Case Study: 25-Year-Old Woman Referred to Clinic for Erythrocytosis
A 25-year-old woman of Indian ethnicity was referred to hematology clinic for erythrocytosis. She was seen in urgent care for flu-like symptoms, and routine complete blood count revealed elevated hemoglobin and hematocrit levels. The patient noted a history of discoloration in her hands, as well as chronic fatigue. She recalled being told she had a high hemoglobin level when she was 12 years old but is not sure why. She had no symptoms of fever, night sweats, weight loss, pruritus, or burning/redness in her extremities. She also did not have blurry vision or history of venous thrombosis.
She is not a smoker and had no history of heart or lung disease, and no known family history of erythrocytosis or other blood disorders. She denied any history of snoring or daytime sleepiness.
The examination revealed an O2 saturation of 80 percent at rest and 60 percent with moderate activity on pulse oximetry, and no evidence of lymphadenopathy or splenomegaly. Her nail beds and lips showed a bluish discoloration. The rest of her examination was normal.
The patient’s lab results are as follows:
|4.1 (normal differential)
|3.4-9.6 × 109/L
|157-371 × 109/L
Which of the following tests would be most helpful in diagnosis of the cause of this patient’s erythrocytosis?
- Testing for JAK2 V617F mutation
- Arterial blood gas with co-oximetry
- Testing for mutations in the oxygen sensing pathway
- Computed tomography (CT) scan of abdomen/pelvis
- p50 oxygen dissociation curve
Answer: B. Arterial blood gas with co-oximetry
This vignette represents a case of autosomal recessive Type 1 methemoglobinemia. This disorder is often due to a deficiency in cytochrome b5 reductase (cytb5r), which normally aids in the reduction of methemoglobin in red blood cells.1 Methemoglobin is formed when heme Fe2+ is oxidized to Fe3+, which leads to a decreased ability to reversibly bind; thus, deficiencies in cytb5r can cause buildup of methemoglobin and inability to effectively deliver oxygen to tissues. As opposed to the more severe and often fatal type 2 methemoglobinemia, this form of methemoglobinemia is often only associated with cyanosis.2 Treatment of Type 1 methemoglobinemia is often not required; however, methylene blue can be used in very high levels of methemoglobin or in patients with more symptoms, and affected patients should be instructed to avoid exposure to drugs that may cause methemoglobinemia. Other less common causes of congenital methemoglobinemia include cytochrome b5 deficiency and autosomal dominant hemoglobin M.
Pulse oximetry will often show a low SpO2 despite normal SaO2 due to optical interference from high levels of methemoglobin. A difference between the SpO2 on pulse oximetry and PaO2 on arterial blood gas is known as “the saturation gap” and suggests the presence of methemoglobinemia.3
A p50 oxygen dissociation curve will be left-shifted in methemoglobinemia but this left shift can also be seen in carbon monoxide poisoning and high affinity hemoglobin variants and thus answer E is not correct.4 While testing for JAK2 V617F can be helpful to look for polycythemia vera (PV), it is unlikely to yield a diagnosis in this young patient with no symptoms of PV and an elevated erythropoietin level. Mutations in the oxygen sensing pathway such as VHL and PHD2 are rare yet possible causes of congenital erythrocytosis but do not present with cyanosis. A CT abdomen/pelvis can be helpful in ruling out other causes of erythrocytosis such as solid tumors but would not be a first choice for evaluation of a patient with suspected hypoxia-driven erythrocytosis.
Case study submitted by Urshila Durani, MD, MPH, of Mayo Clinic, Rochester, MN.
- Patnaik MM, Tefferi A. The complete evaluation of erythrocytosis: congenital and acquired. Leukemia. 2009 23:834-844.
- Fermo E, Bianchi P, Vercellati C, et al. Recessive hereditary methemoglobinemia: two novel mutations in the NADH-cytochrome b5 reductase gene. Blood Cells Mol Dis. 2008 41:50-55.
- Koduri PR, Kedar PS, Warang P. Erythrocytosis, methemoglobinemia, and the saturation gap. Ann Hematol. 2015 94:509-510.
- McMullin MF, Bareford D, Campbell P, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol. 2005 130:174-195.