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'Acute Leukemia in Congenital Methehemoglobinemia Journal of Community Hospital Internal Medicine Perspectives ISSN: (Print) 2000-9666 (Online) Journal homepage: https://www.tandfonline.com/loi/zjch20 ‘Acute leukemia in congenital methehemoglobinemia - an enigma to explore’ Jaafar F. Al-Khafaji, Mokshya Sharma, Khazi Nayeemuddin, Iman A. Al-Qaysi, Arshad A Al-Mashhadani, Mohamed E. Taha & Abubaker O. Abdalla To cite this article: Jaafar F. Al-Khafaji, Mokshya Sharma, Khazi Nayeemuddin, Iman A. Al-Qaysi, Arshad A Al-Mashhadani, Mohamed E. Taha & Abubaker O. Abdalla (2019) ‘Acute leukemia in congenital methehemoglobinemia - an enigma to explore’, Journal of Community Hospital Internal Medicine Perspectives, 9:1, 55-58, DOI: 10.1080/20009666.2018.1555431 To link to this article: https://doi.org/10.1080/20009666.2018.1555431 © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center. Published online: 06 Dec 2018. Submit your article to this journal Article views: 146 View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=zjch20 JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVES 2019, VOL. 9, NO. 1, 55–58 https://doi.org/10.1080/20009666.2018.1555431 ‘Acute leukemia in congenital methehemoglobinemia - an enigma to explore’ Jaafar F. Al-Khafaji a, Mokshya Sharmaa, Khazi Nayeemuddina, Iman A. Al-Qaysib, Arshad A Al- Mashhadani a, Mohamed E. Taha a and Abubaker O. Abdalla a aDepartment of Internal Medicine, University of Nevada, Reno, NV, USA; bDepartment of Biochemistry, University of Baghdad/College of Nursing, Baghdad, Iraq ABSTRACT ARTICLE HISTORY Congenital methemoglobinemia is a rare disease, resulting in increased oxygen affinity and Received 7 July 2018 impaired oxygen delivery to the tissues. While there have been studies that have linked Accepted 30 November 2018 acquired methemoglobinemia in almost 79% of leukemia patients, to the best of our knowl- edge, this is the first case of leukemia development in a patient with congenital methemo- KEYWORDS globinemia. Chronic deprivation of oxygen to metabolically active bone marrow can Congenital theoretically lead to hematopoietic disorders. It would be interesting to further investigate methemoglobinemia; acute if presence of congenital methemoglobinemia is a risk factor for developing acute leukemia. leukemia; hypoxia; acquired methemoglobinemia; deprivation; oxygen; bone marrow 1. Background antibiotics including 5 days course of azithromycin and additional courses of levofloxacin. Congenital methemoglobinemia is a rare disease His pertinent physical exam later showed an resulting from cytochrome b5 reductase deficiency, acutely ill appearing male, pale with central and per- cytochrome b5 deficiency or a mutation in globin ipheral cyanosis, and vital signs showing afebrile, molecule leading to hemoglobin M formation that respiratory rate 19, hypoxemic with oxygen satura- leads to increased oxygen affinity and impaired oxy- tions of 79% while breathing on 7Litres per minute gen delivery to the tissues [1]. by Oxymask. His Abdominal exam was positive for In normal individuals methemoglobin level is below distension with splenomegaly. 1% (range 0–3%). However, levels may increase to Pertinent Laboratory results showed elevated above 10 % in those with congenital disease. Pulse methemoglobin, leukocytosis with white blood cell oximetry is not an accurate method to assess the level count (WBC) 19.2K (H) which trended up to 86.7K of oxygenation during this condition; consequently associated with significant drop in oxygen saturation oxygen carrying capacity in such patients is determined based on arterial blood gas (ABG) results from 90s to using direct measurements of oxyhemoglobin by co- 80s on the third day of hospitalization. Peripheral oximetry or arterial blood gas [2]. blood smear and CBC revealed: macrocytic anemia, Hypoxia plays an important role in numerous with nucleated erythrocytes, circulating blasts of 85% pathological processes, including carcinogenesis, and by morphology, and severe thrombocytopenia., and metastasis [3]. Studies have shown acquired methe- evidence of coagulopathy with increased INR and moglobinemia developing in almost 79% of leukemia APTT. (Table 1) patients. This is believed to be a result of increased Left posterior iliac crest bone marrows aspirate and oxidant stress generated by immature leukocytes (leu- core biopsy was sent to flow cytometry, cytogenetic kemic cells) leading to oxidization of heme from (karyotype, AML FISH) and molecular (CEBPA, ferrous to the ferric state [2]. To the best of our NPM1, IDH1/IDH2, FLT-3, RUNX1) studies. knowledge, this is the first case of leukemia develop- ment in congenital methemoglobinemia. ● Pertinent findings: normal male karyotype: 46, XY,hypercellular marrow, 95% blasts, Acute myeloid leukemia with NPM1 and FLT3-ITD 2. Case description mutations, CD33 positive