REVIEW CME EDUCATIONAL OBJECTIVE: Readers will recognize and manage acute failure appropriately CREDIT TAVANKIT SINGH, MD NANCY GUPTA, MD NAIM ALKHOURI, MD WILLIAM D. CAREY, MD IBRAHIM A. HANOUNEH, MD Department of Internal , Department of , Department of and Department of Gastroenterology Minnesota Gastroenterology, P.A., Medicine Institute, Westchester Medical Center, , and Department of Pediatric and Hepatology, Digestive Disease Minneapolis, MN Cleveland Clinic New York Medical College, Gastroenterology, Digestive Disease Institute, Cleveland Clinic; Professor, Valhalla, NY Institute, Cleveland Clinic; Assistant Cleveland Clinic Lerner College of Professor, Cleveland Clinic Lerner College Medicine of Case Western Reserve of Medicine of Case Western Reserve University, Cleveland, OH University, Cleveland, OH A guide to managing acute

ABSTRACT hen the liver fails, it usually fails Wgradually. The sudden (acute) onset of Nearly 2,000 cases of occur each year liver failure, while less common, demands in the United States. This disease carries a high mortality prompt management, with transfer to an in- rate, and early recognition and transfer to a tertiary medi- tensive care unit, specific treatment depend- cal care center with transplant facilities is critical. This ing on the cause, and consideration of liver article reviews the definition, epidemiology, etiology, and transplant, without which the mortality rate management of acute liver failure. is high. This article reviews the definition, epide- KEY POINTS miology, etiology, and management of acute liver failure. In the United States, the most common cause of acute liver failure is acetaminophen toxicity, followed by viral ■■ DEFINITIONS . Acute liver failure is defined as a syndrome of acute hepatitis with evidence of abnormal co- Testing for the cause of acute liver failure needs to start agulation (eg, an international normalized ra- as soon as possible so that specific treatment can be initi- tio > 1.5) complicated by the development of ated and the patient can be placed on the transplant list mental alteration (encephalopathy) within 26 if needed. weeks of the onset of illness in a patient without a history of .1 In general, patients Acetylcysteine and either a proton pump inhibitor or have no evidence of underlying chronic liver disease, but there are exceptions; patients with a histamine H2 receptor blocker should be given to all patients with acute liver failure. Liver transplant is the Wilson disease, vertically acquired hepatitis B cornerstone of in patients not responding to virus , or can present with acute liver failure superimposed other treatments. on chronic liver disease or even . The term acute liver failure has replaced There are a number of prognostic scores for acute liver older terms such as fulminant hepatic failure, failure, but each has limitations. hyperacute liver failure, and subacute liver fail- ure, which were used for prognostic purposes. Patients with hyperacute liver failure (defined as development of encephalopathy within 7 days of onset of illness) generally have a good prognosis with medical management, whereas those with subacute liver failure (defined as de- velopment of encephalopathy within 5 to 26 Dr. Alkhouri has disclosed membership on advisory committees or review panels for Bristol-Myers Squibb, Gilead Sciences, and Intercept. Dr. Carey has disclosed ownership interest in Gilead Sci- weeks of onset of illness) have a poor prognosis ences and Pfizer. without liver transplant.2,3 doi:10.3949/ccjm.83a.15101

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Metabolism and hepatotoxicty of acetaminophen Acetaminophen Acetaminophen is generally safe, but excessive doses and conditions that overwhelm its normal metabolic pathways can lead to liver damage.

+ Glucuronic acid Acetaminophen Higher glucuronide doses (excreted in urine) Glucuronidation, sulfation, and subsequent renal excretion normally remove 90% of a therapeutic dose, but these pathways can become Acetaminophen saturated after an acetaminophen overdose. + Sulfates sulfate (excreted in urine) (CYP2E1) (CYP1A2) Cytochrome P450 metabolism produces a toxic metabolite, N-acetyl-p-benzoquinone (CYP3A4) imine (NAPQI). This pathway produces more NAPQI after higher doses, or when the (CYP2A6) relevant cytochrome P450 (CYP) enzymes are induced by other drugs or chronic alcohol consumption.

