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Overuse of Hematocrit Testing After Elective General Surgery at a Veterans Affairs Medical Center
It is common practice to routinely measure postoperative hematocrit levels at US Department of Veterans Affairs (VA) hospitals for a wide range of elective general surgeries. While hematocrit measurement is a low-cost test, the high frequency with which these tests are performed may drastically increase overall costs.
Numerous studies have suggested that physicians overuse laboratory testing.1-10 Kohli and colleagues recommended that the routine practice of obtaining postoperative hematocrit tests following elective gynecologic surgery be abandoned.1 A similar recommendation was made by Olus and colleagues after studying uneventful, unplanned cesarean sections and by Wu and colleagues after investigating routine laboratory tests post total hip arthroplasty.2,3
To our knowledge, a study assessing routine postoperative hematocrit testing in elective general surgery has not yet been conducted. Many laboratory tests ordered in the perioperative period are not indicated, including complete blood count (CBC), electrolytes, and coagulation studies.4 Based on the results of these studies, we expected that the routine measurement of postoperative hematocrit levels after elective general surgeries at VA medical centers would not be cost effective. A PubMed search for articles published from 1990 to 2023 using the search terms “hematocrit,” “hemoglobin,” “general,” “surgery,” “routine,” and “cost” or “cost-effectiveness,” suggests that the clinical usefulness of postoperative hematocrit testing has not been well studied in the general surgery setting. The purpose of this study was to determine the clinical utility and associated cost of measuring routine postoperative hematocrit levels in order to generate a guide as to when the practice is warranted following common elective general surgery.
Although gynecologic textbooks may describe recommendations of routine hematocrit checking after elective gynecologic operations, one has difficulty finding the same recommendations in general surgery textbooks.1 However, it is common practice for surgical residents and attending surgeons to routinely order hematocrit on postoperative day-1 to ensure that the operation did not result in unsuspected anemia that then would need treatment (either with fluids or a blood transfusion). Many other surgeons rely on clinical factors such as tachycardia, oliguria, or hypotension to trigger a hematocrit (and other laboratory) tests. Our hypothesis is that the latter group has chosen the most cost-effective and prudent practice. One problem with checking the hematocrit routinely, as with any other screening test, is what to do with an abnormal result, assuming an asymptomatic patient? If the postoperative hematocrit is lower than expected given the estimated blood loss (EBL), what is one to do?
Methods
This retrospective case-control study conducted at the New Mexico VA Health Care System (NMVAHCS) in Albuquerque compared data for patients who received transfusion within 72 hours of elective surgeries vs patients who did not. Patients who underwent elective general surgery from January 2011 through December 2014 were included. An elective general surgery was defined as surgery performed following an outpatient preoperative anesthesia evaluation ≥ 30 days prior to operation. Patients who underwent emergency operations, and those with baseline anemia (preoperative hematocrit < 30%), and those transfused > 72 hours after their operation were excluded. The NMVAHCSInstitutional Review Board approved this study (No. 15-H184).
A detailed record review was conducted to collect data on demographics and other preoperative risk factors, including age, sex, body mass index (BMI), race and ethnicity, cardiac and pulmonary comorbidities, tobacco use, alcohol intake, diabetes, American Society of Anesthesiologists Physical Status Classification, metabolic equivalent of task, hematologic conditions, and renal disease.
For each procedure, we recorded the type of elective general surgery performed, the diagnosis/indication, pre- and postoperative hemoglobin/hematocrit, intraoperative EBL, length of operation, surgical wound class, length of hospital stay (LOS), intensive care unit (ICU) status, number of hematocrit tests, cardiovascular risk of operation (defined by anesthesia assessment), presence or absence of malignancy, preoperative platelet count, albumin level, preoperative prothrombin time/activated partial thromboplastin time (aPTT), international normalized ratio (INR), hemoglobin A1c, and incidence of transfusion. Signs and symptoms of anemia were recorded as present if the postoperative vital signs suggested low intravascular volume (pulse > 120 beats/minute, systolic blood pressure < 90 mm Hg, or vasoactive medication requirement [per anesthesia postoperative note]) or if the patient reported or exhibited symptoms of dizziness or fatigue or evidence of clinically apparent bleeding (ie, hematoma formation). Laboratory charges for hematocrit tests and CBC at the NMAVAHCS were used to assess cost.11
To stratify the transfusion risk, patients were distributed among 3 groups based on the following criteria: discharged home the same day as surgery; admitted but did not have postoperative hematocrit testing; and admitted and had postoperative hematocrit testing. We also stratified operations into low or high risk based on the risk for postoperative transfusion (Figure). Recognizing that the American College of Chest Physicians guidelines for perioperative management of antithrombotic therapy places bowel resection in a high-risk category, we designated a surgery as high risk when ≥ 2 patients in the transfusion group had that type of surgery over the 4 years of the study.12 Otherwise, the operations were deemed low risk.
Statistical Analysis
Numeric analysis used t tests and Binary and categorical variables used Fisher exact tests. P value ≤ .05 was considered statistically significant. SAS software was used for all statistical analyses.
Results
From 2011 through 2014, 1531 patients had elective general surgery at NMVAHCS. Twenty-two patients with preoperative anemia (hematocrit < 30%) and 1 patient who received a transfusion > 72 hours after the operation were excluded. Most elective operations (70%, n = 1075) were performed on an outpatient basis; none involved transfusion. Inguinal hernia repair was most common with 479 operations; 17 patients were treated inpatient of which 2 patients had routine postoperative hematocrit checks; (neither received transfusion). One patient with inguinal hernia surgery received transfusion without routine postoperative hematocrit monitoring.
Of 112 partial colon resections, 1 patient had a postoperative transfusion; and all but 3 received postoperative hematocrit monitoring. Nineteen patients undergoing partial colon resection had a clinical indication for postoperative hematocrit monitoring. None of the 5 patients with partial gastrectomy received a postoperative transfusion. Of 121 elective cholecystectomies, no patients had postoperative transfusion, whereas 34 had postoperative hematocrit monitoring; only 2 patients had a clinical reason for the hematocrit monitoring.
Of 430 elective inpatient operations, 12 received transfusions and 288 patients had ≥ 1 postoperative hematocrit test (67%). All hematocrit tests were requested by the attending surgeon, resident surgeon, or the surgical ICU team. Of the group that had postoperative hematocrit monitoring, there was an average of 4.4 postoperative hematocrit tests per patient (range, 1-44).
There were 12 transfusions for inpatients (2.8%), which is similar to the findings of a recent study of VA general surgery (2.3%).13 Five of the 12 patients received intraoperative transfusions while 7 were transfused within 72 hours postoperation. All but 1 patient receiving transfusion had EBL > 199 mL (range, 5-3000; mean, 950 mL; median, 500 mL) and/or signs or symptoms of anemia or other indications for measurement of the postoperative hematocrit. There were no statistically significant differences in patients’ age, sex, BMI, or race and ethnicity between groups receiving and not receiving transfusion (Table 1).
When comparing the transfusion vs the nontransfusion groups (after excluding those with clinical preoperative anemia) the risk factors for transfusion included: relatively low mean preoperative hematocrit (mean, 36.9% vs 42.7%, respectively; P = .003), low postoperative hematocrit (mean, 30.2% vs 37.1%, respectively; P < .001), high EBL (mean, 844 mL vs 109 mL, respectively; P = .005), large infusion of intraoperative fluids (mean, 4625 mL vs 2505 mL, respectively; P = .005), longer duration of operation (mean, 397 min vs 183 min, respectively; P < .001), and longer LOS (mean, 14.5 d vs 4.9 d, respectively; P < .001) (Table 2). Similarly, we found an increased risk for transfusion with high/intermediate cardiovascular risk (vs low), any wound not classified as clean, ICU stay, and postoperative symptoms of anemia.
We found no increased risk for transfusion with ethanol, tobacco, warfarin, or clopidogrel use; polycythemia; thrombocytopenia; preoperative INR; preoperative aPTT; preoperative albumin; Hemoglobin A1c; or diabetes mellitus; or for operations performed for malignancy. Ten patients in the ICU received transfusion (5.8%) compared with 2 patients (0.8%) not admitted to the ICU.
Operations were deemed high risk when ≥ 2 of patients having that operation received transfusions within 72 hours of their operation. There were 15 abdominoperineal resections; 3 of these received transfusions (20%). There were 7 total abdominal colectomies; 3 of these received transfusions (43%). We therefore had 22 high-risk operations, 6 of which were transfused (27%).
Discussion
Routine measurement of postoperative hematocrit levels after elective general surgery at NMVAHCS was not necessary. There were 12 transfusions for inpatients (2.8%), which is similar to the findings of a recent study of VA general surgery (2.3%).13 We found that routine postoperative hematocrit measurements to assess anemia had little or no effect on clinical decision-making or clinical outcomes.
According to our results, 88% of initial hematocrit tests after elective partial colectomies could have been eliminated; only 32 of 146 patients demonstrated a clinical reason for postoperative hematocrit testing. Similarly, 36 of 40 postcholecystectomy hematocrit tests (90%) could have been eliminated had the surgeons relied on clinical signs indicating possible postoperative anemia (none were transfused). Excluding patients with major intraoperative blood loss (> 300 mL), only 29 of 288 (10%) patients who had postoperative hematocrit tests had a clinical indication for a postoperative hematocrit test (ie, symptoms of anemia and/or active bleeding). One patient with inguinal hernia surgery who received transfusion was taking an anticoagulant and had a clinically indicated hematocrit test for a large hematoma that eventually required reoperation.
Our study found that routine hematocrit checks may actually increase the risk that a patient would receive an unnecessary transfusion. For instance, one elderly patient, after a right colectomy, had 6 hematocrit levels while on a heparin drip and received transfusion despite being asymptomatic. His lowest hematocrit level prior to transfusion was 23.7%. This patient had a total of 18 hematocrit tests. His EBL was 350 mL and his first postoperative HCT level was 33.1%. In another instance, a patient undergoing abdominoperineal resection had a transfusion on postoperative day 1, despite being hypertensive, with a hematocrit that ranged from 26% before transfusion to 31% after the transfusion. These 2 cases illustrate what has been shown in a recent study: A substantial number of patients with colorectal cancer receive unnecessary transfusions.14 On the other hand, one ileostomy closure patient had 33 hematocrit tests, yet his initial postoperative hematocrit was 37%, and he never received a transfusion. With low-risk surgeries, clinical judgment should dictate when a postoperative hematocrit level is needed. This strategy would have eliminated 206 unnecessary initial postoperative hematocrit tests (72%), could have decreased the number of unnecessary transfusions, and would have saved NMVAHCS about $1600 annually.
Abdominoperineal resections and total abdominal colectomies accounted for a high proportion of transfusions in our study. Inpatient elective operations can be risk stratified and have routine hematocrit tests ordered for patients at high risk. The probability of transfusion was greater in high-risk vs low-risk surgeries; 27% (6 of 22 patients) vs 2% (6 of 408 patients), respectively (P < .001). Since 14 of the 22 patients undergoing high-risk operation already had clinical reasons for a postoperative hematocrit test, we only need to add the remaining 8 patients with high-risk operations to the 74 who had a clinical reason for a hematocrit test and conclude that 82 of 430 patients (19%) had a clinical reason for a hematocrit test, either from signs or symptoms of blood loss or because they were in a high-risk group.
While our elective general surgery cases may not represent many general surgery programs in the US and VA health care systems, we can extrapolate cost savings using the same cost analyses outlined by Kohli and colleagues.1 Assuming 1.9 million elective inpatient general surgeries per year in the United States with an average cost of $21 per CBC, the annual cost of universal postoperative hematocrit testing would be $40 million.11,15 If postoperative hematocrit testing were 70% consistent with our findings, the annual cost for hematocrit tests on 51% of the inpatient general surgeries would be approximately $20.4 million. A reduction in routine hematocrit testing to 25% of all inpatient general surgeries (vs our finding that 19% were deemed necessary) results in an annual savings of $30 million. This conservative estimate could be even higher since there were 4.4 hematocrit tests per patient; therefore, we have about $132 million in savings.
Assuming 181,384 elective VA inpatient general surgeries each year, costing $7.14 per CBC (the NMVAHCS cost), the VA could save $1.3 million annually. If postoperative HCT testing were 70% consistent with our findings, the annual cost for hematocrit tests on 50.4% of inpatient general surgery operations would be about $653,000. A reduction in routine hematocrit testing to 25% of all inpatient general surgeries (vs our 19%) results in annual VA savings of $330,000. This conservative estimate could be even higher since there were on average 4.4 hematocrit levels per patient; therefore, we estimate that annual savings for the VA of about $1.45 million.
Limitations
The retrospective chart review nature of this study may have led to selection bias. Only a small number of patients received a transfusion, which may have skewed the data. This study population comes from a single VA medical center; this patient population may not be reflective of other VA medical centers or the US population as a whole. Given that NMVAHCS does not perform hepatic, esophageal, pancreas, or transplant operations, the potential savings to both the US and the VA may be overestimated, but this could be studied in the future by VA medical centers that perform more complex operations.
Conclusions
This study found that over a 4-year period routine postoperative hematocrit tests for patients undergoing elective general surgery at a VA medical center were not necessary. General surgeons routinely order various pre- and postoperative laboratory tests despite their limited utility. Reduction in unneeded routine tests could result in notable savings to the VA without compromising quality of care.
Only general surgery patients undergoing operations that carry a high risk for needing a blood transfusion should have a routine postoperative hematocrit testing. In our study population, the chance of an elective colectomy, cholecystectomy, or hernia patient needing a transfusion was rare. This strategy could eliminate a considerable number of unnecessary blood tests and would potentially yield significant savings.
1. Kohli N, Mallipeddi PK, Neff JM, Sze EH, Roat TW. Routine hematocrit after elective gynecologic surgery. Obstet Gynecol. 2000;95(6 Pt 1):847-850. doi:10.1016/s0029-7844(00)00796-1
2. Olus A, Orhan, U, Murat A, et al. Do asymptomatic patients require routine hemoglobin testing following uneventful, unplanned cesarean sections? Arch Gynecol Obstet. 2010;281(2):195-199. doi:10.1007/s00404-009-1093-1
3. Wu XD, Zhu ZL, Xiao P, Liu JC, Wang JW, Huang W. Are routine postoperative laboratory tests necessary after primary total hip arthroplasty? J Arthroplasty. 2020;35(10):2892-2898. doi:10.1016/j.arth.2020.04.097
4. Kumar A, Srivastava U. Role of routine laboratory investigations in preoperative evaluation. J Anesthesiol Clin Pharmacol. 2011;27(2):174-179. doi:10.4103/0970-9185.81824
5. Aghajanian A, Grimes DA. Routine prothrombin time determination before elective gynecologic operations. Obstet Gynecol. 1991;78(5 Pt 1):837-839.
6. Ransom SB, McNeeley SG, Malone JM Jr. A cost-effectiveness evaluation of preoperative type-and-screen testing for vaginal hysterectomy. Am J Obstet Gynecol. 1996;175(5):1201-1203. doi:10.1016/s0002-9378(96)70028-5
7. Ransom SB, McNeeley SG, Hosseini RB. Cost-effectiveness of routine blood type and screen testing before elective laparoscopy. Obstet Gynecol. 1995;86(3):346-348. doi:10.1016/0029-7844(95)00187-V
8. Committee on Standards and Practice Parameters, Apfelbaum JL, Connis RT, et al. Practice advisory for preanesthesia evaluation: an updated report by the American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology. 2012;116(3):522-538. doi:10.1097/ALN.0b013e31823c1067
9. Weil IA, Seicean S, Neuhauser D, Schiltz NK, Seicean A. Use and utility of hemostatic screening in adults undergoing elective, non-cardiac surgery. PLoS One. 2015;10(12):e0139139. doi:10.1371/journal.pone.0139139
10. Wu WC, Schifftner TL, Henderson WG, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing non-cardiac surgery. JAMA. 2007;297(22):2481-2488. doi:10.1001/jama.297.22.2481
11. Healthcare Bluebook. Complete blood count (CBC) with differential. Accessed March 28, 2024. https://www.healthcarebluebook.com/page_ProcedureDetails.aspx?id=214&dataset=lab
12. Douketis JD, Spyropoulos AC, Murad MH, et al. Perioperative management of antithrombotic therapy: an American College of Chest Physicians Clinical Practice Guideline. Chest. 2022;162(5):e207-e243. doi:10.1016/j.chest.2022.07.025
13. Randall JA, Wagner KT, Brody F. Perioperative transfusions in veterans following noncardiac procedures. J Laparoendosc Adv Surg Tech A. 2023;33(10):923-931. doi:10.1089/lap. 2023.0307
14. Tartter PI, Barron DM. Unnecessary blood transfusions in elective colorectal cancer surgery. Transfusion. 1985;25(2):113-115. doi:10.1046/j.1537-2995.1985.25285169199.x
15. Steiner CA, Karaca Z, Moore BJ, Imshaug MC, Pickens G. Surgeries in hospital-based ambulatory surgery and hospital inpatient settings, 2014. Healthcare Cost and Utilization Project statistical brief #223. May 2017. Revised July 2020. Agency for Healthcare Research and Quality. Accessed February 26, 2024. https://hcup-us.ahrq.gov/reports/statbriefs/sb223-Ambulatory-Inpatient-Surgeries-2014.pdf
16. US Department of Veterans Affairs, National Surgery Office. Quarterly report: Q3 of fiscal year 2017. VISN operative complexity summary [Source not verified].