by flow cytometry ● A 74 year old Caucasian male with history of con- Negative for (t 15;17) and (t5;17 or t11;17) genital methemoglobinemia (type 1 cytochrome b5 reductase deficiency) had presented to our hospital Pertinent imaging studies with symptoms of malaise, sweating, subjective fever, ● CT pulmonary study showed minimal bilateral and productive cough. He failed to respond to sub-segmental pulmonary embolism, CT thorax CONTACT Jaafar F. Al-Khafaji [email protected] Department of Internal Medicine, University Of Nevada, Reno, NV, USA © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 56 J. F. AL-KHAFAJI ET AL. Table 1. Complete blood picture. started on hydroxyurea to help decrease leukostasis. Component Value Ref Range & Units Initially the patient was started on (7 + 3) cytarabine Methemoglobin % 14.1 (H) 0.4–1.5 % and daunorubicin, given that promyelocytic leukemia WBC 19.3 (H) 4.8–10.8 K/uL Hemoglobin 9.7 (L) 14.0–18.0 g/dL was not excluded, tretinoin was used. The patient was MCV 101.4 (H) 81.4–97.8 fL able to finish the chemotherapy induction. He was also MCHC 33.3 (L) 33.7–35.3 g/dL RDW 61.4 (H) 35.9–50.0 fL noted to have a small PE and right lower extremity deep Platelet Count 24 (LL) 164–446 K/uL venous thrombosis that was initially treated with heparin Neutrophils-Polys 12.60 (L) 44.00–72.00 % Lymphocytes 28.80 22.00–41.00 % drip. The goal of heparin therapy was also to get him Monocytes 4.50 0.00–13.40 % through the initial phases of treatment with goal platelets Eosinophils 0.90 0.00–6.90 % greater than 30K. This unfortunately required daily pla- Basophils 0.00 0.00–1.80 % Neutrophils (Absolute) 2.95 1.82–7.42 K/uL telet transfusions. After discussions with the patient and Lymphocytes (Absolute) 5.56 (H) 1.00–4.80 K/uL family,wedecidedtoplaceanIVCfiltertemporarily. Monocytes (Absolute) 0.87 (H) 0.00–0.85 K/uL Eosinophils (Absolute) 0.17 0.00–0.51 K/uL Heparin drip was continued with a new goal to continue Basophils (Absolute) 0.00 0.00–0.12 K/uL heparin as long as the platelets were greater than 10k. Anisocytosis 1+ Macrocytosis 1+ The patient also had signs of clinical DIC and the goal Microcytosis 1+ fibrinogen levels were greater than 150. Bands-Stabs 2.70 0.00–10.00 % Metamyelocytes 0.90 % However, his hospital course was complicated with Myelocytes 0.90 % continued worsening of respiratory failure, and Other 48.70 % increased oxygen requirement based on arterial PT 20.6 (H) 12.0–14.6 sec INR 1.80 (H) 0.87–1.13 blood gas analysis. This could not be explained by APTT 49.8 (H) 24.7–36.0 sec the small size of pulmonary embolism or the minimal pulmonary base opacity in the previous images. During the hospital stay, he required multiple fresh showed left lower lobe air space opacity, atelec- frozen plasma, cryoprecipitate and platelet transfusions. tasis versus consolidation (Figures 1 and 2) The patient’s condition continued to deteriorate, and the ● CT abdomen showed splenomegaly final decision was to switch the patient to comfort care. ● Doppler of lower extremity showed left deep venous thrombosis at mid distal popliteal vein. 4. Discussion Methemoglobin is associated with impaired oxygen 3. Treatment delivery to the tissues due to increased oxygen affinity Thepatienthadacutemyeloidleukemiaintheblast as hemoglobin oxidized from ferrous to ferric state [1]. phase (48%) and was initially treated with allopurinol Bone marrow oxygen levels in a healthy person range aimed to prevent tumor lysis syndrome. He was also from 1 to 7 %. Bone marrow hypoxia can alter cell Figure 1. CT scan pulmonary artery study shows minimal bilateral sub-segmental pulmonary embolism. JOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVES 57 Figure 2. CT scan thorax shows a left lower lob small infiltration. death signaling pathways, increase the expression of oxygenation which enhances leukemic cell survival and anti-apoptotic proteins Mcl-1 and Bcl-2, modify pro- induces resistance to anti- leukemic drugs and liferation activities and protein expression of cancer radiotherapy. cells. Eventually it promotes survival of leukemic cells Some of the patients with congenital methemoglo- and resistance to chemotherapy and radiotherapy [4]. binemia die early during adulthood. This limited life Several studies conducted on bone marrows of chil- expectancy is especially seen in type 2 cytochrome B5 dren with acute lymphoblastic leukemia (ALL) have reductase deficiencies. The small population who live shown increased expression of hypoxia-inducible fac- long enough to have a prolonged bone marrow tor (HIF-1α) that plays an important role in control hypoxia and potentially increased risk of developing glucose metabolism, angiogenesis and cell survival [5]. acute leukemia. The occurrence of leukemia in con- Our patient was diagnosed with type 1 cytochrome genital methemoglobinemia remains enigmatic.
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