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Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease
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Original article
Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease Y. Gutie´rrez-Grobe a,1, E. Jua´rez-Herna´ndez b,1, B.A. Sa´nchez-Jime´nez a, M.H. Uribe-Ramos b, M.H. Ramos-Ostos c, M. Uribe a, N.C. Cha´vez-Tapia a,b,* a
Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico c Diagnosis and Treatment Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 24 May 2016 Received in revised form 7 February 2017 Accepted 15 February 2017 Available online xxx
Aim. – This cross-sectional study evaluated liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), and compared the characteristics of metabolically healthy obese (MHO) with metabolically unhealthy obese (MUHO) patients. Methods. – The study was nested within a randomized clinical trial (RCT) and included obese patients with NAFLD, as determined by liver ultrasonography. Fibrosis was assessed by transient elastography, and AST-to-platelet ratio index (APRI) and NAFLD score. Patients were compared according to obesity phenotype using various accepted criteria. Results. – The RCT included 1024 patients with NAFLD, of whom 428 (41.7%) were included in the present study. The prevalence of MHO ranged from 1.2% to 63%, depending on the criteria used. According to various criteria for metabolic health, obese patients had less liver fibrosis. MHO patients, as defined by all criteria, showed a significantly lower prevalence of advanced liver fibrosis (F3–F4) than MUHO on transient elastography (16.5% vs. 28%, respectively; P 0.05). Conclusion. – MUHO patients are at higher risk of liver fibrosis and, therefore, the identification of obese patients with ‘healthy’ characteristics is imperative as their entire clinical work-ups are likely to differ.
C 2017 Elsevier Masson SAS. All rights reserved.
Keywords: Chronic liver disease Fibrosis Metabolic syndrome Obesity Prognosis
1. Introduction Obesity is a chronic disorder with an increasing worldwide prevalence due to changes in lifestyle, dietary habits, insufficient physical activity, stress and easy access to ‘fast food’. In the US, the prevalence of obesity exceeds 34% while, in Mexico, the prevalence is 21% in men and 33% in women [1,2]. Abbreviations: BMI, body mass index; MHO, metabolically healthy obese; NAFLD, non-alcoholic liver disease; MUHO, metabolically unhealthy obese; RCT, randomized clinical trial; APRI, AST-to-platelet ratio index; HOMA-IR, homoeostasis model assessment for insulin resistance; NLP3, NOD-like receptor family pyrin domaincontaining 3. * Corresponding author at: Obesity and Digestive Diseases Unit and Translational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150 Toriello Guerra Tlalpan, ZC 14050 Mexico City, Mexico. E-mail address: [email protected] (N.C. Cha´vez-Tapia). 1 These authors contributed equally.
Obesity is a well-known key contributing factor to insulin resistance, type 2 diabetes, dyslipidemia, high blood pressure and cardiovascular disease [3]. However, previous studies have suggested that not all obese patients exhibit the same metabolic features. Sims et al. [4] proposed the presence of a phenotype in obese patients characterized by a lack of comorbidities associated with the metabolic syndrome (MetS), and a lower risk of future cardiovascular events and, therefore, lower mortality. These patients are known as the ‘metabolically healthy obese’ (MHO), and show near-normal insulin sensitivity, no high blood pressure, and normal lipid and hormone profiles. Some studies have suggested that nearly 30% of the obese population exhibit this phenotype of obesity [5,6]. In people with non-alcoholic fatty liver disease (NAFLD), the presence and severity of fibrosis predict their overall and liverrelated mortality. The features most closely related to advanced fibrosis in these patients include advanced age, high body mass
http://dx.doi.org/10.1016/j.diabet.2017.02.007 C 2017 Elsevier Masson SAS. All rights reserved. 1262-3636/
Please cite this article in press as: Gutie´rrez-Grobe Y, et al. Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.02.007
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index (BMI) scores, and the presence of comorbidities associated with obesity and MetS. Liver biopsy is the gold standard for the diagnosis of fibrosis; however, it is an invasive method with some limitations, including a high risk of periprocedural complications and mortality [7]. Because of these limitations, non-invasive methods for assessment of liver fibrosis have been developed, such as transient elastography, which can measure liver stiffness with good sensitivity and specificity [8]. The aim of the present study was to evaluate liver fibrosis in patients with NAFLD diagnosed by non-invasive methods and to compare the characteristics of MHO patients with metabolically unhealthy obese (MUHO) patients. 2. Methods
were calculated for all our study patients, with FibroScan performed in 150 patients (according to the RCT protocol). 2.3. Determination of metabolic health The aim of our study was to evaluate liver fibrosis in MHO and MUHO patients as classified by different accepted criteria, using the available clinical and biochemical data from the RCT, for this reason other criteria were not considered [14–16]. The characteristics used to define MHO patients (Table 1) are criteria that have been applied in cohort [5,17–21] and cross-sectional studies [22,23]. The major differences among them are the inclusion (or not) of C-reactive protein (CRP), waist circumference, triglycerides and patients with diabetes, as well as differences in cut-off values for CRP and waist circumference. These criteria have been compared to evaluate cardiovascular risk in MHO patients [24].
