Introduction

Fulminant hepatic failure (FHF) can be precipitated by a number of causes; the exact etiology varies in different parts of the world and, in many cases, is never precisely established. Thus, while every effort should be made to identify a specific cause, the focus has tended to be on the early identification and treatment of the associated complications. While many patients may recover with specialized care, frequent re-evaluation is essential to identify those factors that predict a poor prognosis without transplantation so that life saving surgery can be offered in a timely manner.

Diagnostic Workup

Viral hepatitis remains an important cause of FHF, although the wide application of hepatitis B vaccination has reduced the numbers of patients seen with acute liver failure due to hepatitis B. Some patients with longstanding hepatitis B infection can present with acute liver failure, generally at the time of HBeAg seroconversion or as result of superinfection with hepatitis D or other hepatotrophic viruses. Hepatitis A is an infrequent cause of FHF in adults, although cases where an otherwise mild infection is aggravated by concomitant acetaminophen use are not uncommon. Acute hepatitis C infection virtually never precipitates FHF; however, hepatitis E is an important cause of FHF in the developing world, particularly in pregnant women, and should be considered in patients with a history of travel to those areas although serologic studies indicate that exposure to hepatitis E occurs in North America. Other viruses, such as herpes simplex, herpes zoster, and HHV-6, in addition to Epstein–Barr virus, cytomegalovirus, and parvovirus, are uncommon causes of FHF, but should be considered particularly in the immunocompromised or pregnant patient. The appropriate serologic investigations are outlined in Box 10.1.

Drugs, including prescription medications, over-the-counter preparations, and natural or herbal products (Box 10.2), are the principal identified cause of FHF in many Western centers. Acetaminophen, or paracetamol, is the leading cause in most published series, either as an overdose or in medicinal quantities in association with other precipitants, for example alcohol. Other classes of drugs, particularly anti-infectives, anticonvulsants, and anti-inflammatories, the latter because of their widespread use, are also relatively frequent causes of FHF, although it is difficult to find any drug that has not been associated with some degree of liver injury. A careful history, toxic screens, and, in some cases, a search of the patient’s home, are essential in identifying the specific agent or agents involved.

A variety of other conditions may be associated with FHF, including hyperthermia, mushroom poisoning with Amanita phalloides, Wilson disease, ischemic hepatopathy (including cocaine-induced ischemic hepatitis), Budd–Chiari syndrome, autoimmune hepatitis, malignancy (usually lymphoma), and pregnancy. Reye syndrome, an acute microvesicular steatosis attributed to acetylsalicylic acid use in children and rarely seen today, is another precipi­tant of acute liver failure. Specific investigations designed to pursue these possibilities are also outlined in Box 10.2. It has also been reported that hematologic malignancies, including lymphoma (non-Hodgkin) and leukemia, may present as acute liver failure.

In some series, over a quarter of FHF cases have no identified cause. This has been referred to as seronegative or indeterminate disease, and tends to have a poorer prognosis than viral hepatitis-related disease.

Patient Management

General Principles: a Multisystem Disease (Box 10.3)

Hepatic Encephalopathy

The development of hepatic encephalopathy is the hallmark of FHF. In contrast to the situation in chronic liver disease, where hepatic encephalopathy is frequently present with fluctuating severity, this complication is associated with a poor outcome in the fulminant setting. A rise in intracranial pressure can occur in a matter of hours following the onset of clinical encephalopathy, and the resultant herniation of brainstem structures may lead to irreversible brain injury that would not be corrected with transplantation. Thus, once hepatic encephalopathy has developed, liver transplantation should become an active consideration and the various models developed for prognosis can be applied.

While lactulose can be administered at the onset of encephalopathy, after colonic cleansing has been achieved its ongoing use achieves little benefit. Elevation in serum ammonia and other substances due to portosystemic shunting, the major mechanisms of encephalopathy in chronic liver disease, is not implicated in FHF. Additional measures include nursing the patient with the head up (15–30° from the horizontal), keeping the patient “dry” by administering only the amount of i.v. fluids necessary to maintain minimum (30 mL/h) urine output when renal function is still preserved and, in more severe cases, the use of intravenous mannitol, phenobarbital-induced coma, and hypothermia. Controversy remains as to whether the insertion of an intracranial pressure monitor is of value, particularly as neurosurgical intervention in this setting may carry a higher risk; some authorities recommend doing so in an effort to identify patients with intractably elevated intracranial pressure who may no longer be transplant candidates.

Renal Dysfunction

With progressive hepatic insufficiency, renal dysfunction is common, with a profile reminiscent of hepatorenal syndrome as seen in chronic liver disease. The avoidance of potential nephrotoxins, including antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and contrast agents, is important, along with treatment of causes of renal hypoperfusion, such as sepsis. However, systemic hypotension is common in FHF, and in an effort to minimize fluid infusions a lower threshold for the use of vasopressors is advocated. Renal replacement therapy is frequently required for the management of the profound acid–base disturbances seen in acute liver failure.

Pulmonary Dysfunction

In addition to the airway and breathing challenges that can arise as patients slip into deepening levels of hepatic coma, primary pulmonary complications can develop, which can further compromise oxygenation. An acute respiratory distress syndrome (ARDS) picture is not infrequent, especially if sepsis is present, and renal failure may result in pulmonary edema. Pneumonia, often due to aspiration, is common in patients with FHF and can further affect pulmonary function.

