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Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic
JCF-01591; No of Pages 6
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic Natasha Armaghanian a,b,⁎, Tania P. Markovic c,d , Jennie C. Brand-Miller d,e , Peter T.P. Bye b , Carmel P. Moriarty b , Kate S. Steinbeck a,b,f a
Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Australia b Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, Australia c Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia d Boden Institute of Obesity, Nutrition and Exercise, University of Sydney, Australia e School of Molecular Bioscience, University of Sydney, Australia f Academic Department of Adolescent Medicine, The Children's Hospital at Westmead, Australia Received 7 April 2017; revised 27 August 2017; accepted 29 November 2017 Available online xxxx
Abstract Background: Hypoglycaemia in cystic fibrosis (CF) is known to occur during oral glucose tolerance tests (OGTT) and continuous glucose monitoring, however demographic, clinical and mechanistic data are limited. The aims of this study were to review patient electronic medical records (EMR) in order to 1) describe patient characteristics of a university teaching hospital CF clinic, 2) determine the prevalence of hypoglycaemia on OGTT and explore associations with demographic and clinical characteristics, and 3) explore patient reported symptoms suggestive of hypoglycaemia documented in the EMR. Methods: Adults who attended the RPA CF clinic between January 2009 to April 2016 were included in the study. The prevalence of hypoglycaemia on OGTT was determined and clinical and demographic data were compared to age, sex and glucose tolerance matched controls. Reported symptoms suggestive of hypoglycaemia documented in EMR were qualitatively explored. Results: Hypoglycaemia on OGTT was prevalent in 25 (3 fasting and 22 reactive) of 169 patients who had an OGTT. They were heavier, less likely to have pancreatic insufficiency and had a lower insulin response at 2-h. Another 14 patients reported symptoms suggestive of hypoglycaemia in their EMR. No patient appropriately suppressed insulin at 2-h on OGTT. Conclusions: This study identified two potentially different presentations of hypoglycaemia occur in different clinic sub-populations. Knowledge gaps in the aetiology and triggers of hypoglycaemia remain. © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Hypoglycaemia; Oral glucose tolerance test
1. Introduction Abbreviations: CF, cystic fibrosis; CFRD, cystic fibrosis related diabetes; CGM, continuous glucose monitoring; NGT, normal glucose tolerance; IGT, impaired glucose tolerance; INDET, indeterminate glucose tolerance; OGTT, oral glucose tolerance test; IFG, impaired fasting glucose ⁎ Corresponding author at: Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Australia. E-mail address: [email protected] (N. Armaghanian).
Complications of cystic fibrosis (CF) have increased in prevalence due to improvements in medical and surgical management, nutrition and hence survival rates. Cystic fibrosis related diabetes (CFRD) and states of abnormal glucose tolerance are the leading complications in patients with CF [1]. An increasingly recognised complication is the phenomenon of
https://doi.org/10.1016/j.jcf.2017.11.015 1569-1993© 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
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N. Armaghanian et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
hypoglycaemia, in the absence of glucose lowering therapies. Hypoglycaemia has been documented in a clinical setting during an oral glucose tolerance test (OGTT) [2–4]. A recent systematic review found that the prevalence of hypoglycaemia ranged between 7 and 69% and was most commonly detected during OGTT or continuous glucose monitoring (CGM) [5]. Annual OGTTs with a 75 g oral glucose load are recommended to screen for CFRD [6]. CGM is often used as a supplementary monitoring tool in the diagnosis of impaired glucose tolerance (IGT) and CFRD [7]. Patients present with varying abnormalities of glucose tolerance and states of truly normal glycaemic control are rarely seen [8]. To date, there has been no consistent association between clinical and demographic characteristics of CF patients and outcomes of hypoglycaemia during OGTT or CGM [5]. Anecdotally, this is a well-recognised problem in pediatric and adult CF clinics where exercise and inadequate food intake may have a role in exacerbating symptoms suggestive of hypoglycaemia [9]. There are limited data on the patient experience and it is unclear whether hypoglycaemia in this population has significant clinical consequences. Several mechanisms for the cause of hypoglycaemia in the absence of glucose lowering therapies have been postulated. A delayed or excessive insulin release seems plausible [6,10,11], and has been reported by several authors, as has disrupted glucagon release [3]. A review of existing clinical practice guidelines found no unifying definition or explanation of spontaneous hypoglycaemia [5]. Of concern is that a lack of empirical evidence around the mechanistic cause for hypoglycaemia in these patients in turn also limits the management advice that can be given. The first aim of this study was to describe the demographic, clinical and biochemical characteristics of patients attending a university teaching hospital. The second aim was to determine the prevalence of hypoglycaemia on OGTT and explore the characteristics of patients who presented in this manner by comparing them to matched controls. The third aim was to qualitatively explore patient reported symptoms suggestive of hypoglycaemia documented in the medical record. 2. Method Adults (≥ 18) who had attended the Royal Prince Alfred (RPA) Hospital Cystic Fibrosis Clinic, Sydney, Australia, between January 2009 and April 2016 (date of data extraction) were included in the study. This is one of three referral centres in the state. Data including age, sex, pancreatic insufficiency, transplant status, genotype, long-term prednisone use, glucose tolerance and insulin use were extracted from electronic medical records (EMR) via PowerChart Software. Annual screening for CFRD in non-diabetic patients is performed with a 2-hour OGTT. These follow consensus guidelines of consuming 75 g oral glucose following a period of fasting for 8 h [6]. Patients are also routinely instructed to consume a minimum of 150 g carbohydrate/day for the three preceding days. The majority of CF patients however consume well in excess of this daily. Glucose and insulin are measured at 0, 60 and 120 min. Plasma glucose and insulin were measured
