Epidemiology of acute liver failure

Acute liver failure (ALF) is an uncommon disorder that leads to jaundice, coagulopathy, and multisystem organ failure. Its definition is based on the timing from onset of jaundice to encephalopathy. In 2005, ALF accounted for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the United States. Several classification systems have been developed for ALF, with the King's College criteria most widely used for prediction of OLT. Specific diagnostic tests should be implemented to identify the cause of ALF, which will help to determine its treatment and prognosis. Viral hepatitis was previously reported to be the most common cause of ALF in the United States, but acetaminophen overdose and idiosyncratic drug reactions have emerged as the most frequent causes in recent studies. Malignancy is an uncommon cause of ALF, and thus imaging studies may not be useful in this setting, but liver biopsy may be beneficial in selected cases. An overall strategy for ALF should start with identifying the cause, assessing the prognosis, and early transfer to a transplantation center for suitable candidates. OLT has emerged as a life-saving procedure leading to marked improvement in survival rates. Improved surgical techniques, immunosuppression, and comprehensive care have led to an overall survival rate of approximately 65% with OLT. N-acetylcysteine is effective in ALF caused by acetaminophen overdose, with results strongly related to how soon it is given rather than the route of administration. Liver support systems show potential for the treatment of ALF, but their role needs validation in large multicenter randomized trials.     

Changing patterns of causation and the use of transplantation in the United kingdom

Acute liver failure (ALF) is a rare condition in the United Kingdom. Comprehensive supportive intensive care of extra-hepatic organ failure and the early recognition of and use of transplantation for those who will not survive form the cornerstone of its management. Over the last 30 years there has been a reduction in the proportion of cases resulting from viral and seronegative hepatitis, and a progressive rise in those resulting from severe acetaminophen-induced hepatotoxicity. The latter cases mostly result from deliberate self-poisoning and formed the major cause of ALF hospital admissions and indication for emergency liver transplantation. The increasing misuse of acetaminophen has paralleled a rise in sales and greater availability of the drug. Introduction of legislation to restrict sales of acetaminophen has been followed by a fall in hospital admissions resulting from self-poisoning, a 20% reduction in deaths, and a 50% fall in the number of patients undergoing emergency liver transplantation. The reduction in acetaminophen-related ALF has been paralleled by an increase in the number of transplants performed in ALF of nonacetaminophen etiologies.     

Acute liver failure in the United States

In the last 5 years the use of a multicenter approach has helped to define acute liver failure (ALF) in the United States. Drug-related hepatotoxicity comprises more than 50% of cases of ALF, including acetaminophen toxicity (40%) and idiosyncratic drugs (approximately 12%). Nearly 20% of cases remain of unknown etiology. Outcome of ALF is determined by etiology; by the degree of hepatic encephalopathy present on admission; and by complications, principally infection. More than 43% survive without a transplant, 28% die, and 29% undergo liver transplantation. Liver support machines have had no impact on this condition to date. A trial of N-acetylcysteine for the treatment of ALF not related to acetaminophen toxicity is underway. Future research in ALF in the United States should focus on limiting the number of cases related to drugs, searching for causes of the indeterminate cases, and developing more effective temporary liver support.     

Acute liver failure

Acute liver failure (ALF) is defined as hepatic encephalopathy complicating acute liver injury. The most common etiologies are acute viral hepatitis A and B, medication overdose (e.g., acetaminophen), idiosyncratic drug reactions, ingestion of other toxins (e.g., amanita mushroom poisoning), and metabolic disorders (e.g., Reye's syndrome). Despite advances in intensive care management, mortality continues to be high (40-80%) and is partly related to ALF's complications, such as cerebral edema, sepsis, hypoglycemia, gastrointestinal bleeding, and acute renal failure. Several prognostic models have been developed to determine which patients will spontaneously recover. Treatment is directed at early recognition of the complications and general supportive measures. The only proven therapy for those who are unlikely to recover is liver transplantation. Therefore, recognition of ALF is paramount, and urgent referral to a transplant center is critical to assess transplantation status.     