It is common practice to routinely measure postoperative hematocrit levels at US Department of Veterans Affairs (VA) hospitals for a wide range of elective general surgeries. While hematocrit measurement is a low-cost test, the high frequency with which these tests are performed may drastically increase overall costs.
Numerous studies have suggested that physicians overuse laboratory testing.1-10 Kohli and colleagues recommended that the routine practice of obtaining postoperative hematocrit tests following elective gynecologic surgery be abandoned.1 A similar recommendation was made by Olus and colleagues after studying uneventful, unplanned cesarean sections and by Wu and colleagues after investigating routine laboratory tests post total hip arthroplasty.2,3
To our knowledge, a study assessing routine postoperative hematocrit testing in elective general surgery has not yet been conducted. Many laboratory tests ordered in the perioperative period are not indicated, including complete blood count (CBC), electrolytes, and coagulation studies.4 Based on the results of these studies, we expected that the routine measurement of postoperative hematocrit levels after elective general surgeries at VA medical centers would not be cost effective. A PubMed search for articles published from 1990 to 2023 using the search terms “hematocrit,” “hemoglobin,” “general,” “surgery,” “routine,” and “cost” or “cost-effectiveness,” suggests that the clinical usefulness of postoperative hematocrit testing has not been well studied in the general surgery setting. The purpose of this study was to determine the clinical utility and associated cost of measuring routine postoperative hematocrit levels in order to generate a guide as to when the practice is warranted following common elective general surgery.
Although gynecologic textbooks may describe recommendations of routine hematocrit checking after elective gynecologic operations, one has difficulty finding the same recommendations in general surgery textbooks.1 However, it is common practice for surgical residents and attending surgeons to routinely order hematocrit on postoperative day-1 to ensure that the operation did not result in unsuspected anemia that then would need treatment (either with fluids or a blood transfusion). Many other surgeons rely on clinical factors such as tachycardia, oliguria, or hypotension to trigger a hematocrit (and other laboratory) tests. Our hypothesis is that the latter group has chosen the most cost-effective and prudent practice. One problem with checking the hematocrit routinely, as with any other screening test, is what to do with an abnormal result, assuming an asymptomatic patient? If the postoperative hematocrit is lower than expected given the estimated blood loss (EBL), what is one to do?
Methods
This retrospective case-control study conducted at the New Mexico VA Health Care System (NMVAHCS) in Albuquerque compared data for patients who received transfusion within 72 hours of elective surgeries vs patients who did not. Patients who underwent elective general surgery from January 2011 through December 2014 were included. An elective general surgery was defined as surgery performed following an outpatient preoperative anesthesia evaluation ≥ 30 days prior to operation. Patients who underwent emergency operations, and those with baseline anemia (preoperative hematocrit < 30%), and those transfused > 72 hours after their operation were excluded. The NMVAHCSInstitutional Review Board approved this study (No. 15-H184).
A detailed record review was conducted to collect data on demographics and other preoperative risk factors, including age, sex, body mass index (BMI), race and ethnicity, cardiac and pulmonary comorbidities, tobacco use, alcohol intake, diabetes, American Society of Anesthesiologists Physical Status Classification, metabolic equivalent of task, hematologic conditions, and renal disease.
For each procedure, we recorded the type of elective general surgery performed, the diagnosis/indication, pre- and postoperative hemoglobin/hematocrit, intraoperative EBL, length of operation, surgical wound class, length of hospital stay (LOS), intensive care unit (ICU) status, number of hematocrit tests, cardiovascular risk of operation (defined by anesthesia assessment), presence or absence of malignancy, preoperative platelet count, albumin level, preoperative prothrombin time/activated partial thromboplastin time (aPTT), international normalized ratio (INR), hemoglobin A1c, and incidence of transfusion. Signs and symptoms of anemia were recorded as present if the postoperative vital signs suggested low intravascular volume (pulse > 120 beats/minute, systolic blood pressure < 90 mm Hg, or vasoactive medication requirement [per anesthesia postoperative note]) or if the patient reported or exhibited symptoms of dizziness or fatigue or evidence of clinically apparent bleeding (ie, hematoma formation). Laboratory charges for hematocrit tests and CBC at the NMAVAHCS were used to assess cost.11
To stratify the transfusion risk, patients were distributed among 3 groups based on the following criteria: discharged home the same day as surgery; admitted but did not have postoperative hematocrit testing; and admitted and had postoperative hematocrit testing. We also stratified operations into low or high risk based on the risk for postoperative transfusion (Figure). Recognizing that the American College of Chest Physicians guidelines for perioperative management of antithrombotic therapy places bowel resection in a high-risk category, we designated a surgery as high risk when ≥ 2 patients in the transfusion group had that type of surgery over the 4 years of the study.12 Otherwise, the operations were deemed low risk.
Statistical Analysis
Numeric analysis used t tests and Binary and categorical variables used Fisher exact tests. P value ≤ .05 was considered statistically significant. SAS software was used for all statistical analyses.
Results
From 2011 through 2014, 1531 patients had elective general surgery at NMVAHCS. Twenty-two patients with preoperative anemia (hematocrit < 30%) and 1 patient who received a transfusion > 72 hours after the operation were excluded. Most elective operations (70%, n = 1075) were performed on an outpatient basis; none involved transfusion. Inguinal hernia repair was most common with 479 operations; 17 patients were treated inpatient of which 2 patients had routine postoperative hematocrit checks; (neither received transfusion). One patient with inguinal hernia surgery received transfusion without routine postoperative hematocrit monitoring.
Of 112 partial colon resections, 1 patient had a postoperative transfusion; and all but 3 received postoperative hematocrit monitoring. Nineteen patients undergoing partial colon resection had a clinical indication for postoperative hematocrit monitoring. None of the 5 patients with partial gastrectomy received a postoperative transfusion. Of 121 elective cholecystectomies, no patients had postoperative transfusion, whereas 34 had postoperative hematocrit monitoring; only 2 patients had a clinical reason for the hematocrit monitoring.
Of 430 elective inpatient operations, 12 received transfusions and 288 patients had ≥ 1 postoperative hematocrit test (67%). All hematocrit tests were requested by the attending surgeon, resident surgeon, or the surgical ICU team. Of the group that had postoperative hematocrit monitoring, there was an average of 4.4 postoperative hematocrit tests per patient (range, 1-44).
There were 12 transfusions for inpatients (2.8%), which is similar to the findings of a recent study of VA general surgery (2.3%).13 Five of the 12 patients received intraoperative transfusions while 7 were transfused within 72 hours postoperation. All but 1 patient receiving transfusion had EBL > 199 mL (range, 5-3000; mean, 950 mL; median, 500 mL) and/or signs or symptoms of anemia or other indications for measurement of the postoperative hematocrit. There were no statistically significant differences in patients’ age, sex, BMI, or race and ethnicity between groups receiving and not receiving transfusion (Table 1).
When comparing the transfusion vs the nontransfusion groups (after excluding those with clinical preoperative anemia) the risk factors for transfusion included: relatively low mean preoperative hematocrit (mean, 36.9% vs 42.7%, respectively; P = .003), low postoperative hematocrit (mean, 30.2% vs 37.1%, respectively; P < .001), high EBL (mean, 844 mL vs 109 mL, respectively; P = .005), large infusion of intraoperative fluids (mean, 4625 mL vs 2505 mL, respectively; P = .005), longer duration of operation (mean, 397 min vs 183 min, respectively; P < .001), and longer LOS (mean, 14.5 d vs 4.9 d, respectively; P < .001) (Table 2). Similarly, we found an increased risk for transfusion with high/intermediate cardiovascular risk (vs low), any wound not classified as clean, ICU stay, and postoperative symptoms of anemia.
We found no increased risk for transfusion with ethanol, tobacco, warfarin, or clopidogrel use; polycythemia; thrombocytopenia; preoperative INR; preoperative aPTT; preoperative albumin; Hemoglobin A1c; or diabetes mellitus; or for operations performed for malignancy. Ten patients in the ICU received transfusion (5.8%) compared with 2 patients (0.8%) not admitted to the ICU.
Operations were deemed high risk when ≥ 2 of patients having that operation received transfusions within 72 hours of their operation. There were 15 abdominoperineal resections; 3 of these received transfusions (20%). There were 7 total abdominal colectomies; 3 of these received transfusions (43%). We therefore had 22 high-risk operations, 6 of which were transfused (27%).
Discussion
Routine measurement of postoperative hematocrit levels after elective general surgery at NMVAHCS was not necessary. There were 12 transfusions for inpatients (2.8%), which is similar to the findings of a recent study of VA general surgery (2.3%).13 We found that routine postoperative hematocrit measurements to assess anemia had little or no effect on clinical decision-making or clinical outcomes.
According to our results, 88% of initial hematocrit tests after elective partial colectomies could have been eliminated; only 32 of 146 patients demonstrated a clinical reason for postoperative hematocrit testing. Similarly, 36 of 40 postcholecystectomy hematocrit tests (90%) could have been eliminated had the surgeons relied on clinical signs indicating possible postoperative anemia (none were transfused). Excluding patients with major intraoperative blood loss (> 300 mL), only 29 of 288 (10%) patients who had postoperative hematocrit tests had a clinical indication for a postoperative hematocrit test (ie, symptoms of anemia and/or active bleeding). One patient with inguinal hernia surgery who received transfusion was taking an anticoagulant and had a clinically indicated hematocrit test for a large hematoma that eventually required reoperation.
Our study found that routine hematocrit checks may actually increase the risk that a patient would receive an unnecessary transfusion. For instance, one elderly patient, after a right colectomy, had 6 hematocrit levels while on a heparin drip and received transfusion despite being asymptomatic. His lowest hematocrit level prior to transfusion was 23.7%. This patient had a total of 18 hematocrit tests. His EBL was 350 mL and his first postoperative HCT level was 33.1%. In another instance, a patient undergoing abdominoperineal resection had a transfusion on postoperative day 1, despite being hypertensive, with a hematocrit that ranged from 26% before transfusion to 31% after the transfusion. These 2 cases illustrate what has been shown in a recent study: A substantial number of patients with colorectal cancer receive unnecessary transfusions.14 On the other hand, one ileostomy closure patient had 33 hematocrit tests, yet his initial postoperative hematocrit was 37%, and he never received a transfusion. With low-risk surgeries, clinical judgment should dictate when a postoperative hematocrit level is needed. This strategy would have eliminated 206 unnecessary initial postoperative hematocrit tests (72%), could have decreased the number of unnecessary transfusions, and would have saved NMVAHCS about $1600 annually.
Abdominoperineal resections and total abdominal colectomies accounted for a high proportion of transfusions in our study. Inpatient elective operations can be risk stratified and have routine hematocrit tests ordered for patients at high risk. The probability of transfusion was greater in high-risk vs low-risk surgeries; 27% (6 of 22 patients) vs 2% (6 of 408 patients), respectively (P < .001). Since 14 of the 22 patients undergoing high-risk operation already had clinical reasons for a postoperative hematocrit test, we only need to add the remaining 8 patients with high-risk operations to the 74 who had a clinical reason for a hematocrit test and conclude that 82 of 430 patients (19%) had a clinical reason for a hematocrit test, either from signs or symptoms of blood loss or because they were in a high-risk group.
While our elective general surgery cases may not represent many general surgery programs in the US and VA health care systems, we can extrapolate cost savings using the same cost analyses outlined by Kohli and colleagues.1 Assuming 1.9 million elective inpatient general surgeries per year in the United States with an average cost of $21 per CBC, the annual cost of universal postoperative hematocrit testing would be $40 million.11,15 If postoperative hematocrit testing were 70% consistent with our findings, the annual cost for hematocrit tests on 51% of the inpatient general surgeries would be approximately $20.4 million. A reduction in routine hematocrit testing to 25% of all inpatient general surgeries (vs our finding that 19% were deemed necessary) results in an annual savings of $30 million. This conservative estimate could be even higher since there were 4.4 hematocrit tests per patient; therefore, we have about $132 million in savings.
Assuming 181,384 elective VA inpatient general surgeries each year, costing $7.14 per CBC (the NMVAHCS cost), the VA could save $1.3 million annually. If postoperative HCT testing were 70% consistent with our findings, the annual cost for hematocrit tests on 50.4% of inpatient general surgery operations would be about $653,000. A reduction in routine hematocrit testing to 25% of all inpatient general surgeries (vs our 19%) results in annual VA savings of $330,000. This conservative estimate could be even higher since there were on average 4.4 hematocrit levels per patient; therefore, we estimate that annual savings for the VA of about $1.45 million.
Limitations
The retrospective chart review nature of this study may have led to selection bias. Only a small number of patients received a transfusion, which may have skewed the data. This study population comes from a single VA medical center; this patient population may not be reflective of other VA medical centers or the US population as a whole. Given that NMVAHCS does not perform hepatic, esophageal, pancreas, or transplant operations, the potential savings to both the US and the VA may be overestimated, but this could be studied in the future by VA medical centers that perform more complex operations.
Conclusions
This study found that over a 4-year period routine postoperative hematocrit tests for patients undergoing elective general surgery at a VA medical center were not necessary. General surgeons routinely order various pre- and postoperative laboratory tests despite their limited utility. Reduction in unneeded routine tests could result in notable savings to the VA without compromising quality of care.
Only general surgery patients undergoing operations that carry a high risk for needing a blood transfusion should have a routine postoperative hematocrit testing. In our study population, the chance of an elective colectomy, cholecystectomy, or hernia patient needing a transfusion was rare. This strategy could eliminate a considerable number of unnecessary blood tests and would potentially yield significant savings.
It is common practice to routinely measure postoperative hematocrit levels at US Department of Veterans Affairs (VA) hospitals for a wide range of elective general surgeries. While hematocrit measurement is a low-cost test, the high frequency with which these tests are performed may drastically increase overall costs.
Numerous studies have suggested that physicians overuse laboratory testing.1-10 Kohli and colleagues recommended that the routine practice of obtaining postoperative hematocrit tests following elective gynecologic surgery be abandoned.1 A similar recommendation was made by Olus and colleagues after studying uneventful, unplanned cesarean sections and by Wu and colleagues after investigating routine laboratory tests post total hip arthroplasty.2,3
To our knowledge, a study assessing routine postoperative hematocrit testing in elective general surgery has not yet been conducted. Many laboratory tests ordered in the perioperative period are not indicated, including complete blood count (CBC), electrolytes, and coagulation studies.4 Based on the results of these studies, we expected that the routine measurement of postoperative hematocrit levels after elective general surgeries at VA medical centers would not be cost effective. A PubMed search for articles published from 1990 to 2023 using the search terms “hematocrit,” “hemoglobin,” “general,” “surgery,” “routine,” and “cost” or “cost-effectiveness,” suggests that the clinical usefulness of postoperative hematocrit testing has not been well studied in the general surgery setting. The purpose of this study was to determine the clinical utility and associated cost of measuring routine postoperative hematocrit levels in order to generate a guide as to when the practice is warranted following common elective general surgery.
Although gynecologic textbooks may describe recommendations of routine hematocrit checking after elective gynecologic operations, one has difficulty finding the same recommendations in general surgery textbooks.1 However, it is common practice for surgical residents and attending surgeons to routinely order hematocrit on postoperative day-1 to ensure that the operation did not result in unsuspected anemia that then would need treatment (either with fluids or a blood transfusion). Many other surgeons rely on clinical factors such as tachycardia, oliguria, or hypotension to trigger a hematocrit (and other laboratory) tests. Our hypothesis is that the latter group has chosen the most cost-effective and prudent practice. One problem with checking the hematocrit routinely, as with any other screening test, is what to do with an abnormal result, assuming an asymptomatic patient? If the postoperative hematocrit is lower than expected given the estimated blood loss (EBL), what is one to do?
