27. Acute liver failure

Akif Altinbas, Lars P. Bechmann, Hikmet Akkiz, Guido Gerken, Ali Canbay

Introduction and definition

Acute liver failure (ALF) is a devastating clinical syndrome, occurring in previously healthy individuals, which is characterised by hepatocellular death and dysfunction (O’Grady 2005). ALF is characterised by onset of coagulopathy (International Normalised Ratio, INR ≥1.5) and hepatic encephalopathy within 26 weeks of symptom appearance in a previously healthy subject (Larson 2010). Exclusion of an underlying liver disease (alcoholic hepatitis, chronic hepatitis B (HBV) and hepatitis C (HCV), autoimmune hepatitis) is mandatory, as management of acute-on-chronic liver failure differs from ALF treatment. The most common causes of ALF in Europe and the US are acetaminophen intoxication, acute HBV infection and non-acetaminophen drug-induced liver injury (Bernal 2010). With progressive loss of hepatic function, ALF leads to hepatic encephalopathy, coagulopathy and multiorgan failure within a short period of time. Established specific therapy regimens and the introduction of liver transplantation improve the prognosis for some etiologies. However, the overall mortality rate remains high (Bernal 2010). ALF accounts for approximately six to eight percent of liver transplantation procedures in the US and Europe (Lee 2008). The accurate and timely diagnosis of ALF, rapid identification of the underlying cause, transfer of the patient to a specialised transplant centre and, if applicable, initiation of a specific therapy and evaluation for liver transplantation are crucial in current ALF management. Therefore, we focus here on epidemiology, pathophysiology, diagnosis and treatment of ALF, including a brief overview of different aetiologies and specific treatment options as well as novel tools to predict prognosis.

Epidemiology and aetiologies

ALF is a rare disease based on multiple causes and varying clinical courses, and exact epidemiologic data is scarce. The overall incidence of ALF is assumed as one to six cases per million people each year (Bernal 2010). Data from the US (Ostapowicz 2002), the UK (Bernal 2004), Sweden (Wei 2007), and Germany (Canbay 2009) reveal drug toxicity as the main cause of ALF, followed by viral hepatitis, followed by unknown aetiology. In contrast, in the Mediterranean, Asia and Africa, viral hepatitis is the main cause of ALF (Escorsell 2007, Koskinas 2008, Mudawi 2007, Oketani 2011).

Intoxication

Drug-induced liver injury

Drug toxicity is the main cause of ALF in high-income societies. Although the incidence of drug-induced liver injury (DILI) in the general population was estimated at 1–2 cases per 100,000 person years (de Abajo 2004), DILI in Germany accounts for approximately 40% of patients with ALF (Hadem 2012). As a structured medical history may be difficult in some cases, a standardised clinical management to identify the cause of DILI and optimise specific treatment has been proposed (Fontana 2010). This includes assessment of clinical and laboratory features, determining the type of liver injury (hepatocellular vs. cholestatic), the clinical course after cessation of the suspected drug, assessment of risk factors (age, sex, alcohol consumption, obesity), exclusion of underlying liver diseases, previous episodes of DILI, liver biopsy and in some cases re-challenge to identify the drug. Furthermore, identifying a cause involves distinguishing between a direct (intrinsic; dose-dependent) and an idiosyncratic (immune-mediated hypersensitivity or metabolic injury) type of liver injury (Larson 2010). Acetaminophen intoxication, as discussed in detail below, is the prototype of a direct, dose-dependent intoxication with acute hepatocellular necrosis. However, most cases of DILI are due to idiosyncratic reactions with a latency period of up to one year after initiation of treatment. Drugs that induce idiosyncratic DILI include narcotics (halothane), antibiotics (amoxicillin/clavulanate; macrolides, nitrofurantoin, isoniazid), antihypertensive drugs (methyldopa) and anticonvulsants and antipsychotic drugs (valproic acid, chlorpromazine) and many others, including herbal medicines. Demonstrating the need for new algorithms and biomarkers of liver injury, Hy Zimmerman’s observation that elevation of transaminase levels above three times the upper limit of normal indicates early DILI is still in use to assess the risk of DILI in drugs in development, since the 1970s (Reuben 2004).

