Is central obesity associated with cirrhosis-related death or hospitalization? A population-based, cohort study
2005; Elsevier BV; Volume: 3; Issue: 1 Linguagem: Inglês
10.1016/s1542-3565(04)00442-2
ISSN1542-7714
AutoresGeorge N. Ioannou, Noel S. Weiss, Edward J. Boyko, Kris V. Kowdley, Steven E. Kahn, Robert L. Carithers, Elaine C. Tsai, Jason A. Dominitz,
Tópico(s)Nutrition and Health in Aging
ResumoBackground & Aims: We aimed to determine the interaction between body fat distribution (central versus peripheral) and increased body mass index (BMI) with regards to the risk of cirrhosis-related death or hospitalization. Methods: Participants included 11,434 persons aged 25–74 years without evidence of cirrhosis at entry into the study or during the first 5 years of follow-up who were subsequently followed for a mean of 12.9 years as part of the first National Health and Nutrition Examination Survey. Participants were categorized into "normal-weight" (BMI < 25 kg/m2, N = 5750), "overweight" (BMI 25 to < 30 kg/m2, N = 3770), and "obese" (BMI ≥ 30 kg/m2, N = 1914). The subscapular to triceps skinfold thickness ratio (SFR) was used to categorize body fat distribution into central (SFR > 1, N = 5211) and peripheral (SFR ≤ 1, N = 6223). Results: Cirrhosis resulted in death or hospitalization of 88 participants during 149,888 person-years of follow-up (59/100,000 person-years). Among persons with a central body fat distribution, cirrhosis-related deaths or hospitalizations were more common in obese persons (115/100,000 person-years, adjusted hazard ratio 2.2, 95% confidence interval [CI] 1.1–4.6) and in overweight persons (94/100,000 person-years, adjusted hazard ratio 1.5, 95% CI 0.8–3.0) compared to normal-weight persons (59/100,000 person-years). However, among persons with a peripheral fat distribution, there was no association between obesity (adjusted hazard ratio 0.7, 95% CI 0.3–1.6) or overweight (adjusted hazard ratio 0.8, 95% CI 0.2–2.8) and cirrhosis-related death or hospitalization. Conclusions: The risk of cirrhosis-related death or hospitalization appears to be increased in the presence of cirrhosis, but only among persons with a central fat distribution. The excess risk associated with central obesity might be related to insulin resistance and hepatic steatosis. Background & Aims: We aimed to determine the interaction between body fat distribution (central versus peripheral) and increased body mass index (BMI) with regards to the risk of cirrhosis-related death or hospitalization. Methods: Participants included 11,434 persons aged 25–74 years without evidence of cirrhosis at entry into the study or during the first 5 years of follow-up who were subsequently followed for a mean of 12.9 years as part of the first National Health and Nutrition Examination Survey. Participants were categorized into "normal-weight" (BMI < 25 kg/m2, N = 5750), "overweight" (BMI 25 to < 30 kg/m2, N = 3770), and "obese" (BMI ≥ 30 kg/m2, N = 1914). The subscapular to triceps skinfold thickness ratio (SFR) was used to categorize body fat distribution into central (SFR > 1, N = 5211) and peripheral (SFR ≤ 1, N = 6223). Results: Cirrhosis resulted in death or hospitalization of 88 participants during 149,888 person-years of follow-up (59/100,000 person-years). Among persons with a central body fat distribution, cirrhosis-related deaths or hospitalizations were more common in obese persons (115/100,000 person-years, adjusted hazard ratio 2.2, 95% confidence interval [CI] 1.1–4.6) and in overweight persons (94/100,000 person-years, adjusted hazard ratio 1.5, 95% CI 0.8–3.0) compared to normal-weight persons (59/100,000 person-years). However, among persons with a peripheral fat distribution, there was no association between obesity (adjusted hazard ratio 0.7, 95% CI 0.3–1.6) or overweight (adjusted hazard ratio 0.8, 95% CI 0.2–2.8) and cirrhosis-related death or hospitalization. Conclusions: The risk of cirrhosis-related death or hospitalization appears to be increased in the presence of cirrhosis, but only among persons with a central fat distribution. The excess risk associated with central obesity might be related to insulin resistance and hepatic steatosis. 