COMPLICANZE DELLA OBESITA’ SEVERA SEMINARI DI FISIOPATOLOGIA CLINICA E TERAPIA CHIRURGICA ANNO XIX COMPLICANZE DELLA OBESITA’ SEVERA GIOVANNI DE PERGOLA Aula “A. De Blasi”, Policlinico di Bari 26 – 27 Novembre 2009

RISCHIO RELATIVO DI MORTE IN RELAZIONE A BMI e WAIST Adams et al, N Engl J Med, 355: 763-778, 2006 RR aggiustato per BMI Pischon et al, N Engl J Med, 359: 2105-20, 2008

Waist circumference (cm) WAIST CIRCUMFERENCE AND RISK OF TYPE 2 DIABETES 24 20 16 Relative risk 12 8 4 <71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 96.4 Waist circumference (cm) Carey et al., Am J Epidemiol, 1997

Associations of Visceral Fat with Insulin Sensitivity 300 200 50 2 4 6 8 10 12 14 16 100 150 250 350 400 Rd (mg x min-1 x FFM-1) Visceral Fat (cm2) Lean control Obese before WL Obese after WL Goodpaster et al, Diabetes, 1999 Ades et al, Int J Obesity, 32: 967-74, 2008

Adipose tissue ↑ Angiotensinogen Nella diapositiva vengono riportati i valori di PAD e PAS in rapporto al 50° percentile di WC e ai terzili di BMI rispettivamente negli uomini(A) e nelle donne(B), dopo aggiustamento per età all’analisi di covarianza. Gli uomini, non obesi, con WC <88 cm, erano caratterizzati da un aumento della PAS che era comparabile ai valori di PAS rilevati negli uomini appartenenti al terzile più alto di BMI (26,6 kg/m2). In merito alla PAD, WC sembra aver avuto una superiore influenza, rispetto al BMI, come determinante degli elevati valori di PAD. Tra le donne la PAS più elevata è stata osservata nei soggetti che erano nel terzile più alto di BMI (24,8 kg/m2) e che erano caratterizzati da una elevata WC (74 cm). Infine le PAD più elevate sono state rilevate tra le donne appartenenti al terzile più alto di BMI e con un elevata WC (B). Poirier P et al Hypertension. 2005;45:363-367. Mathieu et al Hypertension, 53:577,2009

Piccole, dense HDL (basso HDL-C) OBESITA’ VISCERALE E DISLIPIDEMIA Adipociti IA Insulina IR X Fegato FFA Citochine Piccole, dense HDL (basso HDL-C) CE TG (CETP) ( HL) Rene Apo A-1 HDL3  TG  Apo B VLDL (grandi) HDL2 (CETP) TG CE Mechanisms Relating Insulin Resistance and Dyslipidemia Insulin resistance at the site of intra-abdominal adipose tissue leads to impaired inhibition of triglyceride hydrolysis (impaired inhibition of hormone-sensitive TG-lipase in the adipocyte) and release of increased amount of FFA in the splancnic circulation. Insulin resistance in the liver combined with increased flux of FFA results in an increased production of TG (hypertriglyceridemia) and VLDL. Increased levels of VLDL triglyceride in the presence of CETP can promote the transfer of triglyceride into LDL in exchange for LDL cholesteryl ester. The triglyceride-rich LDL can undergo hydrolysis by hepatic lipase (usually increased in the Plurim. Syndrome), which leads to a small, dense, cholesterol-depleted—and, in general, lipid-depleted—LDL particles. On the other hand increased levels of VLDL triglyceride, in the presence of CETP, also promote the transfer of triglyceride into HDL in exchange for HDL cholesteryl ester leading to formation of TG-rich HDL. These are good substrate for hepatic lipase, which leads to lipid-depleted HDL (lower HDL-C) and increased release of free apo A I that is rapidly catabolized in the kidney (lower apo A I). In summary (next slide) LDL ( HL)  LDL piccole e dense LDL FFA: Acidi grassi liberi CETP: Colesteril ester transfer protein HL: Lipasi Epatica 6

ATEROSCLEROSI INSULINO-RESISTENZA E IPERINSULINEMIA Ipertensione URICEMIA INSULINO-RESISTENZA E IPERINSULINEMIA TG HDL-COL LDL DENSE Ipertensione RIDOTTA PRODUZIONE DI OSSIDO NITRICO DA PARTE DELL’ENDOTELIO AUMENTO DELLA REPLICAZIONE DELLE CELLULE MUSCOLARI LISCE DIABETE e IGT PAI-1 ATEROSCLEROSI

INTERHEART STUDY Yusuf et al, Lancet, 366: 1640-9, 2005

Figure 1. Photographs and Abdominal Magnetic Resonance Images Obtained before and after Liposuction. The photographs of one study subject and images of another show the large amount of subcutaneous abdominal fat removed by liposuction. Klein et al, NEJM, 350: 2549-57, 2004