NAPQI is toxic to the liver.

Mercapturic acid + Glutathione (excreted in urine)

Conjugation of sulfhydryl groups of glutathione normally detoxifies NAPQI. However, glutathione can become depleted after large doses of acetaminophen Liver damage or in malnourished people, allowing this toxic metabolite to accumulate.

FIGURE 1. Reprinted from Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleve Clin J Med 2010; 77:19–27.

■■ NEARLY 2,000 CASES A YEAR with acute liver failure.1 Nearly half of them There are nearly 2,000 cases of acute liver present after intentionally taking a single failure each year in the United States, and it large dose, while the rest present with unin- tentional toxicity while taking acetamino- accounts for 6% of all deaths due to liver dis- phen for pain relief on a long-term basis and ease.4 It is more common in women than in ingesting more than the recommended dose.6 men, and more common in white people than After ingestion, 52% to 57% of acetamin- in other races. The peak incidence is at a fairly ophen is converted to glucuronide conjugates, young age, ie, 35 to 45 years. and 30% to 44% is converted to sulfate conju- gates. These compounds are nontoxic, water- ■■ CAUSES soluble, and rapidly excreted in the urine. The most common cause of acute liver fail- However, about 5% to 10% of ingested ure in the United States and other Western acetaminophen is shunted to the cytochrome countries is acetaminophen toxicity, followed P450 system. P450 2E1 is the main isoenzyme by . In contrast, viral hepatitis is involved in acetaminophen metabolism, but the most common cause in developing coun- 1A2, 3A4, and 2A6 also contribute.7,8 P450 tries.5 2E1 is the same isoenzyme responsible for eth- anol metabolism and is inducible. Thus, regu- Acetaminophen toxicity lar alcohol consumption can increase P450 Patients with acetaminophen-induced liver 2E1 activity, setting the stage under certain failure tend to be younger than other patients circumstances for increased acetaminophen

