Menopause: The Journal of The North American Menopause Society Vol. 22, No. 7, pp. 797/799 DOI: 10.1097/gme.0000000000000478 * 2015 by The North American Menopause Society
LETTERS
TO THE
EDITOR
To the Editor: Vitamin D is currently a hot issue for physicians and the public. Vitamin D level is closely correlated with bone health, and many recent reports on 25-hydroxyvitamin D [25(OH)D] levels and cardiovascular disease, inflammation, depression, cancer, pelvic pain, and other conditions have been published. Physicians who treat postmenopausal women reporting sleep disturbances, emotional depression, or chronic fatigue are curious about whether adding vitamin D supplementation to hormone therapy would lead to a synergistic effect on relieving these symptoms. After vitamin D supplementation and hormone therapy had been prescribed to women with serum 25(OH)D levels indicative of vitamin D deficiency, some reported a decrease in menopause-related symptoms. LeBlanc et al1 concluded that there is no evidence linking 25(OH)D levels and menopauserelated symptoms in postmenopausal women. They also hypothesized that estrogen increases the activity of the enzyme responsible for activating vitamin D; we agree with their hypothesis. Administration of estradiol increases the expression of estrogen receptor (which maintains bone strength and bone health) and vitamin D.2 Vitamin D stimulates estradiol biosynthesis in ovaries and in cells pretreated with noncalcemic analogs, which increases the expression of estrogen receptor-> protein.3 What exactly increases the synergistic effect of estrogen and vitamin D? Why are there differences (including ethnic differences) in improvement of menopausal symptoms with vitamin D and hormone therapy among women? We believe that vitamin D affects estrogen levels and that estrogen levels also affect vitamin D levels. We have hypothesized that the vitamin D receptor (VDR) itself and VDR genetic polymorphisms have different effects on women. VDR is a member of a superfamily of nuclear receptors; it mediates the actions of vitamin D. Membrane signaling can be correlated with nongenomic effects of VDR; correlations and effects of vitamin D levels on diseases and conditions such as cancer, immunity, bone pain, cardiovascular disease, and depression have been reported. However, reports on potential effects of VDR on diseases are rare. Another hypothesis is that VDR gene polymorphisms affect menopause-related symptoms. Postmenopausal women and their physicians want evidence-based data on whether levels of vitamin D and estrogen have a synergistic effect on menopauserelated symptoms or other conditions. Therefore, further research on VDR gene polymorphisms and the relationship between VDR or serum vitamin D levels and health conditions, including menopausal symptoms, should be performed.
Funding/support: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014R1A1A3049819).
Financial disclosure/conflicts of interest: None reported.
Tae-Hee Kim, MD, PhD Hae-Hyeog Lee, MD, PhD Department of Obstetrics and Gynecology Soonchunhyang University College of Medicine Bucheon, Republic of Korea Jun-Mo Kim, MD, PhD Department of Urology Soonchunhyang University College of Medicine Bucheon, Republic of Korea
REFERENCES 1. LeBlanc ES, Desai M, Perrin N, et al. Vitamin D levels and menopauserelated symptoms. Menopause 2014;21:1197-1203. 2. Kim TH, Lee HH, Jeon DS, Byun DW. Compression fracture in postpartum osteoporosis. J Bone Metab 2013;20:115-118. 3. Somjen D, Kohen F, Gayer B, et al. A non-calcemic vitamin D analog modulates both nuclear and putative membranal estrogen receptors in cultured human vascular smooth muscle cells. J Steroid Biochem Mol Biol 2004;89-90:397-399.
