-Induced Hepatic Injury 17 Kim Dalhoff

Contents Prognosis ...... 402 Definitions ...... 386 Future Trends ...... 403 Pathogenesis ...... 387 References ...... 404 Etiology and Differential Diagnosis ...... 388 Frequency of Causes ...... 388 Toxic Causes ...... 388 Nontoxic Causes ...... 393 Diagnosis and Complications ...... 395 Coagulopathy ...... 395 Encephalopathy ...... 395 Cerebral Edema ...... 396 Cardiovascular Derangements ...... 397 Renal Failure ...... 397 Pulmonary and Ventilatory Derangements ...... 398 Infection ...... 398 Gastrointestinal Bleeding ...... 398 Metabolic Derangements ...... 398 Diagnostic Studies ...... 399 Treatment ...... 399 Coagulopathy ...... 400 Encephalopathy ...... 400 Cerebral Edema ...... 400 Renal Failure ...... 401 Infection ...... 401 Gastrointestinal Bleeding ...... 401 Metabolic Derangements ...... 401 Nutrition ...... 401 Specific ...... 401

This is an update of a chapter originally written by Thomas Riley and Amit Sadana for the first edition of this book. K. Dalhoff (*) Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark e-mail: [email protected]

# Springer International Publishing AG 2017 385 J. Brent et al. (eds.), Critical Care , DOI 10.1007/978-3-319-17900-1_75 386 K. Dalhoff

The sudden failure of a previously healthy and Definitions functioning liver is a dramatic and devastating event. Acute liver failure is the common final In 1986, Bernuau and colleagues [7] suggested pathway of a multitude of conditions and insults, that the term “fulminant hepatic failure” (FHF) all of which result in massive hepatic necrosis or should be applied to patients in whom encepha- loss of normal hepatic function. The ensuing lopathy developed within 2 weeks of the onset of multiorgan system failure frequently has a fatal jaundice and that subfulminant hepatic failure be outcome, with mortality rates in most series rang- applied to those in whom this interval was 2–12 ing from approximately 55% to 95% [1]. Acute weeks. In 1993, O’Grady and associates [8] pro- liver failure (ALF, previously often referred to as posed the terms hyperacute, acute, and subacute fulminant hepatic failure (FHF)) knows no age liver failure based on whether the interval between boundaries, with many cases occurring in those the appearance of encephalopathy and jaundice younger than 30 years. Short of excellent inten- was 0–7 days, 8–28 days, or 29 days to sive care unit (ICU) support and liver transplanta- 12 weeks, respectively. Both Bernuau and tion in selected cases, few viable treatment O’Grady included cases of preexisting asymp- options are available. Over the past few decades, tomatic chronic liver conditions. In Japan, however, survival has been improved by anticipa- patients with fulminant hepatitis are classified tion, recognition, and early treatment of associ- into two types according to the onset of encepha- ated complications, as well as the application of lopathy (before or after 10 days). Encephalopathy prognostic criteria for early identification of occurring after 8 weeks is defined as late-onset patients requiring liver transplantation (along hepatic failure (LOHF) [9]. with improvement in the techniques and science These classification systems reflect important of transplantation itself). The etiology of ALF differences in the clinical course and prognosis varies from country to country and the incidence observed between patient subgroups, thus facili- change over time. Paracetamol (acetaminophen) tating earlier diagnosis and timely referral for has now replaced viral hepatitis as the leading OLT. For example, both the hyperacute and cause of ALF [2]. In a study from London includ- acute liver failure groups have a high incidence ing 310 patients with ALF in the period of cerebral edema. However, whereas patients in 1994–2004, 42% of the cases were caused by the hyperacute group are more likely to survive paracetamol [3], whereas this was only the cause with medical management, patients in the acute in 2% of 267 patients in Spain from 1992 to 2000 liver failure group tend to die without liver trans- [4]. However, less than 10% of all liver transplants plantation [8]. The subacute failure group has a are performed in patients with ALF [5, 6]. lower incidence of cerebral edema and a higher The aim of this chapter is to help clinicians incidence of portal hypertension manifestations, recognize the presentation and clinical features including ascites and renal failure [8]. Mortality in of - or chemical-induced ALF or liver injury, this group remains high. O’Grady and colleagues anticipate and appropriately manage the compli- found that the hyperacute failure group had a 36% cations of ALF, and recognize the indications for survival rate, as opposed to 7% and 14% in the timely referral for orthotopic liver transplantation acute and subacute failure cohorts, respectively (OLT). The pathophysiology, differential diagno- [8]. Bernuau and coworkers also noted that those sis, appropriate laboratory testing in the evalua- with the most rapid onset of encephalopathy had tion and treatment of ALF, and specific therapies the best chance of survival [7]. Similar observa- available for certain etiologies of ALF will also be tions have been made in Japan [9]. However, it is discussed. Current and future trends in liver trans- important to note that although the interval plantation will be described. between the onset of encephalopathy and jaundice 17 Toxicant-Induced Hepatic Injury 387

Table 1 Definitions of liver failure (hypoalbuminemia, decreased levels of clotting Bernuau Fulminant hepatic failure: encephalopathy factors), gluconeogenesis (hypoglycemia), drug [7] within 2 weeks of onset of jaundice and toxicant metabolism (sensitivity to narcotics Fulminant hepatic failure: encephalopathy and benzodiazepines, hyperammonemia), excre- – within 2 12 weeks of onset of jaundice tory function (hyperbilirubinemia), temperature ’ O Grady Hyperacute liver failure: encephalopathy regulation (hypothermia), and central nervous [8] within 7 days of onset of jaundice system function (encephalopathy) are the result Acute liver failure: encephalopathy within 8–28 days of onset of jaundice of liver failure. Some of these parameters are Tandon Subacute liver failure: encephalopathy used as prognostic factors and markers of severity [12] within 5–12 weeks of onset of jaundice of injury. Mochida ALF defined as liver disease  26 weeks in The exact mechanisms of injury and impair-  [9] duration, INR 1.5, and any degree of ment in hepatocellular function that lead to ALF encephalopathy Fulminant hepatic failure: encephalopathy are poorly understood. Loss of integrity of the within 8 weeks of onset of jaundice hepatocyte plasma membrane secondary to chem- Subclass acute: encephalopathy within ical, immunologic, or a wide variety of other 10 days of onset of jaundice insults is thought to represent the final common Subclass subacute: encephalopathy within 10 days to 8 weeks of onset of jaundice pathway that leads to cell necrosis and ALF [13, 14]. Damage to the cell membrane permits leak- age of enzymes, coenzymes, and electrolytes from the cytosol, followed by an influx of calcium ions, was of prognostic significance in O’Grady’s which eventually results in cell death. The impor- cohort [1], it was not an independent prognostic tance of calcium is underscored by the finding that factor in Bernuau’s cohort [10], thus raising normally vulnerable hepatocytes in vitro do not doubts about its universal applicability. Applica- succumb to the cytotoxic effects of membrane- tion of the O’Grady classification to 423 prospec- active when calcium ions are not included tively studied patients from a tertiary care referral in the culture medium [15]. center in northern India failed to yield any prog- New information is emerging on the role of nostic differences between the groups [11]. growth factors and the inflammatory cascade in