Acetaminophen intoxication

In a recent study, more than seventy percent of the patients with acetaminophen-induced ALF were reported as suicidal intents, the rest as accidents (Canbay 2009). The presence of any ALF risk in the recommended dose range of acetaminophen is controversial. However, the presence of risk factors, particularly obesity and alcohol abuse seem to increase the risk of ALF in patients that use acetaminophen (Canbay 2005, Krahenbuhl 2007). Acetaminophen serum concentration above 300 μg/mL four hours after ingestion is a predictor for severe hepatic necrosis. With high doses of acetaminophen, its metabolite N-acetyl-p-benzoquinone imine (NAPQI) accumulates in hepatocytes and induces hepatocellular necrosis (McGill 2012). In the presence of glutathione, NAPQI is rapidly metabolised to non-toxic products and excreted via the bile (Bessems 2001). In acetaminophen intoxication, the glutathione pool is rapidly diminished, but could easily be restored by N-acetylcysteine therapy (see below).

Amanita intoxication

The spectrum of mushroom poisoning varies from acute gastroenteritis to ALF. Even though the mortality rate of all mushroom poisoning cases is low, the mortality rate of those patients who develop ALF is extremely high, despite the improvement in intensive care management (Broussard 2001). Deadly mushroom poisoning is attributed to Amanita phalloides, the wild mushroom, and occurs mostly in spring and early summer. Amanita toxin has a dose-dependent, direct hepatotoxic effect and disrupts hepatocyte mRNA synthesis (Kaufmann 2007).

Viral hepatitis

Historically the most common cause of ALF in Europe and still today the most prevalent aetiology in developing countries is fulminant viral hepatitis (Hadem 2012). Hepatitis A and E (HAV and HEV), both transmitted via the fecal-oral route are endemic in countries with poor sanitation, tropical and subtropical countries. HEV was determined as the main cause of ALF in some Asian countries. The clinical presentation of HAV is more severe in adults than in children, and HEV is more common in pregnant women, especially in the third trimester (Dalton 2008). Current data indicates that HEV infection might be responsible for up to 10% of ALF in unknown or ambiguous cases in Europe (Manka 2015). Therefore, HEV should be considered as possible cause in unclear ALF cases. Fulminant HBV, transmitted vertically or by infected blood and body fluids, is the most predominant viral cause of ALF in Western countries (Bernal 2010, Canbay 2009). The incidence of fulminant HBV is decreasing with the implementation of routine vaccination. Superinfection with hepatitis D (HDV) in HBV infection is associated with higher risk to develop ALF. HBV infection and treatment is discussed in detail elsewhere. Acute cytomegalovirus, Epstein-Barr virus, parvovirus B19, and herpes simplex virus-1 and -2 are less frequently associated with ALF.

Immunologic etiologies

Autoimmune hepatitis

In rare cases autoimmune hepatitis (AIH) may induce ALF. The acute onset of ALF and its potentially rapid progression causes a diagnostic dilemma since exclusion of other liver diseases might be too time-consuming in patients with ALF secondary to AIH. Thus, IgG elevation and positive ANA titre, combined with typical histological features may be sufficient to induce specific therapy in this instance (Suzuki 2011). However, as DILI might perfectly mimic AIH, a detailed history is key to adequate therapy in all ALF patients with features of AIH (Bjornsson 2010).

Graft-versus-host disease

With the development of new options of donor leukocyte infusion, non-myeloablative methods and umbilical cord blood transplantation, the indications of allogenic haematopoietic stem cell transplantation have been expanding in recent years (Ferrara 2009). Therefore, any hepatopathy in patients who have undergone bone marrow transplant is suspicious for graft-versus-host disease (GVHD). On the other hand, chemotherapy and myeloablation themselves are hepatotoxic and might induce reactivation of HBV, leading to fulminant liver failure.