2.1. Patient population 2.4. Statistical analysis The present cross-sectional study was nested within a randomized clinical trial (RCT; NCT01874249) carried out at the check-up unit of the Medica Sur Clinic & Foundation from June 2012 to September 2014. The study was approved by the Ethics Committee and conformed to the Helsinki Declaration. The study population was selected from a series of consecutive patients diagnosed with NAFLD. All obese patients with a BMI > 30 kg/m2 were included. Patients were randomized into five intervention groups according to the protocol of the RCT. Exclusion criteria included alcohol intakes >20 g/day, known liver disease and current use of medication. The absence of any viral, genetic, autoimmune and drug-induced liver disease was confirmed in every patient by laboratory tests and by a questionnaire about medications taken at the time of the check-up. The anthropometric parameters collected were age, gender, weight, height, blood pressure, waist circumference, hip circumference, body-fat percentage (as measured by body bioelectrical impedance analysis; Tanita Corporation, Tokyo, Japan) and BMI [calculated as weight (kg)/height (m2)]. Complete blood counts, liver function tests and lipid panels were also performed. 2.2. Diagnosis of NAFLD and liver fibrosis The presence of NAFLD was identified by liver ultrasonography based on the presence of a bright liver in fasting patients. A 3.5-MHz transducer (Elegra; Siemens Healthineers, Erlangen, Germany) was used to obtain a sagittal view of the right lobe and transverse view of the lateral segment of the liver, plus any focal areas of altered echotexture. Fibrosis was diagnosed based on liver transient elastography (FibroScanTM 502 Touch, Echosens, Paris, France), using an XL probe (2.5-Hz frequency), from a single measurement performed by a single operator. For the FibroScan procedure, patients were placed in the dorsal decubitus position with the right arm extended [9], and fibrosis was classified by the Brunt score [10]. Other non-invasive methods used to assess fibrosis were the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and NAFLD fibrosis scores, both of which have been validated in Latin American populations [11]. APRI and NAFLD score were calculated using the following equations: APRI = {AST (IU/L)/[upper normal value of 41 (IU/L)]}/platelet count (109/L) 100 [12]; and NAFLD fibrosis score = 1.675 + 0.037 age (years) + 0.094 BMI (kg/m2) + 1.13 abnormal fasting glucose level or diabetes (yes = 1, no = 0) + 0.99 AAR 0.013 number of platelets (109/L) 0.66 albumin concentration (g/dL) [13]. The cut-off values used to define significant fibrosis were >1 for the APRI and >0.676 for the NAFLD score. With the FibroScan procedure, cut-off values for NAFLD were 6.0 kPa for F1–F2 stages and 9.0 kPa for advanced fibrosis (F3–F4). NAFLD and APRI scores
The distribution of variables was determined by the Kolmogorov–Smirnov test, while continuous variables were described using measures of central tendency and the standard deviation (SD) or interquartile range (IQR). Mean values were compared using Student’s t test, while non-parametric data were analyzed by the Mann–Whitney U test. Categorical variables have been expressed as numbers and percentages, and compared using Fisher’s exact test. A P value < 0.05 was considered significant. All statistical analyses were performed using statistical SPSS/PC version 15.0 software (SPSS, Chicago, IL, USA). 3. Results The RCT included 1024 patients with NAFLD, of whom 428 (41.7%) were obese and included in the present substudy. Fig. 1 shows the distribution of the MHO patients according to various diagnostic criteria. Most patients were male (84.6%) with a mean age of 47.6 8.7 years and a mean BMI of 33.4 3.2 kg/m2. Other general patients’ characteristics are shown in Table 2. According to each noninvasive method, the prevalence of fibrosis in MHO and MUHO patients according to NAFLD score was 48.8% (n = 209) for F0–F2 and 4.2% (n = 18) for F3–F4 and, by APRI, 2.3% (n = 10) and, by transient elastography, 13.1% (n = 56) for any stage of fibrosis and 7% (n = 30) for advanced fibrosis; however, 10.9% (n = 16) of the studies were not reliable. In patients with a positive diagnosis of MHO by all criteria, moderate-to-severe steatosis was more commonly seen (59.8% vs. 40.2% in MUHO; P = 0.02). The prevalence of diabetes and high Table 1 Criteria used to define metabolically healthy obese (MHO) subjects. Study
Year
Definition of MHO Body mass index
Number of MetS criteria
Katzmarzyk Song Voulgarie Hosseinpanah Hamer Ortega Irace Khan Consensus
2005 2007 2011 2011 2012 2013 2009 2011 2009
30 kg/m2 30 kg/m2 30 kg/m2 30 kg/m2 30 kg/m2 30 kg/m2 >29.9 kg/m2 >25 kg/m2 >30 kg/m2
<3 <3a <3 <3b <2c 1a <3 <3d <3
a
Waist circumference (WC) excluded. WC 89 cm in women, 91 cm in men, blood pressure 140/85 mmHg. c Triglycerides excluded, but including C-reactive protein (CRP) > 3.0 mg/dL, WC > 88 cm in women, >102 cm in men. d WC excluded, but including CRP 3.0 mg/dL. e Excluding patients with diabetes. b
Please cite this article in press as: Gutie´rrez-Grobe Y, et al. Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.02.007
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Fig. 1. Distribution of metabolically healthy obese (MHO) patients according to diagnostic criteria. *Patients with diabetes not included. NAFLD: non-alcoholic fatty liver disease; BMI: body mass index.
