Nonalcoholic fatty liver disease in Brazil. Clinical and histological profile

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1 Nonlcoholic ftty liver disese in Brzil., 2011; 10 (1): ORIGINAL ARTICLE Jnury-Mrch, Vol. 10 No.1, 2011: Nonlcoholic ftty liver disese in Brzil. Clinicl nd histologicl profile Helm P. Cotrim,* Edison R. Prise,* Cludi P.M.S. Oliveir,* Ntlhie Leite,* An Mrtinelli,* João Glizzi,* Rit de Cássi Silv,* Ângelo Mttos,* Leil Pereir,* Wldir Amorim,* Clúdi Ivntes,* Frncisco Souz,* Mrcelo Cost,* Lizomr Mi,* Mário Pesso,* Frederico Oliveir* ABSTRACT * Brzilin Group for the Study of the NAFLD-Sociedde Brsileir de Heptologi-Brzil. Bckground. The epidemiology nd clinicl chrcteristics of nonlcoholic ftty liver disese (NAFLD) in South Americre not well known. Brzil is lrgest country in this prt of the world nd the present study imed to contribute with this informtion. Methods. This descriptive study included ptients from medicl centers round Brzil, who hd dignosis of NAFLD. They were selected from chrt review nd lso prospectively in Heptology out-clinics. Ptients with history of lcohol intke nd others liver diseses were excluded. Histologicl dignosis included: stetosis or stetoheptitis (stetosis, bllooning of heptocytes or fibrosis). The criteri to perform liver biopsy ws ALT or AST > 1.5 x norml levels. Results. A totl of 1280 ptients from 16 Brzilin centers nd ll five regions were included. The men ge ws ± yers; 53.3% were mles nd 85% were symptomtic. Hyperlipidemi ws observed in 66.8% cses, obesity in 44.7%, overweight in 44.4%, dibetes in 22.7%, nd toxins exposure in 10%. Metbolic syndrome ws observed in 41.3% cses. Elevted levels of ALT, AST nd GGT were observed in 55.8%, 42.2% nd 63.1% cses, respectively. Liver biopsy performed in 437 cses showed: isolte stetosis in 42% cses, stetoheptitis in 58% nd 27% of them lso presented fibrosis. Cirrhosis ws observed in 15.4% nd heptocellulr crcinom in 0.7%. Conclusions. NAFLD in Brzil is more frequent in symptomtic mles; stetoheptitis with fibrosis nd cirrhosis were significnt dignosis. The genetic predisposition nd lifestyle should be influenced in the spectrum; however these findings deserve future investigtion. Key words. Nonlcoholic stetoheptitis. Metbolic Syndrome. Insulin resistnce. NAFLD in South Americ. NASH. MeSH. INTRODUCTION Correspondence nd reprint request: Helm Pinchemel Cotrim, M.D. Progrm de Pós Grdução em Medicin e Súde-PPGMS Ru Pdre Feijó. Hospitl Prof. Edgr Sntos, 5º. ndr CEP: Slvdor-Bhi-Brzil Fone/Fx: E-mil: hpcotrim@ufb.br Mnuscript received: August 16, Mnuscript ccepted: December 08, Nonlcoholic ftty liver disese (NAFLD) my ffect ny ge, ethnic group or country. The prevlence estimted of NAFLD in the generl popultion rnges from 3 to 24%. 1,2 This liver disese ppers to be most strongly ssocited with obesity nd insulin resistnce sttes including dibetes nd with other fetures of the metbolic syndrome, such s high triglycerides nd low HDL. It ppers to be more common in men, nd it increses with incresing ge nd fter menopuse in women. More dvnced stges of NAFLD re ssocited with older ge, higher body mss index, dibetes, hypertension, high triglycerides, nd/or insulin resistnce. 3,4 The high frequency of NAFLD ws described in Mexicn Americns when it ws compred with Africn Americns nd non-hispnic Cucsin. 5 The higher incidence of metbolic syndrome lso hs been described in Amerindin popultions, 2 nd it my suggest tht NAFLD lso is common throughout Ltin Americ. This high prevlence of NAFLD, however, is not exclusive to the Cucsin western popultion. NA- FLD mong helthy Jpnese dults hs reched epidemic proportions in different popultions round the world. 6 In the South Asin Indin some studies hve shown tht this popultion lso is t high risk for development of metbolic syndrome, type 2 dibetes nd crdiovsculr disese, suggesting the possibility of gene vrints tht impct shred moleculr pthwys mongst these clinic entities. 7,8 In Brzil, over the lst two decdes, chnges in humn behvior nd lifestyle hve resulted in dr-

