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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #82
Carol Rees Parrish, R.D., M.S., Series Editor Nutritional Recommendations
for Patients with Non-Alcoholic
Fatty Liver Disease:
An Evidence Based Review
Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of liver disorders due to
abnormal fat deposition in the liver. These range histopathologically from simple steato-
sis to steatohepatitis (NASH) which can progress to cirrhosis and end stage liver disease.
NAFLD is the most common cause of chronic liver disease in the developed world and is
generally a component of the underlying “metabolic syndrome.” It is likely to emerge as
the most common cause of liver disease associated mortality in the next decade. Cur-
rently, there is no specific drug therapy approved for the treatment of this condition.
This article reviews the role of weight loss measures and nutritional supplements such
as antioxidants and n-3 polyunsaturated fatty acids in the treatment of NAFLD.
INTRODUCTION
trum of liver disorders occurring due to abnormal fat Non-alcoholic fatty liver disease (NAFLD) is the deposition in the liver, which ranges in severity from
most common cause of chronic liver disease in simple hepatic steatosis with no inflammation, to the developed world (1). NAFLD refers to a spec- steatohepatitis (NASH) which can progress to liver cir-rhosis. The diagnosis of NAFLD by definition impliesthe exclusion of significant alcohol intake (i.e., >140gm/week in men; >70 gm/week in women). Histologi- Ashutosh S.Naniwadekar, M.B.B.S, M.S., Fellow,Division of Gastroenterology, Hepatology and Nutri- cally, it is characterized by a spectrum of findings rang- tion, Department of Internal Medicine, Virginia Com- ing from macrovesicular steatosis alone, mixed portal monwealth University Medical Center, Richmond, VA.
and lobular inflammation of varying degrees, balloon- PRACTICAL GASTROENTEROLOGY • FEBRUARY 2010
Nutritional Recommendations for Patients
NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #82
ing degeneration of hepatocytes with perisinusoidal PATHOGENESIS OF NAFLD
deposition of collagen, and finally full blown cirrhosis Excess energy intake and obesity, in combination with (2,5). Recent epidemiologic studies support the role of different genetic and environmental factors, can lead antecedent NASH in causing about two-thirds to three- to the development of insulin resistance. A combina- fourths of all cryptogenic cirrhosis cases (3). tion of insulin resistance, along with excess accumula- NAFLD is generally found as a component of the tion of free fatty acids (FFA) and increased “metabolic syndrome” which is characterized by cen- intracellular formation of toxic lipid metabolites (such tral obesity, hypertension, hyperlipedemia, and as products of lipid peroxidation), is thought to elicit impaired glucose tolerance. Up to 90% of patients with an inflammatory response that triggers the progression NAFLD have at least one of these features (4). The to NASH. The accumulation of triglycerides them- incidence of NAFLD and NASH in the general popu- selves in the hepatocytes is merely a marker for the lation varies widely depending on the test used to diag- deranged lipid metabolism and indicates increased nose it. Liver biopsy remains the gold standard of lipid trafficking (12). Since lipotoxicity is thought to diagnosis. However, different tests, including liver be a major player in the pathogenesis, both dietary enzymes (AST, ALT) and imaging (liver ultrasound, modifications and exercise seem theoretically the best MR spectroscopy), have been used. Studies looking at options for preventing the progression to NASH and the Third National Health and Nutrition Examination for management of NASH once it develops. This Survey (NHANES III) using AST and ALT as criteria review focuses on the nutritional interventions that can for NAFLD (after excluding alcohol and hepatitis B, C potentially make a difference in the management of as causes) found a prevalence of 5.4% in the U.S pop- ulation (6,7). However, liver enzymes have beenshown to be non-specific and poorly sensitive forchronic liver disease (8). Use of liver ultrasound to DIETARY MODIFICATIONS AND
diagnose hepatic steatosis has shown a prevalence of LIFESTYLE CHANGES IN NAFLD
NAFLD ranging from 57–75% in obese, non-drinking Several studies have shown beneficial effects of patients (9). Use of MR spectroscopy in a large multi- dietary modification, weight loss and exercise in ethnic patient population shows a prevalence of reducing insulin resistance and in normalization of NAFLD of 34% in the general population with major ALT in patients with NAFLD (13–20). However, only a few studies have evaluated histological improvementin NAFLD based on biopsy results (14,19,20). NATURAL HISTORY OF NAFLD
One of the best studies to date looking at the naturalhistory of NAFLD in the general population was donein the Mayo Clinic by Adams et al. A total of 420 patients in Olmstead County, Rochester, diagnosed Diet Trials in NAFLD