in the hospital's accredited diagnostic laboratory using automated techniques (ABBOTT Architect iSR2097 analyser for insulin assay; Roche Cobas 8000 for glucose assay). The prevalence of fasting and 2-hour hypoglycaemia during an OGTT was determined in patients who had had at least one OGTT recorded during the study period. We only used OGTTs from hospital EMRs although an unknown percentage may have had external OGTTs. Hypoglycaemia was defined as per the American Diabetes Association (ADA) and Endocrine Society definition of ≤3.9 mmol/L [12]. Hypoglycaemia was further categorised as significant if glucose was b 3 mmol/L. This reflects the two-tiered definition presented by Armaghanian et al. [5] as well as the recent guidelines from the International Hypoglycaemia Study Group [13] which defines glucose b 3 mmol/L as clinically significant. Demographic and clinical data including age, sex, BMI, pancreatic insufficiency and lung function were extracted from the clinic visit closest to date of OGTT. Insulin response on the OGTT was described by measurement of the area under the insulin curve and the presence of delayed insulin release. Delayed insulin release was arbitrarily defined as an insulin value at 120 min ≥ 10% greater than an insulin value at 60 min. Incremental area under the insulin curve was calculated using the trapezoidal rule with the fasting value as baseline. Glucose tolerance results on each OGTT were described using the ADA definition which includes indeterminate glucose tolerance (INDET) to describe an abnormal glucose response at 1-h [6]. Insulin resistance (IR) was measured using the homeostasis model assessment for insulin resistance (HOMA) [14]. Patients identified to have hypoglycaemia on OGTT were compared to controls. Controls were age, sex and glucose tolerance matched, pre-transplant patients selected from the clinic that did not have hypoglycaemia, and did not use insulin or other glucose lowering medication. Matching was completed by firstly identifying all possible age, sex and glucose tolerance matched controls from the clinic for each participant with hypoglycaemia on OGTT. The final control was chosen at random and then removed from the possible list of controls to prevent matching again for a different participant. The ratio of cases to controls was 1:1. The prevalence of reported hypoglycaemia was determined by identifying patients who were not on insulin and who had reported symptoms suggestive of hypoglycaemia in free-living situations to the clinic endocrinologist or other clinic health professionals as documented in the medical record. Patient reported hypoglycaemia was concluded from patient symptoms and not supported by home glucose monitoring or CGM. The most recent OGTT for these patients was extracted as well as demographic and clinical parameters from the clinic visit date closest to the OGTT. Independent-Samples Mann-Whitney test was performed to determine differences between non-parametric continuous data between the group with hypoglycaemia on OGTT and controls. Categorical variables were compared using Pearson Chi-square or Fishers Exact Test. Significance was set at p b 0.05. IBM SPSS version 22 was used in the statistical analysis of results. The study was approved by the hospital's research ethics committee (HREC/ 15/RPAH/487; protocol number X15-0358).
Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
N. Armaghanian et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 1 Patient characteristics (n = 244). Characteristic
Value
Age; yr, mean (range) Sex; male, n (%) Pancreatic insufficiency; n (%) a Transplant, n (%) Long term prednisone, n (%) Liver disease, n (%) No. of patients with known glucose tolerance; n (%) NGT INDET IGT CFRD Clinic population on insulin; n (%)
33 (18–70) 122 (50) 205 (84) 25 (10) 24 (10) 23 (9) 220 (90) 78 22 37 83 76 (31)
a
3 missing data.
3. Results 3.1. Characteristics of CF clinic Two hundred and forty-four patients attended the CF clinic between January 2009 and April 2016. Table 1 shows the demographic and clinical characteristics of the clinic population at the time of data extraction. The median clinic BMI was 22 kg/m2 (range 16 to 36 kg/m2). The mean clinic lung function was FEV1 66% predicted (range 20–121%) and FVC 84% predicted (range 36–124%). HbA1c was available in 128 patients, although this is not used as a screening modality. Among these, eight patients had no OGTT result (median 6.2%; range 5.1–9.9%), 20 had NGT (median
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5.5%; range 4.7–6.7%), 7 had INDET (median 6%; range 5.3– 6.4%), 22 had IGT (median 5.7%; range 4–6.8%) and 70 had CFRD (median 6.2%; range 4.5–12.1%).
3.2. Hypoglycaemia on OGTT During the study timeframe, 169 of the total 244 patients had an OGTT. Twenty-five of these patients (15%), seven of whom were female, experienced hypoglycaemia during an OGTT. Three patients experienced fasting hypoglycaemia and 22 experienced hypoglycaemia at 2-h. Five patients had two OGTTs demonstrating hypoglycaemia over the study period. For these the most recent OGTT was selected for the purpose of summary and comparative analysis. Genotype data was not compared due to limited number of known genotypes. The 22 patients with postprandial hypoglycaemia had a median 2-h glucose of 3.4 mmol/L (range 2.7–3.9 mmol/L). Clinical characteristics and comparative data between patients with hypoglycaemic OGTTs at 2-h and matched controls are shown in Table 2. The mean age and sex of the three patients with fasting hypoglycaemia were 26 years and 1 male. Median BMI, FEV1% and FVC% were 22.1 kg/m2, 70% and 87% respectively. All three patients were pancreatic insufficient and had NGT, INDET or IGT. Median (range) AUC for insulin was 16,110 pmol/L (6840– 25,380) and one patient displayed a delayed insulin response. These patients were removed from further analysis due to limited numbers.