To the Editor: In a recent issue of this journal, Wang et al1 reported on the prevalence of nonalcoholic fatty liver disease (NAFLD) and its metabolic risk factors in women of different ages and body mass indexes (BMIs). They stated that obese and postmenopausal women have a high prevalence of NAFLD and severe metabolic disorders and that the prevalence of nonalcoholic steatohepatitis (NASH) is increased in this patient group. Although we appreciate their great contribution to answering an important question regarding the prevalence of NAFLD and NASH in a large series of women of different ages and BMIs, some methodologic points in their well-written article require further clarification and discussion. Although a variety of noninvasive tests have demonstrated reasonable ability to predict the presence of advanced disease with NASH and fibrosis, BAAT (BMI, age, alanine aminotransferase, and triglycerides) score is the least used method for this assessment. BAAT index is calculated as the sum of four distinct variables: BMI, age, alanine aminotransferase, and triglycerides. A score of 0 or 1 has a sensitivity of 100%, a specificity of 45%, and a negative predictive value of 100%; a score of 4 has only 14% sensitivity for the diagnosis of septal fibrosis and cirrhosis.2,3 In other words, the presence of one factor (or the absence of factors) excludes septal fibrosis or cirrhosis in women with NAFLD, but a lack of elevated scores does not rule out advanced fibrosis. In fact, Ratziu et al,4 who first proposed BAAT score, replaced this test with FibroTest-FibroSURE because of the low sensitivity of the Menopause, Vol. 22, No. 7, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
797
BAAT scoring system. In view of this information, the calculations made by Wang et al1Vbased on BAAT scoreVto detect the prevalence of NASH and fibrosis in the defined patient population might not reflect the actual proportions. Second, the article by Wang et al1 recalled the important question on the necessity and desirability of percutaneous liver biopsy for assessing advanced liver disease in women with NAFLD/NASH. Sonographic examination cannot distinguish simple liver steatosis from steatohepatitis, and liver biopsy is regarded as the gold standard in the diagnosis and grading of NAFLD.5,6 Moreover, liver biopsy is considered to be useful in differentiating NASH from other liver diseases, in estimating prognosis, and in judging the effects of therapeutic intervention. Third, despite ultrasonography_s wide accessibility and safety for detecting fatty liver, its results have been inconsistent in terms of accuracy and reliability. Reported sensitivity and specificity ranged from 55% to 100% and from 26% to 100%, respectively.7 These wide ranges could be the result of a number of distinct variables, including technical qualities, performance of ultrasound device, and ultrasound criteria for defining fatty liver. Because it is not realistic to perform liver biopsy on all women with NAFLD, especially those in population-based studies, the grading of fatty change derived from sonographic examination should not be used as an evaluation criterion for NAFLD severity.8 We congratulate Wang et al1 for their excellent work. However, future studies stratifying women with NAFLD by widely validated and standardized fibrosis scoring systems, with or with histologic confirmation, would be more valuable. Financial disclosure/conflicts of interest: None reported.
Fatma Beyazit, MD Department of Obstetrics and Gynecology Canakkale State Hospital Canakkale, Turkey Alpaslan Tanoglu, MD Department of Gastroenterology GATA Haydarpasa Training Hospital Istanbul, Turkey REFERENCES 1. Wang Z, Xu M, Hu Z, Shrestha UK. Prevalence of nonalcoholic fatty liver disease and its metabolic risk factors in women of different ages and body mass index. Menopause 2015;22:667-673. 2. Pearce SG, Thosani NC, Pan JJ. Noninvasive biomarkers for the diagnosis of steatohepatitis and advanced fibrosis in NAFLD. Biomark Res 2013;1:7. 3. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000;118:1117-1123. 4. Ratziu V, Massard J, Charlotte F, et al.; LIDO Study Group, CYTOL Study Group. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2006;6:6. ¨ zenirler S, Degertekin CK, Erkan G, et al. Serum liver fatty acid binding 5. O protein shows good correlation with liver histology in NASH. Hepatogastroenterology 2013;60:1095-1100. 6. Kobyliak N, Abenavoli L. The role of liver biopsy to assess non-alcoholic fatty liver disease. Rev Recent Clin Trials 2014;9:159-169.
798
Menopause, Vol. 22, No. 7, 2015
7. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 2011;54:1082-1090. 8. Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and noninvasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis. World J Gastroenterol 2014;20:475-485.
