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 Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 45  |  Issue : 2  |  Page : 118-120

Dilemma in diagnosis of diabetes in a patient with chronic lymphocytic leukemia treated with cyclophosphamide − a paradoxical effect of immunosuppressive agent: a case report


1 Department of Haematology and Blood Transfusion, University of Calabar Teaching Hospital, Calabar, Nigeria
2 Department of Internal Medicine, University of Calabar Teaching Hospital, Calabar, Nigeria
3 Department of Pathology, University of Calabar Teaching Hospital, Calabar, Nigeria

Date of Submission30-Dec-2019
Date of Acceptance16-Apr-2020
Date of Web Publication29-Dec-2020

Correspondence Address:
Akaba Kingsley
Department of Haematology and Blood Transfusion, University of Calabar, Teaching Hospital, Calabar, Cross River State. Zip Code: 540242, Calabar,
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_64_19

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  Abstract 


A case report of a 56-year-old female patient who was managed for chronic lymphocytic leukemia with intravenous cyclophosphamide regimen who suddenly developed hyperglycemic state with no previous/family history of diabetes or steroid is presented. Laboratory investigation showed glycated hemoglobin of 6.1% and normal electrolyte and liver function. Diagnosis of prediabetic state was made, and the patient was commenced with oral hypoglycemic agent (metformin). Since then, blood glucose has been normalized.

Keywords: chronic lymphocytic leukemia, cyclophosphamide, diabetes


How to cite this article:
Kingsley A, Enang O, Hilary I, Edakabasi A. Dilemma in diagnosis of diabetes in a patient with chronic lymphocytic leukemia treated with cyclophosphamide − a paradoxical effect of immunosuppressive agent: a case report. Egypt J Haematol 2020;45:118-20

How to cite this URL:
Kingsley A, Enang O, Hilary I, Edakabasi A. Dilemma in diagnosis of diabetes in a patient with chronic lymphocytic leukemia treated with cyclophosphamide − a paradoxical effect of immunosuppressive agent: a case report. Egypt J Haematol [serial online] 2020 [cited 2021 Jul 31];45:118-20. Available from: http://www.ehj.eg.net/text.asp?2020/45/2/118/305407




  Introduction Top


Diabetes mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia, which is a result of defect in insulin secretion, action, or both, and the metabolic complications of carbohydrate, lipid, and proteins result from the deficient anabolic effect of insulin hormone [1-3]. Diabetes can be classified as proposed by American Diabetes Association in 1997 into type 1, type 2, gestational DM, latent autoimmune diabetes of the adult, and maturity-onset diabetes of the young. However, ∼10% of patients may prove difficult to classify [1]

Type 1 diabetes mellitus (T1DM) is mostly associated with other autoimmune diseases, and in this type of diabetes, the CD4 and CD8 T cells play a crucial role in the initiation and progression of this disease. The activation and recruitment of lymphocyte causes production of inflammatory cytokines that accelerate the destruction of beta cell, leading to depletion in insulin production [2]. Owing to the counterregulatory hormonal effect and insulin depletion, DM may occur [3].

Cyclophosphamide is an alkylating cytotoxic chemotherapeutic agent used in the treatment of many hematological malignancies, for example, chronic lymphocytic leukemia, which is characterized by abnormal proliferation and accumulation of lymphocyte in both the bone marrow and blood. Chronic lymphocytic leukemia is the most common malignancy in Nigeria, with male to female ratio of 1 : 1, and occurs within the age range 50–59 years [4]. It is associated with several risk factors such as organophosphorus compounds, familial, and infection.

There is a possible relationship between cyclophosphamide and T1DM, which has been suggested in experimental animal models owing to its immune-modulatory properties. It has been documented to promote susceptibility to T1DM [2],[5],[6],[7],[8]. Thus, the mechanism of action is not clear, but several theories have been propounded such as cyclophosphamide causes the destabilization of the local immune-regulatory balance by temporarily depleting suppressor cells. Paradoxically, cyclophosphamide has been used in addition to other immune modulators as a treatment for type B insulin resistance syndrome [9],[10].