Hemodynamic Disturbances

As mentioned earlier, systemic hypotension is frequent, and is associated with tachycardia and increased cardiac output, the so-called “hyperdy­namic circulation”. Invasive monitoring, often including a pulmonary artery catheter, is usually required to navigate through this complication; diminishing cardiac performance can further exacerbate pulmonary function, and patients end up on maximal pressors and fractional inspired oxygen (FIO₂) as FHF progresses.

Coagulopathy/Thrombocytopenia

A rapidly rising and highly elevated INR is the norm in patients with FHF. This is due both to the impaired production of clotting factors by the failing liver and, in many cases, to increased factor consumption attributable to disseminated intravascular coagulation, a common complication. While the administration of FFP to correct an elevated INR may be appropriate in the setting of active bleeding or prior to carrying out an invasive procedure, serial measurement of INR carries enormous prognostic information in its role as an index of liver function, and should not be manipulated without careful consideration.

Gastrointestinal Complications

Upper gastrointestinal bleeding, usually due to gastritis, is often seen, and is of course exacerbated by the coexisting coagulopathy of FHF. Prophylaxis with proton pump inhibitors is recommended. Further, albeit rarely, bleeding esophageal varices can develop in the setting of acute liver injury, and aggressive intervention, with correction of coagulopathy, resuscitation and emergency endoscopy with variceal ligation, may be required. Acute pancreatitis has also been described in FHF, with unclear etiology, and should be managed as it would be in any other patient.

Hypoglycemia

While not included in any prognostic model, hypoglycemia is common in FHF, and should be sought out and corrected when present as it may complicate the interpretation of altered mental status and contribute to brain injury. Frequent glucometer readings are recommended, with the institution of intravenous dextrose supplementation when blood glucose readings begin to fall, especially in patients in deeper levels of hepatic encephalopathy.

Sepsis

The impaired level of consciousness of FHF, with its associated risks of aspiration, the insertion of intravenous and urinary catheters, the development of pulmonary edema, and the loss of hepatic Kupffer cell function, as well as other factors, contribute to high rates of bacterial and fungal sepsis in FHF. Broad-spectrum intravenous antibacterials are usually started as soon as hepatic coma begins to develop, with the subsequent addition of antifungals. Regular surveillance cultures of blood and urine are recommended, along with frequent chest radiographs, so that infections can be identified and managed early. They represent the next most important cause of death (second to elevated intracranial pressure) in FHF.

Etiology-Specific Measures

Viral Hepatitis

There is no specific treatment for liver failure due to hepatitis A virus. In the case of hepatitis B, the use of lamivudine or other more potent nucleoside/nucleotide analogues has not been convincingly shown to improve prognosis. In the situation where a flare of chronic hepatitis B has precipitated liver failure, oral antiviral drugs may be used, perhaps not for immediate effect but to reduce viral load and lower the risk of recurrent hepatitis B following liver transplantation. Superinfection with delta virus suppresses HBV DNA.

When other viruses, such as herpesviruses (cytomegalovirus, herpes simplex, etc.) are involved, specific antiviral therapy can be administered. Acyclovir has been shown to be of benefit in herpes simplex virus-related FHF.

Acetaminophen Intoxication

N-acetylcysteine (NAC), given either orally or intravenously, is the specific antidote for acetaminophen-related hepatic failure. It should be administered according to widely available algorithms as soon as the diagnosis is suspected, and many authorities recommend its continuation well beyond 16 hours, often until the INR has approached normal. Although the best evidence supports its use in the first 24 hours following acetaminophen ingestion, there is little harm in starting it beyond that window.

Fulminant Hepatic Failure Related to Pregnancy

Early delivery is recommended in almost all cases of pregnancy-related fulminant liver failure (acute fatty liver of pregnancy, HELLP syndrome, acute hepatitis E), not only for the safety of the fetus, but as treatment for the disease process itself. Hence, liver transplantation is rarely required for this indication.

Other Etiologies

NAC is also often administered in FHF of non-acetaminophen etiology, as it is relatively non-toxic and may improve outcome in those situations as well. A recent randomized controlled trial did demonstrate improvement in transplant-free survival in patients with Stages I and II encephalopathy, although there was no survival benefit in the overall group.

There is no specific treatment for Wilson disease with a fulminant presentation, although there are case reports suggesting possible benefit of plasmapheresis and chelation therapy. These modalities may serve as a bridge to early transplantation, rather than directly affecting the natural history of the disease.

Corticosteroids or other immunosuppressive medications have not been established as effective treatment in fulminant autoimmune hepatitis; indeed, corticosteroids may be associated with a higher risk of sepsis, particularly fungal, and introduce potential complications if liver transplantation is being considered.

Prognosis and Liver Transplantation

Several models have been developed to assist in determining prognosis in patients with FHF (Box 10.4). The mostly widely used prognostic criteria are the King’s College Hospital criteria, which incorporate the etiology of FHF along with a variety of biochemical markers. Those who fulfill criteria are highly unlikely to survive without urgent liver transplantation. Other widely used models include the Clichy criteria, which are based on the measurement of factor V levels. In addition, serum lactate has been proven to be an independent predictor of poor outcome in acetaminophen-induced liver failure, and MELD (Model for End-stage Liver Disease) may be of some value, although it is not currently in use for organ allocation in patients with FHF.