In reply: I thank the authors for their comments. However, two issues raised by their letter need to be addressed. (1) Reported sensitivity and specificity ranged from 55% to 100% and from 26% to 100%, respectively. In the study by Hernaez et al,1 they explained that these differences could be the result of several factors. First, technical quality and performance of ultrasound varied across studies. Technological advances in ultrasound equipment have been achieved, which could potentially explain part of this variation for studies conducted from 1979 to 2010. Second, the ultrasound criteria used to define fatty liver differed across studies. Although most of the studies included individuals who underwent liver biopsy with some suspicion of liver disease, there was a wide range in the severity of the underlying disease. Finally, the composition of the comparison group (ie, normal liver or other liver diseases such as inflammation and fibrotic liver disease) also differed across studies, adding to heterogeneity. No doubt, biopsy is the pathological diagnostic criterion for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and liver fibrosis. This meta-analysis1 concluded that liver ultrasonography is an accurate and reliable tool for detecting moderate to severe fatty liver, with sensitivity and specificity of 84.8% and 93.6%, respectively. Ultrasonography, compared with histology, allows for reliable and accurate detection of moderate to severe fatty liver. Because of its low cost, safety, and accessibility, ultrasound is likely to be the imaging technique of choice for screening fatty liver in clinical and population settings. (2) BAAT (body mass index, age, alanine aminotransferase, and triglycerides) score is the least used method for this assessment. Ratziu et al2 proposed a simple scoreVBAATVincorporating body mass index, age, alanine aminotransferase, and triglycerides. Although not sensitive, it yielded a specificity of 100%.3 It is a nonalcoholic fatty liver disease fibrosis scoring system that has been validated and is being used as a tool for selecting individuals for liver biopsy.3 The multitude of fibrosis scores available may lead to tremendous confusion regarding what tool to use in clinical practice. However, whether or not BAAT score is a strongVand least usedVsurrogate marker for predicting advanced liver fibrosis, more studies are needed to validate its future significant applications in clinical practice. Because of a lack of parameters, other fibrosis scores could not be used in the study.4 However, the study combined the diagnostic panels of BAAT score and aspartate aminotransferaseYtoYalanine aminotransferase * 2015 by The North American Menopause Society
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
LETTERS
TO THE
EDITOR
To the Editor: Vitamin D is currently a hot issue for physicians and the public. Vitamin D level is closely correlated with bone health, and many recent reports on 25-hydroxyvitamin D [25(OH)D] levels and cardiovascular disease, inflammation, depression, cancer, pelvic pain, and other conditions have been published. Physicians who treat postmenopausal women reporting sleep disturbances, emotional depression, or chronic fatigue are curious about whether adding vitamin D supplementation to hormone therapy would lead to a synergistic effect on relieving these symptoms. After vitamin D supplementation and hormone therapy had been prescribed to women with serum 25(OH)D levels indicative of vitamin D deficiency, some reported a decrease in menopause-related symptoms. LeBlanc et al1 concluded that there is no evidence linking 25(OH)D levels and menopauserelated symptoms in postmenopausal women. They also hypothesized that estrogen increases the activity of the enzyme responsible for activating vitamin D; we agree with their hypothesis. Administration of estradiol increases the expression of estrogen receptor (which maintains bone strength and bone health) and vitamin D.2 Vitamin D stimulates estradiol biosynthesis in ovaries and in cells pretreated with noncalcemic analogs, which increases the expression of estrogen receptor-> protein.3 What exactly increases the synergistic effect of estrogen and vitamin D? Why are there differences (including ethnic differences) in improvement of menopausal symptoms with vitamin D and hormone therapy among women? We believe that vitamin D affects estrogen levels and that estrogen levels also affect vitamin D levels. We have hypothesized that the vitamin D receptor (VDR) itself and VDR genetic polymorphisms have different effects on women. VDR is a member of a superfamily of nuclear receptors; it mediates the actions of vitamin D. Membrane signaling can be correlated with nongenomic effects of VDR; correlations and effects of vitamin D levels on diseases and conditions such as cancer, immunity, bone pain, cardiovascular disease, and depression have been reported. However, reports on potential effects of VDR on diseases are rare. Another hypothesis is that VDR gene polymorphisms affect menopause-related symptoms. Postmenopausal women and their physicians want evidence-based data on whether levels of vitamin D and estrogen have a synergistic effect on menopauserelated symptoms or other conditions. Therefore, further research on VDR gene polymorphisms and the relationship between VDR or serum vitamin D levels and health conditions, including menopausal symptoms, should be performed.
