Article

Acute liver failure: A review for emergency physicians

a b s t r a c t

Introduction: Acute liver failure (ALF) remains a high-risk clinical presentation, and many patients require emer- gency department (ED) management for complications and stabilization.

Objective: This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of ALF. Discussion: While ALF remains a rare clinical presentation, surveillance data suggest an overall incidence between 1 and 6 cases per million people every year, accounting for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the U.S. The definition of ALF includes Neurologic dysfunction, an international normalized ratio >= 1.5, no prior evidence of liver disease, and a disease course of <=26 weeks, and can be further divided into hyperacute, acute, and subacute presentations. There are many underlying etiologies, including Acetaminophen toxicity, drug induced liver injury, and hepatitis. Emergency physicians will be faced with several complications, including encephalopathy, coagulopathy, infectious processes, renal injury, and hemodynamic instability. Critical patients should be evaluated in the resuscitation bay, and consultation with the transplant team for appropriate patients improves patient outcomes. This review provides several guiding principles for management of Acute complications. Using a pathophysiological-guided approach to the management of ALF associated complications is essential to optimizing patient care.

Conclusions: ALF remains a rare clinical presentation, but has significant morbidity and mortality. Physicians must rapidly diagnose these patients while evaluating for other diseases and complications. Early consultation with a transplantation center is imperative, as is identifying the Underlying etiology and initiating symptomatic care.

Introduction

Although acute liver failure (ALF) is a rare clinical presentation in the emergency department (ED), it carries high morbidity and mortality. ALF occurs most often in younger patients without preexisting liver dis- ease, presenting unique challenges in clinical management. Across the developing world, the underlying etiology is primarily viral, with hepa- titis B and E infections recognized as the leading causes in many coun- tries. In the U.S. and much of Europe, the incidence of virally associated liver failure has declined substantially, with the large major- ity of cases now arising secondary to drug-induced liver injury, fre- quently from acetaminophen or idiosyncratic drug reactions [1,2]. While data from Developing countries are sparse, surveillance reports from the developed world suggest an overall incidence between 1 and 6 cases per million people every year, close to 2000 cases per year [1,2]. ALF accounts for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the U.S. each year [3,4]. The rarity of ALF, as

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States.

E-mail address: [email protected] (B. Long).

well as its severity and heterogeneity in presentation, has resulted in a limited evidence base to guide management [5]. However, survival rates have improved in recent years due to advances in critical care management and the advent of emergent liver transplantation [6]. This review outlines the etiologies and clinical manifestations of acute liver failure and discuss current approaches to patient care in the ED.

Discussion

Definition of acute liver failure

While there are N40 definitions of acute liver failure in use, many of the modern definitions recognize distinct disease phenotypes and seek to differentiate ALF based on the interval between the onset of symp- toms and the development of encephalopathy [7-9]. Presently, the most widely accepted definition comes from the American Association for the Study of Liver Diseases (AASLD) (Table 1) [10].

Quantifying the time course of the disease provides clues to the un- derlying etiology, complications, and prognosis with supportive medical care alone. One of the most common Classification systems, developed by O’Grady and colleagues, remains the most common description of

https://doi.org/10.1016/j.ajem.2018.10.032 0735-6757/

Table 1

Definition of acute liver failure from the American Association for the Study of Liver Dis- eases (AASLD).

Definition of acute liver failure International normalized ratio >= 1.5

Neurologic dysfunction with any degree of Hepatic encephalopathy No prior evidence of liver disease

Disease course of <=26 weeks

acute liver failure in adults [11]. This classification recognizes the prog- nostic importance of encephalopathy and Altered consciousness after initial Hepatic injury and subdivides the clinical presentation into three groups: hyperacute, acute, and subacute, as determined by the in- terval between development of jaundice and onset of encephalopathy (Table 2) [11]. Hyperacute presentations, which develop in b1 week, are most commonly caused by acetaminophen toxicity or a viral infec- tion. More slowly evolving, or subacute, cases may be confused with Chronic liver disease and are often the result of idiosyncratic drug- induced liver injury or idiopathic in nature. Patients who present sub- acutely, despite having less markED presentations, have a consistently worse outcome with medical treatment alone compared to those in whom the illness develops more rapidly [12].

