Novel Insights from Clinical Practice
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
Received: December 9, 2013 Accepted: April 8, 2014 Published online: July 23, 2014
An Uncommon Cause of Hypoglycemia: Insulin Autoimmune Syndrome Senay Savas-Erdeve Sebahat Yılmaz Agladioglu Asan Onder Havva Nur Peltek Kendirci Veysel Nijat Bas Elif Sagsak Semra Cetinkaya Zehra Aycan Pediatric Endocrinology Division, Dr. Sami Ulus Training and Research Children’s Hospital, Ankara, Turkey
Established Facts • Insulin autoimmune syndrome in childhood is very rare and there is only scant information on its treatment. • A correct diagnosis is extremely important because it may spare a hypoglycemic patient from an unnecessary pancreatic surgical procedure.
Novel Insights
Key Words Hyperinsulinemic hypoglycemia · Insulin autoimmune syndrome · Insulin antibody
Abstract Background: Insulin autoimmune syndrome (IAS) is a condition characterized by hypoglycemia associated with the presence of autoantibodies to insulin in patients who have not been injected with insulin. Case Report: A female patient (aged 16 years and 3 months) presented with the complaint of being overweight. Physical examination revealed a body
© 2014 S. Karger AG, Basel 1663–2818/14/0824–0278$39.50/0 E-Mail [email protected] www.karger.com/hrp
weight of 78.2 kg (+2.6 SD) and a height of 167 cm (+0.73 SD). While the patient’s fasting blood glucose level was found to be 40 mg/dl, blood ketone was negative and the serum insulin level was determined as 379 mIU/ml. The patient was diagnosed with hyperinsulinemic hypoglycemia. Abdominal ultrasound, pancreas MRI and endoscopic ultrasound were normal. The daily blood glucose profile revealed postprandial hyperglycemia and reactive hypoglycemia in addition to fasting hypoglycemia. The results of anti-insulin antibody measurements were as high as 41.8% (normal range 0–7%). A 1,600-calorie diet containing 40% carbohydrate and divided into 6 meals a day was given to the patient. Sim-
Senay Savas-Erdeve 2432. Cad. Ağaçseven Sok. 312 Ulusoy Evleri. B Blok. No. 46 TR–06830 Çayyolu, Ankara (Turkey) E-Mail senaysavas @ yahoo.com
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 10:43:03 AM
• We present the case of a patient whose hypoglycemia could be controlled by a low-carbohydrate diet and discuss the diagnostic and therapeutic approaches.
© 2014 S. Karger AG, Basel
Introduction
Insulin autoimmune syndrome (IAS) is a rare condition characterized by hyperinsulinemic hypoglycemia associated with high titers of antibody to endogenous insulin, in the absence of pathological abnormalities of the pancreatic islets and prior exposure to exogenous insulin [1]. The syndrome was first described by Hirata in 1970 [2]. In Japan, IAS is the third leading cause of severe hypoglycemia after insulinoma and extrapancreatic neoplasms. In IAS, the insulin levels are markedly elevated, usually above 100 mIU/ml, free insulin levels are normal or high, C-peptide levels are markedly elevated and insulin antibodies show a high percentage of binding to insulin. A diagnosis of IAS can be made by measuring the anti-insulin antibodies, which are typically elevated. The disease is extremely uncommon in Western countries. IAS affects men and women equally and is seen more frequently in patients older than 40 years of age. Reported cases of IAS in childhood and adolescence are extremely rare [1, 3]. Herein, we present a case of IAS diagnosed in adolescence and we discuss the case along with a survey of the medical literature.