Wilson’s Disease

Wilson’s Disease (WD), the autosomal recessive disorder of copper metabolism, is a rare cause of ALF. The prognosis of WD patients presenting with ALF is devastating, and almost all die without liver transplantation (Lee 2008). Very high serum bilirubin and low alkaline phosphatase, ALT and AST are typical laboratory readings, and renal failure is a common clinical feature in WD (Eisenbach 2007).

Vascular disorders

Acute systemic hypotension secondary to heart failure or systemic shock syndromes may induce acute liver injury (Herzer 2012). Occlusion of at least two liver veins in Budd-Chiari syndrome or veno-occlusive disease is a rare cause of ALF. Anticoagulatory or lysis therapy is the management of choice; in severe cases, emergency TIPSS or surgical shunt placement may be indicated, as well as a thorough workup to identify any underlying prothrombotic conditions (Fox 2011).

Pregnancy-induced liver injury

Besides acute fatty liver of pregnancy (AFLP), which usually occurs in the third trimester of pregnancy, HELLP syndrome (haemolysis, elevated liver enzymes, low platelet level) is a rare complication of pregnancy and presents with ALF. HELLP syndrome typically presents with LDH, ALT and bilirubin elevation and thrombocytopenia. Hepatopathy usually completely reverses after termination of pregnancy. Patients are at increased risk for complications in future pregnancies (Hay 2008, Westbrook 2010).

Undetermined

Despite dramatic improvements in diagnostic tests in approximately twenty percent of patients with ALF, the aetiology remains undetermined (Canbay 2009, Hadem 2008, Hadem 2012).

Molecular mechanisms and clinical presentation

As mentioned above, ALF occurs on the basis of acute hepatocellular injury caused by toxic, viral or metabolic stress or hypotension. However, regardless of the initial type of liver injury, ALF propels a series of events inducing hepatocellular necrosis and apoptosis, reducing the regeneration capacity of the liver. Massive loss of hepatocytes reduces the functional capacity of the liver for glucose, lipid and protein metabolism, biotransformation, synthesis of coagulation factors, leading to encephalopathy, coagulopathy, hyperglycaemia, infections, renal and multi-organ failure. In fact, even the pattern of hepatic cell death might be of clinical importance, as necrosis or apoptosis seem to be specific for different causes and are associated with clinical outcome (Bechmann 2008, Volkmann 2008).

Apoptosis, programmed cell death, occurs when ATP-dependent processes lead to activation of caspases that induce a cascade of events, ending in the breakdown of the nucleus into chromatin bodies, interruption of membrane integrity and finally total breakdown of the cell into small vesicles, called apoptotic bodies. Upon massive cell injury, ATP depletion leads to necrosis with typical swelling of the cytoplasm, disruption of the cell membrane, imbalance of electrolyte homeostasis and karyolysis. Necrosis typically leads to local inflammation, induction of cytokine expression and migration of inflammatory cells (Jaeschke 2007). However, apoptosis itself might induce mechanisms that lead to necrosis and the ratio of apoptosis vs. necrosis seems to play an important role in liver injury rather than the individual events (Canbay 2004). This hypothesis is supported by observations that a death receptor agonist triggers massive necrosis secondary to the induction of apoptosis (Rodriguez 1996).

The rates of apoptosis or necrosis in ongoing ALF processes seem to be different according to the underlying aetiologies (Bechmann 2010, Herzer 2012). The degree of apoptosis and necrosis, assessed by specific ELISA assays were significantly increased in amanita intoxication compared to other causes. Apoptosis is the predominant type of cell death in HBV and amanita-related ALF, vs. necrosis in acetaminophen and congestive heart failure. Furthermore, entecavir treatment of fulminant HBV significantly reduces serum cell death markers and improves clinical outcome (Jochum 2009).

