Clopidogrel caused insulin autoimmune syndrome in 1 case

preface

Insulin autoimmune syndrome (IAS) is characterized by hypoglycemia, hyperinsulinemia, and high-titer insulin autoimmune antibodies (IAA) [1].

Studies have found that the pathogenesis of IAS is caused by certain triggers on the basis of genetic immune defects, and taking drugs containing sulfhydryl groups is one of the main triggers for the pathogenesis of IAS [2].

Clopidogrel is a classic antiplatelet aggregation drug widely used in cardiovascular diseases such as myocardial infarction, which can produce sulfhydryl-containing metabolites in the body, induce the production of IAA and cause IAS
.
Hypoglycemia is considered one of the risk factors for cardiovascular disease and can cause poor prognosis in patients with myocardial infarction [3].

Therefore, if patients with cardiovascular and cerebrovascular diseases have unexplained hypoglycemia, they should be alert to the possibility
of IAS-induced hypoglycemia caused by clopidogrel.
This article reports the diagnosis and treatment of a patient with acute coronary syndrome caused by clopidogrel IAS, in which IAA detection has differential diagnostic value for patients with hypoglycemia after myocardial infarction and is an important test index
to evaluate the condition and efficacy.

Case history

The patient, a male, 82 years old, was admitted to the hospital
"intermittently sweating for more than 1 month".
In June 2020, due to chest tightness and sweating, ECG showed ST-T segment depression in V3–V5 leads, with elevated cTnI, and non-ST-segment elevation myocardial infarction (NSTEMI) was considered in the external hospital, and stent therapy was not performed, and aspirin and clopidogrel were continued due
to severe coronary lesions.
Since October 16, 2020, intermittently before the next meal, fasting for a long time, sweating at about 12 o'clock at night, no palpitations, hand tremors, dizziness, loss of consciousness, the lowest blood glucose measurement at the time of the attack is 2.
18mmol/L, insulin > 1000 μU/mL, IAA (+), and can improve
after eating 。 Previous hypertension and hyperlipidemia for 10 years; Take aspirin 0.
1g QD, clopidogrel 75mg QD, perindopril 4mg QD, amlodipine besylate 5mg QD, isosorbide mononitrate 20mg BID, atorvastatin 20mg QN, finasteride 5mg QN; Denial of history of use of sulfhydryl drugs such as methimazole and reduced glutathione; Denial of history of insulin secretagogues, exogenous insulin use; Denial of history of
autoimmune disease.
There is a sister in the family, an atrial fibrillation, a sister insulinoma, and a nephew with type 1 diabetes
.
On November 17, 2020, he was admitted to the endocrinology ward of our hospital
.

Patients conform to the classic Whipple triad, and the diagnosis of hypoglycemia is clear
.
The patient did not use exogenous insulin and hypoglycemic drugs, but had recurrent episodes of hypoglycemia, and the simultaneous insulin and IAA titers were significantly increased, consistent with IAS
.
Sulfhydryl-containing drugs are a common cause of IAS, and only clopidogrel metabolism in vivo is related to sulfhydryl production in the patient's drug history, considering that its hypoglycemia is caused by clopidogrel caused
by IAS.

During hospitalization, patients are regularly monitored for blood glucose, insulin, and IAA, and are advised to eat small, frequent meals and low-carbohydrate diets
.
On November 20, clopidogrel was discontinued, and due to concerns about the effect of IAA on platelet aggregation, anti-plate drugs were not added, and rivaroxaban 5 mg qd→ 5 mg BID anticoagulated
according to the European Society of Cardiology guidelines 4.
BECAUSE OF CONCERNS ABOUT T-SPOT.
TB AND CHEST CT NOT EXCLUDING OLD TUBERCULOSIS FOCI, GLUCOCORTICOIDS
WERE NOT ADDED.
On November 26, he developed unstable angina after one episode of hypoglycemia, and has not complained of chest tightness, palpitation, sweating and other discomfort
since then.
Blood glucose stabilized at normal levels, and IAA concentrations decreased from 7280 RU/mL to 326.
03 RU/mL within 12 days, with meal intervals q2.
25h →q4h
.
On December 17, he was discharged from the hospital and followed up as an outpatient visit, and did not complain of discomfort
.
On April 8, 2021, rivaroxaban was discontinued for percutaneous coronary intervention, and pre-preponderor 90 mg QD
.
On June 2, coronary artery stent treatment was performed in the hospital, and after surgery, aspirin 50 mg qd, ticagrelor 90 mg bid double antiplate, the last follow-up on July 9, blood glucose was normal, IAA 8.
36 RU/mL (upper limit of normal 20 RU/mL).