Etiologies of acute liver failure

ALF is the clinical manifestation of sudden and severe hepatic injury and has a variety of underlying etiologies, including drug toxicity, viral infections, autoimmune and Genetic disorders, thrombosis, malignancy, heat injury, and ischemia. Metabolic disorders like Wilson disease (WD), HELLP (hemolysis, elevated Liver enzymes, low platelets) syn- drome, acute fatty liver of pregnancy, Reye’s syndrome, galactosemia, hereditary fructose intolerance, hemochromatosis, ?1-antitrypsin defi- ciency, and tyrosinemia may also cause ALF (Table 3) [14]. Overall, ALF is much less common in the developed world compared to the develop- ing world, where viral infections (hepatitis A, B, and E) predominate. Public health measures, notably vaccination and improved sanitation, are among the factors leading to the reduced incidence of these infec- tions in the U.S. and Western Europe, where drug-induced liver injury, particularly acetaminophen, is the most common etiology of ALF. After abrupt loss of hepatic metabolic and immunological function, ALF can result in hepatic encephalopathy, coagulopathy, and in many cases, pro- gressive multiorgan failure and death, unless emergent liver transplan- tation occurs [13].

Viruses

Viral Hepatitis is the most common cause of ALF worldwide, with the largest burden of disease in developing countries. Hepatitis A, B (+-D), and E infections have been widely implicated, as well as other less com- mon viral etiologies, including herpes simplex virus, Epstein-Barr virus, cytomegalovirus, and parvoviruses. Globally, hepatitis A and E infec- tions are responsible for the majority of ALF, with reported case fatality rates exceeding 50% throughout the developing world [15,16]. Hepatitis

Table 2

Classification, clinical features, and prognosis of acute liver failure subtypes [13].

Classification, clinical features, and prognosis of acute liver failure subtypes Clinical feature Hyperacute Acute Subacute

Time from jaundice to encephalopathy 0-1 week 1-4 weeks 4-12 weeks Severity of coagulopathy Severe Moderate Mild

Severity of jaundice Mild Moderate Severe Degree of Intracranial hypertension Moderate Moderate Mild

Table 3

Etiologies of acute liver failure. NSAID = nonsteroidal anti-inflammatory drug, CMV = cy- tomegalovirus, EBV = Epstein-Barr virus, HELLP = hemolysis, elevated liver enzymes, low platelet count.

Etiologies of Acute Liver Failure

Drug-induced Liver Injury

Acetaminophen

Antibiotics: amoxicillin-clavulanate, ciprofloxacin, nitrofurantoin, minocycline, dapsone, doxycycline, trimethoprim-sulfamethoxazole, efavirenz, didanosine, abacavir, ketoconazole

Anti-epileptics: Valproic acid, phenytoin, carbamazepine

Anti-tuberculosis drugs: isoniazid, rifampin-isoniazid, pyrazinamide

Anti-hypertensives: methyldopa, hydralazine, labetalol, nicotinic acid (slow release) NSAIDs: diclofenac, ibuprofen, indomethacin, naproxen

Herbs and supplements: ma huang, kava kava, herbalife, Green tea Extract, Ginseng, Black Cohosh, anabolic steroids

Anesthetics: halothane

Miscellaneous: propylthiouracil, amitriptyline, statins, amiodarone, methotrexate

Viral Hepatitis

Hepatitis A, B (+/- D), C, and E

CMV, EBV, Herpes virus, Parvovirus, varicella zoster virus

Pregnancy-related Liver Disease Acute fatty liver of pregnancy HELLP syndrome

Preeclampsia-associated liver disease Acute hepatic rupture

Ischemic Hepatitis Systemic hypotension Budd-Chiari syndrome Hepatic Artery thrombosis Congestive hepatopathy Reversible etiologies Autoimmune hepatitis

