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Acute Liver Failure and Bioartificial Liver Support
The failing liver represents a syndrome with profound morbidity and mortality. The morbidity of liver failure is secondary to the tremendous decline in metabolic and synthetic functions inherent to the liver. With the decline in metabolic activity, accumulation of toxic substances occurs. The most notable of these toxins is ammonia. Cerebral edema (the most feared complication) is strongly associated with elevated levels of ammonia. In addition to ammonia accumulation, drugs metabolized by the liver require strict regulation, if they are used at all. One of the leading synthetic functions of the liver is the production of coagulation factors. As the time in failure progresses, the patient will become more coagulopathic. In addition, the liver is home to an abundant source of resident macrophages, Kupffer cells, which are believed to produce cytokines leading to systemic inflammation in the setting of the failing liver. The systemic inflammatory response syndrome (SIRS) occurs in approximately 60% of patients with a failing liver. The SIRS can lead to failure of other organ systems (kidneys, lungs, etc.), further complicating the course and treatment of patients with failing livers.
The failing liver can be separated into two groups: acute liver failure (ALF) and acute decompensation of a cirrhotic liver ( Fig. 128.1 ). Patients suffering from a failing liver have the possibility of recovering spontaneously. However, for the patients who are not likely to recover spontaneously, the only proven treatment is liver transplantation. Before liver transplantation, the mortality rate of patients with acutely failing livers was greater than 80%. Nowadays this mortality rate has decreased to approximately 30%, thanks to liver transplantation and the high level of intensive care now available. Nonetheless, there are still issues with liver transplantation. For example, these patients are fated to lifetime immunosuppression. More importantly, there is shortage of livers for patients on the transplant waiting list. Thus adding patients in ALF or acute decompensation to this already overextended list only worsens the problem. According to work done by the US ALF Study Group, patients with ALF currently wait a median of 1 day for transplant after listing. However, ALF patients on the transplant list who waited 3 days or longer had a much greater risk of death.
Liver disease is separated into acute and chronic forms with prevalences of approximately 20,000 and 5 million cases per year, respectively. The cases requiring hospitalization are shown here on a spectrum of severity. Groups 1 and 4 represent those cases that do not lead to hospitalization. However, group 2 (acute decompensation) and group 3 (acute liver failure) are recognized by those that lead to hospitalization. Unfortunately, approximately 35% of the acute liver failure group and 20% of the acutely decompensated group die as a result of their failing liver.
The solution to this shortage is unclear but likely requires multiple advances, including improved knowledge of the etiology, high-quality medical care, and some form of artificial liver support until the supply of donor liver organs can be increased. Over the course of this chapter, the most common etiologies of ALF will be reviewed, current medical protocols will be listed, artificial liver support systems will be described, and potential future directions will be explored.
Definition
The current definition of ALF is acute liver injury associated with coagulopathy (international normalized ratio [INR] of 1.5 or greater) and altered mental status (encephalopathy) for less than 26 weeks and no past history of liver disease. After a patient has been diagnosed with ALF, management ensues based upon the level of encephalopathy and the specific etiology (if identified). The most complete set of guidelines for acutely failing liver management are listed in a position paper on the American Association for the Study of Liver Diseases website ( www.aasld.org ).
Etiology of Acute Liver Failure
The incidence of ALF in the United States has been estimated to be approximately 2000 to 3000 per year. However, defining good estimates of the causes of ALF in the United States was difficult due to small sample sizes. In an effort to better define and treat ALF in the United States, the US Food and Drug Administration and the National Institutes of Health (NIH) allotted funding for the development of the US ALF Study Group. Since then, the group has accumulated a robust sampling of ALF patients (2102 patients) between 1998 and 2014 in the United States ( Fig. 128.2 ). This sampling has allowed for a high-quality estimation of the various etiologies of ALF common to the United States.
Acetaminophen and Drug Induced
Acetaminophen overdose leads to a buildup of its reactive intermediate N-para-aminoquinonimine (NAPQI). The sulfhydryl groups of glutathione bind to NAPQI and form nontoxic by-products. After glutathione is depleted from hepatocytes, a centrilobular pattern of hepatocyte necrosis ensues. Acetaminophen-induced liver failure most commonly occurs at dose greater than 12 g/day. However, ALF after consumption of 3 to 4 g/day has been observed. Forty-six percent of ALF cases are secondary to acetaminophen overdose. It is the most common cause of ALF in the United States. According to ALF Study Group registry data in 2015, 23% of the patients were listed for transplant, 8% received a liver transplant, 73% recovered spontaneously, and 19% died without receiving a liver transplant. Data showed that patients who recovered spontaneously from acetaminophen had an 89.5% 2-year survival rate, whereas patients who received a liver transplant had a 92.4% 2-year survival rate. For patients who ingested acetaminophen within 4 hours, activated charcoal can be effective in decontamination. Besides advances in intensive care, the use of N-acetylcysteine has proven efficacious and safe in preventing liver injury and has shown promise in improving brain dysfunction (encephalopathy) in animal models.
Another 11% of the cases of ALF from the US ALF Study Group were caused by other drug toxicities. More than 60 different drugs, alone or in combination, are thought to induce ALF. Antimicrobials (46% of total cases), especially antituberculosis medications, are the most commonly implicated offenders. The outcome is less favorable than acetaminophen overdose. Only 27.1% of these patients spontaneously recovered (less than half of those who had acetaminophen-induced ALF), and 54.9% of these patients required transplantation. Patients who received liver transplant had a 92.9% 3-week survival rate. Liver transplant remains the most efficacious treatment.
Viral
The two main causes of viral hepatitis leading to ALF are hepatitis A virus (HAV) and hepatitis B virus (HBV). Combined, these two viral etiologies account for 10% (HAV—3%, HBV—7%) of the ALF cases seen in the United States. Patients with HAV-induced ALF have a better prognosis both with spontaneous recovery (58% vs. 24%) and overall survival (87% vs. 61%) compared with those with HBV-induced ALF. Treatment for HAV-related ALF remains supportive care because no virus-specific treatment has proven to be effective so far. Because of the lower spontaneous recovery and the need for more transplantation, patients with HBV-induced ALF may be considered for antiviral therapy.
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