2 34 Cotrim HP, et l., 2011; 10 (1): mtic increse in the prevlence of obesity. According the lst Census by Brzilin Institute of Geogrphy 40% of Brzilin dult popultion is overweight nd 8.9% mles nd 13% of femles were obese. 9,10 OBJECTIVE The present study imed to describe the clinicl nd histologicl spects of NAFLD in Brzil nd to contribute with informtion bout chrcteristics of NAFLD in this prt of South Americ. PATIENTS AND METHODS Study design nd ptients selection This descriptive study included ptients with NAFLD dignosis from the five regions nd sixteen centers round Brzil. They cme from sttes of South (Rio Grnde do Sul nd Prná), North (Prá), Northest (Prib, Pernmbuco nd Bhi), Southest (São Pulo, Rio de Jneiro e Mins Geris) nd Center (Federl District- Brsili). The ptients were selected from chrt review nd prospectively from heptology out-clinics. The study ws pproved by the Ethics Committee for Medicl Reserch-Progrm de Pós Grdução em Medicin e Súde Universidde Federl d Bhi, Brzil nd in ll centers tht the ptients were included. NAFLD criteri Ptients were included when they presented the following criteri: presence of stetosis on bdominl ultrsound nd ltertions of heptic enzymes (ALT/ALT); history of lcohol intke 20 g/dy; exclusion of others liver diseses (B nd C virus infection, hemochromtosis, Wilson s disese nd utoimmune heptitis). The pttern of lcohol consumption ws obtined from medicl consulttions with physicins nd inter-views with ptient reltives. Ptients evlution A questionnire ws used to obtin medicl history, demogrphic dt, to evlute lcohol consumption, nd the use of medictions. Dt of physicl exm, lbortory tests nd bdominl ultrsound were included. Anthropometry. Body mss index (BMI) ws clculted s body weight (kg)/height (m 2 ) nd ptients were ctegorized s norml weight (< 25.0 kg/m 2 ), overweight ( 25.0 nd 29.9 kg/ m 2 ) nd obese ( 30.0 kg/m 2 ). The obesity ws clssified in grde I ( kg/m 2 ), grde II ( kg/m 2 ) nd grde III ( 40.0 kg/ m 2 ). 11 Lbortory tests. ALT, AST, GGT, fsting glucose, insulin, nd lipid profile (triglycerides, totl cholesterol, HDL-C (high-density lipoprotein), LDL-C (low-density lipoprotein), serologicl tests for heptitis B nd C, ferritin nd trnsferin sturtion. Insulin resistnce (IR) ws evluted by clculting the Homeostsis Model Assessment of Insulin Resistnce (HOMA-IR). 12 To pply HOMA-IR to the insulin resistnce index, HOMA-IR 3 ws used. 13 Metbolic syndrome ws evluted in ll cses nd defined s ATP III criteri. 14 Liver biopsy nd histologicl dignosis Criteri for liver biopsy included serum ALT/AST determintions greter thn 1.5 the norml level in more thn two occsions, seprte by t lest 1 month. Liver tissue ws fixed in 4% formol sline, processed in n uto-technicon pprtus nd stined with hemtoxylin-eosin (HE) nd Msson s trichrome. The following histologicl vribles were nlyzed: mcro- nd microvcuolr ftty chnge, zonl distribution, foci of necrosis, portl nd perivenulr fibrosis, nd inflmmtory nd fibrotic infiltrte with zonl distribution. All specimens were scored by liver pthologist with expertise in NAFLD. A preview protocol to histologicl dignosis ws done nd sent for ll Brzilin pthologists, nd the prticipnt s centers hve used the sme histologicl score. The ptients were clssified s hving stetosis; stetoheptitis (stetosis, bllooning of heptocytes, nd inflmmtory infiltrted with or without fibrosis). Fibrosis ws clssified into 5 stges: S 0: Without fibrosis. S 1: Fibrosis limited to the perivenulr or per sinusoidl re in zone 3. S 2: Perivenulr nd per sinusoidl fibrosis with portl fibrosis.