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This is problematic because the BMI and measures of fat distribution (such as the waist to hip ratio) might vary greatly after the development of advanced liver disease, thus leading to uncertainty about whether the accumulation of body fat preceded or followed the development of cirrhosis. In addition, most of these studies used intermediate end points such as steatosis and fibrosis, whereas cirrhosis would be a more clinically meaningful end point, especially if it is advanced enough to cause death or hospitalization. The aim of this study was to determine whether peripheral obesity and central obesity are different with respect to the risk of cirrhosis-related death or hospitalization by using a population-based, cohort study design. Baseline data were collected from 1971–1974 as part of the first National Health and Nutrition Examination Survey (NHANES I) and included interviews, physical examinations, and laboratory investigations on 14,407 participants aged 25–74 years who comprised a probability sample of the civilian, noninstitutionalized population of the coterminous United States. 22Miller H.W. Plan and operation of the Health and Nutrition Examination Survey United States 1971-1973.Vital Health Stat 1. 1973; 10a: 1-46PubMed Google Scholar The NHANES I participants were subsequently followed up in 1982–1984, 1986, 1987, and finally in 1992 as part of the NHANES Epidemiologic Follow-up Study (NHEFS). 23Cohen B.B. Barbano H.E. Cox C.S. Feldman J.J. Finucane F.F. Kleinman J.C. Madans J.H. Plan and operation of the NHANES I Epidemiologic Follow-up Study 1982–1984.DHHS publication no. (PHS) 87-1324. National Center for Health Statistics, Hyattsville, MD1987Google Scholar At each follow-up, subjects (or their proxies) were interviewed again, death certificates were obtained for subjects who had died, and hospital and nursing home records were obtained for overnight stays that had occurred since the most recent contact. Of 14,407 NHANES I participants, 13,861 (96.2%) were successfully traced at least once. Because we aimed to identify incident cases of cirrhosis during follow-up, we attempted to exclude participants who might have already had chronic liver disease or cirrhosis at the time of entry into the study. Therefore, we excluded from the analysis 1227 participants who reported a history of jaundice; were found to have hepatomegaly or splenomegaly on physical examination; or had a serum albumin level less than 3 g/dL. Platelet count, prothrombin time, and serum bilirubin levels, which can also be abnormal in patients with cirrhosis, were not measured or were measured only in a small subsample of participants and therefore could not be used to help identify participants who had cirrhosis at the time of entry into the study. To reduce the possible effects of subclinical liver disease on BMI and fat distribution, we also eliminated the first 5 years of follow-up from the analysis; this excluded 565 participants who either died or had a diagnosis of liver cirrhosis in their hospitalization records within the first 5 years after entry into the study. Finally, we excluded 635 participants with missing information for any one of the independent variables included in our models (BMI, skinfold thickness, age, alcohol consumption, gender, race, educational attainment, household income, and geographical location in the United States), leaving 11,434 participants in the main analysis. BMI was calculated at entry into the study as the measured weight in kilograms divided by the square of the measured height in meters. We used the BMI to categorize participants into normal-weight (BMI < 25 kg/m2), overweight (BMI 25 to < 30 kg/m2), and obese (BMI ≥ 30 kg/m2). 24Paolisso G. Rizzo M.R. Mazziotti G. Tagliamonte M.R. Gambardella A. Rotondi M. Carella C. Giugliano D. Varricchio M. D'Onofrio F. Advancing age and insulin resistance role of plasma tumor necrosis factor-alpha.Am J Physiol. 1998; 275: E294-E299PubMed Google Scholar The subscapular to triceps skinfold thickness ratio (SFR) was used as a measure of body fat distribution. 25Gillum R.F. Mussolino M.E. Madans J.H. Body fat distribution, obesity, overweight and stroke incidence in women and men the NHANES I Epidemiologic Follow-up Study.Int J Obes Relat Metab Disord. 