Case Report A female patient (aged 16 years and 3 months) presented with the complaint of being overweight over the last 2 years. Her physical examination revealed a body weight of 78.2 kg (+2.6 SD), a height of 167 cm (+0.73 SD) and a body mass index of 27.9 (+1.96 SD score); acanthosis nigricans was not present, and the stage of puberty was consistent with Tanner stage 5. She had no history of chronic disease or medication use. Her family history revealed type 2 diabetes mellitus in her father and uncle that was controlled only by diabetic diet. The results of laboratory examinations consisting of complete blood count, liver and kidney function tests, thyroid function tests and lipid profile were found to be within normal limits. While her fasting blood glucose level was found to be 44 mg/dl, the fasting insulin level (ADVIA Centaur Insulin Assay; direct chemiluminescent technology) was 69 mIU/ml and the repeat fasting blood glucose level was 40 mg/dl, while blood ketone was negative, insulin level was determined as 379 mIU/ml and C-peptide level (Immulite 2000 C-peptide; solid-phase, two-
Insulin Autoimmune Syndrome
site chemiluminescent immunometric assay) was determined as 5.1 ng/ml (normal range 0.9–4). Based on these findings, the patient was diagnosed with hyperinsulinemic hypoglycemia. Abdominal ultrasonography and pancreas MRI scans for insulinoma, which is common in the differential diagnosis of hyperinsulinemic hypoglycemia, revealed normal results. The endoscopic ultrasound performed in the department of gastroenterological surgery did not reveal any abnormal finding. No insulinoma could be localized. When the daily profile of blood glucose levels of the patient was obtained and continuous glucose monitoring was performed, in addition to fasting hypoglycemia, postprandial hyperglycemic values as well as reactive hypoglycemia were observed. Hunger was the only manifestation during the hypoglycemic period; namely, the hypoglycemic episodes were in the form of a mildly symptomatic hypoglycemia. The glycemic profile revealed by continuous glucose monitoring led to the measurement of insulin autoantibodies for diagnosis. The serum anti-insulin antibody level (DIAsource ImmunoAssays S.A.; radioimmunoassay) was 41.8% (normal range 0–7%). The measurements of serum insulin, anti-insulin antibody and C-peptide levels performed simultaneously with the measurements of blood glucose levels are shown in table 1. The patient underwent an extended oral glucose tolerance test. The alterations in the blood glucose, insulin and C-peptide levels are given in figure 1. During the oral glucose tolerance test, at 0 min, the blood glucose level was determined as 66 mg/dl, the insulin level was 54 mIU/ml and the Cpeptide level was 9.44 ng/ml; at the 120th minute, these values were 270 mg/dl, 54 mIU/ml and 16.2 ng/ml, respectively, and during the hypoglycemic episode that developed at the 300th minute, the blood glucose level was 46 mg/dl, insulin level was 104 mIU/ ml and C-peptide level was 14.2 ng/ml. In spite of postprandial hyperglycemic values, serum levels of HbA1c were found to be 5.3%. The elevated levels of insulin persisted during the hypoglycemic episode that developed at the 300th minute. According to these findings, the patient was diagnosed with IAS. The attempt of diazoxide treatment was unsuccessful in preventing hypoglycemic episodes. A 1,600-calorie diet including 40% carbohydrate divided into 6 meals a day was given to the patient. Simple sugars were excluded from the diet. Hypoglycemic episodes were not observed as long as the patient complied with the low and frequent carbohydrate intake; however, mildly symptomatic hypoglycemia occurred in the case of noncompliance with the diet. In the inquiry into the etiology of IAS, there was no history of medication use, and in the assessments for hematological and rheumatic diseases, complete blood count and biochemical parameters were within normal limits, antinuclear antibody was positive, anti-double-stranded DNA and rheumatoid factor were negative, and the levels of C3 and C4 and immunoglobulins G, A and M, perinuclear antineutrophil cytoplasmic antibody and cytoplasmic antineutrophil cytoplasmic antibody were normal. Although anti-nuclear antibody (ANA) was positive, the patient did not reveal any clinical sign of collagen vascular diseases. The results of kidney function tests and C3/C4 levels were normal. It was planned to observe the patient in terms of ANA positivity. In the second year of observation, at the patient’s last follow-up visit, when her calendar age was 18 years and 3 months, she was 78 kg in weight and did not show any increase in body weight; the fasting glucose level was 53 mg/dl, fasting insulin level was 300 mIU/ml, C-peptide level was 6.6 ng/ml, anti-insulin antibody was found to be 52.6% and HbA1c was determined as 5.3%.
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
279
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 10:43:03 AM
ple sugars were excluded from the diet. Hypoglycemic episodes were not observed, but during 2 years of observation, serum levels of insulin and anti-insulin antibodies remained elevated. Conclusion: In all hyperinsulinemic hypoglycemia cases, IAS should be considered in the differential diagnosis and insulin antibody measurements should be carried out.