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metabolism through this pathway. TABLE 1 Metabolism of acetaminophen through the cytochrome P450 pathway results in pro- Advice to patients taking acetaminophen duction of N-acetyl-p-benzoquinone imine Acetaminophen is used to treat pain and fever. Overall, it is safe, but if (NAPQI), the compound that damages the you take too much (more than 4,000 mg per day), it can damage the liver. NAPQI is rendered nontoxic by bind- liver. If you are taking it, please do the following: ing to glutathione, forming NAPQI-glutathi- Read the label. Many contain acetaminophen, so you one adducts. Glutathione capacity is limited, could be taking too much without knowing. however. With too much acetaminophen, glu- tathione becomes depleted and NAPQI accu- Don’t drink. Drinking alcohol increases the likelihood of acetamino- mulates, binds with proteins to form adducts, phen-induced liver toxicity. and leads to necrosis of hepatocytes (Figure Get help. If you or your child may have taken too much acetamino- 1).9,10 phen, call the American Association of Poison Control Centers hotline Acetylcysteine, used in treating acetamin- at 1-800-222-1222 right away. ophen toxicity, is a substrate for glutathione Keep acetaminophen (and all drugs) out of the hands of children. synthesis and ultimately increases the amount of glutathione available to bind NAPQI and prevent damage to hepatocytes.11 Statins can also cause acute liver failure, Acetaminophen is a dose-related toxin. especially when combined with other hepato- Most ingestions leading to acute liver failure toxic agents.16 exceed 10 g/day (> 150 mg/kg/day). Moder- The herbal supplements and weight-loss ate chronic ingestion, eg, 4 g/day, usually leads agents Hydroxycut and Herbalife have both to transient mild elevation of liver enzymes been reported to cause acute liver failure, with in healthy individuals12 but can in rare cases patients presenting with either the hepatocel- cause acute liver failure.13 lular or the cholestatic pattern of liver injury.17 Whitcomb and Block14 retrospectively The exact chemical in these supplements that identified 49 patients who presented with ac- causes liver injury has not yet been determined. etaminophen-induced hepatotoxicity in 1987 The National Institutes of Health main- Acetylcysteine through 1993; 21 (43%) had been taking ac- tains a database of cases of liver failure due is the main etaminophen for therapeutic purposes. All 49 to and supplements at livertox. patients took more than the recommended nih.gov. The database includes the pattern of drug used for limit of 4 g/day, many of them while fasting hepatic injury, mechanism of injury, manage- treating and some while using alcohol. Acute liver fail- ment, and outcomes. acetaminophen ure was seen with ingestion of more than 12 g/ day—or more than 10 g/day in alcohol users. Viral hepatitis toxicity The authors attributed the increased risk to Hepatitis B virus is the most common viral cause of acute liver failure and is responsible activation of cytochrome P450 2E1 by alcohol 18 and depletion of glutathione stores by starva- for about 8% of cases. tion or alcohol abuse. Patients with chronic hepatitis B virus in- Advice to patients taking acetaminophen fection—as evidenced by positive hepatitis B is given in Table 1. surface antigen—can develop acute liver fail- ure if the infection is reactivated by the use Other drugs and supplements of immunosuppressive drugs for solid-organ A number of other drugs and herbal supple- or bone-marrow transplant or medications ments can also cause acute liver failure (Table such as anti-tumor necrosis agents, rituximab, 2), the most common being antimicrobial or chemotherapy. These patients should be and antiepileptic drugs.15 Of the antimicrobi- treated prophylactically with a nucleoside als, antitubercular drugs (especially isoniazid) analogue, which should be continued for 6 are believed to be the most common causes, months after immunosuppressive therapy is followed by trimethoprim-sulfamethoxazole. completed. Phenytoin is the antiepileptic drug most often Hepatitis A virus is responsible for about implicated in acute liver failure. 4% of cases.18

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HELLP (hemolysis, elevated liver enzymes TABLE 2 and low platelets) syndrome. Mechanism of toxicity of drugs and herbal supplements known to cause acute liver failure ■■ MANY PATIENTS NEED LIVER TRANSPLANT Drug or supplement Pattern of injury Many patients with acute liver failure ultimately require orthotopic liver transplant,21 especially if Terbinafine Cholestatic and mixed they present with severe encephalopathy. Other aspects of treatment vary according to the cause Sulfasalazine Cholestatic or mixed of liver failure (Table 3). Trimethoprim- Cholestatic or mixed sulfamethoxazole ■■ SPECIFIC MANAGEMENT Management of acetaminophen toxicity Isoniazid Hepatocellular If the time of ingestion is known, checking Carbamazepine Hepatocellar, cholestatic, or mixed the acetaminophen level can help determine the cause of acute liver failure and also predict Valproic acid Hepatocellular the risk of hepatotoxicity, based on the work of Rumack and Matthew.22 Calculators are Phenytoin Hepatocellular, cholestatic, or mixed available, eg, http://reference.medscape.com/ calculator/acetaminophen-toxicity. Herbalife Hepatocellular If a patient presents with acute liver failure several days after ingesting acetaminophen, Hydroxycut Hepatocellular, cholestatic, or mixed the level can be in the nontoxic range, how- Kava kava Hepatocellular ever. In this scenario, measuring acetamin- ophen-protein adducts can help establish OxyElite Pro Hepatocellular acetaminophen toxicity as the cause, as the adducts last longer in the serum and provide 100% sensitivity and specificity.23 While most laboratories can rapidly measure acetamino- Hepatitis C virus rarely causes acute liver phen levels, only a few can measure acetamin- failure, especially in the absence of hepatitis A ophen-protein adducts, and thus this test is 3,19 and hepatitis B. not used clinically. Hepatitis E virus, which is endemic in ar- Acetylcysteine is the main drug used for eas of Asia and Africa, can cause liver disease acetaminophen toxicity. Ideally, it should be in pregnant women and in young adults who given within 8 hours of acetaminophen inges- have concomitant liver disease from another tion, but giving it later is also useful.1 cause. It tends to cause acute liver failure more Acetylcysteine is available in oral and in- frequently in pregnant women than in the rest travenous forms, the latter for patients who of the population and carries a mortality rate have encephalopathy or cannot tolerate oral of more than 20% in this subgroup. intake due to repeated episodes of vomit- TT (transfusion-transmitted) virus was ing.24,25 The oral form is much less costly and is reported in the 1990s to cause acute liver thus preferred over intravenous acetylcysteine failure in about 27% of patients in whom no in patients who can tolerate oral intake. In- 20 other cause could be found. travenous acetylcysteine should be given in a Other rare viral causes of acute liver fail- loading dose of 150 mg/kg in 5% dextrose over ure include Epstein-Barr virus, cytomegalovi- 15 minutes, followed by a maintenance dose rus, and herpes simplex virus types 1, 2, and 6. of 50 mg/kg over 4 hours and then 100 mg/ Other causes kg given over 16 hours.1 No dose adjustment Other causes of acute liver failure include is needed in patients who have renal toxicity ischemic hepatitis, autoimmune hepatitis, (acetaminophen can also be toxic to the kid- Wilson disease, Budd-Chiari syndrome, and neys).

