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    Home > Active Ingredient News > Endocrine System > Case sharing l Rare hypoglycemia: elderly men-repeated hypoglycemia for 4 months-isoniazid-hyperinsulinemia

    Case sharing l Rare hypoglycemia: elderly men-repeated hypoglycemia for 4 months-isoniazid-hyperinsulinemia

    • Last Update: 2021-03-23
    • Source: Internet
    • Author: User
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    Introduction: The department diagnosed and treated a rare case of hypoglycemia, which was considered to be related to the anti-tuberculosis drug isoniazid, and it was considered that isoniazid may cause insulin autoimmune syndrome.

    IAS caused by isoniazid is rarely reported in domestic and foreign literature (not available in mainland China).
    The following cases and related literature are shared.

    Medical record data 1.
    General medical history: ZRB5391180, male, 77 years old, 2020.
    9.
    2-9.
    7 Main complaint: recurrent episodes of unconsciousness for more than 4 months, another 1 hour present medical history: the patient was in a local foreign hospital more than 6 months ago (2020.
    2) Diagnosed "pulmonary tuberculosis", and then irregularly took "isoniazid, rifampicin, ethambutol" anti-tuberculosis treatment.

    In the evening before April (2020.
    4), there was no obvious cause for sudden sweating, unconsciousness after heart palpitations, and family members who did not respond.
    She was sent to a local hospital for a diagnosis of "hypoglycemia: insulinoma?".

    She was discharged from the hospital after her condition improved, without self-monitoring of blood glucose, sweating and palpitations after being discharged many times, and unconsciousness, can be relieved after feeding or infusion in the clinic.

    2020.
    8.
    12-8.
    17 I was hospitalized in a hospital in Huai'an.
    Insulinoma was not considered, no medication was given, and isoniazid should be avoided when discharged from the hospital.

    At 8 o'clock in the morning (2020.
    9.
    2), he was unconscious again, and his family members were sent to our hospital.
    The peripheral blood glucose was measured at 1.
    8mmol/l in the emergency department.
    After intravenous push with 50% glucose injection 60ml, the consciousness became clear.
    Proposed "hypoglycemia" is admitted to our department.

    During the course of the illness, he repeatedly coughed and coughed up white and sticky sputum, without fever, loss of appetite, and a recent weight loss of about 5kg.

    Past history, personal history and family history: deny the history of "diabetes, hypertension, cardiovascular and cerebrovascular diseases, thyroid diseases, pituitary and adrenal diseases, various operations", usually do not drink alcohol, deny other Chinese and Western medicines, health care except anti-tuberculosis drugs A history of product taking, denying a history of similar seizures in the past, and no family history.

    Physical examination: BP160/80mmHg, mental wilt, weight loss, black acanthosis sign (-), small thyroid, thick lungs with thick breath sounds, scattered dry and wet rales, heart rate 78 beats/min, flat and soft abdomen, both lower limbs No edema, normal muscle tone of the limbs, pathological signs (-).

    Auxiliary examination: CT scan + enhanced pancreas and adrenal glands (2020.
    8.
    13, Outer Hospital): There are no obvious abnormalities in the pancreas and bilateral adrenal glands; slightly larger lymph nodes in the retroperitoneum; multiple cysts in the liver and both kidneys.

    2.
    After diagnosis and treatment, after the patient was admitted to the hospital until the next morning, repeated hypoglycemia occurred, and intravenous glucose was applied many times.

    Peripheral blood glucose monitoring curve graph Intravenous application of glucose doctor's order general test items Note: The insulin and C-peptide that are accompanied by a significant increase in hypoglycemia are consistent with endogenous hyperinsulinemia.

    When hypoglycemia, ACTH and F are both above the cut point, and adrenal cortex insufficiency is ruled out.

    Glucose tolerance combined with insulin C-peptide release test-4hHLA typing Note: Chest CT of the HLA Test Center of Jiangsu Provincial People's Hospital indicates that the brightness of the two lungs has increased, scattered in round and wallless translucent shadows, and parts of the two lungs are bronchiectasis and tubes.
    Thickened walls, patchy shadows and cord shadows in both lungs, and thickened pleura of both lungs.

    3.
    Treatment and effect consideration is the possible treatment plan for insulin autoimmune syndrome caused by isoniazid.
    Advise a low-carbohydrate, high-dietary fiber, high-protein, high-fat diet, eat small and frequent meals, and give acarbose 50mg tid to delay carbohydrate absorption and inhibit Postprandial glucose and insulin increase to avoid postprandial hypoglycemia.

