Acute Liver Failure: Unraveling a Rare Syndrome Primarily Associated with Toxicity

Acute liver failure (ALF) is a rare syndrome. It comprises the acute reduction in metabolic capacity, characterized by jaundice, coagulopathy and encephalopathy , in patients without a history of liver disease and is mainly due to paracetamol toxicity observed in developed countries.

Less common etiologies include viral hepatitis, drug-induced liver injury, pregnancy-induced liver failure, and autoimmune hepatitis, but a significant proportion are also due to undetermined causes.

The survival of patients with ALF has steadily improved in recent decades, from approximately 20% to more than 60%. This remarkable improvement in survival has been due to a combination of improvements in medical practice and the use of emergency liver transplantation (ELT) in selected patients.

Currently, THE is reserved for a subset of patients who are unlikely to survive on medical care alone. Early recognition and timely initial management in the non-specialized medical center can significantly improve outcomes.

Patients should be discussed simultaneously with a transplant center and referred to intensive care. It is important to maintain close liaison with the transplant center to ensure timely transfer of patients with severe deterioration.

The presentation of ALF varies depending on the etiology, the relative frequency of which varies throughout the world. Consequently, there are several different classification systems but, essentially, they all differentiate rapidly progressive ALF from other forms. This distinction has prognostic significance.

In the United Kingdom the O’Grady classification tends to be used. Patients are classified as "hyperacute", "acute" or "subacute" , depending on the appearance of encephalopathy after the detection of the first symptoms, and jaundice.

The hyperacute presentation frequently develops extrahepatic organ failure and carries a high risk of cerebral edema and intracranial hypertension but, contrary to expectations, it has the best prognosis with medical treatment alone.

Acute and subacute presentations usually have a more indolent course for several weeks, developing extrahepatic organ failure later, and have a lower risk of cerebral edema.

However, these patients are less likely to recover with supportive care alone, and outcomes are worse without a liver transplant. There are possible exceptions to this such as viral hepatitis, which improves with antiviral treatment, but transplantation is usually still necessary if encephalopathy develops.

Recognizing and diagnosing ALF in a timely manner requires a high index of suspicion considering its rarity. It should be suspected in all patients without previous liver disease who develop or present liver injury INR (International normalized ratio) >1.5 and transaminases >3 times the upper limit of normal.

Hepatic encephalopathy in this context defines ALF and can be very subtle in the early stages. Therefore, its presence must be actively sought. In case of drowsiness or confusion and diagnostic doubt, when the cause is not obvious, measuring ammonia can help.

Elevated lactate can also point to the diagnosis while serial lactate measurements can monitor the trajectory of the disease. Identifying the cause of ALF is very important since the treatment and prognosis depend on it. Therefore, once ALF is suspected, the patient’s history should be reviewed and screened for liver disease to determine the cause.

Ultrasound allows evaluation of vascular flow and liver drainage. It is mandatory to evaluate the presence of pre-existing chronic or subacute liver disease, which sometimes requires being ruled out by a CT scan.

Initial treatment involves discontinuing hepatotoxic drugs, restoring volume using crystalloids (0.9% saline or a balanced mixture of crystalloids), initiating broad-spectrum antibiotics and antifungals (these patients are very susceptible to infections), and N -acetyl cysteine ​​(NAC).

Historically, NAC is associated with the treatment of paracetamol overdose, but is now recommended for all etiologies of ALF , due to its likely benefit.

The SNAP study showed that, for the treatment of paracetamol overdose in the emergency department, 300 mg/kg NAC for 12 days obtained better tolerated and better hepatic outcomes than the 21-hour regimen used until now.

However, the best duration of NAC treatment has not yet been definitively established. Caution is warranted when extrapolating the findings of the SNAP study to delayed or graded overdoses, as outcomes tend to be worse.

The synthetic function of the liver is best controlled through the RIN, as it is a factor VII-dependent metric (synthesized by the liver; circulating half-life, 6 hours). Therefore, correction of the INR with blood products deprives the physician of an important prognostic monitor of the evolution of ALF and is not recommended in the absence of hemorrhage. However, if warfarin reversal is required or a nutritional deficiency is suspected, vitamin K can be administered, as these states mask the true extent of liver dysfunction.

Bleeding is rare due to the balanced reduction of anticoagulant factors. In case of bleeding, consultation with hematology and intensive care is recommended, but correction with platelets and fibrinogen, alone, may be appropriate interventions.

In these patients, sedatives, nonsteroidal anti-inflammatory drugs, and intramuscular injections should be avoided, as they may precipitate coma, renal failure, and hemorrhage, respectively.

Early referral to intensive care and referral to a transplant center is recommended if hepatic encephalopathy develops.

Once encephalopathy occurs, deterioration can rapidly precipitate and lead to intracranial hypertension and death. In case of grade 2 or 3 encephalopathy, intubation and sedation are indicated before any interhospital transfer. Rapid increases in hypoglycemia and INR are also warning signs for referral to the intensive care unit.

The use of NAC for paracetamol overdose is well established and its use in ALF has already been discussed. There are specific treatments for other etiologies that may be curable, such as fetal therapy for pregnancy-induced ALF, antiviral therapy for viral hepatitis, and immunosuppression for autoimmune hepatitis.

Considering the multidisciplinary nature of management and the risk of progression, a close relationship with the transplant center is recommended, as their experience and remote advice will guide the optimization of results. The authors highlight that critical care interventions, many of which are modified for ALF, have a significant impact on outcomes.

In ALF, advanced neuroprotection involves sedation, ventilation, close control of arterial CO2 pressure, maintenance of cerebral perfusion pressure and a higher plasma sodium level, active reduction of ammonia levels, avoidance of hypoglycemia and prevention of pyrexia.

Patients with hyperacute ALF also develop a hyperdynamic circulation in the setting of shock, acute renal failure, and marked metabolic acidosis.

Therefore, the real optimal treatment is only that which is done in intensive care, but there are unusual considerations, for example around renal replacement therapy in the context of hyperammonemia (even without acute kidney injury), it also means that the Local ICUs need to contact transplant ICUs to gain expertise.

Frequent feedback on the patient’s progress to a transplant center also minimizes the risk of missing a transfer opportunity due to excessive patient instability.

Patients with persistent pH <7.3 or lactic acidosis after fluid resuscitation, rising INR, acute kidney injury, hypoglycemia, or decreased level of consciousness should be referred to a specialized center.

These indicate patients who are likely to meet the criteria for inclusion on superurgent lists. These criteria, developed on the basis of results from patient cohorts from the 1980s, consistently offer good specificity (82-95%) but have lower sensitivity (58-69%) for mortality.