Acute Liver Failure: Pathogenesis and Management

Acute Liver Failure
Pathogenesis & Management
Pratap Sagar Tiwari, MD
DM Resident, Hepatology
NAMS, Bir Hospital, Nepal

Contents
• Introduction
• Aetiology
Primary causes (emergency transplantation may be an option)
Secondary Causes ( emergency LT is not an option)
• ALF: Pathogenesis
Failure of liver function
Extra hepatic manifestations & Management.
• Prognositc markers
• Liver Transplant

Introduction
• Acute liver failure is defined as ‘‘Severe acute liver injury characterized
by the development of HE and coagulation abnormalities, usually
characterized by an INR of ≥1.5, in pts without preexisting cirrhosis, and
an illness of <26 weeks duration’’. [1]
• Pts with an acute presentation of chronic autoimmune hepatitis, Wilson disease and
Budd-Chiari syndrome are considered as having ALF if they develop HE, despite the
presence of a pre-existing liver disease in the context of appropriate abnormalities in
liver blood tests and coagulation profile.
1. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology. 2005;41:1179–97.
2. O’Grady JG, Schaim SW, Williams R. Acute liver failure: remodeling the syndromes. Lancet. 1993;342:273–5.
[2]

Primary causes of ALF and need for LT
European Association for the Study of the Liver. Clinical practice guidelines panel, Wendon, J, Cordoba J, Dhawan A, Larsen FS, Manns M, Samuel D, Simpson KJ,
Yaron I; EASL Governing Board representative, Bernardi M.EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure.J Hepatol. 2017
May;66(5):1047-1081.

Classification of ALF According to the Interval Between Onset of
Jaundice and Development of HE, and Relationship to Cause
Adapted from O’Grady JG, et al. Acute liver failure: redefining the syndromes. Lancet 1993;342(8866):273-275; and Williams R. Classification and clinical
syndromes of acute liver failure. In: Lee WM, Williams R, editors. Acute liver failure. Cambridge, United Kingdom: Cambridge University Press, 1997: 1-9.

Prevalence of Causes of ALF According to Geography
Adapted from Lee WM. Acute liver failure in the United States. Semin Liver Dis 2003;23:217-226.

Causes of ALF in the US 1997-2015 reported to the U.S. ALF Study Group registry
(Data courtesy of W.M. Lee, Acute Liver Failure Study Group.)

Other uncommon causes of ALF
European Association for the Study of the Liver. Clinical practice guidelines panel, Wendon, J, Cordoba J, Dhawan A, Larsen FS, Manns M, Samuel D,
Simpson KJ, Yaron I; EASL Governing Board representative, Bernardi M.EASL Clinical Practical Guidelines on the management of acute (fulminant) liver
failure.J Hepatol. 2017 May;66(5):1047-1081.

Primary causes (emergency LT may be an option)
• Drug induced ALF: APAP Overdosage
• Acute Viral Hepatitis
• Toxin induced ALF: Mushroom Poisoning
• Autoimmune ALF
• Acute Wilson Disease
• Budd-Chiari syndrome
• Pregnancy Related

Drug-Induced Acute Liver Failure
• Numerous medications, toxins, and herbal remedies have been
associated with liver injury.
• Drug hepatotoxicity accounts for 10% to 20% of ALF in developed
nations, and a much higher proportion if APAP is included.
• Drugs that cause ALF may be intrinsic or idiosyncratic toxins.
• Intrinsic hepatotoxins such as APAP cause ALF in a dose-dependent and
predictable manner, whereas idiosyncratic hepatotoxins cause ALF
rarely in a dose-independent manner.
• Age, sex, nutritional state, concomitant diseases, other drugs, ethanol
consumption, and genetic polymorphisms of drug-metabolizing hepatic
enzymes, most importantly the cytochromes P-450, all contribute to the
risk of idiosyncratic drug-induced ALF.

• DILI is divided into two broad categories. Intrinsic (direct) hepatotoxins
cause a dose-dependent hepatocellular necrosis with a brief period
between exposure to the drug and development of liver toxicity (latent
period).
• Idiosyncratic hepatotoxicity is unpredictable. There is no constant
relationship between the dose and the occurrence or severity of
hepatotoxicity. The latent period is variable and unpredictable.
• Idiosyncratic reactions present as either immune-mediated
hypersensitivity or metabolic injury. While these reactions often occur
within several weeks following initiation of the drug, they can occur after
months to years of drug exposure or even after the drug has been
discontinued.
Drug-Induced Acute Liver Failure

Features of ALF Induced by Intrinsic Versus
Idiosyncratic Drug Hepatotoxicity

A Partial List of Drugs Causing ALF According to
Primary Pathologic Findings
Src: Zakin n Boyer

Src: Zakin n Boyer
A Partial List of Drugs Causing ALF According to
Primary Pathologic Findings

Extra note
• Most drugs cause hepatocellular necrosis, but others injure
mitochondria and lead to microvesicular steatosis, whereas others
damage endothelial cells of terminal hepatic venules, leading to veno-
occlusive disease/sinusoidal obstruction syndrome.
• The clinical course of ALF caused by an idiosyncratic drug reaction often
follows a subacute temp, with high mortality without OLT.
• In addition to ALF, drugs that cause microvesicular steatosis result in
progressive lactic acidosis (e.g., fialuridine), and those that cause hepatic
veno-occlusive disease result in acute right upper quadrant pain, tender
hepatomegaly, and ascites.

Extra note
• Steatosis (also called fatty change, fatty degeneration, or adipose
degeneration) is the process describing the abnormal retention of lipids
within a cell.
• It reflects an impairment of the normal processes of synthesis and
elimination of triglyceride fat. Excess lipid accumulates in vesicles that
displace the cytoplasm.
• When the vesicles are large enough to distort the nucleus, the condition
is known as macrovesicular steatosis; otherwise, the condition is known
as microvesicular steatosis.
• While not particularly detrimental to the cell in mild cases, large
accumulations can disrupt cell constituents, and in severe cases the cell
may even burst.

Extra notes
• Macrovesicular steatosis is the more common form of fatty degeneration and
may be caused by oversupply of lipids due to obesity, obstructive sleep apnea
(OSA), insulin resistance, or alcoholism.
• Nutrient malnutrition may also cause the mobilisation of fat from adipocytes
and create a local oversupply in the liver where lipid metabolism occurs.
• Excess alcohol over a long period of time can induce steatosis. The breakdown
of large amounts of ethanol in alcoholic drinks produces large amounts of
chemical energy, in the form of NADH, signalling to the cell to inhibit the
breakdown of fatty acids (which also produces energy) and simultaneously
increase the synthesis of fatty acids. This "false sense of energy" results in
more lipid being created than is needed.
• Microvesicular steatosis is characterized by small intracytoplasmic fat vacuoles
(liposomes) which accumulate in the cell. Common causes are tetracyclines,
acute fatty liver of pregnancy, Reye's syndrome, and hepatitis C.

