Associations of Metabolic Syndrome and Abdominal Obesity with Anion Gap Metabolic Acidosis among US Adults

Abstract

Background: Obesity is a recently identified risk factor for metabolic acidosis and anion gap elevations in the absence of chronic kidney disease (CKD). Metabolic acidosis is a treatable condition with substantial adverse effects on human health. Additional investigations are needed to characterize at-risk populations and explore potential mechanisms. We hypothesized metabolic syndrome (MetS) and waist circumference (WC) would be closely associated with this pathology. Methods: Adult participants from NHANES 1999 - 2018 meeting study criteria were compiled as main (n = 31,163) and fasting (n = 12,860) cohorts. Regression models adjusted for dietary acid, estimated glomerular filtration rate (eGFR), and other factors examined associations of WC and MetS features with anion gap metabolic acidosis and its components (serum bicarbonate ≤ 23 mEq/L and anion gap > 95th percentile). Results: Greater WC and MetS features were associated with progressively lower bicarbonate, higher anion gap, and greater odds ratios (OR) of metabolic acidosis (MA) and anion gap metabolic acidosis (AGMA). Compared to the reference, participants with the highest WC had ORs for MA and AGMA of 2.26 [1.96 - 2.62] and 2.89 [1.97 - 4.21]; those with three and four vs. zero MetS features had ORs for AGMA of 2.52 [1.95 - 2.94] and 3.05 [2.16 - 3.82]. Associations of body mass index with outcomes were attenuated or absent following adjustment for WC or MetS. Findings were preserved after excluding eGFR < 90 mL/min/1.73m2 and albuminuria. A lower MA cutoff (< 22 mEq/L) raised the estimate of association between MetS and MA (OR for three and four vs zero features: 3.56 [2.53 - 5.02] and 5.44 [3.66 - 8.08]). Conclusions: Metabolic diseases are characterized by metabolic acidosis and anion gap elevations. Metabolic dysfunction may predispose patients without CKD to systemic acidosis from endogenous sources. Comprehensive acid-base analyses may be informative in patients with metabolic diseases.

Acid accumulation is associated with metabolic alterations; higher energy, fat, and protein intake; and energy expenditure

“…Previous studies have identified associations between acid accumulation and higher BMI, lower cardiorespiratory fitness, insulin resistance, higher blood pressure, and metabolic syndrome [4–6, 17, 32] but lacked specific measures such as waist and thigh circumferences, lipid concentrations, and body composition (e.g., body fat percentage and fat mass).The findings of the current study complement prior studies by demonstrating associations with these additional metabolic parameters (Table 2). Williams et al demonstrated that overfeeding diets (45% fat, 15% protein, and 40% carbohydrate) in individuals with obesity lead to acid accumulation.…”

“…Third, EE was carefully measured over 24 h in the WRIC. Fourth, we were able to calculate the CAG, which is a more sensitive disease risk indicator [4]. Despite these strengths, several limitations should be considered.…”

“…Metabolic acidosis, a consequence of accumulated acid from nonrespiratory sources, is typically encountered in the clinical context of advancing chronic kidney disease. However, recent studies have implicated obesity (with normal kidney function) as a risk factor for low serum bicarbonate and increased anion gap (AG), both markers of increased acid accumulation [3,4]. Acid accumulation has been associated with multiple adverse health consequences, including insulin resistance, metabolic syndrome, development of kidney disease, hypertension, bone disease, loss of connective and muscle tissues, and muscle weakness [3][4][5][6][7][8][9][10].…”

Dietary acid load in health and disease

“…2 ) [ 78 ]. Moreover, metabolic acidosis has recently been proposed as a consequence of obesity [ 84 , 86 ]. Importantly, many of the foods contributing to obesity are high in calories but are also considered to be acidogenic due to their high content of animal protein and table salt, especially in a typical Western diet.…”

Minding the Gap Beyond Kidney Disease: Utility of the Anion Gap in Metabolic Syndrome

“…In this issue of Kidney 360 , Lambert and colleagues conducted a retrospective analysis of clinical and biochemical parameters, including MetS features, serum bicarbonate, and AG values in more than 40,000 patients from the National Health and Nutrition Examination Survey (NHANES) (6). The authors had three major goals.…”