Leptospirosis, hepatic amoebiasis, malaria, rickettsial disease

Genetic Wilson Disease Galactosemia

Hereditary fructose intolerance Hemochromatosis

?1-antitrypsin deficiency Tyrosinemia Miscellaneous Malignancy

Mushroom poisoning Heat injury

Reye’s syndrome

A and E viruses are transmitted through the fecal-oral route, usually due to consumption of contaminated food or water. While hepatitis A infec- tion occurs in roughly 1.5 million people a year worldwide, b1% of these patients develop ALF [16]. Hepatitis A infection produces a more severe course in adults as compared to children, resulting in a hyperacute or acute pattern of liver failure. However, a subacute pattern of liver failure may develop in elderly patients. Hepatitis E infection has a mortality rate of b1%, with elderly patients experiencing poorer outcomes. Hepa- titis E virus infection remains an important cause of viral hepatitis in pregnant women and was originally thought to be associated with high rates of mortality, which is not borne out in recent literature [17]. However, hepatitis E infection leads to ALF in more than half of all neo- nates infected through Vertical transmission [17].

ALF may also occur due to hepatitis B infection, common in some Asian and Mediterranean countries [18]. It is transmitted through expo- sure to blood or other bodily fluids of infected persons. While b1% of pa- tients infected with hepatitis B will develop ALF, the mortality of hepatitis B-induced ALF remains higher than in those with hepatitis A or E infection. Particularly poor survival is seen in those patients without established chronic liver disease after reactivation of previously stable subclinical hepatitis B, as seen in patients with treatment-induced im-

Survival without emergency transplantation

Good Moderate Poor

munosuppression for cancer. It is important to note that reactivation

can occur spontaneously, but it is most commonly seen when the pa-

Typical etiology Acetaminophen Hepatitis A &E

Hepatitis B Drug induced

tient is immunocompromised. Hepatitis C virus is not believed to cause ALF in the absence of a coexisting etiology, but rare cases of ALF

from hepatitis C have been reported [19]. Other rare viral causes of ALF include herpes simplex virus, varicella zoster, cytomegalovirus, Epstein-Barr virus, and parvoviruses.

Drug-induced liver injury

Drug-induced liver injury is responsible for approximately 50% of cases of ALF in the U.S. and Western Europe [20,21]. Hepatic injury may be dose-dependent and predictable, as is the case with acetaminophen-induced hepatotoxicity, which remains the most common cause of ALF in the U.S. However, drug-induced liver injury may be unpredictable and independent of dose in some circum- stances [1,4,22]. Acetaminophen-induced hepatic injury is second- ary to the increased production of N-acetyl-p-benzoquinoneimine, a toxic metabolite. Although acute liver failure after acetaminophen ingestion can occur after consumption of a single Large dose, typi- cally at least 10 g/day, the mortality risk is greatest with substantial drug ingestion staggered over hours or days [23,24]. Acetaminophen toxicity is dose related; however, patients with history of alcohol abuse, malnourishment, and those patients on concomitant cyto- chrome P450 enzyme inducing drugs are at a substantially increased risk of developing ALF at lower acetaminophen doses [25]. ALF due to acetaminophen toxicity is associated with Delayed presentation because of unintentional rather than Deliberate self-poisoning [26]. While the list of hepatotoxic drugs is long, idiosyncratic drug- induced liver injury is rare, even among patients who are exposed to potentially hepatotoxic medication. Furthermore, few patients with drug-induced liver injury progress to encephalopathy and ALF [27]. Factors including older age, elevations in blood aminotransfer- ase and bilirubin levels, coagulopathy, and a history of cirrhosis are associated with increased mortality risk [27].

Other causes

Acute ischemic hepatic injury, colloquially known as “shock liver”, primarily occurs in critically ill patients with primary cardiac, circula- tory, or respiratory failure [28]. This may be caused by severe sepsis as- sociated with signs of cardiac failure and major, transient elevations in blood aminotransferase levels, requiring Supportive management as op- posed to specific interventions targeted at the liver injury [29]. Other causes of ALF include neoplastic infiltration, autoimmune hepatitis, acute Budd-Chiari syndrome, heatstroke, metabolic diseases such as ?-1 antitrypsin disease, and toxic mushroom ingestion, with Amanita phalloides being the most common mushroom to cause hepatotoxicity [20,30]. ALF may be seen in certain Systemic Infections such as leptospi- rosis, rickettsial infections, hepatic amoebiasis, dengue, malaria, and ty- phoid [31-33]. Pregnancy-specific liver diseases may result in ALF and are associated with significant morbidity and mortality for mother and fetus [34]. Preeclampsia-associated liver diseases, acute fatty liver of pregnancy, and HELLP syndrome can lead to ALF [35-37].