We present the case of a patient with chronic lymphocytic leukemia not previously diagnosed as having diabetes, who develop diabetes after two cycles of cyclophosphamide and fludarabine therapy.


  Case report Top


A 63-year-old black African woman present to our Hematology Day Care Unit with symptom of generalized body weakness, dehydration, and drowsiness 7 days after the administration of intravenous 1000 mg of cyclophosphamide. The patient is well known to the department and is being managed for chronic lymphocytic leukemia. Her weakness was so severe that it distorted her daily activities. She presented with normal body mass index and no stigmata associated with insulin resistance. Laboratory results showed random blood glucose of 28 mmol/l (504 mg/dl), and on the account of this, the patient was admitted. Although her electrolytic urea, creatinine, liver function test, lipase, and amylase were essentially normal and glycated hemoglobin was 6.1% (normal range 4.0–6.3%), a diagnosis of prediabetic state was made. She was commenced on an aggressive intravenous administered fluid. Patient was also given insulin for 48 h and later was commenced on oral hypoglycemic agent (Metformin) 500 mg 12 hourly. The patient was then discharged after a week of hospital admission; she was administered metformin and had a fasting blood glucose level of 6.1 mmol/l (115 mg/dl). Patient was then asked to return back to the clinic for the next cycle of chemotherapy in 14 days. The patient presented back for the chemotherapy and her fasting blood glucose was 6.0 mmol/l. Two days after the intravenous administration of cyclophosphamide, her fasting blood glucose rose to 14.2 mmol/l (261 mg/dl), and the patient was re-commenced metformin 500 mg. Presently, the patient’s fasting blood glucose is 7.1 mmol/l, and she is stable.


  Discussion Top


Atypical diabetes accounts for ∼10% of cases of DM. Differential diagnosis is important to initiate the best line of management, especially in patients with comorbidities in which there is glucose elevation, thereby affecting their quality of life and over all well-being. In the index case, we had three possible diagnoses, these included drug-induced DM, T1DM, and cyclophosphamide-associated diabetes. Our index patient was not on any form of steroid.

After excluding all common causes of diabetes, we considered that hyperglycemic crisis may be associated with cyclophosphamide use in the management of this patient; thus, there is paucity of information on the relationship of the aforementioned medication and hyperglycemia. Cyclophosphamide is an alkylating and cytostatic drug used for treatment of malignancy and other autoimmune disease. This drug may have a contradictory effect on the immune system, which might affect the pancreas and insulin secretion. This effect is dose dependent; at low dose, it is associated with immune response, whereas at high dose, it is associated with immunosuppression [11]. At low dose, there is selective subclass suppression of T cell (Treg cells) [11]. Similarly, a study by Harada and Makino [12] reported that cyclophosphamide promotes the onset of DM in some nonobese mice, and another study by Carlton et al. [13] also reported that cyclophosphamide induced T1DM in nonobese mice. The mechanism of action of cyclophosphamide is through selective apoptotic loss of CD4+CD25+FOXP3+ Treg cells. These Treg cells are involved in the suppression of effector T cell that attack the pancreatic β cell [5],[7]. Furthermore, cyclophosphamide also induces the production of interferon and from T-helper type 1, which is capable of directly causing destruction of islet cells. In our patient, we suspected that cyclophosphamide could have precipitated hyperglycemia by cytotoxicity mechanism, but other unknown mechanisms could also contribute. We also think the effect may have been cytotoxic but not cytocidal. Thus, association of other factors predisposing to hyperglycemia cannot be completely ruled out in most cases. The frequency of atypical diabetes associated with cyclophosphamide has been underdiagnosed for many reasons, and this could be attributed to more focus on the disease leading to the use of cyclophosphamide. Another reason may be that most cases presented with less aggressive form of diabetes that does not trigger the alarm for atypical diabetes. Moreover, the presence of other risk factors and drugs makes it difficult to assign this risk to cyclophosphamide limitation.

