https://imcjms.com/public Ibrahim Medical College Journal of Medical Science https://imcjms.com/public/registration/journal_full_text/312 Thu, 24 Jan 2019 12:09:35 +0000 Abstract Spontaneous hypoglycemia is an important entity that may affect multiple organs. The differential diagnosis is broad in individuals with hypoglycemia in the absence of diabetes mellitus. Multiple etiologies may be present concurrently. Drugs, critical illnesses, hormone deficiencies, and non-islet cell tumors should be considered in those who are ill or taking medications. In apparently healthy individuals, endogenous hyperinsulinism due to insulinoma, functional β-cell disorders, or insulin autoimmune conditions are possible, as are accidental, surreptitious or factitious causes of hypoglycemia. Investigations should be guided by clinical scenario. Irrespective of the exact cause of the spontaneous hypoglycemia, treatment consists of correcting the glycemic state and preventing recurrence by alleviating underlying pathology. This review discusses the causes, diagnosis and management of spontaneous hypoglycemia. IMC J Med Sci 2019; 13(1): 001. EPub date: 24 January 2019. DOI: https://doi.org/10.3329/imcjms.v13i1.42048 Address for Correspondence: Dr. Sultana Marufa Shefin, Assistant Professor, Department of Endocrinology, BIRDEM General Hospital, 122 Kazi Nazrul Islam, Shahbag, Dhaka, Bangladesh. Email: shefin_neon@yahoo.com   Introduction In our day to day clinical practice, hypoglycemia is a common clinical problem in patients with diabetes mellitus (DM) using insulin or insulin secretagogues for maintaining the recommended glycemic status [1]. The diagnosis and treatment of a hypoglycemic event in a diabetic case, having medication to lower plasma glucose level are therefore simple. However, hypoglycemia occurring spontaneously in a person without diabetes, a condition referred to as a ‘spontaneous hypoglycemia’ is a puzzling clinical problem and needs its understanding both by the endocrinologist and physicians of all disciplines. Glucose homeostasis in the human body is under strict and continuous regulation of multiple hormones, the delicate balance of which maintains plasma glucose concentrations within the normal range to ensure sufficient nutritional support to organs. Spontaneous hypoglycemia is therefore, an important entity that may affect multiple organs in the body with a wide spectrum of clinical manifestations with significant morbidity in the affected individual [2]. In response to a falling blood glucose level, our body sets up an adaptive response that consists of rapid decline of endogenous insulin secretion, augmented glucagon secretion and sympathetic over-activity. This response is further enhanced with increased secretion of growth hormone and cortisol. When these adaptive physiological mechanisms fail, hypoglycemia becomes evident. Hence, spontaneous hypoglycemia merits a critical consideration in non-diabetic subjects [3,4,5]. The metabolic homeostasis of glucose in the body depends on several glucoregulatory organs such as pancreas, liver, adrenal glands, kidneys, pituitary gland, and the hypothalamus. It is also under the strict control of multiple hormones namely insulin, glucagon, catecholamines, cortisol, and growth hormone [6]. Hence, spontaneous hypoglycemia is unlikely without significant derangements of these systems [2]. Hypoglycemia may develops when the glucose utilization from blood by brain, red blood cells, renal medullae and insulin sensitive tissues, such as muscles exceeds glucose delivery into circulation from dietary carbohydrates and glucose produced from liver and kidneys [6,7]. Under physiological condition, glucose production is high when in need. Hypoglycemia may occur when this capacity falls absolutely or relatively below glucose utilization. In profound hypoglycemia, assays reveal derangement of plasma insulin, C-peptide and pro-insulin levels [6-8]. Therefore, recent progress in identifying etiology, diagnosis and management of spontaneous hypoglycemia is discussed in this review.   