Fulminant Hepatic Failure

Nattaphol Uransilp

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. - Hyperacute <7 days - Acute 7-28 days - Subacute >28 days

Etiology
Viral hepatitis
Hepatitis A Hepatitis B Hepatitis C Hepatitis D - coinfects with Hep B Hepatitis E Hepatitis non A-G CMV, HSV

Toxins
Carbon tetrachloride Phosphorus Amanita phalloides (antidote penicillin and silybin) Industrial cleaning solvents

Etiology
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 disease Budd Chiari Veno-occlusive disease

Clinical Presentation
Typically - nonspecific symptoms, nausea, malaise, jaundice, altered mental status, coma all over a few days. Mental status changes often start with agitation, delusions, irritability before progressing to lethargy, stupor, and coma.

Clinical Presentation
Laboratory
Transaminases usually high (>1000) Bilirubin usually mixed hyperbilirubinemia Ammonia usually elevated Coagulopathy with prolonged PT, PTT, decreased factors DIC Respiratory alkalosis Metabolic acidosis, increased lactate

Hepatic Encephalopathy
Etiology uncertain. Suggested mechanisms: Depressed neural energy metabolism

Decreased hepatic clearance of neuro toxic substances

Hepatic Encephalopathy Grading 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

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 Edema

Signs of increased ICP (may not be present until late) Increased muscle tone Increased DTRs Dilated sluggish pupils Hyperventilation Cushing reflex (very late)

Coagulopathy
Decreased production of liver clotting factors (all but factor VIII), fibrinogen, ATIII, thrombocytopenia (splenic sequestration, DIC, other) PT/PTT prolonged

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.

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 failure common

Prerenal azotemia Acute tubular necrosis Hepatorenal syndrome

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

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 Organisms: Predominantly gram positive (strep and staph), gram negatives also occur. 30% have fungal infection.

Treatment

Hepatic Encephalopathy
Protect airway - Most patients with grade III to IV should be intubated. Avoid precipitants: Excessive protein load - particularly in form of GI bleed Infection Electrolyte abnormalities Respiratory alkalosis

Hepatic Encephalopathy
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
Beware and intervene for cerebral edema ICP monitoring - somewhat controversial because studies have not shown altered outcome and risk is significant because of coagulopathy.
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
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 - 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

Coagulopathy
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. Maintain platelet count >50K, or 100K if bleeding

Infectious Disease Issues

Prophylactic antibiotics have not been shown to
change outcome and most authors recommend meticulous surveillance and aggressive intervention with antibiotics when infection suspected.

Therapy
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.

Kings College Criteria

For Acetaminophen poisoning
pH < 7.3 (irrespective grade of encephalopathy) or PT > 100 seconds (INR >6.5)and serum creatinine > 3.4 in patients with grade III or IV encephalopathy

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 (Seronegative hepatitis) Jaundice for > 10 days prior to encephalopathy PT > 50 seconds,INR >3.5 Serum bilirubin > 17.5

Contraindications
Uncontrolled sepsis Multi-organ system failure Irreversible brain damage By neurologic exam Imaging studies Sustained ICP > 50, or CPP < 40 for 1 - 2 hours

Therapy
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