|Year : 2018 | Volume
| Issue : 2 | Page : 83-88
A study on etiological spectrum of hypoglycemia in nondiabetic patients in a rural medical teaching institution
Gouranga Santra, Dipu Roy
Department of Medicine, Midnapore Medical College, Paschim Medinipur, West Bengal, India
|Date of Web Publication||2-May-2018|
Dr. Gouranga Santra
Block-P, Flat No. 306, Binayak Enclave, 59 Kalicharan Ghosh Road, Kolkata - 700 050, West Bengal
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Awareness regarding etiological distribution of nondiabetic hypoglycemia is poor among physicians. No study of etiological spectrum of hypoglycemia is found in rural West Bengal. We conducted this study to identify different causes of hypoglycemia in nondiabetics in a rural area of the western part of West Bengal.
METHODS: Nondiabetic patients admitted in general medical ward with clinical or laboratory features of hypoglycemia with blood sugar level <70 mg/dl were evaluated clinically and from laboratory investigations to identify the underlying disorders. Relationship with food intake and recurrence of hypoglycemia were assessed.
RESULTS: A total of 55 patients were included in this study. The most common cause of hypoglycemia was alcoholism (27.27%). Next common cause was steroid withdrawal (18.18%), especially in rheumatic patients. The third common cause was sepsis (12.73%), followed by panhypopituitarism (10.91%). Sheehan syndrome was seen in three cases. Hypoglycemia was detected in one chronic kidney disease (CKD) patient after hemodialysis (HD) and two CKD patients without HD. Hypoglycemia developed in one case of fulminant hepatitis, two cases of decompensated cirrhosis (hepatitis B and alcoholic), and two cases of congestive cardiac failure. Hypoglycemia developed in two cases of primary adrenocortical insufficiency due to tuberculosis and histoplasmosis of bilateral adrenal glands. All patients had fasting hypoglycemia except one case of dumping syndrome due to Billroth II gastrojejunostomy surgery. Other rare causes were insulinoma, malnutrition, and malignancy.
CONCLUSION: Knowledge regarding different causes of hypoglycemia will increase the alertness and suspicion of possible hypoglycemia in appropriate situations. It will also help to identify underlying disorders in cases of hypoglycemia.
Keywords: Alcoholism, hypoglycemia, panhypopituitarism, sepsis, steroid withdrawal
|How to cite this article:|
Santra G, Roy D. A study on etiological spectrum of hypoglycemia in nondiabetic patients in a rural medical teaching institution. Int J Health Allied Sci 2018;7:83-8
|How to cite this URL:|
Santra G, Roy D. A study on etiological spectrum of hypoglycemia in nondiabetic patients in a rural medical teaching institution. Int J Health Allied Sci [serial online] 2018 [cited 2019 Feb 21];7:83-8. Available from: http://www.ijhas.in/text.asp?2018/7/2/83/231694
| Introduction|| |
Hypoglycemia is less common in nondiabetic population than diabetics. It is often overlooked in nondiabetic patients because of lack of awareness among physicians. In nondiabetic critically ill patients with underlying metabolic or physical disorders, symptoms of hypoglycemia may be insidious and may present as subacute neuroglycopenia without any premonitory symptoms. Hence, hypoglycemia may be overlooked. If hypoglycemia is not recognized and corrected, it can lead to coma and death. Studies have revealed that hypoglycemia has strong prognostic significance of inhospital mortality in nondiabetic critically ill patients.,, Nondiabetic hypoglycemic patients may also have acute presentations with premonitory symptoms. Awareness regarding different etiologies of nondiabetic hypoglycemia may increase the alertness and suspicion among physicians for early recognition of this grave condition. Etiological distribution of nondiabetic hypoglycemia is rarely reported in literature from different geographic locations and ethnic groups. Researchers are focused mainly on hypoglycemia in diabetic patients but rarely on hypoglycemia in nondiabetic patients. No study of etiological spectrum of hypoglycemia in nondiabetic patients is found in rural West Bengal. We conducted this study to identify distribution of different causes of hypoglycemia in nondiabetics in a rural area of the western part of West Bengal.
| Methods|| |
Both male and female patients admitted in general medical ward in our institution over 3-year period with clinical or laboratory features of hypoglycemia such as tremor, anxiety, palpitation, hunger, sweating, paresthesias, dizziness, blurred vision, lethargy, confusion, coma, seizure, and/or blood sugar level <70 mg/dl were included in the study. Known diabetic patients were excluded from the study.
