine in the blood. The
increased homocysteine levels caused the patient to have deep vein thrombosis,
which is the pain in her leg and calf that brought her to the hospital. The successful
treatment is what confirmed these factors and patients taking metformin must
regularly test their vitamin B12 status.