Case studies

Inspection Case Study:

In patients with hypoglycemia, the laboratory physician assists in measuring and analyzing blood glucose, insulin, C-peptide, and related antibody levels
.
In this patient, at the onset of hypoglycemia before admission, the simultaneous measurement of insulin and C-peptide levels was elevated, IAA (+); After admission, fasting hypoglycemia was measured without seizure, blood glucose 4.
7 mmol/L, insulin 74.
0 μIU/mL, C-peptide 3.
00 ng/mL, IAA> 400 RU/mL
.
Analyzing the above test results, the patient's insulin and C-peptide were higher than the upper limit of normal, and IAA was significantly increased, which was in line with the characteristics of
IAS.

Looking back at the main mechanism of hypoglycemia caused by IAS, after eating stimulation, insulin secretion and combined with IAA, so it can not play a hypoglycemic effect, blood sugar briefly rises, further stimulates insulin secretion, part of it still forms a complex with IAA, part of it plays a physiological role in a free state, and blood sugar levels return to normal
.
Due to the low IAA affinity, the insulin-IAA complex gradually dissociates, releasing biologically active insulin that triggers hypoglycemia[2].

In order to further confirm the diagnosis of IAS, the laboratory physician measured free insulin and total insulin
by PEG precipitation and acidification treatment.
The results showed that free insulin was 53 μIU/mL, total insulin was 831 μIU/mL, the proportion of free insulin was 6.
38%, and the total insulin was much higher than that of free insulin, indicating that a large amount of insulin was in the state
of binding to IAA.

The occurrence of IAS is related to the genetic background, and previous studies have shown that patients with specific HLA alleles are more likely to develop the disease
.
Asian patients have been reported to be more susceptible to IAS
because they carry these alleles more frequently.
The laboratory physician recommended that the patient complete the HLA genotyping, and the DRB1*0403 and DQB1*0302 loci of the patient were all gene loci that had been reported to be related to the occurrence of IAS [5–8], which once again confirmed the diagnosis
of IAS.

Because the combination of IAA and insulin is the cause of hypoglycemia, and insulin secretion is affected by blood sugar fluctuations, the laboratory physician recommends regular monitoring of the patient's IAA level
。 At the time of admission, IAA was 7290.
4 RU/mL (measured after dilution 20 times), and after stopping the causative drug clopidogrel for 12 days, the IAA decreased to 326.
03 RU/mL, the retest of free insulin was 103 μIU/mL, the total insulin was 616 μIU/mL, and the proportion of free insulin increased to 16.
7%, and the clinical improvement of hypoglycemia symptoms was observed, indicating that clopidogrel was related to IAA, and withdrawal was an effective treatment measure
.
Since then, rivaroxaban and ticagrelor have been used as antithrombotic drugs
for the treatment of the primary disease.
As shown in Figure 1, the patient's IAA level continued to decline and stabilized at the last follow-up visit to the normal range of IAA 8.
36 RU/mL (upper limit of 20 RU/mL of normal).

Therefore, IAA is an important evaluation index
for the disease changes and treatment effect of patients with IAS caused by clopidogrel.

Fig.
1 Changes in
IAA levels from admission to last follow-up.
The arrows indicate that clopidogrel was discontinued on 20 November, rivaroxaban was added on 24 November, and ticagrelor
was added on 8 April.

Clinical Case Study:

After the laboratory physician assisted the patient with the diagnosis of IAS, the clinician analyzed
the cause.
Approximately 50% of patients with IAS have taken drugs containing sulfhydryl groups, possibly by the mechanism that sulfhydryl groups break the disulfide bonds of insulin, altering the molecular conformation, making insulin immunogenic, triggering an immune response to produce IAA [1].

