Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description

Figures & data

Table 1 Main Epidemiological Studies on Insulin Autoimmune Syndrome (IAS)

Authors	Year	Study Population	Estimated Incidence/Prevalence of IAS	Ethnicity of the Study Population	Reference
Takayama-Hasumi et al	1990	Patients admitted to 2094 Japanese hospitals for hypoglycemic episodes	Prevalence: 11.7% of a selected cohort (41 cases over 350 patients)	Japanese	[^Citation16]
Uchigata et al	1994	Reports of IAS published/presented in Japan from 1970 to 1992	Incidence: 9 cases per year (197 cases over 22 years)	Japanese	[^Citation22]
Uchigata et al	2000	Review of the published cases from 1970 to 1997	Incidence: 9 cases per year (244 cases over 27 years)	Japanese	[^Citation20]
			Incidence: 1 case per year (26 cases over 27 years)	Caucasian
Uchigata et al	2009	Review of the published cases from 1970 to 2007	Incidence: 10.3 cases per year (380 cases over 37 years)	Worldwide	[^Citation14]
Woo et al	2015	Patients hospitalized for hyperinsulinemic hypoglycemia	Prevalence: 6% of a selected cohort (5 cases over 84 patients)	Korean	[^Citation18]
Wang et al	2015	Patients identified by a nationwide questionnaire survey on IAS	Incidence: 2.6 cases per year (73 cases over 28 years)	Chinese	[^Citation19]
Yamada et al	2019	Patients identified by a nationwide survey on endogenous hyperinsulinemic hypoglycemia	Prevalence: 4.9% of a selected cohort (22 cases over 447 patients). Estimated prevalence in the general population: 0.017 cases per 100.000 population	Japanese	[^Citation17]

Table 2 List of Medications Associated with the Development of Insulin Autoimmune Syndrome

Class	Medication	References	Strenght of the Association
Antithyroid drugs	Methimazole	[^Citation9,Citation11,Citation23,Citation29,Citation37^–^Citation41]	High
	Carbimazole	[^Citation42^–^Citation47]	Medium
Supplements	Alpha-lipoic acid	[^Citation33^–^Citation35,Citation48^–^Citation52]	High
	Pyritinol	[^Citation53,Citation54]	Low
	Glutathione	[^Citation21]	Low
	Methionine	[^Citation55]	Low
Antihypertensives	Captopril	[^Citation22,Citation36]	Low
	Hydralazine	[^Citation56,Citation57]	Low
	Procainamide	[^Citation56]	Low
	Diltiazem	[^Citation22]	Low
Antiplatelet drugs	Clopidogrel	[^Citation58,Citation59]	Low
Oral antidiabetics	Tolbutamide	[^Citation22]	Low
	Gliclazide	[^Citation60]	Low
Anti-inflammatory drugs	Steroids	[^Citation22]	Low
	Loxoprofen-sodium	[^Citation61]	Low
	Diclofenac	[^Citation22]	Low
Muscle relaxants	Tolperisone hydrochloride	[^Citation22]	Low
Antibiotics	Penicillamine	[^Citation62,Citation63]	Low
	Imipenem	[^Citation64]	Low
	Penicillin G	[^Citation65]	Low
	Isoniazid	[^Citation66]	Low
Proton pump inhibitors	Pantoprazole	[^Citation67]	Low
	Omeprazole	[^Citation68]	Low
Plasma proteins	Albumin	[^Citation69]	Low
Orphan drugs	Tiopronin (Mercaptopropionyl glycine)	[^Citation21,Citation22]	Low

Notes: The strength of the association has been defined as low (less than 5 reports), medium (between 5 and 9 reports), or high (more than 10 reports).

Figure 1 The insulin autoimmune syndrome pathogenesis.

Notes: Panel (A) schematic overview of the physiologic insulin secretion and action: following glucose intake, pancreatic beta-cells secrete insulin which enters into the bloodstream, getting to peripheral tissues when it exerts its physiological functions in order to maintain glucose homeostasis. Panel (B) schematic overview of the double-phase mechanism of the insulin autoimmune syndrome. Following glucose intake, pancreatic beta-cells secrete insulin which enters into the blood stream getting included in the insulin-IAA macro-complexes. In the early postprandial phase, inclusion intro macro-complexes prevents insulin to act on its receptors in peripheral tissues, thus inducing hyperglycemia (phase 1). Due to the relatively low affinity for insulin, IAA subsequently release insulin molecules irrespective of plasma glucose concentrations, thus inducing hypoglycemic episodes (phase 2). Below both panels is reported a schematic representation of glucose and insulin concentrations over time: the continuous line represents plasma glucose concentrations, dotted line represents total insulin, pointed line represents free unbound insulin.

Figure 2 Flowchart for the diagnosis of insulin autoimmune syndrome.

Abbreviations: PEG, polyethylene glycol; IAA, insulin autoantibodies.

Table 3 Diagnostic Tools for the Differential Diagnosis Between Hypoglycemias of Different Origins

	Insulin	C-Peptide	Proinsulin	Insulin/C-Peptide Molar Ratio	Presence of Oral Hypoglycemic Agent in a Blood Sample	Insulin Recovery Following Precipitation with PEG	Antibodies Assays	Imaging Studies
Insulinoma	↑	↑/inappropriately normal	↑/inappropriately normal	< 1	Negative	Normal (> 70%)	Antibody- negative	May be positive
Nesidioblastosis	↑	↑/inappropriately normal	↑/inappropriately normal	< 1	Negative	Normal (> 70%)	Antibody- negative	Generally negative
Exogenous insulin administration	↑	↓	↓	> 1	Negative	Normal (> 70%)	Antibody- negative	Generally negative
Oral hypoglycemic agents administration	↑	↑/ inappropriately normal	↑/ inappropriately normal	< 1	Positive	Normal (> 70%)	Antibody- negative	Generally negative
Type B insulin resistance	↑↑/↑	↑↑/↑/ inappropriately normal	↑↑/↑/ inappropriately normal	< 1	Negative	Normal (> 70%)	Antireceptor insulin antibodies	Generally negative
Insulin autoimmune syndrome	↑↑/↑ (depending on the insulin assay)	↑↑/↑ (depending on IAA affinity for the C-peptide)	↑↑/↑ (depending on IAA affinity for the C-peptide)	Generally > 1	Negative	Low (5-10%)	IAA (false negative if IAA different from IgG with some laboratory kits)	Generally negative

Notes: ↑ indicates an increase, whereas ↓ indicates a decrease. The magnitude of the increase/decrease is indicated by the number of arrows. 

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