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  • Figure 7-1. Estimated prevalence of common causes of acute liver failure worldwide. Great variation is observed between the United Kingdom (high prevalence of acetaminophen toxicity) and India (predominantly hepatitis B and others, including a large percentage of hepatitis E cases) [24]. An increasing proportion of acute liver failure in the United States is attributable to acetaminophen. Although generally with better outcomes, these cases may account for more than 50% of patient hospital admissions for acute liver failure in certain urban areas [2], [13]. Furthermore, significant numbers of unintentional acetaminophen poisoning cases are being recognized, in which the medication is taken to relieve pain, without suicidal intent. Whether ethanol abuse is a cofactor in these cases is not entirely clear. References: [24]. Lee WM, Schiodt FV, Fulminant hepatic failure. In Schiff's Textbook of Liver Diseases. Edited by Schiff ER, Sorrell MF, Maddrey WC. New York: Lippincott-Raven; 1999 [2]. Lee WM, Medical progress: acute liver failure. N Engl J Med 1993 329 1862-1874 [13]. Schiodt FV, Rochling FA, Casey DL, Lee WM, Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997 337 1112-1117
  • Table 7-2. Principal causes of acute liver failure. Cause of acute liver failure is important because it determines prognosis. In some instances, initial management must be directed at the specific cause. Disease-specific treatments include antidotes to acetaminophen and mushroom poisoning that must be given immediately on patient admission to the hospital. Identification of severe heart failure as the cause indicates proper resuscitation and correction of any fluid balance disturbance. Likewise, recognition of acute fatty liver of pregnancy leads to consideration of delivery of the mother as the logical treatment for this condition. Patients with fulminant Wilson disease carry such a poor prognosis that urgent listing for transplantation must be immediately undertaken once this diagnosis is made, although therapy with trientine or penicillamine is often initiated.
  • Figure 7-4. Acetaminophen metabolic pathway. The main metabolic pathways for xenobiotic metabolism by the liver are divided into phase I (using cytochromes P-450), phase II (sulfation and glucuronidation), and the glutathione-S-transferase system. Acetaminophen is a prime example of a well-understood metabolic pathway that uses all three mechanisms. Acetaminophen in therapeutic doses undergoes sulfation and glucuronidation (phase II reactions) but is metabolized by cytochrome P-450 2E1 (phase I reaction) to the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) if the capacity of the phase II reactions is exceeded or if the cytochrome is induced. Glutathione-S-transferase is capable of detoxifying NAPQI to mercapturic acid if glutathione is available; N-acetylcysteine is an excellent source of glutathione substrate. Acetaminophen serves as an example of a direct toxin, one in which toxicity occurs in all individuals and is dose related, and in which all animal models demonstrate similar reactions. In alcoholic patients or individuals who are malnourished, glutathione depletion accentuates the liver injury. In addition, induction of P-450 2E1 by ethanol and some other drugs may enhance formation of NAPQI. This metabolite may cause hepatocyte damage via covalent binding to intracellular proteins [26]. Derangements in the regulation of apoptosis may also contribute to hepatocyte destruction [27], and the xenobiotic receptor CAR (constitutive androstane receptor) has recently been identified as a key regulator of acetaminophen metabolism and hepatoxicity in mice, suggesting new possibilities for potential hepatoprotective therapies in humans [28].CAR—constitutive androstane receptor; NAPQI—N-acetyl-p-benzoquinoneimine. References: [26]. Ostapowicz G, Lee WM, Management of acetaminophen toxicity. In Drugs and the Liver. Edited by Deleve L, Kaplowitz N. : ; 2002 327-344 [27]. Reed JC, Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med 2001 7 314-319 [28]. Zhang J, Huang W, Chua SS, et al. Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 2002 298 422-424
  • Table 7-6. Drugs implicated in idiosyncratic liver injury leading to acute liver failure. A wide variety of medications have been associated at one time or another with acute liver injury. Although some drugs have never been implicated, others are well known as occasional acute hepatotoxins. The frequency of such reactions may vary from one in 100 patients receiving isoniazid to one in 10,000 patients receiving halothane, or less with many other compounds. Implication of a given drug requires that the physician make a careful listing of all agents taken by the patient, the time period involved, and the quantity ingested. Most examples of hepatotoxicity occur within the first 4 to 8 weeks of drug initiation. Combination agents may have enhanced toxicity in comparison to that experienced with either ingredient alone. It is important to note that certain herbal preparations and other nutritional supplements have been implicated in causing liver injury, so that inquiry about such substances must be made during a complete medication history [30]. References: [30]. Stedman C, Herbal hepatotoxicity. Semin Liver Dis 2002 22 195-206
  • Figure 7-8. Basic physical findings in acute liver failure. Typical features observed in the patient with acute liver failure include confusion, agitation, and possibly hallucination. Mental status may deteriorate quickly to coma, making history taking difficult. Most patients will be icteric, although some barely so. Spider angiomata as seen in cirrhotic patients should be absent. Tachycardia, tachypnea, and relative hypotension are common. Asterixis, so commonly observed in chronic hepatic encephalopathy, is rarely seen. Fetor hepaticus, a sweet but pungent odor caused by mercaptans excreted in the breath, is often noted. Percussion over the rib cage to detect hepatic dullness may reveal a considerably decreased liver span; at times no dullness may be appreciated as evidence of the loss of hepatic mass. At autopsy, the normal liver mass of approximately 1600 g may be reduced to as little as 600 g. Edema is not observed initially but may develop during the course. Although the extremities are often cold, after resuscitation "warm shock" is the rule.
