The term acute liver failure is frequently used as a generic expression to describe a large and diffuse cohort of patients presenting with or developing an acute episode of liver dysfunction, usually manifested by deterioration in liver blood tests and other organ dysfunction.
This chapter largely addresses a cohort of patients with primary acute liver failure (ALF), that is patients with acute liver dysfunction manifested by transaminitis, coagulopathy, and encephalopathy in the setting of a previously normal liver. The etiology of these disturbances should be primarily liver in aetiology and as such, the coagulopathy and altered conscious level should be attributable to the liver failure as opposed to other etiologies such as systemic disease processes or sepsis. The later processes are typically described in the context of a secondary liver injury.
Management of patients with ALF should focus upon prevention and removal of any potentiating agents and support of the liver and other organs to facilitate regeneration and recovery. A small proportion of patients with ALF will have a liver injury that does not have the capacity to repair and regenerate and as such will need the option of emergent liver transplantation.
ALF: DESCRIPTION AND AETIOLOGY
ALF describes a syndrome incorporating sudden loss of liver function denoted by the features of coagulopathy and encephalopathy in a patient without previous liver disease. The disease process should result from primary liver insult, and the coagulopathy and altered conscious level should occur as a result of liver failure as opposed to a systemic process such as sepsis.1,2
ALF was subdivided, by O’Grady and colleagues, into hyperacute, acute and subacute, while previous descriptions had utilized fulminant and subfulminant terminologies, with times lines of up to 8 weeks and 8 to 24 weeks, respectively.3 For practical reasons acute and hyperacute have been merged to describe management. Disease processes resulting in encephalopathy after 24 weeks are categorized as chronic liver disease and fall outside the scope of this chapter.
Similarities of disease process and complications are seen for hyperacute, acute, and fulminant groups; while the subacute and subfulminant groups have different presentations and characteristics.4
The acute type presentations demonstrate severe coagulopathy, transaminitis, and initially only moderate, if any, increases in bilirubin; by contrast, the subfulminant/subacute often present with minor transaminitis, deep jaundice, and mild to moderate coagulopathy. Their disease process is often such that they present with a liver that is shrinking in volume; splenomegaly is a feature and ascites may be present. This group has a very poor chance of spontaneous survival while the acute/fulminant presentations have a greater chance of spontaneous recovery despite having a greater manifestation of extrahepatic organ failure.
The etiology of ALF syndromes can be seen in Table 106-1.
Etiology and Nature of Acute Liver Failure
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Etiology and Nature of Acute Liver Failure
|Precipitant ||Examples ||Presentation |
|Viral ||hepatitis A, hepatitis E, hepatitis B (less frequent CMV, HSV, hepatitis C) ||Acute |
|Drugs/toxins ||Acetaminophen, Phosphorous, ||Acute |
|Amanita phalloides |
| ||Antituberculous chemotherapy, statins, NSAIDs, phenytoin, carbamazepine, ecstasy, flucloxacillin and others ||Acute and subacute |
|Vascular ||Budd-Chiari ||Acute and subacute |
| ||Hypoxic hepatitis, ecstasy ||Acute |
|Pregnancy ||Preeclamptic liver rupture, HELLP syndrome, fatty liver of pregnancy ||Acute |
|Others ||Wilson disease, autoimmune, lymphoma, hemophagocytic lymphohistiocytosis (HLH) || |
The table does not provide an exhaustive list of etiologies; rather, it lists the common aetiologies.5 The category “other” provides for the description of various diseases, which may be categorized as ALF but have certain unique features. Wilson disease is, by definition, a chronic disease process with features of cirrhosis and splenomegaly at presentation. Patients, children and young adults, present with acute coagulopathy and encephalopathy, often with no previous diagnosis of any disease process. In some, this may represent an intercurrent viral illness with hepatic presentation of ALF and in others it may relate to a discontinuation of chelating therapy. The characteristic features are those of a low alkaline phosphate level, often a hemolytic anemia (not direct antiglobulin test [DAT] positive) and features of splenomegaly with or without Kayser-Fleischer rings on slit lamp examination of the eyes. The development of high level encephalopathy (grade III/IV) and coagulopathy in this disease presentation effectively always requires transplantation.