blood pressure in these patients was 4.1% (n = 11) and 20.7% (n = 56), respectively, whereas, in MUHO patients, this was 17.2% (n = 27) and 24.8% (n = 39), respectively. Patients were stratified into two subgroups according to diagnostic criteria of metabolic health. A diagnosis of fibrosis by APRI score did not differ between MHO and MUHO patients; however, when fibrosis was evaluated by NAFLD score, the prevalence of significant fibrosis (F3–F4) was lower in the MHO using Song criteria and all criteria for metabolic health in obesity [33.3%, (n = 6) and 64.4% (n = 12), respectively; P = 0.001]. In Table 2 Main characteristics of study patients (n = 428). Female Age (years) Weight (kg) Height (m) Body mass index (kg/m2) Waist circumference (cm) Hip circumference (cm) Body fat mass (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Diabetes mellitus Hypertension Smoking Cardiovascular disease HBV or HAV history Glucose (mg/dL) C-reactive protein (mg/L) Albumin (mg/dL) Alkaline phosphatase (U/L) Total bilirubin (mg/dL) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Haemoglobin (mg/dL) Platelets (103/mL) Leucocytes (103/mL) Triglycerides (mg/dL) Cholesterol (mg/dL) High-density lipoprotein (mg/dL) Low-density lipoprotein (mg/dL) Liver fibrosis NAFLD score APRI Transient elastography
66 (15.4) 47.6 8.7 96.9 14.1 1.92 4.54 33.4 3.2 110.2 9.1 111.5 7.7 35.6 5.8 118.4 11.2 78.9 9.1 38 (8.9) 95 (22.2) 119 (27.8) 12 (2.8) 57 (13.3) 106.4 30.7 2.9 [1.5–5.0] 4.1 0.3 71.4 20.7 0.8 0.4 32.8 13.1 43.4 25.4 15.7 1.3 220.4 61.0 6.8 1.7 220.4 61.0 205.6 43.0 40.3 9.2 122.5 34.4 18 (4.2) 10 (2.3) 30 (7.0)
Data are n (%), means SD or medians [IQR]. HBV: hepatitis B virus; HAV: hepatitis A virus; NAFLD: non-alcoholic liver disease; APRI: AST-to-platelet ratio index.
addition, the prevalence of F0–F2 according to NAFLD score was evaluated in these patient groups, and showed that the prevalence of those stages of fibrosis was lower in MHO patients (Fig. 2). MHO patients, as defined by all criteria, also had significantly lower prevalences of advanced liver fibrosis by transient elastography (F3–F4; 16.5% vs. 28% in MUHO patients, respectively; P 0.05); these differences according to each criterion are shown in Fig. 3. Criteria for MHO patients differed in some values and some elements of MetS. Evaluation of the relationship between these components and liver fibrosis, diagnosed by any method, revealed that patients with lower levels of high-density lipoprotein (HDL) cholesterol had a greater prevalence of any stage of fibrosis by transient elastography [odds ratio (OR): 2.14; 95% confidence interval (CI): 1.06–4.33; P = 0.03], and those with higher levels of fasting glucose had an increased risk of advanced fibrosis by NAFLD score (OR: 4.4; 95% CI: 1.43–13.6; P 0.05) while patients with high blood pressure had an increased risk of F3–F4 by transient elastography (OR: 1.33; 95% CI: 1.05–1.69; P 0.05). Other components of the MetS were not associated with fibrosis. 4. Discussion According to data from the World Health Organization, 1.7 billion people worldwide are currently classified as overweight, and the prevalence of obesity continues to increase as unhealthy dietary and exercise habits spread globally [25]. Previous attempts to classify obesity metabolically used two general body shapes: a ‘pear-shaped’ distribution of adipose tissue apparently indicates no metabolic complications; whereas ‘apple-shaped’ obesity, with a central distribution of adipose tissue, is associated with the MetS and cardiovascular disease. However, the identification of obese patients with metabolically healthy characteristics is important because these patients may exhibit no metabolic complications, and their management will most likely differ from that of MUHO patients [26]. There has been much recent interest in the relationship between inflammatory pathways, adipose tissue and metabolic diseases [27,28]. Esser et al. [29] provided evidence that, compared with MHO patients, MUHO patients have greater activation of the NOD-like receptor family pyrin domain-containing 3 (NLP3) inflammasomes in macrophages in visceral adipose tissue, which favour the inflammatory response [30]. NLP3 has also recently
Please cite this article in press as: Gutie´rrez-Grobe Y, et al. Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.02.007
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Fig. 2. Prevalence of liver fibrosis (F0–F2) according to NAFLD scores for each criterion of metabolic health. *P 0.05; **P 0.0001; patients with diabetes not included. MHO: metabolically healthy obese; MUHO: metabolically unhealthy obese.