Although these classifications may be useful in ALF. Transforming growth factor-β1 (TGF-β1) highlighting differences in clinical course and has been identified as exerting an inhibitory effect prognosis among patient subgroups, the contribu- on hepatic regeneration, with its effects being tion of other independent prognostic indicators counteracted by hepatocyte growth factor (etiology of ALF, patient age, prothrombin time, (HGF). ALF patients with viral hepatitis have factor V level, renal function, mental status) demonstrated an increase in total TGF-β1 with a should not be overlooked. Table 1 provides a less elevated HGF level, thus suggesting an summary of the various definitions of liver failure. imbalance in growth factor interplay as a cause of impaired hepatic regeneration [16]. This mech- anism has also been suggested by research Pathogenesis performed in posttransplant patients [17]. Studies suggest that activation of the cytokine network Measuring about 1500 mL in volume, the liver is may represent the common final pathway for the the second largest organ in the body and plays a development of ALF [18]. Although multiple critical role in its homeostasis. At no time is this inflammatory cascades come into play, interleu- role more apparent than during an episode of acute kin-1, interleukin-6, and tumor necrosis factor-α injury. Derangements in synthetic function have been identified as the more important 388 K. Dalhoff mediators, along with endotoxin and nitric oxide. drug-induced hepatitis. In the USA, drug-induced In response to the initial hepatic insult, interplay liver injury is responsible for almost 50% of ALF among these mediators sets into motion a vicious [21, 22] most often caused by APAP. In London, self-perpetuating cycle resulting in continued UK, APAP poisoning was responsible for 57% of hepatic injury and multiorgan failure. Furthermore, ALF cases seen at King’s College Hospital higher levels of circulating interleukin-8 and inter- between 1973 and 1991, whereas in France, feron-γ have been demonstrated in patients with APAP was identified as the etiology in only 2% ALF than in healthy volunteers and those with of ALF cases between 1972 and 1990 [23, 24]. A chronic liver disease, thus suggesting a pathogenic multicenter study from the USA of 295 patients in role in acute hepatic injury. Although no relation- whom ALF was diagnosed between 1994 and ship was found between the levels of these two 1996 found that the most common etiologies markers and the clinical course, elevated levels of were APAP (20%), viral hepatitis (10% interleukin-10 were found to be predictive of hepatitis B, 7% hepatitis A), cryptogenic (15%), improved outcome [19]. and drug reactions (12%) [25]. Outside of the USA and Europe, are less likely to cause ALF. In a Japanese study [26], the percentage of Etiology and Differential Diagnosis drug allergy-induced ALF in 432 patients col- lected in the period 1998–2006 was 2% in contrast Careful diagnostic evaluation is important to viral infection which was diagnosed as the because the etiology can have prognostic implica- cause in 16% of the patients (13% with hepatitis tions (e.g., the prognosis is worse with Wilson’s B). Even though APAP overdose was found to disease and idiosyncratic drug reactions, better represent one-sixth of all causes of ALF leading with viral- and acetaminophen-induced ALF), to registration for liver transplantation in Europe, influence treatment options (e.g., N-acetylcysteine there was a 50-fold difference in the relative risk [NAC] for ALF induced by acetaminophen [ace- of ALF leading to registration for liver transplan- tyl-para-aminophenol or paracetamol]), and indi- tation between countries with a low incident rate cate the need for genetic testing of family (e.g., Italy with 0.03 ALF per million inhabitants members (e.g., Wilson’s disease) [20]. Etiologies per year) and high incident rate (e.g., Ireland with of ALF can be divided into toxic and nontoxic. 7.13 ALF per million inhabitants per year). The Toxic causes include pharmaceuticals, drugs of reasons for these differences remain unclear, but abuse, chemicals, and biologic agents. Nontoxic may be related to national differences in pack size causes include, but are not limited to, infections, restriction of APAP or treatment ischemia, metabolic derangements, malignancy, regimens [27]. autoimmune problems, and primary graft failure after liver transplantation. Because ALF repre- sents the common final pathway of injury, it is Toxic Causes difficult to differentiate between the aforemen- tioned causes based solely on clinical presentation Pharmaceuticals and disease progression. A detailed patient history Hepatotoxicity can result from therapeutic or is invaluable, and a multitude of helpful diagnos- toxic doses of many medications by a multitude tic testing tools are available to help uncover the of mechanisms. It can be manifested as asymp- etiology of ALF in the majority of cases (Table 2). tomatic elevations of liver enzymes, but some cases can progress to ALF. Hepatocyte injury can occur directly from disruption of intracellular Frequency of Causes function or membrane integrity or indirectly from immune-mediated membrane disruption. Drugs Although the frequency varies geographically, the can also cause cholestasis, steatosis, idiosyncratic most common causes of ALF remain viral and reactions, fibrosis, veno-occlusive disease, 17 Toxicant-Induced Hepatic Injury 389

Table 2 Etiology of acute liver failure Metabolic/ Infections Toxins/chemicals Vascular others Viral hepatitis Cyclopeptide Budd–Chiari syndrome Wilson’s mushrooms disease Hepatitis A virus Amanita Veno-occlusive disease Fatty liver of phalloides pregnancy HBV A. verna Heatstroke Reye’s syndrome HCV (rare, coinfection) A. virosa Chronic heart failure Galactosemia HDV (coinfection) A. tenuifolia Ischemia Hereditary fructose intolerance HEV (rare in the USA) A. brunnescens Myocardial infarction, Hereditary Herpesviruses (herpes simplex A. bisporigera pulmonary embolism, tyrosinemia virus/cytomegalovirus/varicella Galerina autumnalis tamponade, , Jejunoileal zoster virus/Epstein–Barr virus in intraoperative hypotension, etc. bypass immunosuppressed) Malignant infiltration Autoimmune hepatitis Yellow fever G. venenata Primary graft failure Coxiella burnetii G. marginata Plasmodium falciparum Lepiota josserandii Amebic abscesses L. helveola Tuberculosis (disseminated) Herbals Bacillus cereus Kava Chaparral Gentian Scutellaria Germander Alchemilla Senna Shark cartilage Sea anemone sting Carbon tetrachloride Aflatoxin Halogenated hydrocarbons Toluene Trichloroethylene Tetrachloroethane Chloroform Phosphorus Ethanol Cocaine MDMA (3,4-methylenedioxy- N-methylamphetamine or Ecstasy) Drugs (see Table 3) A, Amanita; CHF, congestive heart failure; CMV, cytomegalovirus; EBV, Epstein–Barr virus; G, Galerina; HAV,hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus; HEV, hepatitis E virus; HSV, herpes simplex virus; L, Lepiota; MI, myocardial infarction; PE, pulmonary embolism; VOD, vascular occlusive disease; VZV, varicella zoster virus 390 K. Dalhoff vasculitis, and granulomatous reactions. Catego- covalently binds to key hepatocyte membrane rization of these toxic reactions suggests the type and cellular proteins and causes necrosis [22, 23]. and duration of exposure. Concurrent use of certain medications can fur- Acute APAP overdose (both deliberate and ther amplify the production of hepatotoxic inter- unintentional/supratherapeutic ingestion) remains mediates by induction of the cytochrome family one of the most common causes of ALF in the responsible for metabolism of the parent drug. For USA and UK (see ▶ Chap. 59, “Acetaminophen/ example, alcohol [34], INH [35], and possibly Paracetamol”). The maximum daily approved phenytoin [36] cause induction of the P-450 sys- dose may vary depending on the country, but is tem, which enhances the conversion of APAP to generally in the range of 80 mg/kg APAP for NAPQI. In addition, alcohol inhibits the synthesis children and 3–4 g for adults. The minimum of GSH, thereby decreasing clearance of NAPQI dose for toxicity from a single ingestion is gener- [37]. Chronic alcohol abusers are also more likely ally 150 mg/kg for children and 7.5–10 g for to be malnourished and have an antecedent fasting adults [28]. Doses greater than 350 mg/kg almost period, which also depletes GSH stores. Thus, always result in severe hepatotoxicity without supratherapeutic doses of APAP in conjunction antidotal treatment [23]. However, APAP toxicity with regular alcohol use can result in elevated is increasingly being recognized as a cause of NAPQI levels and subsequent hepatic injury – ALF even when used in supratherapeutic doses, the so-called therapeutic misadventure [38]. It is and such “therapeutic misadventures” may repre- important to note that starvation, a GSH-depleted sent the most common cause of ALF in the USA state, is an independent risk factor for a therapeu- [29]. These cases usually occur when APAP is tic misadventure with APAP, regardless of con- misused in the setting of chronic pain and alcohol current alcohol use. Another example of use or less commonly with medications that synergistic toxicity is noted in patients treated induce the cytochrome P-450 system (e.g., isoni- with INH and rifampin, where rifampin-induced azid [INH], rifampin, phenytoin) or in the setting cytochrome induction can potentiate INH of starvation (depleted glutathione [GSH] stores) hepatotoxicity [39]. [30, 31]. High aminotransferase levels are typical Whereas APAP-induced injury is predictable of such cases, with values usually peaking above and dose dependent, other drugs (e.g., valproic 4000 U/L and sometimes above 10,000 U/L. acid, troglitazone, amiodarone) can cause rare The metabolic activation of certain drugs by idiosyncratic and unpredictable hepatotoxic the liver into hepatotoxic intermediates is an effects. Hypersensitivity reactions can occur with important phenomenon in drug-induced ALF. the use of phenytoin, para-aminosalicylate, chlor- The resultant toxic metabolites covalently bind promazine, and sulfonamides, with catastrophic to important macromolecular constituents of the results. Idiosyncratic reactions do not exhibit cell and prevent normal functioning or cause dose-related toxicity, and some can result in ALF necrosis of the cell. Acetaminophen metabolism with a single dose. They occur in a small fraction (Fig. 1) serves as a pertinent example. Most of the of susceptible individuals and are unpredictable. ingested APAP is conjugated with glucuronide or Patients with chronic liver disease may be at sulfate and excreted as a harmless metabolite [32, increased risk for such reactions. The formation 33]. In therapeutic doses, approximately 5% of of immunologically stimulating drug-protein APAP is oxidized by the P-450 system to N-ace- complexes (neoantigens) with a resultant “inno- tyl-p-benzoquinoneimine (NAPQI), a toxic inter- cent bystander” effect is thought to be one of the mediate that is readily detoxified by reaction with pathogenic mechanisms of injury [40]. GSH [32, 33]. An APAP overdose overwhelms The halogenated anesthetics enflurane, the sulfation and glucuronidation pathways and methoxyflurane, and isoflurane have uncom- drives the formation of NAPQI, detoxification of monly been associated with the development of which depletes GSH stores [32, 33]. Once the toxic hepatitis, but hepatic failure is rare. They binding capacity of GSH is exceeded, NAPQI usually develop after multiple exposures to these 17 Toxicant-Induced Hepatic Injury 391

