Acute liver failure (ALF), also referred as “fulminant hepatic failure,” is a rare syndrome characterized by rapid onset of severe hepatic dysfunction in the absence of preexistent liver disease. The principal manifestations of ALF include jaundice, hepatic encephalopathy, and coagulopathy, often owing to massive or submassive hepatic necrosis. An estimated 2000 to 3000 cases of ALF occur in the United States every year. The syndrome has diverse etiologies that manifest wide geographic distribution. In North America and Western Europe, acetaminophen and idiosyncratic drug hepatotoxicity are the predominant causes. In contrast, viral hepatitis B and E are the major causes in Asia. Without specialized intensive care management and the availability of liver transplantation, a diagnosis of ALF portends a poor outcome. This article summarizes current practice and recent advances in the management of ALF.
Diagnosis and Initial Management
Early diagnosis of ALF is crucial. Although jaundice and hepatic encephalopathy are the cardinal manifestations of ALF, many patients present with nonspecific symptoms of generalized malaise, nausea, and abdominal discomfort. Thus, concern for severe liver injury is often triggered by abnormal laboratory values. Hepatic encephalopathy develops rapidly in patients with hyperacute failure sometimes preceding jaundice. Careful clinical evaluation and laboratory and imaging studies are required to help exclude cirrhosis and to establish the etiology of the disease. The role of liver biopsy is limited and it is often problematic in view of cerebral and hemodynamic instability, and associated coagulopathy.
Patients with ALF are best managed in an intensive care unit. Once diagnostic criteria are met, transfer to a tertiary facility with a liver transplant program is urgent. Transfer may be considered earlier if a patient with severe acute liver injury is deemed likely to progress to ALF. Worsening coagulopathy and behavioral changes are particularly relevant in this regard. A decision regarding tracheal intubation should be made before transfer. Intubation is particularly recommended for patients with grades III or IV hepatic encephalopathy. Rapid development of hypoglycemia is a concern and should be addressed by a continuous intravenous dextrose infusion and frequent monitoring of blood sugar levels. Encephalopathy in ALF may be associated with agitation and seizures; therefore, a quiet environment is needed to minimize external stimuli.
Cerebral Edema
Cerebral edema and intracranial hypertension (ICH) are among the most serious complications of ALF. As cerebral edema progresses, fatal uncal herniation may ensue. Residual neurologic deficits have been noted among survivors. Cerebral edema should be suspected in patients with progressive hepatic encephalopathy. Although it is rare among those with grades I or II, its incidence is 25% to 35% with grade III and as high as 65% to 75% with grade IV hepatic encephalopathy. A high index of suspicion is needed because patients may not exhibit classic features including headache, vomiting, bradycardia, hypertension, blurred vision, papilledema, brisk reflexes, and decerebrate rigidity.
The pathogenesis of ICH from ALF is not fully understood; however, hyperammonemia is considered to be a key factor. Once ammonia traverses the blood–brain barrier, astrocytes detoxify it by conversion to glutamine through its reaction with glutamic acid, a process facilitated by the enzyme glutamine synthetase. Glutamine has a direct osmotic effect resulting in astrocyte swelling. In addition, it serves as a “Trojan horse” by releasing ammonia inside the cell that causes mitochondrial dysfunction and oxidative stress, which in turn results in cytotoxicity and cellular edema. Furthermore, release of inflammatory cytokines leads to systemic vasodilation and increased intracranial blood volume.
Intracranial Pressure Monitoring
Although leading transplant centers in the United States tend to employ intracranial pressure (ICP) measurement, there are no randomized trials or consensus guidelines to support this practice. ICP is often measured to have an objective parameter to aid in management and prognostication. However, target values are not well-defined and monitor placement is associated with the risk of intracerebral bleeding that may occur in 8% to 10% of cases, although less frequently with an epidural catheter. This risk has been shown to be mitigated by the use of recombinant activated factor VII (rFVIIa). Some centers use ICP monitors routinely, whereas others employ it in patients who are at the highest risk of cerebral edema, including those with grades III to IV hepatic encephalopathy, or those receiving vasopressors. Intracranial monitors are more frequently used among patients listed for liver transplantation. The United States Acute Liver Failure Study Group endorses the use of ICP monitors in patients with a high risk of ICH, including nontransplant candidates who have increased likelihood of spontaneous survival.