Clinical features of acute liver failure

The manifestation, timing, and severity of ALF’s clinical features vary according to its underlying etiology, and a high index of suspicion is re- quired to make an early diagnosis. The initial manifestation of ALF may range from non-specific constitutional symptoms including malaise, an- orexia, fatigue, nausea, vomiting, and abdominal pain to severe hypo- tension, sepsis, seizures, and hepatic encephalopathy (Fig. 1) [38,39]. The clinical course of ALF follows that of multiple organ failure. The loss of hepatocyte function results in liver necrosis, as well as a release of toxins and cytokines leading to severe systemic inflammation and secondary bacterial infections from decreased immunity [40-42]. Direct hepatic necrosis causes severe and rapid loss of metabolic function, resulting in decreased gluconeogenesis, clearance of lactate and ammo- nia, and synthetic capacity, which present clinically as hypoglycemia, lactic acidemia, hyperammonemia, and coagulopathy, respectively [43]. The release of cytokines, Inflammatory mediators, and subsequent

systemic inflammatory response leads to a variety of clinical manifesta- tions, including circulatory dysfunction, pancreatitis, immunosuppres- sion, bone marrow suppression, acute lung injury, and acute respiratory distress syndrome [44-47].

Coagulopathy is a hallmark clinical manifestation of ALF, as all clotting factors with the exception of von Willebrand factor and Factor VIII are synthesized in the liver, and many have a half-life measured in hours. The primary mechanism for abnormal coagulation tests in ALF is the decreased production of clotting factors II, V, VII, IX, and X. Fur- thermore, intravascular coagulation and fibrinolysis consumes platelets and coagulation factors, exacerbating coagulopathy. Thrombocytopenia and platelet dysfunction secondary to uremia are common in patients with ALF, reported in N60% of patients [10].

ALF results in circulatory dysfunction, initially due to poor oral in- take and increased fluid loss leading to hypovolemia [48]. Following liver necrosis and release of cytokines, a systemic inflammatory state begins, characterized by vasodilation and increased cardiac output re- sembling septic shock [49-51]. This in turn leads to hypoperfusion of vital organs, exacerbating multiorgan failure. Likewise, acute renal fail- ure and hepatorenal syndrome are important complications of ALF and are primarily a result of the hemodynamic alterations in ALF [52- 54]. Initially renal injury is prerenal in etiology secondary to hypovole- mia, but acute tubular necrosis rapidly develops due to ongoing ische- mia of renal tubules [55,56]. Additionally, direct renal toxicity may be seen, as in the case of acetaminophen toxicity, Amanita poisoning, or an idiosyncratic reaction to trimethoprim-sulfamethoxazole [57,58]. Sig- nificant renal dysfunction may occur in N50% of patients with ALF and is more common in the elderly and in patients with acetaminophen- induced hepatotoxicity [59].

Hypoglycemia and electrolyte abnormalities remain important

complications of ALF. The main mechanisms contributing to hypo- glycemia in ALF include impaired gluconeogenesis and decreased in- sulin uptake by dysfunctional hepatocytes [14]. This increased level of insulin in the peripheral circulation results in severe hypoglyce- mia. Electrolyte abnormalities including hyponatremia, hypokale- mia, hypophosphatemia, and acid-base imbalances are common. Hyponatremia is commonly caused by hypervolemia [43,48]. Central nervous system induced hyperventilation precipitates a respiratory alkalosis, in turn causing the kidneys to exchange hydrogen ions for potassium, resulting in hypokalemia. Fortunately, these electro- lyte abnormalities rarely result in cardiac arrhythmias [13].

