Diagnosis and Management of Acute Liver Failure

Anne M. Larson


Curr Opin Gastroenterol. 2010;26(3):214-221. 

In This Article

Clinical Course and Management

Early clinical features of ALF are nonspecific. The degree of serum aminotransferase elevation and the rate of their recovery do not predict prognosis. In fact, improvement of aminotransferase levels in conjunction with worsening bilirubin and PT/INR signals complete liver failure. Once the loss of hepatocyte mass becomes severe enough, multiorgan system failure (MOSF) is the rule, and death results from one of numerous complications.[18–20]

Hepatic Encephalopathy and Cerebral Edema

ALF-induced hepatic encephalopathy is differentiated from that of cirrhosis by the development of cerebral edema. Toxin buildup within the brain, particularly ammonia, is believed to be the predominant mechanism.[21–23] Elevated serum ammonia levels are exacerbated by decreased hepatic urea synthesis, renal failure, and impaired skeletal muscle function.[24] Disruption of the blood–brain barrier allows toxins to more freely enter the cerebrospinal fluid.[22,25,26] Cerebral detoxification of ammonia occurs predominantly in the astrocytes, which convert ammonia to glutamine. This leads to lactate accumulation, decreased tricarboxylic acid cycle activity, less efficient production of phosphate compounds (e.g., ATP), and ultimate swelling of the astrocytes and cerebral edema.[27••] Free radical formation within the astrocyte mitochondria further mediates cellular dysfunction.[24,28] There is also loss of cerebral autoregulation, such that the brain is more susceptible to changes in peripheral blood pressure, which compromises cerebral perfusion.[22,25,27••] In addition, development of the systemic inflammatory response syndrome (SIRS) is associated with progression of hepatic encephalopathy in ALF, as the weakened blood–brain barrier allows influx of inflammatory cytokines.[29,30] Arterial ammonia levels over 200 μg/dl have been strongly correlated with cerebral herniation and death.[31]

Outcome worsens with increasing grades of hepatic encephalopathy – cerebral edema occurring in approximately 80% of patients with grade 4 hepatic encephalopathy (Table 2).[32–35] Increased intracranial hypertension further compromises cerebral perfusion pressure (CPP), leading to ischemic brain damage or brainstem herniation, which accounts for up to half of ALF mortality. Survivors may suffer from long-term neurological deficits.

Physical examination changes occur only after significant edema has developed and are, therefore, generally not helpful in the diagnosis of cerebral edema. Head computed tomography is insensitive in early stages of encephalopathy, but is recommended once stages 3 and 4 hepatic encephalopathy develops.

Simple therapeutic measures, which can be performed on all patients, include elevation of the head of the bed to 30° and minimizing stimulation. Acute hyperventilation fails to reduce episodes of cerebral edema, and it does not delay onset of herniation.[36] Likewise, lactulose has never been shown to improve overall survival in ALF; however, it may help prolong survival and could be used in the setting of grades 1 and 2 hepatic encephalopathy.[18,37]

Intracranial pressure (ICP) monitors may help to diagnose intracranial hypertension and optimize management, although their use remains contentious.[38,39] Nonrandomized trials have shown no survival advantage.[38] Management of cerebral pressures requires maintenance of the CPP over 50 mmHg and the ICP less than 20 mmHg. Sustained pressures greater than this for over 2 h are associated with irreversible brain injury.[40] Mannitol is an established therapy in this setting and improves survival, although its use may be limited in patients with concomitant renal failure.[41] Other potential therapies include thiopental or phenobarbital coma, phenytoin, and mild-to-moderate hypothermia.[37,42•,43] Corticosteroids have no role in this setting.[41]

Coagulopathy and Thrombocytopenia

Spontaneous hemorrhage in ALF is extremely rare.[44,45] Coagulopathy develops following decreased hepatic synthesis of factors 2, 5, 7, and 10. As this group of factors is vitamin K dependent, deficiency must be excluded. Underproduction of protein C, protein S, and anti-thrombin III also occurs.[44] Hypofibrinogenemia follows decreased hepatic synthesis and increased catabolism and can be corrected with the administration of cryoprecipitate – generally, if the level is below 100 mg/dl and bleeding is evident. The PT/INR is one of the most sensitive liver function tests available and mirrors prognosis and course of disease. Fresh frozen plasma (FFP) should be used only for active bleeding or when needed to perform invasive procedures. Prophylactic administration of FFP is not necessary, may contribute to volume overload, and hinders prognostic evaluation. Recombinant factor VII may be used under certain conditions such as prior to an invasive procedure.[46] Platelets may also decline; reaching a nadir of less than 100 000 × 109/l in about 70% of patients, but rarely drop below 25 000 × 109/l.[47]