Lymphoma can present with a picture of ALF as can other malignancies causing diffuse infiltration of the liver. Such etiologies should always be considered as secondary ALF and not suitable for consideration for transplantation. An elevated LDH and alkaline phosphate are characteristic features of lymphoma.
Auto-immune liver disease may rarely present as an acute or subacute presentation, often but not always with elevated globulin fraction and positive autoantibodies.
Acetaminophen causes ALF (acute) in a dose dependent manner with toxicity being seen in doses above 150 mg/kg although lower ingested doses have also been reported as causing severe hepatotoxicity especially in the face of chronic alcohol abuse6 and chronic use of enzyme-inducing drugs. Presentation and treatment with the antidote (N-acetyl cysteine) within 16 hours of presentation normally prevents progression to ALF.7,8 Later presentations and staggered ingestion are associated with a worse prognosis.
Many drugs can cause ALF or acute liver injury9 and the categories are described as hepatotoxic, cholestatic, or mixed. Withdrawal of putative drugs should always be considered and scoring systems are available to aid this decision process. Guidelines have been issued by various thoracic societies for management and withdrawal of antituberculous chemotherapy in patients who develop transaminitis or jaundice.10
Recreational drugs such as ecstasy may result in ALF from a heat shock type injury or as a more indolent course. Cocaine may similarly result in ALF with an ischemic aetiology.
Budd-Chiari may present as ALF, either with an acute or subacute presentation albeit usually with ascites. The routine screening investigations of all patients are pivotal in this diagnosis demonstrating loss of flow on the hepatic veins.
Hypoxic hepatitis has a prevalence of between 1.2% and 11% in intensive care with three etiological subgroups: respiratory failure, cardiac failure, and septic shock.11 It is a secondary form of ALF and as such the primary presenting organ failure needs to be addressed and managed to facilitate liver recovery; transplantation of the liver should not normally be considered. An essential component to this presentation appears to be conditioning of the liver with passive congestion and then a subsequent insult of hypotension and/or hypoxia. Transaminase elevations, as can be seen with acetaminophen and ecstasy, are frequently greater than 7000 to 10,000 IU/L with an associated coagulopathy.
Pregnancy related liver disease is a spectrum of disease presentation where an individual patent may have features of all or only one component. Preeclampsia is a systemic disease of the microcirculation with hypertension and proteinuria. A liver-specific complication of preeclampsia is that of liver rupture presenting with right upper quadrant pain and transaminitis. Large subcapsular hematoma can result in secondary ischemic injury to the liver and potential limitation of hepatic venous outflow. HELLP syndrome is characterized by hemolysis, abnormal liver function tests, and low platelets. Fatty liver disease of pregnancy is characterized by hypoglycemia in addition to other features and is often complicated by other organ failure including pancreatitis. Elevated urate levels are also seen.
INITIAL INVESTIGATIONS AND MANAGEMENT
Patients should be screened for the etiology of their acute liver injury or failure. This includes routine liver blood tests and full coagulation screen. Viral screening should be undertaken for acute hepatitis A (IgM), hepatitis E (IgM), hepatitis B (IgM core Ab, surface Ab, and hepatitis B DNA). Viral PCR for CMV and HSV should also be considered. Immune screening should be undertaken in the form of immunoglobulin and autoantibodies. Hemolysis screen should be undertaken if there is unconjugated component with a DAT negative screen raising the consideration of Wilson disease. Elevated alkaline phosphatase and lactate dehydrogenase raise the possibility of infiltrative processes within the liver.
All patients should undergo an ultrasound of the abdomen, with interrogation of the hepatic and portal veins, assessment of spleen size and texture, and reflectivity of the liver. While the liver ultrasound is being undertaken, assessment of pancreas, ascites, and kidneys should be performed. Axial imaging in the form of CT may also be required—especially if there is concern for malignancy or a nodular outline of liver when further information is required to assess perfusion, liver contour, and presence of nodes. The role of liver biopsy is controversial. It may be required to define the presence or absence of cirrhosis or a specific aetiology, which is amenable to therapeutic intervention. Examples include autoimmune or alcoholic hepatitis, which may be treated with corticosteroids, or hepatosplenic lymphoma, which would be offered chemotherapy. Though there have been some suggestions that a liver biopsy assessing percentage necrosis allows assessment of prognosis, this is now thought to be less appropriate given the risk of sampling error.
