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Liver disease

Liver disease. Hana Maxová Department of Pathophysiology 2nd Faculty of Medicine Charles University in Prague. Liver disease. I nflammation. Alcohol. Autoimunne d. Acute x Chronic Focal x Diffuse Mild x Severe Reversible x Irreversible. Toxins. Innate diseases. Acute.

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Liver disease

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  1. Liver disease Hana Maxová Department of Pathophysiology 2nd Faculty of Medicine Charles University in Prague

  2. Liver disease Inflammation Alcohol Autoimunne d. Acute x Chronic Focal x Diffuse Mild x Severe Reversible x Irreversible Toxins Innate diseases Acute Chronic Rightside card. failure Cirhosis Liver failure

  3. Liver organization Liver lobule Portaltriad - hepaticartery - bileduct - portalvein Centralvein Liver acinus Zone I - periportal II - intermedial III - central

  4. Liver organization • Hepatocyte (apical, basolateral • membrane) • Endothelialcells • Kupffercells(macrophages) • Stellatecells(Itocells) • Space of Disse • Uniquefeatures: • - fenestratedendothelia • lack of a typicalbesementmembrane • lowpressurecircuit

  5. Liver dysfunction 1. Protein metabolism Albumin Bloodcoagulationfactors (II,VII, IX, X - vit. K, fibrinogen) Transport proteins (transferrin, steroids, thyroxine) Acutephasereactantproteins (1 – antitrypsin, ceruloplasmin, haptoglobin, CRP) Aminoacids  ammonia -  urea synthesis, circulationwithouttraversinghepaticsinusoids (encephalopathy) aromatic -  degradation x  branchedchain -  peripheralutilization (musles) 2. Carbohydratemetabolism Hyperglycemia (porto-systemicshunting, insulinoresistance) Hypoglycemia ( in hepatocellularmass, end-stage of failure) 3. Lipid metabolism Dyslipoproteinemia  HDL,  LDL,  cholesterol – effect of cholestasis fattyliver - accumulation of triglycerides (imbalancebetweensynthesis and secretion) 4. Hormone metabolism Estrogens- gynecomastia  Renin, Hyperaldosteronism - sodiumretention

  6. Liver dysfunction 5. Bilirubin and bileacidsmetabolism Icterus– prehapatic, hepatic, posthepatic Enterohepatalcirculation of bileacids Cholestasis - intrahepatic, extrahepatic Malabsorption - dietarylipids (steatorhoe) and fat-solublevitamins (K) Biliarycirhosis

  7. Liver functiontests Dg: combinationof history, physicalexamination, laboratorytesting, radiologicalstudies, biopsy ALT – damagedhepatocytes AST – lessspecific (heartattack) ALP – non specific (bone, kidney, intestine, bileducts) GGT – sensitive (bileducts, alcohol) Bilirubin Albumin PT (prothrombintime), INR Serum protein electrophoresis (ratio abumin/globulin) SerumIg (IgM – primarybiliarycirhosis, IgA –alcoholic, IgG – chronicactive hepatitis) Specificantibodies Ammonia AFP Child-Pughscore

  8. Acute liver failure The rapid development of hepatocellular dysfunction, specifically coagulopathy and mental status changes (encephalopathy) in a patient without known prior liver disease Etiology: Acute HBV infection, HDV superinfection, atypical – cytomegalovirus, EBV, Herpes simplex Paracetamol overdose, drugs - ecstasy, mushroomtoxins Metabolicdiseases (Wilson's disease, Reye´ssyndrome, alpha 1 antitrypsin defficiency) Vascular (Budd–Chiari syndrome, heartfailure, shock) Pathogenesis: NO, bacterial endotoxin, TNF, IL-1, IL-6, hyperamonemia, multisystem organ failure Complications: Cerebraledema Hepatorenalsy ARDS (hypoxemia, hyperventilation, respiratoryalcalosis) Bleeding (GIT) Sepsis ABR and electrolytesdysbalance (respiratoryalcalosis, metab. acdidosis, hyponatremia, hypokalemia) Fulminant hepatitis

  9. Chronic hepatitis • One of several types of liver disease persisting for longer than 6 months, often progressing to cirrhosis. • Chronic persistent hepatitis (no cell necrosis) • Chronic active hepatitis (cell necrosis) • Steatosis-accumulation of triglycerideswithinparenchymalcells (reversible) • Fibrosis -excessdeposition of components of ECM (collagens, glycoproteins, proteoglycans) within the liver • Liver cirhosis-diffusehepaticprocesscharacterized by fibrosis and the conversion of normal liver architectureintostructurallyabnormalnodules Liver failure Insult Hepatocellular carcinoma