Unchanged Parent Drug O O H H N CH3 N CH3

~5%

− CO − 2 O O NAC O O S OH O O UDP-glucuronosyl- O Phenolsulfo- HO transferase Acetaminophen H transferase OH (40 - 67%) Sulfate N CH3 (20 - 46%) Acetaminophen Glucuronide 2 NADPH + O2

+ 2 NADP + 2H2O CYP450 OH Acetaminophen O NAC (APAP) NAC N CH O 3

Mercapturate & H N CH Cellular Other Conjugates 3 Toxicity

Glutathione O SG (GSH) NAPQI OH Acetaminophen Glutathione NAC

Fig. 1 Acetaminophen (paracetamol) metabolism agents and are thought to be of combined toxic (752 DILI cases per 100,000 inhabitants) and and allergic origin. Nonsteroidal anti- infliximab (675 DILI cases per 100,000 inflammatory drugs, especially sulindac and inhabitants). diclofenac, have also been known to cause liver Tetracycline demonstrates yet another mecha- disease, with an incidence of 1.1–3.7 cases per nism of hepatotoxicity. It is known to bind hepa- 100,000 prescriptions [41]. The macrolide antibi- tocyte tRNA and impair apoprotein synthesis, otics erythromycin and clarithromycin are rare thereby causing triglyceride buildup in the liver. causes of hepatic failure that exhibit primarily It may also cause concurrent derangements in cholestasis on biopsy and, uncommonly, hepatic fatty acid uptake, formation, and oxidation by necrosis [42]. hepatocytes, which can culminate in the loss of In a nationwide prospective study [43], the hepatic function secondary to acute incidence of drug-induced liver injury (DILI) microvesicular fatty infiltration [44]. Aspirin, was investigated in a population-based cohort in valproic acid, amiodarone, and zidovudine are Iceland. The most commonly implicated agent also known to cause microvesicular steatosis. over the 2-year study period was amoxicillin- clavulanate with a rate of 43 DILI cases per Herbal Medications 100,000 inhabitants. The highest risk of hepato- Widespread use of herbal remedies in Europe and toxicity was associated with the use of azathioprin their ever-growing popularity in the USA have 392 K. Dalhoff

