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Fulminant Hepatic Failure & Liver Transplantation. Fulminant Hepatic Failure. Definition - Altered mental status with coagulopathy in setting of acute liver disease. Hepatic encephalopathy occurring within 8 weeks of onset of illness defines FHF. Viral hepatitis Hepatitis A - rarely

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fulminant hepatic failure
Fulminant Hepatic Failure

Definition - Altered mental status with coagulopathy in setting of acute liver disease. Hepatic encephalopathy occurring within 8 weeks of onset of illness defines FHF.

etiology
Viral hepatitis

Hepatitis A - rarely

Hepatitis B - appx 1% of hep B

Hep C -- probably not, but ??

Hep D -- delta agent coinfects with Hep B

Hep E

CMV, HSV

Toxins

Carbon tetrachloride

Phosphorus

Amanita phalloides (antidote penicillin and silybin)

Industrial cleaning solvents

Etiology
etiology4
Drugs

Acetaminophen

Acetaminophen in Tx doses with alcohol

Idiosyncratic reaction -- halothane, sulfonamides, phenytoin, and others.

Vascular

Heart failure -- centrolobular necrosis

Sinusoidal obstruction secondary to metastatic dz

Budd Chiari

Veno-occlusive disease

Etiology
pathology
Pathology
  • Viral, toxic -- hepatocellular necrosis, diffuse, extensive, resulting in caseating necrosis.
  • Cardiac -- similar, with particularly severe centrolobular necrosis from higher intravascular pressure and watershed effect. Blood flows from portal triad (hepatic artery and portal vein) to central veins to hepatic vein. With poor cardiac output, splanchnic flow markedly decreased, resulting in markedly decreased portal flow, which is a large proportion of flow to liver.
pathology6
Pathology
  • Fatty liver of pregnancy and Reye’s show microvesicular collections of fat in hepatocytes and much less necrosis.
  • Special stains -- iron in hemochromatosis, copper in Wilson’s, etc.
clinical presentation
Clinical Presentation
  • Typically -- nonspecific symptoms, nausea, malaise, jaundice, altered mental status, coma -- all over a few days.
  • The altered mental status occasionally precedes clinical jaundice.
  • Mental status changes often start with agitation, delusions, irritability before progressing to lethargy, stupor, and coma.
clinical presentation8
Clinical Presentation
  • Laboratory --
      • Transaminases usually high (>1000)
      • Bilirubin -- usually mixed hyperbilirubinemia
      • Ammonia -- usually elevated
      • Coagulopathy with prolonged PT, PTT, decreased factors
      • Low level DIC
      • Low level fibrinolysis
      • Respiratory alkalosis
      • Metabolic acidosis, increased lactate
hepatic encephalopathy etiology
Hepatic EncephalopathyEtiology

Etiology uncertain.

Suggested mechanisms:

Depressed neural energy metabolism -- but autopsied animals show no changes of ischemia

Decreased hepatic clearance of neuro toxic substances

hepatic encephalopathy neurotoxins
Hepatic EncephalopathyNeurotoxins
  • Ammonia -- correlates poorly with encephalopathy
  • Amino acids --aromatic and straight chain aa are increased in liver failure -- tryptophan may be preferentially transported into CNS
  • Methionine, mercaptans
  • Gamma aminobutyric acid (GABA) -- this is an inhibitory neurotransmitter. GABA receptor is site of benzodiazepine action. GABA levels and endogenous benzodiazepines are elevated in hepatic failure. Enteric bacteria produce GABA and this may be absorbed across gut. Flumazenil anecdotally improves encephalopathy.
hepatic encephalopathy grading system
Hepatic EncephalopathyGrading System
  • Grade 0 -- Normal
  • Grade I -- Altered spatial orientation, sleep patterns, and affect
  • Grade II -- Drowsy but arousable, slurred speech, confusion, and asterixis
  • Grade III-- Stuporous but responsive to painful stimuli
  • Grade IV-- Unresponsive, with or without decorticate or decerebrate posturing
hepatic encephalopathy cerebral edema
Hepatic EncephalopathyCerebral Edema
  • Etiology uncertain -- Correlated with degree of encephalopathy. Occurs in 50 - 85% of patients with late grade 3 to grade 4 encephalopathy.
  • Evidence of altered blood brain barrier
  • Impaired cellular Na+K+ -ATP pump resulting in glial cell edema
  • Inappropriate cerebral vasodilatation
hepatic encephalopathy cerebral edema13
Hepatic EncephalopathyCerebral Edema

Signs of increased ICP (may not be present until late)

