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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

The pathogenesis of alcoholic liver disease is complex and still remains unclear, the metabolites of the oxidative metabolism in the liver; acetaldehyde and reactive oxygen species are thought to be involved in the toxic effects of ethanol on the liver.[1]

Pathophysiology

Pathogenesis

  • Ethanol metabolism in the liver is carried out mainly by two enzymes; alcohol dehydrogenase and aldehyde dehydrogenase. Both of these enzymes use NAD+ as a cofactor. Alcohol is converted to acetaldehyde and acetaldehyde is then further oxidized to acetate. Acetaldehyde is the toxic metabolite in this process.[1]
  • The metabolism of alcohol in the liver ends up producing an excess of reduced nicotinamide adenine dinucleotide(NADH). This changes the reduction-oxidation potential in the liver and inhibits key metabolic processes in the liver such as, the tricarboxylic acid cycle and the oxidation of fatty acids and thereby ends up promoting lipogenesis.[2]
  • Since acetaldehyde has an electrophilic nature it can form covalent chemical bonds with proteins, lipids and DNA. These covalent bonds that are formed are extremely pathogenic, as they have the ability to alter cell environments, protein structures and they can enable DNA damage and mutation.[3][4][5][6][7][8][9][10]
  • The cytochrome P450 enzymes(CYP) are a part of the microsomal ethanol oxidizing system. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.[11]
  • There is an ethanol inducible form of CYP enzymes that is working in a small amount under normal physiological conditions. This enzyme CYP2E1 is converting ethanol to acetaldehyde and then to acetate. When there is chronic alcohol abuse, there is induction of the microsomal system and there is an increase in the expression of CYP2E1. This increase in CYP2E1 expression under chronic ethanol consumption can be hazardous, as this oxidation reaction can produces many different ROS; O2-, H2O2, OH- and hydroxyethyl radical (HER).[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]





Genetics

  • [Disease name] is transmitted in [mode of genetic transmission] pattern.
  • Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
  • The development of [disease name] is the result of multiple genetic mutations.