Color version available online
300 270 240
Plasma glucose
210 180 150 120
Total insulin
90 60
C-peptide
30 0
Fig. 1. Glucose (mg/dl), total insulin (mIU/
0
30
60
90
120
150
180
210
240
270
300
Time (min)
ml) and C-peptide (ng/ml) responses to 75 g of oral glucose.
Table 1. Plasma glucose, insulin and anti-insulin antibody levels measured sequentially in our patient
Day
Plasma glucose, mg/dl Insulin, mIU/ml AIA, %
20
21
23
24
26
27
28
29
30
43 >300 41.8
45 334 44.94
46 361 41.8
51 >300 40.5
58 334 39.89
65 380 47.89
70 379 57.84
237 >300 57
208 379 43.77
Discussion
Hypoglycemia can be classified as an insulin-mediated or a non-insulin-mediated condition. The most common cause of hyperinsulinemic hypoglycemia is insulinoma. Insulinoma should be kept in mind in the presence of fasting hypoglycemia in otherwise healthy patients. It may rarely present with postprandial hypoglycemia. A fasting test is the main diagnostic test in this condition [4]. We considered insulinoma in the differential diagnosis of our patient. Abdominal ultrasonography, pancreas MRI and endoscopic pancreas ultrasonography were all normal. While we were planning further invasive diagnostic tests, continuous glucose monitoring demonstrated fasting hypoglycemia, postprandial hyperglycemia and reactive hypoglycemia, which led us to consider autoimmune hypoglycemia. There are two types of autoimmune hypoglycemia, namely IAS and type B insulin resistance. In the first form, antibodies are directed against endogenous insulin, and in the second form antibodies are directed against the cell surface insulin receptor. Both 280
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
conditions may be associated with inappropriately elevated insulin, and both conditions may also be associated with postprandial hypoglycemia, fasting hypoglycemia or both. The autoimmune forms of hypoglycemia are frequently seen in association with hematologic and rheumatologic diseases, or they may be medication induced. Making the correct diagnosis might change therapeutic choices and avoid needless pancreatic surgical procedures, to be reserved for nonautoimmune causes of hyperinsulinemic hypoglycemia [3]. IAS is characterized by episodes of hyperinsulinemic hypoglycemia that occur most often postprandially, although fasting hypoglycemia and hypoglycemia exacerbated by exercise have been reported. Paradoxically, hyperglycemia may occur immediately following a meal or oral glucose challenge. Of the cases with data reported, 19 patients (42%) had reactive hypoglycemia and 14 patients (31%) had fasting hypoglycemia. In 11 patients (24%), the episodes of hypoglycemia occurred in both postprandial and fasting states [3]. In our case, continuous glucose monitoring was performed, and in addition to fasting hySavas-Erdeve et al.
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 10:43:03 AM
AIA = Anti-insulin antibody (normal range 0–7%).
matoid factor and had an abnormal blood count, urine and serum protein electrophoresis and bone marrow examination [2, 7]. Our patient has no history of medication use and no evidence was found other than ANA positivity in the screening for hematological and rheumatic diseases. Nevertheless, the patient did not reveal any clinical sign, and it was planned to observe the patient for the development of a rheumatic disease; however, the patient did not develop any additional sign during the 2 years of follow-up. In the majority of IAS patients, since the condition develops in the context of a coexisting autoimmune disease rather than a precipitating medication, hypoglycemia was transient and spontaneously resolved without causing any permanent sequelae in these patients. Uchigata et al. [7] reported a spontaneous remission of the disease within 3–6 months in 82% of the patients in Japan. It was reported that while the symptoms resolved in a couple of weeks or months, the antibodies persisted over a few years. A variety of treatments have been tried in patients with severe and prolonged symptoms and in case the likelihood of a spontaneous recovery is low. Frequent, small meals or the reduction of all or fast-absorbing carbohydrates have been used to prevent the rapid elevation of blood glucose level. Glycosidase inhibitors have been used before meals, and steroids and plasmapheresis have been tried to lower serum autoantibody titers in certain cases. While 4 patients underwent pancreatic surgery for a suspect insulinoma, another patient underwent a subtotal pancreatectomy as a consequence of resistant hypoglycemia. Meals containing reduced amounts of carbohydrate and steroid therapy were reported as the most effective treatments in the medical literature [3, 5]. Owing to the mildly symptomatic hypoglycemic episodes, we treated our patient with a low-carbohydrate diet and we observed a substantial resolution of hypoglycemia and hyperglycemia on the follow-up tests. However, neither spontaneous recovery nor a reduction in the anti-insulin antibody titers was observed during the 2-year follow-up period. IAS should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia, and insulin antibody measurements should be carried out in all cases of hyperinsulinemic hypoglycemia. Cases diagnosed with IAS in childhood are particularly rare. Making the correct diagnosis might change therapeutic choices and avoid needless pancreatic surgical procedures, to be reserved for nonautoimmune causes of hyperinsulinemic hypoglycemia. Long-term follow-up of these patients will be crucial to define the clinical course of the disease.