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Most patients with acetaminophen-induced liver failure survive with medical management TABLE 3 alone and do not need a liver transplant.3,26 Management of acute liver failure Cirrhosis does not occur in these patients. Transfer the patient to the intensive care unit in a tertiary care center Management of viral acute liver failure with facilities for liver transplant When patients present with acute liver fail- Neurologic complications ure, it is necessary to look for a viral cause by serologic testing, including hepatitis A virus Grade 2–3 encephalopathy: order computed tomography of the brain IgM antibody, hepatitis B surface antigen, and to rule out secondary causes of encephalopathy; avoid hyponatremia hepatitis B core IgM antibody. and use of sedatives Hepatitis B can become reactivated in Grade 3–4 encephalopathy: intubate; elevate the head end of bed to immunocompromised patients, and therefore 30 degrees; consider giving mannitol or hypertonic saline the hepatitis B virus DNA level should be Infectious complications checked. Detection of hepatitis B virus DNA in a patient previously known to have unde- Give a broad-spectrum if infection is suspected, and add tectable hepatitis B virus DNA confirms hepa- an antifungal agent if there is no improvement with initial antibiotic titis B reactivation. coverage Patients with hepatitis B-induced acute Gastrointestinal complications liver failure should be treated with entecavir Give a histamine H2 receptor blocker or a proton pump inhibitor to or tenofovir. Although this treatment may prevent upper gastrointestinal bleeding not change the course of acute liver failure or accelerate the recovery, it can prevent rein- Determining the cause of acute liver failure fection in the transplanted liver if liver trans- Obtain a thorough history of ingestion of drugs from the patient and plant becomes indicated.27–29 family Herpes simplex virus should be suspected Laboratory testing, including toxicology screen, acetaminophen or in patients presenting with anicteric hepatitis acetaminophen-protein adduct levels; serologic testing for hepatitis with fever. Polymerase chain reaction testing A, hepatitis B, hepatitis C, herpes simplex virus, autoimmune hepatitis, for herpes simplex virus should be done,30 and and serum and urine copper and serum ceruloplasmin levels if positive, patients should be given intrave- nous acyclovir.31 Despite treatment, herpes simplex virus disease is associated with a very rate in acute liver failure from Wilson disease poor prognosis without liver transplant. reaches 100% without liver transplant. Autoimmune hepatitis Wilson disease is caused by a genetic de- The autoantibodies usually seen in autoim- fect that allows copper to accumulate in the mune hepatitis are antinuclear antibody, an- liver and other organs. However, diagnosing tismooth muscle antibody, and anti-liver-kid- Wilson disease as the cause of acute liver fail- ney microsomal antibody, and patients need ure can be challenging because elevated serum to be tested for them. and urine copper levels are not specific to Wil- The diagnosis of autoimmune hepatitis can son disease and can be seen in patients with be challenging, as these autoimmune markers acute liver failure from any cause. In addition, can be negative in 5% of patients. Liver biop- the ceruloplasmin level is usually normal or sy becomes essential to establish the diagnosis high because it is an acute-phase reactant. Ac- in that setting.32 cumulation of copper in the liver parenchyma Guidelines advise starting prednisone 40 is usually patchy; therefore, qualitative cop- to 60 mg/day and placing the patient on the per staining on random liver biopsy samples liver transplant list.1 provides low diagnostic yield. Quantitative copper on liver biopsy is the gold standard test Wilson disease to establish the diagnosis, but the test is time- Although it is an uncommon cause of liver consuming. Kayser-Fleischer rings around the failure, Wilson disease needs special attention iris are considered pathognomic for Wilson because it has a poor prognosis. The mortality disease when seen with acute liver failure, but