  10. Chronic hepatitis Etiology: Postviral Metabolic - Non-alcoholicfatty liver disease(NAFLD), Wilson'sdisease, alpha-1-antitrypsin deficiency. Toxic and drugs: Alcoholicliver disease Autoimmune: Autoimmunehepatitis, Primarybiliarycirrhosis, Primarysclerosingcholangitis Symptoms and signs: Nonspecificsymptoms - fatigue, anorexia, musclepains, arthralgia, weightloss

  11. Fibrosis Alteration in the normallybalancedprocesses of extracellular matrix production and degradation Stelatecells - ECM production, capillarization and constriction of sinusoidsportal hypertension Space of Disse -collagendeposition

  12. Cirhosis Finalcommonhistologicpathwayfor a wide variety of chronic liver diseases. Progressionmayoccuroverweeks to years. CIRRHOSIS Portal resistence Encephalopathy „shunting“ Portal hypertension Hepatopulmonarysy Splanchnicvasodilatation  Arterialfilling Cappilarypressure Arterial and cardiopulmonalreceptors  Vasoconstrictors  Lymphformation  Waterexcretion Na and waterretention Renalvasoconstriction Ascites Dilutionalhypernatremia Hepatorenalsy  Plasma volume

  13. Portal hypertension Increase of pressure gradient betweenportalvein and systemiccirculationabove 5 mmHg. • Patogenesis: • Higherintrahepatalvascular resistence (NO x endotelin) • Hyperkineticcirculation, splanchnicvasodilatation(NO,  TNF) • Consequences: • Collaterals „shunting“ • Ascites • Splenomegaly, hypersplenism • Varices (oesophageal, hemoroids) - bleeding • Classification: 1. Presinusoidal a) extrahepatal – thrombosis of v. portae b) intrahepatal – congenitalfibrosis, toxiclesions 2. Hepatal a) intrahepatal – cirhosis b) postsinusoidal – thrombosis of hepaticveins

  14. Encephalopathy Complex of reversibleneurologic and psychiatricssigns in chronic liver disease (damagedhepatocytes + portosystemicshunts) or in acute liver failure Manifest x latent • Pathogenesis: • - falseneurotransmiters • - GABA receptors • - Aminoacidsmetabolism • - impairment of HEB • - brain edema (vasogenic, cytotoxic) • Signs: • - malaise • - mooddisturbances • - loss of socialbariers • - inability to concentrate • - flapping tremor • - foetorhepaticus • - coma  HEB permeability GABA in synapse  amonia  benzodiazepins  act. GABAArec.  GABA-ergictransmision  inhibition of transmision encephalopathy

  15. Ascites

  16. Hepatorenalsy, Hepatopulmonarysy Hepatorenalsy (HRS) Type 1 - associated with rapid kidney failure Type 2 - associated with more gradual kidney damage Hepatopulmonarysy Triad: chronic liver disease pulmonary vasculardilatations hypoxemia

  17. Jaundice • Clinical symptom • infiltration of the skin, mucousmembranes, sclera • - increase of bilirubin plasma concentration 35 mol/l

  18. Differentialdiagnosis of hyperbilirubinemia

  19. Inheriteddisorders of bilirubin metabolism Unconjugated – deffect of conjugationto glucuronic acid Gilbert syndrome Crigler-Najjarsy type I. Crigler-Najjarsy type II. Conjugated – deffects in transport of bilirubin afterconjugation Dubin – Johnson´ssyndrome Rotor´s syndrome

  20. Prehepatic - hemolytic Icterusneonatorum (physiologicaljaundice of the newborn) 60 % fysiologicalinfants, unconjugated bilirubin to 205mo/l Pathogenesis: - overproductionof bilirubin 8-10 mg/kg - defectof transporters in hepatocytes (theirexpressionstartsafterweeks) - absence of intestinalmicroflora420-470 nm - higheractivity of –glukuronidase in mother´smilk Bilirubin encephalopathy (kernicterus) - bilirubin is potentially neurotoxic - haematoencefalic barrier is more permeable in infants - interference with a number of cellular processes – inhibition (apathy, hypotoniaortonicspasm, coma, affectionof basal ganglia – rigidity, chorea, mentalimpairment) - higher risk in prematures -presence of infections, hypoxemia, lessactivity of glucuronyltransferase, decrease of binding capacity of the albumine, acidosis, hypoglycaemia

  21. Prehepatic - hemolytic Erythroblastosisfetalis (icterusneonatorum gravis) - severe case of jaundice, - destruction of red cells as a result of immune-mediateedhemolysis – Rh-incompatibility Rh- mother (without D amtigen) – develops anti Rhaglutininswhen the fetus isRh+ (baby has inheritedRh+ antigen from the father) - incidence risesprogressivelywithsubsequentpregnancies - severe intrauterineanemia -hydrops fetalis, kernicterus, death Treatment: - preventiveadministration of anti-D globulin - replace the infantśbloodwithRh- blood

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