Insulin Autoimmune Syndrome
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
281
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poglycemia, postprandial hyperglycemic values as well as reactive hypoglycemia were observed. The glycemic profile obtained by continuous glucose monitoring led us to measure insulin autoantibodies for diagnosis. The serum anti-insulin antibody level was 41.8% (normal range 0–7%). The hypoglycemic episodes in IAS appear to be caused by the binding and release of insulin from the antibodies, which occur out of synchrony with the prevailing glucose concentration. After a meal or oral glucose load, patients often demonstrate initial hyperglycemia, followed by hypoglycemia a few hours later. The hyperglycemia is caused by the anti-insulin antibodies that bind the insulin secreted in response to rising blood glucose levels after a meal. This binding reduces the availability of the secreted insulin to the receptors in the liver and peripheral tissues, resulting in hyperglycemia and further insulin secretion. As the blood glucose concentration begins to decrease and insulin secretion declines, the insulin bound to the antibodies is released, resulting in inappropriately high free insulin concentrations for the blood glucose, causing hypoglycemia [5]. In our patient, the diabetic value obtained at the 120th minute of the extended oral glucose tolerance test and hypoglycemia at the 300th minute related to the freed insulin as a consequence of the decreased level of blood glucose were found to be consistent with the antibody-binding kinetics in IAS. Dozio et al. [6] investigated the mechanism of hypoglycemia by using 125I-labeled insulin scintigraphic scanning in an IAS patient. After an intravenous injection of 125I-labeled insulin, the patient demonstrated persistent labeled insulin activity in the blood and absence of uptake of the labeled hormone in the liver or kidneys. After treatment with prednisone and plasmapheresis, insulin autoantibody levels decreased and the clearance of 125I-labeled insulin from the blood pool increased. Most patients diagnosed with IAS had associated comorbidities or exposure to various medications containing the sulfhydryl group. In about 47% of the non-Asian patients, IAS seemed to be triggered by exposure to different medications (captopril, penicillamine, pyritinol, carbimazole, imipenem, propylthiouracil, hydralazine, procainamide, isoniazid, penicillin G). In non-Asian patients, this syndrome is often associated with rheumatologic diseases such as systemic lupus erythematosus or rheumatoid arthritis. Some of the patients who developed anti-insulin antibodies had an underlying hematologic disease, ranging from benign monoclonal gammopathy to multiple myeloma. Many patients had positive antinuclear antibodies, anti-double-stranded DNA and rheu-
References
282
4 Vaidakis D, Karoubalis J, Pappa T, Piaditis G, Zografos GN: Pancreatic insulinoma: current issues and trends. Hepatobiliary Pancreat Dis Int 2010;9:234–241. 5 Redmon JB, Nuttall FQ: Autoimmune hypoglycemia. Endocrinol Metab Clin North Am 1999;28:603–618.
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
6 Dozio N, Scavini M, Beretta A, Sarugeri E, Sartori S, Belloni C, Dosio F, Savi A, Fazio F, Sodoyez JC, Pozza G: Imaging of the buffering effect of insulin antibodies in the autoimmune hypoglycemic syndrome. J Clin Endocrinol Metab 1998;83:643–648. 7 Uchigata Y, Eguchi Y, Takayama-Hasumi S, Omori Y: Insulin autoimmune syndrome (Hirata disease): clinical features and epidemiology in Japan. Diabetes Res Clin Pract 1994;22:89–94.
