Table 2.

Scientific Rationale Behind the Proposed Harmonized Definition of the MHO Phenotype

Question 1: Definition of obesity based on BMI, BF%, or WC?
 Facts 1: It is internationally accepted by researchers, clinicians, and major organizations, such as the World Health Organization,139 that obesity must be defined as having a BMI≥30 kg/m2. Nearly all previous studies focused on the MHO phenotype have defined obesity using this index and cut-point. On the contrary, a few studies have referred to MHO but have actually included not only obese but also overweight individuals (ie, BMI≥25 kg/m2).111 This would be a different concept because overweight is not so strongly related to CVD as it is obesity. In fact, a large meta-analysis showed that overweight individuals could have even a reduced risk of CVD mortality compared with normal-weight individuals.5,140 Although these findings have been controversial and not everybody agrees with the methods used and therefore with the conclusions obtained in that meta-analysis, we strongly recommend to keep the MHO term linked exclusively to obese individuals (not overweight), otherwise results on prevalence and prognosis of MHO would be largely affected. Similarly, Plourde and Karelis75 recently recommend, in relation with the MHO definition, that obesity should be defined using WC cut-points (particularly those proposed by the IDF, ie, 94/80 cm for men/women, respectively) instead of BMI≥30 kg/m2. Although we agree with the authors that abdominal obesity is a powerful predictor of metabolic disorders and CVD even within BMI categories,141143 this would be a new concept and new phenotype that could be termed as metabolically health but abdominally obese. However, from a clinical and public health point of view, obesity as such (based on BMI) is targeted for interventions and treatments, and it is needed to standardized a definition so that obese individuals can be classified into risk groups based on their metabolic profile (ie, MHO and MAO). Finally, obesity can also be defined using BF%. In line with this, our previous study with the ACLS data examined the MHO phenotype defining obesity based on both BMI and BF%.105 The use of BF% instead of BMI in this context has some drawbacks: First, methods for assessing BF% are more expensive, take more time and evaluators need to be more trained. Second, there is no consensus on which is the cut-point in BF% to define obesity. Although some authors have used 25%/30% for men and women, respectively,45,105 other have proposed age and ethnic-specific cut-points.144 In addition, the estimated BF% values largely differ depending on the methods used, even among reference methods such as air-displacement plethysmography (eg, Bod-Pod) vs dual-energy x-ray absorptiometry.145 Weight and height used to calculate BMI are more simple and estable measures, increasing the comparability of the data and the use of a standardized cut-point. BMI remains as a powerful predictor of CVD mortality,146 being perhaps an even stronger predictor of CVD than BF%.18
 Recommendation 1: From a research point of view, it is interesting to test the same hypothesis using different adiposity markers. However, from a clinical and practical point of view, we recommend to keep definitions as simple and consistent as possible, which means to define obesity based on BMI≥30 kg/m2 when studying the MHO phenotype
Question 2: MHO definitions based on MetS criteria versus insulin resistance/sensitivity cut-points?
 Facts 2: Although many definitions have been used, they can be organized into 2 groups: (1) those based on MetS criteria, and (2) those based on insulin resistance/sensitivity cut-points. Recent reviews on this topic concluded that most of previous studies focused on MHO used definitions based on MetS criteria.104,111 In addition, the markers of insulin resistance/sensitivity normally used are more costly than the markers included in the MetS definition, which reduces the feasibility and potential usefulness of the MHO in clinical and other settings. This is also the reason why fasting glucose is used for the MetS definition, instead of more expensive measures such as fasting insulin (or indexes derived from it, eg, homeostatic model assessment or quantitative insulin sensitivity check index) or the gold standard diagnostic test, the hyperinsulinemic euglycemic glucose clamp. This test is particularly costly, labor intensive for the investigator, and largely uncomfortable for the participant/patient
 Recommendation 2: To limit the definition of MHO to those criteria included in the MetS definition, which are simple, inexpensive and quick to be measured
Question 3: Which definition of MetS should be used for defining MHO?
 Facts 3: Although different definitions of MetS are available, the one published by Alberti et al54 is no doubt the most accepted by the scientific and clinical community, and it is the result of a consensus from major International Organizations: the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Many authors have used this definition but with small modifications in its cut-points, as well as adding other criteria to the definition (eg, inflammation markers).65,100Any small deviation from the most internationally accepted definition of MetS54 goes against current and future comparability of the data. Likewise, Plourde and Karelis75 suggested to use the cut-points of 120/80 mm Hg for systolic/diastolic blood pressure instead of the 130/85 suggested in the harmonized definition of MetS.54 Plourde and Karelis75 based this decision on the fact that prehypertension (also predicts CVD mortality.147 We agree that pre- hypertension is a risk factor, perhaps also prehypercholesterolemia and other lower cut-points in the rest of MetS criteria, but modifications from the most consensused and accepted definition of MetS hampers future comparability of the data. Likewise, there is evidence supporting than other factors such as hepatic fat markers and low inflammation markers are also important characteristics of the MHO concept.111 However, we think that for the MHO concept to be clinically useful must be kept simple and relatively cheap to be assessed and interpreted
 Recommendation 3: To strictly stick to the latest and most accepted MetS definition proposed by major international organization, which is the one published by Alberti et al.54 We recommend not using additional criteria, nor modifying the cut-points established for the MetS definition, to increase the comparability of existing and future data
Question 4: Should WC be included as criteria when defining MHO?