Blood sugar was tested at bedside with glucometer, and samples were sent for sugar estimation before resuscitation of patients with intravenous dextrose infusion. Blood sugar test was repeated regularly during their hospital stay to document recurrent hypoglycemia. Bed history tickets were reviewed in previously admitted patients. Proper history taking, clinical examination, and laboratory investigation were done to reach the diagnosis of underlying disorders in undiagnosed cases. History was taken regarding basic demographic data. History was taken or reviewed regarding alcoholism, steroid withdrawal, fever, episodes of nausea, vomiting and hypotension, food habit, weight loss or gain, snakebite, postpartum hemorrhage (PPH), lactational failure, amenorrhea, jaundice, suggestive features of liver, kidney or cardiac disorders or any neoplasm, drug history such as quinine, hemodialysis (HD), and gastrointestinal or bariatric surgery. History of similar attacks, frequencies of attacks, and relation with timings of food intake were asked. Physical examination was done or reviewed regarding any stigmata of alcoholism, jaundice, hypotension, neck vein engorgement, pigmentation of skin and oral mucosa, moon facies, signs of liver disease, chronic kidney disease (CKD), cardiac and rheumatological disorders, malnutrition and obesity, sites of any septic focus, scar marks of any abdominal surgery, and tumors. Laboratory investigations were done or reviewed as required in individual basis including complete blood count, urea, creatinine, blood culture, liver function test, serum sodium and potassium levels, thyroid function test (free T3, free T4, and thyroid-stimulating hormone), luteinizing hormone, follicle-stimulating hormone, cortisol, insulin, C-peptide, electrocardiogram, echocardiography, ultrasonography and computed tomography scan of the abdomen, magnetic resonance imaging of the hypothalamic–pituitary axis, and fine-needle aspiration cytology, biopsy, or Papanicolaou stain of appropriate samples in cases of neoplasm. Fasting and postprandial hypoglycemia was diagnosed from a history of relationship with food intake. After different causes were identified, they were tabulated.
The procedures followed in the study were in accordance with ethical standards of responsible committee on human experimentation and with Helsinki Declaration on 1975, as revised in 2010. Institutional ethics committee permission was taken for conducting the study. Informed consent was taken from the patients or family members for inclusion in the study.
Percentage (%), mean value, 95% confidence interval (CI), and standard deviation were used for data representation. GraphPad QuickCalcs online statistical calculator (GraphPad Software Inc, La Jolla, California, USA) was used for data analysis (http://www.graphpad.com/quickcalcs).
| Results|| |
A total of 55 patients were included in the study. The mean age of the patients (n = 55) was 42.84 ± 10.09 years (95% CI: 40.11–45.56). Males outnumbered the females (29 vs. 26 cases). Majority (76%) were from lower socioeconomic status. Education level was below tenth standard in most (69%). All cases were from rural areas. [Table 1] shows the demographic features of the study patients.
[Table 2] shows the frequencies of different causes of hypoglycemia in nondiabetic patients with few of their salient features. The mean blood glucose in hypoglycemic cases was 44.05 ± 7.11 mg/dL (95% CI: 42.13–45.98). Causes of hypoglycemia in nondiabetic patients found were alcoholism, steroid withdrawal, sepsis, panhypopituitarism, primary adrenocortical insufficiency (PAI), CKD, liver diseases, congestive cardiac failure (CCF), insulinoma, dumping syndrome, malnutrition, malignancy, and multifactorial in different frequencies.