Funding/support: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2014R1A1A3049819).
Financial disclosure/conflicts of interest: None reported.
Tae-Hee Kim, MD, PhD Hae-Hyeog Lee, MD, PhD Department of Obstetrics and Gynecology Soonchunhyang University College of Medicine Bucheon, Republic of Korea Jun-Mo Kim, MD, PhD Department of Urology Soonchunhyang University College of Medicine Bucheon, Republic of Korea
REFERENCES 1. LeBlanc ES, Desai M, Perrin N, et al. Vitamin D levels and menopauserelated symptoms. Menopause 2014;21:1197-1203. 2. Kim TH, Lee HH, Jeon DS, Byun DW. Compression fracture in postpartum osteoporosis. J Bone Metab 2013;20:115-118. 3. Somjen D, Kohen F, Gayer B, et al. A non-calcemic vitamin D analog modulates both nuclear and putative membranal estrogen receptors in cultured human vascular smooth muscle cells. J Steroid Biochem Mol Biol 2004;89-90:397-399.
To the Editor: In a recent issue of this journal, Wang et al1 reported on the prevalence of nonalcoholic fatty liver disease (NAFLD) and its metabolic risk factors in women of different ages and body mass indexes (BMIs). They stated that obese and postmenopausal women have a high prevalence of NAFLD and severe metabolic disorders and that the prevalence of nonalcoholic steatohepatitis (NASH) is increased in this patient group. Although we appreciate their great contribution to answering an important question regarding the prevalence of NAFLD and NASH in a large series of women of different ages and BMIs, some methodologic points in their well-written article require further clarification and discussion. Although a variety of noninvasive tests have demonstrated reasonable ability to predict the presence of advanced disease with NASH and fibrosis, BAAT (BMI, age, alanine aminotransferase, and triglycerides) score is the least used method for this assessment. BAAT index is calculated as the sum of four distinct variables: BMI, age, alanine aminotransferase, and triglycerides. A score of 0 or 1 has a sensitivity of 100%, a specificity of 45%, and a negative predictive value of 100%; a score of 4 has only 14% sensitivity for the diagnosis of septal fibrosis and cirrhosis.2,3 In other words, the presence of one factor (or the absence of factors) excludes septal fibrosis or cirrhosis in women with NAFLD, but a lack of elevated scores does not rule out advanced fibrosis. In fact, Ratziu et al,4 who first proposed BAAT score, replaced this test with FibroTest-FibroSURE because of the low sensitivity of the Menopause, Vol. 22, No. 7, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
797
BAAT scoring system. In view of this information, the calculations made by Wang et al1Vbased on BAAT scoreVto detect the prevalence of NASH and fibrosis in the defined patient population might not reflect the actual proportions. Second, the article by Wang et al1 recalled the important question on the necessity and desirability of percutaneous liver biopsy for assessing advanced liver disease in women with NAFLD/NASH. Sonographic examination cannot distinguish simple liver steatosis from steatohepatitis, and liver biopsy is regarded as the gold standard in the diagnosis and grading of NAFLD.5,6 Moreover, liver biopsy is considered to be useful in differentiating NASH from other liver diseases, in estimating prognosis, and in judging the effects of therapeutic intervention. Third, despite ultrasonography_s wide accessibility and safety for detecting fatty liver, its results have been inconsistent in terms of accuracy and reliability. Reported sensitivity and specificity ranged from 55% to 100% and from 26% to 100%, respectively.7 These wide ranges could be the result of a number of distinct variables, including technical qualities, performance of ultrasound device, and ultrasound criteria for defining fatty liver. Because it is not realistic to perform liver biopsy on all women with NAFLD, especially those in population-based studies, the grading of fatty change derived from sonographic examination should not be used as an evaluation criterion for NAFLD severity.8 We congratulate Wang et al1 for their excellent work. However, future studies stratifying women with NAFLD by widely validated and standardized fibrosis scoring systems, with or with histologic confirmation, would be more valuable. Financial disclosure/conflicts of interest: None reported.