Table 2 Characteristics between patients with hypoglycaemic OGTT and controls. Characteristic
Hypoglycaemia on OGTT n = 22
Controls n = 22
Age; y Sex; f:m BMI; median (range) FEV1% predicted; median (range) FVC % predicted; median (range) Genotype; n ΔF508/ΔF508 Other Pancreatic insufficiency; n (%) Liver disease; n Transplant; n Glucose tolerance; n NGT INDET Insulin0; median (range) Insulin60; median (range) Insulin120; median (range) AUC Insulin; pmol/L; median (range) Delayed insulin response; n (%) IFG; n (%) HOMA-IR; median (range)
27 (18–47) 5:17 24.3 (20.1–35.9) 76 (36–117) 91 (52–117)
27 (18–47) 5:17 22.5 (19.1–29.4) 72 (29–96) 90 (40–117)
8a 9 13 (59) 0 0
7b 3 20 (95) c 2 (9) 0
18 4 27 (6–102) 213 (78–1164) 48 (18–294) 14,580 (5760–70,920) 1 (5) 3 (14) 0.5 (0.1–1.9)
18 4 30 (12–48) 237 (78–438) 129 (12 − 300) 19,800 (9180–33,120) 6 (27) 6 (27) 0.6 (0.2–0.9)
P-Value
0.028 0.302 0.716
0.012 0.457
0.766 0.888 0.000 0.526 0.095 0.457 0.823
The entries in bold are statistically significant (p b 0.05). a 5 unknown. b 12 unknown. c 1 missing data. Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
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Those patients that had hypoglycaemia at 2-h on OGTT were heavier, less likely to have pancreatic insufficiency and had a lower insulin response at 2-h. Five patients had significant hypoglycaemia (glucose b 3 mmol/L) and median glucose was 2.8 mmol/L (range 2.7–2.8 mmol/L). Median age and sex were 26 years and 3 males. Median BMI, FEV1% and FVC% were 23.8 kg/m2, 76% and 100% respectively. Four of the five patients were pancreatic sufficient, one had a delayed insulin response, three patients had NGT and two had INDET. There were no significant differences in BMI, lung function, pancreatic insufficiency, delayed insulin response and insulin AUC between those with significant hypoglycaemia and their age, sex and glucose tolerance matched controls. Those with significant hypoglycaemia however did have a significantly lower insulin response at 2-h compared to controls [48 pmol/L (range 24–96) vs 138 pmol/L (range 96–240); p-value = 0.008]. 3.3. Patient reported hypoglycaemia Fourteen patients had reported symptoms suggestive of hypoglycaemia in their EMR or during their hospital admission, five of which were female. The clinical characteristics of these patients are displayed in Table 3. The timing of symptoms consistent with hypoglycaemia was documented in the medical records and the situations when these symptoms occurred included: heavy physical work, missing or being late for a meal, postprandially after a high glycaemic load meal and following an oral glucose tolerance test. The medical record indicated that ten of the 14 participants had been educated by the dietitian following their appointment with the clinic endocrinologist. They had not received any education on hypoglycaemia management strategies prior to this clinic visit. The education provided by the dietitian included information on following a Table 3 Characteristics of reported hypoglycaemia group. Characteristic
Reported hypoglycaemia n = 14
Age; y Sex; f:m BMI; median (range) FEV1% predicted; median (range) FVC % predicted; median (range) Liver disease; n (%) Pancreatic insufficiency; n (%) Transplant; n (%) Glucose tolerance NGT INDET IGT CFRD Insulin0; median (range) Insulin60; median (range) Insulin120; median (range) AUC Insulin; uIU/mL, median (range) Delayed insulin response; n (%) IFG; n (%) HOMA-IR; median (range)
30 (19–56) 3:4 21.7 (19–24) 66 (20 − 120) 75 (50–124) 4 (29) 14 (100) 3 (21) 1 1 8 4 24 (18–60) 165 (96–672) 249 (66–636) 19,170 (9000–60,660) 10 (71) 3 (21) 0.5 (0.3–1.11)
lower glycaemic index (GI) diet. Only one patient in the reported hypoglycaemia group also showed hypoglycaemia on their OGTT and this presented as fasting hypoglycaemia. 4. Discussion The aim of this study was to better understand hypoglycaemia in the absence of glucose lowering therapies in an adult CF Clinic. Our recent systematic review [5] identified that hypoglycaemia in CF in the absence of diabetes and glucose lowering therapies is a recognised but not well understood phenomenon. This retrospective review study also showed that hypoglycaemia is not uncommon in our clinic population and similar to previous reports of hypoglycaemia during OGTTs [2]. The prevalence of NGT, INDET, IGT and CFRD in the clinic was similar to previously published data [1]. The novel finding was that hypoglycaemia during OGTT is not related to an abnormal insulin response as previously described. Reactive hypoglycaemia during OGTT occurred in patients who had a modestly higher BMI and were less likely to have pancreatic insufficiency compared to age and sex matched controls. Collectively, these characteristics are suggestive of better physical health in CF. A recent study in a pediatric population found that hypoglycaemia was more likely to occur in females, in those with poorer lung function and was related to a delayed and larger insulin response [15]. Using an insulin cut-off of 18 pmol/L as quoted in Cryer et al. (2009), no participant in this study appropriately suppressed insulin at 2-h. Interestingly, those with hypoglycaemia on OGTT seemed to suppress insulin more than their controls, and also more than the reported hypoglycaemia group. The absence of an exaggerated insulin response in participants with hypoglycaemia on OGTT compared to controls in this study indicates that the underlying mechanism for hypoglycaemia could be due to abnormal glucose metabolism related to glucagon and other incretins. A broader study involving the measurement of additional gut hormones during OGTT may better describe hypoglycaemia on OGTT and provide clinically useful information. If OGTTs are extended to 3 or 4 h, the rates of hypoglycaemia studies are higher (31% and 59%) and also more severe [2,3,16]. These observations raise the question whether patients should be monitored for symptomatic hypoglycaemia following the OGTT, particularly if two-hour readings are borderline [17]. Five participants had more significant post-prandial hypoglycaemia. These patients had favourable glucose tolerances (NGT and INDET), no delay in their peak insulin response and again showed characteristics of better physical health in CF. However due to small numbers, these results should be treated with caution and a larger cohort would be required to support this finding. Hypoglycaemia on OGTT is a commonly accepted phenomenon as an early indicator of abnormal glucose metabolism in Type 2 Diabetes (T2DM), where it likely associated with insulin resistance [18,19]. Post-prandial hypoglycaemia has been observed on OGTT in patients with early T2DM and this could be due to delayed initial release of insulin followed by an excessive, compensatory response [20]. However there
Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
N. Armaghanian et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
are limited rigorous studies on this topic and only in those with T2DM. A recent study found that hypoglycaemia during an OGTT was associated with increased insulin sensitivity and interestingly, those that had hypoglycaemia on OGTT in this study were also more likely to have a favourable glycaemic profile and NGT [19]. Previous studies have explored the predictive value of hypoglycaemia for the development of CFRD with varying results [2,4,21–23]. Prospective follow-up of the hypoglycaemia on OGTT group would help determine any association with the development of abnormal glucose tolerance and overt CFRD. Fasting hypoglycaemia in CF is likely to be related to a different mechanism to reactive hypoglycaemia. The literature reports fasting hypoglycaemia as reflecting states of malnutrition or increased energy expenditure [6]. The low number of fasting hypoglycaemia detected in this study limited any further analysis. Interestingly, only one patient in the hypoglycaemia on OGTT group, who presented with fasting hypoglycaemia on their OGTT, had reported symptoms suggestive of hypoglycaemia in the EMR. Strengths of this study include the large population and availability of both glucose and insulin measures in OGTT. The limitations were the retrospective nature of the study and absence of confirmatory non-OGTT related hypoglycaemia using CGM or home blood glucose monitoring. The specific symptoms suggestive of hypoglycaemia were absent for the majority of participants in this study. The clinician's diagnosis of possible hypoglycaemia was included in the medical record as well as trigger events of exercise or missed meals and rapid response to carbohydrate ingestion. 5. Conclusion OGTT related and symptomatic hypoglycaemia are not uncommon in CF, however the aetiology remains to be elucidated. We have found that hypoglycaemia on OGTT did not appear related to an abnormal insulin response and this warrants further study. Patients presenting with symptomatic hypoglycaemia were educated on modification of carbohydrate intake including following a low GI diet. These recommendations have been documented in existing clinical guidelines [10,24], and seem appealing due to their effects on glycaemic control in non-CF diabetic populations [25]. However empirical evidence in CF populations is required to support their uptake in clinical practice. Acknowledgements The authors would like to thank Amy Brown, administrative assistant at the Department of Respiratory Medicine, RPA Hospital, for her assistance in data retrieval, Liz Barnes for her assistance in statistical analyses and staff at the RPA CF clinic. Author's contributions N Armaghanian extracted data, analysed data, completed draft manuscript and following review, revised subsequent drafts. T P Markovic critically reviewed and revised manuscript.
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J C Brand-Miller critically reviewed and revised manuscript. P T Bye critically reviewed and revised manuscript. C P Moriarty critically reviewed and revised manuscript. K S Steinbeck conceptualised study, critically reviewed and revised draft manuscripts.
Conflicts of interest None declared.
References [1] Moran A, et al. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care 2009;32(9):1626–31. [2] Battezzati A, et al. Spontaneous hypoglycemia in patients with cystic fibrosis. Eur J Endocrinol 2007;156(3):369–76. [3] Hirsch IB, et al. Hypoglycemia in adults with cystic fibrosis during oral glucose tolerance testing. Diabetes Care 2013;36(8):e121-. [4] Radike K, et al. Prognostic relevance of hypoglycemia following an oral glucose challenge for cystic fibrosis-related diabetes. Diabetes Care 2011; 34(4):e43. [5] Armaghanian N, et al. Hypoglycaemia in cystic fibrosis in the absence of diabetes: a systematic review. J Cyst Fibros 2016;15(3):274–84. [6] Moran A, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the pediatric Endocrine Society. Diabetes Care 2010;33(12):2697–708. [7] Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol 2013;1(1):52–8. [8] Kelly A, Moran A. Update on cystic fibrosis-related diabetes. J Cyst Fibros 2013;12(4):318–31. [9] Watson RR. Diet and exercise in cystic fibrosis. Elsevier Science; 2014. [10] Brunzell C, et al. Managing cystic fibrosis-related diabetes (CFRD): an instruction guide for patients and families. 4th Edition. Cystic Fibrosis Foundation; 2008. [11] Moran A, et al. Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes 2014;15(S20):65–76. [12] Seaquist ER, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013;36(5):1384–95. [13] International Hypoglycaemia Study, G. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2017; 40(1):155–7. [14] Matthews D, et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412–9. [15] Haliloglu B, et al. Hypoglycemia is common in children with cystic fibrosis and seen predominantly in females. Pediatr Diabetes 2017;18(7): 607–13. [16] Thomas M, et al. Late hypoglycemia during glucose tolerance testing in cystic fibrosis. Pediatr Pulmonol 2004;38(S27):A344. [17] Fiato KW, et al. Annual cystic fibrosis oral glucose tolerance test: safety concerns and implications for patient care. Pediatric pulmonology. 111 River St, Hoboken 07030–5774, NJ USA: Wiley-Blackwell; 2015. [18] Brun JF, Fédou C, Mercier J. Postprandial reactive hypoglycemia. Diabetes Metab 2000;26(5):337–52. [19] Parekh S, et al. Clinical characteristics of people experiencing biochemical hypoglycaemia during an oral glucose tolerance test: cross-sectional analyses from a UK multi-ethnic population. Diabetes Res Clin Pract 2014;104(3): 427–34. [20] Seltzer HS, Fajans SS, Conn JW. Spontaneous hypoglycemia as an early manifestation of diabetes mellitus. Diabetes 1956;5(6):437–42.
Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
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[21] Verma A, et al. Follow up of the outcomes of patients with hypoglycaemic glucose tolerance tests in the Manchester Adult Cystic Fibrosis Centre, UK. Pediatr Pulmonol 2004;38(S27):A345. [22] Verma A, et al. Outcomes of patients with hypoglycaemic glucose tolerance tests an adult cystic fibrosis centre. J Cyst Fibros 2003;2(S1):S79. [23] Neff KJ, et al. The prognostic significance of hypoglycaemia on oral glucose tolerance tests in adults with cystic fibrosis (CF): a prospective cohort study. Ir J Med Sci 2013;182:S403.
[24] Perano S, et al. Cystic fibrosis related diabetes—a new perspective on the optimal management of postprandial glycemia. J Diabetes Complications 2014;28(6):904–11. [25] Thomas D, Elliott EJ. Low glycaemic index, or low glycaemic load, diets for diabetes mellitus. Cochrane Libr 2009(1).
Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic Natasha Armaghanian a,b,⁎, Tania P. Markovic c,d , Jennie C. Brand-Miller d,e , Peter T.P. Bye b , Carmel P. Moriarty b , Kate S. Steinbeck a,b,f a
Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Australia b Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, Australia c Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia d Boden Institute of Obesity, Nutrition and Exercise, University of Sydney, Australia e School of Molecular Bioscience, University of Sydney, Australia f Academic Department of Adolescent Medicine, The Children's Hospital at Westmead, Australia Received 7 April 2017; revised 27 August 2017; accepted 29 November 2017 Available online xxxx
Abstract Background: Hypoglycaemia in cystic fibrosis (CF) is known to occur during oral glucose tolerance tests (OGTT) and continuous glucose monitoring, however demographic, clinical and mechanistic data are limited. The aims of this study were to review patient electronic medical records (EMR) in order to 1) describe patient characteristics of a university teaching hospital CF clinic, 2) determine the prevalence of hypoglycaemia on OGTT and explore associations with demographic and clinical characteristics, and 3) explore patient reported symptoms suggestive of hypoglycaemia documented in the EMR. Methods: Adults who attended the RPA CF clinic between January 2009 to April 2016 were included in the study. The prevalence of hypoglycaemia on OGTT was determined and clinical and demographic data were compared to age, sex and glucose tolerance matched controls. Reported symptoms suggestive of hypoglycaemia documented in EMR were qualitatively explored. Results: Hypoglycaemia on OGTT was prevalent in 25 (3 fasting and 22 reactive) of 169 patients who had an OGTT. They were heavier, less likely to have pancreatic insufficiency and had a lower insulin response at 2-h. Another 14 patients reported symptoms suggestive of hypoglycaemia in their EMR. No patient appropriately suppressed insulin at 2-h on OGTT. Conclusions: This study identified two potentially different presentations of hypoglycaemia occur in different clinic sub-populations. Knowledge gaps in the aetiology and triggers of hypoglycaemia remain. © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Hypoglycaemia; Oral glucose tolerance test
1. Introduction Abbreviations: CF, cystic fibrosis; CFRD, cystic fibrosis related diabetes; CGM, continuous glucose monitoring; NGT, normal glucose tolerance; IGT, impaired glucose tolerance; INDET, indeterminate glucose tolerance; OGTT, oral glucose tolerance test; IFG, impaired fasting glucose ⁎ Corresponding author at: Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Australia. E-mail address: [email protected] (N. Armaghanian).