Aetiology and outcome of acute hepatic failure in Greece: experience of two academic hospital centres

Introduction: In Western countries, the most frequent aetiology of acute liver failure (ALF) is acetaminophen overdose, while in developing countries viral infections [hepatitis A virus and hepatitis B virus (HBV)] predominate. Aim: To evaluate the epidemiology, clinical characteristics, outcome and prognostic factors of survival of patients with ALF in Greece during the last 6 years. Results: A total of 40 patients, 28 females (70%), with a median age of 37.4±18.6 years (range: 15–84) with ALF were studied. HBV infection was the cause in 53% of them (compared with 74% from a previous study reported in the early 1980s), drug toxicity in 15% and undetermined in 13%. The overall survival was 57.5%, including 94% with and 15% without liver transplantation. Forty‐five per cent of our patients had emergency liver transplantation in European Centers within a median time of 3.3 days (1–9) from admission. The total bilirubin level at admission and the development of infections were found to be significantly associated with poor outcome. Conclusions: Hepatitis B virus still remains the most important cause of ALF in Greece, but shows a significant decrease as compared with studies in the early 1980s. Almost half of our patients needed emergency liver transplantation and had a very good survival rate. The other 15% of the patients presented spontaneous survival only with intensive medical support.     

Measurement of serum acetaminophen-protein adducts in patients with acute liver failure

BACKGROUND & AIMS: Acetaminophen toxicity is the most common cause of acute liver failure (ALF) in the United States and Great Britain, but may be underrecognized in certain settings. Acetaminophen-protein adducts are specific biomarkers of drug-related toxicity in animal models and can be measured in tissue or blood samples. Measurement of serum adducts might improve diagnostic accuracy in acute liver failure (ALF) patients. METHODS: We measured serum acetaminophen-protein adducts using high-pressure liquid chromatography with electrochemical detection in coded sera of 66 patients with ALF collected prospectively at 24 US tertiary referral centers. Samples were included from 20 patients with well-characterized acetaminophen-related acute liver failure, 10 patients with ALF owing to other well-defined causes, 36 patients with ALF of indeterminate etiology, and 15 additional patients without ALF but with known acetaminophen overdose and minimal or no biochemical liver injury. RESULTS: Acetaminophen-protein adducts were detected in serum in 100% of known acetaminophen ALF patients and in none of the ALF patients with other defined causes, yielding a sensitivity and specificity of 100%. In daily serial samples, serum adducts decreased in parallel with aminotransferase levels. Seven of 36 (19%) indeterminate cases demonstrated adducts in serum suggesting that acetaminophen toxicity caused or contributed to ALF in these patients. Low adduct levels were present in 2 of 15 patients with acetaminophen overdose without significant liver injury. CONCLUSIONS: Measurement of serum acetaminophen-protein adducts reliably identified acetaminophen toxicity, and may be a useful diagnostic test for cases lacking historical data or other clinical information.     

A case of acute liver failure caused by herpes simplex type 2

Unlike mucocutaneous infections, disseminated herpes simplex virus infections are rare and often fatal owing to acute liver failure (ALF). Typically, the course of the disease is rapid and the lack of specific symptoms may result in delay in diagnosis. This study reports a case of genital herpes caused by herpes simplex-type 2 that resulted in ALF. The patient was a 24-y-old woman with a 1 y history of Crohn's disease, treated with oral prednisolone. She was hospitalized with fatigue, anorexia and abdominal pain. Blood tests showed pancytopenia, renal failure and coagulopathy. Pelvic examination revealed signs of severe colpitis and prompt therapy with parenteral acyclovir was initiated. Despite the early institution of antiviral therapy, progressive hepatic coma, gastrointestinal bleeding, oliguria and severe intracranial hypertension characterized the clinical course. The patient received intensive supportive care and recovered without liver grafting. A subsequent screening for immunodeficiency diseases revealed an immeasurable blood mannose-binding lectin (MBL) concentration. 10 weeks after admission, she was discharged for further rehabilitation. This case stresses the importance of suspecting disseminated herpes virus infection in patients with ALF without known aetiology as it may secure prompt initiation of antiviral therapy and reduce the risk that transplantation is needed for survival.     

Treatment of the severe refractory irritable bowel patient

Opinion statement Determining which patients with irritable bowel syndrome (IBS) are “refractory” is highly subjective. The duration, severity, and type of symptoms and a host of other epidemiologic and psychosocial factors play a role in this determination. Long duration of symptoms alone does not portray the severe IBS patient. Several studies have shown that patients concerned with pain rather than altered bowel habits (diarrhea and constipation) are more likely to be disabled by their disease. Pragmatically, refractory patients can be defined as those who fail to improve on multiple drug regimens and who have high health care utilization despite aggressive therapy. In some cases, psychosocial and psychiatric comorbidity can also contribute to an inability to improve despite reasonable medical management. Finally, IBS patients who are unhappy about their care and who have the unrealistic expectation of “cure” may become refractory. The key to dealing with so-called “refractory” IBS patients is to understand that their behaviors often relate to underlying needs that the patients may have difficulty communicating to the physician. Unfortunately, these patients are often labeled as “difficult,” “unpleasant,” or “crazy,” and are often dismissed by their treating physicians. This leads to a continued cycle of pain, frustration, and health care over-utilization, with patients seeking the elusive “cure.” Failure to understand these correlates leads to continued frustration and treatment failure, which unfortunately often characterizes the care of these patients.     