TOXIC DOSE
• The therapeutic dose of APAP for children <12 years is 10-15 mg/kg per dose, every four
to six hours, not to exceed five doses per 24-hour period (max daily dose 75 mg/kg).
The therapeutic dose for children 12 years and older and adults is 325-1000 mg per
dose every 4-6 hrs (max daily dose 4 g). Therapeutic serum concentrations range from
10 to 20 mcg/mL (66 to 132 µmol/L).
• The toxic dose may vary among individuals according to baseline glutathione levels and
other factors, but in general:
• The minimal toxic dose for an acute ingestion is 150 mg/kg for a child or 7.5 to 10 g for
an adult [ 1 ].
• Toxicity is likely to occur with single ingestions >250 mg/kg or ingestions of >12 g in a
24-hour period [ 2,3 ].
• Virtually all pts who ingest doses in excess of 350 mg/kg develop severe liver toxicity
(defined as peak AST or ALT levels >1000 IU/L) [2].
• In chronic overdose (eg, multiple supratherapeutic oral or rectal doses), the minimum toxic
threshold for children appears to be 150 to 175 mg/kg over 2-4 days, particularly in the setting
of a febrile illness and decreased oral intake [ 4,5,6].
1. Lewis RK, Paloucek FP. Assessment and treatment of acetaminophen overdose. Clin Pharm 1991; 10:765.
2. Prescott LF. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 1983; 25:290.
3. Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology 1995; 109:1907.
4. Sztajnkrycer MJ, Bond GR. Chronic acetaminophen overdosing in children: risk assessment and management. Curr Opin Pediatr 2001; 13:177.
5. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130:300.
6. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures with acetaminophen: hepatoxicity after multiple doses in children. J Pediatr 1998; 132:22.
Acetaminophen(APAP) Overdosage

• Following ingestion, about 2% of APAP is excreted in the urine
unchanged [1]. Over 90% is metabolized via conjugation – 2/3rd via
glucuronidation (urine diphosphate (UDP) glucuronosyltransferases) and
1/3rd through sulfation (sulfotransferases) [2]. The inactive nontoxic
conjugates are largely excreted in the urine and bile.
• The remaining 5–9% undergoes oxidative conversion via several
cytochromes (CYP1A2, CYP2A6, CYP2E1, CYP3A4) to the highly toxic
metabolite N-acetyl-p-benzoquinone imine (NAPQI) [3].
• NAPQI is a highly reactive that can act as an oxidant. Normally, it is
rapidly metabolized by conjugation to intracellular glutathione (GSH)
forming a nontoxic APAP-GSH conjugate (3-(glutathione-S-yl)-APAP) [4].
• Subsequent processing leads to its urinary excretion as mercapturic acid and cysteine conjugates [4].
• However, under conditions where the supply of NAPQI exceeds the amount of available glutathione, the former covalently binds
hepatocellular proteins, initiating hepatocyte necrosis.
APAP: metabolism
1. Mitchell JR, Thorgeirsson SS, Potter WZ, et al. Acetaminopheninduced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 1974;16:676–84.
2. Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000;67:275–82.
3. Chen W, Koenigs LL, Thompson SJ, et al. Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A6. Chem Res Toxicol 1998;11:295–301.
4. Kaplowitz N. Acetaminophen hepatoxicity: what do we know,what don’t we know, and what do we do next? Hepatology 2004;40:23–6.
Schiff’s disease of liver

Extra note
• In the absence of GSH, covalent binding of NAPQI to the cysteine groups
on hepatocyte macromolecules occurs, forming NAPQI–cysteine adducts .
This is the initial and irreversible step in the development of cell injury .
• GSH depletion further contributes to cellular oxidant stress . With NAPQI
binding to critical cellular targets such as mitochondrial proteins,
mitochondrial dysfunction and loss of cellular adenosine triphosphate
(ATP) occurs .
• Hepatocytes subsequently experience overall energy failure (cellular
exhaustion). The ultimate result is alteration in calcium homeostasis,
mitochondrial dysfunction with ATP depletion, DNAdamage, and
intracellular protein modification, leading to necrotic cell death.

• The hepatotoxicity of APAP may be enhanced by agents that either
increase production of NAPQI or reduce the supply of glutathione.
• High doses of APAP saturate the enzymes involved in conjugation,
increasing the amount of the substrate for the oxidative pathway.
• Ethanol and certain drugs (e.g, isoniazid, barbiturates) induce the activity
of cytochromes P-450, thereby increasing NAPQI production; the increased
toxicity of APAP caused by ethanol appears to be predominantly from
inducing cytochrome P-450 2E1.
• In contrast, fasting and malnutrition, such as that seen with long-term
alcohol abuse, decrease glutathione synthesis and theoretically deplete
the hepatocyte’s ability to detoxify NAPQI.
Acetaminophen(APAP) Overdosage

Pts often have few signs/symptoms within 1st 24 hrs following an acute overdose , but
may develop N/V, and malaise.
Lab studies are usually N during this period, and early symptoms may completely
resolve.
Clinical and laboratory evidence of hepatotoxicity appears from 24-72 hrs after
ingestion.
Pts may develop abdominal pain or liver tenderness and elevations in serum AST, ALT, PT,
and bilirubin.
Acetaminophen(APAP) Overdosage: manifestations
STAGE 1
STAGE 2

72–96 hrs, the most severe abnormalities occur –HE, coagulopathy, hyperbilirubinemia (median 4.5
mg/dL), renal dysfunction, and lactic acidosis.
Marked AT elevations (median ∼4,100 IU/L) are often seen and this degree of elevation is highly
correlated with APAP poisoning [1,2].
During this stage, death most often occurs from cerebral herniation or from MOSF.
Once the signs of ALF (i.e., HE and coagulopathy) have developed, the risks of complications and death increase
significantly, with overall mortality approaching 30% [1,3].
Acetaminophen(APAP) Overdosage: manifestations
STAGE 3
1. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42:1364–72.
2. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995;22:767–73.
3. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947–54.
4. Smilkstein MJ. Acetaminophen. In: Goldfrank's Toxicologic Emergencies, Goldfrank LR, Flomenbaum NE, Lewin NA, et al. (Eds), Appleton & Lange, Stamford 1998. p.541.
4d-2 wks — Pts who survive s3 enter a recovery phase that usually begins by day 4 and is complete by 7 d
after overdose [ 4]. Symptoms and lab values may not normalize for several wks.
Histologic changes in the liver vary from cytolysis to centrilobular necrosis. The centrilobular region (zone
III) is preferentially involved because it is the area of greatest conc of CYP2E1 and therefore the site of
maximal production of NAPQI.
Histologic recovery lags behind clinical recovery and may take up to 3 mnths. When recovery occurs, it is
complete; chronic hepatic dysfunction is not a sequela of APAP poisoning.
STAGE 4

