ABSTRACT

Purpose: Several case reports have highlighted symptomatic hypoglycemia as a serious but uncommon Hereditary ovarian cancer adverse effect of hydroxychloroquine (HCQ) in nondiabetic subjects.

Methods: This study describes a nondiabetic patient who experienced serious hypoglycemia related to HCQ.

Findings: In the course of treatment, the patient experienced multiple episodes of hypoglycemia at night and in the early morning. The hypoglycemia was usually accompanied by nausea, fatigue, and dizziness. The lowest value of blood glucose in the fingertip was 2.6 mmol/L.

Keywords: Connective tissue disease, Gastrointestinal bleeding, Hydroxychloroquine, Hypoglycemia.

INTRODUCTION

Hydroxychloroquine sulfate (HCQ) is a hydroxylated analogue of chloroquine (CQ). HCQ was initially used as an antimalarial agent because it inhibits Plasmodium heme polymerase.In addition, a number of experimental and clinical observations have shown the efficacy of HCQ in long-term treatment of connective tissue disease (CTD), including Sj gren’s syndrome, rheumatoid arthritis, and systemic lupus erythematosus (SLE).1 Early studies have shown that antimalarial agents may improve glucose tolerance, with hypoglycemia being a rare adverse effect of their use.2 In recent years, there have been several reports of hypoglycemia caused by HCQ.3e5 However, this adverse effect is more often seen in patients with underlying diabetes mellitus. The present article describes a nondiabetic patient with CTD who developed hypoglycemia with HCQ treatment.We also discuss the possible mechanisms of hypoglycemia due to HCQ.

CASE DESCRIPTION

A 41-year-old woman (weight, 42 kg) had been diagnosed with breast cancer 4 years ago. She underwent a modified radical and 8 rounds of chemotherapy (cyclophosphamide and epirubicin), with the last session in October 2015. In June 2019, the patient was diagnosed with “connective tissue disease” (SLE or Sj gren’s syndrome). She was then prescribed methylprednisolone (8 mg once daily), HCQ (200 mg BID), and loxoprofen 60 mg (as needed). A history of adverse drug reactions to cephalosporins was confirmed by the presence of oral discomfort.On August 16, 2019, the patient presented with black stools as well as fatigue and paroxysmal abdominal pain. She was admitted for the treatment of “gastrointestinal bleeding” on August 21, 2019. The patient was then given proton pump inhibitors and somatostatin for acid suppression and rehydration treatment after admission. On the second day after admission, the treatment regimen of CTD was changed: methylprednisolone was discontinued, and the use of HCQ was adjusted to 400 mg once daily.

During hospitalization, the patient experienced multiple episodes of hypoglycemia at night and in the early morning (Figure 1). Hypoglycemia occasionally occurred during the day, sometimes accompanied by clinical manifestations of fatigue. At ~7:00 PM on day 11 after admission, the patient developed nausea and discomfort accompanied by fatigue and dizziness. Blood glucose in the fingertip was immediately measured, which indicated 2.6 mmol/L. The patient was then immediately given 40 mL of 50% glucose intravenously, and fluid rehydration therapy of 10% glucose (500 mL) and sodium chloride (500 mL) was then started. At 2:10 AM the next morning, the patient again reported weakness, and blood glucose measured in the fingertip was 3.3 mmol/L. Although the symptoms did not subsequently recur during the day, hypoglycemia occurred again at night. The same treatment was given as before.Due to repeated episodes of hypoglycemia in the treatment process, the patient underwent various tests for insulinoma, including insulin, C-peptide, blood cortisol, adrenocorticotropic hormone, growth hormone, and others. The patient also underwent imaging examinations. Detailed results are shown in Table I.Following these tests, the patient was discharged from the hospital because her blood glucose level had been maintained at 3.6 mmol/L during the day and at night; continued follow-up by the Outpatients Department was recommended. HCQ was prescribed to be taken in the morning, and changes in blood glucose were monitored.At the time of the present case report, the follow-up records of the patient were consulted, and no clinical symptoms related to hypoglycemia were described. Furthermore, no blood glucose monitoring was conducted, and thus the actual changes in blood glucose were unknown.

