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Acute Liver Failure. Definition. The development of prolonged prothrombin time and encephalopathy within 8 weeks of symptom onset in patient with no previous liver disease U.S. annual incidence about 2,000 cases per year (1) High mortality. Causes of Acute Liver Failure.

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Acute Liver Failure


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    1. Acute Liver Failure

    2. Definition • The development of prolonged prothrombin time and encephalopathy within 8 weeks of symptom onset in patient with no previous liver disease • U.S. annual incidence about 2,000 cases per year (1) • High mortality

    3. Causes of Acute Liver Failure • Varies by geographic region • In the U.S., acetaminophen hepatotoxicity most common • Indeterminate cause • Idiosyncratic drug reactions – Isoniazid most common

    4. Causes of ALF • Hepatitis B – U.S. 4th most common cause; world wide # 1 cause • Hepatitis A – endemic areas • Autoimmune hepatitis • Ischemia • Wilson’s Disease

    5. Causes of ALF • Budd Chiari Syndrome • Pregnancy – acute fatty liver of pregnancy and the HELP syndrome (hemolysis, elevated liver chemistries, low platelets)

    6. Transplant-free Survival • Highest in APAP hepatotoxicity • Followed by drug reaction • Followed by indeterminate cause • Best when ALF develops hyper acutely i.e., within seven days

    7. The Phenomenon • Highly unpredictable • Dramatic • Requires aggressive intensive care management, anticipation of complications, and evaluation/listing for liver transplantation

    8. Survival • Correlates with degree of encephalopathy and coagulopathy • Encephalopathy may be abrupt and rapidly progressive • Subtle mood change - > seizures - > obtunded - > decorticate posture • Associated with cerebral edema rather than portosystemic shunting of toxins seen in cirrhosis

    9. Acetaminophen Overdose • Accidental • Suicide gesture/attempt • Emergency Room administration of antidote: p.o. NAC or I.V. Acetadote (contraindicated in sulfa allergy)

    10. Accidental Overdose • High dose APAP for an extended period • Inadvertent simultaneous administration of APAP w/ combination drugs: • OTC Sinus and cold preparations • OTC Narcotic pain relievers • OTC Sleep preparations • In combination w/ alcohol

    11. Pathophysiology • Dose dependent; known liver toxin • Also influenced by the presence of malnutrition, concomitant ethanol, co-administered drugs, and CYP 384 polymorphisms • Centrilobular necrosis without inflammation

    12. Signs and Symptoms • Anorexia, nausea, vomiting, malaise, right upper quadrant discomfort • Dark urine, pale stool, icterus • Transaminases rise within 10 – 12 hours, often to dramatic levels AST > ALT, peak at day three and rapidly improve • Jaundice develops quickly, total bilirubin not as high as that seen in other causes of ALF

    13. Case Study

    14. Questions and Answers

    15. Cirrhosis and Portal Hypertension The Final Stage of Chronic Liver Disease Due to Any Cause

    16. Cirrhosis • Excess extracellular matrix/fibrosis in liver • Fibrosis spans portal-central areas • portal-portal or central-central also seen • Fibrosis encases groups of hepatocytes • Results in distorted architecture and vasculature

    17. Normal Cirrhosis Nodules surrounded by fibrous tissue

    18. GROSS IMAGE OF A CIRRHOTIC LIVER Cirrhotic liver Nodular, irregular surface Nodules

    19. Portal Hypertension • Cirrhosis - > increased resistance to flow of blood in sinuosoids and in liver • Increased resistance = increased portal pressure = portal hypertension • Pressure in PV causes release of vasodilators, i.e., nitric oxide (NO) • NO causes splanchnic arteriolar vasodilation and increased splanchnic inflow of blood • This increased flow maintains portal hypertension in spite of development of low resistance collaterals

    20. SINUSOIDAL PORTAL HYPERTENSION Sinusoidal Portal Hypertension Portal systemic collaterals Cirrhotic liver Portal vein

    21. Consequences ofPortal Hypertension • Splenomegaly • Thrombocytopenia • Palpable spleen; splenectomy harmful • Varices • On imaging may be peri-gastric, esophageal, or splenic • On gastroscopy of variable size • Risk for bleed increases w/ advancing liver failure • Treat w/ nonselective beta blocker, banding

    22. Consequences ofPortal Hypertension • Ascites: The accumulation of fluid in the peritoneal cavity • An important clue to the presence of advanced cirrhosis • Result of sinusoidal HTN caused by blocked hepatic venous outflow 2/2 regenerative nodules and fibrosis • Result of plasma volume expansion, sodium, and water retention

    23. Serum to Ascites Albumin Gradient“SAAG” • The concentration of ascitic fluid protein is much lower than the concentration of serum protein • This is due to sinusoidal capillarization, decreased permeability to plasma proteins • Protein concentration in ascitic fluid in cirrhosis correlates inversely w/ the degree of portal hypertension

    24. Ascites • Associated conditions: • Hyponatremia • Umbilical hernia • Hepatic hydrothorax • Complication of ascites: • Spontaneous bacterial peritonitis • Pneumococus common etiology • Gram negative bacteria

    25. Ascites • Treatment: • Sodium restriction, diuretics, paracentesis • Transjugular intrahepatic portosystemic shunt • TIPS often worsens encephalopathy • Prognosis: continuum of uncomplicated ascites - > refractory ascites - > hepatorenal syndrome • Mortality approximately 20%/year

    26. THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT Hepatic vein TIPS Splenic vein Portal vein Superior mesenteric vein

    27. Consequences ofPortal Hypertension • Hepatic encephalopathy • Episodic vs persistent • Usually precipitated by events such as: • Bleeding • Infection • Use of sedatives or hypnotics • Dehydration

