Seminario Fisiopatología de la cirrosis alcohólica
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Seminario Fisiopatología de la cirrosis alcohólica
- 1. Fisiopatología de la cirrosis alcohólica Sandra Milena Acevedo Rueda MD Residente Medicina Interna, 2do año Junio de 2013
- 3. Impacto de la enfermedad 5 a 30 casos por 100.000 habitantes (Europa) Mayor mortalidad 35 a 65 años Consumo diario de alcohol 4,8 a 11,8% Europa Incidencia de VIH mayor “Heavy alcoholics consuming at least 80 g of alcohol per day for more than 10 years will develop liver disease at a rate of nearly 100%”
- 4. Impacto de la enfermedad 5 a 30 casos por 100.000 habitantes (Europa) Mayor mortalidad 35 a 65 años Consumo diario de alcohol 4,8 a 11,8% Europa Incidencia de VIH mayor “Formerly 40-60 g of undiluted� alcohol (i.e. 2-3 beers per day� � used to be reported as a safe limit for men less (20 g/d for�� � women)”
- 5. Impacto de la enfermedad Definición de “trago” National Insitute of Alcohol Abuse and Alcoholism 11-14 g de alcohol Vino, cerveza, whisky
- 7. Función hepática Interpretación de las pruebas de laboratorio Enfermedad Pico ALT xLSN Radio AST:ALT Pico de bilirrubina, mg/dl Prolongación del PT Hepatitis viral 10-40 <1 <15 <3 Hepatitis alcohólica 2-8 >2 <15 1-3 Tóxicos >40 >1 Temprano <5 >5 (transitorio) Injuria por isquémia >40 >1 Temprano <5 >5 (transitorio)
- 8. Glasgow Alcohol Hepatitis Score
- 9. Maddrey Score Estudios prospectivos han mostrado que el índice resulta muy útil especialmente en el pronóstico de mortalidad a corto plazo (30 días) Un valor superior a 32 implica una peor respuesta con un rango de mortalidad entre 35% y 45% a los 30 días de evaluación
- 12. Metabolismo del etanol y metabolitos tóxicos Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Hígado y estómago: Metabolismo del alcohol Sistemas enzimáticos • Alcohol deshidrogenasa - ADH • Citocromo P450 2E1 • Catalasa Bajas concentraciones: ADH Altas concentraciones: CYP450 2E1 (10mM)
- 13. Metabolismo del etanol y metabolitos tóxicos Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 14. Metabolismo del etanol y metabolitos tóxicos Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Acetaldehído: Flushing Náusea Cefalea “Síndrome de Flushing Oriental” Forma inactiva de ALDH Acetaldehído (cisteínas): Toxicidad directa Autoinmunidad Transporte mitocondrial glutation Sensibilidad muerte mediada por FNT
- 15. Metabolismo del etanol y metabolitos tóxicos Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. La oxidación del etanol usa NAD+ como un electron aceptor y por tanto modifica el radio NAD reducido (NADH) a NAD + a un estado más reducido La oxidación del etanol usa NAD+ como un electron aceptor y por tanto modifica el radio NAD reducido (NADH) a NAD + a un estado más reducido Alteración en el metabolismo lipídico y de los carbohidratos ATP Esteatosis hepática Alteración en el metabolismo lipídico y de los carbohidratos ATP Esteatosis hepática
- 16. Fisiopatología de la Cirrosis hepática Rev. gastroenterol. Perú v.28 n.4 Lima Oct./2008
- 17. Otros mecanismos metabólicos… Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Estrés oxidativo Imbalance ROS, RNS Metabolismo normal Injuria hepática : sobreproducción, inadecuado nivel de antioxidantes Niveles de Isoprostano (marcador de peroxidación lipídica) ESTRÉS OXIDATIVO Anión superoxido, peróxido de hidrogeno, radical hidroxilo Oxido nítrico, peroxinitrito, acido hipohalo
- 18. Otros mecanismos metabólicos… Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Estrés oxidativo Marcadores indirectos de EO (1)Oxidación de proteínas (e.j., protein thiol - carbonyl products) (2)Oxidación lipídica (e.j., isoprostanos, malondialdehído); (3) Oxidación DNA (e.j., oxodeoxiguanosina) (4) Depleción o inducción de antioxidantes (e.j., vitamin E, glutation, tioredoxina) Sobre-expresión de CYP450 2E1: Ratones knockout PMN Mieloperoxidasa : acido hipoclorico , RNS Kupffer NADPH oxidasa, iNOS
- 19. Otros mecanismos metabólicos… Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Estrés oxidativo Dos grandes vías (1)Marcadores de injuria directa (2)Vías –señales
- 20. Otros mecanismos metabólicos… Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Disfunción mitocondrial Consume O2 Produce ROS Mitocondria no cuenta con Catalasa Glutation protege a la mitocondria del estrés oxidativo Alcohol: Depleción de glutatión Sensibililización a TNF