Table 3 Examples of drugs commonly implicated in heart failure, complicated by the occurrence of acute liver failure disseminated intravascular coagulation (DIC) Acetaminophen (paracetamol) and renal failure. The histologic pattern is both Amiodarone centrilobular necrosis and microvesicular Carbon tetrachloride steatosis. MDMA causes a syndrome similar to Gold that of cocaine: hyperthermia, DIC, and rhabdo- Halothane myolysis, complicated further by dehydration and Isoniazid acute renal failure. Toxic hepatitis may be imme- Ketoconazole diate or delayed, and the histopathology is char- Methyldopa acterized by central and midzonal necrosis or by Monoamine oxidase inhibitors steatosis and eosinophilic infiltration [48]. The Nonsteroidal anti-inflammatory drugs latter suggests an immune mechanism of Phenytoin Rifampin MDMA hepatotoxicity, and liver transplantation Sulfonamides has been required in some cases [49]. Tetracycline Tricyclic antidepressants Chemicals Valproic acid Industrial exposure to cleaning solvents containing fluorinated or halogenated hydrocar- bons is a well-documented cause of hepatic necro- brought to light many case reports of associated sis, fatty infiltration, and, ultimately, ALF. Carbon hepatotoxicity. Herbals and alternative medications tetrachloride’s hepatotoxic effects, noted in the implicated include chaparral, gentian, germander, 1920s–1940s, led to its abandonment as an anes- and senna, but they rarely result in liver failure thetic and anthelmintic by the FDA, but it is still [45]. However, in 2001 and 2002 two case reports used in the production of solvents, refrigerants, suggesting a causal relationship between kava and aerosol propellants. The fluorinated hydrocar- (a herbal supplement used for the treatment of anx- bon chloroform, a potent central nervous system iety) and ALF requiring transplantation were depressant once used as an anesthetic, has also published [46, 47]. Twenty-four other reports of been banned by the FDA because of its hepato- kava-related hepatotoxicity have led to a ban on toxicity, but it is still found in industrial use. kava in Switzerland and Germany. The US Food and Drug Administration (FDA) currently has the Biologic Agents supplement on so-called MedWatch alert status. Hepatotoxicity secondary to accidental ingestion Although virtually any drug can cause acute liver of poisonous mushrooms has been on the rise injury, more common examples are listed in Table 3. because of popular interest in gathering and eating uncultivated mushrooms [50]. An increase in the Drugs of Abuse incidence of mushroom poisoning is usually seen Severe liver injury and even hepatic failure can after periods of heavy rainfall or during the fall, result from recreational drug use, including abuse when the conditions for growth are optimal. Inges- of cocaine, 3,4-methylenedioxymethamphetamine tion of cyclopeptide-containing mushrooms (MDMA or Ecstasy), and phencyclidine, or from accounts for up to 90% of mushroom-related deaths recreational inhalation of solvents containing tolu- worldwide [50–54]. The genus Amanita is the ene or trichloroethylene [48]. Hepatic failure in source of most of these poisonings, especially these cases may be the result of liver ischemia, A. phalloides (death cap), A. verna (death angel), hypoxemia, severe hyperpyrexia, rhabdomyolysis, and A. virosa (destroying angel). Galerina and and/or direct hepatotoxic effect. Lepiota species can also be hepatotoxic (see In addition to these effects, cocaine’s hepato- Table 2). Amanita species are found primarily in toxicity is thought to be due primarily to ischemia the temperate coastal regions of the west coast of the from systemic arterial vasospasm and congestive USA, but they have also adapted to the mid-Atlantic 17 Toxicant-Induced Hepatic Injury 393 coast and the northeast. A. phalloides is the predom- are related to hepatitis A and E infections globally inant hepatotoxic European mushroom. The mush- with death rates of more than 50% reported from room itself has no distinct taste, smell, or the developing world [59, 60]. Also hepatitis B appearance. Ingestion is usually followed 6–12 h infection may lead to ALF [61]. It is unclear why later by fever, nausea, vomiting, and severe diar- ALF develops in a select proportion of the rhea. Renal and hepatic impairment may become infected population, but historical review of pre- evident by 24–48 h while the patient appears to be vious epidemics reveals that this number remains recovering clinically. However, renal failure and surprisingly constant at approximately 0.4% hepatic failure progress and tend to become severe [62]. The hepatocellular necrosis seen in cases of by day 3–5, with the development of jaundice, ALF caused by hepatitis A and B is thought to be encephalopathy, and possibly death. Liver trans- due in part to a direct cytopathic effect of the virus. plantation has been carried out successfully for This mechanism is supported by the relative lack cases of severe Amanita poisoning [53]. Some of inflammation seen in the livers of patients with Amanita mushrooms such as A. muscaria and viral ALF. However, the normal humoral and cell- A. pantherina do not contain hepatotoxins. mediated response to a massively infected liver The cyclopeptide mushrooms contain two also plays a role. One study found that the amount cyclic oligopeptide hepatotoxins: phallotoxins of hepatitis A virus (HAV) isolated from the livers and amatoxins. Both are heat stable and resistant of patients with HAV-associated ALF was higher to drying [52, 54]. Phallotoxins are not absorbed than titers from patients with nonfulminant HAV from the gastrointestinal (GI) tract and therefore hepatitis [63]. In addition, CD8+ T lymphocytes are not thought to play a role in the symptoms isolated from the livers of two patients with acute associated with human poisoning [55]. α-Amani- HAV infection demonstrated the ability to kill tin is a dialyzable octapeptide that inhibits RNA HAV-infected fibroblasts in culture, thus implying polymerase II, thus interfering with mRNA syn- that the liver damage seen in virally induced ALF thesis [56]. The cell is robbed of its ability to is in part cell mediated [64]. produce vital structural proteins and undergoes ALF secondary to HAV infection is a rare necrosis. Tissues with a high rate of protein syn- event: 0.35% of HAV infections will progress to thesis (liver, kidneys, brain) suffer the most dam- ALF [58]. Patients have a comparatively low age [56]. α-Amanitin is easily absorbed from the mortality rate (<40%) and usually recover with- intestinal epithelium and enters the hepatocyte via out liver transplantation. Acute hepatitis B infec- bile transport carriers [57]. It demonstrates low tion progresses to ALF in approximately 1% of plasma protein binding and is cleared from plasma infected patients, thus making hepatitis B virus in 36 h [56, 57]. Sixty percent is excreted into bile (HBV) the most common viral cause of ALF and undergoes enterohepatic circulation, whereas [58]. Its role may be underestimated when the the rest is cleared renally [55, 56] (see ▶ Chap. impact of infection with a pre-core mutant (HBV 108, “Cyclopeptide-Containing Mushrooms: The viral infection that does not produce the surface Deadly Amanitas” for a more detailed discussion). [HBsAg] or e antigen) is taken into account, as Case reports of ALF caused by other demonstrated by a study in which it was found noninfectious biologic agents include one that 35% of patients who underwent transplanta- published in 1994 describing ALF secondary to tion for non-A, non-B hepatitis had evidence of a sea anemone sting [58]. HBV infection by polymerase chain reaction [65]. One half to one third of patients with ALF secondary to HBV will clear HBsAg within a few Nontoxic Causes days [66]; such rapid clearance is thought to be the result of a substantial immunologic response to Infections HBV-laden hepatocytes. Interestingly, those who Viral hepatitis remains one of the most common clear HBsAg rapidly have a more favorable prog- causes of ALF worldwide. The majority of cases nosis (47% survival rate) than those with 394 K. Dalhoff continued HBsAg positivity (17% survival rate) around 300–400 U/L, whereas bilirubin is usually [13]. Despite being an increasingly common less than 7 mg/dL (120 μmol/L) at onset. The cause of chronic liver disease, isolated infection disease commonly affects women and causes with hepatitis C virus has yet to be definitively severe right upper quadrant pain and implicated in ALF [10]. Though rarely encoun- hepatomegaly. tered in the USA, infection with hepatitis E virus Exertional heatstroke is also an important in pregnant women carries a 40% mortality rate cause of ischemic ALF and is usually seen in [67]. Infection with hepatitis delta virus has been young unconditioned patients pursuing a new implicated in about 30% of HBV-related ALF exercise program in high ambient temperature cases. In fact, the risk of ALF increases dramati- and humidity. Classic (nonexertional) heatstroke cally with any hepatitis virus coinfection [68, 69]. occurs in patients with multiple chronic medical Infection with the viruses herpes simplex, problems or those taking anticholinergic medica- Epstein–Barr, varicella zoster, cytomegalovirus, tions, which leaves them susceptible to disruption or parvoviruses occasionally causes ALF, though of temperature regulatory mechanisms or incapa- usually in an immunocompromised setting. Pedi- ble of escaping the heat. Heatstroke is usually atric ALF in association with parvovirus B19 manifested by hyperthermia (core body tempera- infection has been noted. ture >40.5 C [104.9 F]), mental status changes Case reports detailing other (rare) infectious (including seizures), peripheral vasodilation, and causes of ALF have implicated Coxiella burnetii, a host of metabolic derangements. Leukocytosis Plasmodium falciparum, amebic abscesses, dis- may also be a prominent initial feature. Acute seminated tuberculosis, and Bacillus cereus mortality was 21% in one series [70]. Adverse emetic as causative agents. drug effects (e.g., neuroleptic malignant syn- drome, veno-occlusive disease) can play a role Vascular Events in ischemic ALF. Disruption of sinusoidal The liver has a unique blood supply, with the flow by metastatic cancer has also been described portal vein supplying 70% of total blood flow as a cause of ALF. Gastric, breast, and oat cell and the hepatic artery making up the remaining carcinomas have been implicated, as have leuke- 30%. Disruption of either the inflow or outflow of mia, carcinoid syndrome, and amyloidosis. blood can lead to ischemia, hypoxia, and ulti- mately ALF. Examples include prolonged hypo- Metabolic and Other Causes tension (intraoperative circulatory collapse, acute ALF can occur even without large-scale hepatic myocardial infarction, acute pulmonary embo- necrosis, as demonstrated by patients who suffer lism), gram-negative sepsis and shock, congestive from liver failure secondary to acute fatty liver of heart failure, veno-occlusive disease (chemother- pregnancy (AFLP), Reye’s syndrome, or a fulmi- apy- or bone marrow transplant related), nant manifestation of Wilson’s disease. ALF as an Budd–Chiari syndrome, and hepatic artery throm- initial feature of Wilson’s disease is rare but bosis after OLT. Prolonged hypotension after an carries a very high mortality rate without liver overdose of opiates or cardioactive drugs (e.g., transplantation. A relatively low serum alkaline β-receptor or calcium channel antagonists) or car- phosphatase level and a disproportionately ele- diac arrest from any agent may also produce vated bilirubin level (up to 30 mg/dL [513 μmol/ hepatic failure. It is important to note that almost L]) characterize such a manifestation. The serum all cases of hepatic ischemia secondary to sys- copper level is usually elevated. temic hypotension are associated with very high Whereas loss of hepatocyte function in aminotransferase levels and accompanying renal Wilson’s disease is secondary to hepatic copper dysfunction. In contrast, patients with overload, AFLP results in ALF from an inherited Budd–Chiari syndrome have aminotransferase defect in mitochondrial beta oxidation of long- levels between 100 and 600 U/L, although higher chain fatty acids [71]. AFLP usually occurs in values are possible. Serum alkaline phosphatase is the third trimester and may be associated with 17 Toxicant-Induced Hepatic Injury 395 preeclampsia. Serum aminotransferase levels usu- delayed without an appropriate index of suspi- ally stay below 1000 U/L unless the HELLP syn- cion, and such delay can have catastrophic impli- drome (hemolytic anemia, elevated liver function cations in as much as early diagnosis and tests [LFTs], and low platelet count) is present. appropriate management are important to pre- Infant mortality is high in either case. serve the ability of these patients to receive a Reye’s syndrome has a similar pathogenesis transplant should it become necessary. Overall, and can be seen in pediatric cases with an ante- the presence of coagulopathy in a jaundiced cedent viral illness treated with aspirin. Other rare patient with an altered mental status remains the metabolic anomalies that can cause ALF are listed hallmark of ALF. in Table 2. Rarely, autoimmune hepatitis and pri- mary graft failure after liver transplantation will be manifested as ALF. Coagulopathy

