Differential diagnosis of the leucocytosis, more specifically differential diagnosis of the lymphocytosis secondary to lithium usage, is important because hematologic malignancies may also cause lymphocytosis and quick intervention is essential for hematologic malignancies [1]. Knowledge about the incidence of lithium associated lymphocytosis among lithium using patients are limited but there are some studies showed that among a group consisted of 33 patients, leukocytosis occurred in 13 cases (39%), of which 6 cases (18%) was of transient form, 5 cases (15%) of persistent form, and 2 cases (6%) of unknown type [2]. During toxicity, the incidence can increase up to 85.7% [3]. Lithium often increases white blood cell counts but at the same time reduces blood lymphocyte counts causing lymphopenia, but also lithium stimulates mitogenic response of human lymphocytes in vitro [4],[5]. In this case report, we will describe the differential diagnostic approach for leukocytosis and lymphocytosis in a patient using lithium.

A 26-year-old Caucasian male patient, who had bipolar disease and hypothyroidism and was treated with valproic acid, lamotrigine, lithium, and levothyroxine (25 mcg) and had lymphocyte higher than 4×10³/µL for six months, was referred to hematology for leucocytosis etiology investigation. Body temperature was 36°, blood pressure was 130/85 mmHg, pulse was 85 per minute, and respiratory rate was 16 per minute. He came from a middle-class family with no history of hematological disease. During the referral he had no B symptoms. Hepatosplenomegaly or superficial lymphadenopathy was absent. In systemic evaluation, no infection focus was detected. Complete blood count, cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Epstein–Barr virus (EBV) serologies, thyroid stimulating hormone (TSH), creatinine, albumin, lactate dehydrogenase (LDH), peripheral blood smear, and anteroposterior chest X-ray were requested. Chest X-ray showed no mediastinal, hilum enlargement, or another potential lymphadenopathy. Total white cell count was 13.5×10³/µL. Hemoglobin (15.3 g/dL) and trombocyte counts (337×10³/µL) were within the normal range. Mature lymphocytes with no smudge cells or with no blasts were detected in the peripheral blood smear (Figure 1). Immunoglobulin G (IgG) antibodies were detected for CMV and EBV. Anti-HB antibodies were detected secondary to the vaccination and other serology tests resulted negative. Lactate dehydrogenase (111 U/L), creatinine (0.74 mg/dL), and albumin (4.72 g/dL) were within the normal range and TSH was within the lower half of the normal range. After these initial tests abdominal, axillary, inguinal, and neck ultrasonography were requested for possible lymphadenopathy. T cell receptor (TCR) and B cell receptor (BCR) clonality gene rearrangement polymerase chain reaction (PCR) and chronic lymphocytic leukemia (CLL) flow cytometry were requested from peripheral blood. T cell receptor and B cell receptor clonality was not detected. CD200, CD25, and CD23 were found negative and CD20 and CD5 were found within the normal range (Table 1). During the follow-up, valproic acid levels have remained stable and blood lithium levels have been converted into a graphic to compare with the lymphocyte count (Figure 2). Lamotrigine dose started as 75 mg at July 2022 and gradually increased to the 200 mg within four months. During the follow-up, valproic acid dose has remained same at 2000 mg. The patient was taking 2×450 mg lithium at the beginning of July 2022. After this date dose was reduced to the 1×450 mg. During the interim period, the dosage was continued at 1×450 mg, and later it was increased back to 2×450 mg in July 2023. Even though correlation between the blood lithium level and lymphocyte count did not match perfectly, after possible malignancies were excluded, considering the patient’s drug history, it was decided that lithium was the only drug that had the potential to cause leukocytosis and lymphocytosis, which could cause the patient’s current condition. The patient began to be monitored with a complete blood count and peripheral blood smear.

Lithium is a mood regulator which is widely used in manic depressive patients. Cardiac arrhythmia, ataxia, sleeping disorders, memory impairment, acne vulgaris, dyspepsia, hypercalcemia, hypothyroidism, and nephrogenic diabetes insipidus are the most common side effects of lithium. However, even though it is rare there are case reports that support correlation between lithium blood levels and lymphocyte count [5],[6]. There is a follow-up study that had found no correlation between the lithium blood levels and lymphocyte counts but also showed that lithium users had higher lymphocyte counts [7].

Even though lithium primarily increases the leucocyte count and neutrophil percentage and reduces the percentage of the lymphocyte it also increases the lymphocyte count [2]. For the evaluation of the lymphocytosis, potential infectious causes were eliminated by comprehensive physical examination, food consumption, history, and viral serology studies [8]. B symptoms were questioned. Drug interactions were evaluated. Drugs that he has been using are mostly associated with lymphopenia, but among them lithium was associated with lymphocytosis [7]. The peripheral blood smear evaluated for hematologic malignancies [1]. Even though CLL was not among the suspected diagnosis it should have been eliminated. T cell receptor and B cell receptor gene rearrangement and CLL flow tests were performed to eliminate potential hematologic malignancies [8]. Bone marrow biopsy was not performed because the patient’s hemoglobin and trombocyte counts were normal. The patient’s lymphocyte count slightly correlated with the blood lithium level [2],[7],[9]. After the initial evaluation, the patient was followed up monthly with the psychiatry. During controls, blood count, peripheral smear, and physical examination (for lymphadenopathy and hepatosplenomagaly) were requested.

Lithium is an overlooked and a forgotten cause of lymphocytosis. Before 2000s there have been case reports about lithium and its hematologic side effects. Even though hematologic side effects are rare, especially lymphocytosis, due to lithium’s wide usage, clinicians may encounter cases such as our’s. All patients should be systemically and thoroughly evaluated. All possible causes should be eliminated by minimally invasive and cost-effective methods.