3 Nonlcoholic ftty liver disese in Brzil., 2011; 10 (1): S 3: Bridging fibrosis. S 4: Cirrhosis. 15 Sttisticl nlysis. The Sttisticl Pckge for Socil Sciences (SPSS Inc., Chicgo, IL, USA, nd Relese , 2008) nd Prism (Grph Pd Inc., Sn Diego, CA, USA, Relese 5.01) softwre progrm, version 12.0, ws used to nlyze the dt in this study. RESULTS The study included 1280 ptients with dignosis of NAFLD round Brzil. The men ge of the ptients ws ± yers, 53.3% were mles nd 85% were symptomtic. The evlution of the risk fctors showed: hyperlipidemi in 66.8% cses, obesity in 44.7%, overweight in 44.4% nd dibetes in 22.7%. Toxins exposure ws relted for 10% of the cses. Metbolic Syndrome ws observed in 41.3% cses. Elevted levels of ALT, AST nd GGT were observed in 55.8%, 42.2% nd 63.1% cses, respectively. The tble 1 shows demogrphic, clinicl nd biochemicl prmeters in ptients with isolte stetosis nd NASH. Some differences ws observed in ge nd BMI when compred ptients with NASH nd stetosis. NASH ptients lso presented incresed liver enzymes (AST nd GGT), higher HOMA-IR index nd lower HDL-cholesterol. However, sttisticl significnce ws not chieved. Liver biopsy ws performed in 437 cses of 1280 ptients included. Isolte stetosis ws observed in 41.7%, stetoheptitis without fibrosis in 31.1% nd 11.7% Stge % Stge % 31.1% 27.0% Stetosis Stetoheptitis Stetoheptitis with fibrosis nd cirrhosis Figure 1. Histologicl NAFLD dignosis in Brzilin ptients (n = 437). 7.6% Stge % Stge % Stge 0 Figure 2. Stges of fibrosis in NAFLD Brzilin ptients. Tble 1. Demogrphic, clinicl nd biochemicl dt of ptients with histologicl dignosis of stetosis nd stetoheptitis (NASH) (n=1280). Vrible Ptients with stetoheptitis Ptients with stetosis Age (yers) 56 ± ± 11.9 Dibetes (glucose>110/dl) 37 (58%) 10 (37%) Dislypidemi* 48 (75%) 16 (59%) High-blood pressure* 41 (64%) 9 (33%) BMI (body mss index) 29.6 ± ± 3.9 Fsting glucose (mg/dl) 128 ± ± 99.4 HOMA-IR >2,5 48 (75%) 17 (63 %) AST (U/L) 46 ± 3 42 ± 3 ALT (U/L) 52 ± 3 64 ± 6 Totl cholesterol (mg/dl) 200 ± ± 38.2 HDL (mg/dl) 43 ± ± 15.7 LDL (mg/dl) 113 ± ± 35.1 Triglyceride (mg/dl) 195 ± ± Metbolic Syndrome* 39 (61%) 10(37%) * ATP III (ref 15).