- 21. Otros mecanismos metabólicos… Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Hipoxia Área centrolobulillar: - Mayor susceptibilidad hipoxia El alcohol aumenta el consumo de Oxígeno
- 22. Otros mecanismos metabólicos… Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Función del proteosoma alterado Complejo proteosoma-ubiquitin 26S 2 grandes pasos: unión y degradación Acumulación anormal de proteínas anormales (oxidadas) Inclusiones celulares (ubiquitin) – Cuerpos de Mallory Hepatocito muere : liberación de citocinas IL-8 e IL-18
- 23. Otros mecanismos metabólicos… Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. Metabolismo anormal del Metionina, S-adenosylmetionina, y Folato 1980’s Déficit de SAT en alcohólicos Disminución aclaramiento a administración de bolos de metionina Depleción de Glutatión Esteatosis, esteatohepatitis en modelos knockout sin gen MTHF R
- 24. Otros mecanismos metabólicos… Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010. a) Methionine adenosyltransferase (MAT)
- 25. Mecanismos inflamatorios e inmunológicos • Activación de cél. Kupffer y Producción alterada de citoquinas Células Kupffer : FNT a (pro), IL10 (anti) Células endoteliales sinusoidales: Mol. adhesión Células estrelladas: Colageno en respuesta a transforming growth factor-β(TGF-β) Hepatocitos: peptido mayor quimioatrayente de neutrófilos, IL8, factores angiogénicos Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 26. Mecanismos inflamatorios e inmunológicos • Activación de cél. Kupffer y Producción alterada de citoquinas MAYOR ESTÍMULO PARA LIBERACIÓN DE CITOCINAS PROINFLAMATORIAS Lipopolisacáridos derivados del intestino y especies reactivas de oxígeon Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 27. Mecanismos inflamatorios e inmunológicos • Permeabilidad intestinal incrementada • Endotoxemia • LPS - Kupffer producen FNTa Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 28. Mecanismos inflamatorios e inmunológicos • Muerte por apoptosis y necrosis – Liberación de IL8 e IL18 • FNTa – muerte y severidad de la enfermedad • Reactantes de fase aguda, función hepática reducida y desenlaces clínicos Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 29. Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 30. Mecanismos inflamatorios e inmunológicos FNT a IL10 Mayor severidad en hepatotoxicidad inducida por alcohol Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 31. Mecanismos inflamatorios e inmunológicos • Respuesta inmune a proteínas hepatocelulares alteradas Hepatitis persiste a pesar de suspensión Anticuerpos contra: Fosfolipidos ADH Proteínas de shock térmico Otros antígenos Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 32. Factores genéticos y de género • Mujeres – Factor de riesgo – Progresión acelerada – 20 gramos al día • Polimorfismos genéticos – ADH – CYP2E1 – TNF – IL10 Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 33. Mecanismos emergentes 1. EPIGENÉTICA – Metilación – Modificación de histonas 2. RESPUESTA AL ESTRÉS RE – Proteínas no-desplegadas – Unfolded protein response (UPR) • Colesterol y trigliceridos Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 34. Mecanismos emergentes 3. CANABINOIDES ENDÓGENOS CB1, CB2 Pérdida de peso Disminución hiperlipidemia Fibrosis hepática Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 35. Fibrosis Fibrosis incrementada Estado dinámico, constante remodelación Célula estrellada: Estado quiescente almacenamiento Vitamina A Fenotipo contractil similar al miofibroblasto Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 36. Proceso dinámico Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 37. Fibrosis Metaloproteinasa-1 Degrada colágeno tipo 1 Elevada en enfermedad hepática alcohólica AUMENTO PRODUCCIÓN COLÁGENO Y DISMINUCIÓN DEGRADACIÓN MATRIX Feldman: Sleisenger and Fordtran's Gastrointestinal and Liver Disease, 9th ed. 2010.
- 38. “Clinicians and patients require accurate information about the degree of liver fibrosis in ALD to assess disease severity in order to predict outcome, guide management decisions and monitor disease. Detection of fibrosis in people drinking hazardously at an early stage or before clinical symptoms of hepatic decompensation could provide opportunities for more optimal management.”