2001; 25: 628-638Crossref PubMed Scopus (31) Google Scholar, 26Gillum R.F. Mussolino M.E. Madans J.H. 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Relation of body fat distribution to ischemic heart disease the National Health and Nutrition Examination Survey I (NHANES I) Epidemiologic Follow-up Study.Am J Epidemiol. 1995; 142: 53-63PubMed Google Scholar hypertension, 31van Lenthe F.J. van Mechelen W. Kemper H.C. Twisk J.W. Association of a central pattern of body fat with blood pressure and lipoproteins from adolescence into adulthood the Amsterdam Growth and Health Study.Am J Epidemiol. 1998; 147: 686-693Crossref PubMed Scopus (48) Google Scholar, 32Gillum R.F. The association of body fat distribution with hypertension, hypertensive heart disease, coronary heart disease, diabetes and cardiovascular risk factors in men and women aged 18–79 years.J Chronic Dis. 1987; 40: 421-428Abstract Full Text PDF PubMed Scopus (199) Google Scholar stroke, 25Gillum R.F. Mussolino M.E. Madans J.H. Body fat distribution, obesity, overweight and stroke incidence in women and men the NHANES I Epidemiologic Follow-up Study.Int J Obes Relat Metab Disord. 2001; 25: 628-638Crossref PubMed Scopus (31) Google Scholar diabetes mellitus, 29Resnick H.E. Valsania P. Halter J.B. Lin X. Differential effects of BMI on diabetes risk among black and white Americans.Diabetes Care. 1998; 21: 1828-1835Crossref PubMed Scopus (132) Google Scholar, 33Lipton R.B. Liao Y. Cao G. Cooper R.S. McGee D. Determinants of incident non-insulin-dependent diabetes mellitus among blacks and whites in a national sample the NHANES I Epidemiologic Follow-up Study.Am J Epidemiol. 1993; 138: 826-839PubMed Google Scholar low-density lipoprotein size, 30Rainwater D.L. Mitchell B.D. Comuzzie A.G. Haffner S.M. Relationship of low-density lipoprotein particle size and measures of adiposity.Int J Obes Relat Metab Disord. 1999; 23: 180-189Crossref PubMed Scopus (51) Google Scholar and high-density lipoprotein cholesterol level. 31van Lenthe F.J. van Mechelen W. Kemper H.C. Twisk J.W. Association of a central pattern of body fat with blood pressure and lipoproteins from adolescence into adulthood the Amsterdam Growth and Health Study.Am J Epidemiol. 1998; 147: 686-693Crossref PubMed Scopus (48) Google Scholar Right-sided skinfolds were measured to the nearest 0.5 mm by trained technicians with a Lange skinfold caliper. The subscapular skinfold was measured at the inferior angle of the scapula. The triceps skinfold was measured posteriorly at the halfway point between the outer edge of the acromion process and the olecranon process of the ulna. The median SFR value of 1 was arbitrarily chosen as the threshold value, such that an SFR > 1 was used to define central fat distribution, whereas an SFR ≤ 1 was used to define peripheral fat distribution. Analyses were also performed with quartiles of SFR (0–0.7, >0.7–1, >1–1.3, and >1.3). From hospitals and nursing homes that admitted study participants, the NHEFS investigators requested lists of discharge diagnoses and procedures performed during the admission as well as photocopies of the admission face sheet and the discharge summary. Specially trained NHEFS personnel used all available hospital records to assign the principal diagnosis as "the condition established after study to be chiefly responsible for occasioning the admission of the patient to the health care facility." 23Cohen B.B. Barbano H.E. Cox C.S. Feldman J.J. Finucane F.F. Kleinman J.C. Madans J.H. Plan and operation of the NHANES I Epidemiologic Follow-up Study 1982–1984.DHHS publication no. (PHS) 87-1324. National Center for Health Statistics, Hyattsville, MD1987Google Scholar Causes of death were abstracted from the death certificates. Death or hospitalization due to cirrhosis was defined by one of the following International Classification of Diseases, Ninth Revision (ICD-9) diagnoses, recorded either on the death certificate or as the principal diagnosis of hospitalization: 571.2 (alcoholic cirrhosis), 571.5 (cirrhosis without mention of alcohol), 571.6 (biliary cirrhosis), 456.0 (esophageal varices with bleeding), 456.1 (esophageal varices, no mention of bleeding), 572.2 (hepatic coma), 572.3 (portal hypertension), 