Pulmonary Dysfunction

Acute lung injury, seen in up to 40% of patients, significantly contributes to overall morbidity and mortality. Increased pulmonary vascular permeability as well as structural alterations in the pulmonary vasculature is seen. The use of protective ventilator strategies in the treatment of adult respiratory distress syndrome (ARDS) may worsen cerebral edema.[48]

Renal Failure

Renal failure develops in up to 70% of patients and is multifactorial. Contributors include dehydration, direct nephrotoxicity from medications (i.e., APAP and nonsteroidal anti-inflammatories), hypotension, sepsis, disseminated intravascular coagulopathy, or all. Hepatorenal syndrome may also contribute, but its presence does not correlate with the severity of ALF. The presence of SIRS predicts renal dysfunction in non-APAP-induced ALF.[49] Intravenous fluid challenge should first be judiciously attempted to exclude prerenal azotemia. Renal replacement therapy is often needed, with continuous forms preferred, as they minimize circulatory and cerebral fluctuations in pressure.[50]

Hemodynamic Abnormalities

A hyperdynamic circulatory picture is common, with low systemic and pulmonary vascular resistance, elevated cardiac output and metabolic rate, and hypotension. This is likely due to circulating endotoxin and tumor necrosis factor, and is often exacerbated by the decreased oral intake and dehydration, which accompanied the prodromal illness. It can be difficult to distinguish from sepsis. Abnormal peripheral oxygen transport and utilization leads to acidosis. Hypovolemia should be corrected (crystalloid resuscitation), and vasopressors may be required.[18] Norepinephrine is often the recommended vasopressor in this setting, although dopamine may have a more beneficial effect on peripheral oxygen delivery.[18,51]

Infection and Sepsis

Immune system function is altered in ALF, with decreased complement/opsonization and an impaired innate immune system. The risk of developing infection is greater in the setting of subacute ALF and increases with increasing time in the ICU, and infection causes death in up to 37% of patients. Distinguishing sepsis from ALF-induced hemodynamic changes is difficult. Patients may not develop leukocytosis or fever. Clinical or culture evidence of bacterial infection is seen in up to 80–90% of patients, predominantly pulmonary (47%), blood (26%), and urine (23%). Gram negative enteric bacteria (i.e., Escherichia coli) and Staphylococcal or Streptococcal species are the organisms usually identified. Fungal infections, especially by Candida species, are seen in about 30% of patients, occur later, particularly after use of antibiotics, and are often associated with bacterial infection.[52] Infection worsens both hepatic encephalopathy and cerebral edema.[52]

Infection can also trigger the SIRS, thought to be the byproduct of multiple inflammatory pathways mediated by chemokine–cytokine responses. In ALF, SIRS is linked to ARDS, sepsis syndrome, and MOSF. Prophylactic antibiotics decrease the number of infections, but do not change the overall outcome. Periodic surveillance cultures can help detect bacterial and fungal infections early.

Electrolyte and Acid–Base Imbalance

Serum electrolyte abnormalities occur throughout the course of ALF. Decreased free water clearance is seen with renal sodium reabsorption and hyponatremia. Serum and total body deficits of potassium follow. Hypophosphatemia is likely secondary to renal loss.[53] Persistently elevated phosphate levels may be associated with a poorer prognosis in the setting of APAP-induced ALF.[53,54] Mixed acid–base disturbances are common.


Hepatic derangements lead to hypoglycemia in up to 45% of ALF patients, as the liver is unable to mobilize glycogen, and gluconeogenesis is impaired. Frequent glucose monitoring is required and i.v. dextrose may be necessary to maintain normoglycemia.

Gastrointestinal Bleeding

There is increased risk for gastrointestinal bleeding. The use of i.v. antacids reduces both morbidity and mortality, and should be considered standard of care.[18,55]