Alcoholic liver disease pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Alcoholic liver disease}}
{{Alcoholic liver disease}}
{{CMG}}
{{CMG}}; {{AE}} {{MKA}}
 
==Overview==
==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==
==Pathophysiology==
Fatty change and alcoholic hepatitis are probably reversible. The later stages of fibrosis and cirrhosis tend to be irreversible but can usually be quite well managed for long periods of time.


'''The cause of fatty change are:'''
===Pathogenesis===
* The excess generation of NAD by the enzymes alcohol dehydrogenase and aldehyde dehydrogenase which cause shunting of normal substrates from catabolism towards lipid biosynthesis.
*[[Ethanol]] [[metabolism]] in the [[liver]] is carried out mainly by two [[enzymes]]:<ref name="pmid25548474">{{cite journal |vauthors=Ceni E, Mello T, Galli A |title=Pathogenesis of alcoholic liver disease: role of oxidative metabolism |journal=World J. Gastroenterol. |volume=20 |issue=47 |pages=17756–72 |year=2014 |pmid=25548474 |pmc=4273126 |doi=10.3748/wjg.v20.i47.17756 |url=}}</ref>
* Impaired assembly and secretion of lipoproteins and increased peripheral lipid catabolism may also contribute
**[[Alcohol dehydrogenase]]
**[[Aldehyde dehydrogenase]]
*Both of these [[enzymes]] use [[Nicotinamide adenine dinucleotide|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 (chemistry)|reduction]]-[[Oxidation-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 acid|fatty acids]] and thereby ends up promoting lipogenesis.<ref name="pmid15194557">{{cite journal |vauthors=You M, Crabb DW |title=Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=287 |issue=1 |pages=G1–6 |year=2004 |pmid=15194557 |doi=10.1152/ajpgi.00056.2004 |url=}}</ref>
*Since [[acetaldehyde]] has an [[electrophilic]] nature it can form [[covalent]] chemical bonds with [[Protein|proteins]], [[Lipid|lipids]] and [[DNA]]. These [[Covalent bond|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]].<ref name="pmid16088993">{{cite journal |vauthors=Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR |title=Recent advances in alcohol-induced adduct formation |journal=Alcohol. Clin. Exp. Res. |volume=29 |issue=7 |pages=1310–6 |year=2005 |pmid=16088993 |doi= |url=}}</ref><ref name="pmid17590995">{{cite journal |vauthors=Niemelä O |title=Acetaldehyde adducts in circulation |journal=Novartis Found. Symp. |volume=285 |issue= |pages=183–92; discussion 193–7 |year=2007 |pmid=17590995 |doi= |url=}}</ref><ref name="pmid11841919">{{cite journal |vauthors=Tuma DJ |title=Role of malondialdehyde-acetaldehyde adducts in liver injury |journal=Free Radic. Biol. Med. |volume=32 |issue=4 |pages=303–8 |year=2002 |pmid=11841919 |doi= |url=}}</ref><ref name="pmid15540799">{{cite journal |vauthors=Tuma DJ, Casey CA |title=Dangerous byproducts of alcohol breakdown--focus on adducts |journal=Alcohol Res Health |volume=27 |issue=4 |pages=285–90 |year=2003 |pmid=15540799 |doi= |url=}}</ref><ref name="pmid16054980">{{cite journal |vauthors=Brooks PJ, Theruvathu JA |title=DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis |journal=Alcohol |volume=35 |issue=3 |pages=187–93 |year=2005 |pmid=16054980 |doi=10.1016/j.alcohol.2005.03.009 |url=}}</ref><ref name="pmid17718399">{{cite journal |vauthors=Seitz HK, Becker P |title=Alcohol metabolism and cancer risk |journal=Alcohol Res Health |volume=30 |issue=1 |pages=38–41, 44–7 |year=2007 |pmid=17718399 |pmc=3860434 |doi= |url=}}</ref><ref name="pmid9857222">{{cite journal |vauthors=Biewald J, Nilius R, Langner J |title=Occurrence of acetaldehyde protein adducts formed in various organs of chronically ethanol fed rats: an immunohistochemical study |journal=Int. J. Mol. Med. |volume=2 |issue=4 |pages=389–96 |year=1998 |pmid=9857222 |doi= |url=}}</ref><ref name="pmid17543846">{{cite journal |vauthors=Seitz HK, Meier P |title=The role of acetaldehyde in upper digestive tract cancer in alcoholics |journal=Transl Res |volume=149 |issue=6 |pages=293–7 |year=2007 |pmid=17543846 |doi=10.1016/j.trsl.2006.12.002 |url=}}</ref>
 
