Does alpha-lipoic acid cause insulin autoimmune syndrome? (Hirata’s disease)?

Alpha-lipoic acid is not likely an independent cause of Hirata’s disease, but it may be a trigger in susceptible people.

A fundamental aspect of autoimmune disease is the loss of immune tolerance to the “self”, causing the immune system to attack the body’s own proteins and tissues. The causal factors resulting in this loss of self-tolerance are typically elusive, but commonly involve both genetic and environmental factors. For example, people with lupus often receive their initial diagnosis after a severe sunburn. Sunburn doesn’t cause autoimmune disease by itself, but it may be a trigger for a lifelong battle with autoimmunity in a genetically predisposed individual.

Insulin autoimmune syndrome (IAS) is a rare disease caused by an autoimmune response to insulin.^[1] IAS is associated with high insulin levels and hypoglycemia (particularly after consuming a meal), as well as high levels of antibodies against insulin.^[2] The cause of IAS isn’t clear, but it has been associated with certain variants in human leukocyte antigen (HLA) genes. The HLA genes encode specialized sets of proteins that help the immune system distinguish “self” molecules of the body from harmful foreign pathogens. There is a strong association with certain HLA variants and different types of autoimmunity, which seems to also be the case for people with IAS induced by lipoic acid (LA).^[3]

IAS can be triggered by LA, as well as other drugs.^[2] Although not completely understood, the mechanism by which LA or other drugs may trigger IAS in susceptible individuals may occur because LA disrupts disulfide bonds in the insulin molecule. LA and other drugs known to trigger IAS have in common the presence of sulfhydryl groups capable of disrupting (reducing) one or more disulfide bonds in insulin molecules.^[2][4][5] In people with certain HLA gene variants, this may be sufficient to trigger an autoimmune response against insulin.^[6]

Although 80% of cases of IAS tend to be transient and resolve within 3–6 months after discontinuing the instigating agent and receiving medical treatment,^[7]PMID: 30532998] some people may develop chronic hypoglycemia.^[2]

Recovery from LA-induced IAS may be immediate (within two days or a single week) or may take two months and require corticosteroid treatment.^{[8] [9]}

Symptoms of IAS

Autonomic nervous system symptoms and neurological hypoglycemia are the main clinical manifestations of hypoglycemia, occurring mostly during the night and early morning. Less commonly, but also frequently observed, are critically low blood glucose levels after meals and during prolonged fasting. Symptoms to be aware of include hunger, sweating, palpitations, and hand tremor (reported in 81.1% of case reports), as well as neurological symptoms: dizziness, weakness, blurred vision, aphasia, loss of consciousness, coma, fainting, loss of coordination, and partial amnesia (reported in 64.9% of 37 patients in Chinese and English case reports).^[9]

Genetic component, unknown mechanism, and dose-risk coefficient

With the majority of case reports coming from the Asia-Pacific region, scientists have long suspected that the immune attack on insulin known as Hirata’s disease^[1] may have a strong genetic component. In fact, several papers have identified candidate genes that put certain groups of people of Asian, as well as European, ancestry at risk.^[10][5][11] In a 2021 statement, the European Commission’s EFSA Panel on Nutrition confirmed that “consumption of ALA added to foods, including food supplements, is likely to increase the risk of developing IAS in individuals with certain genetic polymorphisms that cannot be readily identified without genetic testing.”^[12] However, neither the underlying mechanism nor a threshold intake above which IAS is more likely to occur has yet been established.

Keep an eye out for possible symptoms

The EFSA report mentioned above does not suggest any immediate regulatory action and refers to the low incidence of IAS. While specific data on LA-induced IAS are lacking, data from Japan estimate the number of cases in the general population to be 0.017 per 100,000 people (i.e. a total of 22 cases in these years).^[13] The numbers are presumably much lower in Europe.^[6] For supplement users, it still makes sense to closely monitor whether potential side effects occur, especially after meals and long(er) periods of fasting.