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 to be the best therapy for acute liver failure, however medical therapy does assist in the recovery of liver tissue, and acts as a bridging treatment prior to transplantation. Type of treatment chosen depends mainly on the underlying etiologies, and the complications that may arise. Liver support systems help in supporting the patients until the liver recovers, or can also be used as a bridging aid for transplantation.

Medical Therapy

The goal of medical therapies are to treat, correct, or prevent the following conditions:

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

Treatment of Complications

General measures

• Treatment always involves admission to hospital; often the intensive care unit, or a close observation unit is required.
• Supportive treatment with adequate nutrition and optimization of fluid balance should be a main goal.
• Intubation and mechanical ventilation are indicated for stage 3 or 4 encephalopathy.
• Infections and sepsis are common occurrences with fulminant liver failure. Though prophylactic antibiotics decrease the risk of infection, it is not routinely recommended during acute liver failure, as no proven survival benefits from doing so. Nevertheless, broad coverage with antibiotics is recommended in suspected cases of sepsis.
• Routine administration of steroids for adrenal insufficiency are not recommended.
• H2 receptor blockers and proton pump inhibitors are indicated to prevent and treat stress gastropathy.
• Early transfer to a liver transplantation center should be considered based on a patient's clinical status.

Management of Encephalopathy

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

Management of Increased Intracranial Pressure

• Monitoring for increased intracranial pressure 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 is indicated for reducing cerebral edema.
• Mannitol should be avoided in patients with advanced chronic kidney disease.
• Hypernatremia (145-155 mEq/L) can be induced through intravenous hypertonic saline infusion to reduce intracranial hypertension.
• Hypothermia (32–34 °C) may reduce intracranial pressure in refractory cases.
• Other measures such as elevation of the head of the bed to 30 degrees, hyperventilation and intravenous prostaglandin E1 can also be used.
• Short-acting barbiturates, propofol, or IV indomethacin can be used for refractory intracranial hypertension.

Management of Infection

• The use of antimicrobials as a prophylaxis may reduce infections in a few patients with acute liver failure, but has no survival benefit.
• If prophylaxis is not started, there should be ongoing surveillance for the development of infections.
• There is an association of SIRS (systemic inflammatory response syndrome) with infection, which may worsen prognosis.

Management of Coagulopathy and Bleeding Complications

• Coagulopathy constitutes a part of the definition for acute liver failure.
• If there is no evidence of bleeding and INR is not in the normal range, treating the INR with fluids such as plasma may lead to volume overload and may cause transfusion related lung injury.
• Vitamin K should be administered routinely (5- 10 mg SC) as there is decreased synthesis of clotting factors from the liver tissue.
• In high risk procedures, or clinically significant bleeding, clotting factor deficiencies should be treated.
• Bleeding mainly occurs from the capillaries, and is usually from mucosal surfaces of the stomach and lung. Esophageal varices are uncommon in acute liver failure.
• H₂ receptor blocking agents help in protecting the mucosal surface of stomach from the acid due to stress.

Management of Hemodynamic and Metabolic Disturbances

• Decreased tissue perfusion leading to poor oxygenation and multi-organ failure is a major concern in acute liver failure.
• Patients should be resuscitated with normal saline first, then half normal saline containing 75 mEq/L of bicarbonate should be used. This fluid should be administered before the use of vasopressors.
• For hypoglycemia, a dextrose solution should be used.
• If a patient is not responding to fluid or vasopressors, the infusion rate should be slowed down to prevent intense vaso-constriction causing ischemia of tissues.
• In patients progressing to acute renal failure care must be taken to avoid NSAIDs and nephrotoxic agents. Dialysis should be used in a continuous mode rather than intermittent mode.
• Continuous monitoring of glucose and electrolytes is required as they may worsen the condition further.

Treatment for the Specific Underlying Cause

Acetaminophen Poisoning

• • Acetylcysteine is used for acetaminophen poisoning up to 72 hours after ingestion.
  • Acetylcysteine 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, and give 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.

Mushroom Poisoning

• Penicillin G - 300,000 to 1 million units/kg/day or

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 such as DRESS (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

• Supportive care
• 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's Disease

• Plasmapheresis + D-penicillamine are used in Wilson's disease.

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

• Patients with autoimmune hepatitis are candidates for corticosteroid therapy.
• These patients should be considered for liver transplantation without delaying assessment to consider 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 fatal complications of HELLP syndrome requiring immediate resuscitation and intervention.
• Early diagnosis of the complications, and delivery of the baby helps in improving the outcome.
• 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 in shock liver 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 Budd-Chiari syndrome 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

Liver support systems are support devices which help in resting the liver to provide it some time to recover. These can also be used as a bridge to transplantation. There are two kinds of devices; sorbent based artificial systems and cell based bio-artificial systems. There is no good evidence showing a decrease in mortality with their use in acute liver failure. They are not currently recommended outside of clinical trials.

2011 AASLD Recommendations for Acute Liver Failure (DO NOT EDIT)

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.

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.

Infections (DO NOT EDIT)

Class III

1. Periodic surveillance cultures are recommended to detect bacterial and fungal pathogens as early as possible. Antibiotic treatment should be initiated promptly according to surveillance culture results at the earliest sign of active infection or deterioration (progression to high grade hepatic encephalopathy or elements of the SIRS)

2. Prophylactic antibiotics and antifungals have not been shown to improve overall outcomes in ALF and therefore cannot be advocated in all patients, particularly those with mild hepatic encephalopathy.

Bleeding and Coagulopathy (DO NOT EDIT)

Class I

1. Patients with ALF in the ICU should receive prophylaxis with H2 blocking agents or proton pump inhibitors (or sucralfate as a second-line agent) for acid-related gastrointestinal bleeding associated with stress.

Class III

1. Replacement therapy for thrombocytopenia and/or prolonged prothrombin time is recommended only in the setting of hemorrhage or prior to invasive procedures.

Hemodynamic and Metabolic Disturbances (DO NOT EDIT)

Class I

1. If dialysis support is needed for acute renal failure, it is recommended that a continuous mode rather than an intermittent mode be used.

Class II

1. Goals of circulatory support in patients with ALF are a MAP 75 mmHg and CPP 60-80 mmHg

Class II-1

2. Systemic vasopressor support with agents such as norepinephrine should be administered in volume refractory hypotension or to ensure adequate CPP. Vasopressin or terlipressin can be added to norepinephrine in norepinephrine-refractory cases, but should be used cautiously in severely encephalopathic patients with intracranial hypertension.

Class III

1. Fluid resuscitation and maintenance of adequate intravascular volume are recommended on presentation in patients with ALF. The initial treatment of hypotension should be with intravenous normal saline.

2. Pulmonary artery catheterization is rarely necessary in patients with ALF and is associated with significant morbidity. Instead, appropriate volume status should be ensured with a volume challenge.

3. Metabolic homeostasis must be carefully maintained in ALF patients. Overall nutritional status as well as glucose, phosphate, potassium and magnesium levels should be monitored frequently, with expeditious correction of derangements.

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 (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.