- 40. “Here we present our study of patho-etiological factors that may be causally involved in the development of specific complications to alcoholic cirrhosis; it was based on a model of cirrhosis pathophysiology encompassing hepatic metabolic capacity, continued alcohol consumption, and circulatory dysfunction”
- 42. “In conclusion, reduced hepatic metabolic capacity, continued alcohol consumption, and circulatory dysfunction had distinct adverse effects on the risks of first-time hepatic encephalopathy, first-time ascites, first-time variceal bleeding, and death”
Notas del editor
- For practical purposes�� alcohol intake is rated by the count of “drinks”�� �he National Institute on Alcohol Abuse and Alcoholism defines a standard drink as 11 to�14 g of alcohol�� which corresponds to approximately one drink of 40% spirit�� one glass of wine or one 0..33 l (12-oz� 33 l (12-oz 33 l (12-oz� beer. Hence�� a “safe” daily intake of alcohol should not be more than two “drinks”. On the contrary�� moderate ethanol consumption (mainly wine� may mean a reduced cardiovascular risk[11] �� especially in women[12]
- Acetaldehyde also has been shown to impair mitochondrial glutathione transport and to sensitize hepatocytes to tumor necrosis factor (TNF)-mediated killing
- The term "redox" comes from two concepts involved with electron transfer: reduction and oxidation. [1] It can be explained in simple terms: Oxidation is the loss of electrons or an increase in oxidation state by a molecule , atom , or ion . Reduction is the gain of electrons or a decrease in oxidation state by a molecule, atom, or ion.
- Because hepatic mitochondria lack catalase, glutathione plays a critical role in protecting mitochondria against oxidative stress. Mitochondria do not make glutathione but instead import it from the cytosol. In alcoholic liver disease, the transport of glutathione into mitochondria is impaired, and selective mitochondrial glutathione depletion is observed. [23] Glutathione depletion also sensitizes the liver to the toxic effects of TNF, and TNF also impairs mitochondrial function. Finally, an increase in mitochondrial membrane depolarization and permeability leads to hepatocyte death, especially apoptotic (programmed), rather than necrotic, cell death.
- The proteasome system is now considered a cellular defense mechanism because it also removes irregular and damaged proteins generated by mutations, translational errors, or oxidative stress. [25] This pathway involves two major steps: (1) covalent attachment of multiple ubiquitin molecules to the protein substrate and (2) degradation of the targeted protein by the 26S proteasome complex. The 26S ubiquitin-proteasome pathway may play a pathogenic role in the development of alcoholic liver disease.
- Hepatic methionine metabolism. Chronic alcohol consumption causes S-adenosylmethionine (SAM) deficiency and an increase in homocysteine and S-adenosylhomocysteine (SAH) levels. a, methionine adenosyltransferase; b, enzymes involved in transmethylation reactions, including phosphatidylethanolamine N-methyltransferase; c, SAH hydrolase; d, cystathionine B-synthase; e, betaine-homocysteine ethyltransferase; f, methionine synthetase; g, glutamate-cysteine synthetase; h, glutathione (GSH) synthetase. ↑↓, effects of alcohol; T HF, tetrahydrofolate.
- Cytokine production in alcoholic liver disease. Kupffer cells are primed to overproduce cytotoxic cytokines in response to a lipopolysaccharide stimulus, and hepatocytes are sensitized to the hepatotoxic effects of these cytokines through mechanisms such as decreased production of anti-apoptotic survival proteins. Hepatocyte death causes increased production of interleukin-8 (neutrophil chemoattractant)and interleukin-18 (which primes tumor necrosis factor release and a type 1 helper T -cell response) (see text for details). NF-κB, nuclear factor kappa B; ROS, reactive oxygen species.
- Alcoholic hepatitis may persist histologically for many months after exposure to ethanol has ceased, suggesting an ongoing immune or autoimmune response. Autoimmune reactions are now well documented in patients with alcoholic liver disease, with autoantibodies directed against phospholipids, alcohol dehydrogenase, heat shock protein, and other potential antigens
- It normally exists in a quiescent state and serves as a major storehouse for vitamin A. Matrix metalloproteinase-1 plays a major role in degrading type I collagen. TIMP-1 levels also are elevated in alcoholic liver disease. The result appears to be an increase in stellate cell activation and collagen production on the one hand and a decrease in matrix degradation on the other hand.
- .
- It normally exists in a quiescent state and serves as a major storehouse for vitamin A. Matrix metalloproteinase-1 plays a major role in degrading type I collagen. TIMP-1 levels also are elevated in alcoholic liver disease. The result appears to be an increase in stellate cell activation and collagen production on the one hand and a decrease in matrix degradation on the other hand.
- Common components of these panels are HA (in 3 panels), alpha macroglobulin (in 2 panels), GGT (in 2 panels). One panel (Tran ndex) reported a very high specificity and PPV compared to other panels. Simpler panels with ≤3components (for example PGA- rothrombin Index, GGT and Apolipoprotein A1)