A 51-year-old man with a past medical history of chronic alcoholism was admitted for a planned fasting test due to suspected hypoglycemia. Despite previous evaluations by cardiology and neurology revealing no evident etiology, his syncopal episodes were suspected be associated with inconsistent hypoglycemic episodes. During his hospital admission, the patient experienced several syncopal episodes with associated seizures, which, at the time, were not related to hypoglycemia. This led to further investigation, including the exclusion of other causes, such as a possible autonomic dysfunction. Neurology consequently expanded the assessment, identifying subtle signs of mild parkinsonism and symptoms suggestive of a REM sleep disorder, which shifted the diagnostic suspicion.
This case underscores the importance of considering other clinical conditions when evaluating hypoglycemia, especially when classic symptoms are absent or inconsistently presented, and an endocrinological origin has been ruled out.
Se trata de un varón de 51 años con antecedentes de alcoholismo crónico, que ingresa de manera programada para realizar un test de ayuno por sospecha de hipoglucemia. Aunque los estudios previos por parte de cardiología y neurología no mostraron causas evidentes, se sospechaba que los síncopes podían estar relacionados con hipoglucemias que no se presentaban de forma consistente. Durante su ingreso, el paciente sufrió varios episodios sincopales con convulsiones asociadas, en ese momento sin relación con hipoglucemia, lo que llevó a descartar otras etiologías, entre las que se encontraba un posible trastorno autonómico. Esto hizo que neurología ampliara el estudio, observando signos sutiles de parkinsonismo y clínica sugestiva de un trastorno del sueño REM que reorientaron la sospecha diagnóstica. Este caso resalta la importancia de considerar otras entidades clínicas en el abordaje de la hipoglucemia cuando los síntomas clásicos están ausentes o se manifiestan de forma inconsistente, especialmente tras haber descartado un origen endocrinológico.
The patient, a 51-year-old caucasian male, was admitted to the Endocrinology and Nutrition Department for a scheduled 72-h fasting test. He had an alcohol use disorder (daily intake of 1–2l of beer since the age 20), with variable abstinence periods for which he remained on 250mg of disulfiram daily. From a nutritional point of view, he was overweight according to his BMI (26.1kg/m2). His personal and family medical history was otherwise unremarkable, apart from alcoholism. The patient had experienced syncopal episodes over the past 2 years, which involved loss of consciousness and postural tone, lasting 1–2min with complete subsequent recovery. These events were not triggered by effort and were not accompanied by chest pain or dyspnea, nor were associated with muscle jerks, sphincter relaxation, or tongue biting. Although prodromal autonomic or neuroglycopenic symptoms were reported by the patient, they were not consistent in all episodes.
The patient had been previously evaluated by cardiology, ruling out structural heart disease and placed an insertable cardiac monitor device Medtronic Reveal LINQ™ to screen for possible heart rate disturbances. Neurology, on its end, found no signs of seizure activity. He was referred to endocrinology for suspected hypoglycemia as a trigger for syncope, given that during some episodes, the patient exhibited recorded capillary glucose levels<50mg/dL (48mg/dL). However, hypoglycemia was not consistently present during syncopal episodes, as the patient was most often euglycemic at the time of consciousness loss.
Targeted anamnesis revealed that hypoglycemic episodes were mostly postprandial, following carbohydrate intake, without fasting hypoglycemia. Initial investigations considered postprandial hypoglycemia, and comprehensive blood tests were ordered, including pancreatic reserve (C-peptide levels), insulin levels, and 24-h urinary catecholamines. Differential diagnoses included pheochromocytoma, endogenous hyperinsulinism (insulinoma, pancreatic tumors, idiopathic etiology), exogenous hyperinsulinism, diabetes mellitus (DM), adrenal insufficiency, hypothyroidism, growth hormone (GH) deficiency, insulin-like growth factor 2 (IGF-2) overproduction (Doege–Potter syndrome), dumping syndrome, GI disorders (celiac disease, inflammatory bowel disease, or intestinal malabsorption), liver disease (due to alterations in glycogen production or storage), and autonomic failure.