DISCUSSION

There have been very few case reports in the literature about nondiabetic patients treated for CTD who developed hypoglycemia as a result of HCQ treatment.5,6 Although the present patient is still undiagnosed, specialist clinicians are more inclined to diagnose her with SLE. At any rate, this report describes a still rather rare case.The patient had no predisposing disorder that could lead to hypoglycemia, such as ethanol intake, oral antidiabetic, or exogenous insulin therapy before admission. There were also no clinical or laboratory manifestations of starvation, liver failure, or sepsis that could have caused hypoglycemia at admission. During the treatment period of gastrointestinal hemorrhage, the patient was treated Diagnostic serum biomarker with somatostatin for a short time. Some literature support the theory that somatostatin can inhibit the secretion of glucagon and lead to drug-induced hypoglycemia.7,8 However, the patient’s symptoms of hypoglycemia occurred repeatedly throughout the whole hospitalization period, and thus the factor of somatostatin usage can be disregarded.

Figure 1. Dynamic changes of the lowest value of daily blood glucose.

Normal range electrocardiogram

Head and facial features: There was no obvious abnormality on plain scan and slight inlammation in both ethmoid sinuses Abdomen: There is a slight calciication in the right liver. No
obvious abnormal density shadow was found on plain scan of spleen, pancreas, kidney, and adrenal gland ACTH = adrenocorticotropic hormone.By analyzing the timing of the hypoglycemic episodes (Figure 2), we made an interesting observation that the patient’s hypoglycemia symptoms mostly occurred from midnight to 6:00 AM, and before sleep. However, previous descriptions of hypoglycemia that developed after treatment with HCQ did not mention any particular timing of the hypoglycemic episodes.4,9 We therefore concluded that the occurrence of hypoglycemia symptoms in this case was related to the time of administration because HCQ was given to this patient once daily and at a higher dose (400 mg) 0.5 h after dinner. This regimen was different from the usual BID regimen with lower HCQ doses. Subsequently, the patient showed symptoms of hypoglycemia within a short time after taking the drug. Meanwhile, the fasting time at night is longer, and the blood glucose level itself is also at a low level, thus increasing the probability of severe hypoglycemia. As the drug is metabolized, this effect gradually decreases during the day. In addition, blood glucose levels did not vary during the day, which may be due to the fact that more glucose-containing preparations were given throughout the day, which also had a certain impact on blood glucose levels.

Thorough examinations of the patient during hospitalization revealed that the levels of serum insulin and serum C-peptide at 1 and 2 h after meals were higher than normal. Insulinoma diagnosis was excluded from other relevant examinations (Table I). The results are inconsistent with those of Quatraro et al.10 In their study, among 38 patients with treatment-refractory type 2 diabetes mellitus, glycemic control improved, not worsened, in those taking HCQ. This outcome was not attributed to increased insulin secretion because serum C-peptide levels were unchanged. Thus, our results are more similar to those of Powrie et al.11 In their insulin clamp study of 20 treatment-refractory patients with type 2 diabetes mellitus, they found that CQ affects insulin metabolism both by reducing insulin clearance from the circulation and by increasing insulin secretion. The latter conclusion was made on the basis of increased C-peptide levels. We therefore believe that HCQ had an effect similar to that Abexinostat of CQ.

Figure 2. Total frequency of hypoglycemia in each time interval (TI) during hospitalization. According to the time point measured by the blood glucose spectrum, a day is divided into 8 TIs: TI1 (midnighte3:00 AM); TI2 (3:00e6:00 AM); TI3 (6:00e9:00 AM); TI4 (9:00 AMe12:00 PM); TI5 (12:00e3:00 PM); TI6 (3:00e6:00 PM); TI7 (6:00e9:00 PM); and TI8 (9:00 PMemidnight).

The mechanisms of hypoglycemia caused by HCQ treatment are unclear and may be inferred from the studies of CQ. Hypoglycemia manifestations may occur due to the inhibition of intracellular degradation of insulin,12 increased insulin secretion in pancreatic islet cells,13 or inhibition of hepatocyte gluconeogenesis.The use of the Naranjo Adverse Drug Reaction Probability scale indicated a probable relationship (score of 7) between the development of hypoglycemia in the present patient and HCQ therapy.15 This finding further supports the notion that her hypoglycemia was caused by HCQ. The full list of answers to the Naranjo scale questions is shown in Table II.

CONCLUSIONS

To our knowledge, this is one of the first reports about a nondiabetic patient with CTD who experienced hypoglycemia after treatment with HCQ. Hypoglycemia is more likely to occur at night or in the early morning. We hope that this rare case will prompt nonrheumatology physicians to pay more attention to unexplained hypoglycemia symptoms when using HCQ, especially in nondiabetic patients. Future studies should strive to elucidate the exact mechanisms of this phenomenon.