Methods
This retrospective case-control study conducted at the New Mexico VA Health Care System (NMVAHCS) in Albuquerque compared data for patients who received transfusion within 72 hours of elective surgeries vs patients who did not. Patients who underwent elective general surgery from January 2011 through December 2014 were included. An elective general surgery was defined as surgery performed following an outpatient preoperative anesthesia evaluation ≥ 30 days prior to operation. Patients who underwent emergency operations, and those with baseline anemia (preoperative hematocrit < 30%), and those transfused > 72 hours after their operation were excluded. The NMVAHCSInstitutional Review Board approved this study (No. 15-H184).
A detailed record review was conducted to collect data on demographics and other preoperative risk factors, including age, sex, body mass index (BMI), race and ethnicity, cardiac and pulmonary comorbidities, tobacco use, alcohol intake, diabetes, American Society of Anesthesiologists Physical Status Classification, metabolic equivalent of task, hematologic conditions, and renal disease.
For each procedure, we recorded the type of elective general surgery performed, the diagnosis/indication, pre- and postoperative hemoglobin/hematocrit, intraoperative EBL, length of operation, surgical wound class, length of hospital stay (LOS), intensive care unit (ICU) status, number of hematocrit tests, cardiovascular risk of operation (defined by anesthesia assessment), presence or absence of malignancy, preoperative platelet count, albumin level, preoperative prothrombin time/activated partial thromboplastin time (aPTT), international normalized ratio (INR), hemoglobin A1c, and incidence of transfusion. Signs and symptoms of anemia were recorded as present if the postoperative vital signs suggested low intravascular volume (pulse > 120 beats/minute, systolic blood pressure < 90 mm Hg, or vasoactive medication requirement [per anesthesia postoperative note]) or if the patient reported or exhibited symptoms of dizziness or fatigue or evidence of clinically apparent bleeding (ie, hematoma formation). Laboratory charges for hematocrit tests and CBC at the NMAVAHCS were used to assess cost.11
To stratify the transfusion risk, patients were distributed among 3 groups based on the following criteria: discharged home the same day as surgery; admitted but did not have postoperative hematocrit testing; and admitted and had postoperative hematocrit testing. We also stratified operations into low or high risk based on the risk for postoperative transfusion (Figure). Recognizing that the American College of Chest Physicians guidelines for perioperative management of antithrombotic therapy places bowel resection in a high-risk category, we designated a surgery as high risk when ≥ 2 patients in the transfusion group had that type of surgery over the 4 years of the study.12 Otherwise, the operations were deemed low risk.
Statistical Analysis
Numeric analysis used t tests and Binary and categorical variables used Fisher exact tests. P value ≤ .05 was considered statistically significant. SAS software was used for all statistical analyses.
Results
From 2011 through 2014, 1531 patients had elective general surgery at NMVAHCS. Twenty-two patients with preoperative anemia (hematocrit < 30%) and 1 patient who received a transfusion > 72 hours after the operation were excluded. Most elective operations (70%, n = 1075) were performed on an outpatient basis; none involved transfusion. Inguinal hernia repair was most common with 479 operations; 17 patients were treated inpatient of which 2 patients had routine postoperative hematocrit checks; (neither received transfusion). One patient with inguinal hernia surgery received transfusion without routine postoperative hematocrit monitoring.
Of 112 partial colon resections, 1 patient had a postoperative transfusion; and all but 3 received postoperative hematocrit monitoring. Nineteen patients undergoing partial colon resection had a clinical indication for postoperative hematocrit monitoring. None of the 5 patients with partial gastrectomy received a postoperative transfusion. Of 121 elective cholecystectomies, no patients had postoperative transfusion, whereas 34 had postoperative hematocrit monitoring; only 2 patients had a clinical reason for the hematocrit monitoring.
Of 430 elective inpatient operations, 12 received transfusions and 288 patients had ≥ 1 postoperative hematocrit test (67%). All hematocrit tests were requested by the attending surgeon, resident surgeon, or the surgical ICU team. Of the group that had postoperative hematocrit monitoring, there was an average of 4.4 postoperative hematocrit tests per patient (range, 1-44).
There were 12 transfusions for inpatients (2.8%), which is similar to the findings of a recent study of VA general surgery (2.3%).13 Five of the 12 patients received intraoperative transfusions while 7 were transfused within 72 hours postoperation. All but 1 patient receiving transfusion had EBL > 199 mL (range, 5-3000; mean, 950 mL; median, 500 mL) and/or signs or symptoms of anemia or other indications for measurement of the postoperative hematocrit. There were no statistically significant differences in patients’ age, sex, BMI, or race and ethnicity between groups receiving and not receiving transfusion (Table 1).
When comparing the transfusion vs the nontransfusion groups (after excluding those with clinical preoperative anemia) the risk factors for transfusion included: relatively low mean preoperative hematocrit (mean, 36.9% vs 42.7%, respectively; P = .003), low postoperative hematocrit (mean, 30.2% vs 37.1%, respectively; P < .001), high EBL (mean, 844 mL vs 109 mL, respectively; P = .005), large infusion of intraoperative fluids (mean, 4625 mL vs 2505 mL, respectively; P = .005), longer duration of operation (mean, 397 min vs 183 min, respectively; P < .001), and longer LOS (mean, 14.5 d vs 4.9 d, respectively; P < .001) (Table 2). Similarly, we found an increased risk for transfusion with high/intermediate cardiovascular risk (vs low), any wound not classified as clean, ICU stay, and postoperative symptoms of anemia.
We found no increased risk for transfusion with ethanol, tobacco, warfarin, or clopidogrel use; polycythemia; thrombocytopenia; preoperative INR; preoperative aPTT; preoperative albumin; Hemoglobin A1c; or diabetes mellitus; or for operations performed for malignancy. Ten patients in the ICU received transfusion (5.8%) compared with 2 patients (0.8%) not admitted to the ICU.
Operations were deemed high risk when ≥ 2 of patients having that operation received transfusions within 72 hours of their operation. There were 15 abdominoperineal resections; 3 of these received transfusions (20%). There were 7 total abdominal colectomies; 3 of these received transfusions (43%). We therefore had 22 high-risk operations, 6 of which were transfused (27%).
Discussion
Routine measurement of postoperative hematocrit levels after elective general surgery at NMVAHCS was not necessary. There were 12 transfusions for inpatients (2.8%), which is similar to the findings of a recent study of VA general surgery (2.3%).13 We found that routine postoperative hematocrit measurements to assess anemia had little or no effect on clinical decision-making or clinical outcomes.
According to our results, 88% of initial hematocrit tests after elective partial colectomies could have been eliminated; only 32 of 146 patients demonstrated a clinical reason for postoperative hematocrit testing. Similarly, 36 of 40 postcholecystectomy hematocrit tests (90%) could have been eliminated had the surgeons relied on clinical signs indicating possible postoperative anemia (none were transfused). Excluding patients with major intraoperative blood loss (> 300 mL), only 29 of 288 (10%) patients who had postoperative hematocrit tests had a clinical indication for a postoperative hematocrit test (ie, symptoms of anemia and/or active bleeding). One patient with inguinal hernia surgery who received transfusion was taking an anticoagulant and had a clinically indicated hematocrit test for a large hematoma that eventually required reoperation.
Our study found that routine hematocrit checks may actually increase the risk that a patient would receive an unnecessary transfusion. For instance, one elderly patient, after a right colectomy, had 6 hematocrit levels while on a heparin drip and received transfusion despite being asymptomatic. His lowest hematocrit level prior to transfusion was 23.7%. This patient had a total of 18 hematocrit tests. His EBL was 350 mL and his first postoperative HCT level was 33.1%. In another instance, a patient undergoing abdominoperineal resection had a transfusion on postoperative day 1, despite being hypertensive, with a hematocrit that ranged from 26% before transfusion to 31% after the transfusion. These 2 cases illustrate what has been shown in a recent study: A substantial number of patients with colorectal cancer receive unnecessary transfusions.14 On the other hand, one ileostomy closure patient had 33 hematocrit tests, yet his initial postoperative hematocrit was 37%, and he never received a transfusion. With low-risk surgeries, clinical judgment should dictate when a postoperative hematocrit level is needed. This strategy would have eliminated 206 unnecessary initial postoperative hematocrit tests (72%), could have decreased the number of unnecessary transfusions, and would have saved NMVAHCS about $1600 annually.
Abdominoperineal resections and total abdominal colectomies accounted for a high proportion of transfusions in our study. Inpatient elective operations can be risk stratified and have routine hematocrit tests ordered for patients at high risk. The probability of transfusion was greater in high-risk vs low-risk surgeries; 27% (6 of 22 patients) vs 2% (6 of 408 patients), respectively (P < .001). Since 14 of the 22 patients undergoing high-risk operation already had clinical reasons for a postoperative hematocrit test, we only need to add the remaining 8 patients with high-risk operations to the 74 who had a clinical reason for a hematocrit test and conclude that 82 of 430 patients (19%) had a clinical reason for a hematocrit test, either from signs or symptoms of blood loss or because they were in a high-risk group.
While our elective general surgery cases may not represent many general surgery programs in the US and VA health care systems, we can extrapolate cost savings using the same cost analyses outlined by Kohli and colleagues.1 Assuming 1.9 million elective inpatient general surgeries per year in the United States with an average cost of $21 per CBC, the annual cost of universal postoperative hematocrit testing would be $40 million.11,15 If postoperative hematocrit testing were 70% consistent with our findings, the annual cost for hematocrit tests on 51% of the inpatient general surgeries would be approximately $20.4 million. A reduction in routine hematocrit testing to 25% of all inpatient general surgeries (vs our finding that 19% were deemed necessary) results in an annual savings of $30 million. This conservative estimate could be even higher since there were 4.4 hematocrit tests per patient; therefore, we have about $132 million in savings.
Assuming 181,384 elective VA inpatient general surgeries each year, costing $7.14 per CBC (the NMVAHCS cost), the VA could save $1.3 million annually. If postoperative HCT testing were 70% consistent with our findings, the annual cost for hematocrit tests on 50.4% of inpatient general surgery operations would be about $653,000. A reduction in routine hematocrit testing to 25% of all inpatient general surgeries (vs our 19%) results in annual VA savings of $330,000. This conservative estimate could be even higher since there were on average 4.4 hematocrit levels per patient; therefore, we estimate that annual savings for the VA of about $1.45 million.
Limitations
The retrospective chart review nature of this study may have led to selection bias. Only a small number of patients received a transfusion, which may have skewed the data. This study population comes from a single VA medical center; this patient population may not be reflective of other VA medical centers or the US population as a whole. Given that NMVAHCS does not perform hepatic, esophageal, pancreas, or transplant operations, the potential savings to both the US and the VA may be overestimated, but this could be studied in the future by VA medical centers that perform more complex operations.
Conclusions
This study found that over a 4-year period routine postoperative hematocrit tests for patients undergoing elective general surgery at a VA medical center were not necessary. General surgeons routinely order various pre- and postoperative laboratory tests despite their limited utility. Reduction in unneeded routine tests could result in notable savings to the VA without compromising quality of care.
Only general surgery patients undergoing operations that carry a high risk for needing a blood transfusion should have a routine postoperative hematocrit testing. In our study population, the chance of an elective colectomy, cholecystectomy, or hernia patient needing a transfusion was rare. This strategy could eliminate a considerable number of unnecessary blood tests and would potentially yield significant savings.
1. Kohli N, Mallipeddi PK, Neff JM, Sze EH, Roat TW. Routine hematocrit after elective gynecologic surgery. Obstet Gynecol. 2000;95(6 Pt 1):847-850. doi:10.1016/s0029-7844(00)00796-1
2. Olus A, Orhan, U, Murat A, et al. Do asymptomatic patients require routine hemoglobin testing following uneventful, unplanned cesarean sections? Arch Gynecol Obstet. 2010;281(2):195-199. doi:10.1007/s00404-009-1093-1
3. Wu XD, Zhu ZL, Xiao P, Liu JC, Wang JW, Huang W. Are routine postoperative laboratory tests necessary after primary total hip arthroplasty? J Arthroplasty. 2020;35(10):2892-2898. doi:10.1016/j.arth.2020.04.097
4. Kumar A, Srivastava U. Role of routine laboratory investigations in preoperative evaluation. J Anesthesiol Clin Pharmacol. 2011;27(2):174-179. doi:10.4103/0970-9185.81824
5. Aghajanian A, Grimes DA. Routine prothrombin time determination before elective gynecologic operations. Obstet Gynecol. 1991;78(5 Pt 1):837-839.
6. Ransom SB, McNeeley SG, Malone JM Jr. A cost-effectiveness evaluation of preoperative type-and-screen testing for vaginal hysterectomy. Am J Obstet Gynecol. 1996;175(5):1201-1203. doi:10.1016/s0002-9378(96)70028-5
7. Ransom SB, McNeeley SG, Hosseini RB. Cost-effectiveness of routine blood type and screen testing before elective laparoscopy. Obstet Gynecol. 1995;86(3):346-348. doi:10.1016/0029-7844(95)00187-V
8. Committee on Standards and Practice Parameters, Apfelbaum JL, Connis RT, et al. Practice advisory for preanesthesia evaluation: an updated report by the American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology. 2012;116(3):522-538. doi:10.1097/ALN.0b013e31823c1067
9. Weil IA, Seicean S, Neuhauser D, Schiltz NK, Seicean A. Use and utility of hemostatic screening in adults undergoing elective, non-cardiac surgery. PLoS One. 2015;10(12):e0139139. doi:10.1371/journal.pone.0139139
10. Wu WC, Schifftner TL, Henderson WG, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing non-cardiac surgery. JAMA. 2007;297(22):2481-2488. doi:10.1001/jama.297.22.2481
11. Healthcare Bluebook. Complete blood count (CBC) with differential. Accessed March 28, 2024. https://www.healthcarebluebook.com/page_ProcedureDetails.aspx?id=214&dataset=lab
12. Douketis JD, Spyropoulos AC, Murad MH, et al. Perioperative management of antithrombotic therapy: an American College of Chest Physicians Clinical Practice Guideline. Chest. 2022;162(5):e207-e243. doi:10.1016/j.chest.2022.07.025
13. Randall JA, Wagner KT, Brody F. Perioperative transfusions in veterans following noncardiac procedures. J Laparoendosc Adv Surg Tech A. 2023;33(10):923-931. doi:10.1089/lap. 2023.0307
14. Tartter PI, Barron DM. Unnecessary blood transfusions in elective colorectal cancer surgery. Transfusion. 1985;25(2):113-115. doi:10.1046/j.1537-2995.1985.25285169199.x
15. Steiner CA, Karaca Z, Moore BJ, Imshaug MC, Pickens G. Surgeries in hospital-based ambulatory surgery and hospital inpatient settings, 2014. Healthcare Cost and Utilization Project statistical brief #223. May 2017. Revised July 2020. Agency for Healthcare Research and Quality. Accessed February 26, 2024. https://hcup-us.ahrq.gov/reports/statbriefs/sb223-Ambulatory-Inpatient-Surgeries-2014.pdf
16. US Department of Veterans Affairs, National Surgery Office. Quarterly report: Q3 of fiscal year 2017. VISN operative complexity summary [Source not verified].
1. Kohli N, Mallipeddi PK, Neff JM, Sze EH, Roat TW. Routine hematocrit after elective gynecologic surgery. Obstet Gynecol. 2000;95(6 Pt 1):847-850. doi:10.1016/s0029-7844(00)00796-1
2. Olus A, Orhan, U, Murat A, et al. Do asymptomatic patients require routine hemoglobin testing following uneventful, unplanned cesarean sections? Arch Gynecol Obstet. 2010;281(2):195-199. doi:10.1007/s00404-009-1093-1
3. Wu XD, Zhu ZL, Xiao P, Liu JC, Wang JW, Huang W. Are routine postoperative laboratory tests necessary after primary total hip arthroplasty? J Arthroplasty. 2020;35(10):2892-2898. doi:10.1016/j.arth.2020.04.097
4. Kumar A, Srivastava U. Role of routine laboratory investigations in preoperative evaluation. J Anesthesiol Clin Pharmacol. 2011;27(2):174-179. doi:10.4103/0970-9185.81824
5. Aghajanian A, Grimes DA. Routine prothrombin time determination before elective gynecologic operations. Obstet Gynecol. 1991;78(5 Pt 1):837-839.