N-Acetylcysteine for Acetaminophen Overdose
• The use of an antidote may decrease hepatic injury and reverse ALF in
specific circumstances.
• NAC remains the treatment of choice for APAP overdose , and in theory
may protect the liver from other toxins that cause hepatotoxicity by
generating free radicals, such as carbon tetrachloride or trichlorethylene.
• The administration of NAC for APAP overdose replenishes glutathione,
thereby detoxifying NAPQI.
For pts with known or suspected APAP overdose<4 hours of presentation, give activated
charcoal just prior to starting N-acetylcysteine dosing (I). AASLD 2011

Extra note : GI DECONTAMINATION
• Adult patients who present soon after a potentially toxic ingestion of APAP
(single dose ≥7.5 g) are likely to benefit from gastrointestinal decontamination.
• We suggest treatment with activated charcoal (AC), 1 g/kg (maximum dose 50
g) by mouth in all patients who present within four hours of a known or
suspected acetaminophen ingestion, unless there are contraindications to its
administration.
• Charcoal should be withheld in patients who are sedated and may not be able
to protect their airway, unless endotracheal intubation is performed first.
However, endotracheal intubation should not be performed solely for the
purpose of giving charcoal.
• Asymptomatic patients who present more than four hours after a reported
ingestion are unlikely to benefit from AC, and we do not recommend routine
treatment in these patients

The 20 hour IV protocol has been used in the UK since the 1970s.
The approved 20 hour IV dosing regime is performed as follows:
• Administer an initial loading dose of 150 mg/kg IV over 15 to 60 minutes (we recommend 60 minutes).
• Next, administer a 4 hour infusion at 12.5 mg/kg per hour IV.
• Finally, administer a 16 hour infusion at 6.25 mg/kg per hour IV.
This treatment protocol provides a total of 300 mg/kg over 20 to 21 hours [ 1 ]. The treatment period is often extended
when patients have large ingestions or elevated serum AT activity.
20 hour IV protocol
72 hour oral protocol
The 72 hour oral dosing protocol has been used successfully in the US for >30 years. It is performed as follows:
• Give a loading dose of 140 mg/kg PO.
• Next, give a dose of 70 mg/kg PO every four hours for a total of 17 doses.
The dose does not need to be adjusted if the patient has been treated with activated charcoal .
The incidence of hepatotoxicity for patients treated within 8 hrs of ingestion is <10 %, but increases to approximately
40 % if treatment is delayed beyond 16 hrs.
N-Acetylcysteine for Acetaminophen Overdose
1. Prescott LF, Park J, Ballantyne A, et al. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet 1977; 2:432.
The full course of NAC therapy should not be discontinued prematurely even after APAP levels have become
undetectable; resolution of HE and correction of the INR to <1.5 have been advocated as criteria for discontinuation.

Extra Note
• The early administration of NAC (within 8 hours of the overdose)
minimizes hepatotoxicity regardless of the initial plasma concentration
of APAP.
• The time after which NAC administration is no longer effective, however,
remains controversial, with some studies documenting benefit of
administration up to 24 to 36 hours after ingestion.
• On the basis of these observations, it has been recommended that NAC
“be used whenever there is any doubt concerning the timing, dose
ingested, or plasma concentration because the use of the antidote is
much less hazardous than the consequences of withholding it.”

IV versus oral : NAC
• There are no head-to-head trials comparing the 20 hour IV and the 72 hour oral
treatment protocols in pts treated early after ingestion.
• The best available data suggest that both routes are effective and differences
are minimal. In most pts, either the oral or IV route is acceptable.
IV administration is favored for pts with any of the following:
• Vomiting
• CI to oral administration (ie, pancreatitis, bowel ileus/obstruction, bowel injury)
• Hepatic failure
• Patients who refuse oral administration
The essential elements of treating APAP overdose do not differ significantly in the pregnant pt. Many toxicologists
prefer to give NAC IV to pregnant pts to reduce the risk of vomiting and ensure more rapid delivery to the fetus.

Nomogram depicting the risk of hepatotoxicity from APAP according to
plasma APAP concentration and time after ingestion.
A standard treatment line for
administration of NAC was derived
empirically.
Pts with plots above the standard
treatment line have significant risk of
hepatotoxicity and should receive NAC
immediately;
pts with plots below the line have a low
risk of hepatotoxicity and do not require
NAC.
(From Makin A, Williams R. Acetaminophen-induced acute liver failure. In: Lee
WM, Williams R, editors. Acute liver failure. 1st ed. Cambridge, United Kingdom:
Cambridge University Press, 1997: 32-42.)

Other treatment for APAP Overdosage
• Cimetidine-an inhibitor of APAP metabolism[ 1 ]. While this RX was useful in
animal models, it had no effect in a clinical trial where pts were MX with NAC[
2 ].
• Older studies evaluated therapies such as methionine, cysteamine , and
dimercaprol [ 3,4,5], but these treatments were limited by A/E and play no role
in current MX.
• Indications for extracorporeal removal -Although APAP is cleared by HD [ 6,7],
the safety and efficacy of NAC leaves no role for dialysis in the management of
APAP poisoning if NAC is available. Extracorporeal removal may be useful for
lowering serum APAP conc. if NAC is not available, but there are no
systematic studies to evaluate the effectiveness of this treatment.
• Hemodialysis should never be considered an alternative to acetylcysteine
therapy.
1. Speeg KV Jr, Mitchell MC, Maldonado AL. Additive protection of cimetidine and N-acetylcysteine treatment against acetaminophen-induced hepatic necrosis in the rat. J Pharmacol Exp Ther 1985; 234:550.
2. Burkhart KK, Janco N, Kulig KW, Rumack BH. Cimetidine as adjunctive treatment for acetaminophen overdose. Hum Exp Toxicol 1995; 14:299.
3. Vale JA, Meredith TJ, Goulding R. Treatment of acetaminophen poisoning. The use of oral methionine. Arch Intern Med 1981; 141:394.
4. Prescott LF, Sutherland GR, Park J, et al. Cysteamine, methionine, and penicillamine in the treatment of paracetamol poisoning. Lancet 1976; 2:109.
5. Hamlyn AN, Lesna M, Record CO, et al. Methionine and cysteamine in paracetamol (acetaminophen) overdose, prospective controlled trial of early therapy. J Int Med Res 1981; 9:226.
6. Wu ML, Tsai WJ, Deng JF, Yang CC. Hemodialysis as adjunctive therapy for severe acetaminophen poisoning: a case report. Zhonghua Yi Xue Za Zhi (Taipei) 1999; 62:907.
7. Marbury TC, Wang LH, Lee CS. Hemodialysis of acetaminophen in uremic patients. Int J Artif Organs 1980; 3:263.