Early metabolic acidosis and coma after acetaminophen ingestion

Metabolic acidosis and coma may develop in patients who experience severe hepatic injury after acetaminophen poisoning. The onset of acidosis and coma soon after acetaminophen overdose, but preceding manifest hepatic injury, contrasts with the typical course of poisoning. This pattern has been reported in a limited number of cases. Coingestions and the rare occurrence of these findings after an overdose have engendered controversy as to whether acetaminophen alone is the cause of early coma and acidosis. We describe 4 separate overdoses among 3 patients who arrived at the emergency department comatose with a metabolic acidosis soon after ingesting large amounts of acetaminophen without evidence of toxic liver injury. Our cases support the view that early metabolic acidosis with coma does indeed occur after acetaminophen poisoning, independent of hepatic failure or its complications.     

N-Acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms

N-acetylcysteine (NAC) is an effective antidote to treat acetaminophen (APAP)-induced acute liver failure (ALF). NAC is hepatoprotective and prevents the neurological complications of ALF, namely hepatic encephalopathy and brain edema. The protective effect of NAC and its mechanisms of action in ALF due to other toxins, however, are still controversial. In the present study, we investigated the effects of NAC in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 μg/g; i.p.) or saline and sacrificed at coma stage of encephalopathy in parallel with AOM mice administered NAC (1.2 g/kg; i.p.). AOM administration led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels and brain GSH/GSSG ratios as well as increased expression of plasma proinflammatory cytokines. NAC treatment of AOM mice led to reduced hepatic damage and improvement in neurological function, normalization of brain and hepatic glutathione levels as well as selective attenuation in expression of plasma proinflammatory cytokines. These findings demonstrate that the beneficial effects of NAC in experimental non-APAP-induced ALF involves both antioxidant and anti-inflammatory mechanisms.     

Approach to the patient with severe,refractory irritable bowel syndrome

Opinion statement Defining which patients with irritable bowel syndrome (IBS) are “refractory” is a highly subjective undertaking. Duration of symptoms, severity of symptoms, type of symptoms, and a host of other medical, epidemiologic, and psychosocial variables all play a role in this determination. It is safe to say that a long duration of disease per se does not constitute a refractory patient. A number of studies have given us some suggestion of what constitutes refractoriness in IBS. Patients who have a predominant pain complaint as opposed to those who are mainly concerned about their bowel habit (either diarrhea or constipation) are more likely to be disabled by their IBS. However, at a clinical level, patients who are considered refractory are usually seen as individuals who fail to improve on a variety of drug therapies or who have high healthcare utilization despite aggressive treatment of their IBS. Finally, patients who are unhappy about their care and/or are assertive in their request to “be cured” can also be seen as refractory because of unrealistic expectations they set for both themselves and the physician. The key to effectively dealing with patients with “refractory” IBS is to understand that their behaviors most often have correlates and underlying issues that need to be dealt with in order to effectively address the patient’s concerns. Unfortunately, most patients who fall into this category are quickly identified as “difficult,” “unpleasant,” or even “crazy” and are not infrequently dismissed by their treating physician. This leads to an ever-enlarging circle of healthcare utilization, with patients seeking out physicians and other practitioners looking for the elusive cure. A key component of this process is an increasing frustration and cynicism regarding the healthcare system and physicians in particular, which does no good for anyone involved. It is clearly critical for the physician dealing with a patient with IBS and a history of poor response to treatment to understand these correlates. Failure to do so creates a continuation of the cycle of treatment failure and frustration that so often characterizes these patients’ care.     

Acute liver failure: Summary of a workshop

Acute liver failure (ALF) is a rare but challenging clinical syndrome with multiple causes; a specific etiology cannot be identified in 15% of adult and 50% of pediatric cases. The course of ALF is variable and the mortality rate is high. Liver transplantation is the only therapy of proven benefit, but the rapidity of progression and the variable course of ALF limit its use. Currently in the United States, spontaneous survival occurs in approximately 45%, liver transplantation in 25%, and death without transplantation in 30% of adults with ALF. Higher rates of spontaneous recovery (56%) and transplantation (31%) with lower rates of death (13%) occur in children. The outcome of ALF varies by etiology, favorable prognoses being found with acetaminophen overdose, hepatitis A, and ischemia (approximately 60% spontaneous survival), and poor prognoses with drug-induced ALF, hepatitis B, and indeterminate cases (approximately 25% spontaneous survival). Excellent intensive care is critical in management of patients with ALF. Nonspecific therapies are of unproven benefit. Future possible therapeutic approaches include N-acetylcysteine, hypothermia, liver assist devices, and hepatocyte transplantation. Advances in stem cell research may allow provision of cells for bioartificial liver support. ALF presents many challenging opportunities in both clinical and basic research.     