Coagulopathy is universally present and can be Diagnosis and Complications the first sign of impending liver failure. It is due mainly to decreased hepatic synthesis of clotting ALF is the common final pathway of a variety of factors [72]. Therefore, serial measurements of insults, and thus the features remain remarkably prothrombin time and factor V levels have prog- similar regardless of the etiology. Nonspecific nostic significance and provide the best measure flu-like symptoms, including fatigue, nausea, of whether hepatic function is improving or dete- loss of appetite, and malaise, are the initial symp- riorating. DIC and local fibrinolysis do occur in toms in previously healthy patients. These symp- ALF, and though not usually severe, they can be toms are followed by jaundice and then alteration exacerbated by infection or by the infusion of of mental status with rapid progression to coma. activated clotting factors [73]. Administration of Other helpful signs on physical examination fresh frozen plasma in the absence of bleeding is include decreased or absent dullness to percussion not recommended because it has not been shown in the right upper quadrant, indicative of reduced to be of value [72] and will alter the prothrombin hepatic mass secondary to necrosis. Fetor time, thus hindering patient assessment. Platelet hepaticus is usually present, but recognition of function is altered (prolonged capillary bleeding this condition is somewhat subjective. Ascites is time), and thrombocytopenia secondary to bone more common with subfulminant hepatic failure. marrow suppression, hypersplenism, and intra- Stigmata of chronic liver disease do not support a vascular consumption is present in up to two diagnosis of ALF as per the classic definition. thirds of patients [74]. If invasive procedures are Low blood pressure (decreased systemic vascular necessary, correction of coagulation abnormalities resistance) and hypothermia may also be evident. may be relevant and needed. Laboratory derangements include high serum aminotransferase levels, low blood glucose levels, and a prolonged prothrombin time. Metabolic aci- Encephalopathy dosis with respiratory compensation may be evi- dent on arterial blood gas measurement. Unlike the conditions observed in chronic hepatic Complications seen in the course of the illness disease, the encephalopathy associated with ALF include cerebral edema; renal failure; cardiovas- can be manifested as agitated delirium, paranoid cular, pulmonary, and metabolic derangements; behavior, or even a psychotic state. Seizures may and problems with infection, GI bleeding, and occur. The initial stages of encephalopathy are malnutrition. Multiorgan failure is commonly secondary to bilateral forebrain dysfunction, encountered. There is an inverse relationship with the latter being secondary to brainstem between the presence and number of complica- impairment. Table 4 delineates the grading system tions and patient survival. The diagnosis is often used for acute hepatic encephalopathy; the 396 K. Dalhoff

Table 4 Progressive stages of hepatic encephalopathy Stage Level of consciousness Neuromuscular changes Behavioral/intellectual changes I Reversal of sleep pattern Mild asterixis Euphoria/depression Mild confusion Impaired handwriting Short-term memory lapses II Slow responses Asterixis/ataxia Inappropriate behavior Increasing drowsiness Slurred speech Loss of time/amnesia III Disorientation Rigidity/spasticity Stuporous/incoherent Somnolence Loss of continence Marked confusion/paranoia IV A/B Comatose Decorticate/decerebrate Comatose A: responds to pain Hyperreflexic B: no response to pain presence of stupor or coma portends a poorer illness [77]. Although it is a distinct entity, its prognosis. Although the exact pathogenesis signs and symptoms may be missed because of remains elusive, the encephalopathy is reversible the presence of concurrent encephalopathy – often and thought to be metabolic. Structural changes with deadly consequences. Herniation of the cer- such as those seen with Alzheimer’s disease are ebellar tonsils or the uncinate process of the tem- not part of the syndrome. It is postulated that poral lobe is a significant cause of death, and elevated levels of neuroactive humoral substances evidence of herniation is present in up to secondary to decreased hepatic clearance cause 25–30% of patients with cerebral edema [78]. the observed mental status changes. It is important The causative metabolic and pathophysiologic to note that the blood–brain barrier is disrupted in derangements that lead to cerebral edema have yet ALF, and this increased permeability makes it to be fully elucidated. Research indicates a com- unnecessary for a substance to be present in plex interplay among vasogenic (alterations in greater than normal concentration in plasma to blood flow), cytotoxic (loss of osmoregulation), affect cerebral function. In addition, with the and hydrocephalic (extracellular expansion) fac- blood–brain barrier demonstrating marked tors. Even though earlier histologic studies of the regional differences in permeability, the concen- brain revealed no abnormalities [79], more recent tration of potentially encephalopathic agents at data have found alterations in cell membrane critical subcellular sites may be more important integrity and blood–brain barrier permeability than their concentration in cerebrospinal fluid or [80, 81], changes probably responsible for the plasma [75]. Studies have implicated increased increased water content and weight of the brain. GABAergic (transmitting or secreting Although patients with cirrhosis rarely have cere- γ-aminobutyric acid) tone, mediated by an bral edema, a marked decrease in intracranial endogenous benzodiazepine-like ligand, as a blood flow has been noted in those with acute or cause of the hepatic encephalopathy seen in ALF chronic encephalopathy [82]. This decreased [76]. Treatment with flumazenil (a benzodiaze- blood flow, along with the systemic hypotension pine receptor antagonist) has been shown to tem- commonly found in ALF (see the next section) porarily improve the coma grade of patients and the increased ICP secondary to cerebral suffering from this syndrome. edema, predisposes the brain to ischemic injury. Cerebral perfusion pressure (CPP = mean arterial pressure [MAP] – ICP) below 40–50 mmHg is Cerebral Edema associated with ischemic brain injury and can have permanent consequences, even if the liver Cerebral edema with resultant increased intracra- recovers fully. A persistent and refractory perfu- nial pressure (ICP) is a common complication of sion pressure of less than 40 mmHg precludes ALF, with up to 81% of patients demonstrating transplantation [83]. Signs of increased ICP are signs of increased ICP during the course of the noted in Table 5. Because they are manifested 17 Toxicant-Induced Hepatic Injury 397