6. Ransom SB, McNeeley SG, Malone JM Jr. A cost-effectiveness evaluation of preoperative type-and-screen testing for vaginal hysterectomy. Am J Obstet Gynecol. 1996;175(5):1201-1203. doi:10.1016/s0002-9378(96)70028-5
7. Ransom SB, McNeeley SG, Hosseini RB. Cost-effectiveness of routine blood type and screen testing before elective laparoscopy. Obstet Gynecol. 1995;86(3):346-348. doi:10.1016/0029-7844(95)00187-V
8. Committee on Standards and Practice Parameters, Apfelbaum JL, Connis RT, et al. Practice advisory for preanesthesia evaluation: an updated report by the American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology. 2012;116(3):522-538. doi:10.1097/ALN.0b013e31823c1067
9. Weil IA, Seicean S, Neuhauser D, Schiltz NK, Seicean A. Use and utility of hemostatic screening in adults undergoing elective, non-cardiac surgery. PLoS One. 2015;10(12):e0139139. doi:10.1371/journal.pone.0139139
10. Wu WC, Schifftner TL, Henderson WG, et al. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing non-cardiac surgery. JAMA. 2007;297(22):2481-2488. doi:10.1001/jama.297.22.2481
11. Healthcare Bluebook. Complete blood count (CBC) with differential. Accessed March 28, 2024. https://www.healthcarebluebook.com/page_ProcedureDetails.aspx?id=214&dataset=lab
12. Douketis JD, Spyropoulos AC, Murad MH, et al. Perioperative management of antithrombotic therapy: an American College of Chest Physicians Clinical Practice Guideline. Chest. 2022;162(5):e207-e243. doi:10.1016/j.chest.2022.07.025
13. Randall JA, Wagner KT, Brody F. Perioperative transfusions in veterans following noncardiac procedures. J Laparoendosc Adv Surg Tech A. 2023;33(10):923-931. doi:10.1089/lap. 2023.0307
14. Tartter PI, Barron DM. Unnecessary blood transfusions in elective colorectal cancer surgery. Transfusion. 1985;25(2):113-115. doi:10.1046/j.1537-2995.1985.25285169199.x
15. Steiner CA, Karaca Z, Moore BJ, Imshaug MC, Pickens G. Surgeries in hospital-based ambulatory surgery and hospital inpatient settings, 2014. Healthcare Cost and Utilization Project statistical brief #223. May 2017. Revised July 2020. Agency for Healthcare Research and Quality. Accessed February 26, 2024. https://hcup-us.ahrq.gov/reports/statbriefs/sb223-Ambulatory-Inpatient-Surgeries-2014.pdf
16. US Department of Veterans Affairs, National Surgery Office. Quarterly report: Q3 of fiscal year 2017. VISN operative complexity summary [Source not verified].
Oxidative Stress in Patients With Melasma: An Evaluation of the Correlation of the Thiol/Disulfide Homeostasis Parameters and Modified MASI Score
Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.1 Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.2 Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.3 Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.5 However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.6
The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.5
Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.11,12
The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.
Materials and Methods
Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.
Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.13 The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.4
Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.14 Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).14
Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.
Results
Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.
Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.
eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).
All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.
We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).
There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.
Comment
Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.1 It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.5
Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.4 Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.7 Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.4
Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. 5
In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.8 Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.8
In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.15
Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,17 seborrheic dermatitis,11 atopic dermatitits,18 and rosacea.19 In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.
Seçkin et al7 evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma
In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.8
Choubey et al9 found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.9
In a study with 50 melasma patients and 50 controls, Rahimi et al10 examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.10
In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.
Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.20 In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.21 Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.
Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.
Conclusion
In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.
- Handel AC, Miot LD, Miot HA. Melasma: a clinical and epidemiological review. An Bras Dermatol. 2014;89:771-782.
- Tamega Ade A, Miot LD, Bonfietti C, et al. Clinical patterns and epidemiological characteristics of facial melasma in Brazilian women. J Eur Acad Dermatol Venereol. 2013;27:151-156.
- Rajanala S, Maymone MBC, Vashi NA. Melasma pathogenesis: a review of the latest research, pathological findings, and investigational therapies. Dermatol Online J. 2019;25:13030/qt47b7r28c.
- Abou-Taleb DA, Ibrahim AK, Youssef EM, et al. Reliability, validity, and sensitivity to change overtime of the modified melasma area and severity index score. Dermatol Surg. 2017;43:210-217.
- Katiyar S, Yadav D. Correlation of oxidative stress with melasma: an overview. Curr Pharm Des. 2022;28:225-231.
- Mahmoud BH, Ruvolo E, Hexsel CL, et al. Impact of long-wavelength UVA and visible light on melanocompetent skin. J Invest Dermatol. 2010;130:2092-2097.
- Seçkin HY, Kalkan G, Bas¸ Y, et al. Oxidative stress status in patients with melasma. Cutan Ocul Toxicol. 2014;33:212-217.
- Sarkar R, Devadasan S, Choubey V, et al. Melatonin and oxidative stress in melasma—an unexplored territory; a prospective study. Int J Dermatol. 2020;59:572-575.
- Choubey V, Sarkar R, Garg V, et al. Role of oxidative stress in melasma: a prospective study on serum and blood markers of oxidative stress in melasma patients. Int J Dermatol. 2017;56:939-943.
- Rahimi H, Mirnezami M, Yazdabadi A. Bilirubin as a new antioxidant in melasma. J Cosmet Dermatol. 2022;21:5800-5803.
- Emre S, Kalkan G, Erdog˘an S, et al. Dynamic thiol/disulfide balance in patients with seborrheic dermatitis: a case-control study. Saudi J Med Med Sci. 2020;8:12-16.
- Erel Ö, Erdog˘an S. Thiol-disulfide homeostasis: an integrated approach with biochemical and clinical aspects. Turk J Med Sci. 2020;50:1728-1738.
- Pandya AG, Hynan LS, Bhore R, et al. Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol. 2011;64:78-83, 83.E1-E2.
- Erel O, Neselioglu S. A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem. 2014;47:326-332.
- Guzelcicek A, Cakirca G, Erel O, et al. Assessment of thiol/disulfide balance as an oxidative stress marker in children with β-thalassemia major. Pak J Med Sci. 2019;35:161-165.
- Georgescu SR, Mitran CI, Mitran MI, et al. Thiol-Disulfide homeostasis in skin diseases. J Clin Med. 2022;11:1507.
- Üstüner P, Balevi A, Özdemir M, et al. The role of thiol/disulfide homeostasis in psoriasis: can it be a new marker for inflammation? Turk Arch Dermatol Venereol. 2018;52:120-125.
- Karacan G, Ercan N, Bostanci I, et al. A novel oxidative stress marker of atopic dermatitis in infants: Thiol–disulfide balance. Arch Dermatol Res. 2020;312:697-703.
- Demir Pektas S, Cinar N, Pektas G, et al. Thiol/disulfide homeostasis and its relationship with insulin resistance in patients with rosacea. J Cosmet Dermatol. 2021;11:14477.
- Adil M, Amin SS, Mohtashim M. N-acetylcysteine in dermatology. Indian J Dermatol Venereol Leprol. 2018;84:652-659.
- Njoo MD, Menke HE, Pavel W, et al. N-acetylcysteine as a bleaching agent in the treatment of melasma. J Eur Acad Dermatol Venereol. 1997;9:86-87.
Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.1 Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.2 Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.3 Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.5 However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.6
The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.5
Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.11,12
The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.
Materials and Methods
Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.
Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.13 The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.4
Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.14 Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).14
Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.
Results
Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.
Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.
eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).
All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.
We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).
There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.
Comment
Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.1 It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.5
Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.4 Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.7 Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.4
Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. 5
In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.8 Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.8
In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.15
Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,17 seborrheic dermatitis,11 atopic dermatitits,18 and rosacea.19 In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.
Seçkin et al7 evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma
In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.8
Choubey et al9 found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.9
In a study with 50 melasma patients and 50 controls, Rahimi et al10 examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.10
In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.
Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.20 In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.21 Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.
Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.
Conclusion
In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.
Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.1 Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.2 Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.3 Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.5 However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.6
The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.5
Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.11,12
The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.
Materials and Methods
Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.
Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.13 The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.4
Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.14 Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).14
Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.
Results
Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.
Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.
eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).
All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.
We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).
There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.
Comment
Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.1 It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.5
Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.4 Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.7 Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.4
Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. 5
In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.8 Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.8
In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.15
Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,17 seborrheic dermatitis,11 atopic dermatitits,18 and rosacea.19 In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.
Seçkin et al7 evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma
In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.8
Choubey et al9 found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.9
In a study with 50 melasma patients and 50 controls, Rahimi et al10 examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.10
In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.
Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.20 In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.21 Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.
Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.
Conclusion
In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.
- Handel AC, Miot LD, Miot HA. Melasma: a clinical and epidemiological review. An Bras Dermatol. 2014;89:771-782.
- Tamega Ade A, Miot LD, Bonfietti C, et al. Clinical patterns and epidemiological characteristics of facial melasma in Brazilian women. J Eur Acad Dermatol Venereol. 2013;27:151-156.
- Rajanala S, Maymone MBC, Vashi NA. Melasma pathogenesis: a review of the latest research, pathological findings, and investigational therapies. Dermatol Online J. 2019;25:13030/qt47b7r28c.
- Abou-Taleb DA, Ibrahim AK, Youssef EM, et al. Reliability, validity, and sensitivity to change overtime of the modified melasma area and severity index score. Dermatol Surg. 2017;43:210-217.
- Katiyar S, Yadav D. Correlation of oxidative stress with melasma: an overview. Curr Pharm Des. 2022;28:225-231.
- Mahmoud BH, Ruvolo E, Hexsel CL, et al. Impact of long-wavelength UVA and visible light on melanocompetent skin. J Invest Dermatol. 2010;130:2092-2097.
- Seçkin HY, Kalkan G, Bas¸ Y, et al. Oxidative stress status in patients with melasma. Cutan Ocul Toxicol. 2014;33:212-217.
- Sarkar R, Devadasan S, Choubey V, et al. Melatonin and oxidative stress in melasma—an unexplored territory; a prospective study. Int J Dermatol. 2020;59:572-575.
- Choubey V, Sarkar R, Garg V, et al. Role of oxidative stress in melasma: a prospective study on serum and blood markers of oxidative stress in melasma patients. Int J Dermatol. 2017;56:939-943.
- Rahimi H, Mirnezami M, Yazdabadi A. Bilirubin as a new antioxidant in melasma. J Cosmet Dermatol. 2022;21:5800-5803.
- Emre S, Kalkan G, Erdog˘an S, et al. Dynamic thiol/disulfide balance in patients with seborrheic dermatitis: a case-control study. Saudi J Med Med Sci. 2020;8:12-16.
- Erel Ö, Erdog˘an S. Thiol-disulfide homeostasis: an integrated approach with biochemical and clinical aspects. Turk J Med Sci. 2020;50:1728-1738.
- Pandya AG, Hynan LS, Bhore R, et al. Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol. 2011;64:78-83, 83.E1-E2.
- Erel O, Neselioglu S. A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem. 2014;47:326-332.
- Guzelcicek A, Cakirca G, Erel O, et al. Assessment of thiol/disulfide balance as an oxidative stress marker in children with β-thalassemia major. Pak J Med Sci. 2019;35:161-165.
- Georgescu SR, Mitran CI, Mitran MI, et al. Thiol-Disulfide homeostasis in skin diseases. J Clin Med. 2022;11:1507.
- Üstüner P, Balevi A, Özdemir M, et al. The role of thiol/disulfide homeostasis in psoriasis: can it be a new marker for inflammation? Turk Arch Dermatol Venereol. 2018;52:120-125.
- Karacan G, Ercan N, Bostanci I, et al. A novel oxidative stress marker of atopic dermatitis in infants: Thiol–disulfide balance. Arch Dermatol Res. 2020;312:697-703.
- Demir Pektas S, Cinar N, Pektas G, et al. Thiol/disulfide homeostasis and its relationship with insulin resistance in patients with rosacea. J Cosmet Dermatol. 2021;11:14477.
- Adil M, Amin SS, Mohtashim M. N-acetylcysteine in dermatology. Indian J Dermatol Venereol Leprol. 2018;84:652-659.
- Njoo MD, Menke HE, Pavel W, et al. N-acetylcysteine as a bleaching agent in the treatment of melasma. J Eur Acad Dermatol Venereol. 1997;9:86-87.
- Handel AC, Miot LD, Miot HA. Melasma: a clinical and epidemiological review. An Bras Dermatol. 2014;89:771-782.
- Tamega Ade A, Miot LD, Bonfietti C, et al. Clinical patterns and epidemiological characteristics of facial melasma in Brazilian women. J Eur Acad Dermatol Venereol. 2013;27:151-156.
- Rajanala S, Maymone MBC, Vashi NA. Melasma pathogenesis: a review of the latest research, pathological findings, and investigational therapies. Dermatol Online J. 2019;25:13030/qt47b7r28c.
- Abou-Taleb DA, Ibrahim AK, Youssef EM, et al. Reliability, validity, and sensitivity to change overtime of the modified melasma area and severity index score. Dermatol Surg. 2017;43:210-217.
- Katiyar S, Yadav D. Correlation of oxidative stress with melasma: an overview. Curr Pharm Des. 2022;28:225-231.
- Mahmoud BH, Ruvolo E, Hexsel CL, et al. Impact of long-wavelength UVA and visible light on melanocompetent skin. J Invest Dermatol. 2010;130:2092-2097.
- Seçkin HY, Kalkan G, Bas¸ Y, et al. Oxidative stress status in patients with melasma. Cutan Ocul Toxicol. 2014;33:212-217.
- Sarkar R, Devadasan S, Choubey V, et al. Melatonin and oxidative stress in melasma—an unexplored territory; a prospective study. Int J Dermatol. 2020;59:572-575.
- Choubey V, Sarkar R, Garg V, et al. Role of oxidative stress in melasma: a prospective study on serum and blood markers of oxidative stress in melasma patients. Int J Dermatol. 2017;56:939-943.
- Rahimi H, Mirnezami M, Yazdabadi A. Bilirubin as a new antioxidant in melasma. J Cosmet Dermatol. 2022;21:5800-5803.
- Emre S, Kalkan G, Erdog˘an S, et al. Dynamic thiol/disulfide balance in patients with seborrheic dermatitis: a case-control study. Saudi J Med Med Sci. 2020;8:12-16.
- Erel Ö, Erdog˘an S. Thiol-disulfide homeostasis: an integrated approach with biochemical and clinical aspects. Turk J Med Sci. 2020;50:1728-1738.
- Pandya AG, Hynan LS, Bhore R, et al. Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol. 2011;64:78-83, 83.E1-E2.
- Erel O, Neselioglu S. A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem. 2014;47:326-332.
- Guzelcicek A, Cakirca G, Erel O, et al. Assessment of thiol/disulfide balance as an oxidative stress marker in children with β-thalassemia major. Pak J Med Sci. 2019;35:161-165.
- Georgescu SR, Mitran CI, Mitran MI, et al. Thiol-Disulfide homeostasis in skin diseases. J Clin Med. 2022;11:1507.
- Üstüner P, Balevi A, Özdemir M, et al. The role of thiol/disulfide homeostasis in psoriasis: can it be a new marker for inflammation? Turk Arch Dermatol Venereol. 2018;52:120-125.
- Karacan G, Ercan N, Bostanci I, et al. A novel oxidative stress marker of atopic dermatitis in infants: Thiol–disulfide balance. Arch Dermatol Res. 2020;312:697-703.
- Demir Pektas S, Cinar N, Pektas G, et al. Thiol/disulfide homeostasis and its relationship with insulin resistance in patients with rosacea. J Cosmet Dermatol. 2021;11:14477.
- Adil M, Amin SS, Mohtashim M. N-acetylcysteine in dermatology. Indian J Dermatol Venereol Leprol. 2018;84:652-659.
- Njoo MD, Menke HE, Pavel W, et al. N-acetylcysteine as a bleaching agent in the treatment of melasma. J Eur Acad Dermatol Venereol. 1997;9:86-87.
Practice Points
- Melasma is a common pigmentation disorder that causes brown or grayish patches on the skin.
- Disulfide/native thiol and disulfide/total thiol ratios were higher in patients with melasma compared with controls, which indicated the presence of oxidative stress in melasma.
- The evaluation of modified melasma area and severity index score with disulfide/native thiol and disulfide/total thiol values suggests that oxidative stress is correlated with melasma disease severity.