Checking the patient's drug history, clopidogrel itself does not contain sulfhydryl groups, but can be converted into active metabolites containing sulfhydryl groups after a two-step reaction, which is the only drug related to sulfhydryl production, and the combined drugs do not affect the metabolism of clopidogrel, considering that the patient's IAS is caused by
taking clopidogrel.

In terms of treatment, IAS is usually self-limited after discontinuation of causative drugs based on previous treatment experience
.
Traditional treatments include small, frequent meals, low-carb diets, and glucocorticoids, but drugs such as diazoxide, octreotide, and acarbose have been used to regulate insulin secretion and glucose metabolism [9,10], and plasma exchange or rituximab are often used to improve symptoms in patients with refractory hypoglycemia [9,11,12].

Although glucocorticoids can significantly improve clinical symptoms and rapidly reduce IAA levels, they are not selected
because of the risk of inducing lesion activity in this patient considering T-SPOT.
TB and lung imaging lesions considering old pulmonary tuberculosis.

Therefore, the clinician took a treatment plan
of discontinuation and dietary modification for this patient.
Unlike other sulfhydryl-containing drugs, clopidogrel is the key drug in the dual antiplate therapy of acute coronary syndromes, so at least one antithrombotic drug
should be added after discontinuation.
Ticagrelor, prasugrel, and rivaroxaban are NSTEMI antithrombotic agents
recommended by the European Society of Cardiology guidelines [4].
To analyze the structural formula and chemical metabolic processes of these three drugs (Figure 2), prasugrel contains sulfhydryl groups and cannot be selected
.
Due to concerns about the influence of the IAS autoimmune process on platelet aggregation, ticagrelor was temporarily ruled out, and the patient was first switched to rivaroxaban anticoagulation
in combination with the consultation opinion of the cardiologist.
After the patient was followed up with discharge to monitor a steady decrease in IAA levels, rivaroxaban was changed to ticagrelor plates
.
Ticagrelor and the patient's own aspirin form a double anti-plate, which creates a smooth transition
for the patient to percutaneous coronary intervention.

Figure 2.
Tiagrelor, prasugrel, rivaroxaban chemical structure.

Pradogrel contains sulfhydryl groups
.

Knowledge development

This patient was previously diagnosed with coronary heart disease, a history of NSTEMI, sweating, sympathetic nerve excitation symptoms, blood glucose less than 2.
8 mmol/L at the time of attack, insulin significantly increased, and relieved
after eating.
The most prominent clinical feature is hyperinsulinic hypoglycemia after the onset of acute coronary syndrome, and when similar symptoms are encountered in clinical practice, differential diagnostic analysis should be carried out in two steps:

1.
Identification of hypoglycemia after myocardial infarction: (1) Mistakenly taking aspirin exceeding the recommended therapeutic dose, previous studies have shown that high-dose (>1.
8 g/d) aspirin exerts hypoglycemic effects by stimulating insulin secretion and improving insulin resistance [13–15], and the patient in this case took aspirin at a dose of 0.
1 qd, which can be excluded; (2) After myocardial infarction, there is insufficient blood supply to the organs, nutritional deficiency, causing blood sugar to decrease, and hypoglycemia is more likely to occur when combined with severe liver disease, heart failure, kidney failure, malignant tumors and other systemic diseases, this patient is evaluated as having good liver and kidney function after admission, negative imaging and tumor index screening, and the possibility of consideration is small; (3) Glucogenic hormone deficiency or excessive insulin caused by pituitary, adrenal or pancreatic lesions, such as anterior pituitary hypofunction, adrenal insufficiency, insulinoma, etc.
, the insulin and IAA titer are elevated during the episode of hypoglycemia in this patient, and it is possible
to consider such causes.