Lottati et al, Obesity, 17: 674-680, 2009

ALTERAZIONI CARDIOVASCOLARI INDOTTE DALLA OBESITA’ CARDIOPATIA ISCHEMICA IPERTROFIA DEL VENTRICOLO SINISTRO DISFUNZIONE DIASTOLICA DEL VENTRICOLO SINISTRO SCOMPENSO CARDIACO FIBRILLAZIONE ATRIALE MORTE IMPROVVISA ANEURISMA AORTA ADDOMINALE ICTUS (ISCHEMICO)

LA OBESITA’ VISCERALE E’ ASSOCIATA A PATOLOGIE RESPIRATORIE DEFICIT RESPIRATORIO DI TIPO RESTRITTIVO SINDROME DELLE APNEE DURANTE IL SONNO (OSAS) COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE) ATELETTASIE ASMA INSUFFICIENZA RESPIRATORIA

Obesity and Cancer Risk ACS Cancer Prevention Study II, 1982–1998 Women Mortality from Cancer (RR) In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. We examined the relation in men and women between the body-mass index in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate proportional-hazards models. We calculated the proportion of all deaths from cancer that was attributable to overweight and obesity in the U.S. population on the basis of risk estimates from the current study and national estimates of the prevalence of overweight and obesity in the U.S. adult population. results The heaviest members of this cohort (those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of at least 40) had death rates from all cancers combined that were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight. For men, the relative risk of death was 1.52 (95 percent confidence interval, 1.13 to 2.05); for women, the relative risk was 1.62 (95 percent confidence interval, 1.40 to 1.87). In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin’s lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women. On the basis of associations observed in this study, we estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women. conclusions Increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites. Reference Calle E.E., Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults, New England Journal of Medicine Apr 24, 2003; 348:1625-38 n=495,477 16 yr study Body Mass Index (BMI) Calle et al, NEJM, 348: 1625-38, 2003 © 2003, Wellsource Inc.

Obesità Viscerale e NAFLD FFA Lipolisi Grasso viscerale Sistema portale Steatosi NAFLD

Obesità Viscerale e Calcolosi Biliare  Grasso viscerale Obesità Viscerale e Calcolosi Biliare  Lipolisi FFA Sistema Portale Steatosi Tsai et al, Arch Intern Med, 166: 2369, 2006  Sintesi di colesterolo  Secrezione biliare di colesterolo  Indice di saturazione biliare 20 22 24 26 28 30 1 2 3 4 5 6 BMI Colelitiasi Realative risk

Jacobson et al, NEJM, 354: 2340, 2006

Il grasso addominale correla con i livelli plasmatici di FT3 e con una maggiore conversione della FT4 in FT3 Queste modificazioni hanno il significato di meccanismo di compenso all’accumulo di grasso De Pergola et al, Clinical Endocrinology, 2007

De Pergola et al, Obesity, 14: 1954-1960, 2006

P = ns P=ns NUMERO DI FOLLICOLI OVARICI IN FASE FOLLICOLARE De Pergola et al, Obesity, 14: 1954-1960, 2006

Tra le 266 donne obese e in sovrappeso esaminate: 171 (64,3%) avevano un normale ciclo mestruale 57 (21,4%) erano affette da oligomenorrea 38 (14,3%) presentavano ipermenorrea e/o polimenorrea De Pergola et al, J Endocrinol Invest, 32: 98-101, 2009

ALTERAZIONI NEFROLOGICHE E UROLOGICHE INDOTTE DALLA OBESITA’ VISCERALE MICROALBUMINURIA INSUFFICIENZA RENALE CALCOLOSI DELLE VIE URINARIE COMPRESSIONE DELLA VESCICA INCONTINENZA URINARIA

Osteoartrite (mani, bacino, ginocchia) Dolore di schiena Iperostosi scheletrica diffusa idiopatica Alterazioni della andatura Alterazioni dei tessuti molli (s. del tunnel carpale, fascite plantare) Osteoporosi Gotta Fibromialgia Artrite reumatoide Anandacoomarasamy et al, Int J Obesity, 2008

COMPLICANZE DELLA OBESITA’ ALTERAZIONI DEL CIRCOLO VENOSO E LINFATICO Varici Venose Ulcere Venose Linfedema Tromboflebiti

ALTERAZIONI DERMATOLOGICHE ASSOCIATE ALLA OBESITA’ Vieira et al, Am J Clin Nutr, 82: 504-9, 2005 Setty et al, Arch Intern Med, 167: 1670-5, 2007

OBESITA’ VISCERALE E RISCHIO DI DEMENZA Rosengren et al, Arch Intern Med, 165: 321-326, 2005 Kivipelto et al, Arch Neurol, 62: 1556-60, 2005 KWhitmer et al, BMJ, 330: 1360, 2005 Beydoun et al, Obesity Rev, 9: 204-218, 2008

Keith et al, Obesity, 16: 377-83, 2008

OBESITA’ E ALTERAZIONI OCULARI CATARATTA ALTERAZIONI MICROVASCOLARI RETINICHE Cheung et al, Obesity, 15: 209-215, 2007 Taylor et al, Int J Obesity, 31: 1527-33, 2007