4 36 Cotrim HP, et l., 2011; 10 (1): stetoheptitis with fibrosis in 27% (totl of NASH- 58%) (Figure 1). Stges of fibrosis: S zero: 29.2%, S1: 36.1%, S2 in 11.7%, S3 in 7.6%, cirrhosis in 15.4% (Figure 2) nd three of them hve heptocellulr crcinom (HCC). DISCUSSION The present study involves lrge series of ptients with NAFLD in Brzil nd represents contribution to describe profile of these ptients in South Americ, where there re no much informtion bout this liver disese. Among the 1280 cses of the NAFLD evluted, the mjority of them were symptomtic mle; with men ge of fifty yers, nd the most frequent risk fctor to NAFLD were hyperlipidemi, obesity or overweight. Metbolic Syndrome (ATP III) ws observed in 41.3% cses. All these fetures in Brzilins NAFLD ptients re similr to other countries. 15 A popultion-bsed study performed in the USA demonstrtes tht up to 34% of the dult generl popultion hs excessive ft ccumultion in the liver, mostly unrelted to lcohol buse. 17 This high prevlence of NAFLD is most likely result of the incresing prevlence of obesity, type 2 dibetes nd metbolic syndrome in the generl US popultion. 3 In Jpn, the results of series of cross-sectionl dt obtined from ptients presenting for helth checkup demonstrted tht the prevlence of ftty liver on ultrsound incresed from 12.6% in 1989, peked t 30.3% in 1998, nd ws 28.4% in Furthermore, unless uniform dtre vilble over the time period, the prevlence estimtes of NAFLD could lso be ffected by chnge in scertinment bsed on incresed wreness. Nevertheless, becuse of the mrked increse in the prevlence of both obesity nd type 2 dibetes, it is ssumed tht the prevlence of NAFLD is incresing s well. 16 All these studies hve suggested tht ethnic differences my hve role in susceptibility to NAFLD, especilly the progressive disese tht cnnot be explined simply on the bsis of diet or socioeconomic differences. The higher incidence of NASH in US popultions of Hispnic origin reltive to Cucsin, nd lower incidence in Africn-Americns, despite higher rte of obesity hve suggested it. 17,18 This Brzilin study showed tht the mjority of ptients were mles, with men ge of fifty yers. This result re similr popultion-bsed studies, 19,20 however it is different of others studies lso performed in ptients selected of out-clinics, tht hve shown cses of NAFLD most common in middle-ged women. The ethnic differences were not studied in this simple. In Brzil, the mixed rcil heritge is recognized nd it is n importnt subject to be investigted. It would be useful in future to identify them more precisely using ccepted rcil origin genetic mrkers, nd it will be relevnt to be used to set public policy in regrds to popultion screening nd/or public helth intervention strtegies. Stetoheptitis with fibrosis nd cirrhosis ws frequent in ptients, who underwent liver biopsy nd three of heptocellulr crcinom ws observed. These results showed tht NAFLD hs high potentil of progression in this popultion. The mechnism of this progression is complex nd remins to be understood. It clerly is multifctoril. Mny cses re relted to lifestyle; however, it is likely tht genetic predisposition plys n importnt role in determining which individuls hve incresed risk for development of cirrhosis nd HCC in ptients with NAFLD. CONCLUSION The study contributes with informtion bout chrcteristics of NAFLD in South Americ. It describes the profile of NAFLD in Brzil, the lrgest country in South Americ. The ptients did not present symptoms, however, the most frequent histologicl dignosis in these simple ws stetoheptitis with fibrosis nd significnt number of cses lredy presented cirrhosis. These findings deserve future investigtion. Although the present study did not im to evlute pthogenic mechnisms, the genetic predisposition nd lifestyle should be influenced in the spectrum of NAFLD in Brzil nd the high frequency of severe disese in this popultion. ABBREVIATIONS NAFLD: Nonlcoholic Ftty Liver Disese. NASH: Nonlcoholic Stetoheptitis. MS: Metbolic Syndrome. BMI: Body Mss Index. IR: Insulin Resistnce. ALT: Alnine minotrnsferse. AST: Asprtte minotrnsferse. GGT: Gmm Glutmyl Trnspeptidse. HDL-C: High-density lipoprotein cholesterol. LDL-C: Low-density lipoprotein cholesterol.