N-Acetylcysteine for Nonacetaminophen ALF
• From experience in pts with ALF because of APAP overdose, three trials of NAC in
non-APAP ALF have recently been completed, only one of which was randomized and
placebo controlled.
• The U.S. ALF Study Group trial concluded that IV administered NAC
improved spontaneous (nontransplanted) survival compared with a
placebo, but only in pts with Grade 1 or Grade 2 HE.[1]
• Suspected mushroom poisoning should be treated initially with ipecac
and charcoal to decrease the Amanita toxin load if the ingestion has
occurred recently (within 30 minutes to a few hours). NAC is also
frequently advocated, although with scant supporting data.
1. Lee WM, et al: Intravenous N-acetylcysteine improves transplant free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 137(3):856–864, 2009.
N-AC may be beneficial for ALF due to drug-induced liver injury (I).AASLD 2011

KING’S COLLEGE CRITERIA
PARACETAMOL INDUCED NON PARACETAMOL INDUCED
pH <7.3 (irrespective of HE) or LACTATE >3.5 mmol/l
OR ALL OF BELOW
INR> 6.5 OR PT >100 SEC OR ATLEAST 3 OF BELOW
• INR >6.5 OR PT> 100 SEC
• S CREAT > 3.5 mg/dl or 300 umol/l
• HE G 3/4
• AGE <10 OR >40 YRS
• INR > 3.5 or PT> 50 SEC
• BILIRUBIN >17.5 mg/dl or 300 umol/l
• CAUSE: HEPATITIS C, HALOTHANE, IDIOSYNCRATIC
DRUG REACTION, INDETERMINATE
• TIME INTERVAL ICTERUS TO HE (any grade)>7 D
O'Grady J, Alexander G, Hayllar K, Williams R (1989). "Early indicators of prognosis in fulminant hepatic failure.". Gastroenterology. 97 (2): 439–45
The positive predictive value of the criteria in predicting death from ALF has ranged from 70% to 100%.[1,2,3]
A Canadian meta-analysis assessing various prognostic indices found that the specificity of the King's College criteria
in predicting mortality exceeded 90%, with a sensitivity of 69%.[4]
As a result, the AASLD has recommended the KCC as being helpful early parameters in ascertaining the need for LT in
patients with ALF.[1]
1. Polson J, Lee W (2005). "AASLD position paper: the management of acute liver failure.". Hepatology. 41 (5): 1179–97.
2. Shakil A, Kramer D, Mazariegos G, Fung J, Rakela J (2000). "Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria.". Liver Transpl. 6 (2): 163–9.
3. Anand A, Nightingale P, Neuberger J (1997). "Early indicators of prognosis in fulminant hepatic failure: an assessment of the King's criteria.". J Hepatol. 26 (1): 62–8.
4. Bailey B, Amre D, Gaudreault P (2003). "Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation.". Crit Care Med. 31 (1): 299–305

Extra note: The positive and negative predictive
values
• The positive and negative predictive values (PPV and NPV respectively)
are the proportions of positive and negative results in statistics and
diagnostic tests that are true positive and true negative results,
respectively.
• The PPV and NPV describe the performance of a diagnostic test or
other statistical measure. A high result can be interpreted as indicating
the accuracy of such a statistic.
• The PPV and NPV are not intrinsic to the test; they depend also on the
prevalence. The PPV can be derived using Bayes' theorem.

KING’S COLLEGE CRITERIA
• The most widely accepted prognostic tool for pts who present with ALF. They
were developed through a retrospective analysis of 588 consecutive pts with
ALF who were admitted to the King's College Hospital Liver Unit between 1973
and 1987. [1]
• Although fulfillment of these criteria has a high specificity for mortality, the
sensitivity and negative predictive value remain low. Therefore, not fulfilling
the criteria does not ensure survival. [2,3,4,5,6]
• The King's College Criteria has a sensitivity of 68%-69% and a specificity of
82%-92%. [7]
• Although the King's College criteria have been validated in adult cohorts with
ALF, data suggest they may not reliably predict outcomes in the pediatric
population. [8]
1. O'Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:339-345
2. Pauwels A, Mostefa-Kara N, Florent C, et al. Emergency liver transplantation for acute liver failure. Evaluation of London and Clichy criteria. J Hepatol. 1993;17:124-127.
3. Anand AC, Nightingale P, Neuberger JM. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King's criteria. J Hepatol. 1997;26:62-68
4. Shakil AO, Kramer D, Mazariegos GV, et al. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria. Liver Transpl. 2000;6:163-169
5. Bailey B, Amre DK, Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003;31:299-305
6. McPhail MJ, Wendon JA, Bernal W. Meta-analysis of performance of Kings's College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure. J Hepatol. 2010;53:492-499
7. American Association for the Study of Liver Diseases. AASLD position paper: the management of acute liver failure: update 2011. November 2011.
8. Sundaram V, Shneider BL, Dhawan A, et al. King's College Hospital Criteria for non-acetaminophen induced acute liver failure in an international cohort of children. J Pediatr. 2013;162:319-323.e1

Hepatotropic Viruses
• All of the commonly recognized hepatotropic viruses—hepatitis A virus
(HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus
(HDV), and hepatitis E virus (HEV)—have been reported to cause ALF,
although the relative risk of ALF in acute infection—the clinical course
of ALF—and prognosis differs significantly.

Acute Liver Failure Due to Hepatotropic Viruses:
Comparison of Clinical and Diagnostic Features
Zakim n Boyer

Hepatitis A
• Acute infection with HAV remains an important cause of ALF because of
its worldwide distribution but is uncommon in the US.
• The risk of ALF after acute HAV infection ranges between 0.01% and 0.1%
and is higher in older pts and in pts living in or traveling to endemic areas.
• ALF due to HAV is diagnosed by the presence of IgM antibodies, which are
present in 95% of cases.