*The [[cytochrome]] [[Cytochrome P450|P450]] enzymes (CYP) are a part of the [[Microsomal Ethanol Oxidizing System|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.<ref name="pmid3678578">{{cite journal |vauthors=Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV |title=Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans |journal=Biochem. Soc. Trans. |volume=15 |issue=4 |pages=576–8 |year=1987 |pmid=3678578 |doi= |url=}}</ref>
 
*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; O<sub>2</sub><sup>-</sup>, H<sub>2</sub>O<sub>2</sub>, OH<sup>-</sup> and hydroxyethyl radical (HER).<ref name="pmid36785782">{{cite journal |vauthors=Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV |title=Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans |journal=Biochem. Soc. Trans. |volume=15 |issue=4 |pages=576–8 |year=1987 |pmid=3678578 |doi= |url=}}</ref><ref name="pmid5009602">{{cite journal |vauthors=Lieber CS |title=Metabolism of ethanol and alcoholism: racial and acquired factors |journal=Ann. Intern. Med. |volume=76 |issue=2 |pages=326–7 |year=1972 |pmid=5009602 |doi= |url=}}</ref><ref name="pmid4402282">{{cite journal |vauthors=Lieber CS, DeCarli LM |title=The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo |journal=J. Pharmacol. Exp. Ther. |volume=181 |issue=2 |pages=279–87 |year=1972 |pmid=4402282 |doi= |url=}}</ref><ref name="pmid9114822">{{cite journal |vauthors=Lieber CS |title=Cytochrome P-4502E1: its physiological and pathological role |journal=Physiol. Rev. |volume=77 |issue=2 |pages=517–44 |year=1997 |pmid=9114822 |doi= |url=}}</ref><ref name="pmid2333153">{{cite journal |vauthors=Hansson T, Tindberg N, Ingelman-Sundberg M, Köhler C |title=Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system |journal=Neuroscience |volume=34 |issue=2 |pages=451–63 |year=1990 |pmid=2333153 |doi= |url=}}</ref><ref name="pmid17760783">{{cite journal |vauthors=Donohue TM, Cederbaum AI, French SW, Barve S, Gao B, Osna NA |title=Role of the proteasome in ethanol-induced liver pathology |journal=Alcohol. Clin. Exp. Res. |volume=31 |issue=9 |pages=1446–59 |year=2007 |pmid=17760783 |doi=10.1111/j.1530-0277.2007.00454.x |url=}}</ref><ref name="pmid17854134">{{cite journal |vauthors=Osna NA, Donohue TM |title=Implication of altered proteasome function in alcoholic liver injury |journal=World J. Gastroenterol. |volume=13 |issue=37 |pages=4931–7 |year=2007 |pmid=17854134 |pmc=4434615 |doi= |url=}}</ref><ref name="pmid18078827">{{cite journal |vauthors=Lu Y, Cederbaum AI |title=CYP2E1 and oxidative liver injury by alcohol |journal=Free Radic. Biol. Med. |volume=44 |issue=5 |pages=723–38 |year=2008 |pmid=18078827 |pmc=2268632 |doi=10.1016/j.freeradbiomed.2007.11.004 |url=}}</ref><ref name="pmid1545775">{{cite journal |vauthors=Yun YP, Casazza JP, Sohn DH, Veech RL, Song BJ |title=Pretranslational activation of cytochrome P450IIE during ketosis induced by a high fat diet |journal=Mol. Pharmacol. |volume=41 |issue=3 |pages=474–9 |year=1992 |pmid=1545775 |doi= |url=}}</ref><ref name="pmid2005876">{{cite journal |vauthors=Raucy JL, Lasker JM, Kraner JC, Salazar DE, Lieber CS, Corcoran GB |title=Induction of cytochrome P450IIE1 in the obese overfed rat |journal=Mol. Pharmacol. |volume=39 |issue=3 |pages=275–80 |year=1991 |pmid=2005876 |doi= |url=}}</ref><ref name="pmid11826398">{{cite journal |vauthors=Woodcroft KJ, Hafner MS, Novak RF |title=Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression |journal=Hepatology |volume=35 |issue=2 |pages=263–73 |year=2002 |pmid=11826398 |doi=10.1053/jhep.2002.30691 |url=}}</ref><ref name="pmid7700245">{{cite journal |vauthors=De Waziers I, Garlatti M, Bouguet J, Beaune PH, Barouki R |title=Insulin down-regulates cytochrome P450 2B and 2E expression at the post-transcriptional level in the rat hepatoma cell line |journal=Mol. Pharmacol. |volume=47 |issue=3 |pages=474–9 |year=1995 |pmid=7700245 |doi= |url=}}</ref><ref name="pmid9765518">{{cite journal |vauthors=Peng HM, Coon MJ |title=Regulation of rabbit cytochrome P450 2E1 expression in HepG2 cells by insulin and thyroid hormone |journal=Mol. Pharmacol. |volume=54 |issue=4 |pages=740–7 |year=1998 |pmid=9765518 |doi= |url=}}</ref><ref name="pmid1822117">{{cite journal |vauthors=Terelius Y, Norsten-Höög C, Cronholm T, Ingelman-Sundberg M |title=Acetaldehyde as a substrate for ethanol-inducible cytochrome P450 (CYP2E1) |journal=Biochem. Biophys. Res. Commun. |volume=179 |issue=1 |pages=689–94 |year=1991 |pmid=1822117 |doi= |url=}}</ref><ref name="pmid9726291">{{cite journal |vauthors=Wu YS, Salmela KS, Lieber CS |title=Microsomal acetaldehyde oxidation is negligible in the presence of ethanol |journal=Alcohol. Clin. Exp. Res. |volume=22 |issue=5 |pages=1165–9 |year=1998 |pmid=9726291 |doi= |url=}}</ref><ref name="pmid9309320">{{cite journal |vauthors=Brooks PJ |title=DNA damage, DNA repair, and alcohol toxicity--a review |journal=Alcohol. Clin. Exp. Res. |volume=21 |issue=6 |pages=1073–82 |year=1997 |pmid=9309320 |doi= |url=}}</ref>
 