Supplementary test results excluded DM [fasting plasma glucose 79mg/dL (70–100mg/dL), glycated hemoglobin (HbA1c) 5% and preserved pancreatic reserve with C-peptide 1.42ng/mL (1.09–4.41ng/mL)]; hypothyroidism [thyrotropin 2.11μIU/mL (0.37–4.20μIU/mL), thyroxine 1.12ng/dL (0.90–1.70ng/dL)]; exogenous hyperinsulinism [insulin 6.54μIU/mL (2.6–24.9μIU/mL), with no evidence of insulin injection marks or access to insulin by other DM patients in his near environment); secretagogue use (undetectable plasma levels); pheochromocytoma (normal 24-h urinary catecholamines); and autoimmune hyperinsulinemic hypoglycemia [insulin autoantibodies 9.7U/mL (0–20U/mL) and insulin-receptor autoantibodies 0.31 (<1)]. A mixed-meal test was performed, yielding negative results. Additionally, basal cortisol levels [12.9μg/dL (3.7–19.4μg/dL)] and the adrenocorticotropic hormone (ACTH) stimulation test fell within normal ranges, ruling out adrenal insufficiency.
Additional studies, including abdominal computed tomography (CT) and a fine needle aspiration under endoscopic ultrasound guidance merely demonstrated mild pancreatic atrophy, which tested negative for neoplasm after histological examination (nesidioblastosis was ruled out as well). Since major endocrine and digestive etiologies had been excluded, the patient was admitted for further hypoglycemia investigation via 72-h fasting test.
During the fasting test, no incidents occurred within the first 24h. However, on day 2, the patient exhibited a seizure. Nurses reported that he had felt dizzy and short of breath after rising from a chair, lost consciousness, and briefly convulsed before rapidly regaining consciousness without latter confusion. Post-episode measurements showed normal blood glucose (105mg/dL) and blood pressure (100/90mmHg). The patient denied tongue biting, sphincter relaxation, or chest pain and stated the event was similar to his previous syncopal events.
The cardiology service then checked the cardiac monitor device, confirming that it was functioning normally without arrhythmic events linked to the episode. Additional syncopal evaluation revealed a normal electrocardiogram, showing sinus rhythm at 60bpm with no ST-segment deviations, a normal PR interval, narrow QRS complexes; and negative troponin I levels. Elevated D-dimer levels [916ng/mL (0–500ng/mL)] prompted a chest CT angiography, which ruled out pulmonary embolism.
Since hypoglycemia had not triggered the event, the fasting test continued, and the episode was labeled as a convulsive syncope. The patient later reported through directed history a “floating sensation,” with his partner noting common memory lapses and excessive night-time movements. Given a possible vitamin B12 deficiency, its levels were tested and found normal.
On day 3, a similar syncopal episode occurred, this time after the patient took a shower, for which he had been standing for 10min. Again, he denied associated chest pain, dyspnea or other symptoms, and reported cold sweats and dizziness before losing consciousness. At that time, capillary blood glucose was measured, revealing levels above the hypoglycemic range [58mg/dL (<55mg/dL in individuals without diabetes)].
Due to these recurrent syncopal episodes, memory lapses, and suspected autonomic dysfunction, neurology consultation was requested. After examination (positive orthostatic test), autonomic dysfunction was suspected, possibly atypical parkinsonism or, less likely, autonomic neuropathy. Neurological tests were expanded, including dopamine transporter imaging (DaTSCAN), brain magnetic resonance (MRI), single-photon emission computed tomography (SPECT), neurophysiological study, and polysomnography. Fludrocortisone was added to the treatment regimen, managing to alleviate symptoms by reducing syncopal frequency. Neurological findings included Parkinson-like signs, notably mild right-upper-limb rigidity and reduced arm swing on the right side while walking, as well as reduced uptake in the right caudate nucleus demonstrated by DaTSCAN. Nerve conduction study was not pathological.