with NAFLD, using imaging or with a liver biopsy,were followed for a median period of 7 years. Twenty- • Daily 600–800 calorie intake reduction (13) one patients (5%) developed cirrhosis during this • Restriction of caloric intake to <25 kcals/kg/day of period, and thirteen (3.1%) developed complications of cirrhosis, including two patients who developed • Restriction of total dietary fat content to <30% of the hepatocellular cancer (11). Even though only a minor- caloric intake with <10% of the caloric intake from ity (<10%) of patients with NAFLD develop cirrhosis • Restriction of caloric intake to <30 kcals/kg/day (18) and end stage liver disease, the sheer numbers of • Low calorie/low carbohydrate(40–45% of caloric patients who have NAFLD in the general population make this a significant health care concern.
PRACTICAL GASTROENTEROLOGY • FEBRUARY 2010
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Different diets have all documented a normaliza- weight reduction program, showed that a higher per- tion of the ALT levels 1–3 months after initiation of centage of patients receiving orlistat with reduced ALT dietary changes (see Table 1). At least three studies on levels (48% in orlistat group vs. 26% in placebo).
weight loss in NAFLD patients (14,19,20) have docu- There was a statistically significant reduction in fatty mented histologic improvement in steatosis and liver by ultrasound in the orlistat group compared to inflammation with biopsies, including one in children placebo. This was despite a similar reduction in BMI (20). Studies comparing the efficacy of different types of diets (i.e., traditional low fat vs. calorie restriction In the largest meta-analysis looking at the use of with low carbohydrate diet) in producing weight loss orlistat in obese patients, a total of 16 clinical trials with have not been able to prove the superiority of one over 10,631 patients were identified (29). Orlistat improved the other. However, none of these studies have looked blood pressure and glycemic control, decreased LDL and total cholesterol levels, and reduced the incidence Of interest, all studies support the fact that even of diabetes, and produced a mean weight reduction of small degrees of weight loss of around 5–10% of the 2.9 kg compared to the placebo group when followed total body weight show a clear benefit. This seems to for one year (29). However, NAFLD was not specifi- indicate that changes in the amount of fat delivery to the liver related to dietary fats and the subsequent Orlistat should therefore be considered in obese alterations in lipid metabolism are as important as the patients with NAFLD, particularly when they fail to actual weight loss (19). This would be an important lose weight, despite an adequate program of nutritional point for clinicians to emphasize to NAFLD patients during weight loss counseling, as the weight loss itselfis just one of the goals of the intervention. There is concern that very rapid weight loss (gen- ANTIOXIDANTS IN NAFLD
erally >1.6 kg/week) may cause worsening of the A recently published Cochrane database meta-analysis inflammation with NASH, and thereby accelerate pro- looked at six trials which used a combination of gression of the disease by drastically increasing vis- different antioxidants including selenium, vitamin C ceral adipose tissue breakdown and delivery to the and vitamin E to evaluate their effects on the progres- sion of NAFLD. It concluded that there was insuffi- All of the above studies combined dietary changes cient evidence to support or refute a role for these in with aerobic exercise in varying intervals and varying NAFLD patients (30). Another recently published levels of supervision. No studies looking at exercise study looked at the effects of lifestyle changes and alone without the confounding effect of weight loss weight loss with or without the use of vitamin C and E in 53 children with NAFLD. The authors showedthat a mean weight loss of around 4.7 kg produced sig-nificant histologic improvement in the degree of ROLE OF ORLISTAT IN AUGMENTING
steatosis, lobular inflammation and ballooning degen- WEIGHT LOSS IN NAFLD PATIENTS:
eration in hepatocytes as determined by a liver biopsy Orlistat is an inhibitor of gastric and pancreatic lipase, at 24 months of treatment. The study showed no addi- which reduces the absorption of long chain fatty acids tional effect of using vitamin C or E over weight loss and cholesterol by approximately 30%, with the unab- sorbed fat excreted in the stool. Four published studies Betaine is a methyl group donor which increases have shown the benefit of adding orlistat in obese the hepatic S-adenosyl-methionine levels and thereby patients with NAFLD (25–28). A double blind, may help combat oxidative stress in the liver. A recent placebo controlled study with 44 patients randomized randomized controlled trial looking at the effect of to either receive orlistat 120 mg thrice daily or placebo daily betaine supplementation in patients with NASH for six months, with all patients undergoing a similar failed to show a clear benefit (31).