Fatma Beyazit, MD Department of Obstetrics and Gynecology Canakkale State Hospital Canakkale, Turkey Alpaslan Tanoglu, MD Department of Gastroenterology GATA Haydarpasa Training Hospital Istanbul, Turkey REFERENCES 1. Wang Z, Xu M, Hu Z, Shrestha UK. Prevalence of nonalcoholic fatty liver disease and its metabolic risk factors in women of different ages and body mass index. Menopause 2015;22:667-673. 2. Pearce SG, Thosani NC, Pan JJ. Noninvasive biomarkers for the diagnosis of steatohepatitis and advanced fibrosis in NAFLD. Biomark Res 2013;1:7. 3. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology 2000;118:1117-1123. 4. Ratziu V, Massard J, Charlotte F, et al.; LIDO Study Group, CYTOL Study Group. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2006;6:6. ¨ zenirler S, Degertekin CK, Erkan G, et al. Serum liver fatty acid binding 5. O protein shows good correlation with liver histology in NASH. Hepatogastroenterology 2013;60:1095-1100. 6. Kobyliak N, Abenavoli L. The role of liver biopsy to assess non-alcoholic fatty liver disease. Rev Recent Clin Trials 2014;9:159-169.
798
Menopause, Vol. 22, No. 7, 2015
7. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 2011;54:1082-1090. 8. Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and noninvasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis. World J Gastroenterol 2014;20:475-485.
In reply: I thank the authors for their comments. However, two issues raised by their letter need to be addressed. (1) Reported sensitivity and specificity ranged from 55% to 100% and from 26% to 100%, respectively. In the study by Hernaez et al,1 they explained that these differences could be the result of several factors. First, technical quality and performance of ultrasound varied across studies. Technological advances in ultrasound equipment have been achieved, which could potentially explain part of this variation for studies conducted from 1979 to 2010. Second, the ultrasound criteria used to define fatty liver differed across studies. Although most of the studies included individuals who underwent liver biopsy with some suspicion of liver disease, there was a wide range in the severity of the underlying disease. Finally, the composition of the comparison group (ie, normal liver or other liver diseases such as inflammation and fibrotic liver disease) also differed across studies, adding to heterogeneity. No doubt, biopsy is the pathological diagnostic criterion for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and liver fibrosis. This meta-analysis1 concluded that liver ultrasonography is an accurate and reliable tool for detecting moderate to severe fatty liver, with sensitivity and specificity of 84.8% and 93.6%, respectively. Ultrasonography, compared with histology, allows for reliable and accurate detection of moderate to severe fatty liver. Because of its low cost, safety, and accessibility, ultrasound is likely to be the imaging technique of choice for screening fatty liver in clinical and population settings. (2) BAAT (body mass index, age, alanine aminotransferase, and triglycerides) score is the least used method for this assessment. Ratziu et al2 proposed a simple scoreVBAATVincorporating body mass index, age, alanine aminotransferase, and triglycerides. Although not sensitive, it yielded a specificity of 100%.3 It is a nonalcoholic fatty liver disease fibrosis scoring system that has been validated and is being used as a tool for selecting individuals for liver biopsy.3 The multitude of fibrosis scores available may lead to tremendous confusion regarding what tool to use in clinical practice. However, whether or not BAAT score is a strongVand least usedVsurrogate marker for predicting advanced liver fibrosis, more studies are needed to validate its future significant applications in clinical practice. Because of a lack of parameters, other fibrosis scores could not be used in the study.4 However, the study combined the diagnostic panels of BAAT score and aspartate aminotransferaseYtoYalanine aminotransferase * 2015 by The North American Menopause Society
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