    Treatment effect After treatment, the patient had no episodes of hypoglycemia during hospitalization.
    After discharge, there was no hypoglycemia during the telephone follow-up and the second hospitalization (2020-9-28 to 10-3, admitted to the infectious disease department of our hospital due to fever). Part of blood glucose monitoring records during hospitalization IV.
    Discharge diagnosis of hypoglycemia: Isoniazid may cause IAS.
    The clinical thinking is based on the "Williams Endocrinology 14th Edition" and the 2009 American Endocrine Society's adult hypoglycemia evaluation and treatment guidelines.
    Insulin criteria: 1.
    Plasma glucose <55mg/dl (3.
    0mmol/l) 2.
    Insulin (ICMA) ≥ 3.
    0uU/ml (18pmol/l) 3.
    C peptide ≥ 0.
    6ng/ml (200pmol/l) 4.
    Proinsulin ≥5.
    0pmol/l.
    When the patient's blood glucose is 1.
    38mmol/l, synchronous insulin is 157.
    55pmol/l and C-peptide is 2345pmol/l, far exceeding the above cut point, and the diagnosis of endogenous hyperinsulinemic hypoglycemia is established.

    The cause of hypoglycemia is in accordance with the causes of hypoglycemia listed in the guidelines.
    This case should be considered as the disease listed in Article 5: 1.
    Insulinoma: It is a typical cause of endogenous hyperinsulinemic hypoglycemia.
    Patients with insulinoma usually It is manifested by symptoms of neurological hypoglycemia after absorption (fasting).

    The patient had no history of hypoglycemia in the past (before 4 months), negative imaging, and relief of hypoglycemia after acarbose treatment.
    The patient did not meet the clinical manifestations of insulinoma and could be ruled out.

    2.
    Non-insulinoma pancreatic hypoglycemia syndrome (NIPHS): NIPHS is characterized by neurohypoglycemia and is caused by endogenous hyperinsulinemia.
    It mostly occurs after meals and is more common in men.

    The pathological changes are diffuse proliferation of pancreatic islet cells (hypertrophy of pancreatic islets, sometimes accompanied by proliferation, and hyperchromic β-cell nuclei).

    The result of imaging location examination was negative.

    The establishment of the diagnosis depends on the positive result of the selective arterial calcium stimulation test.

    Under the guidance of calcium stimulation test results, partial pancreatectomy is expected to improve symptoms.

    The incidence of NIPHS is much lower than that of insulinoma (the incidence of insulinoma is 1/250000/year).

    Similarly, the patient had no previous history of hypoglycemia, and hypoglycemia was relieved after acarbose treatment, which did not meet the NIPHS performance and could basically be ruled out.

    3.
    Hypoglycemia after gastric bypass: the patient had no history of surgery, so it was excluded. 4.
    Insulin Autoimmune Syndrome (IAS): The patient has no history of hypoglycemia before 4 months, and after taking the drug that can induce IAS (see the figure below) isoniazid frequently develops endogenous hyperinsulinemic hypoglycemia coma after 2 months, and is discontinued Isoniazid, changes in diet, and hypoglycemia relieved after oral acarbose, which supports the diagnosis of IAS caused by isoniazid.

    Unsupported point: negative insulin antibody.

    Possible explanation: IAS is mostly self-limiting, and gradually resolves within 3-6 months after stopping the drug.

    When the patient was hospitalized in our hospital, the insulin antibody was 4.
    55% (0-5%), which was within the upper limit of the normal range.
    It is speculated that the possible cause is that the patient has stopped using isoniazid for a period of time.
    By the end of the disease, the insulin antibody titer is in our hospital.
    Decline, there is still hyperinsulinemia that has not yet recovered.

    You can refer to another case of IAS caused by clopidogrel in our department (see the figure below), which shows that the insulin antibody titer in the early stage of the disease exceeded the laboratory measurable upper limit, and the insulin reached 153397.
    16pmol/l.
    After 1 month, the insulin antibody remained positive and the insulin level decreased.
    After 5 months, the insulin antibody turned negative and the insulin level continued to decrease, but the peak value still reached 1397.
    75pmol/l, suggesting that the insulin antibody titre and insulin level gradually decreased as the condition of IAS relieved, but the rate of insulin returning to normal was slower than that of insulin.
    The antibody, that is, the hyperinsulinemia has not fully recovered when the antibody turns negative, leading to the phenomenon of endogenous hyperinsulinemic hypoglycemia with negative insulin antibodies.

    To support this case of IAS diagnosis.

    Clopidogrel, a drug that can induce IAS, causes IAS—early disease.
    Note: IAA exceeds the upper limit of laboratory measurability, and the peak value of insulin exceeds 150,000 pmol/l.

    Clopidogrel induced IAS—more than one month later.
    Note: After more than one month, IAA remained positive, and the peak insulin decreased to 17557.
    5 pmol/l.