Need a Wood Lamp Alternative? Grab Your Smartphone
Practice Gap
The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).1 Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.2
Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.1
Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.3 Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.
The Tools
Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.
The Technique
UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.4 Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).
Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.
Practice Implications
Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.
- Dyer JM, Foy VM. Revealing the unseen: a review of Wood’s lamp in dermatology. J Clin Aesthet Dermatol. 2022;15:25-30.
- Scanni G. Facilitations in the clinical diagnosis of human scabies through the use of ultraviolet light (UV-scab scanning): a case-series study. Trop Med Infect Dis. 2022;7:422. doi:10.3390/tropicalmed7120422
- USA Medical and Surgical Supplies. Top 9 medical diagnostic applications for a Woods lamp. February 26, 2019. Accessed May 20, 2024.
- Huang Y, Hsiang E-L, Deng M-Y, et al. Mini-led, micro-led and OLED displays: present status and future perspectives. Light Sci Appl. 2020;9:105. doi:10.1038/s41377-020-0341-9
Practice Gap
The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).1 Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.2
Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.1
Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.3 Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.
The Tools
Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.
The Technique
UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.4 Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).
Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.
Practice Implications
Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.
Practice Gap
The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).1 Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.2
Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.1
Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.3 Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.
The Tools
Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.
The Technique
UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.4 Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).
Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.
Practice Implications
Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.
- Dyer JM, Foy VM. Revealing the unseen: a review of Wood’s lamp in dermatology. J Clin Aesthet Dermatol. 2022;15:25-30.
- Scanni G. Facilitations in the clinical diagnosis of human scabies through the use of ultraviolet light (UV-scab scanning): a case-series study. Trop Med Infect Dis. 2022;7:422. doi:10.3390/tropicalmed7120422
- USA Medical and Surgical Supplies. Top 9 medical diagnostic applications for a Woods lamp. February 26, 2019. Accessed May 20, 2024.
- Huang Y, Hsiang E-L, Deng M-Y, et al. Mini-led, micro-led and OLED displays: present status and future perspectives. Light Sci Appl. 2020;9:105. doi:10.1038/s41377-020-0341-9
- Dyer JM, Foy VM. Revealing the unseen: a review of Wood’s lamp in dermatology. J Clin Aesthet Dermatol. 2022;15:25-30.
- Scanni G. Facilitations in the clinical diagnosis of human scabies through the use of ultraviolet light (UV-scab scanning): a case-series study. Trop Med Infect Dis. 2022;7:422. doi:10.3390/tropicalmed7120422
- USA Medical and Surgical Supplies. Top 9 medical diagnostic applications for a Woods lamp. February 26, 2019. Accessed May 20, 2024.
- Huang Y, Hsiang E-L, Deng M-Y, et al. Mini-led, micro-led and OLED displays: present status and future perspectives. Light Sci Appl. 2020;9:105. doi:10.1038/s41377-020-0341-9
Olive Oil Shows Promise for Wound Healing of Ulcers
Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.1 Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.2 Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.3
Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.4 Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.1 Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.
The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.5 Studies also have shown that olive oil can promote re-epithelialization in tissues.6 Thus, use of olive oil in wound therapy has been of great interest.
This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.
Diabetic Foot Ulcers
Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.
A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.9 A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.9 The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.
Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.10 Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).10
There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al11 presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi12 observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.7 Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.13
Pressure Ulcers
A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.14 Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.
In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.14 Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).14 The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.
In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.15 The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.15 These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.
Perineal Ulcers
Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.16 Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.
A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.17 Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).17 This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.
A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.18 This study encourages further investigation of the benefits of olive oil for care after an episiotomy.
Chronic Ulcers
Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.19 Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’
Final Thoughts
This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.
- Emmons EW, Fedeli E, Firestone D. Olive oil introduction and history. In: Hui YH, ed. Bailey’s Industrial Oil & Fat Products, Vol. 2. Edible Oil and Fat Products: Edible Oils. 5th ed. John Wiley & Sons, Ltd; 241-269.
- Gorzynik-Debicka M, Przychodzen P, Cappello F, et al. Potential health benefits of olive oil and plant polyphenols. Int J Mol Sci. 2018;19:686. doi:10.3390/IJMS19030686
- Tuck KL, Hayball PJ. Major phenolic compounds in olive oil: metabolism and health effects. J Nutr Biochem. 2002;13:636-644. doi:10.1016/S0955-2863(02)00229-2
- Rabiei Z, Enferadi ST. Traceability of origin and authenticity of olive oil. In: Boskou D, ed. Olive Oil: Constituents, Quality, Health Properties and Bioconversions. InTech; 2012.
- Wardhana, Surachmanto ES, Datau EA. The role of omega-3 fatty acids contained in olive oil on chronic inflammation. Acta Med Indones. 2011;43:138-143.
- Aboui MM, Eidi A, Mortazavi P. Study of effect of olive oil on re-epithelialization of epithelial tissue in excision wound healing model in rats. J Comp Pathobiol. 2016;13:1875-1884.
- Aldana PC, Cartron AM, Khachemoune A. Reappraising diabetic foot ulcers: a focus on mechanisms of ulceration and clinical evaluation.Int J Low Extrem Wounds. 2022;21:294-302. doi:10.1177/1534734620944514
- Aldana PC, Khachemoune A. Diabetic foot ulcers: appraising standard of care and reviewing new trends in management. Am J Clin Dermatol. 2020;21:255-264. doi:10.1007/s40257-019-00495-x
- Nasiri M, Fayazi S, Jahani S, et al. The effect of topical olive oil on the healing of foot ulcer in patients with type 2 diabetes: a double-blind randomized clinical trial study in Iran. J Diabetes Metab Disord. 2015;14:38. doi:10.1186/S40200-015-0167-9
- Karimi Z, Behnammoghadam M, Rafiei H, et al. Impact of olive oil and honey on healing of diabetic foot: a randomized controlled trial. Clin Cosmet Investig Dermatol. 2019;12:347-354. doi:10.2147/CCID.S198577
- Haghighian HK, Koushan Y, Asgharzadeh A. Treatment of diabetic foot ulcer with propolis and olive oil: a case report. Knowl Health. 2012;6:35-38.
- Zahmatkesh M, Rashidi M. Case report of diabetic foot ulcer with topical honey and olive oil. J Med Plants. 2008;8:36-41.
- Cicerale S, Lucas LJ, Keast RS. Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil. Curr Opin Biotechnol. 2012;23:129-135. doi:10.1016/J.COPBIO.2011.09.006
- Miraj S, Pourafzali S, Ahmadabadi ZV, et al. Effect of olive oil in preventing the development of pressure ulcer grade one in intensive care unit patients. Int J Prev Med. 2020;11:23. doi:10.4103/IJPVM.IJPVM_545_18
- Díaz‐Valenzuela A, García‐Fernández FP, Carmona Fernández P, et al. Effectiveness and safety of olive oil preparation for topical use in pressure ulcer prevention: multicentre, controlled, randomised, and double‐blinded clinical trial. Int Wound J. 2019;16:1314-1322. doi:10.1111/IWJ.13191
- Carroli G, Mignini L. Episiotomy for vaginal birth. Cochrane Database Syst Rev. 2009;CD000081. doi:10.1002/14651858.CD000081.PUB2
- Amani R, Kariman N, Mojab F, et al. Comparison of the effects of cold compress with gel packs and topical olive oil on episiotomy wound healing. J Babol Univ Med Sci. 2015;17:7-12. doi:10.22088/JBUMS.17.11.7
- Behmanesh F, Aghamohammadi A, Zeinalzadeh M, et al. Effects of olive oil sitz bath on improvement of perineal injury after delivery. Koomesh. 2013;14:309-315.
- Vitsos A, Tsagarousianos C, Vergos O, et al. Efficacy of a Ceratothoa oestroides olive oil extract in patients with chronic ulcers: a pilot study. Int J Low Extrem Wounds. 2019;18:309-316. doi:10.1177/1534734619856143
Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.1 Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.2 Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.3
Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.4 Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.1 Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.
The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.5 Studies also have shown that olive oil can promote re-epithelialization in tissues.6 Thus, use of olive oil in wound therapy has been of great interest.
This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.
Diabetic Foot Ulcers
Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.
A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.9 A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.9 The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.
Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.10 Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).10
There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al11 presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi12 observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.7 Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.13
Pressure Ulcers
A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.14 Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.
In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.14 Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).14 The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.
In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.15 The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.15 These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.
Perineal Ulcers
Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.16 Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.
A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.17 Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).17 This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.
A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.18 This study encourages further investigation of the benefits of olive oil for care after an episiotomy.
Chronic Ulcers
Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.19 Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’
Final Thoughts
This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.
Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.1 Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.2 Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.3
Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.4 Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.1 Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.
The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.5 Studies also have shown that olive oil can promote re-epithelialization in tissues.6 Thus, use of olive oil in wound therapy has been of great interest.
This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.
Diabetic Foot Ulcers
Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.
A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.9 A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.9 The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.
Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.10 Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).10
There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al11 presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi12 observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.7 Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.13
Pressure Ulcers
A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.14 Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.
In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.14 Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).14 The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.
In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.15 The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.15 These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.
Perineal Ulcers
Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.16 Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.
A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.17 Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).17 This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.
A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.18 This study encourages further investigation of the benefits of olive oil for care after an episiotomy.
Chronic Ulcers
Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.19 Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’
Final Thoughts
This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.
- Emmons EW, Fedeli E, Firestone D. Olive oil introduction and history. In: Hui YH, ed. Bailey’s Industrial Oil & Fat Products, Vol. 2. Edible Oil and Fat Products: Edible Oils. 5th ed. John Wiley & Sons, Ltd; 241-269.
- Gorzynik-Debicka M, Przychodzen P, Cappello F, et al. Potential health benefits of olive oil and plant polyphenols. Int J Mol Sci. 2018;19:686. doi:10.3390/IJMS19030686
- Tuck KL, Hayball PJ. Major phenolic compounds in olive oil: metabolism and health effects. J Nutr Biochem. 2002;13:636-644. doi:10.1016/S0955-2863(02)00229-2
- Rabiei Z, Enferadi ST. Traceability of origin and authenticity of olive oil. In: Boskou D, ed. Olive Oil: Constituents, Quality, Health Properties and Bioconversions. InTech; 2012.
- Wardhana, Surachmanto ES, Datau EA. The role of omega-3 fatty acids contained in olive oil on chronic inflammation. Acta Med Indones. 2011;43:138-143.
- Aboui MM, Eidi A, Mortazavi P. Study of effect of olive oil on re-epithelialization of epithelial tissue in excision wound healing model in rats. J Comp Pathobiol. 2016;13:1875-1884.
- Aldana PC, Cartron AM, Khachemoune A. Reappraising diabetic foot ulcers: a focus on mechanisms of ulceration and clinical evaluation.Int J Low Extrem Wounds. 2022;21:294-302. doi:10.1177/1534734620944514
- Aldana PC, Khachemoune A. Diabetic foot ulcers: appraising standard of care and reviewing new trends in management. Am J Clin Dermatol. 2020;21:255-264. doi:10.1007/s40257-019-00495-x
- Nasiri M, Fayazi S, Jahani S, et al. The effect of topical olive oil on the healing of foot ulcer in patients with type 2 diabetes: a double-blind randomized clinical trial study in Iran. J Diabetes Metab Disord. 2015;14:38. doi:10.1186/S40200-015-0167-9
- Karimi Z, Behnammoghadam M, Rafiei H, et al. Impact of olive oil and honey on healing of diabetic foot: a randomized controlled trial. Clin Cosmet Investig Dermatol. 2019;12:347-354. doi:10.2147/CCID.S198577
- Haghighian HK, Koushan Y, Asgharzadeh A. Treatment of diabetic foot ulcer with propolis and olive oil: a case report. Knowl Health. 2012;6:35-38.
- Zahmatkesh M, Rashidi M. Case report of diabetic foot ulcer with topical honey and olive oil. J Med Plants. 2008;8:36-41.
- Cicerale S, Lucas LJ, Keast RS. Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil. Curr Opin Biotechnol. 2012;23:129-135. doi:10.1016/J.COPBIO.2011.09.006
- Miraj S, Pourafzali S, Ahmadabadi ZV, et al. Effect of olive oil in preventing the development of pressure ulcer grade one in intensive care unit patients. Int J Prev Med. 2020;11:23. doi:10.4103/IJPVM.IJPVM_545_18
- Díaz‐Valenzuela A, García‐Fernández FP, Carmona Fernández P, et al. Effectiveness and safety of olive oil preparation for topical use in pressure ulcer prevention: multicentre, controlled, randomised, and double‐blinded clinical trial. Int Wound J. 2019;16:1314-1322. doi:10.1111/IWJ.13191
- Carroli G, Mignini L. Episiotomy for vaginal birth. Cochrane Database Syst Rev. 2009;CD000081. doi:10.1002/14651858.CD000081.PUB2
- Amani R, Kariman N, Mojab F, et al. Comparison of the effects of cold compress with gel packs and topical olive oil on episiotomy wound healing. J Babol Univ Med Sci. 2015;17:7-12. doi:10.22088/JBUMS.17.11.7
- Behmanesh F, Aghamohammadi A, Zeinalzadeh M, et al. Effects of olive oil sitz bath on improvement of perineal injury after delivery. Koomesh. 2013;14:309-315.
- Vitsos A, Tsagarousianos C, Vergos O, et al. Efficacy of a Ceratothoa oestroides olive oil extract in patients with chronic ulcers: a pilot study. Int J Low Extrem Wounds. 2019;18:309-316. doi:10.1177/1534734619856143
- Emmons EW, Fedeli E, Firestone D. Olive oil introduction and history. In: Hui YH, ed. Bailey’s Industrial Oil & Fat Products, Vol. 2. Edible Oil and Fat Products: Edible Oils. 5th ed. John Wiley & Sons, Ltd; 241-269.
- Gorzynik-Debicka M, Przychodzen P, Cappello F, et al. Potential health benefits of olive oil and plant polyphenols. Int J Mol Sci. 2018;19:686. doi:10.3390/IJMS19030686
- Tuck KL, Hayball PJ. Major phenolic compounds in olive oil: metabolism and health effects. J Nutr Biochem. 2002;13:636-644. doi:10.1016/S0955-2863(02)00229-2
- Rabiei Z, Enferadi ST. Traceability of origin and authenticity of olive oil. In: Boskou D, ed. Olive Oil: Constituents, Quality, Health Properties and Bioconversions. InTech; 2012.
- Wardhana, Surachmanto ES, Datau EA. The role of omega-3 fatty acids contained in olive oil on chronic inflammation. Acta Med Indones. 2011;43:138-143.
- Aboui MM, Eidi A, Mortazavi P. Study of effect of olive oil on re-epithelialization of epithelial tissue in excision wound healing model in rats. J Comp Pathobiol. 2016;13:1875-1884.
- Aldana PC, Cartron AM, Khachemoune A. Reappraising diabetic foot ulcers: a focus on mechanisms of ulceration and clinical evaluation.Int J Low Extrem Wounds. 2022;21:294-302. doi:10.1177/1534734620944514
- Aldana PC, Khachemoune A. Diabetic foot ulcers: appraising standard of care and reviewing new trends in management. Am J Clin Dermatol. 2020;21:255-264. doi:10.1007/s40257-019-00495-x
- Nasiri M, Fayazi S, Jahani S, et al. The effect of topical olive oil on the healing of foot ulcer in patients with type 2 diabetes: a double-blind randomized clinical trial study in Iran. J Diabetes Metab Disord. 2015;14:38. doi:10.1186/S40200-015-0167-9
- Karimi Z, Behnammoghadam M, Rafiei H, et al. Impact of olive oil and honey on healing of diabetic foot: a randomized controlled trial. Clin Cosmet Investig Dermatol. 2019;12:347-354. doi:10.2147/CCID.S198577
- Haghighian HK, Koushan Y, Asgharzadeh A. Treatment of diabetic foot ulcer with propolis and olive oil: a case report. Knowl Health. 2012;6:35-38.
- Zahmatkesh M, Rashidi M. Case report of diabetic foot ulcer with topical honey and olive oil. J Med Plants. 2008;8:36-41.
