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Alcoholic Liver Disease #4

Laura Laureano Mark Sakr Jennifer Flannery

Alcohol liver disease

Describe the pathogensis of alcoholic fatty liver, alcoholic hepatitis and alcohol induced cirrhosis of the liver. Include significance of the patients liver biopsy.

Stages of Alcoholic liver Disease

Occurs in stages  Fatty liver  Alcohol hepatitis  Alcohol induced cirrhosis

Fatty Liver

Fatty Liver (Steatosis) An accumulation of fat in the livers hepatocytes. ADH level are high in the attempt to rid the body of alcohol toxin. ADH causes an increase NADH (Plenty of ATP). This causes a decrease in the oxidation of Fatty Acids and its accumulation in the liver

Aldehyde (end product) will also adduct to tubulin preventing the secretion of VLDL from the liver thus the cause of inflammation. This explains why his triacylglycerol levels (via liver biopsy) is well above the normal range (35-170) of 420 (35mg/DL as well as his cholesterol (140-200) of 223. (140His abdominal pains are form the liver inflammation

Alcoholic Hepatitis

The previous condition if continued, will lead to Alcoholic hepatitis The patient presented a WBC of 23,000 cells/ ul (rr 4,300-10,800) 4,300This condition leads to scarring of the liver in the lobule hepatocytes with a pathology of mallory bodies which are aggregations of intermediate filaments as well as proteins that are released from the scarring. Neutraphillic reactions and lymphatic infiltrates which usually collect around the mallory bodies are also in congruence with the increase of WBC. The above pathology is indicative of alcoholic hepatitis.

Liver Cirrhosis

Necrosis is occurring Damaged liver hepatocytes are being replaced with fibrotic tissue and hyperblastic nodules. Circulation from the portal vein is blocked leading to further exacerbation of necrosis as well as other lab findings.

Percentages of liver Deterioration


consumption  100% Fatty Liver  35% Alcohol Hepatitis  50% go on to develop cirrhosis  10-15% of all alcoholics will develop 10cirrhosis.

Role of Cytokines

Cytokines are chemical messengers that are important to the bodys initial response to infection.

Attract and activate components of the immune system Promote blood clotting Facilitate the release of additional chemical messengers Emphasizing inflammatory and immune responses Downplaying normal metabolism
(McClain 1997)

Induce liver to shift its physiological function:


Cytokines in ALD

Persistent alcohol use causes excessive cytokine production in the liver, leading to chronic inflammation. AlcoholAlcohol-induced chronic inflammation of the liver (alcoholic hepatitis) is characterized by:

Fever Jaundice Loss of appetite

Condition may progress to alcoholic cirrhosis, which is marked by progressive development of scar tissue that chokes off blood vessels and distorts the normal architecture of the liver. Because of the livers crucial role in many aspects of bodily function, either condition can be fatal.
(McClain 1997)

Kupffer Cell Cytokine Production

The liver plays a role in the inflammatory response, both as a potential site of chronic inflammatory disease (ALD) and as a source of phagocytes and cytokines. Most of the bodys fixed macrophages reside in the liver as Kupffer cells that screen the blood for infectious or toxic substances picked up from the digestive tract. Alcohol consumption increases the permeability of the intestine, permitting certain toxic bacterial products (endotoxin) to pass through the intestinal wall into the bloodstream. Upon reaching the liver, endotoxin stimulates the Kupffer cells to produce cytokines, mainly TNF ,which contributes to subsequent liver inflammation.
(McClain 1997)

(McClain 1997)

Immunological Activity

Patients with ALD will exhibit high levels of:


TNF Interleukins 1, 6, and 8 MCPMCP-1.

Elevated levels of TNF (inflammatory response) in blood are correlated with poor prognosis in patients with alcoholic hepatitis. Levels of IL-6 markedly increase during the initial ILhospitalization of ALD patients, subsiding as liver function improved. MCPMCP-1 promotes monocyte infiltration of liver.
(McClain 1997)

Immunological Activity

ILIL-8 promotes neutrophilia, increased neutrophil levels in the blood, as well as neutrophil infiltration of liver tissue in ALD. Conversely, production of IL-10 by monocytes is decreased ILin patients with ALD.

This cytokine normally helps curb the inflammatory response. Inadequate levels of IL-10 contribute to the uncontrolled production ILof inflammatory cytokines such as TNF.

This abnormal cytokine activity not only causes inflammation, but T cell, macrophage, monocyte and neutrophil mediated apoptosis will occur, further damaging the liver.
(McClain 1997)

(McClain 1997)

Protein-Aldehyde Adduct Production Protein

Ethanol consumption activates several systems that generate oxygen free radicals. These reactive oxygen species, namely reactive aldehydes (CH3CHO), products of lipid peroxidation, can bind to proteins forming stable adducts. This leads to several adverse consequences:

Interference with protein function Improper stimulation of fibrogenesis Induction of immune responses
(Niemel 1999)

Protein-Aldehyde Adducts Protein

Malondialdehyde (MDA) is a highly reactive dialdehyde originating from nonenzymatic lipid peroxidation of a variety of unsaturated fatty acids. The free radical mediated oxidation of long-chain longpolyunsaturated fatty acids leads to the production of 44hydroxynonenal (HNE), which can react with the sulfhydryl groups of proteins. Oxidative modification of proteins with MDA and HNE through covalent binding to proteins is known to interfere with protein function particularly when there is a lysine residue in a functionally critical location, such as in tubulin.

