Liver Failure
Deanna Blisard
I. Acute Liver Failure
Introduction
Fulminant hepatic failure (FHF) is synonymous with acute liver failure (ALF).
Approximately 2,000 cases of ALF occur in the United States per year.
ALF is the rapid deterioration of liver function, which results in altered mental status and coagulopathy in previously normal individuals.
Loss of hepatic function can quickly lead to multiorgan failure and death.
Definition
Most widely accepted definition of ALF is the presence of coagulation abnormalities and any degree of encephalopathy in a patient without preexisting cirrhosis, with an illness of <26 weeks duration.
Classified according to length of illness:
Hyperacute: <7 days
Acute: 7 to 21 days
Subacute: >21 days and <26 weeks
Length of illness has no prognostic significance distinct from cause of the illness.
Etiology
Major indicator of prognosis; also dictates specific management options.
Viral—hepatitis A, hepatitis B, herpes, cytomegalovirus, Epstein–Barr virus.
Vascular—Budd–Chiari syndrome, right heart failure, shock liver.
Metabolic—Wilson’s disease, HELLP syndrome, acute fatty liver of pregnancy, tyrosinemia.
Drugs and toxins—acetaminophen, Amanita phalloides, Bacillus cereus toxin, herbal remedies.
Miscellaneous/indeterminate—malignant infiltration, autoimmune hepatitis, severe sepsis.
Acetaminophen
Acetaminophen toxicity is the leading cause of ALF in the United States, accounting for 40% of cases.
Suspected when evidence of excessive ingestion, usually as a suicidal attempt or ingestion of supratherapeutic quantities of pain medications.
Dose related toxin, most ingestions that lead to ALF exceeding 10 g/day.
Acetaminophen overdose leads to the accumulation of N-acetyl-p-benzoquinone imine, a metabolite normally conjugated by glutathione that is toxic to hepatocytes.
Acetaminophen levels should be drawn on all patients presenting with ALF, and the agent N-acetylcysteine (NAC) started.
Excessive ingestion of acetaminophen leads to depletion of glutathione stores, and NAC augments glutathione levels.
NAC should be started as early as possible, but can be useful even 48 hours or more after ingestion.
The oral dosing is 140 mg/kg diluted to 5% solution, followed by 70 mg/kg by mouth q4h × 17 doses.
The intravenous dosing is a loading dose of 150 mg/kg in 5% dextrose over 15 minutes, followed by maintenance dosing of 50 mg/kg over 4 hours, followed by 100 mg/kg administered over 16 hours.
Presentation of ALF
Presenting symptoms are often nonspecific. ALF patients are heterogeneous but share the common disease process of acute hepatocyte necrosis and its sequelae.
Symptoms include fatigue, malaise, anorexia, nausea, abdominal pain, fever, and jaundice.
Often these symptoms progress to severe coagulopathy and encephalopathy and/or coma.
Initial treatment
Regular monitoring including frequent vital signs, blood glucose, and neurologic status.
Initial laboratory testing should include:
Complete blood count
Biochemical panel, including renal function, liver function tests
Hematologic panel
Immunologic panel
Hepatitis panel
Toxic drug screens
Arterial blood gas and lactate levels to assess metabolic disturbances.
Radiographic tests include:
Chest x-ray
Abdominal ultrasound with Doppler studies to evaluate hepatic and portal venous flow patterns
Triphasic CT scan to evaluate hepatic parenchyma for tumors, ischemia/necrosis, and fatty infiltration.
Clinical deterioration can be rapid, and any worsening in the clinical condition should prompt referral to a transplant center.
Patients who present in full ALF often have severe metabolic acidosis, hypoglycemia, coagulopathy, and encephalopathy/coma.
Stabilization includes volume resuscitation, mechanical ventilation, and hemodynamic support.
Hepatic encephalopathy (HE) and intracranial hypertension (ICH)
Definition
Hallmark feature of ALF.
Prognosis is inversely correlated with the degree of encephalopathy.
Most serious complication of ALF is cerebral edema and ICH, affecting 50% to 80% of patients with severe ALF (grade III or IV coma).
Presentation
HE can vary from subtle changes in affect, insomnia, or difficulties with concentration (grade I) to deep coma (grade IV). Table 40-1 illustrates encephalopathy grades.
Grades I and II encephalopathy seldom have signs of cerebral edema.
Progression to grade III portends 25% to 35% increased risk of edema; 65% to 75% or more in patients reaching grade IV HE.
