Alcoholic liver disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]
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.
Pathophysiology
Pathogenesis
- Ethanol metabolism in the liver is carried out mainly by two enzymes:[1]
- 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.
- 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]
- Ethanol metabolism additionally promotes lipogenesis through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound transcription factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.[28][29][30]
- Two key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are:[31][32]
- Endotoxin is associated to the lipopolysaccharide (LPS) component of the outer wall of gram-negative bacteria and is thought to be the key trigger in this inflammatory process.[33][34]
- Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation.[35][36]
- The fact that long term exposure to alcohol increases gut permeability has been observed in humans as LPS-endotoxin levels have been found to be elevated in patients with alcoholic liver injury.[37]
- After the entry of LPS-endotoxin in to the portal circulation it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to alcohol ingestion.[38]
- The LPS-LPS binding protein complex binds to the CD14 receptor on the cell surface membrane of the Kupffer cells in the liver.
- Activation of these Kupffer cells requires 3 main cellular proteins:[39]
- The TLR4 then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.[42]
- The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells.[43]
- EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production.
- In mice the absence of EGR1 prevents alcohol induced liver injury.[44]
- Ethanol administration stimulates the release of mitochondrial cytochrome c and the expression of the Fas ligand, this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway.[45]
- The cumulative effect of TNF-α and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the liver.[46]
Genetics
- Susceptibility to alcoholic liver disease could be determined by functional polymorphisms in the ADH2 gene.[47][48]
- Polymorphism at position -238 of the TNF-α promoter region.[49][50]
Associated Conditions
Conditions associated with alcoholic liver disease include:[1][51]
- Obesity
- Chronic viral hepatitis
- Iron overload
- Cirrhosis
- Hepatocellular carcinoma
Gross Pathology
- On gross pathology, characteristic findings of alcoholic liver disease include:[52]
- Hepatomegaly
- Nodules
- Macronodules
- Micronodules
- Firm in consistency
- Portal vein dilation
Microscopic Pathology
On microscopic histopathological analysis characteristic findings of alcoholic liver disease include:[53][54][55][56][57][58][59][60]
- Non-cirrhotic liver
- Steatosis
- Macrovesicular steatosis - the cytoplasm of hepatocytes is occupied by large lipid droplets that end up displacing the nucleus and other organelles peripherally
- Proliferation of the smooth endoplasmic reticulum
- Distortion of the mitochondria (giant mitochondria)
- Hepatocyte balooning (Mallory-Denk bodies)
- Steatosis
- Cirrhotic liver:
- Fibrous septae that are made up of collagen surrounding the hepatocytes which results in pseudo lobule formation.
- This produces a nodular appearance of the liver and then progresses from micro nodular to macro nodular cirrhosis with time.
- Proliferation of the bile ducts may also be seen.
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Niemelä O (2007). "Acetaldehyde adducts in circulation". Novartis Found. Symp. 285: 183–92, discussion 193–7. PMID 17590995.
- ↑ Tuma DJ (2002). "Role of malondialdehyde-acetaldehyde adducts in liver injury". Free Radic. Biol. Med. 32 (4): 303–8. PMID 11841919.
- ↑ Tuma DJ, Casey CA (2003). "Dangerous byproducts of alcohol breakdown--focus on adducts". Alcohol Res Health. 27 (4): 285–90. PMID 15540799.
- ↑ 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.
- ↑ Seitz HK, Becker P (2007). "Alcohol metabolism and cancer risk". Alcohol Res Health. 30 (1): 38–41, 44–7. PMC 3860434. PMID 17718399.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Lieber CS (1972). "Metabolism of ethanol and alcoholism: racial and acquired factors". Ann. Intern. Med. 76 (2): 326–7. PMID 5009602.
- ↑ 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.
- ↑ Lieber CS (1997). "Cytochrome P-4502E1: its physiological and pathological role". Physiol. Rev. 77 (2): 517–44. PMID 9114822.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Brooks PJ (1997). "DNA damage, DNA repair, and alcohol toxicity--a review". Alcohol. Clin. Exp. Res. 21 (6): 1073–82. PMID 9309320.
- ↑ Fischer M, You M, Matsumoto M, Crabb DW (2003). "Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice". J. Biol. Chem. 278 (30): 27997–8004. doi:10.1074/jbc.M302140200. PMID 12791698.
- ↑ You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW (2004). "The role of AMP-activated protein kinase in the action of ethanol in the liver". Gastroenterology. 127 (6): 1798–808. PMID 15578517.
- ↑ Ji C, Chan C, Kaplowitz N (2006). "Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model". J. Hepatol. 45 (5): 717–24. doi:10.1016/j.jhep.2006.05.009. PMID 16879892.
- ↑ Tsukamoto H, Reidelberger RD, French SW, Largman C (1984). "Long-term cannulation model for blood sampling and intragastric infusion in the rat". Am. J. Physiol. 247 (3 Pt 2): R595–9. PMID 6433728.
- ↑ Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG (2001). "Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice". Hepatology. 34 (1): 101–8. doi:10.1053/jhep.2001.25350. PMID 11431739.
- ↑ Wiest R, Garcia-Tsao G (2005). "Bacterial translocation (BT) in cirrhosis". Hepatology. 41 (3): 422–33. doi:10.1002/hep.20632. PMID 15723320.
- ↑ Nanji AA, Khettry U, Sadrzadeh SM (1994). "Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease)". Proc. Soc. Exp. Biol. Med. 205 (3): 243–7. PMID 8171045.
- ↑ Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG (1995). "Antibiotics prevent liver injury in rats following long-term exposure to ethanol". Gastroenterology. 108 (1): 218–24. PMID 7806045.
