• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. What are the two types of autoimmune Hypoglycemia?
  • 1. Insulin autoimmune syndrome (Hirata's disease)
    • Also called Hirata's disease
  • 2. Type B Insulin resistance
    • Antibody against the insulin receptor
• Q. What are the definition and diagnostic criteria for Insulin autoimmune syndrome (Hirata's disease)?
  • All of the following criteria must be present
    • (I) hyperinsulinemic Hypoglycemia ;
    • (II) elevated Insulin autoantibody (IAA) titers;
    • (III) no prior exposure to exogenous insulin ;
    • (IV) no pathological abnormalities of the pancreatic islets.
  • Recently however many cases have been observed in which the patient has had exposure to insulin. Hence point III is not considered redundant
• Q. Which other autoimmune disease is Insulin autoimmune syndrome (Hirata's disease) most closely linked with?
  • Graves' disease
  • It could be because of
    • 1. Common autoimmune source
    • 2. Induced by the use of antithyroid drugs
• Q. Which commonly used drugs have been linked with Insulin autoimmune syndrome (Hirata's disease)?
  • 1. antithyroid drugs - Carbimazole, Methimazole
  • 2. Alpha lipoic acid
  • 3. Clopidogrel
  • 4. Steroids
  • 5. Diclofenac
  • 6. Imipenem
  • 7. Isoniazid
  • 8. Pantoprazole
  • 9. Omeprazole
• Of these methimazole and alpha lipoic acid have the strongest link to the disease
• 
• Q. Which HLA has a strong link with the development of Insulin autoimmune syndrome (Hirata's disease)?
  • HLA DRB1*0406
  • This is more common in Asians hence the disease is more common in Asians
• Q. How many weeks after starting the offending medication does the disease develop?
  • It typically develops 4-6 weeks after starting the offending medication
• Q. Apart from medications, which other triggers have been identified?
  • 1. Viral infections
  • 2. Hematological diseases
• Q. Which viruses are known to be triggers?
  • 1. Hepatitis C
  • 2. Measles
  • 3. Mumps
  • 4. Coxsackie B
  • 5. Varicella zoster
  • 6. Rubella
• Q. Which hematological disorders have been linked?
  • Multiple myeloma
  • Monoclonal gammopathy
• Q. What type of hypersensitivity is Insulin autoimmune syndrome (Hirata's disease)?
  • it is Type VII hypersensitivity
  • It is a novel category of hypersensitivity
• Q. Which is the key pathogenic antibody causing this disease?
  • Insulin autoantibody (IAA)
  • This is an IgG antibody
• Q. Does the mere presence of IAA produce the disease?
  • No
  • Low titers of the antibody in circulation do not produce the disease
• Q. What are the clinical phases of Insulin autoimmune syndrome (Hirata's disease)?
  • Initially, the antibodies bind to the insulin leading to a transient reduction in insulin levels and hence transient postprandial hyperglycemia
  • After this, the insulin dissociates from the antibody irrespective of the glucose levels leading to the development of Hypoglycemia
• Q. How does one distinguish between Insulinoma and Insulin autoimmune syndrome (Hirata's disease)?
  • 1. Clinically
    • Insulin autoimmune syndrome produces mainly post-prandial Hypoglycemia. It can also produce fasting and exercise-induced Hypoglycemia
    • Insulinoma- mainly produces fasting Hypoglycemia
  • 2. Insulin: C-peptide ratio
    • Convert insulin to pmol/l
    • Conver C-peptide to pmol/l using units lab
    • Insulin: C-peptide ratio calculated
      • Less than 1 → suggestive of Insulinoma
      • More than 1 → suggestive of Insulin autoimmune syndrome (Hirata's disease)
  • 
• Q. Why does the insulin: C-peptide ratio show what it shows?
  • Insulin in circulation has a short half-life compared to C-peptide
  • In Insulinoma there is a release of C-peptide and insulin both in large quantities released in equal concentration. C-peptide having a higher half-life is often found more easily in circulation
  • In Insulin autoimmune syndrome (Hirata's disease) the C-peptide is released at its rate while the insulin is stuck to the antibody. Hence in these cases, insulin levels tend to be disproportionately more than C-peptide
• Q. Name two conditions in which insulin levels tend to be disproportionate compared to C-peptide levels.
  • Insulin autoimmune syndrome (Hirata's disease)
  • Exogenous insulin use
• Q. What is the problem with the measurement of insulin autoantibodies?
  • Here only the IgG subclass of antibody is detected in the commercial assay
  • Hence we may have false negative values
• Q. What should be done in case of false negative Insulin autoantibodies with high suspicion of the disease?
  • Precipitation of the serum with PEG is done followed by recovery of the insulin from the supernatant
  • In patients with Insulin autoimmune syndrome (Hirata's disease)
    • After PEG precipitation- the bound insulin levels are higher than free insulin levels
    • In normal people- free insulin is higher than bound insulin
• Q. What are the clinical features of patients having antibodies to insulin receptors?
  • Here there is initially Hyperglycemia along with extreme insulin resistance
  • the antibodies may be both blocking and stimulating
  • in case blocking antibodies remain- they mainly lead to hyperglycemia and Insulin resistance
  • In case of stimulating antibody present- they start developing hypoglycemia
• Q. Which tumors are associated with these insulin autoimmune syndromes?
  • Antibody against insulin seen in multiple myeloma
  • Antibody against insulin receptor sen in Hodgkin lymphoma
• Q. What is the treatment for this condition?
  • Most cases are self-resolving
  • It is because if the antigen is withdrawn- the antibody slowly withdraws over a while
  • Generally within 3-6 months
• Q. What are the other treatment options?
  • Small frequent meals with low carbohydrate content
  • Acarbose
  • Glucocorticoids
  • Diazoxide
  • Octreotide
  • Partial pancreatectomy
  • Plasmapheresis
  • Other immunosuppressants
    • Azathioprine
    • Cyclophosphamide
    • Mycophenolate
    • Rituximab
• References:
  • Boro H, Gupta U, Singh C, Malhotra R, Khadgawat R. Insulin Autoimmune Syndrome - A Case Series. Eur Endocrinol. 2020 Oct;16(2):168-171. doi: 10.17925/EE.2020.16.2.168. Epub 2020 Oct 6. PMID: 33117451; PMCID: PMC7572167.
  • Cappellani D, Macchia E, Falorni A, Marchetti P. Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description. Diabetes Metab Syndr Obes. 2020 Apr 1;13:963-978. doi: 10.2147/DMSO.S219438. PMID: 32308449; PMCID: PMC7136665.