Evaluation, etiology and diagnosis of hypoglycemia The diagnostic process starts by the recognition of hypoglycemia as a cause of the presenting symptoms such as confusion, altered level of consciousness, seizure or any of the other autonomic and neuroglycopenic symptoms as mentioned in Table-1 [5, 9]. Diagnosis is difficult because the symptoms are not exclusive for hypoglycemia. Confirmation is done by documenting Whipple's triad [10,11]. The triad consists of (i) symptoms or signs consistent with hypoglycemia [Table 1], (ii) a plasma glucose level less than 55 mg/dl (3.1mmol/L) in venous blood sample and (ii) resolution of symptoms after raising plasma glucose level [11]. After documenting Whipple's triad, the two key elements in the management of non-diabetic subjects with hypoglycemia are: (a) identification of the hypoglycemic etiopathology, and (b) management of the low blood glucose level [8].   Table-1: Symptoms of hypoglycemia [9].     Symptoms that arise first are the autonomic symptoms, mediated by the adrenergic and cholinergic axes of the sympathetic nervous system. Adrenergic symptoms consist of palpitations, tremor, and anxiety and are mediated by an up-regulation of norepinephrine and epinephrine. Cholinergic symptoms include hunger, sweating, and paresthesia and are derived from the acetylcholine released by postganglionic sympathetic neurons. These responses are part of the physiological counter regulatory mechanism, directed against a decrease in plasma glucose level [3,11]. Although, the sympathetic response generates the first type of symptoms, it is not the first counter regulatory mechanism against hypoglycemia. The first physiological response to a decreasing plasma glucose level is a down-regulation of insulin secretion, followed by a second defense of heightened glucagon secretion when blood glucose level falls below 70 mg/dl (3.9 mmol/L). Only when these fail to halt the decreasing plasma glucose, a sympathetic response becomes apparent when blood glucose level falls below 60 mg/dl (3.3mmol/L) [4,12]. The second type of symptoms is the neuroglycopenic symptoms. These symptoms arise due to central nervous system glucose deprivation when blood glucose level falls below 50 mg/dl (2.8 mmol/L). Neuroglycopenic symptoms range from confusion to amnesia, blurred vision, diplopia, dysarthria, seizure and if sufficient, profound loss of consciousness [13]. Prolonged hypoglycemia can cause brain death and hypoglycemia has shown to increase all-cause mortality in cardiac patients [14,15]. Mortality is especially higher for the spontaneous hypoglycemia in non-diabetics [16]. The presence of neuroglycopenic symptoms in patients without diabetes is strongly suggestive of a hypoglycemic disorder [17]. Conversely, there is a low likelihood of a hypoglycemia disorder in those with the presence of neurogenic symptoms in the absence of a low plasma glucose concentration [18]. Capillary blood glucose measurements should not be used in the evaluation of hypoglycemia due to poor accuracy [17]. Symptoms of hypoglycemia may be absent in patients with hypoglycemia due to decreased sympathetic response to recurrent hypoglycemia, prior exercise or sleep [17,19-21]. Hypoglycemia disorders are traditionally classified as being post absorptive hypoglycemia (fasting hypoglycemia) and postprandial hypoglycemia (re-active hypoglycemia). Fasting hypoglycemia is caused by organic pathologies that presents mostly with neuroglycopenic symptoms and re-active hypoglycemia arises from functional disorder which presents often with autonomic features. An insulinoma can present with postprandial or a post-absorptive hypoglycemia [4,5,22]. This approach has limitation as it neither expedites diagnosis nor facilitates an understanding of the pathophysiology of the disorders. The differential diagnosis is broad when hypoglycemia occurs in individuals with hypoglycemia in the absence of diabetes mellitus (Table 2) [17]. Multiple etiologies may be present concurrently. Different causes of hypoglycemia should be considered in patients who are apparently healthy compared to those who are ill. Drugs, critical illnesses, hormone deficiencies, and non-islet