The regenerative capacity of the liver depends on the patient’s gender, age, weight and previous history of liver diseases. Important mediators of liver regeneration include cytokines, growth factors and metabolic pathways for energy supply. In the adult liver, most hepatocytes are in the G0 phase of the cell cycle and non-proliferating. Upon stimulation with the proinflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), growth factors like transforming-growth factor α (TGFα), epidermal growth factor (EGF) and hepatocyte growth factor (HGF) are able to induce hepatocyte proliferation. TNF and IL-6 also induce downstream pathways related to NFκB and STAT3 signalling. Both transcription factors are mandatory for coordination of the inflammatory response to liver injury and hepatocyte proliferation (Dierssen 2008). Emerging data supports an important role for hepatic progenitor and oval cells as well as vascular endothelial growth factor (VEGF)-mediated angiogenesis in liver regeneration (Ding 2010, Dolle 2010).

TNF-α, IL-1 and IL-6 are also important mediators of the hyperdynamic circulation by alterations of nitric oxide synthesis in ALF (Larson 2010). Renal failure, hepatic encephalopathy and brain oedema are the results of these pathophysiologic changes. Hyperammonaemia correlates with brain oedema and survival (Clemmesen 1999). Decreased hepatic urea synthesis, renal insufficiency, the catabolic state of the musculoskeletal system and impaired blood-brain barrier leads to ammonia accumulation and alterations in local perfusion, which induces brain oedema in ALF. Interestingly, brain oedema is a presentation of ALF rather than cirrhosis, and the risk of brain oedema increases with the grade of hepatic encephalopathy. After acute and massive hepatic cell death, the release of proinflammatory cytokines and intracellular material result in low systemic blood pressure leading to impairment of splanchnic circulation. Indeed, renal failure in ALF patients is common, up to 70% (Larsen 2011). Reduced qualitative and quantitative functions of platelets and inadequate synthesis of prothrombotic factors are the causes of coagulopathy. Leukopaenia and impaired synthesis of complement factors in ALF patients increases the risk for infections, which might result in sepsis. Infections increase the duration of ICU stays and the mortality rate in ALF dramatically. With the impairment of hepatic gluconeogenesis, hypoglycaemia is a frequent feature of patients with ALF (Canbay 2011).

Recent data indicates that high-density lipoprotein (HDL) could be a marker for the severity of ALF (Etogo-Asse 2012). Data in ALF patients regarding lipid-associated parameters is limited, but HDL and cholesterol seem to be important for liver cell regeneration. In patients with ALF, HDL was suppressed, correlated with serum ALT levels, and was lower in patients without spontaneous remission (i.e., deceased or requiring transplantation) (Manka 2014). However, further studies are required to confirm which mechanisms play a role and what effects can be expected. More recently it was shown that liver biopsy by laparoscopy can assist in prognosis of ALF course and outcome, as immunohistochemical assessment of regeneration (i.e., KI67) and cell death (M30) become available (Dechêne 2014).

Prognosis

With persistently high, although variable, mortality rates from ten to ninety percent, accurate prediction of the clinical course is crucial for accurate management and decision-making. Most importantly, identification of the underlying aetiology improves prognosis and opens the door for specific treatment. The degree of hepatic encephalopathy is traditionally considered an important indicator of prognosis (O’Grady 1989). Cerebral oedema and renal failure worsen the prognosis dramatically. In some studies, the INR was determined as the strongest single parameter in predicting the prognosis of ALF. Another interesting point is that the presence of hepatic encephalopathy means a poor prognosis for acetaminophen-induced ALF, which in contrast has little meaning for amanita mushroom poisoning. Liver transplantation is the last treatment option in patients with ALF, when conservative treatment options fail and a lethal outcome is imminent. Therefore, assessment of likelihood of the individual patient to undergo a fatal course is important for timely listing of the patient. Standardised prognosis scores based on reproducible criteria are important in times of donor organ shortage and to avoid liver transplantation in patients that might fully recover without liver transplantation (Canbay 2011).