  • Figure 11-40. Factors precipitating acute episodes of encephalopathy. Precipitants of hepatic encephalopathy in 100 consecutive patients with hepatic encephalopathy at the West Haven Veterans Administration Hospital, West Haven, Connecticut. The most common precipitant was azotemia, which occurred in one third of the patients [42]. In about half of them the azotemia had been precipitated by diuretic agents such as furosemide. Precipitation of hepatic encephalopathy by tranquilizers, sedatives, or analgesic agents appears to be primarily responsible for induction of impaired mental state in a quarter of the episodes. Ninety-seven episodes had occurred in cirrhotic patients, 13 of whom had portacaval anastomoses. The severity of the encephalopathy tended to be milder in the azotemic and drug-induced patients. Hypokalemic alkalosis, which had been caused by vomiting, diarrhea, or diuretic drugs, was seen in 10% of the patients. The most severe encephalopathy occurred in association with gastrointestinal bleeding, infection, or azotemia. (Adapted from Fessel and Conn [42].) References: [43]. Fessel JM, Conn HO, An analysis of the causes and prevention of hepatic coma [abstract]. Gastroenterology 1972 62 191

Hipertension portal us Hipertension portal us Presentation Transcript

  • CESAR GARCIA CASALLAS MEDICINA INTERNA FARMACOLOGIA CLINICA HIPERTENSIÓN PORTAL
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  • Examen de LÍQUIDO Gradiente sero-ascítico de Albúmina >1.1 g indica hipertensión portal. DD con otras causas Numero polimorfonucleares: > 250 mm3 indica infección (PBE) Cultivo en frasco de hemocultivo (>sensibilidad) Proteínas totales: < 1g/dl factor de riesgo para PBE
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  • HIPERTENSION PORTAL ANATOMIA
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  • Estimated prevalence of common causes of acute liver failure worldwide
  • Principal causes of acute liver failure Toxinas
  • Acetaminophen metabolic pathway N-acetyl-p-benzoquinoneimine
  • Drugs implicated in idiosyncratic liver injury leading to acute liver failure
  • Daño Hepático agudo crónico cirrosis necrosis Insuficiencia hepática hipertensión portal encefalopatía hepática hepatocarcinoma regeneración
  • Insuficiencia hepática Disminución síntesis hemorragia edema Disminución depuración ictericia encefalopatía hiperestrogenismo hipoglicemia
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  • Circulación colateral en hipertensión portal.  