- Cicerale S, Lucas LJ, Keast RS. Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil. Curr Opin Biotechnol. 2012;23:129-135. doi:10.1016/J.COPBIO.2011.09.006
- Miraj S, Pourafzali S, Ahmadabadi ZV, et al. Effect of olive oil in preventing the development of pressure ulcer grade one in intensive care unit patients. Int J Prev Med. 2020;11:23. doi:10.4103/IJPVM.IJPVM_545_18
- Díaz‐Valenzuela A, García‐Fernández FP, Carmona Fernández P, et al. Effectiveness and safety of olive oil preparation for topical use in pressure ulcer prevention: multicentre, controlled, randomised, and double‐blinded clinical trial. Int Wound J. 2019;16:1314-1322. doi:10.1111/IWJ.13191
- Carroli G, Mignini L. Episiotomy for vaginal birth. Cochrane Database Syst Rev. 2009;CD000081. doi:10.1002/14651858.CD000081.PUB2
- Amani R, Kariman N, Mojab F, et al. Comparison of the effects of cold compress with gel packs and topical olive oil on episiotomy wound healing. J Babol Univ Med Sci. 2015;17:7-12. doi:10.22088/JBUMS.17.11.7
- Behmanesh F, Aghamohammadi A, Zeinalzadeh M, et al. Effects of olive oil sitz bath on improvement of perineal injury after delivery. Koomesh. 2013;14:309-315.
- Vitsos A, Tsagarousianos C, Vergos O, et al. Efficacy of a Ceratothoa oestroides olive oil extract in patients with chronic ulcers: a pilot study. Int J Low Extrem Wounds. 2019;18:309-316. doi:10.1177/1534734619856143
Practice Points
- Interventions that effectively reduce excessive and prolonged inflammation can help promote timely wound healing. Consider integrating anti-inflammatory treatments into wound care protocols to enhance healing outcomes.
- Utilization of olive oil in wound therapy, particularly for conditions such as diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers, has shown promise for promoting healing.
- Regularly review and incorporate findings from recent studies on the use of olive oil and other novel interventions in wound therapy to ensure the application of the most current and effective treatment strategies.
Gastroenterology Data Trends 2024
In this issue:
- Eosinophilic Gastrointestinal Diseases: Beyond EoE
Nirmala Gonsalves, MD, AGAF, FACG - The Changing Face of IBD: Beyond the Western World
Gilaad G. Kaplan, MD, MPH, AGAF; Paulo Kotze, MD, MS, PhD; Siew C. Ng, MBBS, PhD, AGAF - Role of Non-invasive Biomarkers in the Evaluation and Management of MASLD
Julia J. Wattacheril, MD, MPH - The Emerging Role of Liquid Biopsy in the Diagnosis and Management of CRC
David Lieberman, MD, AGAF - Cannabinoids and Digestive Disorders
Jami A. Kinnucan, MD, AGAF, FACG - AI and Machine Learning in IBD: Promising Applications and Remaining Challenges
Shirley Cohen-Mekelburg, MD, MS - Simulation-Based Training in Endoscopy: Benefits and Challenges
Richa Shukla, MD - Fluid Management in Acute Pancreatitis
Jorge D. Machicado, MD, MPH
In this issue:
- Eosinophilic Gastrointestinal Diseases: Beyond EoE
Nirmala Gonsalves, MD, AGAF, FACG - The Changing Face of IBD: Beyond the Western World
Gilaad G. Kaplan, MD, MPH, AGAF; Paulo Kotze, MD, MS, PhD; Siew C. Ng, MBBS, PhD, AGAF - Role of Non-invasive Biomarkers in the Evaluation and Management of MASLD
Julia J. Wattacheril, MD, MPH - The Emerging Role of Liquid Biopsy in the Diagnosis and Management of CRC
David Lieberman, MD, AGAF - Cannabinoids and Digestive Disorders
Jami A. Kinnucan, MD, AGAF, FACG - AI and Machine Learning in IBD: Promising Applications and Remaining Challenges
Shirley Cohen-Mekelburg, MD, MS - Simulation-Based Training in Endoscopy: Benefits and Challenges
Richa Shukla, MD - Fluid Management in Acute Pancreatitis
Jorge D. Machicado, MD, MPH
In this issue:
- Eosinophilic Gastrointestinal Diseases: Beyond EoE
Nirmala Gonsalves, MD, AGAF, FACG - The Changing Face of IBD: Beyond the Western World
Gilaad G. Kaplan, MD, MPH, AGAF; Paulo Kotze, MD, MS, PhD; Siew C. Ng, MBBS, PhD, AGAF - Role of Non-invasive Biomarkers in the Evaluation and Management of MASLD
Julia J. Wattacheril, MD, MPH - The Emerging Role of Liquid Biopsy in the Diagnosis and Management of CRC
David Lieberman, MD, AGAF - Cannabinoids and Digestive Disorders
Jami A. Kinnucan, MD, AGAF, FACG - AI and Machine Learning in IBD: Promising Applications and Remaining Challenges
Shirley Cohen-Mekelburg, MD, MS - Simulation-Based Training in Endoscopy: Benefits and Challenges
Richa Shukla, MD - Fluid Management in Acute Pancreatitis
Jorge D. Machicado, MD, MPH
Cannabinoids and Digestive Disorders
- Leung J, Chan G, Stjepanović D, Chung JYC, Hall W, Hammond D. Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada. Psychopharmacology (Berl). 2022;239(5):1509-1519. doi:10.1007/s00213-021-06047-8
- Ahmed W, Katz S. Therapeutic use of cannabis in inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2016;12(11):668-679.
- Ravikoff Allegretti J, Courtwright A, Lucci M, Korzenik JR, Levine J. Marijuana use patterns among patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(13):2809-2814. doi:10.1097/01.MIB.0000435851.94391.37
- Marijuana legality by state - updated February 1, 2024. DISA. Accessed March 1, 2024. https://disa.com/marijuana-legality-by-state
- The Cannigma Staff. Where is weed legal around the globe? The Cannigma. Updated July 3, 2022. Accessed March 1, 2024. https://cannigma.com/regulation/cannabis-regulation-around-the-world/
- Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):833. doi:10.3390/ijms19030833
- Maselli DB, Camilleri M. Pharmacology, clinical effects, and therapeutic potential of cannabinoids for gastrointestinal and liver diseases. Clin Gastroenterol Hepatol. 2021;19(9):1748-1758.e2. doi:10.1016/j.cgh.2020.04.020
- Buckley MC, Kumar A, Swaminath A. Inflammatory bowel disease and cannabis: a practical approach for clinicians. Adv Ther. 2021;38(7):4152- 4161. doi:10.1007/s12325-021-01805-8
- Chang L, Cash BD, Lembo A, et al. Efficacy and safety of olorinab, a full agonist of the cannabinoid receptor 2, for the treatment of abdominal pain in patients with irritable bowel syndrome: results from a phase 2b randomized placebo-controlled trial (CAPTIVATE). Neurogastroenterol Motil. 2023;35(5):e14539. doi:10.1111/nmo.14539
- Doeve BH, van de Meeberg MM, van Schaik FDM, Fidder HH. A systematic review with meta-analysis of the efficacy of cannabis and cannabinoids for inflammatory bowel disease: what can we learn from randomized and nonrandomized studies? J Clin Gastroenterol. 2021;55(9):798-809. doi:10.1097/MCG.0000000000001393
- Gotfried J, Naftali T, Schey R. Role of cannabis and its derivatives in gastrointestinal and hepatic disease [published correction appears in Gastroenterology. 2021;160(5):1904]. Gastroenterology. 2020;159(1):62-80. doi:10.1053/j.gastro.2020.03.087
- Goyal H, Singla U, Gupta U, May E. Role of cannabis in digestive disorders. Eur J Gastroenterol Hepatol. 2017;29(2):135-143. doi:10.1097/MEG.0000000000000779
- van Orten-Luiten AB, de Roos NM, Majait S, Witteman BJM, Witkamp RF. Effects of cannabidiol chewing gum on perceived pain and well-being of irritable bowel syndrome patients: a placebo-controlled crossover exploratory intervention study with symptom-driven dosing. Cannabis Cannabinoid Res. 2022;7(4):436-444. doi:10.1089/can.2020.0087
- Adejumo AC, Ajayi TO, Adegbala OM, Bukong TN. Higher odds of irritable bowel syndrome among hospitalized patients using cannabis: a propensity matched analysis. Eur J Gastroenterol Hepatol. 2019;31(7):756-765. doi:10.1097/MEG.0000000000001382
- Antoniou T, Bodkin J, Ho JM. Drug interactions with cannabinoids. CMAJ. 2020;192(9):E206. doi:10.1503/cmaj.191097
- Karila L, Roux P, Rolland B, et al. Acute and long-term effects of cannabis use: a review. Curr Pharm Des. 2014;20(25):4112-4118. doi:10.2174/13816128113199990620
- Venkatesan T, Levinthal DJ, Li BUK, et al. Role of chronic cannabis use: cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome. Neurogastroenterol Motil. 2019;31(suppl 2):e13606. doi:10.1111/nmo.13606
- Leung J, Chan G, Stjepanović D, Chung JYC, Hall W, Hammond D. Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada. Psychopharmacology (Berl). 2022;239(5):1509-1519. doi:10.1007/s00213-021-06047-8
- Ahmed W, Katz S. Therapeutic use of cannabis in inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2016;12(11):668-679.
- Ravikoff Allegretti J, Courtwright A, Lucci M, Korzenik JR, Levine J. Marijuana use patterns among patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(13):2809-2814. doi:10.1097/01.MIB.0000435851.94391.37
- Marijuana legality by state - updated February 1, 2024. DISA. Accessed March 1, 2024. https://disa.com/marijuana-legality-by-state
- The Cannigma Staff. Where is weed legal around the globe? The Cannigma. Updated July 3, 2022. Accessed March 1, 2024. https://cannigma.com/regulation/cannabis-regulation-around-the-world/
- Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):833. doi:10.3390/ijms19030833
- Maselli DB, Camilleri M. Pharmacology, clinical effects, and therapeutic potential of cannabinoids for gastrointestinal and liver diseases. Clin Gastroenterol Hepatol. 2021;19(9):1748-1758.e2. doi:10.1016/j.cgh.2020.04.020
- Buckley MC, Kumar A, Swaminath A. Inflammatory bowel disease and cannabis: a practical approach for clinicians. Adv Ther. 2021;38(7):4152- 4161. doi:10.1007/s12325-021-01805-8
- Chang L, Cash BD, Lembo A, et al. Efficacy and safety of olorinab, a full agonist of the cannabinoid receptor 2, for the treatment of abdominal pain in patients with irritable bowel syndrome: results from a phase 2b randomized placebo-controlled trial (CAPTIVATE). Neurogastroenterol Motil. 2023;35(5):e14539. doi:10.1111/nmo.14539
- Doeve BH, van de Meeberg MM, van Schaik FDM, Fidder HH. A systematic review with meta-analysis of the efficacy of cannabis and cannabinoids for inflammatory bowel disease: what can we learn from randomized and nonrandomized studies? J Clin Gastroenterol. 2021;55(9):798-809. doi:10.1097/MCG.0000000000001393
- Gotfried J, Naftali T, Schey R. Role of cannabis and its derivatives in gastrointestinal and hepatic disease [published correction appears in Gastroenterology. 2021;160(5):1904]. Gastroenterology. 2020;159(1):62-80. doi:10.1053/j.gastro.2020.03.087
- Goyal H, Singla U, Gupta U, May E. Role of cannabis in digestive disorders. Eur J Gastroenterol Hepatol. 2017;29(2):135-143. doi:10.1097/MEG.0000000000000779
- van Orten-Luiten AB, de Roos NM, Majait S, Witteman BJM, Witkamp RF. Effects of cannabidiol chewing gum on perceived pain and well-being of irritable bowel syndrome patients: a placebo-controlled crossover exploratory intervention study with symptom-driven dosing. Cannabis Cannabinoid Res. 2022;7(4):436-444. doi:10.1089/can.2020.0087
- Adejumo AC, Ajayi TO, Adegbala OM, Bukong TN. Higher odds of irritable bowel syndrome among hospitalized patients using cannabis: a propensity matched analysis. Eur J Gastroenterol Hepatol. 2019;31(7):756-765. doi:10.1097/MEG.0000000000001382
- Antoniou T, Bodkin J, Ho JM. Drug interactions with cannabinoids. CMAJ. 2020;192(9):E206. doi:10.1503/cmaj.191097
- Karila L, Roux P, Rolland B, et al. Acute and long-term effects of cannabis use: a review. Curr Pharm Des. 2014;20(25):4112-4118. doi:10.2174/13816128113199990620
- Venkatesan T, Levinthal DJ, Li BUK, et al. Role of chronic cannabis use: cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome. Neurogastroenterol Motil. 2019;31(suppl 2):e13606. doi:10.1111/nmo.13606
- Leung J, Chan G, Stjepanović D, Chung JYC, Hall W, Hammond D. Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada. Psychopharmacology (Berl). 2022;239(5):1509-1519. doi:10.1007/s00213-021-06047-8
- Ahmed W, Katz S. Therapeutic use of cannabis in inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2016;12(11):668-679.