*[[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 (genetics)|transcription]] factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.<ref name="pmid12791698">{{cite journal |vauthors=Fischer M, You M, Matsumoto M, Crabb DW |title=Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice |journal=J. Biol. Chem. |volume=278 |issue=30 |pages=27997–8004 |year=2003 |pmid=12791698 |doi=10.1074/jbc.M302140200 |url=}}</ref><ref name="pmid15578517">{{cite journal |vauthors=You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW |title=The role of AMP-activated protein kinase in the action of ethanol in the liver |journal=Gastroenterology |volume=127 |issue=6 |pages=1798–808 |year=2004 |pmid=15578517 |doi= |url=}}</ref><ref name="pmid16879892">{{cite journal |vauthors=Ji C, Chan C, Kaplowitz N |title=Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model |journal=J. Hepatol. |volume=45 |issue=5 |pages=717–24 |year=2006 |pmid=16879892 |doi=10.1016/j.jhep.2006.05.009 |url=}}</ref>
 
*Two key factors that play an important role in the [[inflammatory]] process that leads to the alcohol mediated liver injury are:<ref name="pmid6433728">{{cite journal |vauthors=Tsukamoto H, Reidelberger RD, French SW, Largman C |title=Long-term cannulation model for blood sampling and intragastric infusion in the rat |journal=Am. J. Physiol. |volume=247 |issue=3 Pt 2 |pages=R595–9 |year=1984 |pmid=6433728 |doi= |url=}}</ref><ref name="pmid11431739">{{cite journal |vauthors=Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG |title=Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice |journal=Hepatology |volume=34 |issue=1 |pages=101–8 |year=2001 |pmid=11431739 |doi=10.1053/jhep.2001.25350 |url=}}</ref>
**[[Endotoxin]]
**[[Gut]] [[permeability]]
*[[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 [[Inflammation|inflammatory]] process.<ref name="pmid15723320">{{cite journal |vauthors=Wiest R, Garcia-Tsao G |title=Bacterial translocation (BT) in cirrhosis |journal=Hepatology |volume=41 |issue=3 |pages=422–33 |year=2005 |pmid=15723320 |doi=10.1002/hep.20632 |url=}}</ref><ref name="pmid8171045">{{cite journal |vauthors=Nanji AA, Khettry U, Sadrzadeh SM |title=Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease) |journal=Proc. Soc. Exp. Biol. Med. |volume=205 |issue=3 |pages=243–7 |year=1994 |pmid=8171045 |doi= |url=}}</ref>
*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.<ref name="pmid7806045">{{cite journal |vauthors=Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG |title=Antibiotics prevent liver injury in rats following long-term exposure to ethanol |journal=Gastroenterology |volume=108 |issue=1 |pages=218–24 |year=1995 |pmid=7806045 |doi= |url=}}</ref><ref name="pmid6141332">{{cite journal |vauthors=Bjarnason I, Peters TJ, Wise RJ |title=The leaky gut of alcoholism: possible route of entry for toxic compounds |journal=Lancet |volume=1 |issue=8370 |pages=179–82 |year=1984 |pmid=6141332 |doi= |url=}}</ref>