Table 5 Signs of increased intracranial pressure in fulmi- Table 6 Factors that increase intracranial pressure nant hepatic failure Arterial hypotension Brainstem respiratory pattern, apnea Coughing Decerebrate posturing/rigidity Fever Focal seizures Head and body movement Increased muscle tone Hypercapnia Loss of oculovestibular reflex Isometric muscle contraction Myoclonus Neck vein compression Unequal, fixed, or abnormally reacting pupils Noxious stimuli Positive end-expiratory pressure Psychomotor agitation only late in the course of events (i.e., only if ICP is Respiratory suction Seizures greater than 30 mmHg), these signs cannot be Severe hypoxemia used to gauge the need for therapeutic Shivering intervention. Sneezing Although computed tomography (CT) scans Trendelenburg position are often used to exclude intracerebral hemor- Valsalva maneuver rhage as a cause of a sudden change in mental Vasodilatory agents state, their static nature in this rapidly evolving Vomiting syndrome makes them unsuitable as a manage- ment guide. ICP monitoring provides reliable data on which treatment decisions can be made, and changes may occur. Exacerbating factors include placement of a subdural or epidural transducer is hypoxemia, acidosis, hyperkalemia, and cerebral indicated in patients being considered for trans- edema [85]. plantation. Patients should be transferred to a transplant center early in the course of the disease; transportation after the onset of cerebral edema Renal Failure and coma is fraught with danger because even positional changes can raise ICP with disastrous Renal impairment is present in up to 75% of consequences. Factors that tend to increase ICP patients with ALF [86] more frequent in the are noted in Table 6. Even without herniation, elderly and in patients with APAP-induced ALF cerebral edema remains the most common cause [87] and includes prerenal azotemia, hepatorenal of death in ALF. syndrome, and acute tubular necrosis. Hepatorenal syndrome is a diagnosis of exclusion and is characterized by a serum creatinine concen- Cardiovascular Derangements tration greater than 1.5 mg/dL (133 μmol/L), a urinary sodium concentration less than 10 mEq/ Systemic hypotension occurs in most patients L (without taking diuretics), lack of improvement with ALF and is mediated in part by decreased with volume expansion, and a bland urinary sed- systemic vascular resistance (resembling septic iment [88]. Systemic hypotension and splanchnic shock), bacteremia, hemorrhage, hypovolemia, vasodilation (probably nitric oxide driven) acti- and increased interstitial edema (increased capil- vate the renin-angiotensin axis, with resultant lary permeability) and ICP. An etiology is not renal vasoconstriction. Renal vasoconstriction found in up to 60% of cases [84]. Nearly all leads to a drop in renal perfusion pressure, which patients with stage IV encephalopathy suffer is reflected by a decreased glomerular filtration from arrhythmias. Although sinus tachycardia is rate and increased sodium retention (causing asci- most common, the spectrum includes heart block tes and edema). The presence of oliguric renal and cardiac arrest. ST segment and T wave failure portends a poorer prognosis [89]. Renal 398 K. Dalhoff impairment may also occur secondary to the toxic with the upper GI tract being the most frequent effects of substances that caused the ALF, such as site of bleeding [101]. Diffusely hemorrhagic gas- APAP, hepatotoxic mushrooms, hydrocarbons, tritis, esophagitis, and nasogastric tube trauma are and MDMA. common etiologies. Exacerbating factors include tissue hypoxia from hypotension, microcircula- tory disruption, and hypoxemia, along with DIC, Pulmonary and Ventilatory bacteremia, and ventilator-associated platelet dys- Derangements function. Large episodes of bleeding lead to fur- ther hypotension and tissue (including cerebral) Up to 30% of patients will have evidence of pulmo- hypoxia and can cause worsening renal failure as a nary edema during the course of their illness, espe- result of prerenal azotemia, as well as exacerbat- cially those with cerebral edema [90, 91]. Accurate ing hepatic encephalopathy. Despite the numerous determination of volume status by pulmonary artery risk factors for hemorrhage, infusion of fresh fro- pressure monitoring has been shown to improve zen plasma or platelets for correction of survival [92]. Intrapulmonary arteriovenous coagulopathy or thrombocytopenia is not indi- shunting, peripheral capillary blockage with cellular cated in the absence of bleeding. debris from necrotic hepatocytes, or low-grade DIC, interstitial edema, and increased vasomotor tone ultimately lead to lactic acidosis secondary to Metabolic Derangements anaerobic metabolism, which can exacerbate cere- bral ischemia [93, 94]. The use of NAC and pros- Electrolyte and acid–base disturbances are com- tacyclin to improve tissue oxygenation remains mon in ALF and can exacerbate encephalopathy experimental and controversial [94–96]. and cause arrhythmias. Despite renal retention of sodium, hyponatremia occurs frequently and is due to impaired renal free water excretion. Hypo- Infection kalemia is present and can be profound; etiologies are multiple and include renal losses (secondary to Metabolic inhibition of polymorphonuclear leuko- hyperaldosteronism and sodium retention, as well cytes, decreased opsonization, and impaired cell- as secondary to hydrogen ion resorption to com- mediated and humoral immunity greatly predispose pensate for respiratory alkalosis), GI losses patients with ALF to bacteremia and fungemia [58, (decreased intake, vomiting), and iatrogenic 97]. Patients have increased risk of infection second- causes (e.g., diuretics, nasogastric tube ary to multiple indwelling catheters, antacid therapy, suctioning, lactulose use). Hypophosphatemia, artificial ventilation, coma, and treatment with hypomagnesemia, and hypocalcemia can also broad-spectrum antibiotics. Skin flora organisms occur. Complex acid–base disturbances with mul- (Staphylococcus and Streptococcus spp.) are most tiple processes at play are seen – respiratory alka- commonly isolated in patients with ALF [98]. In a losis as a result of spontaneous hyperventilation is prospective study of 50 patients with acute liver commonly present early in the course of the dis- failure, infection was suspectedin45patientsand ease. However, with disease progression and proved by positive cultures in 40 [99]. However, depression of the central respiratory drive second- prophylactic antibiotic treatment has not been ary to edema or circulating toxins, respiratory shown to improve survival [100]. acidosis can develop. Hypokalemia is associated with metabolic alkalosis, whereas tissue hypoxia and massive hepatic necrosis give rise to meta- Gastrointestinal Bleeding bolic acidosis with elevated levels of lactic acid, free fatty acid, and other organic acids. The pres- The severe coagulopathy seen with ALF predis- ence of lactic acidosis is a poor prognostic indica- poses patients to hemorrhage from the GI tract, tor. Impaired glucose release, loss of glycogen 17 Toxicant-Induced Hepatic Injury 399 reserves, and decreased gluconeogenesis are in Table 7 Initial diagnostic testing in fulminant hepatic combination responsible for severe hypoglycemia failure (blood glucose <40 mg/dL [2.2 mmol/L]) in up to Parameter Rationale 40% of patients. Decreased hepatic metabolism of Electrolytes and minerals Imbalances are common; insulin resulting in inappropriately elevated can cause arrhythmias, worsen encephalopathy. plasma insulin levels also plays a pathogenic Hypophosphatemia is role. If unrecognized and untreated, the fall in common in blood glucose can be rapid and may lead to irre- acetaminophen overdose versible brain injury. BUN/creatinine Renal failure is typical; affects management and prognosis. Etiology (e.g., toxic effect of ingested Diagnostic Studies substances) may alter therapy (e.g., Laboratory and radiographic testing should be ) performed to confirm the diagnosis, elucidate the Glucose Hypoglycemia is common; can have etiology of ALF, evaluate for the presence of permanent neurologic complications, and obtain data necessary for man- sequelae agement, prognostication, and preparation of the CBC with platelets Assess for sepsis patient for possible liver transplantation. See (leukocytosis), GI bleeding (anemia), and Table 7 for a list of recommended initial diagnos- risk of hemorrhage tic tests for ALF. Serum glucose should be mon- (thrombocytopenia) itored frequently (every 2 h), and other parameters Liver profile Assess degree of damage, such as electrolytes, hematocrit, and arterial blood follow course of illness gas should be monitored at least three times daily. Coagulation profile Prognostic indicators (PT, Coagulation parameters and LFTs are usually factor V level), assess risk of hemorrhage checked twice a day. Further testing, such as Arterial blood gases Prognostic significance tomographic studies of the head to rule out intra- (lactic acidosis), cerebral hemorrhage or cerebral edema as a cause derangements common of acute worsening of mental status, is performed Blood group Preparation for as clinically indicated. transplantation; type and crossmatch in anticipation of bleeding Toxicology, virology, Etiology affects Treatment autoimmune panel, management (e.g., NAC ceruloplasmin, medication for acetaminophen, Because of the unpredictable nature of the disease, history charcoal for Amanita) and prognosis. Refer to Table 2 the risk of acute decompensation, and the severity for various etiologies of of the illness/complications, patients with ALF ALF should be managed in an ICU setting, preferably Blood and urine cultures Surveillance for sepsis; at a liver transplant center. Hospitals without liver aggressive treatment transplant programs should transfer patients with warranted if positive ALF to such transplant centers as soon as possible ECG May affect management, preparation for because increased ICP and severe coagulopathy transplantation make transfer later in the course of the disease Chest radiograph Sepsis surveillance; much more hazardous. Uncompromised ICU sup- evaluate for ARDS, port is necessary to give these patients the best pulmonary edema chance for survival. Specific treatment strategies Abdominal ultrasound Evaluate for vascular thrombosis, preparation for commonly encountered complications are for transplantation discussed in the following sections. (continued) 400 K. Dalhoff

