Acute liver failure medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2]

Overview

Liver transplantation remains the ultimate therapy for acute liver failure but medical therapy assists in recovery of liver tissue. It acts like a bridge to transplantation. Treatment mainly depends on the underlying etiologies and the complications arising out of it. Liver support systems help in supporting the patients until the liver recovers or can be used as a bridging aid for transplantation.

Medical Therapy

Goal

• Metabolic abnormalities
• Coagulation defects
• Electrolyte and acid-base disturbances
• Advanced chronic kidney disease
• Hypoglycemia
• Encephalopathy

Treatment strategies

General measures

• Treatment involves admission to hospital; often intensive care unit admission or very close observation are required.
• Supportive treatment with adequate nutrition and, optimization of the fluid balance should be done
• Mechanical ventilation, intubation is indicated for stage 3 or 4 encephalopathy
• Sepsis and infections are common with fulminant liver failure. Though prophylactic antibiotic decreases the risk of infection, but is not routinely recommended as no survival benefits have been proved. Nevertheless, broad coverage with antibiotics is recommended for suspected cases of sepsis.
• Routine administration of steroids for adrenal insufficiency is not recommended.
• H2 receptor blocker and proton pump inhibitors are indicated to prevent and treat stress gastropathy.
• Early transfer to a liver transplantation center should be decided based on patient's clinical status.

2011 AASLD Recommendations : General Measures (DO NOT EDIT)

Class III

1. Patients with ALF should be hospitalized and monitored frequently, preferably in an ICU.

2. The precise etiology of ALF should be sought to guide further management decisions.

Management of Encephalopathy

• Grade I can be managed in the floors with adequate skilled nursing staff in a calm atmosphere. It helps in reducing agitation.
• Grade II encephalopathy has to be managed in ICU setting.
• For Grade III/IV encephalopathy intubation and mechanical ventilation are required to manage these patients.
• Monitoring and management of hemodynamic and renal parameters as well as glucose, electrolytes and acid/base status is very important.

Management of increased intracranial pressure

• Intracranial pressure monitoring in severe encephalopathy and impending cerebral edema should be done with extradural sensors

• The goal should be to maintain the intracranial pressure below 20 mm Hg and the cerebral perfusion pressure above 70 mm Hg.
• Lactulose is indicated in cases of encephalopathy.
• Mannitol, 0.5 g/kg, or 100–200 mL of a 20% solution by intravenous infusion over 10 minutes for reducing cerebral edema
• Mannitol should be avoided in patients with advanced chronic kidney diseases.
• Hypernatremia (145-155 mEq/L) through intravenous hypertonic saline infusion to induce hypernatremia may be used to reduce intracranial hypertension.
• Hypothermia (32–34 °C) may reduce intracranial pressure in refractory cases can be tried.
• Other measures like elevation of head end to 30 degrees, hyperventilation and intravenous prostaglandin E1can also be used.
• Short-acting barbiturate, propofol, or i/v indomethacin for refractory intracranial hypertension.

2011 AASLD Recommendations : Encephalopathy and Intracranial Pressure(DO NOT EDIT)

Class I

1. In ALF patients at highest risk for cerebral edema (serum ammonia > 150 lM, grade 3/4 hepatic encephalopathy, acute renal failure, requiring vasopressors to maintain MAP), the prophylactic induction of hypernatremia with hypertonic saline to a sodium level of 145-155 mEq/L is recommended.

2. Corticosteroids should not be used to control elevated ICP in patients with ALF.

Class II-2

1. In the event of intracranial hypertension, a mannitol bolus (0.5-1.0 gm/kg body weight) is recommended as first-line therapy; however, the prophylactic administration of mannitol is not recommended.

Class II-3

1. Short-acting barbiturates and the induction of hypothermia to a core body temperature of 34-35oC may be considered for intracranial hypertension refractory to osmotic agents as a bridge to liver transplantation.

Class III

1. In early stages of encephalopathy, lactulose may be used either orally or rectally to effect a bowel purge, but should not be administered to the point of diarrhea, and may interfere with the surgical field by increasing bowel distention during liver transplantation.

2. Patients who progress to high-grade hepatic encephalopathy (grade III or IV) should undergo endotracheal intubation.

3. Seizure activity should be treated with phenytoin and benzodiazepines with short half-lives. Prophylactic phenytoin is not recommended.

4. Intracranial pressure monitoring is recommended in ALF patients with high grade hepatic encephalopathy, in centers with expertise in ICP monitoring, in patients awaiting and undergoing liver transplantation.

5. In the absence of ICP monitoring, frequent (hourly) neurological evaluation is recommended to identify early evidence of intracranial hypertension.

Treatment for specific underlying cause

Acetaminophen or Paracetamol poisoning

• • Acetylcysteine for paracetamol poisoning up to 72 hours after ingestion
  • It improves cerebral blood flow and increases transplant-free survival in patients with stage 1 or 2 encephalopathy due to hepatic failure of any cause.
  • Its treatment can increase prothrombin time giving a false alarm of worsening liver failure.
    • 140 mg/kg orally followed by 70 mg/kg orally every 4 hours for an additional 17 doses or
    • 150 mg/kg in 5% dextrose intravenously over 15 minutes followed by 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours.