ICH presents with signs of systemic hypertension, bradycardia, abnormal papillary signs, aggravation of HE, epileptiform activity, and decerebrate posturing.
Pathophysiology
Two theories for ICH in ALF:
Brain edema due to osmotic astrocyte swelling secondary to ammonia-induced accumulation of glutamine or
Alteration of cerebral blood flow (CBF) regulation with increased intracranial blood volume.
Typical course of grade III/IV HE includes reduction in CBF along with a reduction in cerebral metabolic rate early, followed by gradual cerebral vasodilatation due to loss of autoregulation.
Preterminal phase shows marked reduction in CBF resulting from cerebral edema, with cerebral herniation as the end result.
Testing and monitoring
Table 40-1 Stages of Encephalopathy in Acute Liver Failure
Stage
Mental status
Tremor
EEG
I
Euphoria, occasional depression, fluctuant mild confusion, slowness of mentation and affect, untidy, slurred speech
Slight
Usually normal
II
Accentuation of stage I, drowsiness, inappropriate behavior, able to maintain sphincter control
Present (easily elicited)
Abnormal, generalized slowing
III
Sleeps most of the time but is arousable, incoherent speech, marked confusion
Usually present if patient cooperative
Always abnormal
IV
Not arousable, may or may not respond to painful stimuli
Usually absent
Always abnormal
Most accurate method to diagnose ICH is intracranial pressure (ICP) monitoring.
Advantages not yet demonstrated by a randomized study.
ICP monitoring may be helpful to establish the presence of ICH and guide specific therapy.
ICP transducers can be in the brain parenchyma, epidural, or subdural spaces; epidural devices have lower complication rates (3.8%) versus subdural bolts (20%) or parenchymal monitors (22%).
Epidural transducers may be the safest choice to monitor ICP even though they are less precise than the other devices.
The use of recombinant factor VIIa (rFVIIa) appears to minimize the associated risk of hemorrhage when placing these monitors. A single dose of 40 μg/kg is recommended prior to placement.
Transcranial Doppler (TCD) is a noninvasive measurement of the systolic flow velocity of the middle cerebral artery.
Normal systolic velocity is less than 120 cm/second.
Attenuation of the diastolic flow signal may signal ICH and decreased cerebral perfusion.
A pulsatility index (systolic velocity − diastolic velocity/systolic velocity) greater than 1.6 is a poor prognostic sign.
Arterio-jugulovenous oxygen difference (AVjDO2) changes in response to changes in CBF, which is a reflection of the ratio of the flow to metabolism.
Catheter is placed in the internal jugular vein toward the base of the skull.
A normal AVjDO2 is 5 to 6 mL/100 mL.
A narrow AVjDO2 difference is suggestive of cerebral hyperemia.
A widened AVjDO2 is suggestive of cerebral ischemia.
Treatment
Treatment of elevated ICPs involves decreasing brain volume or decreasing the CBF and intracranial blood volume.
Mannitol works by increasing blood osmolarity, thereby inducing fluid movement from the brain to the vascular space.
Mannitol (0.5 to 1 g/kg IV) repeated once or twice as needed is recommended, not exceeding serum osmolality of 320 mOsm/L.
Efficacy is affected by acute renal failure.
Hypertonic saline works similarly to mannitol.
Recent controlled trial of 3% hypertonic saline to maintain serum sodium levels of 145 to 155 mEq/L suggested induction and maintenance of hypernatremia can be used to prevent a rise in ICP values.
A survival benefit was not demonstrated in this trial.
Hyperventilation, indomethacin, thiopental, and induced hypothermia reduce ICP through vasoconstriction of cerebral blood vessels, thereby decreasing CBF.
The American Association for the Study of Liver Diseases (AASLD) position paper on the management of ALF does not support prophylactic hyperventilation; hyperventilation may be used temporarily to acutely lower ICP and prevent impending herniation.
Indomethacin induces cerebral vasoconstriction through inhibition of the endothelial cyclooxygenase pathway, alterations in extracellular pH, and reduction in cerebral temperature. Studies are small and need further evaluation before widespread use.
Thiopental induces cerebral vasoconstriction possibly by inhibition of nitric oxide synthase, thought to be important in the pathogenesis of increased ICP in ALF.
Continuous infusions are started and titrated based upon the EEG (5 to 10 second EEG burst suppression), ICP, and hemodynamics.
Systemic hypotension limits use of thiopental, and pressors or inotropes may be needed to maintain adequate mean arterial pressures.
Cardiovascular
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