Echocardiography should be considered in patients where there is any concern of hypoxic hepatitis (HH) and allows assessment of right and left heart function. The presence of hepatopulmonary syndrome may also be sought as this can be seen in some 50% of patients with HH.
EARLY MANAGEMENT AND REFERRAL PRACTICE
Presenting features are likely to be very different depending on nature of disease process. It is important to consider early discussion with a tertiary center to obtain guidance on investigations and management.
Removal and treatment of potential aetiological agents is essential. Particular issues to consider are those patients with carriage of hepatitis B who are otherwise asymptomatic and are then in receipt of chemotherapy or immunological therapy such as Rituximab.12,13 Such patients are at high risk of developing ALF or injury (coagulopathy and no encephalopathy) as a result of reactivation of hepatitis B. Such reactivation may present with a fulminant course of acute liver failure. This can be prevented by pretreatment with antivirals14 (eg, lamivudine, entecavir, tenofovir); if a patient presents in this manner, antivirals should be commenced. CMV and HSV should be considered and treated.
N-acetylcysteine (NAC) is recommended in patients with acetaminophen-induced ALF/injury. This drug is highly effective if used within 16 hours of drug ingestion. The Rumack-Matthew treatment nomogram15 should be followed utilizing a high-risk treatment line if the patients fall into high-risk groups (eg, chronic alcohol use, malnourished status, or enzyme inducting drugs). Acetaminophen levels should be interpreted with caution; they are not useful if the time of ingestion is unclear or staggered. In these circumstances, treatment should be offered while awaiting further investigations; likewise, if patients present late, treatment should be commenced while awaiting acetaminophen levels. Patients who have ingested acetaminophen, either as a single dose or staggered, and present with coagulopathy with or without encephalopathy (ie, usually after 48 hours) will not have elevated acetaminophen levels.16 The characteristic picture is a significantly elevated transaminitis (usually >5000 IU/L) and a history compatible with acetaminophen-induced hepatotoxicity. The evidence for using NAC after 16 hours is based on relatively old studies showing decreased incidence of organ failure, as well as a mortality benefit. There are also data showing the beneficial effects of NAC on oxygen extraction, cytokine modulation, and cGMP levels. NAC is, however, an inhibitor of NFKB and as such is an immune-modulating agent. Accordingly, most intensive care clinicians use NAC for a maximum of 5 days.
The role of NAC in non-acetaminophen-induced ALF is supported by the randomized control trial of the USA ALF group. This showed benefit in those patients in grade I or II coma but not in deeper grades of coma.8 This finding is not surprising given that those with a high level of encephalopathy in this cohort of non-acetaminophen-induced ALF will frequently require transplantation, and as such an expectation that NAC may alter outcomes is probably unrealistic. In a recent study of children with non-acetaminophen-induced ALF, NAC was not found to be effective17; this should be considered in the context that the cohort-included patients with inborn errors of metabolism, a circumstance where NAC would not likely be effective.
Any drug with potential hepatotoxicity should be withdrawn. If a patient has evidence of hypoxic hepatitis, management of the cardiovascular and/or respiratory systems needs to be optimized.
Most patients presenting with ALF have developed systemic vasodilation with a decrease of effective central blood volume. Early presentation with lactic acidosis is likely to reflect volume depletion and will respond to appropriate volume loading. Following effective volume challenge ongoing lactic acidosis is likely to reflect liver failure and severity of disease.
Assessment of volume status can be achieved through echocardiographic techniques or utilizing invasive monitoring, usually pulse contour or other similar techniques (see Chap. 34 on Judging Fluid Responsiveness). Caution should be exercised to avoid significantly increased right-sided pressures as this may be detrimental to liver venous outflow and hence liver function/recovery.