*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.<ref name="pmid11236841">{{cite journal |vauthors=Urbaschek R, McCuskey RS, Rudi V, Becker KP, Stickel F, Urbaschek B, Seitz HK |title=Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease |journal=Alcohol. Clin. Exp. Res. |volume=25 |issue=2 |pages=261–8 |year=2001 |pmid=11236841 |doi= |url=}}</ref>
 
*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.<ref name="pmid11884468">{{cite journal |vauthors=Uesugi T, Froh M, Arteel GE, Bradford BU, Wheeler MD, Gäbele E, Isayama F, Thurman RG |title=Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice |journal=J. Immunol. |volume=168 |issue=6 |pages=2963–9 |year=2002 |pmid=11884468 |doi= |url=}}</ref>
*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 cell|Kupffer cells]] requires 3 main cellular proteins:<ref name="pmid8045507">{{cite journal |vauthors=Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG |title=Inactivation of Kupffer cells prevents early alcohol-induced liver injury |journal=Hepatology |volume=20 |issue=2 |pages=453–60 |year=1994 |pmid=8045507 |doi= |url=}}</ref>
**[[CD14]] (monocyte differentiation antigen)<ref name="pmid11254735">{{cite journal |vauthors=Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG |title=Reduced early alcohol-induced liver injury in CD14-deficient mice |journal=J. Immunol. |volume=166 |issue=7 |pages=4737–42 |year=2001 |pmid=11254735 |doi= |url=}}</ref>
**Toll-like receptor 4 (TLR4)<ref name="pmid18792393">{{cite journal |vauthors=Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G |title=The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88 |journal=Hepatology |volume=48 |issue=4 |pages=1224–31 |year=2008 |pmid=18792393 |doi=10.1002/hep.22470 |url=}}</ref>
**MD2, a protein, binds [[TLR 4|TLR4]] with LPS-LPS binding protein
*The [[TLR 4|TLR4]] then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.<ref name="pmid11477402">{{cite journal |vauthors=Akira S, Takeda K, Kaisho T |title=Toll-like receptors: critical proteins linking innate and acquired immunity |journal=Nat. Immunol. |volume=2 |issue=8 |pages=675–80 |year=2001 |pmid=11477402 |doi=10.1038/90609 |url=}}</ref> 
*The nuclear factor-kB ([[NF-kB]]) and the [[TLR 4|TLR4]] adapter also play an important role in the activation of the [[Kupffer cell|kupffer cells]].<ref name="pmid18713975">{{cite journal |vauthors=Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK |title=TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol |journal=J. Immunol. |volume=181 |issue=5 |pages=3049–56 |year=2008 |pmid=18713975 |pmc=3690475 |doi= |url=}}</ref> 
*EGR1 plays the pivotal role in [[lipopolysaccharide]]-stimulated [[Tumor necrosis factor-alpha|TNF-α]] production. 
*In mice the absence of EGR1 prevents [[alcohol]] induced [[liver]] injury.<ref name="pmid15940638">{{cite journal |vauthors=McMullen MR, Pritchard MT, Wang Q, Millward CA, Croniger CM, Nagy LE |title=Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice |journal=Gastroenterology |volume=128 |issue=7 |pages=2066–76 |year=2005 |pmid=15940638 |pmc=1959407 |doi= |url=}}</ref>
 