King’s College criteria (KCC) were established in the 1990s based on findings from a cohort of 588 patients with ALF (O’Grady 1989). The authors also introduced a classification based on the onset of encephalopathy after an initial rise in bilirubin levels into hyperacute (<7 days), acute (8–28 days) and subacute (5–12 weeks) liver failure (O’Grady 1993). KCC includes assessment of encephalopathy, coagulopathy (INR), acid homeostasis (pH), bilirubin and age. For patients with acetaminophen-induced ALF, a KCC formula was implied, deviating from that in patients with non-acetaminophen-induced liver injury. Clichy criteria were introduced for patients with fulminant HBV infection and include the degree of encephalopathy and factor V fraction as a measure for hepatic synthesis (Bernuau 1986). The model for end stage liver disease (MELD) was designed to predict the likelihood of survival after transjugular portacaval shunt (TIPS) in cirrhotic patients. However, it has recently been established as an allocation tool for liver transplantation in patients with cirrhosis in the US and Europe. It was tested as a model for prediction of ALF and was found to be superior to KCC and Clichy criteria in independent studies (Schmidt 2007, Yantorno 2007). Novel approaches that include mechanistic characteristics of ALF like the CK-18 modified MELD, which includes novel markers for hepatocellular death or lactate are promising, but need validation in prospective cohorts (Bechmann 2010, Hadem 2008, Rutherford 2012). In a recent, large, prospective study, a prognostic model was developed using dynamic changes of four independent variables (atrial ammonia, INR, serum bilirubin, hepatic encephalopathy) over three days, to predict mortality (Kumar 2012). Recently an association of thyroid hormone status and outcome of ALF has been demonstrated. Since thyroid hormones are involved in hepatocellular regeneration, thyroid status might be useful as early indicator for severity of ALF (Anastasiou 2015).

Treatment

General management

Given the high risk of deterioration and development of hepatic coma, immediate transfer of the patient presenting with ALF to the ICU is mandatory. Early referral or at least consultation of an experienced transplant centre is indicated in any ALF patient, since liver transplantation is the ultimate treatment for ALF in case conservative therapy fails. The cause of ALF should be determined as soon as possible. Besides specific detailed history taking, laboratory and radiologic tests need to be done in order to establish the diagnosis of ALF and identify the underlying cause. Diagnostic studies include, but are not limited to, arterial blood gas analysis, glucose, electrolytes, bilirubin, ammoniac, lactate, protein, albumin, C-reactive protein (CRP), procalcitonin (PCT), urine electrolytes, urinalysis, and chest X-ray, cranial computed tomography (CT) in patients with advanced hepatic encephalopathy as well as assessment of intracranial pressure (ICP) in some cases. Beyond specific diagnostic studies (HBV serology, coeruloplasmin, urine copper concentration, etc.), transjugular or laparoscopic liver biopsy might be indicated to identify the underlying disease (Canbay 2011).

Hepatic encephalopathy

In general in patients with hepatic encephalopathy, sedative agents should be avoided and if necessary restricted to short-acting benzodiazepines or propofol, as it might decrease intracranial pressure (Wijdicks 2002). Some studies favour utilisation of ICP monitoring, especially in patients with hepatic encephalopathy grade III/IV, and clinical signs of brain oedema. Mannitol therapy (0.5–1 g/kg) might be beneficial in some patients. Head elevation, induction of hypothermia and hyperventilation are recommended by some experts in patients with increased ICP. With worsening of brain oedema, patients present with systemic hypertension and bradycardia (Cushing reflex), dilated and fixed pupils, and in the end respiratory arrest. The target ICP should remain below 20 mmHg, with cerebral perfusion pressure above 70 mmHg and jugular venous saturation of 55 to 80%. Phenytoin is the drug of choice for treatment of seizures and hypertonic sodium chloride might be beneficial on ICP (Larsen 2011). Symptomatic treatment of encephalopathy includes bowel decontamination with neomycin or rifaximin, induction of diarrhoea and reduction of colonic pH and thus reduction of ammonia absorption by lactulose as well as treatment with branched-chain aminoacids to improve peripheral ammonia metabolism, although large, randomised clinical trials have failed to show clinical improvement (Larson 2010, Nguyen 2011).