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Clinical features of acute liver failure

Cerebral edema due to elevated Acute respiratory distress syndrome intracranial pressure

Upper gastrointestinal bleeding from stress-related ulcers and coagulopathy High-output cardiac failure

Hypoadrenalism: lack of glucocorti- coid and mineralocorticoid production Hypoglycemia, lactic acidosis, coagulopathy

Acute kidney injury

Pancreatitis, particularly in acetaminophen-induced acute liver failure

Infectious diseases from impaired leukocyte function

CCF FIGURE 2. Medical Illustrator: Jeffrey Loerch ©2016 they are seen in only about 50% of patients.33 dialysis, continuous hemofiltration, plasma- A unique feature of acute Wilson disease pheresis, and plasma exchange,1 but the evi- is that most patients have very high bilirubin dence supporting their use is limited. levels and low alkaline phosphatase levels. An alkaline phosphatase-to-bilirubin ratio less ■■ NONSPECIFIC MANAGEMENT than 2 in patients with acute liver failure is Acute liver failure can affect a number of organs 34 highly suggestive of Wilson disease. and systems in addition to the liver (Figure 2). Another clue to the diagnosis is that pa- tients with Wilson disease tend to develop General considerations Coombs-negative hemolytic anemia, which Because their condition can rapidly deterio- leads to a disproportionate elevation in ami- rate, patients with acute liver failure are best notransferase levels, with aspartate amino- managed in intensive care. transferase being higher than alanine amino- Patients who present to a center that does transferase. not have the facilities for liver transplant Once Wilson disease is suspected, the pa- should be transferred to a transplant center as tient should be listed for liver transplant be- soon as possible, preferably by air. If the pa- cause death is almost certain without it. For tient may not be able to protect the airway, patients awaiting liver transplant, the Ameri- endotracheal intubation should be performed can Association for the Study of Liver Diseas- before transfer. es guidelines recommend certain measures to The major causes of death in patients with lower the serum copper level such as albumin acute liver failure are cerebral edema and in-