Encephalopathy in ALF remains a key neurological manifestation and is necessary to make a diagnosis of ALF. Encephalopathy comprises a number of clinical manifestations of differing severity, ranging from drowsiness, slowed mentation, cognitive impairment, confusion, and euphoria to deep coma [60]. Hepatic encephalopathy is classified based on severity, ranging from grade 1 to grade 4 [61]. Grade 1 is de- fined as altered behavior with euphoria, anxiety, and decreased atten- tion span, while grade 2 is distinguished by disorientation, lethargy, or asterixis. Grade 3 presents with marked disorientation, incoherent speech, and somnolence. Grade 4 is defined as a patient becoming co- matose or unresponsive to verbal or pain stimuli. Severity of ALF corre- sponds to the grade of encephalopathy upon presentation, with higher grades of encephalopathy portending a worse prognosis [62].

While the pathogenesis of hepatic encephalopathy is not fully un- derstood, it is believed that inflammatory mediators and circulatory neurotoxins, such as ammonia, alter cerebral blood flow and blood- brain barrier permeability [63,64]. Acute liver failure leads to both sys- temic inflammation and local inflammation in the brain, resulting in the release of cytokines and neurotoxins, which cause astrocyte swell- ing, cerebral edema, and encephalopathy. Additionally, ammonia, a byproduct of nitrogen compound catabolism, is toxic at high serum con- centrations. The body utilizes the Urea cycle to excrete ammonia, which occurs primarily in the liver [62]. The urea cycle converts toxic ammonia to metabolically inert urea, while also metabolizing other nitrogenous wastes to nonToxic substances. Within the brain, astrocytes metabolize

Fig. 1. Clinical manifestations of acute liver failure [13].

ammonia to a minor extent by utilizing glutamate, which is then con- verted to glutamine [63]. In ALF, increased levels of ammonia and other toxic nitrogenous compounds in the serum result in increased ex- posure to ammonia by the brain, thereby increasing production of glu- tamine in the astrocytes [64]. As glutamine is osmotically active, water moves into the astrocytes causing cerebral edema and encephalopathy. Similarly, seizures may occasionally be seen in patients with ALF, lead- ing to Cerebral hypoxia, exacerbating cerebral edema and intracranial hypertension (ICH) [64].

Hemodynamic instability and systemic hypotension associated with ALF further contribute to encephalopathy. Cerebral edema is seen in 75-80% of patients with ALF and grade 4 hepatic encephalopathy [65]. This edema can be life threatening, as it can progress to ICH, accounting for 20-25% of deaths in ALF [38]. Signs suggestive of ICH include systolic hypertension, bradycardia, and irregular respirations. Untreated, this may progress to muscle hypertonicity, decerebrate posturing, loss of pu- pillary reflex, and eventually respiratory failure. A high index of suspi- cion for the presence of intracranial hypertension is necessary, as it can develop before other clinical signs of ALF and may result in cerebel- lar herniation prior to any intervention [66].

Considerations in history and physical examination

The diagnosis of ALF is established through focused history and ex- amination, including chronology of events prior to presentation, and supportive laboratory studies. Specific historical information is impor- tant to help better decide the potential cause of the patients’ presenta- tion to the ED and necessary investigations. Assessment of risk factors and potential exposures, including current medications, drug inges- tions, alcohol or substance abuse, pregnancy status, family history, and recent travel, is helpful in discovering the underlying etiology. Further qualifying any exposure to specific hepatotoxins, such as the Amanita phalloides mushroom, is imperative, as this information may change management strategies and therapy. Key historical risk factors for ALF include age N 40 years, Female gender, poor Nutritional status, preg- nancy, chronic hepatitis, and the use of multiple acetaminophen- containing medications for chronic pain [67-70]. Clarification of the

time course of the illness, specifically the interval from the onset of jaundice to the development of encephalopathy, allows the clinician to further classification ALF into categories based on hyperacute, acute, or subacute presentations, which has Diagnostic and prognostic value [11,12].