- Ravikoff Allegretti J, Courtwright A, Lucci M, Korzenik JR, Levine J. Marijuana use patterns among patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(13):2809-2814. doi:10.1097/01.MIB.0000435851.94391.37
- Marijuana legality by state - updated February 1, 2024. DISA. Accessed March 1, 2024. https://disa.com/marijuana-legality-by-state
- The Cannigma Staff. Where is weed legal around the globe? The Cannigma. Updated July 3, 2022. Accessed March 1, 2024. https://cannigma.com/regulation/cannabis-regulation-around-the-world/
- Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):833. doi:10.3390/ijms19030833
- Maselli DB, Camilleri M. Pharmacology, clinical effects, and therapeutic potential of cannabinoids for gastrointestinal and liver diseases. Clin Gastroenterol Hepatol. 2021;19(9):1748-1758.e2. doi:10.1016/j.cgh.2020.04.020
- Buckley MC, Kumar A, Swaminath A. Inflammatory bowel disease and cannabis: a practical approach for clinicians. Adv Ther. 2021;38(7):4152- 4161. doi:10.1007/s12325-021-01805-8
- Chang L, Cash BD, Lembo A, et al. Efficacy and safety of olorinab, a full agonist of the cannabinoid receptor 2, for the treatment of abdominal pain in patients with irritable bowel syndrome: results from a phase 2b randomized placebo-controlled trial (CAPTIVATE). Neurogastroenterol Motil. 2023;35(5):e14539. doi:10.1111/nmo.14539
- Doeve BH, van de Meeberg MM, van Schaik FDM, Fidder HH. A systematic review with meta-analysis of the efficacy of cannabis and cannabinoids for inflammatory bowel disease: what can we learn from randomized and nonrandomized studies? J Clin Gastroenterol. 2021;55(9):798-809. doi:10.1097/MCG.0000000000001393
- Gotfried J, Naftali T, Schey R. Role of cannabis and its derivatives in gastrointestinal and hepatic disease [published correction appears in Gastroenterology. 2021;160(5):1904]. Gastroenterology. 2020;159(1):62-80. doi:10.1053/j.gastro.2020.03.087
- Goyal H, Singla U, Gupta U, May E. Role of cannabis in digestive disorders. Eur J Gastroenterol Hepatol. 2017;29(2):135-143. doi:10.1097/MEG.0000000000000779
- van Orten-Luiten AB, de Roos NM, Majait S, Witteman BJM, Witkamp RF. Effects of cannabidiol chewing gum on perceived pain and well-being of irritable bowel syndrome patients: a placebo-controlled crossover exploratory intervention study with symptom-driven dosing. Cannabis Cannabinoid Res. 2022;7(4):436-444. doi:10.1089/can.2020.0087
- Adejumo AC, Ajayi TO, Adegbala OM, Bukong TN. Higher odds of irritable bowel syndrome among hospitalized patients using cannabis: a propensity matched analysis. Eur J Gastroenterol Hepatol. 2019;31(7):756-765. doi:10.1097/MEG.0000000000001382
- Antoniou T, Bodkin J, Ho JM. Drug interactions with cannabinoids. CMAJ. 2020;192(9):E206. doi:10.1503/cmaj.191097
- Karila L, Roux P, Rolland B, et al. Acute and long-term effects of cannabis use: a review. Curr Pharm Des. 2014;20(25):4112-4118. doi:10.2174/13816128113199990620
- Venkatesan T, Levinthal DJ, Li BUK, et al. Role of chronic cannabis use: cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome. Neurogastroenterol Motil. 2019;31(suppl 2):e13606. doi:10.1111/nmo.13606
AI and Machine Learning in IBD: Promising Applications and Remaining Challenges
- Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003
- Sharma P. AI shows promise in diagnosis, treatment of IBD, but limitations, concerns remain. Healio. Published June 19, 2023. Accessed January 5, 2024. https://www.healio.com/news/gastroenterology/20230606/ai-shows-promise-in-diagnosis-treatment-of-ibd-but-limitations-concerns-remain
- Artificial intelligence (AI) vs. machine learning. Columbia Engineering.Accessed January 5, 2024. https://ai.engineering.columbia.edu/ai-vs-machine-learning/
- Zhang B, Shi H, Wang H. Machine learning and AI in cancer prognosis, prediction, and treatment selection: a critical approach. J Multidiscip Healthc. 2023;16:1779-1791. doi:10.2147/JMDH.S410301
- Cohen-Mekelburg S, Berry S, Stidham RW, Zhu J, Waljee AK. Clinical applications of artificial intelligence and machine learning-based methods in inflammatory bowel disease. J Gastroenterol Hepatol. 2021;36(2):279-285. doi:10.1111/jgh.15405
- Uche-Anya E, Anyane-Yeboa A, Berzin TM, Ghassemi M, May FP. Artificial intelligence in gastroenterology and hepatology: how to advance clinical practice while ensuring health equity. Gut. 2022;71(9):1909-1915. doi:10.1136/gutjnl-2021-326271
- Stafford IS, Gosink MM, Mossotto E, Ennis S, Hauben M. A systematic review of artificial intelligence and machine learning applications to inflammatory bowel disease, with practical guidelines for interpretation. Inflamm Bowel Dis. 2022;28(10):1573-1583. doi:10.1093/ibd/izac115
- Gubatan J, Levitte S, Patel A, Balabanis T, Wei MT, Sinha SR. Artificial intelligence applications in inflammatory bowel disease: emerging technologies and future directions. World J Gastroenterol. 2021;27(17):1920-1935. doi:10.3748/wjg.v27.i17.1920
- Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003
- Sharma P. AI shows promise in diagnosis, treatment of IBD, but limitations, concerns remain. Healio. Published June 19, 2023. Accessed January 5, 2024. https://www.healio.com/news/gastroenterology/20230606/ai-shows-promise-in-diagnosis-treatment-of-ibd-but-limitations-concerns-remain
- Artificial intelligence (AI) vs. machine learning. Columbia Engineering.Accessed January 5, 2024. https://ai.engineering.columbia.edu/ai-vs-machine-learning/
- Zhang B, Shi H, Wang H. Machine learning and AI in cancer prognosis, prediction, and treatment selection: a critical approach. J Multidiscip Healthc. 2023;16:1779-1791. doi:10.2147/JMDH.S410301
- Cohen-Mekelburg S, Berry S, Stidham RW, Zhu J, Waljee AK. Clinical applications of artificial intelligence and machine learning-based methods in inflammatory bowel disease. J Gastroenterol Hepatol. 2021;36(2):279-285. doi:10.1111/jgh.15405
- Uche-Anya E, Anyane-Yeboa A, Berzin TM, Ghassemi M, May FP. Artificial intelligence in gastroenterology and hepatology: how to advance clinical practice while ensuring health equity. Gut. 2022;71(9):1909-1915. doi:10.1136/gutjnl-2021-326271
- Stafford IS, Gosink MM, Mossotto E, Ennis S, Hauben M. A systematic review of artificial intelligence and machine learning applications to inflammatory bowel disease, with practical guidelines for interpretation. Inflamm Bowel Dis. 2022;28(10):1573-1583. doi:10.1093/ibd/izac115
- Gubatan J, Levitte S, Patel A, Balabanis T, Wei MT, Sinha SR. Artificial intelligence applications in inflammatory bowel disease: emerging technologies and future directions. World J Gastroenterol. 2021;27(17):1920-1935. doi:10.3748/wjg.v27.i17.1920
- Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003
- Sharma P. AI shows promise in diagnosis, treatment of IBD, but limitations, concerns remain. Healio. Published June 19, 2023. Accessed January 5, 2024. https://www.healio.com/news/gastroenterology/20230606/ai-shows-promise-in-diagnosis-treatment-of-ibd-but-limitations-concerns-remain
- Artificial intelligence (AI) vs. machine learning. Columbia Engineering.Accessed January 5, 2024. https://ai.engineering.columbia.edu/ai-vs-machine-learning/
- Zhang B, Shi H, Wang H. Machine learning and AI in cancer prognosis, prediction, and treatment selection: a critical approach. J Multidiscip Healthc. 2023;16:1779-1791. doi:10.2147/JMDH.S410301
- Cohen-Mekelburg S, Berry S, Stidham RW, Zhu J, Waljee AK. Clinical applications of artificial intelligence and machine learning-based methods in inflammatory bowel disease. J Gastroenterol Hepatol. 2021;36(2):279-285. doi:10.1111/jgh.15405
- Uche-Anya E, Anyane-Yeboa A, Berzin TM, Ghassemi M, May FP. Artificial intelligence in gastroenterology and hepatology: how to advance clinical practice while ensuring health equity. Gut. 2022;71(9):1909-1915. doi:10.1136/gutjnl-2021-326271
- Stafford IS, Gosink MM, Mossotto E, Ennis S, Hauben M. A systematic review of artificial intelligence and machine learning applications to inflammatory bowel disease, with practical guidelines for interpretation. Inflamm Bowel Dis. 2022;28(10):1573-1583. doi:10.1093/ibd/izac115
- Gubatan J, Levitte S, Patel A, Balabanis T, Wei MT, Sinha SR. Artificial intelligence applications in inflammatory bowel disease: emerging technologies and future directions. World J Gastroenterol. 2021;27(17):1920-1935. doi:10.3748/wjg.v27.i17.1920
Simulation-Based Training in Endoscopy: Benefits and Challenges
- Hayden EM, Khatri A, Kelly HR, Yager PH, Salazar GM. Mannequinbased telesimulation: increasing access to simulation-based education. Acad Emerg Med. 2018;25(2):144-147. doi:10.1111/acem.13299
- Khan R, Scaffidi MA, Grover SC, Gimpaya N, Walsh CM. Simulation in endoscopy: practical educational strategies to improve learning. World J Gastrointest Endosc. 2019;11(3):209-218. doi:10.4253/wjge.v11.i3.209
- Bhushan S, Anandasabapathy S, Shukla R. Use of augmented reality and virtual reality technologies in endoscopic training. Clin Gastroenterol Hepatol. 2018;16(11):1688-1691. doi:10.1016/j.cgh.2018.08.021
- Bienstock J, Heuer A. A review on the evolution of simulationbased training to help build a safer future. Medicine (Baltimore). 2022;101(25):e29503. doi:10.1097/MD.0000000000029503
- Emergen Research. Global augmented and virtual reality in healthcare market size to reach USD 20.76 billion in 2032. GlobeNewswire. Published October 12, 2023. Accessed January 5, 2024. https://www.globenewswire.com/news-release/2023/10/12/2759433/0/en/GlobalAugmented-and-Virtual-Reality-in-Healthcare-Market-Size-to-ReachUSD-20-76-Billion-in-2032-Emergen-Research.html
- Hippe DS, Umoren RA, McGee A, Bucher SL, Bresnahan BW. A targeted systematic review of cost analyses for implementation of simulation-based education in healthcare. SAGE Open Med. 2020;8:2050312120913451. doi:10.1177/2050312120913451
- Hayden EM, Khatri A, Kelly HR, Yager PH, Salazar GM. Mannequinbased telesimulation: increasing access to simulation-based education. Acad Emerg Med. 2018;25(2):144-147. doi:10.1111/acem.13299
- Khan R, Scaffidi MA, Grover SC, Gimpaya N, Walsh CM. Simulation in endoscopy: practical educational strategies to improve learning. World J Gastrointest Endosc. 2019;11(3):209-218. doi:10.4253/wjge.v11.i3.209
- Bhushan S, Anandasabapathy S, Shukla R. Use of augmented reality and virtual reality technologies in endoscopic training. Clin Gastroenterol Hepatol. 2018;16(11):1688-1691. doi:10.1016/j.cgh.2018.08.021
- Bienstock J, Heuer A. A review on the evolution of simulationbased training to help build a safer future. Medicine (Baltimore). 2022;101(25):e29503. doi:10.1097/MD.0000000000029503
- Emergen Research. Global augmented and virtual reality in healthcare market size to reach USD 20.76 billion in 2032. GlobeNewswire. Published October 12, 2023. Accessed January 5, 2024. https://www.globenewswire.com/news-release/2023/10/12/2759433/0/en/GlobalAugmented-and-Virtual-Reality-in-Healthcare-Market-Size-to-ReachUSD-20-76-Billion-in-2032-Emergen-Research.html
- Hippe DS, Umoren RA, McGee A, Bucher SL, Bresnahan BW. A targeted systematic review of cost analyses for implementation of simulation-based education in healthcare. SAGE Open Med. 2020;8:2050312120913451. doi:10.1177/2050312120913451
- Hayden EM, Khatri A, Kelly HR, Yager PH, Salazar GM. Mannequinbased telesimulation: increasing access to simulation-based education. Acad Emerg Med. 2018;25(2):144-147. doi:10.1111/acem.13299
- Khan R, Scaffidi MA, Grover SC, Gimpaya N, Walsh CM. Simulation in endoscopy: practical educational strategies to improve learning. World J Gastrointest Endosc. 2019;11(3):209-218. doi:10.4253/wjge.v11.i3.209
- Bhushan S, Anandasabapathy S, Shukla R. Use of augmented reality and virtual reality technologies in endoscopic training. Clin Gastroenterol Hepatol. 2018;16(11):1688-1691. doi:10.1016/j.cgh.2018.08.021
- Bienstock J, Heuer A. A review on the evolution of simulationbased training to help build a safer future. Medicine (Baltimore). 2022;101(25):e29503. doi:10.1097/MD.0000000000029503
- Emergen Research. Global augmented and virtual reality in healthcare market size to reach USD 20.76 billion in 2032. GlobeNewswire. Published October 12, 2023. Accessed January 5, 2024. https://www.globenewswire.com/news-release/2023/10/12/2759433/0/en/GlobalAugmented-and-Virtual-Reality-in-Healthcare-Market-Size-to-ReachUSD-20-76-Billion-in-2032-Emergen-Research.html
- Hippe DS, Umoren RA, McGee A, Bucher SL, Bresnahan BW. A targeted systematic review of cost analyses for implementation of simulation-based education in healthcare. SAGE Open Med. 2020;8:2050312120913451. doi:10.1177/2050312120913451
The Changing Face of IBD: Beyond the Western World
- Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(1):56-66. doi:10.1038/s41575-020-00360-x
- Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease [published correction appears in Gastroenterology. 2017;152(8):2084]. Gastroenterology. 2017;152(2):313-321.e2. doi:10.1053/j.gastro.2016.10.020
- Balderramo D, Quaresma AB, Olivera PA, et al. Challenges in diagnosis and treatment of inflammatory bowel disease in Latin America. Lancet Gastroenterol Hepatol. 2024; 9(3):263-272. doi:10.1016/S2468-1253(23)00284-4
- Song EM, Na SY, Hong SN, Ng SC, Hisamatsu T, Ye BD. Treatment of inflammatory bowel disease–Asian perspectives: the results of a multinational web-based survey in the 8th Asian Organization for Crohn’s and Colitis meeting. Intest Res. 2023;21(3):339-352. doi:10.5217/ir.2022.00135
- GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17-30. doi:10.1016/S2468-1253(19)30333-4
- Chen X, Xiang X, Xia W, et al. Evolving trends and burden of inflammatory bowel disease in Asia, 1990-2019: a comprehensive analysis based on the Global Burden of Disease Study. J Epidemiol Glob Health. 2023;13(4):725-739. doi:10.1007/s44197-023-00145-w
- Zhao M, Feng R, Ben-Horin S, et al. Systematic review with meta-analysis: environmental and dietary differences of inflammatory bowel disease in Eastern and Western populations. Aliment Pharmacol Ther. 2022;55(3):266-276. doi:10.1111/apt.16703
- Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003
- Quaresma AB, Damiao AOMC, Coy CSR, et al. Temporal trends in the epidemiology of inflammatory bowel diseases in the public healthcare system in Brazil: a large population-based study. Lancet Reg Health Am. 2022;13:100298. doi:10.1016/j.lana.2022.100298
- Gordon H, Burisch J, Ellul P, et al. ECCO guidelines on extraintestinal manifestations in inflammatory bowel disease. J Crohns Colitis. 2024;18(1):1-37. doi:10.1093/ecco-jcc/jjad108
- Coward S, Benchimol EI, Bernstein CN, et al; Canadian Gastro-Intestinal Epidemiology Consortium (CanGIEC). Forecasting the Incidence and Prevalence of Inflammatory Bowel Disease: A Canadian Nationwide Analysis. Am J Gastroenterol. 2024 Mar 18. doi:10.14309/ajg.0000000000002687. Epub ahead of print. PMID: 38299598.
- Dorn-Rasmussen M, Lo B, Zhao M, Kaplan GG, Malham M, Wewer V, Burisch J. The Incidence and Prevalence of Paediatric- and Adult-Onset Inflammatory Bowel Disease in Denmark During a 37-Year Period: A Nationwide Cohort Study (1980-2017). J Crohns Colitis. 2023;17(2):259- 268. doi:10.1093/ecco-jcc/jjac138. PMID: 36125076.
- Watermeyer G, Katsidzira L, Setshedi M, et al. Inflammatory bowel disease in sub-Saharan Africa: epidemiology, risk factors, and challenges in diagnosis. Lancet Gastroenterol Hepatol. 2022;7(10):952-961. doi:10.1016/S2468-1253(22)00047-4
- Stulman MY, Asayag N, Focht G, et al. Epidemiology of Inflammatory Bowel Diseases in Israel: A Nationwide Epi-Israeli IBD Research Nucleus Study. Inflamm Bowel Dis. 2021;27(11):1784-1794. doi:10.1093/ibd/izaa341
- Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies [published correction appears in Lancet. 2020;396(10256):e56]. Lancet. 2017;390(10114):2769-2778. doi:10.1016/S0140-6736(17)32448-0
- Busingye D, Pollack A, Chidwick K. Prevalence of inflammatory bowel disease in the Australian general practice population: A cross-sectional study. PLoS One. 2021;16(5):e0252458. Published 2021 May 27. doi:10.1371/ journal.pone.0252458
- Gecse KB, Vermeire S. Differential diagnosis of inflammatory bowel disease: imitations and complications. Lancet Gastroenterol Hepatol. 2018;3(9):644-653. doi:10.1016/S2468-1253(18)30159-6
- Inflammatory bowel disease (IBD): comorbidities. Centers for Disease Control and Prevention. Last reviewed April 14, 2022. Accessed February 21, 2024. https://www.cdc.gov/ibd/data-and-statistics/comorbidities.html
- Mosli MH, Alsahafi M, Alsanea MN, Alhasani F, Ahmed M, Saadah O. Multimorbidity among inflammatory bowel disease patients in a tertiary care center: a retrospective study. BMC Gastroenterol. 2022;22(1):487. doi:10.1186/s12876-022-02578-2
- Inflammatory bowel disease (IBD). Mayo Clinic. September 3, 2022. Accessed February 21, 2024. https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/diagnosis-treatment/drc-20353320
- Ng SC, Tang W, Ching JY, et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn’s and Colitis Epidemiology Study. Gastroenterology. 2013;145(1):158-165.e2. doi:10.1053/j.gastro.2013.04.007
- Ng SC, Tsoi KK, Kamm MA, et al. Genetics of inflammatory bowel disease in Asia: systematic review and meta-analysis. Inflamm Bowel Dis. 2012;18(6):1164-1176. doi:10.1002/ibd.21845
- Banerjee R, Pal P, Mak JWY, Ng SC. Challenges in the diagnosis and management of inflammatory bowel disease in resource-limited settings in Asia. Lancet Gastroenterol Hepatol. 2020;5(12):1076-1088. doi:10.1016/S2468-1253(20)30299-5
- Ng SC, Mak JWY, Pal P, Banerjee R. Optimising management strategies of inflammatory bowel disease in resource-limited settings in Asia. Lancet Gastroenterol Hepatol. 2020;5(12):1089-1100. 10.1016/S2468-1253(20)30298-3
- Ng SC. Emerging trends of inflammatory bowel disease in Asia. Gastroenterol Hepatol (N Y). 2016;12(3):193-196. PMID: 27231449
- Ran Z, Wu K, Matsuoka K, et al. Asian Organization for Crohn’s and Colitis and Asia Pacific Association of Gastroenterology practice recommendations for medical management and monitoring of inflammatory bowel disease in Asia. J Gastroenterol Hepatol. 2021;36(3):637-645. doi:10.1111/jgh.15185
- Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979-986. doi:10.1038/ng.3359
- Yamamoto-Furusho JK, Parra-Holguín NN, Juliao-Baños F, et al; for the EPILATAM study group. Clinical differentiation of inflammatory bowel disease (IBD) in Latin America and the Caribbean. Medicine (Baltimore). 2022;101(3):e28624. doi:10.1097/MD.0000000000028624
- Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(1):56-66. doi:10.1038/s41575-020-00360-x
- Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease [published correction appears in Gastroenterology. 2017;152(8):2084]. Gastroenterology. 2017;152(2):313-321.e2. doi:10.1053/j.gastro.2016.10.020
- Balderramo D, Quaresma AB, Olivera PA, et al. Challenges in diagnosis and treatment of inflammatory bowel disease in Latin America. Lancet Gastroenterol Hepatol. 2024; 9(3):263-272. doi:10.1016/S2468-1253(23)00284-4
- Song EM, Na SY, Hong SN, Ng SC, Hisamatsu T, Ye BD. Treatment of inflammatory bowel disease–Asian perspectives: the results of a multinational web-based survey in the 8th Asian Organization for Crohn’s and Colitis meeting. Intest Res. 2023;21(3):339-352. doi:10.5217/ir.2022.00135
- GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17-30. doi:10.1016/S2468-1253(19)30333-4
- Chen X, Xiang X, Xia W, et al. Evolving trends and burden of inflammatory bowel disease in Asia, 1990-2019: a comprehensive analysis based on the Global Burden of Disease Study. J Epidemiol Glob Health. 2023;13(4):725-739. doi:10.1007/s44197-023-00145-w
- Zhao M, Feng R, Ben-Horin S, et al. Systematic review with meta-analysis: environmental and dietary differences of inflammatory bowel disease in Eastern and Western populations. Aliment Pharmacol Ther. 2022;55(3):266-276. doi:10.1111/apt.16703
- Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003
- Quaresma AB, Damiao AOMC, Coy CSR, et al. Temporal trends in the epidemiology of inflammatory bowel diseases in the public healthcare system in Brazil: a large population-based study. Lancet Reg Health Am. 2022;13:100298. doi:10.1016/j.lana.2022.100298
- Gordon H, Burisch J, Ellul P, et al. ECCO guidelines on extraintestinal manifestations in inflammatory bowel disease. J Crohns Colitis. 2024;18(1):1-37. doi:10.1093/ecco-jcc/jjad108
- Coward S, Benchimol EI, Bernstein CN, et al; Canadian Gastro-Intestinal Epidemiology Consortium (CanGIEC). Forecasting the Incidence and Prevalence of Inflammatory Bowel Disease: A Canadian Nationwide Analysis. Am J Gastroenterol. 2024 Mar 18. doi:10.14309/ajg.0000000000002687. Epub ahead of print. PMID: 38299598.