Acute liver failure

Acute liver failure (ALF) (sometimes referred to as fulminant hepatic failure) is a clinical syndrome from a variety of causes resulting from rapid loss in hepatocyte function, typically associated with coagulopathy and encephalopathy in a patient without preexisting liver disease or cirrhosis. Cerebral edema is a cardinal feature and may produce uncal herniation, yielding brain stem compression and death. The typical interval from onset of symptoms to onset of encephalopathy is 1 to 2 weeks, but cases evolving more slowly, up to 6 months, may still be included in the definition. ALF is rare, affecting 2000 patients annually in the United States, and comprises ～7% of liver transplants annually. Currently, in the United States, acetaminophen accounts for ～50% of all cases of ALF, but other etiologies include hepatitis, drug-induced liver injury, autoimmune hepatitis. Prior to the availability of liver transplantation (LT), mortality of ALF was extremely high, often exceeding 90%; most common causes of death were multiorgan failure, hemorrhage, infection, and cerebral edema. Fortunately, survival has improved considerably in the last 3 decades (overall survival now exceeds 60%). In large part, this improved survival reflects the option of LT but also reflects the high frequency of acetaminophen toxicity as a cause of ALF. In fact, most patients with ALF are not candidates for LT. Critical care of patients with ALF is key to their survival, and decisions must sometimes be made with inadequate information. We review standard practices (medical, pharmacological, and LT) and new research initiatives and findings for this interesting but vexing orphan disease. Particular attention will be paid to practical matters for clinicians to consider in approaching the ALF patient.     

Acute Liver Failure Due To Amoxicillin and Amoxicillin/Clavulanate

The aim of our study is to report upon the presentation of two patients with life-threatening acute liver failure (ALF) due to amoxicillin and amoxicillin/clavulanate. A 59-year-old, Caucasian male presented with ALF 34 days after receiving amoxicillin/clavulanate. Despite aggressive supportive care, he died on hospital day 10. A 42-year-old, Caucasian female presented with ALF 21 days after receiving amoxicillin. She underwent successful liver transplantation on hospital day 19. In both cases, all competing causes of ALF had been excluded, liver pathology was consistent with drug-induced hepatitis, and cases were deemed “definite/highly probable” using causality assessment. Amongst 14 prior ALF/death cases due to amoxicillin/clavulanate, the mean age (62 years), male predominance (57%), and mean delay from drug cessation to presentation (17 days) is similar to what has been reported in patients with self-limited cholestatic hepatitis. Acute liver failure is a rare manifestation of amoxicillin and amoxicillin/clavulanate hepatotoxicity with no obvious clinical features at presentation portending a poor prognosis. Early transfer of patients with severe drug-induced hepatotoxicity (i.e., encephalopathy or coagulopathy) to a transplant center is recommended due to their poor likelihood of recovery.     

Acute liver failure; clinical features and management.

Acute liver failure (ALF) is uncommon and may be associated with a high mortality rate. Its aetiology shows considerable geographical variation, with viral hepatitis the most common worldwide, whilst acetaminophen (paracetamol) induced hepatotoxicity forms the most common precipitant in many developed countries. Its management requires meticulous intensive care and the effective management of haemodynamic, septic and cerebral complications. The early identification of patients unlikely to survive without emergency liver transplantation is important to maximize the possibility of an available graft. Survival in those patients who undergo transplantation may be in excess of 75%.     

Potentiation of Acetaminophen Hepatotoxicity by Phenytoin,Leading to Liver Transplantation

We report the case of a 22-year-old man who developed fulminant hepatic failure 3 days after an intentional acetaminophen overdose. The patient had a history of a seizure disorder for which he was taking phenytoin. The acetaminophen level at presentation was in the “nontoxic” range. Emergent liver transplantation was performed 4 days after the ingestion. This is the first reported case of successful liver transplantation for acetaminophen-induced fulminant hepatic failure in the setting of phenytoin therapy.     