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n-3 POLYUNSATURATED FATTY ACIDS
(n-3 PUFA) AND NAFLD
Practical Recommendations for Management of NAFLD
Animal studies have shown that n-3 PUFA enricheddiets reduce hepatic triglyceride content and the devel- 1. Nutritional counseling and appropriate follow-up opment of steatohepatitis (45). The benefit is thought with a dietitian is the first line of therapy with spe- to be due to the modulation of lipid processing by n-3 cific emphasis on the role of daily exercise/activity.
PUFA’s by acting as ligands of the peroxisome prolif- 2. Walking or some form of daily aerobic exercise at least 30–45 minutes daily is encouraged.
erator-activated receptor α (PPARα) and reducing 3. No clear evidence to recommend the traditional low hepatic inflammation and oxidative stress (32). fat vs. the newer high fat, low carbohydrate diets. The first clinical trial studying the role of n-3 4. Losing even 5–10% of total body weight can be PUFA in NAFLD was published in 2006 by Capanni et sufficient to create a significant improvement in al (33). Both biochemical (ALT, GGT) and ultrasound NAFLD and metabolic syndrome in general.
improvement in NAFLD was shown in the 42 patients 5. Avoid excessively rapid weight loss (>1.6 kg/week), who received 1 gm n-3 PUFA daily over a period of 12 as it may increase the progression of NAFLD.
months. Another larger study evaluated a total of 134 6. Careful attention to the management of the accom- patients randomized to a control group (which received panying metabolic syndrome—hyperlipidemia, heart a calorie restricted diet and placebo) and a study group (which received the recommended diet and 2 gm thrice 7. Morbidly obese patients (BMI >40 or BMI >35 with daily of n-3 PUFA). The authors showed a 53% reduc- co-morbidities) should be considered for referral forbariatric surgery.
tion in fatty liver in those patients receiving n-3 PUFA 8. n-3 PUFA appear to be encouraging as potential compared to 35% in patients receiving dietary manage- treatment for NAFLD, but further studies are needed ment alone (34). Similar biochemical and imaging improvement in NAFLD was seen in two more studies 9. Trial of orlistat in patients failing diet therapy.
using n-3 PUFA (35,36). No adverse events were 10. Avoid foods with HFCS and trans-fats.
reported in any of these studies. n-3 PUFA may have arole in the management of NAFLD, but more studiesare needed to confirm its benefit and define dosing andduration of administration.