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fection. Gastrointestinal bleeding was a major tion must be exercised in patients with renal cause of death in the past, but with prophylac- dysfunction. The other pharmacologic option tic use of histamine H2 receptor blockers and is 3% hypertonic saline. proton pump inhibitors, the incidence of gas- Therapeutic hypothermia is a newer treat- trointestinal bleeding has been significantly ment for cerebral edema. Lowering the body reduced. temperature to 32 to 33°C (89.6 to 91.4°F) Although initially used only in patients using cooling blankets decreases intracranial with acetaminophen-induced liver failure, ace- pressure and cerebral blood flow and improves tylcysteine has also shown benefit in patients the cerebral perfusion pressure.43 With this with acute liver failure from other causes. In treatment, patients should be closely moni- patients with grade 1 or 2 encephalopathy on a tored for side effects of infection, coagulopa- scale of 0 (minimal) to 4 (comatose), the trans- thy, and cardiac arrythmias.1 plant-free survival rate is higher when acetyl- l-ornithine l-aspartate was successfully used cysteine is given compared with placebo, but to prevent brain edema in rats, but in humans, this benefit does not extend to patients with a no benefit was seen compared with placebo.44,45 higher grade of encephalopathy.35 The underlying basis for this experimental treatment is that supplemental ornithine and Cerebral edema aspartate should increase glutamate synthesis, and intracranial hypertension which should increase the activity of enzyme Cerebral edema is the leading cause of death glutamine synthetase in skeletal muscles. With in patients with acute liver failure, and it de- 36 the increase in enzyme activity, conversion of velops in nearly 40% of patients. ammonia to glutamine should increase, thereby The mechanism by which cerebral edema decreasing ammonia circulation and thus de- develops is not well understood. Some have creasing cerebral edema. proposed that ammonia is converted to gluta- Patients with cerebral edema have a high mine, which causes cerebral edema either di- 37,38 incidence of seizures, but prophylactic antisei- rectly by its osmotic effect or indirectly by zure medications such as phenytoin have not decreasing other osmolytes, thereby promot- been proven to be beneficial.46 Drinking ing water retention.39 Cerebral edema leads to intracranial hy- Infection and fasting pertension, which can ultimately cause cere- Nearly 80% of patients with acute liver failure increase bral herniation and death. Because of the high develop an infectious complication, which can the risk of mortality rate associated with cerebral edema, be attributed to a state of immunodeficiency.47 invasive devices were extensively used in the The respiratory and urinary tracts are the acetaminophen past to monitor intracranial pressure. How- most common sources of infection.48 In pa- overdose ever, in light of known complications of these tients with bacteremia, Enterococcus species devices, including bleeding,40 and lack of evi- and coagulase-negative Staphylococcus species49 dence of long-term benefit in terms of mortal- are the commonly isolated organisms. Also, in ity rates, their use has come under debate. patients with acute liver failure, fungal infec- Treatments. Many treatments are avail- tions account for 30% of all .50 able for cerebral edema and intracranial hy- Infected patients often develop worsen- pertension. The first step is to elevate the ing of their encephalopathy51 without fever or head of the bed about 30 degrees. In addition, elevated white blood cell count.49,52 Thus, in hyponatremia should be corrected, as it can any patient in whom encephalopathy is wors- worsen cerebral edema.41 If patients are in- ening, an evaluation must be done to rule out tubated, maintaining a hypercapneic state is infection. In these patients, systemic inflam- advisable to decrease the intracranial pressure. matory response syndrome is an independent Of the two pharmacologic options, man- risk factor for death.53 nitol is more often used.42 It is given as a bolus Despite the high mortality rate with infec- dose of 0.5 to 1 g/kg intravenously if the serum tion, whether using prophylacti- osmolality is less than 320 mOsm/L.1 Given cally in acute liver failure is beneficial is con- the risk of fluid overload with mannitol, cau- troversial.54,55

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TABLE 4 Prognostic scores of acute liver failure

King’s College Clichy MELD APACHE Factor criteria37,66,67 criteria66,69 score68 score

Age Yes Yes No Yes

Cause of acute liver failure Yes No No No

Presence of encephalopathy Yes Yes No No

Presence of coagulopathy Yes Yes Yes No

Serum bilirubin level Yes No Yes No

Serum creatinine level Yes No Yes Yes

Sensitivity to predict poor outcome without liver transplant Acetaminophen-induced acute liver failure 69% 75% 60% 68% Acute liver failure from other causes 68% 69% 87%