    28. Hepatic Encephalopathy • Pathogenesis: failure of the liver to detoxify portal blood toxins in the setting of decreased hepatic function and/or diminished hepatic perfusion by portal blood. Cerebral edema, ammonia, and disturbances in cell function, esp. astrocytes • Diagnosis: don’t assume it is HE until other potential causes of altered mental status have been considered

    29. EncephalopathyAlternative Explanations • Metabolic: hypoxia, hypoglycemia, hypo/hypernatremia, thyroid disease, hypercalcemia • Central Nervous System: CVA, Subdural hematoma, post ictal state, metastatic cancer • Toxins: alcohol, CNS depressants • Infection: sepsis, meningitis, encephalitis, delerium tremens

    30. StagingWest Haven Criteria • Stage 0: No abnormality • Stage 1: Trivial lack of awareness • Shortened attention span • Euphoria or anxiety • Impairment of addition and subtraction • Stage 2: Lethargy • Time disorientation • Personality change • Inappropriate behavior

    31. Staging Hepatic Encephalopathy West Haven Criteria • Stage 3: Somnolence to semistupor • Response to stimuli • Confusion • Disorientation • Bizarre behavior • Stage 4: Coma • Generalized motor abnormalities common: hyperreflexia, asterixis, Babinski +

    32. Hepatic Encephalopathy • Blood ammonia testing has little role in the diagnosis of HE • Clinical suspicion is the main guide • Treatment: • Supportive care for altered mental state • Identify and treat the precipitating cause • Exclude and/or treat other medical illnesses • Begin empirical therapy: lactulose, nonabsorbable antibiotics, metronidazole

    33. Complications of Cirrhosis • Osteoporosis • Increased risk of infections • Muscle cramps • Increased risk for hepatocellular carcinoma • Malnutrition • Depression • Pruritis

    34. Standard Recommendationsfor All Cirrhotics • Vaccinate against viral hepatitis, pneumococcal pneumonia, influenza • Baseline bone density test – treat osteopenia or osteoporosis as indicated • Baseline ultrasound and AFP and repeat semi-annually for HCC surveillance if cirrhotic • Esophageal varix surveillance – treat as indicated

    35. Standard Recommendationsfor All Cirrhotics • Refer for liver transplantation • Monitor for signs of advancing liver failure • Avoid alcohol • Avoid NSAIDs • Acetaminophen is analgesic of choice • If significant ascites, cane, walker • If Grade II or higher encephalopathy take the car keys, protect from harm

    36. Case Study

    37. Hepatitis C Prototype Chronic Liver Disease

    38. History of Viral Hepatitis • 2000 B.C. 1st recorded hepatitis epidemic • 1963 Australia antigen AKA Hepatitis B surface antigen (Blumberg & Alter) • 1970 Hepatitis B • 1972 National Blood Policy requires testing of blood donors for HBsAg

    39. History of Viral Hepatitis • 1973 Hepatitis A (Feinstone, Kapikian & Purcell) • 1975 “Non-A Non-B Hepatitis” • 1977 Hepatitis D (Rizzetto & Gerin) • 1983 Hepatitis E (Balayan) • 1989 Hepatitis C (Alter, et al. & Chiron Corp)

    40. Disease Burden EstimatesCenter for Hepatitis C, Cornell University

    41. Hepatitis C Prevalence Estimates • Affects both genders, all ages, races and regions of the world: 170 million or 3% world population • 40% of all chronic liver disease in U.S. • Most common blood-borne infection in the U.S.: 1.8% of population • 5.2 million HCV antibody positive, 4.1 million HCV RNA+ • 1.1 million = homeless, incarcerated, institutionalized, undocumented, and military • U.S. prisons estimates: 600,000 HCV RNA+ • 25% - 40% of prison population • 30% released each year (high risk behavior perpetuates transmission) • Born between 1945 and 1964, now age 55-64, have highest mortality

    42. Estimated Incidence of Acute HCV InfectionUnited States, 1960-2001

    43. Hepatitis C Facts • HCV related deaths increased 123% between 1995-2004 (Wise, et al.) • 1.09 deaths per 100,000 in 1995 • 2.44 deaths per 100,000 in 2004 • In 2004: 7,427 deaths, male 2.5 x > female • Middle-aged cohort 45 y/o to 64 y/o • Male Hispanic, AA, NA, Alaska natives • African American males 9% w/ HCV-1

    44. Hepatitis C Facts • Less than 10% of infected are being treated • Most do not know they are infected • 85% of HCV positive individuals can be identified by testing 20-59 year olds with elevated ALT and history of IDU or blood transfusion before 1992 • Those infected for 20 – 30 years • 10% - 20% -> cirrhosis • 1% - 5% -> hepatocellular carcinoma

    45. Who to Screen • Ever injected drugs • Clotting factors before 1972 • Received organ before 1992 • Ever on dialysis • Children of infected mothers • Evidence of liver disease • Workers after needle stick injury

    46. Who Not to Screen • Non-sexual household contacts • Healthcare workers, emergency medical workers, public safety workers • Pregnant women • If have contraindication to treatment • If have limited life expectancy

    47. Hepatitis C Virus • An enveloped, single-stranded, RNA virus with a genome of about 9,600 nucleotides (1 pentose sugar, 1 base + phosphoric acid = structural unit of nucleic acids i.e., RNA and DNA) • Flaviviridae family; other viruses in the family include West Nile virus; others cause yellow fever, dengue

    48. Hepatitis C Virus • Viral replication 1011 to 1012 virion/day (trillions!) • No proof reading ability -> high rate of mutation helps it to escape the immune system -> difficult to eradicate

    49. Genotype: Genetic Sequence • Used to project response to treatment • Six types, multiple subtypes