Acute liver failure complicating jejunojejunal intussusception presentation in a gastric bypass patient

Over 200 000 weight loss procedures are performed annually in the United States. Physicians must there-fore be cognizant of the unique array of complications associated with these procedures. We describe a case of jejunojejunal intussusception in a gastric bypass patient who presented with acute liver failure (ALF) due to acetaminophen (APAP) toxicity. Our patient is a 29 year-old female who had undergone Roux-en-Y gastric bypass surgery seven years prior. She was evaluated in the emergency department for confusion. Her family reported a 3-wk history of progressive abdominal pain and vomiting, for which she had ingested 40 acetamin-ophen/oxycodone tablets over the past 2 d. Physical examination showed icteric sclerae, a distended abdomen, and grade Ⅰencephalopathy. She fulfilled the criteria for ALF and was listed for liver transplantation. Abdominal computed tomography scan revealed a je-junojejunal intussusception. She under went emergent exploratory laparotomy and resection of the infarcted intussusceptum and the previous jejunojejunostomy. She had rapid clinical improvement, with decreasing liver enzymes and improved hepatic synthetic function. She had complete resolution of coagulopathy and encephalopathy, and was removed from the liver transplant list. She was discharged home 20 d after hospitalization with normal liver tests. This case demonstrates that acute abdominal catastrophes can potentiate liver injury in the setting of acetaminophen toxicity. Encephalopathy may obscure history and physical exam findings. This case also exemplifies the pitfalls in the management of the bariatric surgery patient and the importance of multispecialty collaboration in patients presenting with organ failure.     

The critically ill liver patient: fulminant hepatic failure

Fulminant hepatic failure is a challenging medical condition that requires intensive care management to prevent-major complications (cerebral edema, infections, and multi-system organ failure) and assistance from a liver transplant team when it is believed that liver regeneration is unlikely. Unfortunately, there are no specific medical therapies or devices to correct all of the functions of a liver. N-acetylcysteine is used for the treatment of acetaminophen overdose, but for most other causes of fulminant hepatic failure therapy is supportive care. This case illustrates many of the problems that are encountered during medical management of fulminant hepatic failure.     

Subtotal hepatectomy and whole graft auxiliary transplantation for acetaminophen-associated acute liver failure

Background:  An acetominophen overdose (AOD) is the leading cause of acute liver failure (ALF) in the UK and USA. For patients who meet the King''s College Hospital criteria, (mortality risk > 85%), an emergency orthotopic liver transplantation (OLT) is conventionally performed with subsequent life-long immunosuppression. A new technique was developed in 1998 for AOD-induced ALF where a subtotal hepatectomy (right hepatic trisectionectomy) and whole graft auxiliary liver transplant (WGALT) was performed with complete withdrawal of immunosupression during the first year post-operatively.Results:  During 1998–2010, 68 patients were listed for an emergency transplantation for AOD ALF at our institution: 28 died waiting, 16 underwent OLT and 24 a subtotal hepatectomy with WGALT. Eight OLT (50%) and 16 WGALT remain alive (67%); actuarial survival at 5 years OLT 50%, WGALT 63%, P = 0.37. All patients who had successful WGALT are off immunosuppression. Poor prognostic factors in the WGALT group included higher donor age (40.4 versus 53.9, P = 0.043), requirements for a blood transfusion (4.3 versus 7.6, P = 0.0043) and recipient weight (63.1 versus 54 kg, P = 0.036).Conclusion:  Although OLT remains standard practice for AOD-induced ALF, life-long immunosuppression is required. A favourable survival rate using a subtotal hepatectomy and WGALT has been demonstrated, and importantly, all successful patients have undergone complete immunosuppression withdrawal. This technique is advocated for patients who have acetominophen hepatotoxicity requiring liver transplantation.     

Rubbing Salt into Wounds: Hypertonic Saline to Assist with Volume Removal in Heart Failure

Traditionally accepted management strategies for patients with heart failure include sodium and fluid restriction, neurohormonal blockade, and the use of loop diuretics to achieve and maintain euvolemia. Despite continued advances in medical and device therapy, fluid management remains a significant problem in patients with the cardiorenal syndrome (manifested as diuretic resistance and worsening renal function with more aggressive attempts at volume removal). This article examines the counterintuitive use of hypertonic saline as a potential therapy to facilitate diuresis in patients with decompensated heart failure and diuretic resistance. Low-volume hypertonic saline administration offsets counterproductive neurohormonal upregulation, transiently improves hemodynamics, and promotes renal sodium excretion with accompanied net water loss and preservation of renal function. This “new” therapeutic tool should be explored further as an adjunct to current medical therapies in the management of patients with refractory volume overload.