Fig. 3. Differences in significant fibrosis using transient elastography in MHO and MUHO patients.
been found to interact with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase-recruitment domain forming an inflammasome complex. This complex activates nuclear factor (NF)-kB signalling and participates in the regulation of inflammation, immune responses and apoptosis [31,32], a mechanism that has recently been implicated in the regulation of NAFLD progression [33]. As body-fat percentage is known to be a prognostic factor related to the severity of MetS [34], maintaining a low body-fat percentage might prevent the development of metabolic complications in MHO patients. However, different components of the MetS have been related to the severity of liver disease. In our present study, glucose levels were lower in MHO patients; in murine models, increased glucose levels were associated with non-alcoholic steatohepatitis and progression to fibrosis [35]. Jinjuvadia et al. [36] found similar results in a US cohort, where high glucose levels increased the risk of fibrosis in patients with NAFLD. A recent study by Sung et al. [37] investigated the risk of preclinical atherosclerosis and fatty liver in a large South Korean cohort, and found that MHO patients were at risk of fatty liver, but had an attenuated risk of preclinical atherosclerosis, whereas
MUHO and metabolically unhealthy non-obese patients were at risk of fatty liver and preclinical atherosclerosis. However, they did not evaluate fibrosis stage, which predicts the overall and liverrelated mortality in patients with NAFLD [38,39]. Although liver biopsy remains the gold standard for diagnosis of fibrosis, non-invasive strategies are more cost-effective and accessible for most of the population and, thus, should be considered effective tools for the screening and early management of liver fibrosis. This is now an important issue, as the prevalence of obesity and overweight is a serious public-health problem in most of the Western world. Although the NAFLD and APRI scores are useful tools for diagnosing liver fibrosis, our present study has found differences compared with liver fibrosis as measured by FibroScan. In fact, the different physiological responses in obese patients are probably due to their phenotypes, with a greater prevalence of fibrosis in MUHO than in MHO patients. On this basis, it should be possible to predict which obese patients are more likely to develop chronic liver disease in order to design a more intense work-up. In addition, a group of lean patients has been recognized to have metabolic disturbances, mainly insulin resistance, and can be
Please cite this article in press as: Gutie´rrez-Grobe Y, et al. Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.02.007
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called ‘metabolically obese but normal weight’ [40]. In future, clinicians may need to use the same screening and follow-up strategies for such patients as are used for MUHO patients to ensure the prompt detection of liver disease and cardiometabolic disorders. Recently, a role for vitamin D was proposed in the development of MetS and NAFLD. Low levels of vitamin D have been associated with an abnormal lipid panel and fat distribution independently of BMI. Given the hepatic metabolism of vitamin D, impaired serum levels are related to fibrosis development. In our present study, levels of triglycerides, cholesterol, glucose and fat distribution were significantly different between MHO and MUHO patients, which could be related to vitamin D deficiency and insulin resistance. Thus, measuring vitamin D and insulin levels in MHO patients might elucidate the role of this vitamin in the development of liver fibrosis. Supplementation of vitamin D might be a therapeutic option in MHO patients to prevent the development of MetS factors (mainly glucose intolerance and a poor lipid profile) that, in turn, increase the risk of liver fibrosis in such patients [41,42]. 5. Conclusion The present study has revealed a greater prevalence of liver fibrosis in MUHO compared with MHO patients. These findings indicate how important it is to persuade obese patients with NAFLD, especially MUHO patients, to control their alcohol intakes and other risk factors that contribute to liver disease progression. Clinicians should also strongly encourage such patients to change their dietary habits and lifestyles to avoid the progression of fibrosis to cirrhosis, which if left unchecked will increase mortality in this population. Core tips Obese patients can be classified into two phenotypes according to their metabolic status: healthy and unhealthy obesity (MHO and MUHO, respectively). Inflammatory pathways in adipose tissue differ between metabolically healthy and unhealthy obese patients. This is the first study to compare fibrosis status between MUHO and MHO patients. MUHO patients have significantly more severe stages of fibrosis than do MHO patients. Obesity phenotype and metabolic health status could be key features for further studies of the pathophysiology of non-alcoholic fatty liver disease. Author contribution YGG and EJH: contributed equally in conception, design, literature search, analysis and interpretation, writing the article, critical revision of the article, final approval of the article; BASJ: data collection, analysis and interpretation, final approval of the article; MHRU: literature search, writing the article, data collection, critical revision of the article, final approval of the article; MHRO: writing the article, data collection, critical revision of the article, final approval of the article; MU: statistical expertise, critical revision of the article, final approval of the article; NCT: conception and design, statistical expertise, critical revision of the article, final approval of the article. Disclosure of interest The authors declare that they have no competing interest. Acknowledgement This study was supported by the Medica Sur Clinic & Foundation in Mexico City, Mexico.
