A guide to managing acute liver failure
ABSTRACTNearly 2,000 cases of acute liver failure occur each year in the United States. This disease carries a high mortality rate, and early recognition and transfer to a tertiary medical care center with transplant facilities is critical. This article reviews the definition, epidemiology, etiology, and management of acute liver failure.
KEY POINTS
- In the United States, the most common cause of acute liver failure is acetaminophen toxicity, followed by viral hepatitis.
- Testing for the cause of acute liver failure needs to start as soon as possible so that specific treatment can be initiated and the patient can be placed on the transplant list if needed.
- Acetylcysteine and either a proton pump inhibitor or a histamine H2 receptor blocker should be given to all patients with acute liver failure. Liver transplant is the cornerstone of therapy in patients not responding to other treatments.
- There are a number of prognostic scores for acute liver failure, but each has limitations.
Viral hepatitis
Hepatitis B virus is the most common viral cause of acute liver failure and is responsible for about 8% of cases.18
Patients with chronic hepatitis B virus infection—as evidenced by positive hepatitis B surface antigen—can develop acute liver failure if the infection is reactivated by the use of immunosuppressive drugs for solid-organ or bone-marrow transplant or medications such as anti-tumor necrosis agents, rituximab, or chemotherapy. These patients should be treated prophylactically with a nucleoside analogue, which should be continued for 6 months after immunosuppressive therapy is completed.
Hepatitis A virus is responsible for about 4% of cases.18
Hepatitis C virus rarely causes acute liver failure, especially in the absence of hepatitis A and hepatitis B.3,19
Hepatitis E virus, which is endemic in areas of Asia and Africa, can cause liver disease in pregnant women and in young adults who have concomitant liver disease from another cause. It tends to cause acute liver failure more frequently in pregnant women than in the rest of the population and carries a mortality rate of more than 20% in this subgroup.
TT (transfusion-transmitted) virus was reported in the 1990s to cause acute liver failure in about 27% of patients in whom no other cause could be found.20
Other rare viral causes of acute liver failure include Epstein-Barr virus, cytomegalovirus, and herpes simplex virus types 1, 2, and 6.
Other causes
Other causes of acute liver failure include ischemic hepatitis, autoimmune hepatitis, Wilson disease, Budd-Chiari syndrome, and HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome.
MANY PATIENTS NEED LIVER TRANSPLANT
Many patients with acute liver failure ultimately require orthotopic liver transplant,21 especially if they present with severe encephalopathy. Other aspects of treatment vary according to the cause of liver failure (Table 3).
SPECIFIC MANAGEMENT
Management of acetaminophen toxicity
If the time of ingestion is known, checking the acetaminophen level can help determine the cause of acute liver failure and also predict the risk of hepatotoxicity, based on the work of Rumack and Matthew.22 Calculators are available, eg, https://reference.medscape.com/calculator/acetaminophen-toxicity.
If a patient presents with acute liver failure several days after ingesting acetaminophen, the level can be in the nontoxic range, however. In this scenario, measuring acetaminophen-protein adducts can help establish acetaminophen toxicity as the cause, as the adducts last longer in the serum and provide 100% sensitivity and specificity.23 While most laboratories can rapidly measure acetaminophen levels, only a few can measure acetaminophen-protein adducts, and thus this test is not used clinically.
Acetylcysteine is the main drug used for acetaminophen toxicity. Ideally, it should be given within 8 hours of acetaminophen ingestion, but giving it later is also useful.1
Acetylcysteine is available in oral and intravenous forms, the latter for patients who have encephalopathy or cannot tolerate oral intake due to repeated episodes of vomiting.24,25 The oral form is much less costly and is thus preferred over intravenous acetylcysteine in patients who can tolerate oral intake. Intravenous acetylcysteine should be given in a loading dose of 150 mg/kg in 5% dextrose over 15 minutes, followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg given over 16 hours.1 No dose adjustment is needed in patients who have renal toxicity (acetaminophen can also be toxic to the kidneys).
Most patients with acetaminophen-induced liver failure survive with medical management alone and do not need a liver transplant.3,26 Cirrhosis does not occur in these patients.
Management of viral acute liver failure
When patients present with acute liver failure, it is necessary to look for a viral cause by serologic testing, including hepatitis A virus IgM antibody, hepatitis B surface antigen, and hepatitis B core IgM antibody.