572.4 (hepatorenal syndrome), and 155.0 (primary liver cancer). Persons with esophageal varices, hepatic coma, portal hypertension, hepatorenal syndrome, and primary liver cancer have been included as cases because the overwhelming majority of these conditions among Americans can be attributed to liver cirrhosis. If a participant was diagnosed as having acute necrosis of the liver (ICD-9 code 570.0) together with hepatic coma or hepatorenal syndrome, then he/she was not regarded as having cirrhosis. The Cox proportional-hazards model 34Cox D.R. Regression models and life-tables.J R Stat Soc. 1972; 34 ([B]): 187-202Google Scholar was used to determine the hazard ratio, comparing obese or overweight persons to normal-weight persons with respect to the risk of cirrhosis-related death or hospitalization, after adjusting for the following potential confounders that might be associated with both obesity and cirrhosis: age (modeled as a continuous variable), alcohol consumption during the previous 12 months (modeled as a dummy variable with categories: none [which included consuming alcohol less than 2–3 times per year], >0–1 drink/day, >1–2 drinks/day, and >2 drinks/day), gender, race (white, non-white), education (high school graduate or not), household income (modeled as a continuous-categorical variable in $1000 intervals), and geographical location in the US (modeled as a dummy variable with categories: Northeast, Midwest, South, and West). These characteristics were determined by interviews with the participants at the time of entry into the study. An interaction term between BMI category and SFR category was used to determine whether the association between BMI category and cirrhosis-related death or hospitalization was significantly different between persons with SFR >1 and those with SFR ≤1. The likelihood ratio test was used to compare models with and without the interaction term. A P value less than .05 was considered evidence of statistically significant interaction. The date 5 years after the measurement of the BMI was used as time 0 in the model, because the analysis was restricted to participants who remained alive and without a diagnosis of liver cirrhosis for at least 5 years after entry into the study. The date of the first hospitalization with a principal diagnosis of cirrhosis was used as the date of incidence. If cirrhosis was reported as a participant's cause of death and the participant had not been hospitalized for this condition, the date of death was used as the date of incidence. Participants who were not hospitalized with cirrhosis or who did not die of cirrhosis were censored on the date they were last traced alive or the date of death. To assess the robustness of our results, sensitivity analyses were performed in which (1) we included any diagnosis of cirrhosis as an outcome, rather than restricting the outcome to a principal diagnosis of cirrhosis, and (2) we excluded subjects with a new diagnosis of cirrhosis occurring between 3–8 years after initial BMI measurement. A total of 88 cases of cirrhosis-related death or hospitalization were identified in 11,434 participants during 149,888 years of follow-up (Table 1) (incidence rate 59/100,000 person-years). In univariate analyses, overweight (incidence rate 69/100,000 person-years, hazard ratio = 1.55, 95% confidence interval [CI] 1.0–2.5) and obese persons (incidence rate 82/100,000 person-years, hazard ratio = 1.85, 95% CI 1.1–3.2) had a higher incidence of cirrhosis-related death or hospitalization than normal-weight persons. However, after adjustment for the confounders described above, only obesity was still appreciably associated with cirrhosis-related death or hospitalization (hazard ratio = 1.70, 95% CI 1.0–3.0). Although increasing level of SFR was strongly associated with cirrhosis-related death or hospitalization in univariate analysis, there was no significant association in multivariate analysis.Table 1Baseline Characteristics of the Study Cohort and Hazard Ratios for Cirrhosis-Related Death or HospitalizationCharacteristicNumber of subjects (N = 11,434)Person-years (N = 149,888)Hospitalization or death due to cirrhosis (N = 88)Hospitalization or death due to cirrhosis per 100,000 person-yearsCrude