Cerebral Blood Flow Measurement
ALF is associated with the loss of cerebral blood flow autoregulation. Depending on the cerebral perfusion pressure (CPP), either cerebral hyperemia or hypoxia could develop. Measurement of cerebral blood flow (CBF), in addition to ICP monitoring, may therefore help to manage such patients. Still, CBF-oriented therapies are difficult to implement because the metabolic demands of the brain vary depending on the patient’s underlying level of inflammation or sedation, and there is no evidence that CBF monitoring influences outcome. Several tools are available for the indirect measurement of CBF, including the jugular bulb catheter, transcranial Doppler, and xenon-enhanced computed tomography (CT).
Jugular bulb
A jugular bulb catheter may be utilized to assess cerebrovascular autoregulation. This process involves passage of a fine-bore catheter into the internal jugular vein until the tip reaches the jugular bulb, thereby allowing for sampling of blood that drains exclusively from intracranial circulation. Cerebral oxygen uptake is then determined by calculating the arteriojugular oxygen content difference in paired blood samples. During assessment of cerebral autoregulation, it is assumed that cerebral metabolic rate of oxygen remains constant so that the arteriojugular oxygen content difference solely reflects CBF. In reality, the cerebral metabolic rate of oxygen may vary, and that limits the utility of the jugular bulb in the assessment of CBF autoregulation. Jugular bulb placement may also be used to measure brain cytokine production indicative of an inflammatory response that correlates with the severity of ICP.
Transcranial Doppler ultrasonography
Transcranial Doppler ultrasound is a noninvasive method to measure blood flow velocity in the basal intracranial cerebral arteries, thereby indirectly determining CBF via the linear relationship between flow and velocity. Blood flow velocity and CBF measured by transcranial Doppler has been shown to correlate with xenon-enhanced CT determination of CBF. Among patients with ALF, monitoring with transcranial Doppler provides an assessment of cerebral hemodynamics and could be used to predict dynamic changes in CBF and ICP.
Xenon-enhanced CT
CBF measurement with xenon, an inert anesthetic gas, was first described 40 years ago. After the advent of CT, xenon-enhanced scanning was developed to determine regional blood flow. Xenon CT provides both anatomic and functional information that could help to manage patients with ALF. However, there are disadvantages to this modality. For instance, the reproducibility of findings is poor as comparisons of the same region from one study to another are difficult. Furthermore, CBF assessment is restricted to mainly cortical and subcortical regions within the territory of the middle cerebral artery. There is no consensus regarding the use of xenon-enhanced CT in patients with ALF and its application therefore remains limited.
Electroencephalography
Seizure activity is not uncommon among patients with ALF ; however, it is often masked by the use of sedatives and paralytic agents. Seizures may acutely elevate ICP, and may also increase cerebral oxygen consumption resulting in ischemia and worsening cerebral edema. Monitoring by continuous electroencephalography would detect subclinical seizure activity that could be treated with anti-epileptic agents. Studies examining the effect of prophylactic anticonvulsants have remained inconclusive.
Related posts:
Emerging Therapies in Hepatitis C: Dawn of the Era of the Direct-Acting Antivirals
Noninvasive Tools to Assess Hepatic Fibrosis: Ready for Prime Time?
Liver Transplantation in the 21st Century: Expanding the Donor Options
Hepatitis B: Modern End Points of Treatment and the Specter of Viral Resistance
Liver Transplantation in the 21st Century: Expanding the Donor Options
Alcoholic Hepatitis: Prognostic Models and Treatment
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