Hepatitis B can become reactivated in immunocompromised patients, and therefore the hepatitis B virus DNA level should be checked. Detection of hepatitis B virus DNA in a patient previously known to have undetectable hepatitis B virus DNA confirms hepatitis B reactivation.
Patients with hepatitis B-induced acute liver failure should be treated with entecavir or tenofovir. Although this treatment may not change the course of acute liver failure or accelerate the recovery, it can prevent reinfection in the transplanted liver if liver transplant becomes indicated.27–29
Herpes simplex virus should be suspected in patients presenting with anicteric hepatitis with fever. Polymerase chain reaction testing for herpes simplex virus should be done,30 and if positive, patients should be given intravenous acyclovir.31 Despite treatment, herpes simplex virus disease is associated with a very poor prognosis without liver transplant.
Autoimmune hepatitis
The autoantibodies usually seen in autoimmune hepatitis are antinuclear antibody, antismooth muscle antibody, and anti-liver-kidney microsomal antibody, and patients need to be tested for them.
The diagnosis of autoimmune hepatitis can be challenging, as these autoimmune markers can be negative in 5% of patients. Liver biopsy becomes essential to establish the diagnosis in that setting.32
Guidelines advise starting prednisone 40 to 60 mg/day and placing the patient on the liver transplant list.1
Wilson disease
Although it is an uncommon cause of liver failure, Wilson disease needs special attention because it has a poor prognosis. The mortality rate in acute liver failure from Wilson disease reaches 100% without liver transplant.
Wilson disease is caused by a genetic defect that allows copper to accumulate in the liver and other organs. However, diagnosing Wilson disease as the cause of acute liver failure can be challenging because elevated serum and urine copper levels are not specific to Wilson disease and can be seen in patients with acute liver failure from any cause. In addition, the ceruloplasmin level is usually normal or high because it is an acute-phase reactant. Accumulation of copper in the liver parenchyma is usually patchy; therefore, qualitative copper staining on random liver biopsy samples provides low diagnostic yield. Quantitative copper on liver biopsy is the gold standard test to establish the diagnosis, but the test is time-consuming. Kayser-Fleischer rings around the iris are considered pathognomic for Wilson disease when seen with acute liver failure, but they are seen in only about 50% of patients.33
A unique feature of acute Wilson disease is that most patients have very high bilirubin levels and low alkaline phosphatase levels. An alkaline phosphatase-to-bilirubin ratio less than 2 in patients with acute liver failure is highly suggestive of Wilson disease.34
Another clue to the diagnosis is that patients with Wilson disease tend to develop Coombs-negative hemolytic anemia, which leads to a disproportionate elevation in aminotransferase levels, with aspartate aminotransferase being higher than alanine aminotransferase.
Once Wilson disease is suspected, the patient should be listed for liver transplant because death is almost certain without it. For patients awaiting liver transplant, the American Association for the Study of Liver Diseases guidelines recommend certain measures to lower the serum copper level such as albumin dialysis, continuous hemofiltration, plasmapheresis, and plasma exchange,1 but the evidence supporting their use is limited.
NONSPECIFIC MANAGEMENT
Acute liver failure can affect a number of organs and systems in addition to the liver (Figure 2).
General considerations
Because their condition can rapidly deteriorate, patients with acute liver failure are best managed in intensive care.
Patients who present to a center that does not have the facilities for liver transplant should be transferred to a transplant center as soon as possible, preferably by air. If the patient may not be able to protect the airway, endotracheal intubation should be performed before transfer.
The major causes of death in patients with acute liver failure are cerebral edema and infection. Gastrointestinal bleeding was a major cause of death in the past, but with prophylactic use of histamine H2 receptor blockers and proton pump inhibitors, the incidence of gastrointestinal bleeding has been significantly reduced.
Although initially used only in patients with acetaminophen-induced liver failure, acetylcysteine has also shown benefit in patients with acute liver failure from other causes. In patients with grade 1 or 2 encephalopathy on a scale of 0 (minimal) to 4 (comatose), the transplant-free survival rate is higher when acetylcysteine is given compared with placebo, but this benefit does not extend to patients with a higher grade of encephalopathy.35