hazard ratioaAdjusted for age, alcohol consumption, geographical region, gender, race, household income, and educational attainment. (95% CI)Adjusted hazard ratioaAdjusted for age, alcohol consumption, geographical region, gender, race, household income, and educational attainment. (95% CI)BMI Normal-weightbParticipants with this characteristic served as the reference group.575076,320344511 Overweight377049,17234691.55 (1.0–2.5)1.13 (0.7–1.8) Obese191424,39620821.85 (1.1–3.2)1.70 (1.0–3.0)Subscapular to triceps SFRcSFR was categorized into 4 quartiles. ≤0.7bParticipants with this characteristic served as the reference group.292140,294102511 >0.7–≤1330243,65921481.95 (0.9–4.1)1.36 (0.6–2.9) >1–≤1.3244131,88224753.06 (1.5–6.4)1.59 (0.7–3.5) >1.3277034,05333973.94 (1.9–8.0)1.38 (0.6–3.2)Gender MalebParticipants with this characteristic served as the reference group.443154,4215610311 Female700395,46732340.34 (0.2–0.5)0.44 (0.3–0.7)Age (y) 25–<40bParticipants with this characteristic served as the reference group.417961,033132111 40– 0–1519069,90435501.16 (0.7–1.9)1.51 (0.9–2.5) >1–284811,27310892.06 (1.0–4.3)2.51 (1.2–5.4) >26528085172104.92 (2.7–9.1)5.14 (2.6–10)Race WhitebParticipants with this characteristic served as the reference group.9627126,980685411 Non-white180722,98020871.66 (1.01–2.7)1.46 (0.9–2.5)Diabetes mellitusdThere are fewer than 11,434 subjects with this characteristic because it was not ascertained in all states. (self-reported) NobParticipants with this characteristic served as the reference group.8664116,433706011 Yes30129341340.58 (0.1–4.2)0.48 (0.1–3.5)Educational level <12th gradebParticipants with this characteristic served as the reference group.509861,593538611 ≥12th grade633688,29535400.45 (0.3–0.7)0.71 (0.4–1.2)US geographical region NorthwestbParticipants with this characteristic served as the reference group.254233,584216311 Midwest278937,19614380.60 (0.3–1.2)0.63 (0.3–1.2) South306439,32625641.0 (0.6–1.8)0.95 (0.5–1.7) West303939,78228701.1 (0.6–2.0)1.1 (0.6–1.9)Household income <$10,000/ybParticipants with this characteristic served as the reference group.645380,935627711 ≥$10,000/y498168,95326380.49 (0.3–0.8)0.62 (0.4–1.0)a Adjusted for age, alcohol consumption, geographical region, gender, race, household income, and educational attainment.b Participants with this characteristic served as the reference group.c SFR was categorized into 4 quartiles.d There are fewer than 11,434 subjects with this characteristic because it was not ascertained in all states. Open table in a new tab Evidence of significant interaction was identified between BMI category and SFR category (P < .05); hence the association between BMI category and cirrhosis-related death or hospitalization is presented separately for persons with SFR > 1 and ≤ 1 (Table 2 and Figures 1 and 2). No association was found between BMI category and cirrhosis-related death or hospitalization among persons with peripheral fat distribution (SFR ≤ 1). In contrast, among persons with central fat distribution (SFR > 1), obesity was strongly associated with cirrhosis-related death or hospitalization (incidence rate = 115/100,000 person-years, adjusted hazard ratio = 2.2, 95% CI 1.1–4.6), whereas there was a trend toward such an association in the case of overweight (incidence rate = 94/100,000 person-years, adjusted hazard ratio = 1.5, 95% CI 0.8–3.0).Table 2Association Between BMI Category and Cirrhosis-Related Death or Hospitalization Presented Separately for Persons With Subscapular to Triceps SFR > 1 and ≤ 1BMI categoryNumber of subjects (N = 11,434)Person-years (N = 149,888)Death or hospitalization due to cirrhosis (N = 88)Deaths or hospitalizations due to cirrhosis per 100,000 person-yearsCrude hazard ratio (95% CI)Adjusted hazard ratioaAdjusted for age, alcohol consumption, geographical region, gender, race, household income, and educational attainment. (95% CI)Subscapular to triceps SFR > 1 (N = 5211) Normal-weightbNormal-weight participants served as the reference group.188223,542145911 Overweight215327,57626941.6 (0.8–3.0)1.5 (0.8–3.0) Obese117614,817171151.9 (1.0–3.9)2.2 (1.1–4.6)Subscapular to triceps SFR ≤ 1 (N = 6223) Normal-weightbNormal-weight partic
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