Savas-Erdeve et al.
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 10:43:03 AM
1 Basu A, Service FJ, Yu L, Heser D, Ferries LM, Eisenbarth G: Insulin autoimmunity and hypoglycemia in seven white patients. Endocr Pract 2005;11:97–103. 2 Uchigata Y, Hirata Y: Insulin autoimmune syndrome (IAS, Hirata disease). Ann Med Interne (Paris) 1999;150:245–253. 3 Lupsa BC, Chong AY, Cochran EK, Soos MA, Semple RK, Gorden P: Autoimmune forms of hypoglycemia. Medicine 2009;88:141–153.
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
Received: December 9, 2013 Accepted: April 8, 2014 Published online: July 23, 2014
An Uncommon Cause of Hypoglycemia: Insulin Autoimmune Syndrome Senay Savas-Erdeve Sebahat Yılmaz Agladioglu Asan Onder Havva Nur Peltek Kendirci Veysel Nijat Bas Elif Sagsak Semra Cetinkaya Zehra Aycan Pediatric Endocrinology Division, Dr. Sami Ulus Training and Research Children’s Hospital, Ankara, Turkey
Established Facts • Insulin autoimmune syndrome in childhood is very rare and there is only scant information on its treatment. • A correct diagnosis is extremely important because it may spare a hypoglycemic patient from an unnecessary pancreatic surgical procedure.
Novel Insights
Key Words Hyperinsulinemic hypoglycemia · Insulin autoimmune syndrome · Insulin antibody
Abstract Background: Insulin autoimmune syndrome (IAS) is a condition characterized by hypoglycemia associated with the presence of autoantibodies to insulin in patients who have not been injected with insulin. Case Report: A female patient (aged 16 years and 3 months) presented with the complaint of being overweight. Physical examination revealed a body
© 2014 S. Karger AG, Basel 1663–2818/14/0824–0278$39.50/0 E-Mail [email protected] www.karger.com/hrp
weight of 78.2 kg (+2.6 SD) and a height of 167 cm (+0.73 SD). While the patient’s fasting blood glucose level was found to be 40 mg/dl, blood ketone was negative and the serum insulin level was determined as 379 mIU/ml. The patient was diagnosed with hyperinsulinemic hypoglycemia. Abdominal ultrasound, pancreas MRI and endoscopic ultrasound were normal. The daily blood glucose profile revealed postprandial hyperglycemia and reactive hypoglycemia in addition to fasting hypoglycemia. The results of anti-insulin antibody measurements were as high as 41.8% (normal range 0–7%). A 1,600-calorie diet containing 40% carbohydrate and divided into 6 meals a day was given to the patient. Sim-
Senay Savas-Erdeve 2432. Cad. Ağaçseven Sok. 312 Ulusoy Evleri. B Blok. No. 46 TR–06830 Çayyolu, Ankara (Turkey) E-Mail senaysavas @ yahoo.com
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 10:43:03 AM
• We present the case of a patient whose hypoglycemia could be controlled by a low-carbohydrate diet and discuss the diagnostic and therapeutic approaches.
© 2014 S. Karger AG, Basel
Introduction
Insulin autoimmune syndrome (IAS) is a rare condition characterized by hyperinsulinemic hypoglycemia associated with high titers of antibody to endogenous insulin, in the absence of pathological abnormalities of the pancreatic islets and prior exposure to exogenous insulin [1]. The syndrome was first described by Hirata in 1970 [2]. In Japan, IAS is the third leading cause of severe hypoglycemia after insulinoma and extrapancreatic neoplasms. In IAS, the insulin levels are markedly elevated, usually above 100 mIU/ml, free insulin levels are normal or high, C-peptide levels are markedly elevated and insulin antibodies show a high percentage of binding to insulin. A diagnosis of IAS can be made by measuring the anti-insulin antibodies, which are typically elevated. The disease is extremely uncommon in Western countries. IAS affects men and women equally and is seen more frequently in patients older than 40 years of age. Reported cases of IAS in childhood and adolescence are extremely rare [1, 3]. Herein, we present a case of IAS diagnosed in adolescence and we discuss the case along with a survey of the medical literature.