|Table 2: Frequencies of different causes of hypoglycemia with few salient features|
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The most common cause of hypoglycemia was alcoholism (27.27%). Alcoholism was more common in males. However, a significant number of alcoholic patients were female (4 out of 11). The second common cause was steroid withdrawal (18.18%). Seven cases of rheumatoid arthritis, two cases of osteoarthritis, and one case of bronchial asthma developed secondary adrenocortical insufficiency (SAI) with hypoglycemia due to stoppage of steroid. The third common cause was sepsis (12.73%). Four cases had pneumonia and three cases had bacteremia. Panhypopituitarism was more common than PAI (six cases vs. two cases). Panhypopituitarism was more common in females (five out of six patients). One case of panhypopituitarism had history of snakebite. Three had a history of PPH. Two patients had lymphocytic hypophysitis. One patient of PAI had tuberculosis. The another case of PAI had bilateral adrenal histoplasmosis. No autoimmune case was found.
Our single case of insulinoma was a 28-year-old female. She had fasting hypoglycemia with recurrent sweating, tremor, palpitation, lethargy, headache, confusion, and seizures. She had weight gain. Her insulin and C-peptide levels were elevated. A female patient of Billroth II (gastrojejunostomy) surgery done for peptic ulcer disease 20 years back presented with recurrent postprandial hypoglycemia. She had features of late dumping syndrome 1 to 3 h after eating with weakness, sweating, and dizziness.
Two CKD patients without HD developed hypoglycemia insidiously during hospital stay. One CKD patient developed hypoglycemia after HD. Two cases of CCF due to rheumatic heart disease (RHD) and dilated cardiomyopathy (DCM) also developed hypoglycemia. Two cases of decompensated cirrhosis (hepatitis B and alcoholic) developed insidious onset hypoglycemia. A case of acute fulminant hepatitis due to hepatitis B also developed hypoglycemia. A single case of malignancy developed hypoglycemia during hospital stay. She had ascites due to unknown primary. One of our patients had multifactorial etiology with concomitant sepsis, uremia, and malnutrition and developed hypoglycemia insidiously during hospital stay. Malnutrition was a cause of hypoglycemia in a 32-year-old female. In one of our cases, no underlying cause was diagnosed.
All the study patients had fasting hypoglycemia except one. Only the dumping syndrome case had postprandial hypoglycemia. Ten cases developed recurrent hypoglycemia during their hospital stay. Panhypopituitarism cases were seen in relatively younger age (29.33 ± 4.32 years). Older ages were associated with hypoglycemia from CKD (55.67 years), CCF (54 years), malignancy (56 years), and multifactorial causes (63.50 years).
| Discussion|| |
Patients with major organ dysfunction and critical illness have defective counterregulatory mechanisms against hypoglycemia. Defective gluconeogenesis and impaired glycogenolysis (in food-deprived state) can result in hypoglycemia. Furthermore, critical illnesses can increase metabolic stress with increased glucose utilization by tissues. Endogenous hyperinsulinism may also cause hypoglycemia.
Studies on the frequency of different causes of hypoglycemia in nondiabetic patients are very few in literature.,,,,, Sepsis, renal disease, alcoholism, pneumonia, liver disease, CCF, cancer, self-harm, endocrine deficiencies, insulinoma, and malnutrition are the different causes described in different studies in different frequencies.,,,,, Our study also revealed different causes of hypoglycemia and their frequencies from rural West Bengal. In our study, the most common cause of hypoglycemia was alcoholism (27.27%), followed by SAI due to steroid withdrawal (18.18%). Sepsis (12.73%) and panhypopituitarism (10.91%) were the third and fourth common causes, respectively. A study from Birmingham, United Kingdom, also revealed that the most common comorbidities linked to nondiabetic hypoglycemia were sepsis, kidney disease, and alcohol dependence. A study from Central Anatolia, Turkey, revealed that endocrine deficiencies (20%) and malignancy (12%) were the common causes of hypoglycemia next to diabetes therapy (42%). The leading endocrine deficiency was panhypopituitarism and Sheehan syndrome was the most common cause of panhypopituitarism (44%). However, in our study, endocrine deficiency was next to alcoholism, and SAI due to steroid withdrawal was the most common endocrine deficiency. However, Sheehan syndrome was the most common cause of panhypopituitarism (50%) causing hypoglycemia in our study like the Central Anatolia study. In another study from Philadelphia, Pennsylvania, USA, nondiabetic hypoglycemia cases were associated with CKD (25%); alcohol intoxication (15%); and liver failure, sepsis, cancer, and endocrine disorders (each 12%). CKD was relatively less common in our study than Philadelphia study. Differences are due to the geographic, socioeconomic, cultural, and ethnic variations.