• The temporal pattern of ALF in acute hepatitis A is usually hyperacute,
with only very rare subfulminant cases reported.
• Accordingly, spontaneous survival among pts with ALF due to HAV is
relatively high (40-60%) as compared with that among pts with ALF
caused by HBV or cryptogenic ALF.
• Acute hepatitis A is more likely to progress to ALF in pts >40 yrs, with a
history of homosexuality or iv drug abuse and with underlying CHB or
hepatitis C, or ALD.
• LT for HAV-induced ALF may uncommonly result in recurrence of hepatitis in the graft, suggesting that
HAV immunoglobulin should be administered in such pts.
Hepatitis A
Viral hepatitis A- (and E-) related acute liver failure must be treated with supportive
care as no virus-specific treatment has proven to be effective (III). AASLD 2011

Hepatitis B
• The absolute risk of ALF after acute HBV infection is approximately 1%.
• Women and older pts may be at greater risk of ALF from HBV.
• Recent series from the US have shown a marked reduction in HBV-induced ALF, comprising only 10% of
cases, perhaps due to successful vaccination programs.
• In areas of the world endemic for HBV, viral superinfection of chronic HBV
carriers with HCV, HDV, or a cryptic viral agent may be the MC cause of
ALF.
• Preexisting hepatitis B surface antigen carriage greatly increases the risk
of ALF after superinfection by other viruses, including the δ agent,
especially in areas where HBV is endemic.
• The overall spontaneous survival rate after HBV-induced ALF is poor,
ranging between 15% and 36%.

• The diagnosis of HBV in ALF is frequently hampered by a vigorous
immunologic response, which rapidly clears the virus.
• Consequently, serum hepatitis B surface antigen, hepatitis B e antigen,
and HBV DNA may be absent in ALF.
• Because hepatitis B surface antigen may clear in as many as 30% to 50%
of ALF pts within a few days of the onset of illness, the diagnosis of acute
HBV often relies on detection of indirect serologic evidence of infection
(IgM anti–hepatitis B core antigen and/or anti–hepatitis B surface
antigen).
• ALF occasionally follows withdrawal of immunosuppression or
chemotherapy(esp rituximab) in pts with chronic HBV infection.
Hepatitis B
Nucleos(t)ide analogues should be considered for hepatitis B-associated ALF and for
prevention of post-transplant recurrence (III). AASLD 2011

Hepatitis D
• HDV (the δ agent) is an adventitious RNA virus that requires concomitant
HBV infection to complete its life cycle.
• HDV and HBV are acquired by similar parenteral means, and may infect a
pt simultaneously with HBV (coinfection) or may superinfect a pt with
preexisting HBV infection (superinfection); both forms of HDV infection
frequently lead to ALF.
• Although both coinfection and superinfection with HDV increase the risk
of ALF in hepatitis B by twofold to fivefold, the risk appears to be highest
in superinfected individuals (acute mortality 1-10% and 5-20%,
respectively) in whom the replicative machinery of HBV is well established.

Hepatitis C
• Whether HCV independently causes ALF remains controversial.
• Most series from centers in Western nations report few or no cases of
ALF attributable to HCV as the sole cause.
• In contrast, studies from Japan have detected HCV markers (antibody
and/or RNA) in as many as 50% of non-A and non-B cases of ALF.

Hepatitis E
• HEV, a single-stranded RNA virus, has been identified as the agent
responsible for enterically transmitted epidemic hepatitis.
• Infection with HEV occurs almost exclusively in developing nations and
only rarely in the West, usually in émigrés or travelers from endemic
areas.
• Endemic areas of HEV infection include parts of northern Africa and
southern Asia, where HEV is one of the two MC causes of ALF after HBV.
• Young adults and pregnant women appear to be particularly vulnerable
to ALF after acute HEV infection, the latter usually presenting in their
third trimester. In such cases the overall mortality approaches 20%.
Viral hepatitis A- (and E-) related acute liver failure must be treated with supportive
care as no virus-specific treatment has proven to be effective (III). AASLD 2011

Non–Hepatitis A-E Viruses
• Other studies have attempted to identify non–hepatitis A-E viruses in
patients with ALF of indeterminate cause.
• Putative agents have included togavirus, paramyxovirus, human
papilloma virus 6, GB virus C.
Toga: rubella, chikungunya; RNA
Paramyxo: rsv, mumps, measles;. RNA
Hpv6: anogenital wart, mouth n
laryngeal papillomas; DNA
Gbc c: hepatitis g ; occurs in hiv; RNA

Other Viral Infections
• All members of the herpesvirus family have been anecdotally
incriminated in ALF, usually in neonates and immunocompromised adults,
including posttransplant patients.
• The clinical presentation of ALF due to varicella-zoster virus infection
usually involves a vesicular rash, which may be delayed in comparison
with abdominal symptoms.
• Similarly, herpes simplex virus hepatitis can present as part of a
disseminated infection including mucocutaneous vesicles, ALF,
disseminated intravascular coagulation, and death.
• Other reports emphasize the absence of systemic clues except for fever.

Prognosis: Clichy criteria
• Based on a French prospective study of pts presenting with acute viral hepatitis, in
which pts identified as having the lowest survival without LT included those with
HE and low factor V levels. [1]
• These criteria predicted mortality with a positive predictive value of 82% and
negative predictive value of 98% in this cohort.
• However, subsequent studies have reported much lower predictive values which
were inferior to the King's College Criteria in other populations, including APAP
and non-APAP ALF. [2,3]
Presence of hepatic encephalopathy and factor V level:
<20% of normal in patients <30 years of age, or
<30% of normal in patients >30 years of age.
1. Bernuau J, Samuel D, Durand F, et al. Criteria for emergency liver transplantation in patients with acute viral hepatitis and factor V below 50% of normal: a prospective study. Hepatology.
1991;14:49A.
2. Pauwels A, Mostefa-Kara N, Florent C, et al. Emergency liver transplantation for acute liver failure. Evaluation of London and Clichy criteria. J Hepatol. 1993;17:124-127
3. Izumi S, Langley PG, Wendon J, et al. Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure. Hepatology. 1996;23:1507-1511

Mushroom poisoning
• ALF from ingestion of the mushrooms of the genus Amanita (A. phalloides,
A. verna, and A. virosa) occurs occasionally in Europe (50-100 fatal cases
/yr) but rarely in the US), with < 100 fatal cases between 1900- 1994.
• Three medium sized mushrooms (50 g) contain sufficient toxin, α-amanitin
and phalloidin, to cause ALF; the toxins are heat stable and not degraded
by cooking.
• The phallotoxin causes damage to the enterocyte cell membrane [1].
• The a-amanintin toxin (amatoxin) is dose dependent and responsible for
hepatic injury by disrupting hepatocyte messenger RNA synthesis [2,3].
1. Escudie L, Francoz C, Vinel JP, et al. Amanita phalloides poisoning: reassessment of prognostic factors and indications for emergency liver transplantation. J Hepatol 2007;46:466–73.
2. Erguven M, Yilmaz O, Deveci M, et al.Mushroom poisoning. Indian J Pediatr 2007;74:847–52.
3. Scheurlen C, Spannbrucker N, Spengler U, et al. Amanita phalloides intoxications in a family of russian immigrants. Case reports and review of the literature with a focus on orthotopic liver transplantation. Z Gastroenterol
1994;32:399–404.