This can lead to altered microtubule function may subsequently lead to an impairment in protein secretion and plasma membrane fidelity.
(Niemel 1999)

Immunological Activity

AldehydeAldehyde-protein adducts and hydroxyl radicals stimulate immunological responses directed against specific modified proteins. Studies have shown that chronic administration of ethanol to rats leads to the generation of circulating immunoglobulins with anti-acetaldehyde adduct or antiantiantiMDAMDA-adduct specificity.

High levels of both IgA and IgG autoantibody isotypes have been observed in patients with severe alcoholic liver disease. These antibodies have specificity towards the aldehyde-lysine aldehyderesidues. Autoantibodies recognizing cytochrome P450IIE1 hydroxyethyl radical adducts have also been found from the blood of human alcoholics.
(Niemel 1999)

Antibody induced, T cell mediated apoptosis will occur.

Stellate cell activation and collagen synthesis in alcoholic liver disease

Stellate cell (HSC) activation


Stellate cells: major fibrogenic cells in the liver that contribute to collagen accumulation during chronic liver disease Gene induction of stellate cells is a central event in liver fibrosis Oxidative stress activates the transcription factors Nrf2 and AP1 through shared kinase signaling pathways Nrf2 induction of redox protective phase II metabolizing enzymes AP1 stellate cell activation, proliferation, and extracellular matrix accumulation


(Reichard & Petersen, 2004; Friedman 2000; Armendariz-Borunda, Simkevich, et al., 1994) Armendariz-

Stellate cell activation

HSCs undergo myofibroblastic transformation once activated by oxidative stress Transformation is characterized by assembly of smooth muscle actin stress fibers, loss of cytosolic retinol, and increased proliferation Results in accumulation of extracellular matrix and replacement of subendothelial matrix with dense fibril forming matrix

(Reichard & Petersen, 2004; Friedman 2000)

Hepatic Stellate cells

A & B: Inactive stellate cells autofluorescence of cytoplasmic vitamin A C & D: Activated stellate cells immunofluorescent detection of smooth muscle -actin

(Reichard & Petersen, 2004)

MMP and TIMP Activation

Matrix metalloproteinases (MMPs) are expressed and secreted by HSCs Extracellular matrix remodeling proteins contribute to fibril forming matrix Tissue Inhibitors (TIMP) also expressed by HSCs Inhibit collagen degradation

(Xu, Hui, Albanis, et al., 2005)

Role of Activated Hepatic Stellate Cells


Secrete cytokines Increase the deposition of ECM Recruit lymphocytes Express major histocompatibility complex class I (MHC) molecules Enhanced T cell apoptosis Interactions between HSCs and immune cells may contribute to hepatic immune tolerance

(Yu, Chen, et al.; 2004)

Big Picture:
Hepatic stellate cells play an important role in the fibrogenesis of perisinusoidal spaces in the liver through collagen synthesis
(Han, Chung, Ahn, et al.; 2001)

Gene induction of collagen

HSP47 mRNA is expressed in human HSCs HSP47 collagen specific chaperone protein Required for collagen biosynthesis Involved in procollagen processing, maturation, and secretion

(Hendershot & Bulleid, 2000)

Collagen deposition

Thrombin induces collagen deposition through activation of a G protein coupled receptor: Proteinase Activated Receptor 1 (PAR1) PAR1 is expressed by hepatic stellate cells

(Fiorucci, Antonelli, Distrutti, et al., 2004; Singh, Gerard, Hudson, Boros, 2004)

Collagen Liver Fibrosis

Connective tissue is laid down in the sinusoids and around hepatocytes Collagen fibers invade the space of Disse, creating a continuous membrane under the sinusoidal endothelium Amount of deposited hepatic collagen increases with the chronicity of the infection Accumulating collagen leads to liver fibrosis prevalent in alcoholic liver disease

(Han, Chung, Ahn, et al.; 2001)



ArmendarizArmendariz-Borunda, C.P. Simkevich, N. Roy, R. Raghow, A.H. Kang and J.M. Seyer. Activation of Ito cells involves regulation of AP-1 binding proteins and induction of type I collagen gene APexpression. Biochem. J. 1994; 304, 817824. 817 Fiorucci S, Antonelli E, Distrutti E, Severino B, Fiorentina R, Baldoni M, Caliendo G, Santagada V, Morelli A, Cirino G. PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation. Hepatology 2004: 39, 365-75. 365Friedman, S.L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem. 2000: 275, 22472250. 2247 Han NI, Chung KW, Ahn BM, Choi SW, Lee YS, Lee CD, Sun HS. Ultrastructural changes of hepatic stellate cells in the space of Disse in alcoholic fatty liver. Korean Journal of Internal Medicine 2001: 16:160-6. 16:160Hendershot LM, Bulleid NJ. Protein-specific chaperones: the role of hsp47 begins to gel. Curr Biol Protein2000: 10, 91215. 912 Reichard, J. and D.R. Petersen, Hepatic stellate cells lack AP-1 responsiveness to electrophiles and APphorbol 12-myristate-13-acetate. Biochemical and Biophysical Research Communications, 322: 2004, 842-853. 12-myristate-13Communications, 842Singh KP, Gerard HC, Hudson AP, Boros DL. Dynamics of collagen, MMP and TIMP gene expression during the granulomatous, fibrotic process induced by Schistosoma mansoni eggs. Ann Trop Med Parasitol 2004: 98, 581-93. 581Xu L, A Y Hui, E Albanis, MJ Arthur, S M OByrne, W S Blaner, P Mukherjee, S L Friedman, F J Eng. Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis. Gut LXLX2005: 54, 142-151 142Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S. Inhibition of T-cell Tresponses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology 2004: 40, B7-H1T13121312-21.


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