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Original article
Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease Y. Gutie´rrez-Grobe a,1, E. Jua´rez-Herna´ndez b,1, B.A. Sa´nchez-Jime´nez a, M.H. Uribe-Ramos b, M.H. Ramos-Ostos c, M. Uribe a, N.C. Cha´vez-Tapia a,b,* a
Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico Translational Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico c Diagnosis and Treatment Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 24 May 2016 Received in revised form 7 February 2017 Accepted 15 February 2017 Available online xxx
Aim. – This cross-sectional study evaluated liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), and compared the characteristics of metabolically healthy obese (MHO) with metabolically unhealthy obese (MUHO) patients. Methods. – The study was nested within a randomized clinical trial (RCT) and included obese patients with NAFLD, as determined by liver ultrasonography. Fibrosis was assessed by transient elastography, and AST-to-platelet ratio index (APRI) and NAFLD score. Patients were compared according to obesity phenotype using various accepted criteria. Results. – The RCT included 1024 patients with NAFLD, of whom 428 (41.7%) were included in the present study. The prevalence of MHO ranged from 1.2% to 63%, depending on the criteria used. According to various criteria for metabolic health, obese patients had less liver fibrosis. MHO patients, as defined by all criteria, showed a significantly lower prevalence of advanced liver fibrosis (F3–F4) than MUHO on transient elastography (16.5% vs. 28%, respectively; P 0.05). Conclusion. – MUHO patients are at higher risk of liver fibrosis and, therefore, the identification of obese patients with ‘healthy’ characteristics is imperative as their entire clinical work-ups are likely to differ.
C 2017 Elsevier Masson SAS. All rights reserved.
Keywords: Chronic liver disease Fibrosis Metabolic syndrome Obesity Prognosis
1. Introduction Obesity is a chronic disorder with an increasing worldwide prevalence due to changes in lifestyle, dietary habits, insufficient physical activity, stress and easy access to ‘fast food’. In the US, the prevalence of obesity exceeds 34% while, in Mexico, the prevalence is 21% in men and 33% in women [1,2]. Abbreviations: BMI, body mass index; MHO, metabolically healthy obese; NAFLD, non-alcoholic liver disease; MUHO, metabolically unhealthy obese; RCT, randomized clinical trial; APRI, AST-to-platelet ratio index; HOMA-IR, homoeostasis model assessment for insulin resistance; NLP3, NOD-like receptor family pyrin domaincontaining 3. * Corresponding author at: Obesity and Digestive Diseases Unit and Translational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150 Toriello Guerra Tlalpan, ZC 14050 Mexico City, Mexico. E-mail address: [email protected] (N.C. Cha´vez-Tapia). 1 These authors contributed equally.
Obesity is a well-known key contributing factor to insulin resistance, type 2 diabetes, dyslipidemia, high blood pressure and cardiovascular disease [3]. However, previous studies have suggested that not all obese patients exhibit the same metabolic features. Sims et al. [4] proposed the presence of a phenotype in obese patients characterized by a lack of comorbidities associated with the metabolic syndrome (MetS), and a lower risk of future cardiovascular events and, therefore, lower mortality. These patients are known as the ‘metabolically healthy obese’ (MHO), and show near-normal insulin sensitivity, no high blood pressure, and normal lipid and hormone profiles. Some studies have suggested that nearly 30% of the obese population exhibit this phenotype of obesity [5,6]. In people with non-alcoholic fatty liver disease (NAFLD), the presence and severity of fibrosis predict their overall and liverrelated mortality. The features most closely related to advanced fibrosis in these patients include advanced age, high body mass
http://dx.doi.org/10.1016/j.diabet.2017.02.007 C 2017 Elsevier Masson SAS. All rights reserved. 1262-3636/
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index (BMI) scores, and the presence of comorbidities associated with obesity and MetS. Liver biopsy is the gold standard for the diagnosis of fibrosis; however, it is an invasive method with some limitations, including a high risk of periprocedural complications and mortality [7]. Because of these limitations, non-invasive methods for assessment of liver fibrosis have been developed, such as transient elastography, which can measure liver stiffness with good sensitivity and specificity [8]. The aim of the present study was to evaluate liver fibrosis in patients with NAFLD diagnosed by non-invasive methods and to compare the characteristics of MHO patients with metabolically unhealthy obese (MUHO) patients. 2. Methods
were calculated for all our study patients, with FibroScan performed in 150 patients (according to the RCT protocol). 2.3. Determination of metabolic health The aim of our study was to evaluate liver fibrosis in MHO and MUHO patients as classified by different accepted criteria, using the available clinical and biochemical data from the RCT, for this reason other criteria were not considered [14–16]. The characteristics used to define MHO patients (Table 1) are criteria that have been applied in cohort [5,17–21] and cross-sectional studies [22,23]. The major differences among them are the inclusion (or not) of C-reactive protein (CRP), waist circumference, triglycerides and patients with diabetes, as well as differences in cut-off values for CRP and waist circumference. These criteria have been compared to evaluate cardiovascular risk in MHO patients [24].