The patient was discharged with outpatient follow-up in the neurology service, where the possibility of prodromal synucleinopathy was raised due to rapid eye movement (REM) sleep behavior disorder (RBD), cognitive complaints, and DaTSCAN findings. Ambulatory polysomnography confirmed the presence RBD (Table 1), which, in the context of autonomic signs, strongly suggested multiple system atrophy (MSA) with parkinsonism (MSA-P).
Analysis of lower limb movements. A significant increase in their frequency and intensity is observed, especially during the REM phase. PLMS: Periodic Limb Movements during Sleep; N1: N1 stage of sleep; N2: N2 stage of sleep; N3: N3 stage of sleep; REM: Rapid Eye Movement stage of sleep.
| Awake | N1 | N2 | N3 | REM | Total | |
|---|---|---|---|---|---|---|
| Movements in lower limbs | 54 | 11 | 19 | 29 | 4 | 117 |
| PLMS | 7 | 57 | 89 | 177 | 219 | 549 |
Periodic Limb Movement Index: 76.3.
Hypoglycemia in individuals without DM is a relatively rare condition,1 with its prevalence evaluated in only a limited number of small-scale studies.2–5 Diagnosing its origin can sometimes be challenging. To identify hypoglycemia, the presence of Whipple's triad is usually required: symptoms associated with hypoglycemia, a low plasma glucose concentration (<55mg/dL in subjects without diabetes), and symptom improvement upon normalization of blood glucose levels.6–8 Evidence of the presence of a hypoglycemic disorder requires meeting this triad or a strong clinical suspicion usually based on home glucose monitoring, either through a capillary glucometer or using interstitial devices to record glucose levels.
Hypoglycemia symptoms are divided into adrenergic symptoms (with glucose levels around 60mg/dL), such as sweating, anxiety, palpitations, and tremor; and neuroglycopenic symptoms (with glucose levels typically<50mg/dL), including confusion, drowsiness, and behavioral changes. If blood glucose levels fall<30mg/dL, untreated hypoglycemia could lead to irreversible neurological damage and, in severe cases, death.
Historically, hypoglycemia was classified based on whether symptoms occurred during fasting or in the postprandial state. Currently, classification is based on the clinical circumstances of the individual: seemingly ill vs apparently healthy adults.9,10
In seemingly-ill adults, common causes of hypoglycemia include drugs such as insulin, oral antidiabetics, and pentamidine; toxins like alcohol; conditions such as liver, kidney, and heart failure, as well as sepsis; endocrine disorders such as adrenal insufficiency, GH or glucagon deficiency; IGF-2-producing paraneoplastic syndromes11; and anorexia nervosa. Of note, in hospitalized patients, hypoglycemia is usually multifactorial3 and often iatrogenic.
In seemingly healthy adults, other causes of hypoglycemia should be considered, including endogenous hyperinsulinism, most commonly due to an insulinoma (the most common cause of hyperinsulinemic hypoglycemia in adults, with an annual incidence rate of 0.7–4 cases per million in the general population12–15), pancreatic hyperinsulinism syndrome, or as a post-bariatric surgery complication. Autoimmunity vs insulin (anti-insulin antibodies and anti-insulin receptor antibodies) and factitious or accidental hypoglycemia due to insulin, sulfonylurea, or glinide overdose or misuse, should also be considered. Although less common, certain hereditary conditions can also lead to hypoglycemia, such as hypoglycemia–hyperammonemia syndrome, exercise-induced hypoglycemia, and insulin receptor mutations.7
Areas of uncertaintyAlpha-synucleinopathies arise from the accumulation of a protein called alpha-synuclein in the central nervous system (CNS). Normally present in the human brain, alpha-synuclein plays essential roles, such as regulating neurotransmitter release at nerve endings. However, when this protein misfolds, it forms insoluble aggregates that disrupt its proper functioning. These disorders are representative of a spectrum of conditions, including Parkinson's Disease, MSA, and Dementia with Lewy Bodies.16 They are characterized by the parkinsonian syndrome and the presence of insoluble fibrillar aggregates of alpha-synuclein in the CNS.17
In terms of semiology, alpha-synucleinopathies often exhibit a predominance of non-motor signs, such as anosmia, dysautonomia (manifesting as orthostatic hypotension, genitourinary or sphincter dysfunction, and anhidrosis18), cognitive complaints, and notably, clinical suspicion of RBD confirmed by polysomnography. In the absence of secondary causes, RBD is highly specific and indicative of an increased risk of developing alpha-synucleinopathy.