*[[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.<ref name="pmid11438480">{{cite journal |vauthors=Zhou Z, Sun X, Kang YJ |title=Ethanol-induced apoptosis in mouse liver: Fas- and cytochrome c-mediated caspase-3 activation pathway |journal=Am. J. Pathol. |volume=159 |issue=1 |pages=329–38 |year=2001 |pmid=11438480 |pmc=1850406 |doi=10.1016/S0002-9440(10)61699-9 |url=}}</ref> 
*The cumulative effect of [[Tumor necrosis factor-alpha|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]].<ref name="pmid15131799">{{cite journal |vauthors=Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G |title=Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption |journal=Gastroenterology |volume=126 |issue=5 |pages=1387–99 |year=2004 |pmid=15131799 |doi= |url=}}</ref>
 
==Genetics==
*Susceptibility to alcoholic liver disease could be determined by functional [[polymorphisms]] in the ADH2 [[gene]].<ref name="pmid16440362">{{cite journal |vauthors=Zintzaras E, Stefanidis I, Santos M, Vidal F |title=Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease? |journal=Hepatology |volume=43 |issue=2 |pages=352–61 |year=2006 |pmid=16440362 |doi=10.1002/hep.21023 |url=}}</ref><ref name="pmid10189855">{{cite journal |vauthors=Grove J, Daly AK, Burt AD, Guzail M, James OF, Bassendine MF, Day CP |title=Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease |journal=Gut |volume=43 |issue=2 |pages=262–6 |year=1998 |pmid=10189855 |pmc=1727223 |doi= |url=}}</ref>
 
*[[Polymorphism]] at position -238 of the [[Tumor necrosis factor-alpha|TNF-α]] [[promoter]] region.<ref name="pmid9214463">{{cite journal |vauthors=Grove J, Daly AK, Bassendine MF, Day CP |title=Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis |journal=Hepatology |volume=26 |issue=1 |pages=143–6 |year=1997 |pmid=9214463 |doi=10.1002/hep.510260119 |url=}}</ref><ref name="pmid11832442">{{cite journal |vauthors=Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, Fiorelli G, Fargion S |title=Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease |journal=Gastroenterology |volume=122 |issue=2 |pages=274–80 |year=2002 |pmid=11832442 |doi= |url=}}</ref> 
==Associated Conditions==
Conditions associated with alcoholic liver disease include:<ref name="pmid25548474">{{cite journal |vauthors=Ceni E, Mello T, Galli A |title=Pathogenesis of alcoholic liver disease: role of oxidative metabolism |journal=World J. Gastroenterol. |volume=20 |issue=47 |pages=17756–72 |year=2014 |pmid=25548474 |pmc=4273126 |doi=10.3748/wjg.v20.i47.17756 |url=}}</ref><ref name="LuceyMathurin2009">{{cite journal|last1=Lucey|first1=Michael R.|last2=Mathurin|first2=Philippe|last3=Morgan|first3=Timothy R.|title=Alcoholic Hepatitis|journal=New England Journal of Medicine|volume=360|issue=26|year=2009|pages=2758–2769|issn=0028-4793|doi=10.1056/NEJMra0805786}}</ref>
 