2.1. Patient population 2.4. Statistical analysis The present cross-sectional study was nested within a randomized clinical trial (RCT; NCT01874249) carried out at the check-up unit of the Medica Sur Clinic & Foundation from June 2012 to September 2014. The study was approved by the Ethics Committee and conformed to the Helsinki Declaration. The study population was selected from a series of consecutive patients diagnosed with NAFLD. All obese patients with a BMI > 30 kg/m2 were included. Patients were randomized into five intervention groups according to the protocol of the RCT. Exclusion criteria included alcohol intakes >20 g/day, known liver disease and current use of medication. The absence of any viral, genetic, autoimmune and drug-induced liver disease was confirmed in every patient by laboratory tests and by a questionnaire about medications taken at the time of the check-up. The anthropometric parameters collected were age, gender, weight, height, blood pressure, waist circumference, hip circumference, body-fat percentage (as measured by body bioelectrical impedance analysis; Tanita Corporation, Tokyo, Japan) and BMI [calculated as weight (kg)/height (m2)]. Complete blood counts, liver function tests and lipid panels were also performed. 2.2. Diagnosis of NAFLD and liver fibrosis The presence of NAFLD was identified by liver ultrasonography based on the presence of a bright liver in fasting patients. A 3.5-MHz transducer (Elegra; Siemens Healthineers, Erlangen, Germany) was used to obtain a sagittal view of the right lobe and transverse view of the lateral segment of the liver, plus any focal areas of altered echotexture. Fibrosis was diagnosed based on liver transient elastography (FibroScanTM 502 Touch, Echosens, Paris, France), using an XL probe (2.5-Hz frequency), from a single measurement performed by a single operator. For the FibroScan procedure, patients were placed in the dorsal decubitus position with the right arm extended [9], and fibrosis was classified by the Brunt score [10]. Other non-invasive methods used to assess fibrosis were the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and NAFLD fibrosis scores, both of which have been validated in Latin American populations [11]. APRI and NAFLD score were calculated using the following equations: APRI = {AST (IU/L)/[upper normal value of 41 (IU/L)]}/platelet count (109/L) 100 [12]; and NAFLD fibrosis score = 1.675 + 0.037 age (years) + 0.094 BMI (kg/m2) + 1.13 abnormal fasting glucose level or diabetes (yes = 1, no = 0) + 0.99 AAR 0.013 number of platelets (109/L) 0.66 albumin concentration (g/dL) [13]. The cut-off values used to define significant fibrosis were >1 for the APRI and >0.676 for the NAFLD score. With the FibroScan procedure, cut-off values for NAFLD were 6.0 kPa for F1–F2 stages and 9.0 kPa for advanced fibrosis (F3–F4). NAFLD and APRI scores
The distribution of variables was determined by the Kolmogorov–Smirnov test, while continuous variables were described using measures of central tendency and the standard deviation (SD) or interquartile range (IQR). Mean values were compared using Student’s t test, while non-parametric data were analyzed by the Mann–Whitney U test. Categorical variables have been expressed as numbers and percentages, and compared using Fisher’s exact test. A P value < 0.05 was considered significant. All statistical analyses were performed using statistical SPSS/PC version 15.0 software (SPSS, Chicago, IL, USA). 3. Results The RCT included 1024 patients with NAFLD, of whom 428 (41.7%) were obese and included in the present substudy. Fig. 1 shows the distribution of the MHO patients according to various diagnostic criteria. Most patients were male (84.6%) with a mean age of 47.6 8.7 years and a mean BMI of 33.4 3.2 kg/m2. Other general patients’ characteristics are shown in Table 2. According to each noninvasive method, the prevalence of fibrosis in MHO and MUHO patients according to NAFLD score was 48.8% (n = 209) for F0–F2 and 4.2% (n = 18) for F3–F4 and, by APRI, 2.3% (n = 10) and, by transient elastography, 13.1% (n = 56) for any stage of fibrosis and 7% (n = 30) for advanced fibrosis; however, 10.9% (n = 16) of the studies were not reliable. In patients with a positive diagnosis of MHO by all criteria, moderate-to-severe steatosis was more commonly seen (59.8% vs. 40.2% in MUHO; P = 0.02). The prevalence of diabetes and high Table 1 Criteria used to define metabolically healthy obese (MHO) subjects. Study
Year
Definition of MHO Body mass index
Number of MetS criteria
Katzmarzyk Song Voulgarie Hosseinpanah Hamer Ortega Irace Khan Consensus
2005 2007 2011 2011 2012 2013 2009 2011 2009
30 kg/m2 30 kg/m2 30 kg/m2 30 kg/m2 30 kg/m2 30 kg/m2 >29.9 kg/m2 >25 kg/m2 >30 kg/m2
<3 <3a <3 <3b <2c 1a <3 <3d <3
a
Waist circumference (WC) excluded. WC 89 cm in women, 91 cm in men, blood pressure 140/85 mmHg. c Triglycerides excluded, but including C-reactive protein (CRP) > 3.0 mg/dL, WC > 88 cm in women, >102 cm in men. d WC excluded, but including CRP 3.0 mg/dL. e Excluding patients with diabetes. b
Please cite this article in press as: Gutie´rrez-Grobe Y, et al. Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.02.007
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Fig. 1. Distribution of metabolically healthy obese (MHO) patients according to diagnostic criteria. *Patients with diabetes not included. NAFLD: non-alcoholic fatty liver disease; BMI: body mass index.