  • Increased muscle tone
  • Increased DTRs
  • Dilated sluggish pupils
  • Hyperventilation
  • Cushing reflex (very late)
hepatic encephalopathy treatment
Hepatic EncephalopathyTreatment
  • Protect airway -- Most patients with grade III to IV should be intubated.
  • Avoid precipitants:
    • Excessive protein load -- particularly in form of GI bleed
    • CNS depressants
    • Infection
    • Electrolyte abnormalities
    • Respiratory alkalosis
hepatic encephalopathy treatment15
Hepatic EncephalopathyTreatment
  • Prevent hypotension
  • Lactulose -- although not shown to work well in FHF and felt to be less effective than in chronic liver disease.
  • Branch chain amino acids -- theoretically appealing but studies are mixed results -- most authors feel they are not helpful.
hepatic encephalopathy treatment16
Hepatic EncephalopathyTreatment
  • Beware and intervene for cerebral edema
  • ICP monitoring -- somewhat controversial because studies have not shown altered outcome and risk is significant because of coagulopathy. Reasons favoring monitoring:
    • Intracranial hypertension is erratic and can develop rapidly with few clinical signs
    • Monitoring allows for early detection and minute-to-minute titration of therapy
    • Cerebral perfusion pressure is prognostic sign and would spare poor risk patients a transplant (CPP < 50 for 2 hrs)
    • Allows management of intraoperative events
hepatic encephalopathy treatment17
Hepatic EncephalopathyTreatment

Consider ICP monitoring if

  • Grade 3 - 4 with posturing
  • PT corrected to < 20, platelets corrected
  • Patient is listed for transplant and felt to be a candidate for transplant
hepatic encephalopathy treatment18
Hepatic EncephalopathyTreatment
  • Mannitol -- shown to be effective in improving outcome
  • Hyperventilation -- probably useful for acute spikes in ICP. Has not been shown to be effective in hepatic failure. Concerns about effect on cerebral perfusion warrant consideration.
  • Elevation of head -- ?? What is effect on CPP? Keep head midline, perhaps 20 - 30 degrees of elevation.
  • Pentobarbital coma, hypothermia -- unproven, occasionally may be indicated.
  • Steroids -- no good, may worsen outcome
hepatic encephalopathy treatment19
Hepatic EncephalopathyTreatment

Get better liver

or

Get liver better

coagulopathy
Coagulopathy
  • Decreased production of liver clotting factors (all but factor VIII), fibrinogen, ATIII, thrombocytopenia (splenic sequestration, low level DIC, other)
  • PT/PTT prolonged
  • Factors V and VII often followed as they are relatively labile
  • Factor VIII normal or increased if just liver failure, decreased in DIC
  • Euglobulin clot lysis time abnormal in primary fibrinolysis
coagulopathy management
CoagulopathyManagement
  • Avoid bleeding
  • GI prophylaxis
  • Avoid nasal intubation
  • Beware with surgical procedures, line placement, etc.
  • FFP -- Not shown to be effective in changing bleeding risk (?). Most authors discourage routine attempts at normalizing PT. Use for active bleeding and procedures.
  • Antifibrinolytics (Amicar) may be considered if bleeding and primary fibrinolysis is occurring. Caution with DIC.
  • Maintain platelet count >50K, or 100K if bleeding
metabolic considerations
Metabolic Considerations
  • Hypoglycemia -- decreased hepatic glycogen stores, impaired gluconeogenesis results in hyperinsulin state and insulin resistance. There is impaired glucose homeostasis and hypoglycemia.
  • glucagon, insulin secondary to decreased hepatic clearance, leads to decreased insulin/glucagon ratio, which favors catabolism.
  • Aromatic amino acids are increased, probably because of decreased hepatic clearance.
metabolic considerations23
Metabolic Considerations
  • Branch chain amino acids are cleared into skeletal muscle and are not elevated, so AAA > BCAA
  • AAA and BCAA compete for entry to CNS. AAA, particularly tryptophan is converted to serotonin and other possible false neurotransmitters.
  • Supplementing BCAA theoretically may improve encephalopathy, but studies give mixed results and most authorities feel the evidence does not favor their use for this indication.
  • BCAA may also be more readily available for nutrition since the hyperinsulin state favors uptake by muscle, which is not true for other AA. Evidence indicates less catabolism and less muscle wasting with use of BCAA.
hemodynamic effects
Hemodynamic Effects
  • Increased cardiac output
  • Decreased systemic vascular resistance
  • Decreased oxygen extraction ratio and decreased consumption despite increased delivery
  • Oxygen consumption often becomes supply dependent.
  • Lactic acidosis secondary to anaerobic metabolism ensues.
  • Lactic acidosis has been shown to herald a poor prognosis.
renal effects
Renal Effects

Renal failure common

  • Prerenal azotemia
  • Acute tubular necrosis
  • Hepatorenal syndrome
hepatorenal syndrome
Hepatorenal Syndrome
  • Etiology uncertain -- prominent theory is that low SVR results in “arterial underfilling” and subsequent increase in renin, aldosterone, ADH, and norepinephrine resulting in renal arteriole vasoconstriction. Renal vasodilatory prostaglandins are important to attenuate this, so that when NSAIDS are given this compensation is lost. NSAIDS are known precipitants of hepatorenal syndrome.
  • Diagnosis -- in absence of hypovolemia see very low urine sodium, normal urine sediment. Exclude other causes.
  • Treatment -- recover hepatic function, otherwise the renal failure is very recalcitrant. Dialysis as needed and indicated.
respiratory effects
Respiratory Effects