*[[Obesity]]
*Chronic viral [[hepatitis]]
*[[Iron overload disorder|Iron overload]]
*[[Cirrhosis]]
*[[Hepatocellular carcinoma]] 
 
==Gross Pathology==
*On gross pathology, characteristic findings of alcoholic liver disease include:<ref name="pmid24739823">{{cite journal |vauthors=Agrawal P, Vaiphei K |title=Histomorphological features of pancreas and liver in chronic alcoholics--an analytical study in 390 autopsy cases |journal=Indian J Pathol Microbiol |volume=57 |issue=1 |pages=2–8 |year=2014 |pmid=24739823 |doi=10.4103/0377-4929.130842 |url=}}</ref>
**[[Hepatomegaly]]
**[[Nodules]]
***Macronodules
***Micronodules
**Firm in consistency
**[[Portal vein]] dilation
 
==Microscopic Pathology==
On microscopic histopathological analysis characteristic findings of alcoholic liver disease include:<ref name="pmid15763228">{{cite journal |vauthors=Lefkowitch JH |title=Morphology of alcoholic liver disease |journal=Clin Liver Dis |volume=9 |issue=1 |pages=37–53 |year=2005 |pmid=15763228 |doi=10.1016/j.cld.2004.11.001 |url=}}</ref><ref name="pmid5641156">{{cite journal |vauthors=Rubin E, Lieber CS |title=Alcohol-induced hepatic injury in nonalcoholic volunteers |journal=N. Engl. J. Med. |volume=278 |issue=16 |pages=869–76 |year=1968 |pmid=5641156 |doi=10.1056/NEJM196804182781602 |url=}}</ref><ref name="pmid7806041">{{cite journal |vauthors=Fromenty B, Grimbert S, Mansouri A, Beaugrand M, Erlinger S, Rötig A, Pessayre D |title=Hepatic mitochondrial DNA deletion in alcoholics: association with microvesicular steatosis |journal=Gastroenterology |volume=108 |issue=1 |pages=193–200 |year=1995 |pmid=7806041 |doi= |url=}}</ref><ref name="pmid3699404">{{cite journal |vauthors=Chedid A, Mendenhall CL, Tosch T, Chen T, Rabin L, Garcia-Pont P, Goldberg SJ, Kiernan T, Seeff LB, Sorrell M |title=Significance of megamitochondria in alcoholic liver disease |journal=Gastroenterology |volume=90 |issue=6 |pages=1858–64 |year=1986 |pmid=3699404 |doi= |url=}}</ref><ref name="pmid6700382">{{cite journal |vauthors=Uchida T, Kronborg I, Peters RL |title=Giant mitochondria in the alcoholic liver diseases--their identification, frequency and pathologic significance |journal=Liver |volume=4 |issue=1 |pages=29–38 |year=1984 |pmid=6700382 |doi= |url=}}</ref><ref name="pmid6629323">{{cite journal |vauthors=Fauerholdt L, Schlichting P, Christensen E, Poulsen H, Tygstrup N, Juhl E |title=Conversion of micronodular cirrhosis into macronodular cirrhosis |journal=Hepatology |volume=3 |issue=6 |pages=928–31 |year=1983 |pmid=6629323 |doi= |url=}}</ref><ref name="pmid649765">{{cite journal |vauthors=Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH |title=The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization |journal=J. Clin. Pathol. |volume=31 |issue=5 |pages=395–414 |year=1978 |pmid=649765 |pmc=1145292 |doi= |url=}}</ref><ref name="pmid2466751">{{cite journal |vauthors=Van Eyken P, Sciot R, Desmet VJ |title=A cytokeratin immunohistochemical study of alcoholic liver disease: evidence that hepatocytes can express 'bile duct-type' cytokeratins |journal=Histopathology |volume=13 |issue=6 |pages=605–17 |year=1988 |pmid=2466751 |doi= |url=}}</ref>