blood pressure in these patients was 4.1% (n = 11) and 20.7% (n = 56), respectively, whereas, in MUHO patients, this was 17.2% (n = 27) and 24.8% (n = 39), respectively. Patients were stratified into two subgroups according to diagnostic criteria of metabolic health. A diagnosis of fibrosis by APRI score did not differ between MHO and MUHO patients; however, when fibrosis was evaluated by NAFLD score, the prevalence of significant fibrosis (F3–F4) was lower in the MHO using Song criteria and all criteria for metabolic health in obesity [33.3%, (n = 6) and 64.4% (n = 12), respectively; P = 0.001]. In Table 2 Main characteristics of study patients (n = 428). Female Age (years) Weight (kg) Height (m) Body mass index (kg/m2) Waist circumference (cm) Hip circumference (cm) Body fat mass (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Diabetes mellitus Hypertension Smoking Cardiovascular disease HBV or HAV history Glucose (mg/dL) C-reactive protein (mg/L) Albumin (mg/dL) Alkaline phosphatase (U/L) Total bilirubin (mg/dL) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Haemoglobin (mg/dL) Platelets (103/mL) Leucocytes (103/mL) Triglycerides (mg/dL) Cholesterol (mg/dL) High-density lipoprotein (mg/dL) Low-density lipoprotein (mg/dL) Liver fibrosis NAFLD score APRI Transient elastography
66 (15.4) 47.6 8.7 96.9 14.1 1.92 4.54 33.4 3.2 110.2 9.1 111.5 7.7 35.6 5.8 118.4 11.2 78.9 9.1 38 (8.9) 95 (22.2) 119 (27.8) 12 (2.8) 57 (13.3) 106.4 30.7 2.9 [1.5–5.0] 4.1 0.3 71.4 20.7 0.8 0.4 32.8 13.1 43.4 25.4 15.7 1.3 220.4 61.0 6.8 1.7 220.4 61.0 205.6 43.0 40.3 9.2 122.5 34.4 18 (4.2) 10 (2.3) 30 (7.0)
Data are n (%), means SD or medians [IQR]. HBV: hepatitis B virus; HAV: hepatitis A virus; NAFLD: non-alcoholic liver disease; APRI: AST-to-platelet ratio index.
addition, the prevalence of F0–F2 according to NAFLD score was evaluated in these patient groups, and showed that the prevalence of those stages of fibrosis was lower in MHO patients (Fig. 2). MHO patients, as defined by all criteria, also had significantly lower prevalences of advanced liver fibrosis by transient elastography (F3–F4; 16.5% vs. 28% in MUHO patients, respectively; P 0.05); these differences according to each criterion are shown in Fig. 3. Criteria for MHO patients differed in some values and some elements of MetS. Evaluation of the relationship between these components and liver fibrosis, diagnosed by any method, revealed that patients with lower levels of high-density lipoprotein (HDL) cholesterol had a greater prevalence of any stage of fibrosis by transient elastography [odds ratio (OR): 2.14; 95% confidence interval (CI): 1.06–4.33; P = 0.03], and those with higher levels of fasting glucose had an increased risk of advanced fibrosis by NAFLD score (OR: 4.4; 95% CI: 1.43–13.6; P 0.05) while patients with high blood pressure had an increased risk of F3–F4 by transient elastography (OR: 1.33; 95% CI: 1.05–1.69; P 0.05). Other components of the MetS were not associated with fibrosis. 4. Discussion According to data from the World Health Organization, 1.7 billion people worldwide are currently classified as overweight, and the prevalence of obesity continues to increase as unhealthy dietary and exercise habits spread globally [25]. Previous attempts to classify obesity metabolically used two general body shapes: a ‘pear-shaped’ distribution of adipose tissue apparently indicates no metabolic complications; whereas ‘apple-shaped’ obesity, with a central distribution of adipose tissue, is associated with the MetS and cardiovascular disease. However, the identification of obese patients with metabolically healthy characteristics is important because these patients may exhibit no metabolic complications, and their management will most likely differ from that of MUHO patients [26]. There has been much recent interest in the relationship between inflammatory pathways, adipose tissue and metabolic diseases [27,28]. Esser et al. [29] provided evidence that, compared with MHO patients, MUHO patients have greater activation of the NOD-like receptor family pyrin domain-containing 3 (NLP3) inflammasomes in macrophages in visceral adipose tissue, which favour the inflammatory response [30]. NLP3 has also recently
Please cite this article in press as: Gutie´rrez-Grobe Y, et al. Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.02.007
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Fig. 2. Prevalence of liver fibrosis (F0–F2) according to NAFLD scores for each criterion of metabolic health. *P 0.05; **P 0.0001; patients with diabetes not included. MHO: metabolically healthy obese; MUHO: metabolically unhealthy obese.