- ↑ Bjarnason I, Peters TJ, Wise RJ (1984). "The leaky gut of alcoholism: possible route of entry for toxic compounds". Lancet. 1 (8370): 179–82. PMID 6141332.
- ↑ Urbaschek R, McCuskey RS, Rudi V, Becker KP, Stickel F, Urbaschek B, Seitz HK (2001). "Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease". Alcohol. Clin. Exp. Res. 25 (2): 261–8. PMID 11236841.
- ↑ Uesugi T, Froh M, Arteel GE, Bradford BU, Wheeler MD, Gäbele E, Isayama F, Thurman RG (2002). "Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice". J. Immunol. 168 (6): 2963–9. PMID 11884468.
- ↑ Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG (1994). "Inactivation of Kupffer cells prevents early alcohol-induced liver injury". Hepatology. 20 (2): 453–60. PMID 8045507.
- ↑ Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG (2001). "Reduced early alcohol-induced liver injury in CD14-deficient mice". J. Immunol. 166 (7): 4737–42. PMID 11254735.
- ↑ Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G (2008). "The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88". Hepatology. 48 (4): 1224–31. doi:10.1002/hep.22470. PMID 18792393.
- ↑ Akira S, Takeda K, Kaisho T (2001). "Toll-like receptors: critical proteins linking innate and acquired immunity". Nat. Immunol. 2 (8): 675–80. doi:10.1038/90609. PMID 11477402.
- ↑ Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK (2008). "TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol". J. Immunol. 181 (5): 3049–56. PMC 3690475. PMID 18713975.
- ↑ McMullen MR, Pritchard MT, Wang Q, Millward CA, Croniger CM, Nagy LE (2005). "Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice". Gastroenterology. 128 (7): 2066–76. PMC 1959407. PMID 15940638.
- ↑ Zhou Z, Sun X, Kang YJ (2001). "Ethanol-induced apoptosis in mouse liver: Fas- and cytochrome c-mediated caspase-3 activation pathway". Am. J. Pathol. 159 (1): 329–38. doi:10.1016/S0002-9440(10)61699-9. PMC 1850406. PMID 11438480.
- ↑ Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G (2004). "Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption". Gastroenterology. 126 (5): 1387–99. PMID 15131799.
- ↑ Zintzaras E, Stefanidis I, Santos M, Vidal F (2006). "Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?". Hepatology. 43 (2): 352–61. doi:10.1002/hep.21023. PMID 16440362.
- ↑ Grove J, Daly AK, Burt AD, Guzail M, James OF, Bassendine MF, Day CP (1998). "Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease". Gut. 43 (2): 262–6. PMC 1727223. PMID 10189855.
- ↑ Grove J, Daly AK, Bassendine MF, Day CP (1997). "Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis". Hepatology. 26 (1): 143–6. doi:10.1002/hep.510260119. PMID 9214463.
- ↑ Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, Fiorelli G, Fargion S (2002). "Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease". Gastroenterology. 122 (2): 274–80. PMID 11832442.
- ↑ Lucey, Michael R.; Mathurin, Philippe; Morgan, Timothy R. (2009). "Alcoholic Hepatitis". New England Journal of Medicine. 360 (26): 2758–2769. doi:10.1056/NEJMra0805786. ISSN 0028-4793.
- ↑ Agrawal P, Vaiphei K (2014). "Histomorphological features of pancreas and liver in chronic alcoholics--an analytical study in 390 autopsy cases". Indian J Pathol Microbiol. 57 (1): 2–8. doi:10.4103/0377-4929.130842. PMID 24739823.
- ↑ Lefkowitch JH (2005). "Morphology of alcoholic liver disease". Clin Liver Dis. 9 (1): 37–53. doi:10.1016/j.cld.2004.11.001. PMID 15763228.
- ↑ Rubin E, Lieber CS (1968). "Alcohol-induced hepatic injury in nonalcoholic volunteers". N. Engl. J. Med. 278 (16): 869–76. doi:10.1056/NEJM196804182781602. PMID 5641156.
- ↑ Fromenty B, Grimbert S, Mansouri A, Beaugrand M, Erlinger S, Rötig A, Pessayre D (1995). "Hepatic mitochondrial DNA deletion in alcoholics: association with microvesicular steatosis". Gastroenterology. 108 (1): 193–200. PMID 7806041.
- ↑ Chedid A, Mendenhall CL, Tosch T, Chen T, Rabin L, Garcia-Pont P, Goldberg SJ, Kiernan T, Seeff LB, Sorrell M (1986). "Significance of megamitochondria in alcoholic liver disease". Gastroenterology. 90 (6): 1858–64. PMID 3699404.
- ↑ Uchida T, Kronborg I, Peters RL (1984). "Giant mitochondria in the alcoholic liver diseases--their identification, frequency and pathologic significance". Liver. 4 (1): 29–38. PMID 6700382.
- ↑ Fauerholdt L, Schlichting P, Christensen E, Poulsen H, Tygstrup N, Juhl E (1983). "Conversion of micronodular cirrhosis into macronodular cirrhosis". Hepatology. 3 (6): 928–31. PMID 6629323.
- ↑ Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH (1978). "The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization". J. Clin. Pathol. 31 (5): 395–414. PMC 1145292. PMID 649765.
- ↑ Van Eyken P, Sciot R, Desmet VJ (1988). "A cytokeratin immunohistochemical study of alcoholic liver disease: evidence that hepatocytes can express 'bile duct-type' cytokeratins". Histopathology. 13 (6): 605–17. PMID 2466751.