The underlying etiology of ALF is not only established through his- tory and laboratory testing, but also by the exclusion of alternative causes, including acute presentations of chronic liver diseases. Chronic liver diseases, including hepatitis B and autoimmune hepatitis, routinely present as an acute exacerbation with clinical features indistinguishable from ALF, known as “acute-on-chronic” hepatic failure [71-75]. All com- ponents of the physical examination are important in evaluation. For in- stance, jaundice, a Cruveilhier-Baumgarten murmur (a venous hum in patients with portal hypertension), scleral icterus, fetor hepaticus, and Kayser-Fleischer rings may be subtle signs prompting further evaluation of ALF [38,69]. Abdominal examination may reveal hepatomegaly due to acute viral hepatitis, congestive heart failure (CHF) with secondary he- patic congestion, Budd-Chiari syndrome, or infiltrative malignancies. Physical examination findings may provide evidence suggesting the presence of an underlying chronic liver disease, including splenomeg- aly, caput medusa, gynecomastia, spider angiomata, palmar erythema, and ascites [69]. A detailed neurologic examination, especially in the pa- tient presenting with hepatic encephalopathy, is necessary to evaluate for signs of cerebral edema and increased ICH (Fig. 1) [60,66]. Evaluation for any signs and symptoms of a concomitant infectious process, as well as a psychiatric screening for depression and suicidal ideation, may pro- vide significant clinical value [76].

Diagnostic considerations

Laboratory testing

Laboratory and imaging studies should be pursued to confirm the di- agnosis of ALF, evaluate for end organ dysfunction, and provide accurate prognostication of the patient’s clinical condition (Table 4). It is benefi- cial to evaluate for electrolyte and metabolic abnormalities with a basic metabolic panel, venous blood gas, and lactate level. Additionally, he- patic abnormalities should be investigated by obtaining liver enzymes,

Table 4

Initial Investigations in Acute Liver Failure. Ab= antibody; Ag= antigen; ALT= alanine aminotransaminase; AST= aspartate aminotransferase; HAV= hepatitis A virus; HCV= Hepatitis C virus; HEV= hepatitis E virus; HSV= herpes simplex virus; Ig= immunoglob- ulin; INR= international normalized ratio; PCR= polymerase chain reaction; PT= pro- thrombin time; PTT= partial thromboplastin time; TEG= thromboelastogram; VZV= varicella zoster virus. CT= computed tomography; US= ultrasound.

Initial Investigations in Acute Liver Failure

evaluate for CHF causing hepatic congestion and aid in determining fluid status and responsiveness [80].

Acute liver failure management

The most important aspect of management involves the timely diag- nosis of ALF. Diagnosis is the most important management step for the

Serum Chemistries

Basic metabolic panel: sodium, potassium, bicarbonate, calcium, magnesium, phosphate, glucose, blood urea nitrogen, creatinine Amylase, lipase

Serum lactate

Hepatic panel

AST, ALT, Albumin, total bilirubin, alkaline phosphatase

Arterial Blood Blood gas Serum ammonia Toxicologic

Blood alcohol level Acetaminophen level Urine toxicology screen Serum salicylate level Hematologic

Complete blood count Blood type and screen

Coagulation studies: PT/INR, Fibrinogen, PTT, TEG, D-Dimer

Viral Hepatitis Serologies

Anti-HAV IgM

Hep B surface Ag, anti-hep B core Ab IgM

Hep D Ab, hep D RNA

Anti-HCv, +-hepatitis C RNA PCR

+-Anti-HEV IgM Anti-VZV IgM Anti-HSV IgM

Autoimmune Markers Antinuclear antibody Anti-smooth muscle antibody

Serum IgG levels Urine Pregnancy test

Urinalysis and urine culture

Miscellaneous Serum ceruloplasmin Blood cultures Electrocardiogram

Imaging

CT Brain without contrast Abdominal US

Chest x-ray Echocardiogram transcranial Doppler

clinician, as a delay can lead to substantial morbidity and mortality. While there is no proven therapy for ALF, understanding the progres- sion of ALF, from loss of hepatocytes to the development of multiorgan failure, helps the clinician in disease-specific complication manage- ment. Generally speaking, the management of ALF should involve the following tests [81].

Identification of the etiology of ALF whenever possible and initiation of specific treatment.
  • Supportive and symptomatic management of ALF, with timely trans- fer to the critical care unit.
  • Early consultation with liver transplant specialists and transfer of pa- tients to a liver transplant center when necessary.