Alcoholism either acute or chronic can cause hypoglycemia. Excess alcohol intake without other foods depletes hepatic glycogen store. Alcohol inhibits gluconeogenesis by blocking the regulatory enzymes. Malnutrition in chronic alcoholics also inhibits release of free fatty acid from adipose tissue and decreases gluconeogenesis. All these lead to hypoglycemia. In our study, patients mainly used to drink country liquor and they had poor food intake influenced by their poor socioeconomic and educational status. Females of tribal community were also presented with hypoglycemia due to chronic alcoholism (4 cases out of 15). Intake of country liquor by both male and female is a culture of the local tribal community.
Cortisol deficiency due to SAI in steroid withdrawal, PAI, and panhypopituitarism can lead to hypoglycemia. Steroids are very frequently and irrationally advised by unqualified rural medical practitioners, especially in rheumatic disorders in this locality. Hence, SAI due to steroid withdrawal was common in our study. Steroid withdrawal was more common (ten cases) than combined cases of PAI (two cases) and panhypopituitarism (six cases). Both PAI and steroid withdrawal cases presented with nausea, vomiting, and hypotension along with hyponatremia and hypoglycemia. Panhypopituitarism cases had hypotension, hyponatremia, and hypoglycemia with other endocrinal features such as hypothyroidism and amenorrhea and lactational failure in females.
Hypoglycemia is common in diabetic nephropathy due to diabetic medication. However, spontaneous hypoglycemia may also be seen in nondiabetics with CKD.,, HD may also predispose to hypoglycemia in CKD patients because of diffusion of glucose into erythrocytes due to accelerated anaerobic metabolism., Pathogenesis of hypoglycemia in CKD includes factors such as impaired renal gluconeogenesis due to decline in effective renal mass, decreased renal insulin degradation and clearance, anorexia, and poor nutrition leading to decreased glycogen store. In uremic patients, neuroglycopenic manifestations predominate because of frequent autonomic nervous system dysfunction and lack of catecholamine release in response to hypoglycemia. Hypoglycemia should be suspected in CKD patients with any changes in mental or neurologic status. In our study, hypoglycemia was detected in CKD patients who developed drowsiness after HD (one case) or without HD (two cases).
Although glucose metabolism is altered, hypoglycemia is unusual in uncomplicated hepatitis and compensated cirrhosis. Acute fulminant hepatitis can lead to hypoglycemia due to impaired gluconeogenesis and glycogenolysis due to rapid and massive destruction of liver parenchyma. It may also occur in acutely decompensated liver cirrhosis, especially in alcoholics. In liver disease, hypoglycemia may be overlooked because of possibility of hepatic encephalopathy. Occasionally, chronic hepatitis may also have hypoglycemia. Our study also revealed hypoglycemia in two cases of decompensated cirrhosis (hepatitis B and alcoholic) and one case of fulminant hepatitis during routine workup.
Spontaneous hypoglycemia has been reported with CCF due to RHD, cor pulmonale, coronary artery disease, and DCM.,,, Hypoglycemia may be due to combination of factors such as liver dysfunction from passive venous congestion with impaired glycogenolysis and gluconeogenesis, low-calorie intake, poor glucose absorption, and increased glucose utilization by ischemic tissues including the heart.,,, In our study, two cases of CCF due to RHD and DCM developed confusion during hospital stay and subsequent study showed hypoglycemia. In patients with CCF presenting with coma or confusion, blood sugar needs to be checked for possible hypoglycemia.
Hypoglycemia can be seen in severe sepsis such as pneumonia, cellulitis, and bacteremia., In severe sepsis, impaired gluconeogenesis and excessive insulin release on occasion produce hypoglycemia. Sepsis was a common cause of insidious onset hypoglycemia in our study.