Fig. 3. Differences in significant fibrosis using transient elastography in MHO and MUHO patients.
been found to interact with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase-recruitment domain forming an inflammasome complex. This complex activates nuclear factor (NF)-kB signalling and participates in the regulation of inflammation, immune responses and apoptosis [31,32], a mechanism that has recently been implicated in the regulation of NAFLD progression [33]. As body-fat percentage is known to be a prognostic factor related to the severity of MetS [34], maintaining a low body-fat percentage might prevent the development of metabolic complications in MHO patients. However, different components of the MetS have been related to the severity of liver disease. In our present study, glucose levels were lower in MHO patients; in murine models, increased glucose levels were associated with non-alcoholic steatohepatitis and progression to fibrosis [35]. Jinjuvadia et al. [36] found similar results in a US cohort, where high glucose levels increased the risk of fibrosis in patients with NAFLD. A recent study by Sung et al. [37] investigated the risk of preclinical atherosclerosis and fatty liver in a large South Korean cohort, and found that MHO patients were at risk of fatty liver, but had an attenuated risk of preclinical atherosclerosis, whereas
MUHO and metabolically unhealthy non-obese patients were at risk of fatty liver and preclinical atherosclerosis. However, they did not evaluate fibrosis stage, which predicts the overall and liverrelated mortality in patients with NAFLD [38,39]. Although liver biopsy remains the gold standard for diagnosis of fibrosis, non-invasive strategies are more cost-effective and accessible for most of the population and, thus, should be considered effective tools for the screening and early management of liver fibrosis. This is now an important issue, as the prevalence of obesity and overweight is a serious public-health problem in most of the Western world. Although the NAFLD and APRI scores are useful tools for diagnosing liver fibrosis, our present study has found differences compared with liver fibrosis as measured by FibroScan. In fact, the different physiological responses in obese patients are probably due to their phenotypes, with a greater prevalence of fibrosis in MUHO than in MHO patients. On this basis, it should be possible to predict which obese patients are more likely to develop chronic liver disease in order to design a more intense work-up. In addition, a group of lean patients has been recognized to have metabolic disturbances, mainly insulin resistance, and can be
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called ‘metabolically obese but normal weight’ [40]. In future, clinicians may need to use the same screening and follow-up strategies for such patients as are used for MUHO patients to ensure the prompt detection of liver disease and cardiometabolic disorders. Recently, a role for vitamin D was proposed in the development of MetS and NAFLD. Low levels of vitamin D have been associated with an abnormal lipid panel and fat distribution independently of BMI. Given the hepatic metabolism of vitamin D, impaired serum levels are related to fibrosis development. In our present study, levels of triglycerides, cholesterol, glucose and fat distribution were significantly different between MHO and MUHO patients, which could be related to vitamin D deficiency and insulin resistance. Thus, measuring vitamin D and insulin levels in MHO patients might elucidate the role of this vitamin in the development of liver fibrosis. Supplementation of vitamin D might be a therapeutic option in MHO patients to prevent the development of MetS factors (mainly glucose intolerance and a poor lipid profile) that, in turn, increase the risk of liver fibrosis in such patients [41,42]. 5. Conclusion The present study has revealed a greater prevalence of liver fibrosis in MUHO compared with MHO patients. These findings indicate how important it is to persuade obese patients with NAFLD, especially MUHO patients, to control their alcohol intakes and other risk factors that contribute to liver disease progression. Clinicians should also strongly encourage such patients to change their dietary habits and lifestyles to avoid the progression of fibrosis to cirrhosis, which if left unchecked will increase mortality in this population. Core tips Obese patients can be classified into two phenotypes according to their metabolic status: healthy and unhealthy obesity (MHO and MUHO, respectively). Inflammatory pathways in adipose tissue differ between metabolically healthy and unhealthy obese patients. This is the first study to compare fibrosis status between MUHO and MHO patients. MUHO patients have significantly more severe stages of fibrosis than do MHO patients. Obesity phenotype and metabolic health status could be key features for further studies of the pathophysiology of non-alcoholic fatty liver disease. Author contribution YGG and EJH: contributed equally in conception, design, literature search, analysis and interpretation, writing the article, critical revision of the article, final approval of the article; BASJ: data collection, analysis and interpretation, final approval of the article; MHRU: literature search, writing the article, data collection, critical revision of the article, final approval of the article; MHRO: writing the article, data collection, critical revision of the article, final approval of the article; MU: statistical expertise, critical revision of the article, final approval of the article; NCT: conception and design, statistical expertise, critical revision of the article, final approval of the article. Disclosure of interest The authors declare that they have no competing interest. Acknowledgement This study was supported by the Medica Sur Clinic & Foundation in Mexico City, Mexico.
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Please cite this article in press as: Gutie´rrez-Grobe Y, et al. Less liver fibrosis in metabolically healthy compared with metabolically unhealthy obese patients with non-alcoholic fatty liver disease. Diabetes Metab (2017), http://dx.doi.org/10.1016/j.diabet.2017.02.007