Table 7 (continued) metronidazole, 250–500 mg two to three times a Parameter Rationale day, aminopenicillins, 2–4 g/day, or vancomycin, Pulmonary wedge Assess volume status if 1–2 g/day. More recently it has been shown that the pressure hypotension present minimally absorbed oral antibiotic rifaximin main- Intracranial pressure Assess ICP if stage III–IV tains remission from hepatic encephalopathy more encephalopathy present. effectively than placebo [105](GradeI Cerebral edema is the most common cause of death recommendation). ARDS, adult respiratory distress syndrome; BUN, blood urea nitrogen; CBC, complete blood count; ECG, electro- cardiogram; ALF, fulminant hepatic failure; GI, gastroin- Cerebral Edema testinal; ICP, intracranial pressure; NAC, N-acetyl-L- cysteine; PT, prothrombin time Cerebral edema (leading to elevated ICP, ische- mic/hypoxic brain injury, and brainstem hernia- Coagulopathy tion) is the most common cause of death in ALF and is present in up to 80% of patients with grade Decreased synthesis of coagulation factors is a 4 encephalopathy [106]. Given the deadly conse- direct reflection of hepatic dysfunction and can quences of unrecognized cerebral edema and the be used as a prognostic indicator. Therefore, pro- difficulty in diagnosing it clinically, an epidural phylactic correction of coagulopathy in a ICP monitor should be placed in all patients with non-bleeding patient is not recommended because grade 4 encephalopathy. This procedure has a 4% it does not influence mortality, can interfere with morbidity (infection, bleeding) rate and a 1% assessment of disease severity, and may predis- mortality rate and is thus safer than placement of pose the patient to volume overload and worsen- a subdural, parenchymal, or intraventricular cath- ing cerebral edema [24, 102]. Blood products eter [107]. Coagulopathy should be addressed (fresh frozen plasma or, rarely, recombinant before placement of an ICP monitor, and head human factor VIIa) may be used to correct CT should be considered to rule out other causes coagulopathy in cases of active hemorrhage/GI of acute mental status changes such as intracranial bleeding and for invasive procedures [103]. hemorrhage. The aim is to keep ICP lower than 20 mmHg and CPP (MAP – ICP = CPP) higher than 50 mmHg [2] (Grade III recommendation). Encephalopathy Elevated ICP can be treated with mannitol boluses (0.5–1 g/kg to achieve a plasma osmolal- Encephalopathy is part of the definition of ALF and ity between 310 and 325 mOsm/kg) [108]. Clini- as such plays a major role in the patient’s clinical cians should be vigilant for signs of volume findings and course. Patients with grade 4 encepha- overload with mannitol use; concurrent ultrafiltra- lopathy should be intubated for airway protection. tion or other dialysis methods may be needed to Standard treatment with lactulose enemas or avoid hypervolemia. In addition, patients should lactulose via a nasogastric tube, 30 mL three to four be stimulated as little as possible because agitation times a day, is instituted in an attempt to decrease the can increase ICP. Sedatives should be used in the amount of nitrogenous waste (in the form of ammo- lowest dose possible so that the degree of enceph- nia) absorbed from the gut lumen. However, new alopathy can continue to be monitored. Short- evidence suggest that the use of polyethylene glycol acting drugs such as propofol should be used (PEG) may be superior to lactulose in the treatment [109]. Elevating the head of the bed can decrease of encephalopathy in cirrhotic patients [104](GradeI ICP, but it also causes CPP to fall and leads to recommendation). Oral neomycin has traditionally paradoxical increases in ICP when elevation is been added if the encephalopathy is difficult to con- above 30 [102]. In the absence of ICP monitor- trol, but it has possible nephrotoxic and ototoxic side ing, the head of the bed should be elevated 10–20 effects. Modern drugs of choice instead are (Grade III recommendation). The use of positive 17 Toxicant-Induced Hepatic Injury 401 end-expiratory pressure during ventilation can may also be used. Coagulopathy and thrombocy- also worsen cerebral edema [110]. Dexametha- topenia should be corrected in patients with bleed- sone has been proved to be ineffective as treat- ing from the GI tract, but not prophylactically. ment of cerebral edema and should therefore not Large GI bleeds are investigated and treated endo- be used [111]. Hyperventilation to lower PCO2 scopically. If variceal bleeding is suspected, treat- has not been shown to be beneficial [102]. ment with an octreotide IV drip should be initiated without delay for endoscopic confirmation.

Renal Failure Metabolic Derangements Most patients with ALF have evidence of acute kidney injury (AKI), the presence of which carries The various metabolic derangements seen in ALF a grave prognosis. Treatment is centered on preven- have been detailed earlier. As part of supportive tion: the use of nephrotoxic drugs (e.g., ICU care, electrolytes should be checked and aminoglycosides) is avoided, intravascular volume corrected at least twice a day. Hypoglycemia is is optimized with judicious use of colloid supple- common in ALF and needs closer attention. mentation in the form of packed red cells or salt-poor Hypertonic glucose solutions should be adminis- albumin, and MAP is maintained as close to normal tered as an IV drip to keep blood glucose levels as possible. A high index of suspicion should be above 65 mg/dL (3.6 mmol/L). Restriction of free entertained for AKI secondary to the direct toxic water may be needed to treat hyponatremia, but effects of substances such as APAP or hepatotoxic hypertonic saline is rarely required. Acetamino- mushrooms. Although urinary sodium values can be phen-induced ALF without renal impairment is used to guide therapy, the blood urea nitrogen con- commonly associated with hypophosphatemia, centration may underestimate the renal dysfunction which may require therapy [113]. because of decreased hepatic urea production.

Nutrition Infection A diet low in protein is advocated for patients with A decline in renal function or worsening/recalcitrant ALF who are able to tolerate oral intake (grade encephalopathy may be the first clues to an untreated 1–2 encephalopathy). Enteral low-protein tube infection in patients with ALF. Thus, a high index of feeding should be considered early in the course suspicion must be maintained, with a low threshold of the disease for the rest of the patients to prevent for diagnostic testing (including blood, urine, and unnecessary catabolism to preserve muscle bulk sputum cultures, chest x-ray, paracentesis) and and immune function [114] and to optimize man- empirical broad-spectrum antibiotic/antifungal cov- agement before possible liver transplantation. erage. The most common sites of infection include Tube feeding should be administered into the dis- the respiratory system, the urinary tract, and blood tal duodenum/jejunum if possible to decrease the [112]. Although prophylactic antibiotic use has not risk of aspiration. been shown to be helpful, a surveillance culture regimen with aggressive directed therapy if an infec- tion is suspected is recommended. Specific Antidotes

Two of the most common conditions for which Gastrointestinal Bleeding specific treatment of ALF is available are APAP overdose and Amanita mushroom poisoning. All ALF patients deserve stress ulcer prophylaxis Other rare treatable etiologies include AFLP with oral/IV proton pump inhibitors. Sucralfate (treated by delivery), shock liver (treated by 402 K. Dalhoff optimizing hemodynamic status), acute medical care and those who have sustained an Budd–Chiari syndrome (treatment considerations irreversible hepatic insult and will die despite include transjugular intrahepatic portosystemic supportive care. OLT is the best available option stent shunt versus surgical decompression versus for the second cohort; it is not appropriate ther- thrombolysis), herpesvirus infection (treated with apy for the first group. The difficulty lies in acyclovir), and autoimmune hepatitis (treated accurately categorizing patients into one of with steroids). these two groups and doing so in a timely man- ▶ Chapter 59, “Acetaminophen/Paracetamol” ner, before the complications associated with provides detailed discussiononthetreatmentof ALF preclude OLTas a therapeutic option. Over- APAP overdose, but in general, if severe acetamin- all, current estimates reveal that only about 10% ophen toxicity is suspected, intravenous NAC of patients with ALF receive a transplant should be administered without delay. Activated [106]. Posttransplant survival rates have been charcoal (1 g/kg) may decrease APAP absorption estimated at 55% to 75% [116], although rates if administered within 1 or 2 h of ingestion. In most may improve to over 90% with stringent selec- countries, the plasma APAP concentrations are tion criteria [108]. As noted earlier, ALF without determined in all suspected cases and values plotted OLT is associated with very high mortality rates, against the established nomogram to determine and survival remains dismal for those who are whether NAC administration is indicated. However, listed for transplantation but do not receive an in Denmark the use of a nomogram is not organ in time. In general, transplantation is recommended. All patients suspected of APAP poi- recommended if the patient’s survival rate is soning are treated with NAC immediately after hos- estimated to be below 20%. pital admission. Information from patients with **A number of prognostic indicators have suicidal behavior about time of ingestion are often been identified to help clinicians predict the unreliable which may lead to a wrong decision about severity of ALF and identify patients who NAC treatment if a nomogram is used [115]. How- would benefit from transplantation. It is well ever, those with liver injury and suspected acetamin- known that the etiology and the presence/number ophen toxicity, even in the absence of detectable of associated complications can influence the APAP, should receive NAC treatment. survival rate. Time from the onset of jaundice/ Mushroom poisoning can be established by symptoms to the development of hepatic enceph- isolating α-amanitin in serum or urine by radio- alopathy can also predict a survival difference in immunoassay. Its enterohepatic circulation can be certain cohorts, as mentioned in the discussion in interrupted by using repeated doses of activated the “Definitions” section of this chapter. The charcoal, and possibly forced can severity of encephalopathy at admission is increase the rate of renal clearance of the toxin inversely related to survival in patients with acet- (see ▶ Chap. 108, “Cyclopeptide-Containing aminophen toxicity and acute liver failure Mushrooms: The Deadly Amanitas”). Silibinin [25]. Although age younger than 10 or older and IV penicillin G have been used as specific than 40 years has been shown to be a poor prog- therapies for Amanita poisoning. Silibinin is nostic indicator in older studies, it did not play a thought to impede the uptake of α-amanitin by role in survival rates from a more recent US hepatocytes and may be efficacious up to 48 h series [25]. Liver histology is not routinely used after the ingestion of toxin [57]. because it has not been proved to accurately predict outcome [117]. The aforementioned variables (age, etiology, Prognosis degree of encephalopathy, time to onset of symp- toms, etc.), though identifying survival trends, do Patients with ALF can be broadly divided into not allow for an accurate prediction of the need for two categories – those who have enough hepatic transplantation. To better identify high-risk reserve left to survive and recover with optimal patients who would require liver transplantation 17 Toxicant-Induced Hepatic Injury 403