Insulinoma cases have recurrent hypoglycemia at fasting, and weight gain usually occurs due to repeated eating. Our patient had weight gain due to frequent eating to overcome hypoglycemia. She had a benign tumor confirmed after surgical resection and biopsy.
Bariatric surgery for weight loss (Roux-en-Y gastric bypass surgery) can lead to postprandial hypoglycemia due to dumping syndrome. However, bariatric surgery is rarely done in this area. Previously gastric surgeries were performed for acid-peptic disorders. Because of availability of potent proton-pump inhibitors, surgery is rarely required now. However, occasional cases may be found with gastric surgery for peptic ulcer disease decades back having features of dumping syndrome like our case.
Malnourishment with or without cachexia can lead to hypoglycemia. Severe malnutrition has been reported to cause hypoglycemia, especially in anorexia nervosa. One of our cases was severely malnourished due to poor food intake and developed insidious onset hypoglycemia during her hospital stay and detected during routine workup for drowsiness.
Patients may have more than one comorbid condition precipitating hypoglycemia as seen in one case in our study. Our patient had sepsis, uremia, and cachexia contributing to hypoglycemia.
Sometimes etiology of hypoglycemia cases may remain undiagnosed after investigation with available resources. In one of our cases, no underlying cause was diagnosed; however, endogenous hyperinsulinism was found. Imaging did not reveal insulinoma. However, antibodies to insulin or insulin receptor were not tested, and blood levels of sulfonylurea were not assessed because of unavailability and financial reason.
Non-beta-cell tumors such as mesenchymal and epithelial tumors (e.g., hepatoma, adrenocortical carcinoma, and carcinoid) can lead to hypoglycemia due to excess release of incompletely processed form of insulin-like growth factor II (big IGF-II). In our study, the single case of malignancy who developed hypoglycemia during hospital stay had ascites due to unknown primary. IGF-II was not assessed. The patient had cachexia and extreme anorexia which may contribute to hypoglycemia. In our study, no case was detected with factitious or surreptitious use of insulin or sulfonylurea drugs causing hypoglycemia. Hypoglycemia has also been reported with drugs other than antidiabetics. However, we did not get such patients.
Our study has limitations. It is a small single-center study from a specific geographic location. It does not represent all the geographic locations of India. A large multicenter study can identify the causes accurately with its geographic, socioeconomic, and ethnic variations.
| Conclusion|| |
Although diagnosis and confirmation of hypoglycemia are not difficult when it is suspected clinically, a hypoglycemic attack may go unnoticed, especially in nondiabetic patients, because of the lower level of suspicion and awareness. Knowledge regarding different causes of hypoglycemia will increase the alertness and suspicion of physicians regarding possible hypoglycemia in appropriate clinical situations. Hypoglycemia is also a signal to the clinician to search for underlying illnesses.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Marks V. Recognition and differential diagnosis of spontaneous hypoglycaemia. Clin Endocrinol (Oxf) 1992;37:309-16.
Mannucci E, Monami M, Mannucci M, Chiasserini V, Nicoletti P, Gabbani L, et al.
Incidence and prognostic significance of hypoglycemia in hospitalized non-diabetic elderly patients. Aging Clin Exp Res 2006;18:446-51.
Kagansky N, Levy S, Rimon E, Cojocaru L, Fridman A, Ozer Z, et al.
Hypoglycemia as a predictor of mortality in hospitalized elderly patients. Arch Intern Med 2003;163:1825-9.
Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, et al.
Prediction of 90-day mortality in patients without diabetes by severe hypoglycemia: Blood glucose level as a novel marker of severity of underlying disease. Acta Diabetol 2015;52:307-14.
Kok VC, Lee PH. Management of hypoglycemia in nondiabetic palliative care patients: A Prognosis-based approach. Palliat Care 2016;10:1-5.
Güven M, Bayram F, Güven K, Kelestimur F. Evaluation of patients admitted with hypoglycaemia to a teaching hospital in central Anatolia. Postgrad Med J 2000;76:150-2.