Complications of cystic fibrosis (CF) have increased in prevalence due to improvements in medical and surgical management, nutrition and hence survival rates. Cystic fibrosis related diabetes (CFRD) and states of abnormal glucose tolerance are the leading complications in patients with CF [1]. An increasingly recognised complication is the phenomenon of
https://doi.org/10.1016/j.jcf.2017.11.015 1569-1993© 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
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hypoglycaemia, in the absence of glucose lowering therapies. Hypoglycaemia has been documented in a clinical setting during an oral glucose tolerance test (OGTT) [2–4]. A recent systematic review found that the prevalence of hypoglycaemia ranged between 7 and 69% and was most commonly detected during OGTT or continuous glucose monitoring (CGM) [5]. Annual OGTTs with a 75 g oral glucose load are recommended to screen for CFRD [6]. CGM is often used as a supplementary monitoring tool in the diagnosis of impaired glucose tolerance (IGT) and CFRD [7]. Patients present with varying abnormalities of glucose tolerance and states of truly normal glycaemic control are rarely seen [8]. To date, there has been no consistent association between clinical and demographic characteristics of CF patients and outcomes of hypoglycaemia during OGTT or CGM [5]. Anecdotally, this is a well-recognised problem in pediatric and adult CF clinics where exercise and inadequate food intake may have a role in exacerbating symptoms suggestive of hypoglycaemia [9]. There are limited data on the patient experience and it is unclear whether hypoglycaemia in this population has significant clinical consequences. Several mechanisms for the cause of hypoglycaemia in the absence of glucose lowering therapies have been postulated. A delayed or excessive insulin release seems plausible [6,10,11], and has been reported by several authors, as has disrupted glucagon release [3]. A review of existing clinical practice guidelines found no unifying definition or explanation of spontaneous hypoglycaemia [5]. Of concern is that a lack of empirical evidence around the mechanistic cause for hypoglycaemia in these patients in turn also limits the management advice that can be given. The first aim of this study was to describe the demographic, clinical and biochemical characteristics of patients attending a university teaching hospital. The second aim was to determine the prevalence of hypoglycaemia on OGTT and explore the characteristics of patients who presented in this manner by comparing them to matched controls. The third aim was to qualitatively explore patient reported symptoms suggestive of hypoglycaemia documented in the medical record. 2. Method Adults (≥ 18) who had attended the Royal Prince Alfred (RPA) Hospital Cystic Fibrosis Clinic, Sydney, Australia, between January 2009 and April 2016 (date of data extraction) were included in the study. This is one of three referral centres in the state. Data including age, sex, pancreatic insufficiency, transplant status, genotype, long-term prednisone use, glucose tolerance and insulin use were extracted from electronic medical records (EMR) via PowerChart Software. Annual screening for CFRD in non-diabetic patients is performed with a 2-hour OGTT. These follow consensus guidelines of consuming 75 g oral glucose following a period of fasting for 8 h [6]. Patients are also routinely instructed to consume a minimum of 150 g carbohydrate/day for the three preceding days. The majority of CF patients however consume well in excess of this daily. Glucose and insulin are measured at 0, 60 and 120 min. Plasma glucose and insulin were measured
in the hospital's accredited diagnostic laboratory using automated techniques (ABBOTT Architect iSR2097 analyser for insulin assay; Roche Cobas 8000 for glucose assay). The prevalence of fasting and 2-hour hypoglycaemia during an OGTT was determined in patients who had had at least one OGTT recorded during the study period. We only used OGTTs from hospital EMRs although an unknown percentage may have had external OGTTs. Hypoglycaemia was defined as per the American Diabetes Association (ADA) and Endocrine Society definition of ≤3.9 mmol/L [12]. Hypoglycaemia was further categorised as significant if glucose was b 3 mmol/L. This reflects the two-tiered definition presented by Armaghanian et al. [5] as well as the recent guidelines from the International Hypoglycaemia Study Group [13] which defines glucose b 3 mmol/L as clinically significant. Demographic and clinical data including age, sex, BMI, pancreatic insufficiency and lung function were extracted from the clinic visit closest to date of OGTT. Insulin response on the OGTT was described by measurement of the area under the insulin curve and the presence of delayed insulin release. Delayed insulin release was arbitrarily defined as an insulin value at 120 min ≥ 10% greater than an insulin value at 60 min. Incremental area under the insulin curve was calculated using the trapezoidal rule with the fasting value as baseline. Glucose tolerance results on each OGTT were described using the ADA definition which includes indeterminate glucose tolerance (INDET) to describe an abnormal glucose response at 1-h [6]. Insulin resistance (IR) was measured using the homeostasis model assessment for insulin resistance (HOMA) [14]. Patients identified to have hypoglycaemia on OGTT were compared to controls. Controls were age, sex and glucose tolerance matched, pre-transplant patients selected from the clinic that did not have hypoglycaemia, and did not use insulin or other glucose lowering medication. Matching was completed by firstly identifying all possible age, sex and glucose tolerance matched controls from the clinic for each participant with hypoglycaemia on OGTT. The final control was chosen at random and then removed from the possible list of controls to prevent matching again for a different participant. The ratio of cases to controls was 1:1. The prevalence of reported hypoglycaemia was determined by identifying patients who were not on insulin and who had reported symptoms suggestive of hypoglycaemia in free-living situations to the clinic endocrinologist or other clinic health professionals as documented in the medical record. Patient reported hypoglycaemia was concluded from patient symptoms and not supported by home glucose monitoring or CGM. The most recent OGTT for these patients was extracted as well as demographic and clinical parameters from the clinic visit date closest to the OGTT. Independent-Samples Mann-Whitney test was performed to determine differences between non-parametric continuous data between the group with hypoglycaemia on OGTT and controls. Categorical variables were compared using Pearson Chi-square or Fishers Exact Test. Significance was set at p b 0.05. IBM SPSS version 22 was used in the statistical analysis of results. The study was approved by the hospital's research ethics committee (HREC/ 15/RPAH/487; protocol number X15-0358).
Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
N. Armaghanian et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 1 Patient characteristics (n = 244). Characteristic
Value
Age; yr, mean (range) Sex; male, n (%) Pancreatic insufficiency; n (%) a Transplant, n (%) Long term prednisone, n (%) Liver disease, n (%) No. of patients with known glucose tolerance; n (%) NGT INDET IGT CFRD Clinic population on insulin; n (%)
33 (18–70) 122 (50) 205 (84) 25 (10) 24 (10) 23 (9) 220 (90) 78 22 37 83 76 (31)
a
3 missing data.
