Nonalcoholic fatty liver disease

pathogenesis and histological findings, with emphasis on mitochondrial alterations

Authors

  • Gustavo Henrique da Silva Pontifícia Universidade Católica de Campinas
  • Cecilia Amelia Fazzio Escanhoela Pontifícia Universidade Católica de Campinas

Keywords:

Nonalcoholic fatty liver disease , fatty liver , mitochondria, liver, hepatic disease

Abstract

Hepatic steatosis unrelated to alcoholism may occur either by itself or as part of nonalcoholic fatty liver disease. This disease encompasses a wide spectrum of
morphologic alterations, ranging from steatosis to a more severe stage, accompanied by fibrosis, which may lead to cirrhosis. Nonalcoholic fatty liver disease is very important in current clinical practice. First, it has a high prevalence rate, affecting from 15% to 25% of the general population and more than 80% of obese and diabetic patients. Second, there is a diversity of related conditions, such as nutritional factors (malnutrition, total parenteral nutrition), hepatitis C, metabolic disease (Wilson’s disease, glycogenosis, lipodystrophy and others) and drug toxicity (valproate, amiodarone, etc.). Histological changes and the natural history of nonalcoholic fatty liver disease probably reflect a complex multifactorial process in which the genetic environment has considerable importance, since it
is still unknown why some patients have only steatosis while others develop steatohepatitis, cirrhosis or hepatocellular carcinoma. In order to better understand the pathogenesis of nonalcoholic fatty liver disease, there are several articles correlating fatty liver to mitochondrial changes (increase in mitochondrial
size and density, changes in the mitochondrial matrix and cristae as well as the presence of megamitochondria with crystalline inclusions). Early identification of the various forms of steatosis with concomitant mitochondrial changes may have a fundamental importance in the prognosis of the disease. Additionally, microvesicular steatosis, as it relates to these changes, may correspond to early histological damage in NAFLD, with a worse clinical progression of the disease. 

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References

Sokol RJ, Treem WR. Mitochondria and childhood liver diseases. J Pediat Gastroenterol Nut. 1999; 28(1): 4-19.

Mandei H, Hartman C, Berkowitz D, Elpeleg ON, Manov 1, lancu TC. The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies. Hepatology. 2001; 34(4 pt1):776-84.

Bioulac-Sage P, Parrot-Roulaud F, Mazat JP, Lamireau T, Coquet M, Sandler B, et ai. Fatal neonatal liver failure and mitochondrial cytopathy (oxidative phosphorylation deficiency): a light and electron microscopic study of the liver. Hepatology. 1993; 18(4) 839-46

Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et ai. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001; 120(5) 1183-92.

Browning DJ, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin lnvest. 2004; 114(2) 147-52

Zhou YJ, Li YY, Nie YQ, Ma JX, Lu LG, Shi SL, et ai. Prevalence of fatty liver disease and risk factors in the population of South China. World J Gastroenterol. 2007; 13(47):6419-24.

Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology. 2007; 46(2):582-9.

Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol. 2006; 40(1): S5-S1O.

Neuschwander-Tetri B, Caldwell S. Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology. 2003; 37(5) 1202-19.

O. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005; 42(1):44-52

Amarapurkar DN, Hashimoto E, Lesmana LA, Sollano JD, Chen PJ, Goh KL. How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences? J Gastroenterol Hepatol. 2007; 22(6):788-93.

Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, et ai. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol. 2006; 21(1 pt 1):138-43

Bellentani S, Tiribelli C, Saccoccio G, Sodde M, Fratti N, De Martin C, et ai. Prevalence of chronic liver disease in the general population of northern ltaly: the Dionysos Study. Hepatology.1994; 20(6) 1442-9

Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. JPN J Med. 1998; 27(2): 142-9.

Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and the metabolic syndrome. Curr Opin Lipidol. 2005; 16(4):421-7.

Zafrani ES. Non-alcoholic fatty liver disease: an emerging pathological spectrum. Virchows Arch. 2004; 444(1):3-12.

Marion AW, Baker AJ, Dhawan A. Fat liver disease in children. Arch Dis Child. 2004; 89(7):648-52.

Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002; 123(5):1705-25

Day CP, James OF. Hepatic steatosis: innocent bystander or guilty party? Hepatology. 1998; 27(6): 1463-6.

Fromenty B, Pessayre D. lnhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol Ther. 1995; 67(1):101-54.

Oleszczuk A, Spannbauer M, Tannapfel A, Blüher M, Hengstler J, Pietsch UC, et ai. Regenerative capacity differs between micro- and macrovesicular hepatic steatosis. Exp Toxicol Pathol. 2007; 59(3-4):205-13.

Sherlock S. Alcoholic liver disease. Lancet. 1995; 345:227-9.

Bacon BR, Farahvash MJ, Janney CG, Neusschwander­ Tetri BA. Nonalcoholic steatohepatitis: an expanded clinicai entity. Gastroenterology. 1994; 107(4):1103-9.

Reid, AE. Nonalcoholic steatohepatitis. Gastroenterology. 2001; 121(3):710-23.

Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, et ai. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compareci with hepatitis C Hepatology. 2003; 38(2):420-7.

Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology. 1998; 114(4):842-5.

lto K, Kiyosawa N, Kumagai K, Manabe S, Matsunuma N, Yamoto T. Molecular mechanism investigation of cycloheximide-induced hepatocyte apoptosis in rat livers by morphological and microarray analysis. Toxicology. 2006; 219(1-3): 175-86.