Limitation

Further diagnostic investigations were not done owing to technical and financial constraint.


  Conclusion Top


We present a 56-year-old patient with chronic lymphocytic leukemia with difficulty-to-classify diabetes with no family history and not on steroid but was said to have suddenly develop hyperglycemia after administration of intravenous cyclophosphamide.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
American Diabetes Association. Classification and diagnosis of diabetes:standards of medical care in diabetes − 2018. Diabetes Care 2018; 41:S13–S27.  Back to cited text no. 1
    
2.
Brode S, Raine T, Zaccone P, Cooke A. Cyclophosphamide induced type-1 diabetes in the NOD mouse is associated with a reduction of CD4+CD25+Foxp3+regulatory T cells. J Immunol 2006; 177:6603–6612.  Back to cited text no. 2
    
3.
Demirci H, Cosar R, Ciftci O, Sari IK. Atypical diabetic ketoacidosis: case report. Balkan Med J 2015; 32:124–126.  Back to cited text no. 3
    
4.
Akaba K, Nwogoh B, Akpan I, Bassey OB, Effiong O, Petters E et al. Epidemiological pattern of adult haematological malignancies in a tertiary hospital in Cross River State. Int Res J Oncol 2019; 2:1–9.  Back to cited text no. 4
    
5.
Kaur S, Tan WL, Soo C, Cheung CC, Stewart J, Reddy S. An immunohistochemical study on the distribution and frequency of T regulatory cells in pancreatic islets of NOD mice during various stages of spontaneous and cyclophosphamide-accelerated diabetes. Pancreas 2010; 39:1024–1033.  Back to cited text no. 5
    
6.
Reddy S, Bradley J, Ginn S, Pathipati P, Ross JM. Immunohistochemical study of caspase-3-expressing cells within the pancreas of non-obese diabetic mice during cyclophosphamide-accelerated diabetes. Histochem Cell Biol 2003; 119:451–461.  Back to cited text no. 6
    
7.
Caquard M, Ferret-Bernard S, Haurogne K, Ouary M, Allard M, Jegou D et al. Diabetes acceleration by cyclophosphamide in the non-obese diabetic mouse is associated with differention of immunosuppressive monocyts into immunostimulatory cells. Immunol Lett 2010; 129:85–93.  Back to cited text no. 7
    
8.
Antkowiak PF, Stevens BK, Nunemaker CS, McDuffie M, Epstein FH. Manganese-enhanced magnetic resonance imaging detects declining pancreatic beta-cell mass in a cyclophosphamide-accelerated mouse model of type 1 diabetes. Diabetes 2013; 62:44–48.  Back to cited text no. 8
    
9.
Gehi A, Webb A, Nolte M, Davis J Jr. Treatment of systemic lupus erythematosus-associated type B insulin resistance syndrome with cyclophosphamide and myocphenolatemofetil. Arthritis Rheum 2003; 48:1067–1070.  Back to cited text no. 9
    
10.
Yang H, Zhao J, Li Y, Lv F, Zhang S, Li Y. Successful treatment of type B insulin resistance with mixed connective tissue disease by pulse glucocorticoids and cyclophosphamide. J Diabetes Investig 2017; 8:626–628.  Back to cited text no. 10
    
11.
Ahlmann M, Hempel G. The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Cancer Chemother Pharmacol 2016; 78:661–671.  Back to cited text no. 11
    
12.
Harada M, Makino S. Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide. Diabetologia 1984; 27:604–606.  Back to cited text no. 12
    
13.
Charlton B, Bacelj A, Slattery RM, Mandel TE. Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes 1989; 38:441–447.  Back to cited text no. 13
    




 

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