Associated Conditions

Gross Pathology

  • On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

  • On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

References

  1. ↑ 1.0 1.1 Ceni E, Mello T, Galli A (2014). "Pathogenesis of alcoholic liver disease: role of oxidative metabolism". World J. Gastroenterol. 20 (47): 17756–72. doi:10.3748/wjg.v20.i47.17756. PMC 4273126. PMID 25548474.
  2. ↑ You M, Crabb DW (2004). "Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver". Am. J. Physiol. Gastrointest. Liver Physiol. 287 (1): G1–6. doi:10.1152/ajpgi.00056.2004. PMID 15194557.
  3. ↑ Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR (2005). "Recent advances in alcohol-induced adduct formation". Alcohol. Clin. Exp. Res. 29 (7): 1310–6. PMID 16088993.
  4. ↑ Niemelä O (2007). "Acetaldehyde adducts in circulation". Novartis Found. Symp. 285: 183–92, discussion 193–7. PMID 17590995.
  5. ↑ Tuma DJ (2002). "Role of malondialdehyde-acetaldehyde adducts in liver injury". Free Radic. Biol. Med. 32 (4): 303–8. PMID 11841919.
  6. ↑ Tuma DJ, Casey CA (2003). "Dangerous byproducts of alcohol breakdown--focus on adducts". Alcohol Res Health. 27 (4): 285–90. PMID 15540799.
  7. ↑ Brooks PJ, Theruvathu JA (2005). "DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis". Alcohol. 35 (3): 187–93. doi:10.1016/j.alcohol.2005.03.009. PMID 16054980.
  8. ↑ Seitz HK, Becker P (2007). "Alcohol metabolism and cancer risk". Alcohol Res Health. 30 (1): 38–41, 44–7. PMC 3860434. PMID 17718399.
  9. ↑ Biewald J, Nilius R, Langner J (1998). "Occurrence of acetaldehyde protein adducts formed in various organs of chronically ethanol fed rats: an immunohistochemical study". Int. J. Mol. Med. 2 (4): 389–96. PMID 9857222.
  10. ↑ Seitz HK, Meier P (2007). "The role of acetaldehyde in upper digestive tract cancer in alcoholics". Transl Res. 149 (6): 293–7. doi:10.1016/j.trsl.2006.12.002. PMID 17543846.
  11. ↑ Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV (1987). "Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans". Biochem. Soc. Trans. 15 (4): 576–8. PMID 3678578.
  12. ↑ Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV (1987). "Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans". Biochem. Soc. Trans. 15 (4): 576–8. PMID 3678578.
  13. ↑ Lieber CS (1972). "Metabolism of ethanol and alcoholism: racial and acquired factors". Ann. Intern. Med. 76 (2): 326–7. PMID 5009602.
  14. ↑ Lieber CS, DeCarli LM (1972). "The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo". J. Pharmacol. Exp. Ther. 181 (2): 279–87. PMID 4402282.
  15. ↑ Lieber CS (1997). "Cytochrome P-4502E1: its physiological and pathological role". Physiol. Rev. 77 (2): 517–44. PMID 9114822.
  16. ↑ Hansson T, Tindberg N, Ingelman-Sundberg M, Köhler C (1990). "Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system". Neuroscience. 34 (2): 451–63. PMID 2333153.
  17. ↑ Donohue TM, Cederbaum AI, French SW, Barve S, Gao B, Osna NA (2007). "Role of the proteasome in ethanol-induced liver pathology". Alcohol. Clin. Exp. Res. 31 (9): 1446–59. doi:10.1111/j.1530-0277.2007.00454.x. PMID 17760783.
  18. ↑ Osna NA, Donohue TM (2007). "Implication of altered proteasome function in alcoholic liver injury". World J. Gastroenterol. 13 (37): 4931–7. PMC 4434615. PMID 17854134.
  19. ↑ Lu Y, Cederbaum AI (2008). "CYP2E1 and oxidative liver injury by alcohol". Free Radic. Biol. Med. 44 (5): 723–38. doi:10.1016/j.freeradbiomed.2007.11.004. PMC 2268632. PMID 18078827.
  20. ↑ Yun YP, Casazza JP, Sohn DH, Veech RL, Song BJ (1992). "Pretranslational activation of cytochrome P450IIE during ketosis induced by a high fat diet". Mol. Pharmacol. 41 (3): 474–9. PMID 1545775.
  21. ↑ Raucy JL, Lasker JM, Kraner JC, Salazar DE, Lieber CS, Corcoran GB (1991). "Induction of cytochrome P450IIE1 in the obese overfed rat". Mol. Pharmacol. 39 (3): 275–80. PMID 2005876.
  22. ↑ Woodcroft KJ, Hafner MS, Novak RF (2002). "Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression". Hepatology. 35 (2): 263–73. doi:10.1053/jhep.2002.30691. PMID 11826398.
  23. ↑ De Waziers I, Garlatti M, Bouguet J, Beaune PH, Barouki R (1995). "Insulin down-regulates cytochrome P450 2B and 2E expression at the post-transcriptional level in the rat hepatoma cell line". Mol. Pharmacol. 47 (3): 474–9. PMID 7700245.
  24. ↑ Peng HM, Coon MJ (1998). "Regulation of rabbit cytochrome P450 2E1 expression in HepG2 cells by insulin and thyroid hormone". Mol. Pharmacol. 54 (4): 740–7. PMID 9765518.
  25. ↑ Terelius Y, Norsten-Höög C, Cronholm T, Ingelman-Sundberg M (1991). "Acetaldehyde as a substrate for ethanol-inducible cytochrome P450 (CYP2E1)". Biochem. Biophys. Res. Commun. 179 (1): 689–94. PMID 1822117.
  26. ↑ Wu YS, Salmela KS, Lieber CS (1998). "Microsomal acetaldehyde oxidation is negligible in the presence of ethanol". Alcohol. Clin. Exp. Res. 22 (5): 1165–9. PMID 9726291.
  27. ↑ Brooks PJ (1997). "DNA damage, DNA repair, and alcohol toxicity--a review". Alcohol. Clin. Exp. Res. 21 (6): 1073–82. PMID 9309320.

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