    Clopidogrel induced IAS-after 5 months Note: After 5 months, the IAA turned negative, the peak insulin dropped to 1397.
    75 pmol/l, and intermittent hypoglycemia persisted. 5.
    Type B insulin resistance syndrome (TBIRS, type B insulin resistance syndrome): a very rare autoimmune disease that causes a wide range of abnormalities in blood glucose balance in the body, which can manifest hypoglycemia and extreme insulin resistance hyperglycemia, Caused by the presence of insulin receptor autoantibodies (IRAbs).

    It is more common in African-American women.
    The main clinical manifestations are hyperglycemia, acanthosis nigricans, autoimmune diseases, etc.
    A small number of patients will have hypoglycemia during the course of the disease.

    This case is not in compliance and is not considered.

    6.
    Insulin secretagogues: The medical history has been repeatedly asked and can be ruled out.

    7.
    Ectopic insulin secretion: Although there are convincing case reports of ectopic insulin secretion, this situation is determined to be very rare (N Engl J Med.
    1999;341:733–736.
    ).

    Spontaneous remission of hypoglycemia from this patient and treatment response were not considered.

    8.
    Exercise-induced hyperinsulinemic hypoglycemia: rare, this case does not meet the clinical manifestations, so it is not considered.

    9.
    Insulin receptor mutations: rare, the clinical manifestations of this case are not consistent, not considered.

    10.
    Isoniazid interferes with insulin clearance: There are related literature reports (PMID: 6751419), but isoniazid interferes with insulin clearance and causes hypoglycemia to manifest as hyperinsulinemic normal C-peptide, and this case manifests as hyperinsulinemic high C-peptide, which seems to be inconsistent.

    Isoniazid and hypoglycemia isoniazid can cause hypoglycemia in three ways: 1.
    IAS; 2.
    Interference with insulin metabolism; 3.
    Interference with hypoglycemic drugs (such as glimepiride DOI: 10.
    1136/bcr-2012- 008528) Metabolism.

    In this case, hypoglycemia is considered to be the possibility of IAS caused by isoniazid.

    1.
    Pathogenesis IAS is an autoimmune disease that meets the new type VII hypersensitivity reaction, defined as an immune disease caused by autoantibodies against circulating target proteins or hormones. IAS is caused by the presence of a large amount of IAA (circulating insulin autoantibodies).
    Some cases can be found in individuals with definite autoimmunity, such as T1DM patients, especially those with the disease at a younger age Of patients.

    In patients with a certain amount and affinity of IAA, the insulin concentration is low during the fasting period and the IAA is not bound.

    After food intake and blood sugar levels increase, pancreatic beta cells produce insulin, which is bound by IAA, so that insulin cannot be effective and leads to postprandial hyperglycemia.

    This situation then prompted the production of larger amounts of insulin and C-peptide in response to the hyperglycemic effect induced by IAA blockade.

    When insulin secretion exceeds the binding capacity of IAA, pancreatic insulin secretion stops, and the production of IAA-insulin complex actually forms a large amount of insulin reserves.
    When insulin is released from the complex, it causes hypoglycemia.

    Sustained high insulin levels also inhibit the counter-regulatory mechanism of glucose homeostasis, thereby making hypoglycemia last longer.

    The severity and duration of hypoglycemia and the fluctuation from a hyperglycemic state to a hypoglycemic state depend on the intrinsic dissociation rate constant (K-1), titer, and intrinsic affinity/affinity of IAA for insulin (Ka).

    Although the presence of insulin-binding antibodies is a common feature of all cases of IAS, the binding of proinsulin antibodies may be the main one, and if it cross-reacts with the assay kit, it may also be related to higher insulin levels.

    Since proinsulin has only one-tenth of the biological activity of insulin, the symptoms are usually mild in this case.

    In Japanese, most patients with IAS have polyclonal IgG autoantibodies, while in at least two non-Asian reports, the patients' IAA is a monoclonal antibody.

    Although the IgG class of IAA is the most common, there have been reports describing cases of IAS caused by IAA in the IgA and IgM classes.

    Many studies have reported that the pathophysiology in the presence of blood diseases is different from the classic mechanism of hypoglycemia proposed in IAS.

    The first case of myeloma related to IAS was described in 1972.

    Since then, another 10 cases of MGUS/myeloma-related IAS have been reported.

    In this rare case (monoclonal disease characterizing myeloma and MGUS) may be caused by the interaction of monoclonal antibodies produced by B lymphocyte clones with self-antigens.

    If monoclonal antibodies have sufficient affinity for self-antigens, it can lead to clinical syndromes.

    This seems to be due to the pathophysiological background of IAS caused by MGUS/myeloma.

    These disorders are usually characterized by the presence of high-titer/low-affinity antibodies: in this case, IAA usually has a lower affinity for insulin than the insulin receptor.