  • Basic physical findings in acute liver failure
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  • HIPERTENSION PORTAL VARICES ESOFAGICAS SANGRANTES
  • Factors precipitating acute episodes of encephalopathy (diuréticos)
  • Cirrosis Hipertensión portal GPVH > 10 mmHg Clínicamente significativa : Valor Pronostico Predice Desarrollo de Complicaciones Ripoll Hepatology 2006
  • DISFUNCIÓN CIRCULATORIA EN LA CIRROSIS Cirrosis compensada Ascitis tiempo Circulación hiperdinámica (vasodilatación GastoCardiaco Hipovolemia efectiva R etención de Na S.ReninaAngAldosterona SNS HAD Hiponatremia SHR GastoCardiaco Vasodilatación esplácnica
  • ASCITIS. PRONÓSTICO 50% mortalidad a 3 años Ascitis es indicación evaluación para trasplante
  • ASCITIS. TRATAMIENTO
    • Dieta hiposódica (60 a 90 mEq/día = 1,5 - 2 g/d)
    • Único tratamiento en pacientes sin hiperaldosteronismo y con excreción urinaria de Na conservada (10%)
    • Mejora respuesta a diuréticos
    • Esencial en pacientes con pobre respuesta a diuréticos
    Objetivo: corregir balance de Na y disfunción circulatoria
  • ESPIRONOLACTONA Reabsorción distal de Na por ALDOSTERONA FUROSEMIDA SISTEMA NERVIOSO SIMPÁTICO ASCITIS. TRATAMIENTO: DIURÉTICOS Reabsorción proximal de Na
  • TRATAMIENTO DIURÉTICO
    • Espironolactona es elección
    • Furosemida: uso asociado
    • Dosis escalonadas o combinación inicial
    • Dosis máximas: espironolactona 400 mg/d
    • furosemida 160 mg/d
    • Monitoreo de respuesta:
    • Control de peso :
    • descenso <0,5 kg /d en pacientes sin edemas
    • descenso < 1 kg/d en pacientes con edemas
    • Respuesta insuficiente: descenso < 1 kg en 1º sem < 2 kg en siguientes sem
    • Na urinario
    • insuficiente respuesta natriurética vs incumplimiento de dieta
    DIURÉTICOS
    • Complicaciones por diuréticos:
    • deterioro de la función renal 20% (Creatinina)
    • hiponatremia
    • encefalopatía (25% de ascitis severa y dosis altas)
    • hipokalemia
    • hiperkalemia y acidosis metabólica
    • ginecomastia
    • calambres
  • Ruiz del Arbol L, Gastroenterology Incremento en la VASODILATACION arterial Elevación de renina plasmática 71% Insuficiencia renal e hiponatremia 25% No revierte espontáneamente DISFUNCIÓN CIRCULATORIA POST-PARACENTESIS Sin DCPP Con DCPP Debe Prevenirse: Albúmina 8 g/L ascitis evacuada Probabilidad de sobrevida post DisfuncionCPP
  • Ginés, NEJM2004 Distinto PRONÓSTICO ASCITIS REFRACTARIA Y SINDROME HEPATORENAL 1 y 2 Sobrevida medida en meses, semanas y dias
    • Opciones
    • Shunt peritoneo venoso (Leveen)
    • Shunt quirúrgico porto-cava
    • Paracentesis +Albumina
    • TIPS
    • Trasplante hepático
  • TIPS (Transjugular Intrahepatic Portosystemic Shunt) Funciona como shunt porto cava laterolateral quirurgico Descompresión de sistema portal y de sinusoides hepáticos Reduce GPVH Mejora la natriuresis Mejora la respuesta a diuréticos Previene la recurrencia de la ascitis VIGILAR Disfunción del stent, falla cardiaca, encefalopatía Salerno, Hepatology 2004
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  • ALTERACIONES RENALES EN CIRROSIS ↓ Excreción Na ↓ Clearence H2O libre ↓ FGlomerular mEq/día ml/min ml/min ASCITIS HIPONATREMIA SINDROME DILUCIONAL HEPATORENAL
  • Sindrome hepatorenal
  • INSUFICIENCIA RENAL EN LA CIRROSIS
    • Es una complicación frecuente en cirrosis avanzada
    • Asociación con otras complicaciones de cirrosis:
    • - hemorragia gastrointestinal: 11% (Child C 29% )
    • - peritonitis bacteriana espontánea: 30%
    • - sepsis (no PBE): 25%
    • Impacto negativo en evolución / mortalidad
    Cardenas, Hepatology 2001, de Franchis, J Hepatol 2005 Sort P , NEJM1999