Festi D, Colecchia A, Sacco T, Bondi M, Roda E, Marchesini G. Hepatic steatosis in obese patients: clinicai aspects and prognostic significance. Obes Rev. 2004; 5(1):27-42.

Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sei USA. 1997; 94(6):2557-62.

Abdelmalek MF, Diehl A. Mechanisms underlying nonalcoholic steatohepatitis. Drug Discov Today Dis Mech. 2006; 3(4):479-88

Gentile CL, Pagliassotti MJ The role of fatty acids in the development and progression of nonalcoholi

fatty liver disease. J Nutr Biachem. 2008; 19(9) 567-76.

Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Terri BA, Bacon BR. Nonalcoholic steatohepatites a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999; 94(9):2467-74.

Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinicai and pathological severity. Gastroenterology. 1999; 116(6):1413-9

Freitas LAR, Cotrim HP. Esteato-hepatite não alcoólica (NASH). Atlas histológico. Salvador: Nova Agência e Lab. Zambon; 2006.

Treem, RT; Sokol, RJ. Disorders of the mitochondria. Semin Liver Disease. 1998; 18(3):237-53

McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM, Park Y, et ai. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med. 1995; 333(17):1099-105.

Sokol RJ, Treem WR. Mitochondria and childhood liver diseases. J Pediat Gastroenterol Nut. 1999; 28(1): 4-19.

De Vivo DC. Reye syndrome: a metabolic response to na acute mitochondrial insult? Neurology. 1978; 28:105-8.

Mahler H, Pasi A, Kramer JM, Schulte P, Scoging AC, Bar W, et ai. Fulminant liver failure in association with the emetic toxin of Bacillus cereus. N Engl J Med. 1997; 336(16): 1142-8.

lbdah JA, Perlegas P, Zhao Y, Angdisen J, Borgerink H, Shadoan MK, et ai. Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. Gastroenterology. 2005; 128(5):1381-90.

Begriche K, lgoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion. 2006; 6(1):1-28.

Perez-Carreras M, Dei Hoyo P, Martin MA, Rubio JC, Martin A, Castellano G, et ai. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003; 38(4):999-1007.

Cortez-Pinto H, Zhi Lin H, Qi Yang S, Odwin-da-Costa S, Diehl AM. Lipids up-regulate uncoupling protein 2 expression in rat hepatocytes. Gastroenterology. 1999; 116(5):1184-93.

Valeria A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, et ai. TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin lnvest. 2006; 116(1O) 2791-8.

Santamaria E, Avila MA, Latasa MU, Rubio A, Martin-Duce A, Lu se, et ai. Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine. Proc Natl Acad Sei USA. 2003; 100(6):3065-70.

Moraes CT, Shanske S, Tritschler HJ, Aprille JR, Andreetta F, Bonilla E, et ai. MtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am J Hum Genet. 1991; 48(3):492-501.

Morris AA, Taanman JW, Blake J, Cooper JM, Lake BD, Malone M, et ai. Liver failure associated with mitochondrial DNA depletion. J Hepatol. 1998; 28(4): 556-63.

Morris AA. Mitochondrial respiratory chain disorders and the liver. Liver. 1999; 19:357-68.

Hensley K, Kotake Y, Sang H, Pye QN, Wallis GL, Kolker LM, et ai. Dietary choline restriction causes complex 1 dysfunction and increased H(2)O(2) generation in liver mitochondria. Carcinogenesis. 2000; 21(5):983-9.

Berson A, De Beco V, Letteron P, Robin MA, Moreau C , EI Kahwaji J , et ai. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology. 1998; 114(4)

-74.

Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, et ai. Liver specific disruption of PPAR-g in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin lnvest. 2003; 111(5):737-47

Taghibiglou e, Carpentier A, Van lderstine se, Chen B, Rudy D, Aiton A, et ai. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular apoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem. 2000; 275(12):8416-25.

Oleszczuk A, Spannbauer M, Tannapfel A, Blüher M, Hengstler J, Pietsch UC, et ai. Regenerative capacity differs between micro- and macrovesicular hepatic steatosis. Exp Toxicol Pathol. 2007; 59(3-4):205-13.

Ellis AJ, Wendon JA, Portmann B, Williams R. Acute liver damage and ecstasy ingestion. Gut. 1996; 38(3): 454-8.

Fishbein M, Mogren J, Cox S, Jennings R. Undetected hepatomegaly in obese children by primary case physicians: a pitffal in the diagnosis of pediatric nonalcoholic fatty liver disease. Clin Pediatr. 2005; 44(2):135-41

Silva GH, Coelho KIR, Coelho CAR, Escanhoela CAF. Mitochondrial alterations in nonalcoholic fatty liver disease (NAFLD). Pediatric case description of 3 (three) submitted sequential biopsies. J Gastroenterol Liver Dis. 2009; 18(2):21.

Published

2009-12-31

How to Cite

Silva, G. H. da, & Escanhoela, C. A. F. (2009). Nonalcoholic fatty liver disease: pathogenesis and histological findings, with emphasis on mitochondrial alterations. Revista De Ciências Médicas, 18(5/6). Retrieved from https://seer.sis.puc-campinas.edu.br/cienciasmedicas/article/view/626

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