Mushroom Poisoning: Course of poisoning
• Following ingestion, a 6–12-hour asymptomatic phase evolves into three
clinical phases.
• The gastrointestinal phase (phase 1; 12–24 hours), consists of diarrhea,
vomiting, and abdominal pain.
• During the hepatotoxic phase (phase 2: 24–48 hours) signs of liver
damage occur and the disease may progress to the third clinical phase
(4– 7 days), during which ALF, hepatorenal syndrome, hemorrhage,
convulsions, coma, and death occur [1].
• Mortality approaches 10–30% [2,3,4].
1. Enjalbert F, Rapior S, Nouguier-Soule J, et al. Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 2002;40:715–57.
2. Escudie L, Francoz C, Vinel JP, et al. Amanita phalloides poisoning: reassessment of prognostic factors and indications for emergency liver transplantation. J Hepatol 2007;46:466–73.
3. Ganzert M, Felgenhauer N, Zilker T. Reassessment of predictors of fatal outcome in amatoxin poisoning: some critical comments. J Hepatol 2007;47:424–5.
4. GanzertM, Felgenhauer N, Zilker T. Indication of liver transplantation following amatoxin intoxication. J Hepatol 2005;42:202–9.

Mushroom Poisoning
• A combination of penicillin (300,000-1,000,000 U/kg/day, or 250
mg/kg/day iv) and silibinin (20-50 mg/ kg/day iv) has been used as a
specific antidote in those with evidence of liver injury due to Amanita
poisoning.
• These agents are hypothesized to interrupt the enterohepatic circulation of toxins and also to compete
at the hepatocyte membrane for transmembrane transport.
• Because of the rarity of this cause of ALF, the benefits of this regimen remain unproven.
In ALF pts with known or suspected mushroom poisoning, consider administration of
penicillin G and N-acetylcysteine (III). AASLD 2011
Pts with ALF secondary to mushroom poisoning should be listed for transplantation, as
this procedure is often the only lifesaving option (III).AASLD 2011

Other direct hepatotoxins
• A mitochondrial toxin isolated from the foodborne pathogen Bacillus
cereus was also incriminated in a case of ALF in which an autopsy of
the liver showed microvesicular steatosis.
• ALF caused by herbal remedies has been reported with increasing
frequency, and all pts with ALF should be specifically queried about
ingestion of alternative medicines.

Metabolic Causes of Acute Liver Failure: AWD
• Acute Wilson disease, a rare presentation of the autosomal recessive
defect in canalicular copper transport, accounts for approx 3% of ALF
cases in the U.S.ALFailure Study Group registry and is classically difficult
to diagnose.
• The diagnosis of WD-ALF is crucial because it carries a nearly 100%
mortality without LT[1,2].
• DX in the setting of ALF is more difficult.
• Measures of CU metabolism are also of limited value since elevated urinary CU and
alterations in S. CU can be seen in ALF due to other causes [130].
• S. ceruloplasmin is N in up to 15% of WD-ALF cases, and low ceruloplasmin levels
can be seen in ALF from other causes.
• K–F rings are absent in up to 50%.
1. Schiodt FV, Atillasoy E, Shakil AO, et al. Etiology and outcome for 295 patients with acute liver failure in the United States. Liver Transpl Surg 1999;5:29–34.
2. McCullough AJ, Fleming CR, Thistle JL, et al. Diagnosis of Wilson’s disease presenting as fulminant hepatic failure. Gastroenterology 1983;84:161–7.

WD-ALF
• Most pts with WD-ALF will present between the 1ST and 4TH decades,
although both younger/older presentations have been reported.
• WD-ALF is often accompanied by a Coombs-negative hemolytic anemia,
severe hyperbilirubinemia, moderate elevations in AT (<500 IU/L),
hypouricemia and high serum and urinary Cu concentration [1].
• WD-ALF should be strongly considered in the setting of a N to low S alk
PO4 level, an alkPO4/T Bilirubin ratio of <2.0, or an AST /ALT ratio of
>2.0–3.0 [2,3,4,5,6].
1. McCullough AJ, Fleming CR, Thistle JL, et al. Diagnosis of Wilson’s disease presenting as fulminant hepatic failure. Gastroenterology 1983;84:161–7.
2. Eisenbach C, Sieg O, Stremmel W, et al. Diagnostic criteria for acute liver failure due to Wilson disease. World J Gastroenterol 2007;13:1711–14.
3. Emre S, Atillasoy EO, Ozdemir S, et al. Orthotopic liver transplantation for Wilson’s disease: a single-center experience. Transplantation 2001;72:1232–6.
4. Sallie R, Katsiyiannakis L, Baldwin D, et al. Failure of simple biochemical indexes to reliably differentiate fulminant Wilson’s disease from other causes of fulminant liver failure. Hepatology 1992;16:1206–
11.
5. Shaver WA, Bhatt H, Combes B. Low serum alkaline phosphatase activity in Wilson’s disease. Hepatology 1986;6:859–63.
6. Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008;48:1167–74.

• The usual therapies of penicillamine or trientine are ineffective in
acute liver failure and are not recommended.
• Albumin dialysis, CRRT, plasmapheresis or plasma exchange can be
initiated to remove copper and alleviate renal tubular damage until a
graft becomes available [1] .
Patients in whom Wilson disease is the likely cause of acute liver failure must be
promptly considered for liver transplantation (III). AASLD 2011
WD-ALF
1. Roberts EA , Schilsky ML . Diagnosis and treatment of Wilson disease: an update . Hepatology 2008 ; 47 : 2089 – 2111 .

Other Metabolic Causes of Acute Liver Failure
• Reye syndrome, a disorder of hepatocyte mitochondrial metabolism, has
become an extremely rare cause of ALF in the US, with no more than 2
cases/yr reported to the CDC and Prevention between 1994-1997.
• Reye syndrome usually presents in children with an influenza-like viral
prodrome and a history of salicylate ingestion and is followed by
encephalopathy, cerebral edema, and frequently death.
• Liver biopsy shows characteristic microvesicular steatosis with little
necrosis, reflecting mitochondrial injury, which impairs both urea cycle
disposal of ammonium and β-oxidation of fatty acids.
• Other metabolic causes in neonates or children include galactosemia,
fructosemia, tyrosinemia, α1-ATdeficiency, and Niemann-Pick disease Tb.

