**1. Introduction**

Acute liver failure (ALF) is defined as the presence of acute liver injury, that is, a rise in transaminases at least three times the upper limit of normal, jaundice, and coagulopathy, together with the onset of encephalopathy in a person with no previous liver disease [1]. Exceptions to this definition include the acute onset of Wilson disease, autoimmune hepatitis, and the Budd-Chiari syndrome, as well as reactivation of the hepatitis B virus (HBV) [2].

Though no consensus exists on the severity of the coagulopathy or the encephalopathy marking the transition from acute liver injury to ALF, an INR ≥1.5 and any degree of encephalopathy are generally accepted [3]. Clinically, ALF is classified according to the interval between the onset of jaundice, considered as the initial symptom, and the encephalopathy. The ALF is considered to be hyperacute if the encephalopathy appears within

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7 days of the jaundice, acute if it appears between 8 and 28 days, and subacute when it appears beyond 28 days [4]. The disease is considered chronic if it has a history of more than 26 weeks.

**2. Indication for liver transplantation in acute liver failure**

**2.1. Predictive factors**

Liver transplantation in ALF has represented an inflection point in the survival of affected patients, who previously suffered a mortality rate of almost 85% in the pretransplant era [7]. Indicating LT too soon involves the possibility of performing the transplant in patients who may still experience spontaneous recovery with complete liver function, thereby adding the risks associated with an urgent transplant and lifelong immunosuppression, in addition to the waste of a valuable organ. However, delaying the decision to transplant in patients with ALF can increase the risk of infection, irreversible brain damage, multiorgan failure, or even death. Accordingly, selection of ALF patients who need LT should be based on the early identification of factors predicting a poor clinical outcome, as well as application of prognostic models combining different parameters. Unfortunately, the prognostic models available have certain limitations, low sensitivity and specificity, and worse predictive value than desired [8].

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The etiology is considered a predictive factor. Around 60% of patients with ALF due to paracetamol intoxication, hepatitis A, ischemic hepatitis, or pregnancy may survive with no need for transplantation, whereas only 30% of cases with drug-induced liver injury, autoimmune hepatitis, and various cases of unknown etiology achieve spontaneous recovery [9].

The duration of symptoms has traditionally had a prognostic value. The subacute presentation of ALF is associated with a worse prognosis than acute and hyperacute ALF, though

Encephalopathy, although it forms part of the definition of ALF, should also be classified. Patients with grades 1–2 encephalopathy have an excellent prognosis, whereas grades 3–4 encephalopathy is associated with a low likelihood of spontaneous resolution [11] and is thus criteria for admission to the intensive care unit, with a recommendation to measure the intracranial pressure as a marker of the preservation of brain perfusion [12]. Coagulopathy, as a direct indicator of liver function, is considered to predict the severity. Generally measured using the prothrombin time (PT) or the International Normalized Ratio (INR), a PT over 90 s or an INR >4 is associated with a mortality rate above 90% [13]. Factor V levels <20% in patients younger than 30 years and levels <30% in those older than 30 years indicate a worse prognosis. The histologic findings have also been proposed as predictors of the outcome and the likelihood of spontaneous recovery. Though some series have related the risk of death with the presence of >50% hepatocyte necrosis, the little representativity of the samples together with the risk involved in performing a liver biopsy in patients with coagulopathy generally advise against routine histologic study in patients with ALF, and nor should the decision to transplant be based on biopsy findings. A liver biopsy could be indicated in cases of diagnostic doubt, especially to rule out neoplastic causes, which contraindicate LT [14]. Other factors, such as age, body mass index, serum bilirubin, creatinine, hypoglycemia, lactate levels, and

these differences are probably conditioned by the etiology of the subacute failure [10].

pH changes, can also be considered determinant.

**Table 1** summarizes the causes of ALF. Worldwide, infection is the most common cause, though in developed countries drug-induced hepatic injury is responsible for up to 50% of cases. As many as 30% of cases are of unknown etiology [5].

The main causes of death due to ALF are infection and decerebration from cerebral edema. The medical management of patients is based on support measures, early identification, and treatment of complications until spontaneous recovery of liver function or liver transplantation (LT) [6].

Establishing the indication for and time of LT in a patient with ALF should be as precise as possible in order to avoid, on one hand, unnecessary risks for a recoverable patient and on the other an increased likelihood of death associated with a delay in transplantation.

*Viral* HAV, HBV, HCV, HEV CMV, EBV, HSV, VZV, dengue *Pharmacologic/toxic* Paracetamol (acetaminophen) Idiosyncratic drug reaction Amanita phalloides *Vascular* Budd-Chiari Ischemic hepatitis *Pregnancy* Preeclampsia HELLP Fatty liver of pregnancy *Others* Wilson disease Autoimmune hepatitis Lymphomas and other neoplastic diseases Hemophagocytic lymphohistiocytosis *Cryptogenic*

**Table 1.** Etiology of the acute liver failure.