Mendoza A, Kim YN, Chernoff A. Hypoglycemia in hospitalized adult patients without diabetes. Endocr Pract 2005;11:91-6.
Shilo S, Berezovsky S, Friedlander Y, Sonnenblick M. Hypoglycemia in hospitalized nondiabetic older patients. J Am Geriatr Soc 1998;46:978-82.
Nirantharakumar K, Marshall T, Hodson J, Narendran P, Deeks J, Coleman JJ, et al.
Hypoglycemia in non-diabetic in-patients: Clinical or criminal? PLoS One 2012;7:e40384.
Kandi S, Ramana KV. Alcoholism and its relation to hypoglycemia – An overview. Am J Med Stud 2014;2:46-9.
Moen MF, Zhan M, Hsu VD, Walker LD, Einhorn LM, Seliger SL, et al.
Frequency of hypoglycemia and its significance in chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1121-7.
Bonapart IE, Diderich PP, Elte JW, Rietveld AP, Op de Hoek CT. Spontaneous hypoglycaemia in chronic renal failure. Neth J Med 1996;48:180-4.
Kes P, Cunović-Orlić D. Spontaneous hypoglycemia associated with chronic renal failure – A preventable life-threatening complication. Acta Med Croatica 1994;48:207-10.
Rutsky EA, McDaniel HG, Tharpe DL, Alred G, Pek S. Spontaneous hypoglycemia in chronic renal failure. Arch Intern Med 1978;138:1364-8.
Arem R. Hypoglycemia associated with renal failure. Endocrinol Metab Clin North Am 1989;18:103-21.
Senadhi V. Recurrent hypothermia and hypoglycemia as the initial presentation of hepatitis C. Clin Pract 2011;1:e18.
Hedayati HA, Beheshti M. Profound spontaneous hypoglycaemia in congestive heart failure. Curr Med Res Opin 1977;4:501-4.
Hajji R, Elleuch M, Derbali F, Kammoun N, Zribiet S. Persistent hypoglycemia revealing severe heart failure. J Gerontol Geriatr Res 2016;5:303.
Sia AT, Chong JL, Tan CG. Severe mitral stenosis in a parturient with congestive cardiac failure and hypoglycaemia. Int J Obstet Anesth 1998;7:173-6.
Khoury H, Daugherty T, Ehsanipoor K. Spontaneous hypoglycemia associated with congestive heart failure attributable to hyperinsulinism. Endocr Pract 1998;4:94-5.
Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: The myocardial and systemic perspective. J Am Coll Cardiol 2014;64:1388-400.
Drah M, Ghose RR. Hypoglycaemia and heart failure. Postgrad Med J 1992;68:304.
Mellinkoff SM, Tumulty PA. Hepatic hypoglycemia; its occurrence in congestive heart failure. N
Engl J Med 1952;247:745-50.
Miller SI, Wallace RJ Jr. Musher DM, Septimus EJ, Kohl S, Baughn RE, et al.
Hypoglycemia as a manifestation of sepsis. Am J Med 1980;68:649-54.
Rattarasarn C. Hypoglycemia in sepsis: Risk factors and clinical characteristics. J Med Assoc Thai 1997;80:760-6.
Tarchouli M, Ali AA, Ratbi MB, Belhamidi Ms, Essarghini M, Aboulfeth el M, et al.
Long-standing insulinoma: Two case reports and review of the literature. BMC Res Notes 2015;8:444.
Yanai H, Yoshida H, Tomono Y, Tada N. Severe hypoglycemia in a patient with anorexia nervosa. Eat Weight Disord 2008;13:e1-3.
Cryer PE, Davis SN. Hypoglycemia. In: Kasper DL, Hause SL, Jameson JL, Fauci AS, Longo DL, Loscalzo J, editors. Harrison's Principles of Internal Medicine. 19th
ed. New York: McGraw-Hill Education; 2015. p. 2430-5.
Friedrich LV, Dougherty R. Fatal hypoglycemia associated with levofloxacin. Pharmacotherapy 2004;24:1807-12.
[Table 1], [Table 2]