isocaloric diet for 7 days, showed an increase in hepaticfat deposition as assessed by MR spectroscopy (40). Trans-fatty acids (TFA) have been shown to be HIGH FRUCTOSE CORN SYRUP
associated with obesity, insulin resistance and coro- AND TRANS-FATTY ACIDS IN NAFLD
nary artery disease (41). Animal studies have docu- High fructose corn syrup (HFCS) is a common sweet- mented the role of TFA in the pathogenesis of NAFLD ener in soft drinks and fruit drinks. Currently the aver- and NASH (42,43). However, no human studies look- age American consumes 12% of the total energy intake ing at the association of NAFLD and trans-fats have as fructose, primarily as HFCS (38). Porikos et al showed transaminase elevations in healthy people con-suming 25% of their calories in the form of sucrosewhich contains 50% fructose (37). A recent study com- ROLE OF BARIATRIC SURGERY
paring the dietary patterns of 49 patients with NAFLD IN PATIENTS WITH NAFLD
to 24 control patients with other types of chronic liver The most studied intervention in obese patients for disease, found a two fold higher consumption of HFCS weight loss is the use of bariatric surgery. The National in patients with NAFLD (365 kcal vs. 170 kcal) (39).
Institutes of Health (NIH) guidelines recommend Another crossover study with 16 healthy males (with bariatric surgery for obese patients with a BMI >40 history of diabetes in parents) and 8 controls who kg/m2 or >35 kg/m2 for patients with significant co- received either a high calorie and high fructose diet or a morbidities such as heart disease, diabetes or obstruc- PRACTICAL GASTROENTEROLOGY • FEBRUARY 2010
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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #82
tive sleep apnea (44). Currently, the common bariatric References
surgical procedure is the Roux-en-Y gastric bypass 1. Matteoni CA, Younossi ZM, Gramlich T, et al: Nonalcoholic fatty liver disease: a spectrum of clinical and pathological sever- (RYGB). A recent large meta-analysis of the effect of ity. Gastroenterology 1999;116:1413–9.
bariatric surgery on NAFLD and NASH included 15 2. Clark JM: The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 2006;40(Suppl 1):S5–10 studies with 766 total paired liver biopsies. A signifi- 3. Maheshwari A, Thuluvath PJ: Cryptogenic cirrhosis and cant improvement in steatosis was observed in 91%; NAFLD: are they related? Am J Gastroenterol 2006;101:664–8.
steatohepatitis improved in 81%; and fibrosis improved 4. Marchesini G, Bugianesi E, Forlani G, et al: Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology in 65% of the patients (45). This is in addition to the already well documented salutary effect of bariatric 5. Brunt EM: Nonalcoholic steatohepatitis: definition and pathol- ogy. Semin Liver Dis. 2001;21:3–16.
surgery on reducing mortality and morbidity from car- 6. Clark JM, Brancati FL, Diehl AM: Nonalcoholic fatty liver dis- diovascular disease and diabetes (46). Approximately ease: the most common cause of abnormal liver enzymes in the 1–3% of patients undergoing bariatric surgery already U.S. population. Gastroenterology 2001;120(suppl 1):A65.
7. Clark JM, Brancati FL, Diehl AM: Nonalcoholic fatty liver dis- have cirrhosis (47). Patients with advanced fibrosis or ease. Gastroenterology 2002;122:1649–1657.
compensated cirrhosis may also receive some benefit 8. Mofrad P, Contos MJ, Haque M: Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT from bariatric surgery, but there is also a significant risk values. Hepatology 2003;37:1286–1292.
of decompensation with the surgery (48). Bariatric 9. Bellentani S, Saccoccio G, Masutti F, et al: Prevalence of and risk surgery as an option has not been studied in patients factors for hepatic steatosis in Northern Italy. Ann Intern Med.
2000;132:112–117.
with NASH or fibrosis who do not have a BMI >40 (or 10. Browning JD, Szczepaniak LS, Dobbins R et al: Prevalence of >35 with co-morbidities). More data will be needed hepatic steatosis in an urban population in the United States:impact of ethnicity. Hepatology 2004;40:1387–1395.
prior to making a recommendation for surgical inter- 11. Adams LA, Lymp JF, St Sauver J et al: The natural history of non-alcoholic fatty liver disease: a population-based cohort study.