'''The cause of alcoholic hepatitis are:'''
*Non-cirrhotic [[liver]]
*Acetaldehyde formed from alcohol induces lipid peroxidation and acetaldehyde protein adduct formation which disrupt cytoskeleton
**[[Steatosis]]
*Directly affect microtubule organization, mitochondrial function and membrane fluidity
***Macrovesicular [[steatosis]] - the [[cytoplasm]] of [[Hepatocyte|hepatocytes]] is occupied by large [[lipid]] droplets that end up displacing the [[nucleus]] and other organelles peripherally
*Generation of ROS
**Proliferation of the [[smooth endoplasmic reticulum]]
*Neutrophil attack at the site of hepatocyte necrosis
**Distortion of the [[Mitochondrion|mitochondria]] (giant [[Mitochondrion|mitochondria]])
===Fatty change===
**[[Hepatocyte]] balooning (Mallory-Denk bodies)
{{main|Fatty liver}}
* Fatty change, or [[steatosis]] is the accumulation of fat in [[hepatocyte|liver cells]] which can be seen as fatty globules under the microscope.
* [[Alcoholism]] causes large fatty globules (macrovesicular steatosis).
* Other causes of macrovesicular steatosis include [[diabetes]], [[obesity]] and [[starvation]].
* Alcoholic fatty change is probably dose related.
* Small fatty globules have different causes.
===Alcoholic hepatitis===
{{main|Alcoholic hepatitis}}


* Some people get an acute hepatitis or inflammatory reaction to the cells affected by fatty change. This is not directly related to the dose of alcohol.
*Cirrhotic [[liver]]:
* Some people seem more prone to this reaction than others.  This is called alcoholic steatonecrosis and the inflammation probably predisposes to liver fibrosis.
**Fibrous septae that are made up of [[collagen]] surrounding the [[Hepatocyte|hepatocytes]] which results in pseudo [[Lobe (anatomy)|lobule]] formation.
===Liver fibrosis===
**This produces a [[nodular]] appearance of the [[liver]] and then progresses from micro nodular to macro nodular [[cirrhosis]] with time.  
* Liver fibrosis, in itself, is largely asymptomatic but as it progresses it can turn into [[cirrhosis]], where the fibrosis alters the architecture and impairs the function of the liver.
**Proliferation of the [[Bile duct|bile ducts]] may also be seen.
===Cirrhosis ===
{{main|cirrhosis}}
* [[Cirrhosis]] is a late stage of liver disease marked by fibrosis and altered liver architecture.
* It is often progressive and may eventually lead to [[liver failure]].
* Late complications of cirrhosis or liver failure include [[portal hypertension]], [[coagulopathy|coagulation disorders]], [[ascites]] and other complications including [[hepatic encephalopathy]] and the [[hepatorenal syndrome]].
* [[Cirrhosis]] also has number of other causes, such as hepatitis and toxins.  The late stages of cirrhosis (say from viral hepatitis or alcohol) may look similar.  This phenomenon is termed a "final common pathway" for a disease.


==References==
==References==
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{{WH}}
[[Category:Surgery]]
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[[Category:Gastroenterology]]
[[Category:Up-To-Date]]
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Latest revision as of 20:20, 29 July 2020

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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 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]
  • 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]
    • CD14 (monocyte differentiation antigen)[40]
    • Toll-like receptor 4 (TLR4)[41]
    • MD2, a protein, binds TLR4 with LPS-LPS binding protein
  • 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

Associated Conditions

Conditions associated with alcoholic liver disease include:[1][51]

Gross Pathology

  • On gross pathology, characteristic findings of alcoholic liver disease include:[52]

Microscopic Pathology

On microscopic histopathological analysis characteristic findings of alcoholic liver disease include:[53][54][55][56][57][58][59][60]

  • 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. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ Wiest R, Garcia-Tsao G (2005). "Bacterial translocation (BT) in cirrhosis". Hepatology. 41 (3): 422–33. doi:10.1002/hep.20632. PMID 15723320.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ 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.
  48. ↑ 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.
  49. ↑ 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.
  50. ↑ 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.
  51. ↑ 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.
  52. ↑ 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.
  53. ↑ 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.
  54. ↑ 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.
  55. ↑ 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.
  56. ↑ 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.
  57. ↑ 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.
  58. ↑ 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.
  59. ↑ 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.
  60. ↑ 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.

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