Autoimmune Acute Liver Failure
• Autoimmune hepatitis has been reported to present as autoimmune ALF
in 5% of cases. It is not clear that classically defined AIH and autoimmune ALF
represent the same disease entity.
• The presence of other autoimmune disorders in a pt presenting with ALF
should raise suspicion of AIH as the aetiology.
• These pts often have an elevated globulin fraction and positive
autoantibodies, but these may also be absent in a proportion of cases.
• Equally however, mildly positive autoantibodies may be seen in a variety of aetiologies,
and it should not be assumed that autoimmune disease is the primary driver of the
liver injury.
Patients with coagulopathy and mild HE due to AIH may be considered for
corticosteroid treatment (prednisone, 40-60 mg/day) (III). AASLD 2011

• Liver biopsy may be required to determine the diagnosis.
• A histologic hallmark of autoimmune ALF is central perivenulitis, often with a plasma
cell–rich inflammatory infiltrate.
• Treatment with steroids may be effective if given early. [EASL]
• In the context of ALF, however, steroids are often ineffective and potentially
deleterious, as they may favour septic complications .
• Whether the early administration of corticosteroids improves outcome in
autoimmune ALF remains unproven; a recent retrospective analysis of
nonrandomized pts with AI ALF in the U.S.ALF SGroup registry found no benefit.
[ZAKIM/BOYER]
• Thus, a lack of improvement within 7 days should lead to listing for emergency LT
without delay.
Autoimmune Acute Liver Failure
Liver biopsy is recommended when AIH is suspected as the cause of ALF, and
autoantibodies are negative (III). AASLD 2011
Pts with AIH should be considered for LT even while steroids are being administered
(III). AASLD 2011

Pregnancy Related: ALF
• There are two hepatic emergencies which occur in the 3rd trimester of
pregnancy: haemolysis, elevated liver enzymes and low platelets (HELLP)
syndrome and acute fatty liver of pregnancy (AFLP).
• AFLP is characterised by extensive hepatic steatosis and usually presents
with abdominal pain and malaise.
• Transaminases are relatively low. Hypoglycaemia is common, Other organ
failures occur, including pancreatitis [1,2,3].
• Maternal mortality is around 20%.
1. Ichai P, Roque Afonso AM, Sebagh M, Gonzalez ME, Codes L, Azoulay D, et al. Herpes simplex virus-associated acute liver failure: a difficult diagnosis with a poor prognosis. Liver Transpl 2005;11:1550–1555.
2. Westbrook RH, Yeoman AD, Joshi D, Heaton ND, Quaglia A, O’Grady JG, et al. Outcomes of severe pregnancy-related liver disease: refining the role of transplantation. Am J Transplant 2010;10:2520–2526.
3. Holt EW, Guy J, Gordon SM, Hofmann JC, Garcia-Kennedy R, Steady SL, et al. Acute liver failure caused by herpes simplex virus in a pregnant patient: is there a potential role for therapeutic plasma
exchange? J Clin Apher 2013;28:426–429.

• Prompt delivery of the baby in both these emergency scenarios offers a
good outcome, and emergency LTx is rarely needed.
• Persistent elevation of lactate levels in the presence of severe HE
potentially best identifies patients at greatest risk of death or LTx.
• For acute fatty liver of pregnancy or the Hemolysis, Elevated Liver Enzymes, Low
Platelets (HELLP) syndrome, expeditious delivery of the infant is recommended.
• Transplantation may need to be considered if hepatic failure does not resolve
quickly following delivery (III). AASLD 2011
Pregnancy Related: ALF

Hypoxic liver injury
• Hepatic hypoxia, due to decreased hepatic blood flow, can lead to acute
hepatic necrosis and at times ALF [1].
• The MC form of hypoxic liver injury is hypoxic hepatopathy (“shock liver”) seen
after episodes of systemic hypotension or a low blood flow state [2].
• Clinically, AT rapidly increase, sometimes >10,000 IU/L, followed by rapid
resolution. Shock liver may be accompanied by mild coagulopathy and occurs in
about 1% of critically ill pts [3].
• The prognosis depends upon the pt’s underlying disease state, and shock liver is
rarely fatal.
• Severe vascular obstruction is more likely to lead to ALF and death. These
conditions include Budd–Chiari syndrome, sinusoidal obstruction syndrome
(venoocclusive disease) due to medications or herbs, and malignancies
involving the liver (i.e., lymphoma) [4].
1. Schiodt FV, Atillasoy E, Shakil AO, et al. Etiology and outcome for 295 patients with acute liver failure in the United States. Liver Transpl Surg 1999;5:29–34.
2. Birrer R, Takuda Y, Takara T. Hypoxic hepatopathy: pathophysiology and prognosis. Intern Med 2007;46:1063–70.
3. Henrion J. Hypoxic hepatitis: the point of view of the clinician. Acta Gastroenterol Belg 2007;70:214–16.
4. Segev DL, Nguyen GC, Locke JE, et al. Twenty years of liver transplantation for Budd–Chiari syndrome: a national registry analysis. Liver Transpl 2007;13:1285–94.

ALF induced by hemi-hepatectomy
• Extensive loss of liver parenchyma after resection of the liver can
provoke ALF.
• Most pts will recovery spontaneously if resection is performed in the
absence of an advanced liver disease.
• It is not an accepted indication for emergency LTx.
• However, emergency LTx has been reported in cases of ALF induced by
living donor liver graft failure [1].
1. Paugam-Burtz C, Wendon J, Belghiti J, Mantz J. Case scenario: postoperative liver failure after liver resection in a cirrhotic patient. Anesthesiology 2012;116:705–711.
Following extensive liver resection, patients with or without underlying CLD, may develop a clinical
syndrome of jaundice, coagulopathy and HE. The presentation is very similar to that of a posttransplant
‘‘small for size syndrome” scenario. These syndromes are not considered within the scope of ALF, but
do feature in some ALF databases, such as the European Liver Transplant Registry (ELTR).
Extensive liver trauma is also included in ALF databases, but is not a cause of ALF unless there is loss of
both venous and arterial inflows. [EASL 2017]

SHERLOCK’S
Suggested algorithm for diagnosis and treatment of
the patient with ALF.

ACUTE LIVER FAILURE: PATHOGENESIS
• Cardiovascular Consequences
• Pulmonary Consequences
• Renal and Electrolyte Disturbances
• Hematologic Disturbances
• Breakdown of Host Immune Defenses
• Gastrointestinal Consequences
• Neurologic Consequences
• Failure of Hepatobiliary Excretion
• Failure to Metabolize Toxic Substances
• Failure of Intermediary Metabolism
• Failure of Biosynthetic Function of the Liver
Failure of Liver Function
Effects of ALF on Extrahepatic Systems

ACUTE LIVER FAILURE: PATHOGENESIS

ALF: Failure of Liver Function
Failure of Hepatobiliary Excretion
• Notable impairment in hepatobiliary excretory fn results in
hyperbilirubinemia and jaundice.
• The degree of hyperbilirubinemia is accentuated if hemolysis co-exists,
which may result from the oxidant stress associated with the cause of ALF,
or to ALF itself.
• For example, pts with ALF due to Wilson disease, which is often
accompanied by hemolytic anemia, experience marked
hyperbilirubinemia.
JAUNDICEFailure of Hepatobiliary Excretion