2011 AASLD Recommendations : Acetaminophen Hepatotoxicity (DO NOT EDIT)

Class I

1. For patients with known or suspected acetaminophen overdose within 4 hours of presentation, give activated charcoal just prior to starting NAC dosing.

Class II-1

1. Begin NAC promptly in all patients where the quantity of acetaminophen ingested, serum drug level or rising aminotransferases indicate impending or evolving liver injury.

Class III

1. NAC may be used in cases of acute liver failure in which acetaminophen ingestion is possible or when knowledge of circumstances surrounding admission is inadequate but aminotransferases suggest acetaminophen poisoning.

Mushroom poisoning

• Penicillin G - 300,000 to 1 million units/kg/day or
• Silibinin/silymarin/milk thistle (not licensed in the United States)

2011 AASLD Recommendations : Mushroom Poisoning (DO NOT EDIT)

Class III

1. In ALF patients with known or suspected mushroom poisoning, consider administration of penicillin G and N-acetylcysteine.

2. Patients with acute liver failure secondary to mushroom poisoning should be listed for transplantation, as this procedure is often the only lifesaving option.

Drug Induced Hepatoxicity

• Drugs other than acetaminophen rarely cause dose induced toxicity.
• The mechanism of toxicity is mostly due to idiosyncratic toxicity.
• No specific antidotes exist for these idiosyncratic drug reactions.
• Corticosteroids are not indicated unless a drug hypersensitivity(drug rash with eosinophilia and systemic symptoms) syndrome or an autoimmune reaction is suspected.

2011 AASLD Recommendations : Drug Induced Hepatoxicity (DO NOT EDIT)

Class I

1. N-acetylcysteine may be beneficial for acute liver failure due to drug-induced liver injury.

Class III

1. Obtain details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year.

2. Determine ingredients of non-prescription medications whenever possible.

3. In the setting of acute liver failure due to possible drug hepatotoxicity, discontinue all but essential medications.

Chronic viral hepatitis

• Nucleoside analogs - Fulminant hepatitis B

2011 AASLD Recommendations : Viral Hepatitis (DO NOT EDIT)

Class III

1. Viral hepatitis A (and E) related acute liver failure must be treated with supportive care as no virus specific treatment has proven to be effective.

2. Nucleos(t)ide analogues should be considered for hepatitis B-associated acute liver failure and for prevention of post-transplant recurrence.

Herpes simplex hepatitis

• Intravenous acyclovir

2011 AASLD Recommendations : Herpes Simplex Hepatitis (DO NOT EDIT)

Class III

1. Patients with known or suspected herpes virus or varicella zoster as the cause of acute liver failure should be treated with acyclovir (5-10 mg/kg IV every 8 hours) and may be considered for transplantation.

Wilson disease

• Plasmapheresis + D-penicillamine

2011 AASLD Recommendations : Wilson Disease (DO NOT EDIT)

Class III

1. To exclude Wilson disease one should obtain ceruloplasmin, serum and urinary copper levels, slit lamp examination for Kayser-Fleischer rings, hepatic copper levels when liver biopsy is feasible, and total bilirubin/alkaline phosphatase ratio.

2. Patients in whom Wilson disease is the likely cause of acute liver failure must be promptly considered for liver transplantation.

Autoimmune Hepatitis

• These patients are candidates for corticosteroid therapy.
• These patients should be considered for liver transplantation without delay waiting for response of steroid therapy.

2011 AASLD Recommendations : Autoimmune Hepatitis (DO NOT EDIT)

Class III

1. Patients with coagulopathy and mild hepatic encephalopathy due to autoimmune hepatitis may be considered for corticosteroid treatment (prednisone, 40-60 mg/day).

2. Patients with autoimmune hepatitis should be considered for transplantation even while corticosteroids are being administered.

HELLP Syndrome

• Hepatic rupture or hemorrhage are the fatal complication requiring immediate resuscitation and intervention.
• Early diagnosis of the complications and delivery helps in improving the outcomes.
• Transplantation my be considered if there is postpartum deterioration.

2011 AASLD Recommendations : HELLP Syndrome (DO NOT EDIT)

Class III

1. For acute fatty liver of pregnancy or the HELLP syndrome, expeditious delivery of the infant is recommended.Transplantation may need to be considered if hepatic failure does not resolve quickly following delivery.

Shock Liver

• Treatment of underlying cause of ischemia is very important and determines the prognosis of the condition.
• Transplantation is seldom indicated.

2011 AASLD Recommendations : Shock Liver (DO NOT EDIT)

Class III

1. In ALF patients with evidence of ischemic injury, cardiovascular support is the treatment of choice.

Budd-Chiari Syndrome

• Transplantation is considered after confirming the diagnosis and excluding malignancy for venous decompression.

2011 AASLD Recommendations : Budd-Chiari Syndrome (DO NOT EDIT)

Class II-3

1. Hepatic vein thrombosis with acute hepatic failure is an indication for liver transplantation, provided underlying malignancy is excluded.

Liver Support Systems

These are the support devices helping in providing some time to help failing liver to recover. These can also be used as a bridge to transplantation. There are two kinds of devices sorbent based artificial system and cell based bio-artificial system. There is no good evidence showing low mortality with their use in acute liver failure. They are not recommended outside of clinical trials as of now.