    The immune complex of IAA-insulin delays the clearance of insulin.
    Due to its weak binding constant, insulin can dissociate from IAA and bind to its receptors, thereby causing hypoglycemia.

    2.
    Genetic background Beginning in 1992, a strong association between IAS and human leukocyte antigen was observed in the Japanese population: the strongest association with HLA-DR4 (case group 48/50 cases vs control; odds ratio OR 39.
    6), and then Japanese people were found The tendency to suffer from IAS is strongly correlated with DRB1*0406 (42 out of 48 DR4 positive patients; odds ratio is 56.
    6), DRB1*0403 is 1.
    6 (5 out of 48 DR4 positive patients), the advantage is relatively low, DRB1* 0407 is 1.
    1 (1 in 48 DR4 positive patients), the advantage is relatively low.

    This association indicates that the 74th glutamine (shared by all three alleles) in the DRB1 molecule is essential for the occurrence of IAS, and the 37th serine (exclusive to DRB1*0406) greatly increases the individual Susceptibility to the disease.

    By studying the different distributions of HLA-DR4 alleles around the world, we found that its prevalence in other places is low, which also explains the high prevalence of IAS mainly in Japan.

    It has been found that HLA-DRB1*0406 is very common in East Asian patients, while Caucasian IAS patients mainly express HLA-DRB1*0403.

    Therefore, a population with a high prevalence of DRB1*0406 has a higher risk of IAS than a population with a low prevalence of this genetic marker.

    This is an example of a clear association between genetic susceptibility to class II HLA genes and the risk of certain autoimmune diseases.

    The most common condition associated with IAS in Japan is the treatment of GD with ATD, because all GD patients with IAS in Japan express DRB1*0406, while GD patients without this syndrome do not.

    Outside Japan, IAS is very rare in GD patients taking ATD, which may be due to the low frequency of DRB1*0406 in GD patients in these populations.

    Among Koreans, GD susceptibility is more related to HLA DRB1*0803 and DRB1*1602, while DRB1*0406 is only present in 9% of Korean GD patients.

    Studies confirming the strict correlation between HLA status and drug-induced susceptibility have shown that half of GD patients with IAS in South Korea carry DRB1*0406.

    In China, there are related reports that 3 GD patients had IAS during ATD.
    Two of them showed DRB1*0406; the third was a 26-year-old pregnant woman (38 years old) without HLA typing.

    According to investigations, there are no cases of IAS among GD patients taking ATD in Italy, possibly because GD in Italy is usually associated with DRB1*03(39), and cases of DRB1*0406 are very rare.

    Another clear association between drugs and genetic background is between ALA and HLA-DRB1*0406.

    In fact, the 20 Asian patients who developed IAS after taking ALA all carried HLA-DRB1*0406, while only nearly half of the white patients carried HLA-DRB1*0406, and the others were HLA-DRB1*0403.

    In this case, we performed HLA typing, which is shown as DRB1*0405, which is different from previous reports and its significance is unknown.

    Summary Although hypoglycemia caused by isoniazid is relatively rare, but given that isoniazid is a commonly used anti-tuberculosis drug, if hypoglycemia occurs in patients with tuberculosis in the clinic, we need to know when investigating other causes of hypoglycemia-hypoglycemia It is one of the possible side effects of isoniazid.

    References: [1]Censi Simona,Mian Caterina,Betterle Corrado,Insulin autoimmune syndrome: from diagnosis to clinical management.
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    Ann Transl Med, 2018, 6: 335.
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    Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline[J].
    2009,94: 709-28.
    [3]Villaume C,Dollet JM,Beck B et al.
    Hyperinsulinemia associated with normal C -peptide levels in a woman treated with isoniazide.
    [J], 1982, 36: 32-5.
    [4]Ma Wen-Ya,Won Justin GS,Tang Kam-Tsun et al.
    Severe hypoglycemic coma due to insulin autoimmune syndrome[ J].
    2005, 68: 82-6.
    [5]Boglou Panagiotis,Steiropoulos Paschalis,Papanas Nikolaos et al.
    Hypoglycaemia due to interaction of glimepiride with isoniazid in a patient with type 2 diabetes mellitus[J].
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    [6]Ovali F,Samanci N,Sevinç E et al.
    Isoniazid and hypoglycaemia in a premature infant[J].
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    The author introduces Dr.
    Zhang Qianjin, director of the Department of Endocrinology, Shuyang Hospital Affiliated to Xuzhou Medical University, associate chief physician, lecturer, and postgraduate student, Endocrinology Branch of Suqian Medical Association The deputy chairman and deputy chairman of the Suqian Medical Association Integrated Traditional Chinese and Western Medicine Branch.
    He maintains a keen interest in endocrine diseases, especially difficult, rare/rare diseases, and his personal public account is "endocrine regulators.
    "
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