With regard to hypoglycemia, individuals with dysautonomia may experience altered sympathetic signaling, which impairs the efficacy profile of adrenergic response. The sympathoadrenal system plays a critical role in counterregulatory responses to hypoglycemia.19 When blood glucose levels drop, activation of this system triggers the release of catecholamines, such as epinephrine and norepinephrine, which promote glycogenolysis and gluconeogenesis, thus helping to restore blood glucose levels. In conditions such as Multiple System Atrophy (MSA), where sympathetic signaling is impaired,20 these mechanisms may function suboptimally, increasing the risk of hypoglycemic episodes due to inadequate counterregulatory responses. Additionally, in people with significant orthostatic hypotension, hypoglycemia might actually be an artifact of poor peripheral perfusion caused by low blood pressure during the episode. This common complication in dysautonomia reduces blood flow and nutrient delivery to tissues potentially resulting in inaccurate glucose readings that suggest hypoglycemia without an actual deficit of available glucose in the body.
Clinical practice guidelinesThe diagnostic process for hypoglycemia should start with a detailed medical history, including dietary habits, alcohol consumption, drugs and a history of any GI surgical procedures. If Whipple's triad is confirmed, glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, sulfonylureas, and anti-insulin antibodies should be measured during hypoglycemic episodes.21
Following the diagnostic algorithm (Fig. 1), a 72-h fasting test may be conducted to identify the underlying cause. If this test yields a positive result, diagnosis is most likely insulinoma, requiring localization studies followed by surgery. If the test is negative, post-bariatric surgery hypoglycemia or non-insulinoma pancreatogenous hyperinsulinemic hypoglycemia syndrome (NIPHS) should be considered as a possible cause.
Diagnostic algorithm for suspected hypoglycemia in non-diabetic patients (modified from Galati SJ, Rayfield EJ. Endocr Pract 2014; 20:331–40). SU: sulfonylureas; anti-insulin ab: insulin autoantibodies; QX: surgery; US: ultrasound; NIPHS: non-insulinoma pancreatogenous hypoglycemia syndrome. * In case of analytical inconsistencies and/or on the basis of clinical suspicion, consider other etiologies, such as pheochromocytoma adrenal insufficiency, hypothyroidism, growth hormone deficiency, insulin-like growth factor 2 overproduction, dumping syndrome, GI disorders, liver disease and autonomic failure.
If Whipple's triad is negative, other potential causes should be explored, such as idiopathic reactive hypoglycemia (with normal study results or positive anti-insulin antibodies) or autoimmune hypoglycemia syndrome. When hypoglycemic episodes predominantly follow meals, a fractionated diet with multiple small meals throughout the day is recommended, avoiding fast-absorbing carbohydrates and alcohol intake.
Finally, factitious hypoglycemia can be diagnosed by the presence of positive sulfonylureas, inappropriately elevated insulin levels, and low levels of C-peptide and proinsulin.
Conclusions and recommendationsInvestigating hypoglycemia in individuals without diabetes can sometimes be challenging, as the root cause often goes beyond endocrinology and may represent just one part of a more complex syndrome affecting the patient. In light of this, a collaborative, multidisciplinary approach is highly valuable. By involving multiple clinical specialties, the diagnostic process becomes more thorough, increasing the chances of accurately identifying the underlying cause. Teamwork ultimately benefits the patient by enabling a more targeted, individualized treatment that can reduce the overall burden of the disease.