cell tumors should be considered in those who are ill or taking medications. In apparently healthy individuals, endogenous hyperinsulinism due to insulinoma, functional β-cell disorders, or insulin autoimmune conditions are possible, as are accidental, surreptitious or factitious causes of hypoglycemia. Hypoglycemia in patients who have had bariatric surgery is increasingly recognized as the frequency of this surgery is in increase. Artifactual hypoglycemia can occur if blood samples are improperly handled (lack of antiglycolytic agent in the collection tube) and there is a delay in processing. Drugs are the most common cause of hypoglycemia (Table 3) [17]. Drug induced hypoglycemia is more common in older patients with underlying comorbidities and in those taking glucose lowering medications. Hypoglycemia in the setting of critical illness is not unusual. Sepsis, hepatic, renal or cardiac failure and hormone deficiencies (cortisol, glucagon and epinephrine) are other causes of hypoglycemia. Non-islet cell tumors and endogenous hyperinsulinism such as insulinoma, non insulinoma pancreatogenous hypoglycemia, and autoimmune hypoglycemia are rare causes of hypoglycemia [17]. Accidental, surreptitious or malicious hypoglycemia due to administration of insulin or insulin secretagogues need also to be considered.   Table-2: Causes of hypoglycemia in adults [17].     Insulinomas primarily cause hypoglycemia in the fasting state, but may cause symptoms in the postprandial period as well. The incidence is 1/250,000 patient/years. Less that 10% are malignant, or may be present in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome [17]. Non-insulinoma pancreatogenous hypoglycemia( NIPHS) typically causes hypoglycemia in the postprandial state. These patients have diffuse islet involvement with nesidioblastosis (islet hypertrophy, hyperplasia and enlarged hyperchromatic β-cell nuclei) [23].   Table-3: Drugs associated with hypoglycemia [17].     Antibodies to insulin or the insulin receptor are rare causes of hypoglycemia [17,18]. Antibodies to native insulin occur primarily in patients of Japanese and Korean descent [24]. Patients with autoimmune hypoglycemia may have other autoimmune disease or exposure to sulfhydryl containing drugs [25]. Late postprandial hypoglycemia occurs as insulin secreted in response to the meal disassociates from antibodies. Diagnosis is made with documentation of elevated insulin antibody levels in the absence of exposure to exogenous insulin [26]. Spontaneous hypoglycemia can rarely be a result of paraneoplastic syndrome secondary to non-beta-cells tumors and is termed as non-islet cell tumor hypoglycemia (NICTH). A variety of malignant and non-malignant tumors such as solitary fibrous tumor and/or mesotheliomas, hemangiopericytoma, hepatocellular carcinoma, gastrointestinal stromal tumors, adenocarcinomas, sarcomas, and renal cell carcinomas may cause NICTH [27]. Unusual cases of NICTH have been reported with adrenocortical and thyroid cancers, Burkitt’s lymphoma, plasmacytoma, yolk cell tumor, Leydig cell tumor, and phyllodes tumor of the breast. These tumors secrete partially processed precursors of insulin-like growth factor-II (IGF-II), otherwise termed ‘big’-IGF-II or pro IGF-II that causes NICTH [27,28]. Big IGF-II interacts with IGF-I receptors and insulin receptors in the target tissues and results in hypoglycemia [2]. Consideration for hormone deficiencies and non-islet cell tumors should be given. When adrenal insufficiency is considered, an ACTH stimulation test should be performed. If the cause of hypoglycemia is not apparent then further laboratory testing is indicated. Capillary blood glucose measurements should not be used in the diagnosis of hypoglycemic disorders due to their poor accuracy in these situations. If possible, testing should be done during symptomatic hypoglycemia. Simultaneous measurements of plasma glucose, insulin, c-peptide, proinsulin, and beta-hydroxybutyrate and a screen for oral hypoglycemic agents (sulfonylureas and meglitinide) should be performed (Table 4).   2026 Ibrahim Medical College. All rights reserved.