Methotrexate therapy- Case discussion

Case details

A 60-year-old female patient has psoriasis and has been treated with methotrexate for several years. She has no other medical problems and her preventive screenings, including fecal occult blood tests and colonoscopy, have all been normal. She has developed an anemia.

Which of the following would you expect to find when working up her anemia?

A. A macrocytic anemia

B. A microcytic anemia

C. Thalassemia

D. Spherocytosis

E. A low vitamin B12 level

Answer- The correct answer is- A, Macrocytic anemia.

Methotrexate is an antimetabolite, it is recommended as a treatment for psoriasis to inhibit cellular proliferation. It is also used as an anticancer drug.

It acts by inhibiting dihydro folate reductase, which regenerates reduced folates from the oxidized folates produced when thymidine monophosphate is formed from deoxy uridine monophosphate. Without reduced folates, cells die a “thymine-less” death (figure).

THymidylate synthase

Figure- Thymidylate synthesized by the methylation of uridylate (dUMP) in a reaction catalyzed by the enzyme thymidylate synthase. 

All cells, especially rapidly growing cells, must synthesize Thymidylate dTMP) for DNA synthesis. The difference between (T) and (U) is one methyl group at the carbon-5 position. Thymidylate is synthesized by the Methylation of uridylate (dUMP) in a reaction catalyzed by the enzyme Thymidylate synthase. This reaction requires a methyl donor and a source of reducing equivalents, which are both provided by N5, N10-methylene THF).For this reaction to continue, the regeneration of THF from Dihydro folate (DHF) must occur.

The enzyme Dihydro folate reductase (DHFR) catalyzes this reaction, which is a target of the anticancer drugs aminopterin and Methotrexate.

These drugs are analogs of DHF and act as competitive inhibitors of DHFR. Inhibition of this enzyme prevents the regeneration of THF and blocks dTMP synthesis because of the lack of the methyl donor required for the reaction of thymidylate synthase.

Methotrexate blocks the cell’s ability to regenerate THF, leading to inhibition of these biosynthetic pathways. Folic acid is also required for purine nucleotide biosynthesis. The lack of nucleotides prevents DNA synthesis, and these cancer cells cannot divide without DNA synthesis

Unfortunately, the effects of Methotrexate are nonspecific and other rapidly dividing cells such as epithelial cells in the oral cavity, intestine, skin, and blood cells are also inhibited. This leads to the side effects associated with methotrexate (and other cancer chemotherapy drugs) such as mouth sores, low white blood cell counts, stomach upset, hair loss, skin rashes, and itching. Less frequent adverse effects include reversible increases in transaminases and hypersensitivity-like pulmonary syndrome. Chronic low-dose methotrexate can cause hepatic fibrosis.

Hematologic side effects include myelosuppression which is one of the primary toxic effects of methotrexate. Methotrexate suppressed hematopoiesis has been reported to have caused macocytic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, and lymphoproliferative disorders including reversible hypogammaglobulinemia (which has been reported rarely).

Thus in the given case the anemia is due to folic acid deficiency, it is macocytic anemia, it cannot be microcytic anemia, thalassemia or spherocytosis.  Vitamin B12 level should be normal in this patient.

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