5 Nonlcoholic ftty liver disese in Brzil., 2011; 10 (1): HOMA-IR-IR: Homeostsis Model Assessment of Insulin Resistnce. SPSS: Sttisticl Pckge for Socil Sciences. ACKNOWLEDGMENTS The uthors re grteful to the Brzilin Heptologists Groups, to Dr. Luiz Antonio de Freits nd Dr. Venâncio Alves for the support on the protocol to histologicl dignosis, nd to the Sociedde Brsileir de Heptologi. REFERENCES 1. Ong JP, ZM Younossi. Epidemiology nd nturl history of NAFLD nd NASH. Clin Liver Dis 2007; 11: Lzo M, JM Clrk. The epidemiology of nonlcoholic ftty liver disese: globl perspective. Semin Liver Dis 2008; 28: Adms LA, Angulo P. Recent concepts in non-lcoholic ftty liver disese. Dibetes Med 2005; 22: Buginesi E, Mrchesini G, Arthur J. McCullough Insulin resistnce: A metbolic pthwy to chronic liver disese. Heptology 2005; 42(5): Weston SR, Leyden W, Murphy R, Bss NM, Bell BP, Mnos MM, Terrult NA. Rcil nd ethnic distribution of nonlcoholic ftty liver in persons with newly dignosed chronic liver disese. Heptology 2005; 41: Kojim S, Wtnbe N, Numt M, et l. Increse in the prevlence of ftty liver in Jpn over the pst 12 yers: nlysis of clinicl bckground. J Gstroenterol 2003; 38: Petersen KF, Dufour S, Feng J, Befroy D, Dziur J, Mn CD, Cobelli C, Shulmn GI. Incresed prevlence of insulin resistnce nd nonlcoholic ftty liver disese in Asin- Indin men. Proc Ntl Acd Sci USA 2006; 103: Amrpurkr DN, Hshimoto E, Lesmn LA, Sollno JD, Chen PJ, Goh KL. How common is non-lcoholic ftty liver disese in the Asi-Pcific region nd re there locl differences? J Gstroenterol Heptol 2007; 22: Monteiro CA, Conde WL. A tendênci seculr d obesidde segundo estrtos sociis: Nordeste e Sudeste do Brsil, Arq Brs Endocrinol Metb 1999; Sichieri R, Coitinho DC, Leão MM, Recine E, Everhrt JE. High temporl, geogrphic, nd income vrition in body mss index mong dults in Brzil. Am J Public Helth 1994; 84: Seidell JC, Flegl KM. Assessing obesity: clssifiction nd epidemiology. Br Med Bull 1997; 53(2): Mtthews DR, Hosker JP, Rudenski AS, Nylor BA, Trecher DF, Turner RC. Homeostsis model ssessment: insulin resistnce nd b-cell function from fsting plsm glucose nd insulin concentrtions in mn. Dibetologi 1985; 28: Guidorizzi de Siqueir AC, Cotrim HP, Roch R, et l. Nonlcoholic ftty liver disese nd insulin resistnce: importnce of risk fctors nd histologicl spectrum. Eur J Gstroenterol Heptol 2005; 17(8): Executive Summry of the Third Report of the Ntionl Cholesterol Eduction Progrm (NCEP) Expert Pnel on Detection, Evlution nd Tretment of High Blood Cholesterol in Adults (Adult Tretment Pnel III). J Am Med Assoc 2001; 285: Freits LA & Cotrim HP. Atls NASH: Esteto-Heptite Não Alcoólic. São Pulo: Zmbon; 2006, p Flck-Ytter Y, Younossi ZM, Mrchesini G, et l. Clinicl fetures nd nturl history of nonlcoholic stetosis syndromes. Semin Liver Dis 2001; 21: Browning JD, Szczepnik LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et l. Prevlence of heptic stetosis in n urbn popultion in the United Sttes: impct of ethnicity. Heptology 2004; 40: Cldwell SH, Hrris DM, Ptrie JT, Hespenheide EE. Is NASH underdignosed mong Africn Americns? Am J Gstroenterol 2002; 97: Clrk JM, Brncti FL, Diehl AM. The prevlence nd etiology of elevted minotrnsferse levels in the United Sttes. Am J Gstroenterol 2003; 98: Sundborn G, Metclf PA, Gentles D, Scrgg RK, Schf D, Dyll L, et l. Ethnic differences in crdiovsculr disese risk fctors nd dibetes sttus for Pcific ethnic groups nd Europens in the Dibetes Hert nd Helth Survey (DHAH) Aucklnd New Zelnd. NZ Med J 2008; 121: