Fulminant Liver Failure

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by Walid S. Arnaout, M.D., FACS
Cedars-Sinai Medical Center

Fulminant liver failure (FLF) is a relatively uncommon form of liver failure that affects individuals with no previous history of liver disease. It is defined as sudden onset of severe liver failure associated with jaundice and altered mental status known as hepatic encephalopathy. The exact incidence of FLF is unknown; however, it is estimated to be around 5000 cases annually with most cases seen in adults between the ages of 20 to 45 years old. Despite the relatively low incidence and small number of affected individuals, FLF represents one of the most difficult and complex challenges in hepatology and critical care medicine. Unlike most other forms of liver disease, FLF is still associated with a very high mortality despite all the recent advances in surgery and critical care medicine.

Fulminant liver failure is caused by a variety of conditions, all of which lead to massive liver cell injury and inability of the remaining viable liver tissue to carry all of the necessary functions, such as synthesis of essential substances and detoxification of numerous toxins. Acetaminophen overdose (the substance found in Tylenol and many other pain medications) is one of the most common causes of FLF in the Western world. Most cases of acetaminophen overdose are due to suicide attempts; however, accidental intake of large amounts for pain control is also common, especially when taken simultaneously with other hepatotoxic drugs or alcohol. Other causes of FLF include certain forms of viral hepatitis mainly acute hepatitis A and B viral infection as well as non-A, non-B, non-C viral infection. Non-viral causes of FLF include toxins such as mushroom poisoning, chemicals such as carbon tetrachloride and aflatoxin, certain drugs such as the antituberculous drug isoniazid (INH) and antiseizure medications like valproic acid and Dilantin and non-steroidal anti-inflammatory drugs and herbal medicines. Other miscellaneous cases of FLF include Wilson's disease, Reye's syndrome, shock liver, and acute fatty liver of pregnancy, as well as numerous other causes.

Medical management of FLF has been mostly unsuccessful in the past with an overall survival rate of 20-30% in most series. Most patients died due to one or more complications of FLF before the remaining healthy liver tissue could regenerate. Among the numerous complications of FLF, massive swelling of the brain tissue (also known as cerebral edema) and increased intra-cranial pressure were the most common cause of death in these patients. The exact cause of cerebral edema is not known; however, it is thought to be due to accumulation of certain neuro-toxic material in the blood as a result of massive liver cell injury and loss of liver function. Additional complication of FLF can include renal failure, pneumonia, massive bleeding, and disseminated infection that could be lethal.

With the introduction of liver transplantation for FLF, the outcome improved significantly with overall survival rates of 60-70% in most centers. Despite these improved results and better survival rates, several issues associated with liver transplantation still need to be addressed and measured carefully every time a patient presents with FLF. The first problem is the potential of the liver to regenerate itself and that the patient may undergo an unnecessary liver transplantation and be committed to life-long immunosuppression and, therefore, several patients may undergo an unnecessary liver transplant. The latter may impose significant psychological and financial burdens on the patient and their families. Currently, there are several clinical and experimental parameters to predict the potential for liver regeneration and survival without liver transplant; however, none of these parameters is sensitive and specific enough to be used solely as the determinant for the need for liver transplantation. In most instances the decision is made based on a combination of several factors. The second issue has to do with the severe shortage of organ donors and the long waiting list for transplantation during which the patient may develop irreversible brain damage or other fatal complication and therefore, would not be a candidate for liver transplantation.

Because of these problems, scientists and physicians have been working toward developing an artificial liver support system to provide metabolic support and to act as a "bridge" until the native liver regenerates or the patient undergoes liver transplantation. An ideal system should be biologically compatible and safe; it should provide both synthetic and detoxification functions. In addition, it should be readily available, safe, and simple to use. Several systems have been developed over the past three decades using artificial and biologic components or a combination of both. Earlier experience with techniques such as dialysis, plasmapheresis, hemofiltration, hemadsorption, and cross circulation with baboon and porcine livers were mostly unsuccessful and without any significant improvement in outcome or survival. Within the last decade, we have developed and reported our clinical experience with a bioartificial liver (BAL) support system composed of isolated cryopreserved porcine hepatocytes attached to collagen matrix mounted in a hollow fiber bioreactor. Our initial experience with this system revealed several advantages that included better control of the intracranial pressure and cerebral edema, improved renal function, and increased cardiovascular stability. Among 24 patients with FLF, eighteen patients were successfully "bridged" to transplantation while five patients with acetaminophen overdose were "bridged" to spontaneous recovery. All patients had a complete neurologic recovery without any deficit at the time of discharge. The BAL system is now being evaluated in a prospective, multi-center, randomized clinical trial to definitively determine whether the original promising uncontrolled clinical results can be validated. It is expected that the clinical trial will be completed in the year 2000.

In summary, FLF is still one of the most serious and life threatening condition that requires emergency liver transplantation in many cases. Due to the potential for liver regeneration and spontaneous recovery and the severe shortage of organ donors and long waiting lists, alternative therapies are being developed to support the failing liver until either an organ becomes available for transplantation or the native liver recovers. Our initial experience with the BAL has been promising with more than 90% overall survival at our institution. Further research effort in this field is needed to determine the feasibility of application of this technology to the treatment of other forms of liver failure.