The cohort of patients with subacute liver failure and those with acute Budd-Chiari syndrome may present with elevated intra-abdominal pressure. This may alter response to volume loading which will need to be assessed on an individual level (see Chap. 114 on Abdominal Compartment Syndromes).
Following volume loading, persistent hypotension requires institution of vasoactive support, given the normal clinical picture of an elevated cardiac output and decreased vascular tone. The usual initial medication would be norepinephrine, with consideration for addition of low dose vasopressin at 20 to 40 mU/min. Concern had been raised in the literature that use of vasopressin may be detrimental with regard to cerebral complications. However, a study comparing terlipressin and norepinephrine showed that terlipressin increased cerebral perfusion pressure (CPP) without changing intracranial pressure (ICP); norepinephrine increased CPP, but also showed a statistically significant, but small increase in ICP.18
Although the majority of patients will have a hyperdynamic circulation, a proportion of those with hypoxic hepatitis (cardiac and respiratory in etiology) are likely to have evidence of both right- and left-sided dysfunction with or without valvular heart disease. In this setting, optimization of cardiac function will need to be individualized with regard to volume status and inotropic needs. As stated above, right-sided pressures should be minimized to facilitate optimal hepatic venous drainage alongside effective left ventricular output.
Whether there is benefit to giving physiological doses of hydrocortisone to those patients with vasopressor resistant shock is not clear. There are no mortality studies addressing this, although, using a standard ACTH stimulation test, some studies have reported evidence of >50% adrenal dysfunction. There is one study suggesting that use of steroids decreases vasopressor requirements and prolongs time to death or perhaps in this patient cohort, time to obtain a suitable liver for transplantation.19
An elevated troponin has been shown to be predictive of poor outcomes in a study from the USA ALF group,20 although a subsequent study did not repeat this finding.21 It is thought that troponin elevations reflect myocyte stress in the setting of metabolic disarray and multiple organ failure.
If volume loading does not result in resolution of lactic acidosis, early referral to a tertiary center should be undertaken. Failure of volume to resolve hypotension will require use of vasoactive drugs such as norepinephrine. It should be recognized that grossly elevated levels of acetaminophen without evidence of acute liver failure may result in transient, but significant, lactate elevation from temporary mitochondrial standstill. This does not carry the prognostic significance of later lactic acidosis.
Encephalopathic patients are often unable to protect their airway and will require endotracheal intubation to address this problem. Primary respiratory failure as a complication of acute liver failure is relatively rare in the early phase of acute liver failure. Accordingly, patients who require endotracheal intubation for airway protection only may be managed with minimal pressure support/CPAP ventilator settings or even a T-piece. Acute hypercarbia may not be well tolerated in those patients with cerebral edema who are at risk of elevated ICP. Ventilatory strategies should account for this and allow normocarbia during the period of risk. The incidence of ARDS/acute lung injury is relatively rare in patients with ALF and does not appear to contribute to mortality. Those patients who develop ARDS should be managed with a low tidal volume lung protective strategy.
Oral nutrition should be encouraged in those with an acute liver injury who are not encephalopathic. Progressive encephalopathy and/or anorexia are likely to result in decreased calorie intake. Consideration may be given to insertion of an enteral tube to facilitate feeding. Risk-benefit ratio should be assessed at an individual level to account for problems such as bleeding during placement of the enteral tube and for the risk of large nasogastric aspirates and risk of micro-aspiration if encephalopathy progresses.
There is a moderate risk of pancreatitis in patients with acute and hyperacute etiologies of acute liver failure and axial imaging to quantify this may be required if there is clinical suspicion. Management is as per pancreatitis in other critical care settings (see Chap. 108); however, the finding of severe pancreatitis is a relative contraindication to emergent liver transplantation.
Guidance with regard to nutritional needs in patients with ALF is largely empirical. Calorie and protein requirements are as per critically ill populations of other etiologies. Ammonia monitoring may be useful during commencement of feeding to ensure that there is no associated increase in measured levels.
Acid suppression therapy with H2-blockers or proton pump inhibitors is normally prescribed, given that these patients will have a coagulopathy on the basis of their liver failure. H2-blockers are preferred since they are associated with a lower incidence of C dificile infections.