  • CAUSAS DE INSUFICIENCIA RENAL EN CIRROSIS INFECCIÓN BACTERIANA 38% 27% HIPOVOLEMIA 13% ENF INTRÍNSECA RENAL SHR 12% FARMACOS 3% OTRAS 7% Ginés P, Baveno 2005 Moreau, Hepatology 2003
  • IMPORTANCIA PRONOSTICA DE LA CAUSA DE FALLA RENAL EN PACIENTES CON CIRROSIS
    • Causas * Frecuencia Sobrevida 3m
    • Infecciones 213(46%) 31%
    • Hipovolemia 149 (32%) 46%
    • SHR 60(13%) 15%
    • Nefropatías 41( 9%) 73%
    • * En otros 99 pacientes las causas fueron varias
    Martin Llahi, Gastro 2011
  • SINDROME HEPATORENAL Insuficiencia renal funcional Caracterizado por - marcada disfunción circulatoria - sobreactivación de sistemas vasoactivos endógenos - vasoconstricción renal Potencialmente reversible Gran impacto negativo en el pronóstico
    • Cirrosis con HTP:
    • Exagerada VASODILATACION ESPLACNICA
    • con VASOCONSTRICCION RENAL
    • Subgrupo con caida relativa del gasto cardíaco (i.e., gasto cardiaco elevado pero inferior al correspondiente a la caida de postcarga)
    • Falla CARDIO-HEPATO-RENAL ≡
        • Insuficiencia Cardíaca de alto débito
        • Ruiz del Arbol
    Riñon y corazon
  • ENFERMEDAD HEPÁTICA AVANZADA HIPERTENSIÓN PORTAL SEVERA VD renales Progresión espontánea vasodilatación arterial esplácnica intensa hipovolemia efectiva marcada activación de SNS, SRAA, HAD vasoconstricción arterial SHR 2 Precipitante: PBE, hgia, DCPP hepatitis alcohólica Reducción relativa de gasto cardíaco VD renales SHR 1
  • Probabilidad de sobrevida
    • 20% a 1 año
    Arroyo V, J Hepatol 2003 Ginés P, y col, Gastroenterology 1993 Sobrevida media 2 semanas SHR tipo 2 SHR tipo 1 Insuficiencia renal moderada y estable creatinina 1.5 – 2.5 mg/dl Insuficiencia renal rápidamente progresiva duplicación de creatinina a > 2.5 mg/dl en < 2 sem Factor precipitante INDICACIÓN DE TRASPLANTE HEPÁTICO Progresión de disfunción circulatoria Asociado a ascitis refractaria
  • SHR 1: TERLIPRESINA ASOCIADA A ALBÚMINA (Consenso IAC-Gut 2007)
    • Terlipresina 0.5 – 1 mg c/4h , ev
    • Albúmina 1 g/kg en 1º día (hasta 100g), luego 20 – 40 g/d
  • Vasoconstrictores
    • Se recomienda administrarlos con albúmina
    • Análogos de Vasopresina
      • Ornipresina
      • Terlipresina
    • Análogos de Somatostatina
      • Octreótido
    • Agonistas alfa-adrenérgicos
      • Midrodine
      • Noradrenalina
  • Terlipresina
    • En SHR- 1: reduce creatinina por debajo de 1,5 mg/dl en 60- 75% de los pacientes
    • Menos del 5% tiene efectos isquémicos
    • Recurrencia: 17- 64%
    • Cochrane tiene un metaanálisis en curso (volúmen 2, 2005)
  • Agonistas alfa-adrenérgicos Duvoux C, Hepatology 36: 274- 80, 2002
    • Estudio: serie de casos
    • Población: SHR- 1
    • Intervención: Noradrenalina más Albúmina
    • durante 7 días
    • Resultado:
      • Incremento de presión arterial media
      • Reducción en renina activa y aldosterona
  • Asociación de vasoconstrictores Wong F, Hepatology 40: 55- 64, 2004
    • Estudio: serie de casos
    • Población: cirrosis con SHR- 1
    • Intervención: Midrodine, Octreótido y Albúmina durante 14 días
    • Resultado:
      • Reduce creatinina sérica
      • Incrementa excreción renal de sodio
  • Agonistas alfa-adrenérgicos Restuccia T, J Hepatol 40: 140- 6, 2004
    • Estudio: casos y controles
    • Población: SHR tratado con análogos de vasopresina vs falla hepática sin SHR
    • Resultado:
      • No diferencia en la incidencia de falla renal después del trasplante hepático
  • Trasplante hepático
    • Aplicable en SHR-2
    • En postrasplante requieren hemodiálisis:
      • SHR: 35%
      • No SHR: 5%
    • Retardar 48-72 hr Ciclosporina/Tacrolimus
    • Sobrevida a 3 años de SHR tratado con Terlipresina en pretrasplante: 100%
  •