Coagulopathy

In general, without clinical signs of bleeding coagulation factor treatment is not indicated. To exclude vitamin K deficiency, vitamin K challenge should be performed. Platelets and recombinant activated factor VII are indicated in case of bleeding or before invasive procedures. Interestingly, in ALF patients with impaired coagulation according to conventional testing (INR) may not be at risk for bleeding in laparoscopic procedures (Dechêne 2014).

Liver transplantation

Liver transplantation is the therapy of choice for ALF in those individuals with insufficient regeneration capacity and an otherwise fatal prognosis. In patients without contraindications to liver transplantation, the one-year survival rate is as high as 80–90% with a five-year survival of 55%. As mentioned above, with liver transplantation available as the most favourable therapy, the accurate assessment of the patient’s prognosis is crucial to initiate evaluation of the patient for liver transplantation and decision making in this clinical setting. The underlying disease, the clinical condition and the status of the graft influence the patient’s prognosis after the transplant. In times of general organ shortage, the graft pool might be extended by using living-donor transplants, split liver surgery or transplantation of livers in reduced conditions (Canbay 2011).

Extracorporal liver support systems

Extracorporal systems include support devices or bioreactors, which provide individual or a combination of functions that are insufficiently performed by the diseased liver. The scientific and clinical aim of the introduction of these novel techniques is to stabilise the patient until a donor organ is available or ideally until the liver completely recovers. However, adequately powered, randomised studies to establish these techniques in the treatment of ALF are either lacking or have failed to show any benefit over conventional therapy. Thus, treatment with these devices most likely remains a part of a bridging-to-transplantation strategy within an academic setting. The same accounts for novel stem cell and adult hepatocyte transplant approaches (Canbay 2011).

Specific treatment options

Acetaminophen poisoning

Activated oral charcoal (1 g/kg) might be indicated if administered up to four hours after acetaminophen ingestion. N-acetyl cysteine infusion to restore glutathione should be administered until as late as 24 to 36 hours after ingestion, and continued for 20 hours or longer. Monitoring of blood acetaminophen levels might help in decision-making regarding the duration or initiation of treatment. N-acetyl cysteine should be started as soon as possible, even in patients with a low probability of acetaminophen overdose or even in patients with non-paracetamol drug-induced ALF (Lee 2009). Steroid and ursodeoxycholic acid combination seems to be effective in drug-induced severe liver injury (Wree 2011).

Mushroom poisoning

Silibinin, with its cytoprotective affects against amanita toxin is used despite a lack of the controlled trials (Broussard 2001, Ganzert 2008).

Acute HBV infection

Antiviral therapy with lamivudine or entecavir has proven efficient and safe in fulminant HBV infection (Tillmann 2006). Moreover, with initiation of entecavir within the first days of admission, HBsAg concentrations and cell death were significantly reduced (Jochum 2009).

Pregnancy related

Immediate delivery and abortion are the available causal treatments. With early delivery, the rates of foetal death remain high; however the mortality rate of the mother decreases significantly (Westbrook 2010).

Autoimmune hepatitis

Steroid treatment should be initiated and if started in time might help to avoid the need for liver transplantation. With improvement of liver function, prednisone might be tapered and azathioprine treatment added to the regimens. Recent studies identified the topical steroid budesonide as a potential substitute for systemic prednisone therapy (Schramm 2010).

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