Specificityto predict poor outcome without liver transplant Acetaminophen-induced acute liver failure 82% 56% 69% 87% Acute liver failure from other causes 92% 50% 65%

APACHE II = Acute Physiology and Chronic Health Evaluation II; MELD = Model for End-State Liver Disease

Gastrointestinal bleeding of these—the molecular adsorbent recycling The current prevalence of upper gastrointes- system (MARS) and the extracorporeal liver tinal bleeding in acute liver failure patients is assist device (ELAD)—were developed in the about 1.5%.56 Coagulopathy and endotracheal late 1990s. MARS consisted of a highly per- intubation are the main risk factors for upper meable hollow fiber membrane mixed with gastrointestinal bleeding in these patients.57 albumin, and ELAD consisted of porcine The most common source of bleeding is stress hepatocytes attached to microcarriers in the ulcers in the stomach. The ulcers develop from extracapillary space of the hollow fiber mem- a combination of factors, including decreased brane. Both systems allowed for transfer of blood flow to the mucosa causing ischemia water-soluble and protein-bound toxins in the and hypoperfusion-reperfusion injury. blood across the membrane and into the di- Pharmacologic inhibition of gastric acid alysate.59 The clinical benefit offered by these secretion has been shown to reduce upper gas- 60–62 trointestinal bleeding in acute liver failure. A devices is controversial, thus limiting their use to experimental purposes only. histamine H2 receptor blocker or proton pump inhibitor should be given to prevent gastroin- Hepatocyte transplant testinal bleeding in patients with acute liver Use of hepatocyte transplant as a bridge to liv- 1,58 failure. er transplant was tested in 1970s, first in rats and later in humans.63 By reducing the blood ■ ■ EXPERIMENTAL TREATMENTS ammonia level and improving cerebral perfu- Artificial liver support systems sion pressure and cardiac function, replace- Membranes and dialysate solutions have been ment of 1% to 2% of the total liver cell mass developed to remove toxic substances that by transplanted hepatocytes acts as a bridge to are normally metabolized by the liver. Two orthotopic liver transplant.64,65

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■■ PROGNOSIS King’s College criteria.6 66,69 Different criteria have been used to identify The Clichy criteria can also be used. patients with poor prognosis who may eventu- Liver biopsy. In addition to helping es- tablish the cause of acute liver failure, liver ally need to undergo liver transplant. biopsy can also be used as a prognostic tool. The King’s College criteria system is the Hepatocellular necrosis greater than 70% on most commonly used for prognosis (Table 37,66–69 the biopsy predicts death with a specificity of 4). Its main drawback is that it is appli- 90% and a sensitivity of 56%.70 cable only in patients with encephalopathy, Hypophosphatemia has been reported to and when patients reach this stage, their con- indicate recovering liver function in patients dition often deteriorates rapidly, and they die with acute liver failure.71 As the liver regener- 37,66,67 while awaiting liver transplant. ates, its energy requirement increases. To sup-

The Model for End-Stage Liver Disease ply the energy, adenosine triphosphate produc- (MELD) score is an alternative to the King’s tion increases, and phosphorus shifts from the College criteria. A high MELD score on ad- extracellular to the intracellular compartment mission signifies advanced disease, and pa- to meet the need for extra phosphorus during tients with a high MELD score tend to have a this process. A serum phosphorus level of 2.9 worse prognosis than those with a low score.68 mg/dL or higher appears to indicate a poor The Acute Physiology and Chronic prognosis in patients with acute liver failure, as Health Evaluation (APACHE) II score can it signifies that adequate hepatocyte regenera- also be used, as it is more sensitive than the tion is not occurring. ■ ■■ REFERENCES with fasting and ethanol use. JAMA 1994; 272:1845–1850. 15. Chalasani N, Fontana RJ, Bonkovsky HL, et al; Drug Induced Liver 1. 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