Gastroenterology 2005; 129: 113–21.
12. Cusi, K: Role of Insulin Resistance and Lipotoxicity in Non- Alcoholic Steatohepatitis . Clin Liver Dis 2009;13:545–563.
CONCLUSIONS
13. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology NAFLD represents the most common cause of chronic liver disease in the developed world. Progression of 14. Ueno T, Sugawara H, Sujaku K, et al: Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J benign steatosis to steatohepatitis, and finally, cirrho- sis makes it likely to emerge as the major cause of liver 15. Kugelmas M, Hill DB, Vivian B, et al: Cytokines and NASH: a disease related mortality in the next decade. Unfortu- pilot study of the effects of lifestyle modification and vitamin E.
Hepatology 2003;38:413–9.
nately, drug therapy for NAFLD is not currently avail- 16. Schafer S, Kantartzis K, Machann J, et al: Lifestyle intervention able and management must focus on treatment of the in individuals with normal versus impaired glucose tolerance. EurJ Clin Invest 2007;37(7):535–43.
“metabolic syndrome” rather than NAFLD as an indi- 17. Hickman IJ, Jonsson JR, Prins JB, et al: Modest weight loss and vidual entity. This entails an important challenge in physical activity in overweight patients with chronic liver diseaseresults in sustained improvements in alanine aminotransferase, educating clinicians in the recognition of this disease fasting insulin, and quality of life. Gut 2004;53(3):413–9.
and initiation of appropriate interventions targeted at 18. Vajro P, Mandato C, Franzese A, et al: Vitamin E treatment in weight loss in close consultation with a dietitian. There pediatric obesity-related liver disease: a randomized study. JPediatr Gastroenterol Nutr 2004;38(1):48–55.
is enough evidence documenting the salutary effect of 19. Huang MA, Greenson JK, Chao C, et al: One-year intense nutri- weight loss in not only reducing the steatosis and tional counseling results in histological improvement in patientswith nonalcoholic steatohepatitis: a pilot study. Am J Gastroen- inflammation, but also in some cases reversing the fibrosis seen with advanced disease. Patients who do 20. Nobili V, Manco M, Devito R, et al: Lifestyle intervention and not respond well to targeted nutritional intervention antioxidant therapy in children with nonalcoholic fatty liver dis-ease: a randomized, controlled trial. Hepatology 2008; 48(1): can be candidates for using orlistat to augment weight loss. The use of n-3 PUFA is emerging as an encour- 21. Samaha FF, Iqbal N, Seshadri P, et al: A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med aging new treatment adjunct. Patients who meet crite- ria for bariatric surgery should be appropriatelyreferred for such procedures. n PRACTICAL GASTROENTEROLOGY • FEBRUARY 2010
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22. Stern L, Iqbal N, Seshadri P, et al: The effects of low carbohy- and without a family history of type 2 diabetes. Am J Clin Nutr drate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. Ann Intern Med 41. Zaloga GP, Harvey KA, Stillwell W: Trans fatty acids and coro- nary heart disease. Nutr Clin Pract. 2006, 21(5): 505-12.
23. Dansinger ML, Gleason JA, Griffith JL, et al: Comparison of the 42. Tetri LH, Basaranoglu M, Brunt EM, et al: Severe NAFLD with Atkins, Ornish, Weight Watchers, and Zone diets for weight loss hepatic necroinflammatory changes in mice fed trans fats and a and heart disease risk reduction: a randomized trial. JAMA high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 2008; 295:G987–G995.
24. Andersen T, Gluud C, Franzmann MB, et al: Hepatic effects of 43. Koppe SWP, Elias M, Moseley RH, Green RM. Trans fat feeding dietary weight loss in morbidly obese subjects. J Hepatol results in higher serum alanine aminotransferase and increased insulin resistance compared with a standard murine high-fat diet.