Case Report A female patient (aged 16 years and 3 months) presented with the complaint of being overweight over the last 2 years. Her physical examination revealed a body weight of 78.2 kg (+2.6 SD), a height of 167 cm (+0.73 SD) and a body mass index of 27.9 (+1.96 SD score); acanthosis nigricans was not present, and the stage of puberty was consistent with Tanner stage 5. She had no history of chronic disease or medication use. Her family history revealed type 2 diabetes mellitus in her father and uncle that was controlled only by diabetic diet. The results of laboratory examinations consisting of complete blood count, liver and kidney function tests, thyroid function tests and lipid profile were found to be within normal limits. While her fasting blood glucose level was found to be 44 mg/dl, the fasting insulin level (ADVIA Centaur Insulin Assay; direct chemiluminescent technology) was 69 mIU/ml and the repeat fasting blood glucose level was 40 mg/dl, while blood ketone was negative, insulin level was determined as 379 mIU/ml and C-peptide level (Immulite 2000 C-peptide; solid-phase, two-
Insulin Autoimmune Syndrome
site chemiluminescent immunometric assay) was determined as 5.1 ng/ml (normal range 0.9–4). Based on these findings, the patient was diagnosed with hyperinsulinemic hypoglycemia. Abdominal ultrasonography and pancreas MRI scans for insulinoma, which is common in the differential diagnosis of hyperinsulinemic hypoglycemia, revealed normal results. The endoscopic ultrasound performed in the department of gastroenterological surgery did not reveal any abnormal finding. No insulinoma could be localized. When the daily profile of blood glucose levels of the patient was obtained and continuous glucose monitoring was performed, in addition to fasting hypoglycemia, postprandial hyperglycemic values as well as reactive hypoglycemia were observed. Hunger was the only manifestation during the hypoglycemic period; namely, the hypoglycemic episodes were in the form of a mildly symptomatic hypoglycemia. The glycemic profile revealed by continuous glucose monitoring led to the measurement of insulin autoantibodies for diagnosis. The serum anti-insulin antibody level (DIAsource ImmunoAssays S.A.; radioimmunoassay) was 41.8% (normal range 0–7%). The measurements of serum insulin, anti-insulin antibody and C-peptide levels performed simultaneously with the measurements of blood glucose levels are shown in table 1. The patient underwent an extended oral glucose tolerance test. The alterations in the blood glucose, insulin and C-peptide levels are given in figure 1. During the oral glucose tolerance test, at 0 min, the blood glucose level was determined as 66 mg/dl, the insulin level was 54 mIU/ml and the Cpeptide level was 9.44 ng/ml; at the 120th minute, these values were 270 mg/dl, 54 mIU/ml and 16.2 ng/ml, respectively, and during the hypoglycemic episode that developed at the 300th minute, the blood glucose level was 46 mg/dl, insulin level was 104 mIU/ ml and C-peptide level was 14.2 ng/ml. In spite of postprandial hyperglycemic values, serum levels of HbA1c were found to be 5.3%. The elevated levels of insulin persisted during the hypoglycemic episode that developed at the 300th minute. According to these findings, the patient was diagnosed with IAS. The attempt of diazoxide treatment was unsuccessful in preventing hypoglycemic episodes. A 1,600-calorie diet including 40% carbohydrate divided into 6 meals a day was given to the patient. Simple sugars were excluded from the diet. Hypoglycemic episodes were not observed as long as the patient complied with the low and frequent carbohydrate intake; however, mildly symptomatic hypoglycemia occurred in the case of noncompliance with the diet. In the inquiry into the etiology of IAS, there was no history of medication use, and in the assessments for hematological and rheumatic diseases, complete blood count and biochemical parameters were within normal limits, antinuclear antibody was positive, anti-double-stranded DNA and rheumatoid factor were negative, and the levels of C3 and C4 and immunoglobulins G, A and M, perinuclear antineutrophil cytoplasmic antibody and cytoplasmic antineutrophil cytoplasmic antibody were normal. Although anti-nuclear antibody (ANA) was positive, the patient did not reveal any clinical sign of collagen vascular diseases. The results of kidney function tests and C3/C4 levels were normal. It was planned to observe the patient in terms of ANA positivity. In the second year of observation, at the patient’s last follow-up visit, when her calendar age was 18 years and 3 months, she was 78 kg in weight and did not show any increase in body weight; the fasting glucose level was 53 mg/dl, fasting insulin level was 300 mIU/ml, C-peptide level was 6.6 ng/ml, anti-insulin antibody was found to be 52.6% and HbA1c was determined as 5.3%.
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
279
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 10:43:03 AM
ple sugars were excluded from the diet. Hypoglycemic episodes were not observed, but during 2 years of observation, serum levels of insulin and anti-insulin antibodies remained elevated. Conclusion: In all hyperinsulinemic hypoglycemia cases, IAS should be considered in the differential diagnosis and insulin antibody measurements should be carried out.
Color version available online
300 270 240
Plasma glucose
210 180 150 120
Total insulin
90 60
C-peptide
30 0
Fig. 1. Glucose (mg/dl), total insulin (mIU/
0
30
60
90
120
150
180
210
240
270
300
Time (min)
ml) and C-peptide (ng/ml) responses to 75 g of oral glucose.
Table 1. Plasma glucose, insulin and anti-insulin antibody levels measured sequentially in our patient
Day
Plasma glucose, mg/dl Insulin, mIU/ml AIA, %
20
21
23
24
26
27
28
29
30
43 >300 41.8
45 334 44.94
46 361 41.8
51 >300 40.5
58 334 39.89
65 380 47.89
70 379 57.84
237 >300 57
208 379 43.77
Discussion
Hypoglycemia can be classified as an insulin-mediated or a non-insulin-mediated condition. The most common cause of hyperinsulinemic hypoglycemia is insulinoma. Insulinoma should be kept in mind in the presence of fasting hypoglycemia in otherwise healthy patients. It may rarely present with postprandial hypoglycemia. A fasting test is the main diagnostic test in this condition [4]. We considered insulinoma in the differential diagnosis of our patient. Abdominal ultrasonography, pancreas MRI and endoscopic pancreas ultrasonography were all normal. While we were planning further invasive diagnostic tests, continuous glucose monitoring demonstrated fasting hypoglycemia, postprandial hyperglycemia and reactive hypoglycemia, which led us to consider autoimmune hypoglycemia. There are two types of autoimmune hypoglycemia, namely IAS and type B insulin resistance. In the first form, antibodies are directed against endogenous insulin, and in the second form antibodies are directed against the cell surface insulin receptor. Both 280
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
conditions may be associated with inappropriately elevated insulin, and both conditions may also be associated with postprandial hypoglycemia, fasting hypoglycemia or both. The autoimmune forms of hypoglycemia are frequently seen in association with hematologic and rheumatologic diseases, or they may be medication induced. Making the correct diagnosis might change therapeutic choices and avoid needless pancreatic surgical procedures, to be reserved for nonautoimmune causes of hyperinsulinemic hypoglycemia [3]. IAS is characterized by episodes of hyperinsulinemic hypoglycemia that occur most often postprandially, although fasting hypoglycemia and hypoglycemia exacerbated by exercise have been reported. Paradoxically, hyperglycemia may occur immediately following a meal or oral glucose challenge. Of the cases with data reported, 19 patients (42%) had reactive hypoglycemia and 14 patients (31%) had fasting hypoglycemia. In 11 patients (24%), the episodes of hypoglycemia occurred in both postprandial and fasting states [3]. In our case, continuous glucose monitoring was performed, and in addition to fasting hySavas-Erdeve et al.
Downloaded by: Selçuk Universitesi 193.255.248.150 - 12/24/2014 10:43:03 AM
AIA = Anti-insulin antibody (normal range 0–7%).