Respiratory failure can occur by several mechanisms:

  • Neurogenic pulmonary edema
  • Fluid overload because of hyperaldosterone and increased ADH with conservation of salt and water
  • ARDS secondary to sepsis or MSOF
  • Also, some have suggested capillary leak affecting pulmonary and CNS vasculature
  • Hepatopulmonary syndrome
slide28

Hepatopulmonary syndrome

  • Hypoxemia associated with chronic liver disease.
  • Thought to be secondary to intrapulmonary vascular dilatations with a-v shunting as well as diffusion block because of dilated capillaries.
  • Sometimes, but not always resolves with transplant
infectious disease issues
Infectious Disease Issues
  • Impaired host defenses --
      • Defective opsonic activity
      • Impaired PMN function
      • Impaired cell and humoral immunity
      • Decrease clearance of enteric organisms by hepatic RES
      • Ascites -- good culture medium
      • Invasive lines, ETT, etc
infectious disease issues30
Infectious Disease Issues
  • Infection risk: 80% of patients had documented bacterial or fungal invasive infections, with a suspicion of infection in half the remaining patients. 25% had blood stream infection, with a respiratory source predominating in the remainder.
  • Organisms: Predominantly gram positive (strep and staph), gram negatives also occur. 30% have fungal infection.
  • Prophylactic antibioticshave not been shown to change outcome and most authors recommend meticulous surveillance and aggressive intervention with antibiotics when infection suspected.
fulminant hepatic failure therapy
Fulminant Hepatic FailureTherapy

“Authors tend to publish isolated cases with a favorable outcome attributed to a given therapy, but not to publish cases in which therapy has failed. In fact it might be argued that the best future one can wish for a sufferer from SAHF (sudden acute hepatic failure) is to undergo a new treatment and have his case published -- ‘be published or perish!’ “

Benhanou, 1972

fulminant hepatic failure therapy32
Fulminant Hepatic FailureTherapy
  • Tried but failed --
      • Insulin and glucagon to stimulate regeneration
      • Prostaglandin E
      • Corticosteroids
      • Hemofiltration
      • Charcoal hemoperfusion
      • Plasma exchange
  • Liver transplantation -- best results. Greater than 60% one year survival in adult patients with acute liver failure. Only 10% of patients are deemed candidates and successfully supported until transplantation.
fulminant hepatic failure therapy33
Fulminant Hepatic FailureTherapy
  • ELAD (extracorporeal liver assist device) -- most acute liver failure is thought to be recoverable if patient survives long enough. Most patients either die or have regeneration and normal liver function. Goal would be to:
      • Support patient while awaiting recovery - thus avoiding transplant and its risks - short and long term
      • Stabilize patient while awaiting transplant
  • ELAD seems promising in animal studies and has been used on a few patients with encouraging results. Not yet a proven therapy.
kings college london criteria for predicting death and need for liver transplantation
Kings College, LondonCriteria for Predicting Death and Need for Liver Transplantation
  • Depends on etiology
  • For Acetaminophen poisoning
    • pH < 7.3 (irrespective grade of encephalopathy)
    • or PT > 100 seconds and serum creatinine > 3.4 in patients with grade III or IV encephalopathy
kings college london criteria for predicting death and need for liver transplantation35
Kings College, LondonCriteria for Predicting Death and Need for Liver Transplantation
  • All other etiologies
    • PT > 100 seconds (irrespective of grade of encephalopathy)
  • OR any 3 of the following
    • Age < 10 years or > 40
    • Liver failure caused by non-A, non-B hepatitis, halothane, or idiosyncratic drug rxn
    • Jaundice for > 10 days prior to encephalopathy
    • PT > 50 seconds
    • Serum bilirubin > 17.5
united network for organ sharing unos status 1 most urgent level
United Network for Organ Sharing (UNOS)Status 1 - most urgent level
  • Rapid development of grade 3 - 4 encephalopathy
  • Prothrombin time > 25 sec
  • On vasopressors or ventilatory support
  • Have primary graft non-function
  • Are expected to live less than 7 days without a transplant
  • Inborn error of metabolism with metabolites that are toxic to the CNS
transplantation in fhf contraindications
Transplantation in FHFContraindications
  • Uncontrolled sepsis
  • Multi-organ system failure
  • Irreversible brain damage
    • By neurologic exam
    • Imaging studies
    • Sustained ICP > 50, or
    • CPP < 40 for 1 - 2 hours
fulminant hepatic failure recommended readings
Fulminant Hepatic FailureRecommended Readings
  • Lee WM. Acute Liver Failure. N Engl J Med 1993;329:1862 - 1872.
  • Caraceni P, and Van Thiel DH. Acute Liver Failure. Lancet 1995;345:163-9.
  • Riordan SM, and Williams R. Treatment of Hepatic Encephalopathy. N Engl J Med 1997;337:473-9.
  • Whitington PF, et al. Pediatric Liver Transplantation. Seminars in Liver Disease 1994; 14:303-317.