3. Results 3.1. Characteristics of CF clinic Two hundred and forty-four patients attended the CF clinic between January 2009 and April 2016. Table 1 shows the demographic and clinical characteristics of the clinic population at the time of data extraction. The median clinic BMI was 22 kg/m2 (range 16 to 36 kg/m2). The mean clinic lung function was FEV1 66% predicted (range 20–121%) and FVC 84% predicted (range 36–124%). HbA1c was available in 128 patients, although this is not used as a screening modality. Among these, eight patients had no OGTT result (median 6.2%; range 5.1–9.9%), 20 had NGT (median
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5.5%; range 4.7–6.7%), 7 had INDET (median 6%; range 5.3– 6.4%), 22 had IGT (median 5.7%; range 4–6.8%) and 70 had CFRD (median 6.2%; range 4.5–12.1%).
3.2. Hypoglycaemia on OGTT During the study timeframe, 169 of the total 244 patients had an OGTT. Twenty-five of these patients (15%), seven of whom were female, experienced hypoglycaemia during an OGTT. Three patients experienced fasting hypoglycaemia and 22 experienced hypoglycaemia at 2-h. Five patients had two OGTTs demonstrating hypoglycaemia over the study period. For these the most recent OGTT was selected for the purpose of summary and comparative analysis. Genotype data was not compared due to limited number of known genotypes. The 22 patients with postprandial hypoglycaemia had a median 2-h glucose of 3.4 mmol/L (range 2.7–3.9 mmol/L). Clinical characteristics and comparative data between patients with hypoglycaemic OGTTs at 2-h and matched controls are shown in Table 2. The mean age and sex of the three patients with fasting hypoglycaemia were 26 years and 1 male. Median BMI, FEV1% and FVC% were 22.1 kg/m2, 70% and 87% respectively. All three patients were pancreatic insufficient and had NGT, INDET or IGT. Median (range) AUC for insulin was 16,110 pmol/L (6840– 25,380) and one patient displayed a delayed insulin response. These patients were removed from further analysis due to limited numbers.
Table 2 Characteristics between patients with hypoglycaemic OGTT and controls. Characteristic
Hypoglycaemia on OGTT n = 22
Controls n = 22
Age; y Sex; f:m BMI; median (range) FEV1% predicted; median (range) FVC % predicted; median (range) Genotype; n ΔF508/ΔF508 Other Pancreatic insufficiency; n (%) Liver disease; n Transplant; n Glucose tolerance; n NGT INDET Insulin0; median (range) Insulin60; median (range) Insulin120; median (range) AUC Insulin; pmol/L; median (range) Delayed insulin response; n (%) IFG; n (%) HOMA-IR; median (range)
27 (18–47) 5:17 24.3 (20.1–35.9) 76 (36–117) 91 (52–117)
27 (18–47) 5:17 22.5 (19.1–29.4) 72 (29–96) 90 (40–117)
8a 9 13 (59) 0 0
7b 3 20 (95) c 2 (9) 0
18 4 27 (6–102) 213 (78–1164) 48 (18–294) 14,580 (5760–70,920) 1 (5) 3 (14) 0.5 (0.1–1.9)
18 4 30 (12–48) 237 (78–438) 129 (12 − 300) 19,800 (9180–33,120) 6 (27) 6 (27) 0.6 (0.2–0.9)
P-Value
0.028 0.302 0.716
0.012 0.457
0.766 0.888 0.000 0.526 0.095 0.457 0.823
The entries in bold are statistically significant (p b 0.05). a 5 unknown. b 12 unknown. c 1 missing data. Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
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Those patients that had hypoglycaemia at 2-h on OGTT were heavier, less likely to have pancreatic insufficiency and had a lower insulin response at 2-h. Five patients had significant hypoglycaemia (glucose b 3 mmol/L) and median glucose was 2.8 mmol/L (range 2.7–2.8 mmol/L). Median age and sex were 26 years and 3 males. Median BMI, FEV1% and FVC% were 23.8 kg/m2, 76% and 100% respectively. Four of the five patients were pancreatic sufficient, one had a delayed insulin response, three patients had NGT and two had INDET. There were no significant differences in BMI, lung function, pancreatic insufficiency, delayed insulin response and insulin AUC between those with significant hypoglycaemia and their age, sex and glucose tolerance matched controls. Those with significant hypoglycaemia however did have a significantly lower insulin response at 2-h compared to controls [48 pmol/L (range 24–96) vs 138 pmol/L (range 96–240); p-value = 0.008]. 3.3. Patient reported hypoglycaemia Fourteen patients had reported symptoms suggestive of hypoglycaemia in their EMR or during their hospital admission, five of which were female. The clinical characteristics of these patients are displayed in Table 3. The timing of symptoms consistent with hypoglycaemia was documented in the medical records and the situations when these symptoms occurred included: heavy physical work, missing or being late for a meal, postprandially after a high glycaemic load meal and following an oral glucose tolerance test. The medical record indicated that ten of the 14 participants had been educated by the dietitian following their appointment with the clinic endocrinologist. They had not received any education on hypoglycaemia management strategies prior to this clinic visit. The education provided by the dietitian included information on following a Table 3 Characteristics of reported hypoglycaemia group. Characteristic
Reported hypoglycaemia n = 14
Age; y Sex; f:m BMI; median (range) FEV1% predicted; median (range) FVC % predicted; median (range) Liver disease; n (%) Pancreatic insufficiency; n (%) Transplant; n (%) Glucose tolerance NGT INDET IGT CFRD Insulin0; median (range) Insulin60; median (range) Insulin120; median (range) AUC Insulin; uIU/mL, median (range) Delayed insulin response; n (%) IFG; n (%) HOMA-IR; median (range)
30 (19–56) 3:4 21.7 (19–24) 66 (20 − 120) 75 (50–124) 4 (29) 14 (100) 3 (21) 1 1 8 4 24 (18–60) 165 (96–672) 249 (66–636) 19,170 (9000–60,660) 10 (71) 3 (21) 0.5 (0.3–1.11)