matoid factor and had an abnormal blood count, urine and serum protein electrophoresis and bone marrow examination [2, 7]. Our patient has no history of medication use and no evidence was found other than ANA positivity in the screening for hematological and rheumatic diseases. Nevertheless, the patient did not reveal any clinical sign, and it was planned to observe the patient for the development of a rheumatic disease; however, the patient did not develop any additional sign during the 2 years of follow-up. In the majority of IAS patients, since the condition develops in the context of a coexisting autoimmune disease rather than a precipitating medication, hypoglycemia was transient and spontaneously resolved without causing any permanent sequelae in these patients. Uchigata et al. [7] reported a spontaneous remission of the disease within 3–6 months in 82% of the patients in Japan. It was reported that while the symptoms resolved in a couple of weeks or months, the antibodies persisted over a few years. A variety of treatments have been tried in patients with severe and prolonged symptoms and in case the likelihood of a spontaneous recovery is low. Frequent, small meals or the reduction of all or fast-absorbing carbohydrates have been used to prevent the rapid elevation of blood glucose level. Glycosidase inhibitors have been used before meals, and steroids and plasmapheresis have been tried to lower serum autoantibody titers in certain cases. While 4 patients underwent pancreatic surgery for a suspect insulinoma, another patient underwent a subtotal pancreatectomy as a consequence of resistant hypoglycemia. Meals containing reduced amounts of carbohydrate and steroid therapy were reported as the most effective treatments in the medical literature [3, 5]. Owing to the mildly symptomatic hypoglycemic episodes, we treated our patient with a low-carbohydrate diet and we observed a substantial resolution of hypoglycemia and hyperglycemia on the follow-up tests. However, neither spontaneous recovery nor a reduction in the anti-insulin antibody titers was observed during the 2-year follow-up period. IAS should be considered in the differential diagnosis of hyperinsulinemic hypoglycemia, and insulin antibody measurements should be carried out in all cases of hyperinsulinemic hypoglycemia. Cases diagnosed with IAS in childhood are particularly rare. Making the correct diagnosis might change therapeutic choices and avoid needless pancreatic surgical procedures, to be reserved for nonautoimmune causes of hyperinsulinemic hypoglycemia. Long-term follow-up of these patients will be crucial to define the clinical course of the disease.
Insulin Autoimmune Syndrome
Horm Res Paediatr 2014;82:278–282 DOI: 10.1159/000362758
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poglycemia, postprandial hyperglycemic values as well as reactive hypoglycemia were observed. The glycemic profile obtained by continuous glucose monitoring led us to measure insulin autoantibodies for diagnosis. The serum anti-insulin antibody level was 41.8% (normal range 0–7%). The hypoglycemic episodes in IAS appear to be caused by the binding and release of insulin from the antibodies, which occur out of synchrony with the prevailing glucose concentration. After a meal or oral glucose load, patients often demonstrate initial hyperglycemia, followed by hypoglycemia a few hours later. The hyperglycemia is caused by the anti-insulin antibodies that bind the insulin secreted in response to rising blood glucose levels after a meal. This binding reduces the availability of the secreted insulin to the receptors in the liver and peripheral tissues, resulting in hyperglycemia and further insulin secretion. As the blood glucose concentration begins to decrease and insulin secretion declines, the insulin bound to the antibodies is released, resulting in inappropriately high free insulin concentrations for the blood glucose, causing hypoglycemia [5]. In our patient, the diabetic value obtained at the 120th minute of the extended oral glucose tolerance test and hypoglycemia at the 300th minute related to the freed insulin as a consequence of the decreased level of blood glucose were found to be consistent with the antibody-binding kinetics in IAS. Dozio et al. [6] investigated the mechanism of hypoglycemia by using 125I-labeled insulin scintigraphic scanning in an IAS patient. After an intravenous injection of 125I-labeled insulin, the patient demonstrated persistent labeled insulin activity in the blood and absence of uptake of the labeled hormone in the liver or kidneys. After treatment with prednisone and plasmapheresis, insulin autoantibody levels decreased and the clearance of 125I-labeled insulin from the blood pool increased. Most patients diagnosed with IAS had associated comorbidities or exposure to various medications containing the sulfhydryl group. In about 47% of the non-Asian patients, IAS seemed to be triggered by exposure to different medications (captopril, penicillamine, pyritinol, carbimazole, imipenem, propylthiouracil, hydralazine, procainamide, isoniazid, penicillin G). In non-Asian patients, this syndrome is often associated with rheumatologic diseases such as systemic lupus erythematosus or rheumatoid arthritis. Some of the patients who developed anti-insulin antibodies had an underlying hematologic disease, ranging from benign monoclonal gammopathy to multiple myeloma. Many patients had positive antinuclear antibodies, anti-double-stranded DNA and rheu-
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