    Identification and treatment of underlying etiology

    Acetaminophen toxicity. Identification of the underlying cause of ALF is necessary, as treatment varies. The most prevalent cause of ALF in the U.S. is acetaminophen toxicity, with an effective antidote available, N-acetylcysteine (NAC). Hepatotoxicity is not usually seen in the imme- diate period following acetaminophen ingestion, and the treatment of acetaminophen toxicity differs from the treatment of patients with ALF [13,22,24]. The Rumack-Mathew nomogram helps predict the de- velopment of hepatotoxicity in patients with acetaminophen toxicity and should be used to determine the need for NAC [82]. In confirmed cases of acetaminophen toxicity, acetaminophen levels should be plot-

  • alkaline phosphatase, direct/indirect bilirubin, ammonia, albumin, and coagulation studies, including fibrinogen. A pregnancy test should be obtained in any woman of child bearing age at risk for HELLP syndrome, and a blood type and screen sent in cases of suspected gastrointestinal bleed from severe coagulopathy. A complete blood count may reveal leukocytosis, anemia, and thrombocytopenia, while blood cultures may be useful in the febrile patient. The clinician should have a low threshold for obtaining toxicologic studies, including acetaminophen level and any possible co-ingestants. The AASLD recommends obtaining acetaminophen levels in all patients with ALF, regardless of any history of acetaminophen ingestion [10]. Acetaminophen levels in the blood vary depending on the time of consumption, and a low acetaminophen level does not exclude acetaminophen-induced hepatotoxicity [77]. The time of ingestion may be remote, unknown, or occurring over days, and as such, measuring acetaminophen levels in patients with liver tests suggesting liver failure may not yield meaningful diagnostic informa- tion. Other tests should be guided by the physical examination, includ- ing serum ceruloplasmin and copper in suspected presentations of Wilson disease, viral hepatology serologies, autoimmune hepatitis markers, serum ammonia, and viral hepatitis PCR studies. However, these studies may be obtained in the in-hospital setting.

    2.5.2. Imaging

    Imaging, while not necessary to establish a diagnosis of ALF, may be

    ted on the nomogram based on in order to determine the risk of devel- opment of hepatotoxicity, and NAC should be immediately started, as it is most efficacious when given within 8 h of ingestion [83]. However, it may still be effective up to 48 h post-ingestion [84]. NAC has a favorable side-effect profile (predominately nausea and vomiting, while rash, ur- ticaria, and bronchospasm rarely occur) [85]. NAC should be adminis- tered in all patients with suspected or confirmed acetaminophen toxicity even if they present beyond 8 h of presentation [10]. Dosing is demonstrated in Table 5 [10]. Studies suggest oral NAC is as effective as IV NAC and comparatively much cheaper [86]. However, IV NAC is more commonly used due to the fact that the majority of patients with acetaminophen-induced hepatotoxicity suffer from significant nausea, vomiting, or altered mental status, making oral NAC impractical. Furthermore, the administration of activated charcoal, at a dose of 1 g/kg body weight orally, may be useful up to 4 h after ingestion, and acts by decontamination of the GI tract [10]. Administration of activated charcoal prior to NAC does not affect the efficacy of NAC. Thus, it is rec- ommended to give activated charcoal prior to NAC if acetaminophen in- gestion is within 4 h of presentation [10].

    Table 5

    N-acetylcysteine dosing by route.

    useful in the correct Clinical context. Abdominal ultrasound may provide

    information regarding hepatic venous disease or underlying Budd-Chiari syndrome, while a chest x-ray is useful to evaluate for aspiration pneu-

    N-acetylcysteine dosing

    Preparation Loading dose Maintenance dose

    monia in the vomiting patient [78]. In the patient with encephalopathy, a head computed tomography or bedside transcranial Doppler may provide information regarding cerebral edema and ICH [79]. One should have a low threshold for non-contrast CT to evaluate for cerebral edema prior to non-invasive monitoring. A bedside echocardiogram can

    Intravenous 150 mg/kg in 5% dextrose solution over 15 min

    Oral 140 mg/kg by mouth or as a 5% diluted solution through nasogastric tube

    50 mg/kg given over 4 h, followed by 100 mg/kg over 16 h

    70 mg/kg every 4 h for a total

    of 17 doses

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