- Dorn-Rasmussen M, Lo B, Zhao M, Kaplan GG, Malham M, Wewer V, Burisch J. The Incidence and Prevalence of Paediatric- and Adult-Onset Inflammatory Bowel Disease in Denmark During a 37-Year Period: A Nationwide Cohort Study (1980-2017). J Crohns Colitis. 2023;17(2):259- 268. doi:10.1093/ecco-jcc/jjac138. PMID: 36125076.
- Watermeyer G, Katsidzira L, Setshedi M, et al. Inflammatory bowel disease in sub-Saharan Africa: epidemiology, risk factors, and challenges in diagnosis. Lancet Gastroenterol Hepatol. 2022;7(10):952-961. doi:10.1016/S2468-1253(22)00047-4
- Stulman MY, Asayag N, Focht G, et al. Epidemiology of Inflammatory Bowel Diseases in Israel: A Nationwide Epi-Israeli IBD Research Nucleus Study. Inflamm Bowel Dis. 2021;27(11):1784-1794. doi:10.1093/ibd/izaa341
- Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies [published correction appears in Lancet. 2020;396(10256):e56]. Lancet. 2017;390(10114):2769-2778. doi:10.1016/S0140-6736(17)32448-0
- Busingye D, Pollack A, Chidwick K. Prevalence of inflammatory bowel disease in the Australian general practice population: A cross-sectional study. PLoS One. 2021;16(5):e0252458. Published 2021 May 27. doi:10.1371/ journal.pone.0252458
- Gecse KB, Vermeire S. Differential diagnosis of inflammatory bowel disease: imitations and complications. Lancet Gastroenterol Hepatol. 2018;3(9):644-653. doi:10.1016/S2468-1253(18)30159-6
- Inflammatory bowel disease (IBD): comorbidities. Centers for Disease Control and Prevention. Last reviewed April 14, 2022. Accessed February 21, 2024. https://www.cdc.gov/ibd/data-and-statistics/comorbidities.html
- Mosli MH, Alsahafi M, Alsanea MN, Alhasani F, Ahmed M, Saadah O. Multimorbidity among inflammatory bowel disease patients in a tertiary care center: a retrospective study. BMC Gastroenterol. 2022;22(1):487. doi:10.1186/s12876-022-02578-2
- Inflammatory bowel disease (IBD). Mayo Clinic. September 3, 2022. Accessed February 21, 2024. https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/diagnosis-treatment/drc-20353320
- Ng SC, Tang W, Ching JY, et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn’s and Colitis Epidemiology Study. Gastroenterology. 2013;145(1):158-165.e2. doi:10.1053/j.gastro.2013.04.007
- Ng SC, Tsoi KK, Kamm MA, et al. Genetics of inflammatory bowel disease in Asia: systematic review and meta-analysis. Inflamm Bowel Dis. 2012;18(6):1164-1176. doi:10.1002/ibd.21845
- Banerjee R, Pal P, Mak JWY, Ng SC. Challenges in the diagnosis and management of inflammatory bowel disease in resource-limited settings in Asia. Lancet Gastroenterol Hepatol. 2020;5(12):1076-1088. doi:10.1016/S2468-1253(20)30299-5
- Ng SC, Mak JWY, Pal P, Banerjee R. Optimising management strategies of inflammatory bowel disease in resource-limited settings in Asia. Lancet Gastroenterol Hepatol. 2020;5(12):1089-1100. 10.1016/S2468-1253(20)30298-3
- Ng SC. Emerging trends of inflammatory bowel disease in Asia. Gastroenterol Hepatol (N Y). 2016;12(3):193-196. PMID: 27231449
- Ran Z, Wu K, Matsuoka K, et al. Asian Organization for Crohn’s and Colitis and Asia Pacific Association of Gastroenterology practice recommendations for medical management and monitoring of inflammatory bowel disease in Asia. J Gastroenterol Hepatol. 2021;36(3):637-645. doi:10.1111/jgh.15185
- Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979-986. doi:10.1038/ng.3359
- Yamamoto-Furusho JK, Parra-Holguín NN, Juliao-Baños F, et al; for the EPILATAM study group. Clinical differentiation of inflammatory bowel disease (IBD) in Latin America and the Caribbean. Medicine (Baltimore). 2022;101(3):e28624. doi:10.1097/MD.0000000000028624
- Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(1):56-66. doi:10.1038/s41575-020-00360-x
- Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease [published correction appears in Gastroenterology. 2017;152(8):2084]. Gastroenterology. 2017;152(2):313-321.e2. doi:10.1053/j.gastro.2016.10.020
- Balderramo D, Quaresma AB, Olivera PA, et al. Challenges in diagnosis and treatment of inflammatory bowel disease in Latin America. Lancet Gastroenterol Hepatol. 2024; 9(3):263-272. doi:10.1016/S2468-1253(23)00284-4
- Song EM, Na SY, Hong SN, Ng SC, Hisamatsu T, Ye BD. Treatment of inflammatory bowel disease–Asian perspectives: the results of a multinational web-based survey in the 8th Asian Organization for Crohn’s and Colitis meeting. Intest Res. 2023;21(3):339-352. doi:10.5217/ir.2022.00135
- GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17-30. doi:10.1016/S2468-1253(19)30333-4
- Chen X, Xiang X, Xia W, et al. Evolving trends and burden of inflammatory bowel disease in Asia, 1990-2019: a comprehensive analysis based on the Global Burden of Disease Study. J Epidemiol Glob Health. 2023;13(4):725-739. doi:10.1007/s44197-023-00145-w
- Zhao M, Feng R, Ben-Horin S, et al. Systematic review with meta-analysis: environmental and dietary differences of inflammatory bowel disease in Eastern and Western populations. Aliment Pharmacol Ther. 2022;55(3):266-276. doi:10.1111/apt.16703
- Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2. doi:10.1053/j.gastro.2023.07.003
- Quaresma AB, Damiao AOMC, Coy CSR, et al. Temporal trends in the epidemiology of inflammatory bowel diseases in the public healthcare system in Brazil: a large population-based study. Lancet Reg Health Am. 2022;13:100298. doi:10.1016/j.lana.2022.100298
- Gordon H, Burisch J, Ellul P, et al. ECCO guidelines on extraintestinal manifestations in inflammatory bowel disease. J Crohns Colitis. 2024;18(1):1-37. doi:10.1093/ecco-jcc/jjad108
- Coward S, Benchimol EI, Bernstein CN, et al; Canadian Gastro-Intestinal Epidemiology Consortium (CanGIEC). Forecasting the Incidence and Prevalence of Inflammatory Bowel Disease: A Canadian Nationwide Analysis. Am J Gastroenterol. 2024 Mar 18. doi:10.14309/ajg.0000000000002687. Epub ahead of print. PMID: 38299598.
- Dorn-Rasmussen M, Lo B, Zhao M, Kaplan GG, Malham M, Wewer V, Burisch J. The Incidence and Prevalence of Paediatric- and Adult-Onset Inflammatory Bowel Disease in Denmark During a 37-Year Period: A Nationwide Cohort Study (1980-2017). J Crohns Colitis. 2023;17(2):259- 268. doi:10.1093/ecco-jcc/jjac138. PMID: 36125076.
- Watermeyer G, Katsidzira L, Setshedi M, et al. Inflammatory bowel disease in sub-Saharan Africa: epidemiology, risk factors, and challenges in diagnosis. Lancet Gastroenterol Hepatol. 2022;7(10):952-961. doi:10.1016/S2468-1253(22)00047-4
- Stulman MY, Asayag N, Focht G, et al. Epidemiology of Inflammatory Bowel Diseases in Israel: A Nationwide Epi-Israeli IBD Research Nucleus Study. Inflamm Bowel Dis. 2021;27(11):1784-1794. doi:10.1093/ibd/izaa341
- Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies [published correction appears in Lancet. 2020;396(10256):e56]. Lancet. 2017;390(10114):2769-2778. doi:10.1016/S0140-6736(17)32448-0
- Busingye D, Pollack A, Chidwick K. Prevalence of inflammatory bowel disease in the Australian general practice population: A cross-sectional study. PLoS One. 2021;16(5):e0252458. Published 2021 May 27. doi:10.1371/ journal.pone.0252458
- Gecse KB, Vermeire S. Differential diagnosis of inflammatory bowel disease: imitations and complications. Lancet Gastroenterol Hepatol. 2018;3(9):644-653. doi:10.1016/S2468-1253(18)30159-6
- Inflammatory bowel disease (IBD): comorbidities. Centers for Disease Control and Prevention. Last reviewed April 14, 2022. Accessed February 21, 2024. https://www.cdc.gov/ibd/data-and-statistics/comorbidities.html
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Role of Non-invasive Biomarkers in the Evaluation and Management of MASLD
Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-1986. doi:10.1097/HEP.0000000000000520
Wattacheril JJ, Abdelmalek MF, Lim JK, Sanyal AJ. AGA Clinical Practice Update on the Role of Noninvasive Biomarkers in the Evaluation and Management of Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology. 2023;165(4):1080-1088. doi:10.1053/j.gastro.2023.06.013
Di Mauro S, Scamporrino A, Filippello A, et al. Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD. Int J Mol Sci. 2021;22(21):11905. Published 2021 Nov 2. doi:10.3390/ijms222111905
Hsu C, Caussy C, Imajo K, et al. Magnetic Resonance vs Transient Elastography Analysis of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Pooled Analysis of Individual Participants. Clin Gastroenterol Hepatol. 2019;17(4):630-637.e8. doi:10.1016/j.cgh.2018.05.059
Ilagan-Ying YC, Banini BA, Do A, Lam R, Lim JK. Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice. Curr Gastroenterol Rep. 2023;25(10):213-224. doi:10.1007/s11894-023-00883-8
Chen W, Gao Y, Xie W, et al. Genome-wide association analyses provide genetic and biochemical insights into natural variation in rice metabolism. Nat Genet. 2014;46(7):714-721. doi:10.1038/ng.3007
Wu YL, Kumar R, Wang MF, et al. Validation of conventional non-invasive fibrosis scoring systems in patients with metabolic associated fatty liver disease. World J Gastroenterol. 2021;27(34):5753-5763. doi:10.3748/wjg.v27.i34.5753
Kaneva AM, Bojko ER. Fatty liver index (FLI): more than a marker of hepatic steatosis. J Physiol Biochem. Published online October 25, 2023. doi:10.1007/s13105-023-00991-z
Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-1986. doi:10.1097/HEP.0000000000000520
Wattacheril JJ, Abdelmalek MF, Lim JK, Sanyal AJ. AGA Clinical Practice Update on the Role of Noninvasive Biomarkers in the Evaluation and Management of Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology. 2023;165(4):1080-1088. doi:10.1053/j.gastro.2023.06.013
Di Mauro S, Scamporrino A, Filippello A, et al. Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD. Int J Mol Sci. 2021;22(21):11905. Published 2021 Nov 2. doi:10.3390/ijms222111905
Hsu C, Caussy C, Imajo K, et al. Magnetic Resonance vs Transient Elastography Analysis of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Pooled Analysis of Individual Participants. Clin Gastroenterol Hepatol. 2019;17(4):630-637.e8. doi:10.1016/j.cgh.2018.05.059
Ilagan-Ying YC, Banini BA, Do A, Lam R, Lim JK. Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice. Curr Gastroenterol Rep. 2023;25(10):213-224. doi:10.1007/s11894-023-00883-8
Chen W, Gao Y, Xie W, et al. Genome-wide association analyses provide genetic and biochemical insights into natural variation in rice metabolism. Nat Genet. 2014;46(7):714-721. doi:10.1038/ng.3007
Wu YL, Kumar R, Wang MF, et al. Validation of conventional non-invasive fibrosis scoring systems in patients with metabolic associated fatty liver disease. World J Gastroenterol. 2021;27(34):5753-5763. doi:10.3748/wjg.v27.i34.5753
Kaneva AM, Bojko ER. Fatty liver index (FLI): more than a marker of hepatic steatosis. J Physiol Biochem. Published online October 25, 2023. doi:10.1007/s13105-023-00991-z
Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-1986. doi:10.1097/HEP.0000000000000520
Wattacheril JJ, Abdelmalek MF, Lim JK, Sanyal AJ. AGA Clinical Practice Update on the Role of Noninvasive Biomarkers in the Evaluation and Management of Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology. 2023;165(4):1080-1088. doi:10.1053/j.gastro.2023.06.013
Di Mauro S, Scamporrino A, Filippello A, et al. Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD. Int J Mol Sci. 2021;22(21):11905. Published 2021 Nov 2. doi:10.3390/ijms222111905
Hsu C, Caussy C, Imajo K, et al. Magnetic Resonance vs Transient Elastography Analysis of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Pooled Analysis of Individual Participants. Clin Gastroenterol Hepatol. 2019;17(4):630-637.e8. doi:10.1016/j.cgh.2018.05.059
Ilagan-Ying YC, Banini BA, Do A, Lam R, Lim JK. Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice. Curr Gastroenterol Rep. 2023;25(10):213-224. doi:10.1007/s11894-023-00883-8
Chen W, Gao Y, Xie W, et al. Genome-wide association analyses provide genetic and biochemical insights into natural variation in rice metabolism. Nat Genet. 2014;46(7):714-721. doi:10.1038/ng.3007
Wu YL, Kumar R, Wang MF, et al. Validation of conventional non-invasive fibrosis scoring systems in patients with metabolic associated fatty liver disease. World J Gastroenterol. 2021;27(34):5753-5763. doi:10.3748/wjg.v27.i34.5753
Kaneva AM, Bojko ER. Fatty liver index (FLI): more than a marker of hepatic steatosis. J Physiol Biochem. Published online October 25, 2023. doi:10.1007/s13105-023-00991-z