lower glycaemic index (GI) diet. Only one patient in the reported hypoglycaemia group also showed hypoglycaemia on their OGTT and this presented as fasting hypoglycaemia. 4. Discussion The aim of this study was to better understand hypoglycaemia in the absence of glucose lowering therapies in an adult CF Clinic. Our recent systematic review [5] identified that hypoglycaemia in CF in the absence of diabetes and glucose lowering therapies is a recognised but not well understood phenomenon. This retrospective review study also showed that hypoglycaemia is not uncommon in our clinic population and similar to previous reports of hypoglycaemia during OGTTs [2]. The prevalence of NGT, INDET, IGT and CFRD in the clinic was similar to previously published data [1]. The novel finding was that hypoglycaemia during OGTT is not related to an abnormal insulin response as previously described. Reactive hypoglycaemia during OGTT occurred in patients who had a modestly higher BMI and were less likely to have pancreatic insufficiency compared to age and sex matched controls. Collectively, these characteristics are suggestive of better physical health in CF. A recent study in a pediatric population found that hypoglycaemia was more likely to occur in females, in those with poorer lung function and was related to a delayed and larger insulin response [15]. Using an insulin cut-off of 18 pmol/L as quoted in Cryer et al. (2009), no participant in this study appropriately suppressed insulin at 2-h. Interestingly, those with hypoglycaemia on OGTT seemed to suppress insulin more than their controls, and also more than the reported hypoglycaemia group. The absence of an exaggerated insulin response in participants with hypoglycaemia on OGTT compared to controls in this study indicates that the underlying mechanism for hypoglycaemia could be due to abnormal glucose metabolism related to glucagon and other incretins. A broader study involving the measurement of additional gut hormones during OGTT may better describe hypoglycaemia on OGTT and provide clinically useful information. If OGTTs are extended to 3 or 4 h, the rates of hypoglycaemia studies are higher (31% and 59%) and also more severe [2,3,16]. These observations raise the question whether patients should be monitored for symptomatic hypoglycaemia following the OGTT, particularly if two-hour readings are borderline [17]. Five participants had more significant post-prandial hypoglycaemia. These patients had favourable glucose tolerances (NGT and INDET), no delay in their peak insulin response and again showed characteristics of better physical health in CF. However due to small numbers, these results should be treated with caution and a larger cohort would be required to support this finding. Hypoglycaemia on OGTT is a commonly accepted phenomenon as an early indicator of abnormal glucose metabolism in Type 2 Diabetes (T2DM), where it likely associated with insulin resistance [18,19]. Post-prandial hypoglycaemia has been observed on OGTT in patients with early T2DM and this could be due to delayed initial release of insulin followed by an excessive, compensatory response [20]. However there
Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015
N. Armaghanian et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
are limited rigorous studies on this topic and only in those with T2DM. A recent study found that hypoglycaemia during an OGTT was associated with increased insulin sensitivity and interestingly, those that had hypoglycaemia on OGTT in this study were also more likely to have a favourable glycaemic profile and NGT [19]. Previous studies have explored the predictive value of hypoglycaemia for the development of CFRD with varying results [2,4,21–23]. Prospective follow-up of the hypoglycaemia on OGTT group would help determine any association with the development of abnormal glucose tolerance and overt CFRD. Fasting hypoglycaemia in CF is likely to be related to a different mechanism to reactive hypoglycaemia. The literature reports fasting hypoglycaemia as reflecting states of malnutrition or increased energy expenditure [6]. The low number of fasting hypoglycaemia detected in this study limited any further analysis. Interestingly, only one patient in the hypoglycaemia on OGTT group, who presented with fasting hypoglycaemia on their OGTT, had reported symptoms suggestive of hypoglycaemia in the EMR. Strengths of this study include the large population and availability of both glucose and insulin measures in OGTT. The limitations were the retrospective nature of the study and absence of confirmatory non-OGTT related hypoglycaemia using CGM or home blood glucose monitoring. The specific symptoms suggestive of hypoglycaemia were absent for the majority of participants in this study. The clinician's diagnosis of possible hypoglycaemia was included in the medical record as well as trigger events of exercise or missed meals and rapid response to carbohydrate ingestion. 5. Conclusion OGTT related and symptomatic hypoglycaemia are not uncommon in CF, however the aetiology remains to be elucidated. We have found that hypoglycaemia on OGTT did not appear related to an abnormal insulin response and this warrants further study. Patients presenting with symptomatic hypoglycaemia were educated on modification of carbohydrate intake including following a low GI diet. These recommendations have been documented in existing clinical guidelines [10,24], and seem appealing due to their effects on glycaemic control in non-CF diabetic populations [25]. However empirical evidence in CF populations is required to support their uptake in clinical practice. Acknowledgements The authors would like to thank Amy Brown, administrative assistant at the Department of Respiratory Medicine, RPA Hospital, for her assistance in data retrieval, Liz Barnes for her assistance in statistical analyses and staff at the RPA CF clinic. Author's contributions N Armaghanian extracted data, analysed data, completed draft manuscript and following review, revised subsequent drafts. T P Markovic critically reviewed and revised manuscript.
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J C Brand-Miller critically reviewed and revised manuscript. P T Bye critically reviewed and revised manuscript. C P Moriarty critically reviewed and revised manuscript. K S Steinbeck conceptualised study, critically reviewed and revised draft manuscripts.
Conflicts of interest None declared.
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Please cite this article as: Armaghanian N, et al, Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic, J Cyst Fibros (2017), https:// doi.org/10.1016/j.jcf.2017.11.015