2.
Identification of hyperinsulin hypoglycemia (1) exogenous insulin: manifested as high plasma insulin, low plasma C-peptide, low plasma proinsulin, the patient has no history of diabetes, does not use insulin secretagogues and exogenous insulin, and the simultaneous insulin and C-peptide are elevated during the episode of hypoglycemia, which can be excluded; (2) Reactive hypoglycemia: more common in the early stage of type 2 diabetes, due to hyperinsulinemia and delayed peak insulin secretion, mostly manifested as postprandial hypoglycemia, the patient has no previous history of diabetes, the onset is atypical, and the possibility of consideration is small; (3) Insulinoma: manifested as fasting hypoglycemia, pancreatic imaging often suggests a mass, IAA (–), may be primary or multiple endocrine adenoma type 1 involvement, patients pancreatic CT, somatostatin receptor imaging showed no obvious abnormalities, IAA (+), screening anterior pituitary hormone did not show abnormalities, can be excluded; (4) Islet cell hyperplasia: manifested as postprandial hypoglycemia, mostly occurs after gastrointestinal surgery, IAA (–), patients have no relevant clinical manifestations and medical history, can be excluded; (5) Type B insulin resistance: manifested as intractable hyperglycemia, hyperandrogenism, acanthosis nigricans sign or hypoglycemia, which can be the first symptom of autoimmune diseases, patients have no typical clinical manifestations, no nigricans sign on physical examination, no evidence related to autoimmune diseases on screening, IAA (+), can be excluded; (6) IAS: manifested as repeated spontaneous hypoglycemia, elevated blood immunoactive insulin, significantly increased IAA titers, patients in line with the above manifestations, and other causes of hypoglycemia are excluded, including the use of exogenous insulin and hypoglycemic drugs, alcoholic fatty liver, plasma cell disorders, systemic lupus erythematosus, rheumatoid arthritis or Graves disease, etc.
, the disease is likely to be high
.

Case summary

This case successfully diagnosed a case of clopidogrel causing IAS, and there are currently less than 10 similar cases, which is a rare disease; At the same time, it was proposed for the first time that alternative antithrombotic therapy regimens such as rivaroxaban and ticagrelor could be considered after stopping clopidogrel, and good results
were obtained.
During the diagnosis process, the clinician first received and sorted out the medical history, identified the recurrent hypoglycemia after myocardial infarction as the main feature, and improved the tests
required for differential diagnosis after admission.
Based on the simultaneous increase in insulin and IAA positive during the episode of hypoglycemia, combined with clinical record data, the laboratory physician considered the possible cause of hypoglycemia caused by IAS, and measured the level of free insulin and total insulin to confirm the presence of a large amount of IAA combined with insulin in the patient's body, and recommended HLA genotyping also suggested that the patient carried a high-risk site
of IAS.

After the diagnosis of IAS is confirmed, the clinician re-screens the patient's drug history and identifies clopidogrel as the cause
of IAS.
During treatment, the clinician stopped clopidogrel for the patient, switched to rivaroxaban and ticagrelor instead of antithrombotic, and the laboratory physician assisted in regular monitoring of IAA levels, and the continued decline of the antibody to the normal range suggested that the treatment strategy was effective
.

Based on effective communication and cooperation between laboratory and clinic, the patient's health was effectively improved in this case; Relying on the solid theoretical foundation of both sides for the disease, certain diagnosis and treatment results
have been achieved.
At the same time, the IAA test reported in this case has differential diagnostic value for patients with hypoglycemia after myocardial infarction, and is an important test index to evaluate the condition and efficacy, which is the value and help
provided by the test for clinical work.
Laboratory medicine not only escorts clinical practice in daily specimen quality control and numerical measurement, but also analyzes the causes of abnormal deviation values, comprehensively interprets test results, and provides more reasonable and personalized testing project guidance
.
At present, multi-disciplinary treatment (MDT) has become the development trend of comprehensive and precision medicine, and different professional perspectives will promote our deeper understanding of diseases, promote the gradual optimization of diagnosis and treatment, and improve
efficiency.

Expert reviews

Prof.
Chen Shi, Endocrinology, Peking Union Medical College Hospital

This case is a patient with hypoglycemia after myocardial infarction, the laboratory physician and the clinician closely cooperate in the diagnosis and treatment process, and jointly determine that IAS caused by clopidogrel is the cause of repeated hypoglycemia in the patient, and IAA level monitoring is an important diagnostic clue and efficacy evaluation index
after stopping and changing drugs.
In recent years, the incidence and mortality rate of cardiovascular diseases represented by myocardial infarction have increased year by year in China, and have become one of the killers of
chronic diseases that seriously endanger health.
Hypoglycemia is considered to be one of the risk factors for cardiovascular disease and can cause poor prognosis
in patients with myocardial infarction.
Therefore, in the process of clinical application of clopidogrel, we should pay close attention to the symptoms of hypoglycemia and be alert to the IAS
caused by clopidogrel.
Monitor IAA levels when necessary to improve drug safety and avoid adverse reactions
.
After the onset of the disease, the drug is first discontinued, rivaroxaban or ticagrelor can be used instead of antithrombotic, and IAA is continuously monitored until symptoms improve and antibody levels are normal
.
This case fully demonstrates the importance of laboratory medicine in the diagnosis and treatment of diseases, and clinicians and laboratory physicians should further strengthen communication and mutual learning in the future, and give full play to the advantages of MDT to improve the diagnosis and efficacy rate and benefit
more patients.