Table 8 King’s College Criteria (indications for clinically acceptable specificity but more limited transplantation) sensitivity [118]. Acetaminophen Other predictive models have been developed toxicity Non-acetaminophen toxicity to assess the degree of liver injury and identify pH <7.3 (irrespective PT >35 s (US units) or INR patients who need liver transplantation for sur- of other factors) >7.7 (irrespective of degree of encephalopathy) vival. Acute Physiology and Chronic Health Or all three of the Or any three of the following: Evaluation (APACHE) II scores were similar to following: the King’s College Criteria in identifying those Grade III–IV Age <10 or >40 year needing transplantation, but patients were recog- encephalopathy nized earlier in a few cases [119]. Serum PT >100 s Unfavorable etiology (non-A Gc-globulin and plasma factor V levels have Serum creatinine non-B hepatitis, idiosyncratic >3.4 mg/dL drug reaction, halothane been used independently to predict outcome; (300 μmol/L) hepatitis, Wilson’s disease) however, they are specialized laboratory tests Serum bilirubin >17 mg/dL that may not always be available and have not (300 μmol/L) been shown to be any better than the King’s Time from jaundice to encephalopathy >7 days College Criteria [120]. Factor V levels vary by INR >4 age; transplantation is recommended for a factor INR, international normalized ratio; PT, prothrombin time V level less than 20% in ALF patients younger than 30 years or for a factor V level less than 30% for those older than 30 years [121]. However, for survival, a statistical model was developed by patients have recovered without transplantation investigators at King’s College in London. From a with factor V levels less than 10%, in our expe- cohort of 588 patients managed medically rience. Also measurement of arterial blood lac- between 1973 and 1985, a multivariate analysis tatemayimprovethespeedandaccuracyof was performed on a number of biochemical and selection of appropriate candidates for OLT. In clinical variables and their relationship to mortal- a single-center study, the prediction of ity, and recommendations for transplantation were non-surviving APAP-induced ALF patients based on the results. The negative prognostic using lactate was similar to KCH criteria but indicators (also known as King’s College Criteria) identified them earlier [122]. Although early rec- for which transplantation is recommended are ognition of patients most likely to benefitfrom noted in Table 8 [1]. transplantation is important, it is equally impor- The King’s College Criteria have been vali- tant to recognize those in whom liver transplan- dated at other centers and in a prospective manner. tation is contraindicated (Table 9). Patients with ALF but without APAP toxicity demonstrated a mortality rate of 80% with the presence of any one of the negative prognostic Future Trends indicators; mortality rose to 95% with the associ- ation of three negative prognostic factors. Severe The scarcity of donor livers has led to investiga- acidosis (pH <7.3) in patients with APAP toxicity tion of alternatives to transplantation not only for was associated with a mortality rate of 95%. patients who need temporary support while their Excluding acidosis, the presence of any other native liver recovers from the acute insult but also adverse characteristic in this population resulted for those who need a “bridge” to transplantation. in a mortality rate of at least 55%. These mortality A number of novel and promising approaches rates are much higher than those associated with have been tried, including auxiliary liver trans- liver transplantation; thus, patients with even one plantation, liver dialysis systems, artificial hepatic negative prognostic indicator should be consid- assist devices, and xenotransplantation. All are in ered for listing [1]. A subsequent meta-analysis the research phase and need further study with confirmed that the King’s College Criteria have controlled clinical trials to delineate their safety 404 K. Dalhoff

Table 9 Absolute contraindications to liver artificial liver, with the living hepatocytes transplantation performing all the functions of the native liver Severe cardiac or pulmonary disease across the semipermeable capillary membrane. Severe pulmonary hypertension (PA systolic pressure Recent research has focused on trying to repro-  60 mmHg) duce the hepatic architecture in the ELAD car- > Adult respiratory distress syndrome (FiO2 0.6) tridge, identifying the optimal hepatocyte mass Uncontrolled intracranial hypertension/irreversible brain needed to provide the best results, and determin- damage HIV infection/AIDS ing the ideal perfusion time necessary for a favor- Systemic sepsis able outcome. The most extensively studied Extrahepatic malignancy nonbiological device is the molecular adsorbent Portal and mesenteric vein thrombosis recirculating system which has shown some evi- Active alcohol or drug use dence in case series to improve biochemical Severe psychological disorders parameters [125]. Inability to understand/commit to the procedure and the lifetime of responsibility it entails AIDS, acquired immunodeficiency syndrome; HIV, human References immunodeficiency virus; PA, pulmonary artery 1. O’Grady JG, Alexander GJM, Hayllar KM, et al. fi Early indicators of prognosis in fulminant hepatic and ef cacy. Liver dialysis systems have not met failure. Gastroenterology. 1989;97:439–45. with great success. Hemodialysis, charcoal 2. Ichai P, Samuel D. Epidemiology of liver hemoperfusion, and blood and plasma exchange failure. Clinics Res Hepatol Gastroenterol. 2011;35: – have been tried without any demonstrated alter- 610 7. 3. Bernal W, Cross TJ, Auzinger G, et al. Outcome after ation in outcome [102]. wait-listing for emergency liver transplantation in Auxiliary liver transplantation involves place- acute liver failure: a single centre experience. ment of a partial liver graft in either a heterotopic J Hepatol. 2009;50:306–13. location or a space provided by partial hepatec- 4. Escorsell A, Mas A, de la Mata M. Acute liver failure in Spain: analysis of 267 cases. Liver Transpl. tomy. Although the graft is not large enough to 2007;13:1389–95. sustain the patient independently, it provides 5. Simpson KJ, Bates CM, Henderson NC, et al. The enough support to allow the native liver to utilization of liver transplantation in the management recover. No indications for auxiliary transplanta- of acute liver failure: comparison between acetamin- ophen and non-acetaminophen etiologies. Liver tion have been established, and it still requires a Transpl. 2009;15:600–9. donor source in the presence of the current 6. Germani G, Theocharidou E, Adam R, et al. Liver organ shortage. However, a number of transplantation for acute liver failure in Europe: out- patients have recovered when auxiliary grafting comes over 20 years from the ELTR database. J Hepatol. 2012;57:288–96. is used as a bridge, thus obviating the need 7. Bernuau J, Rueff B, Benhamou JP. Fulminant and for whole-organ transplantation and lifelong subfulminant liver failure: definitions and causes. immunosuppression [123]. Semin Liver Dis. 1986;6:97–106. ’ Early experiments of extracorporeal perfusion 8. O Grady JG, Schalm SW, Williams R, et al. Acute liver failure: redefining the syndromes. Lancet. with animal organs led to the idea of hybrid arti- 1993;342:273–5. ficial devices that would combine the efficacy and 9. Takahashi Y, Shimizu M. Aetiology and prognosis of compatibility of a human liver with the ease of fulminant viral hepatitis in Japan: a multicenter study. – hemodialysis. These hybrids, known as extracor- J Gastroenterol Hepatol. 1991;6:159 64. 10. Bernuau J, Goudeau A, Poynard T, et al. Multivariate poreal liver assist devices (ELADs) and analysis of prognostic factors in fulminant hepatitis bioartificial livers, incorporate living human B. Hepatology. 1986;6:648–51. hepatocytes embedded around a nest of hollow 11. Acharya SK, Dasarathy S, Tandon BN. Should we fi redefine acute liver failure? [letter]. Lancet. 1993;342: ber capillaries housed in a cartridge through – ’ 1421 2. which the patient s blood is transfused 12. Tandon BN, Bernauau J, O'Grady J, et al. Recom- [124]. The device functions as an extracorporeal mendations of the International Association for the 17 Toxicant-Induced Hepatic Injury 405

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