 Facts 4: As indicated by its name, MHO individuals are obese and consequently most of them meet the MetS criterion of high WC. Specifically, 80 to 95% of the MHO individuals, depending on the cut-points used (102/88 vs 94/80 cm54), meet the criteria of a high WC.81,105,148
 Recommendation 4: In accordance with previous MHO literature,65,81,105,148151 we suggest to exclude WC among the criteria to be considered for MHO
Question 5: How many MetS criteria should be met to be considered MHO?
 Facts 5: Existing literature is diverse on this point. Many have considered healthy as equivalent to the absence of MetS, so that a patient would be considered MHO when meeting <2 or <3 (depending on whether WC was excluded or not from the counting of criteria) of the MetS criteria. As an example, Wildman and colleagues with the US representative data from National Health and Nutrition Examination Survey80 and our study using the ACLS data105 defined MHO as meeting 0 or 1 of the MetS criteria (WC excluded). However, it has been argued that a person that has hypertension or diabetes, for instance, is not healthy, and therefore the MHO concept should be restricted to those individuals who are obese, but otherwise fully healthy from a metabolic point of view.152 This more restricted MHO concept would be then defined as meeting 0 MetS criteria. Plourde and Karelis have recently supported this concept.75 This concept has also obtained the strong support from the largest collaborative project focused on MHO, the EU-funded Healthy Obese Project, which also defined MHO as meeting 0 MetS criteria (WC excluded).81
 Recommendation 5: Based on the latest evidence on this topic, we recommend defining MHO when meeting 0 MetS criteria (WC excluded).
Question 6: How to define and name those obese individuals who are not MHO?
 Facts 6: We find two options to answer this question. Option 1: Obese individuals who meet the MetS definition, ie, meeting 2–4 of the criteria (WC excluded for the reasons explained in question 4). Based on this definition and using term/abbreviations already used in the literature, this group could be named as MAO65,66,104,105,153155 or MUHO.75,94,101,111,117,156 This definition would be problematic from both a clinical and analytic point of view, how would be considered/treated those individuals who meet only 1 criteria and are therefore left out from the MHO group and also from the MAO/MUHO group? Option 2: To define this group as all those obese individuals who are not MHO. Based on this definition a more appropriate name would be non-MHO, which has already been used in the literature.157160 The definition of the opposite group to MHO is extremely important because this would largely influence the analysis/results as well as clinical practice.
 Recommendations 6: Our recommendation is to define as non-MHO every obese person who does not meet the requirements to be considered MHO, ie, individuals meeting 1 to 4 of the MetS criteria (WC excluded). Future analyses would then compare the prognosis of MHO with non-MHO individuals. To avoid confusion to readers, we recommend using the terms and abbreviations proposed in the present harmonized definition (ie, MHO vs non-MHO) from now on
Question 7: How to define MHO in youth?
 Facts 7: It is internationally well accepted that obesity in youth should be defined based on the sex- and age-specific cut-points proposed by Cole and Lobstein77 and supported by the World Obesity Federation (formerly the International Obesity Task Force). These cut-points are equivalent to the adults’ cut-point of BMI≥30 kg/m2, but adapted to be specific by age and sex based on growth curves derived from a large and internationally diverse pooled data set. The definition of metabolically healthy in youth is particularly complicated because abnormalities in the metabolic profile became more apparent in adulthood and there is less consensus about how to define MetS in youth. Nevertheless and for consistency with adults, the MetS cut-points published by Jolliffe and Janssen78 seem to be a good choice because they are equivalent to those proposed for adults by the IDF and ATP-III, and are adjusted to age and sex based on population growth curves in youth. Other definitions for MetS in youth have been proposed, but they are not sex and age specific, which can be a problem because of the marked physiological changes occurring during puberty and growth in general. Therefore, a young patient would be classified as MHO if meeting 0 of the 4 MetS criteria78 (ie, after excluding WC), and as non-MHO if meeting 1 to 4 MetS criteria
 Recommendations 7: (1) To define obesity based on BMI and using the age- and sex-specific cut-points proposed by Cole and Lobstein77 that are internationally accepted. (2) To define MHO as meeting 0 of the 4 MetS criteria (WC excluded) proposed by Jolliffe and Janssen78 which are sex and age specific and equivalent to those proposed in Table 2 for adults. A young patient would be considered as non-MHO if being obese and meeting 1 to 4 MetS criteria (WC excluded)
  • ACLS indicates Aerobics Center Longitudinal Study; BF%, percent body fat; BMI, body mass index; CVD, cardiovascular disease; IDF, International Diabetes Federation; MAO, metabolically abnormal obesity; MetS, metabolic syndrome; MHO, metabolically healthy but obese; MUHO, metabolically unhealthy obese; and WC, waist circumference.