【References】

1.
Jiang Y， Wang L， Shi F， et al.
Insulin Autoimmune Syndrome After Exposure to Clopidogrel： A Case Report.
Endocr Metab Immune Disord Drug Targets.
2020；20(8)：1355-1362.
doi：10.
2174/1871530320666191220111615

2.
D C， E M， A F， P M.
Insulin Autoimmune Syndrome (Hirata Disease)： A Comprehensive Review Fifty Years After Its First Description.
Diabetes， metabolic syndrome and obesity？ ： targets and therapy.
2020；13.
doi：10.
2147/DMSO.
S219438

3.
Frier BM， Schernthaner G， Heller SR.
Hypoglycemia and cardiovascular risks.
Diabetes Care.
2011；34 Suppl 2：S132-137.
doi：10.
2337/dc11-s220

4.
Collet JP， Thiele H， Barbato E， et al.
2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
Eur Heart J.
2021；42(14)：1289-1367.
doi：10.
1093/eurheartj/ehaa575

5.
Eisenbarth GS.
MEDICAL INTELLIGENCE UNIT 13： Molecular Mechanisms of Endocrine and Organ Specific Autoimmunity.
R.
G.
Landes Company； 1999.

6.
Uchigata Y， Hirata Y， Iwamoto Y.
Drug-induced insulin autoimmune syndrome.
Diabetes Res Clin Pract.
2009；83(1)：e19-20.
doi：10.
1016/j.
diabres.
2008.
10.
015

7.
Uchigata Y， Omori Y， Nieda M， Kuwata S， Tokunaga K， Juji T.
HLA-DR4 genotype and insulin-processing in insulin autoimmune syndrome.
Lancet.
1992；340(8833)：1467.
doi：10.
1016/0140-6736(92)92654-x

8.
Uchigata Y， Tokunaga K， Nepom G， et al.
Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata’s disease) and monoclonal insulin autoimmune syndrome.
Diabetes.
1995；44(10)：1227-1232.
doi：10.
2337/diab.
44.
10.
1227

9.
Censi S， Mian C， Betterle C.
Insulin autoimmune syndrome： from diagnosis to clinical management.
Ann Transl Med.
2018；6(17)：335.
doi：10.
21037/atm.
2018.
07.
32

10.
Yuan T， Li J， Li M， et al.
Insulin Autoimmune Syndrome Diagnosis and Therapy in a Single Chinese Center.
Clin Ther.
2019；41(5)：920-928.
doi：10.
1016/j.
clinthera.
2019.
03.
009

11.
Calder GL， Ward GM， Sachithanandan N， MacIsaac RJ.
Insulin Autoimmune Syndrome： A Case of Clopidogrel-induced Autoimmune Hypoglycemia.
J Clin Endocrinol Metab.
2020；105(4)：dgz301.
doi：10.
1210/clinem/dgz301

12.
Yaturu S， DePrisco C， Lurie A.
Severe autoimmune hypoglycemia with insulin antibodies necessitating plasmapheresis.
Endocr Pract.
2004；10(1)：49-54.
doi：10.
4158/EP.
10.
1.
49

13.
Yuan M， Konstantopoulos N， Lee J， et al.
Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.
Science.
2001；293(5535)：1673-1677.
doi：10.
1126/science.
1061620

14.
Baron SH.
Salicylates as hypoglycemic agents.
Diabetes Care.
1982；5(1)：64-71.
doi：10.
2337/diacare.
5.
1.
64

15.
Hundal RS， Petersen KF， Mayerson AB， et al.
Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes.
J Clin Invest.
2002；109(10)：1321-1326.
doi：10.
1172/JCI14955