25. Harrison SA, Fincke C, Helinski D, et al: A pilot study of orlistat Am J Physiol Gastrointest Liver Physiol 2009; 297:G378–G384.
treatment in obese, non-alcoholic steatohepatitis patients. Aliment 44. NIH conference. Gastrointestinal surgery for severe obesity. Con- Pharmacol Ther 2004;20:623–628.
sensus Development Conference Panel. Ann Intern Med 26. Hatzitolios A, Savopoulos C, Lazaraki G, et al: Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic 45. Mummadi RR, Kasturi KS, Chennareddygari S, et al: Effect of fatty liver disease with dyslipidemia. Indian J Gastroenterol bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008; 27. Sabuncu T, Nazligul Y, Karaoglanoglu M, et al: The effects of sibutramine and orlistat on the ultrasonographic findings, insulin 46. Adams TD, Gress RE, Smith SC, et al: Long-term mortality after resistance and liver enzyme levels in obese patients with non- gastric bypass surgery. N Engl J Med 2007;357:753–61.
alcoholic steatohepatitis. Rom J Gastroenterol 2003;12:189–192.
47. Brolin RE, Bradley LJ, Taliwal RV: Unsuspected cirrhosis dis- 28. Zelber-Sagi S, Kessler A, Brazowsky E, et al: A double-blind covered during elective obesity operations. Arch Surg randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 48. Kral JG, Thung SN, Biron S, et al: Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery 29. Rucker D, Padwal R, Li SK, et al: Long term pharmacotherapy for obesity and overweight: updated meta-analysis.BMJ2007;335(7631):1194-9.
30. Lirussi F, Azzalini L, Orando S, et al: Antioxidant supplements for non-alcoholic fatty liver disease and/or steatohepatitis.
Cochrane Database Syst Rev 2007;1: CD004996.
PRACTICAL
31. Abdelmalek M, Schuyler O, Angulo P, et al: Betaine for Nonal- coholic Fatty Liver Disease: Results of a Randomized Placebo-Controlled Trial. Hepatology 2009; Epub GASTROENTEROLOGY
32. Reddy JK: Nonalcoholic steatosis and steatohepatitis. III. Perox- isomal beta-oxidation, PPAR alpha, and steatohepatitis. Am JPhysiol Gastrointest Liver Physiol 2001;281(6): G1333–9.
R E P R I N T S
33. Capanni M, Calella F, Biagini MR, et al: Prolonged n-3 polyun- saturated fatty acid supplementation ameliorates hepatic steatosisin patients with non-alcoholic fatty liver disease: a pilot study.
Practical Gastroenterology reprints are valuable, Aliment Pharmacol Ther 2006;23:1143–1151.
34. Zhu FS, Liu S, Chen XM, et al: Effects of n-3 polyunsaturated authoritative, and informative. Special rates fatty acids from seal oils on nonalcoholic fatty liver disease asso-ciated with hyperlipidemia. World J Gastroenterol 2008; are available for quantities of 100 or more.
35. Spadaro L, Magliocco O, Spampinato D, et al: Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fattyliver disease. Dig Liver Dis 2008;40:194–199.
For further details on rates or to place an order: 36. Andrea J. Cussons, Gerald F. Watts, Trevor A. Mori, et al: Omega-3 Fatty Acid Supplementation Decreases Liver Fat Con-tent in Polycystic Ovary Syndrome: A Randomized Controlled Trial Employing Proton Magnetic Resonance Spectroscopy. JClin Endocrinol Metab 2009;94(10):3842–3848.
37. Porikos KP, Van Itallie TB: Diet induced changes in serum transaminases and triglyceride levels in healthy men. Role of sucrose and excess calories. Am J Med 1983;75:624–630.
38. Havel PJ: Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev2005;63:133–157.
39. Ouyang X, Cirillo P, Sautin Y, et al: Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. www.practicalgastro.com
40. Le K, Ith M, Kreis R, et al: Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with PRACTICAL GASTROENTEROLOGY • FEBRUARY 2010

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