Acute liver failure (ALF) is a complex clinical syndrome characterized by elevated liver biochemistry, coagulopathy, and hepatic encephalopathy without underlying chronic liver disease. The most frequently used classification is the one that O'Grady and collaborators proposed which divides liver failure into 3 categories based on the interval between the development of jaundice and the onset of encephalopathy as hyperacute liver failure (within 7 days), acute (interval of 1 to 4 weeks ) and subacute (5 to 12 weeks).
The most common etiology of acute liver failure in the U.S. and Western Europe is drug-induced liver injury, while in developing countries it is still viral hepatitis. In the United States, about 2800 cases per year of ALF are identified, with acetaminophen being the main cause. Regarding viral hepatitis, hepatitis A and hepatitis E are frequent causes. Over 1.5 million hepatitis A infections occur worldwide, but less than 1% of them progress to ALF. Better sanitary conditions and the use of the hepatitis A vaccine has led to a decrease in the incidence of acute hepatitis A in developed countries. Hepatitis B is responsible for most of the severe viral ALF cases. Hepatitis C does not appear to cause acute liver failure. Hepatitis D infection can lead to acute liver failure in patients with hepatitis B virus co-infection. Hepatitis E is a rare cause of ALF in the USA but represents around a 20 to 40% of ALF cases in developing countries. Herpes simplex virus (HSV) infection is an uncommon cause of ALF. However, if untreated it carries a mortality rate of 80%. The most commonly affected are immunocompromised and pregnant women. Epstein-Barr virus-related ALF is very rare (less than 1% of all ALF cases). Cytomegalovirus is the causal agent of a variety of disease syndromes, including hepatitis. The incidence is low, 19 in 100000 in the general population. Amanita phalloides is the mushroom that most frequently causes hepatotoxicity. Another frequent cause in patients in intensive care is ischemic hepatitis, which occurs when there is a reduction in blood flow and consequently hypoperfusion of hepatocytes leading to liver cell injury. ALF can also result from specific liver diseases of pregnancy as acute fatty liver of pregnancy and HELLP syndrome. Also, Budd-Chiari syndrome, malignancy, and Wilson’s disease can lead to ALF.
The annual incidence of acute liver failure is less than 10 cases per million population in the developed world. In the United States, there are about 2800 cases of ALF per year. The condition is more frequent in developing countries and often affects young people.
The pathophysiology will depend on the etiology of acute liver failure. Liver failure occurs due to massive hepatocyte necrosis and/or apoptosis. The mechanism of necrosis characteristically demonstrates ATP depletion, cerebral edema, mitochondrial depolarization, and cell membrane rupture. However, in apoptosis, there is a preservation of ATP with activation of caspases, chromatin condensation, DNA degradation and reabsorption of cellular components.
If the initial evaluation involves a thorough history and examination, a liver biopsy is rarely necessary (usually a transjugular technique is used).
The initial clinical presentation will depend on the etiology of acute liver failure and the time of evolution from the onset of the disease. Signs and symptoms of acute liver failure may include:
The diagnosis of acute liver failure should start with the history and physical examination followed by laboratories tests and abdominal imaging.
History of prior episodes of jaundice, medication and alcohol use, family history of liver disease, risk factors for acute viral hepatitis are clinically relevant.
Laboratory evaluation is required to establish the cause and evaluate the severity. It should include liver blood tests, INR, renal function, metabolic panel, blood count, viral hepatitis serologies and HIV serology, toxicology screen and acetaminophen level, autoimmune markers and arterial blood gas. Ceruloplasmin level should be required when Wilson disease is suspected. In patients with acute or chronic hepatitis, HBV anti-hepatitis D virus antibodies should be requested. In addition, anti-hepatitis E virus antibodies ordered when there is a history of travel to endemic areas. Abdominal imaging evaluation includes studies ultrasonography to rule out underlying chronic liver disease/cirrhosis.
Acute liver failure is a complex syndrome, and these patients often succumb to its complications. Patient must be managed in the intensive care unit and transferred to a center with a liver transplant facilities. Treatment should commence as soon as possible along with the diagnostic workup. The therapy must address the underlying cause; for example, administer N-acetylcysteine (NAC) for acetaminophen poisoning, antivirals for acute hepatitis B, steroids for autoimmune flare-ups, penicillamine in Wilson disease, and penicillin in mushroom poisoning. NAC has also shown benefit in non-acetaminophen acute liver failure. The mainstay of treatment of ALF is to prevent cerebral edema regardless of etiology; to achieve this one can employ head elevation, mannitol, hyperventilation, and cerebroprotective measures. Few patients need monitoring of intracranial pressure (ICP) with pressure monitors. Other complications include metabolic acidosis, coagulopathy, hypoglycemia, and renal failure. Coagulopathy should only be corrected if there is active bleeding or the patient needs an invasive procedure. In a patient with renal failure, the institution of early renal replacement therapy is necessary. Hypoglycemia is detrimental in patients with ALF and should be prevented by dextrose infusion. Role of prophylactic antibiotics is still controversial. The management of ALF is with aggressive supportive measures to avoid multiorgan failure until there is recovery or liver transplant.
Survival has improved over time with advances in transplant, as identified in an American registry. In 2012 a European registry showed current rates of survival after transplantation of 79% at 1 year and 72% at 5 years. Several clinical factors have prognostic significance in ALF. The presence of encephalopathy is a key indicator, with special attention given to the patient's age and the severity of liver injury, as evaluated by the presence of coagulopathy or jaundice. The most commonly used system for prognosis of ALF prognosis is The King's College Criteria.
Bioartificial liver systems: Various devices have been created to replace or support liver function. They function as a bridge to transplant. However, these are still in the clinical trial phase.
The use of transplanted hepatocytes infused in the peritoneal cavity or the splenic or hepatic portal system is also under investigation.
High-volume plasma exchange (exchange of 8 to 15% of ideal body weight with fresh frozen plasma), is also treatment under study as a liver support system.
Orthotopic liver transplantation remains the only definitive therapy for patients with irreversible liver injury, with a 5-year survival of more than 70%. The majority of deaths are secondary to neurological complications or sepsis and occur in the first 3 months after transplantation. In Asia, living-related liver transplant (LDLT) is common, with reduced waiting time, and offering better outcomes compared to transplant from a deceased donor. Data from Asia have shown right lobe LDLT improves survival in ALF patients. More frequently, in acute cases, ABO-incompatible grafts are being used. However, in these patients, the graft survival is low (30 to 60% 1-year survival). Auxiliary liver transplant retains the recipient's liver and uses a partial lobe of the donor's liver as temporary liver support. Auxiliary liver transplant has a survival of 60 to 65%.
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