Failure to Metabolize Toxic Substances
• The increase in serum ammonia levels with ALF is primarily due to the
failure of the liver to convert ammonia to urea via the urea cycle, and has
been implicated in the pathogenesis of HE and intracranial HTN.
• Most drugs undergo some degree of hepatic modification, and because
ALF impairs drug metabolism, their biologic half-life increases. Other
sources of altered drug and drug metabolite disposal include alteration
volume of distribution, and intravascular protein binding, and renal failure.
These changes in pharmacokinetics enhance the probability of drug
toxicity or worsened liver injury.
• Therefore the use of all medications in the setting of ALF must be carefully
considered in terms of necessity, dosage, and toxicity.
HYPERAMMONIA

Sources and metabolic fate of NH3 & glutamine in ALF
• The primary source of ammonia is the gut, which
under normal conditions is cleared by urea (major
pathway) and glutamine (minor pathway)
synthesis in the liver.
• Hepatocellular insufficiency in ALF results in the
accumulation of ammonia in peripheral tissues,
particularly brain and muscle, which detoxify
ammonia by synthesizing glutamine from
glutamate.
• In turn, glutamine released into blood is taken up
by the intestines, liberating ammonia, or cleared by
the kidneys.
• The capacity of renal excretion of glutamine in ALF
is adversely affected by renal dysfunction.
(From Vaquero J, Chung C, Cahil M, Blei AT. Pathogenesis of hepatic encephalopathy in acute liver failure. Semin
Liver Dis 2003;23:259–269.)
Zakin/boyer

Failure of Intermediary Metabolism
Hypoglycemia
• decreased glycogen stores
• decreased ability to mobilize glycogen
• decreased gluconeogenesis within the liver
Serum concentrations of free fatty acids increase in ALF, resulting in a decrease in
acetoacetate/3-s-hydroxybutryate (arterial ketone body ratio), which may
contribute to hepatic encephalopathy.
ALF is also associated with negative nitrogen balance, which results from the
enhanced catabolism of proteins, including muscle proteins.

Metabolic Consequences of ALF
Zakin/boyer

Failure of Biosynthetic Function of the Liver
• The two most clinically relevant synthetic products of the liver include
albumin and coagulation factors.
• Albumin has a half-life of 15-20 days; consequently, serum concentrations
decrease relatively late in the course of ALF.
• As part of the definition of ALF, elevated INR exists universally, but its
significance in terms of predicting a bleeding diathesis remains unproven.
• Plasma activities of factors synthesized in the liver (factors II, V, VII, IX, and
X), are reduced in all pts with ALF, as are liver-derived proteins involved in
fibrinolysis.
COAGULATION ABNORMALITIES

Model of rebalanced hemostasis in ALF
ZAKIM N BOYER
Despite a high INR and thrombocytopenia, the
three phases of hemostasis depicted on the left
(primary hemostasis, coagulation, and
fibrinolysis) remain generally rebalanced or
favor hypercoagulability.
Mechanisms compensating for the primary liver
synthetic failure appear to be triggered by the
cytokine storm, driving endothelial cell and
platelet activation.
Finally, fibrinolysis is markedly impaired in ALF,
such that clot lysis is frequently absent in vitro,
which may also be ascribed to decreased levels
of liver-derived and increased levels of
endothelial cell–derived regulatory proteins.
TAFI, Thrombin activatable fibrinolysis inhibitor; t-PA, tissue plasminogen activator

Notes :
• Despite a high INR and thrombocytopenia, the three phases of hemostasis
depicted on the left (primary hemostasis, coagulation, and fibrinolysis) remain
generally rebalanced or favor hypercoagulability.
• Mechanisms compensating for the primary liver synthetic failure appear to be
triggered by the cytokine storm, driving endothelial cell and platelet activation.
• Thrombocytopenia is thus compensated for by the production of prohemostatic
microparticles and endothelial cell activation, increasing the level of
vWillebrand factor increasing platelet adherence and aggregation.
• Deficiency of liver-derived procoagulant factors is rebalanced by deficiency of
anticoagulant proteins C and S and antithrombin (AT) as well as increased factor
VIII release from endothelial cells, which may compensate for low levels of
factors V and VI.
• Finally, fibrinolysis is markedly impaired in ALF, such that clot lysis is frequently
absent in vitro, which may also be ascribed to decreased levels of liver-derived
and increased levels of endothelial cell–derived regulatory proteins.
• TAFI, Thrombin activatable fibrinolysis inhibitor; t-PA, tissue plasminogen activator

ACUTE LIVER FAILURE: PATHOPHYSIOLOGY
• Cardiovascular Consequences
• Pulmonary Consequences
• Renal and Electrolyte Disturbances
• Hematologic Disturbances
• Breakdown of Host Immune Defenses
• Gastrointestinal Consequences
• Neurologic Consequences
Effects of ALF on Extrahepatic Systems

ALF: Effects of ALF on Extrahepatic Systems
Neurologic Consequences
• By definition, neurologic dysfunction follows liver injury in pts with ALF,
but differs in several important aspects to pts with cirrhosis.
Seizures and agitation frequently complicate the HE of ALF, but occur
rarely in pts with cirrhosis.
Most importantly, pts with ALF develop cerebral edema and intracranial
hypertension, significant degrees of which generally do not occur in pts
with cirrhosis.

Hepatic encephalopathy and cerebral edema
• HE is a reversible neuropsychiatric syndrome of metabolic disturbance
and depressed consciousness that develops following liver failure.
• Symptoms range from subclinical alterations to deep coma.
• The complete pathophysiology of HE remains poorly understood and is likely
multifactorial.
• Accumulation of toxins in ALF, particularly ammonia, in the CSF has been
postulated as the predominant mechanism of HE [1,2,3,4].
• Serum accumulation of ammonia is further exacerbated by renal failure
and impaired skeletal muscle function [5].
1. Bernal W, Hall C, Karvellas CJ, et al. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 2007;46:1844–52.
2. Bhatia V, Singh R, Acharya SK. Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut 2006;55:98–104.
3. Belanger M, Butterworth RF. Acute liver failure: a critical appraisal of available animal models. Metab Brain Dis 2005;20: 409–23.
4. Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 2002;17:221–7.
5. Wendon J, Lee W. Encephalopathy and cerebral edema in the setting of acute liver failure: pathogenesis and management. Neurocrit Care 2008;9:97–102.

Clinical Stages of HE in ALF (West Haven Criteria (WHC),
also known as the Conn score)

Sources and metabolic fate of ammonia and
glutamine in ALF
• The primary source of ammonia is the gut, which
under normal conditions is cleared by urea (major
pathway) and glutamine (minor pathway) synthesis
in the liver.
• Hepatocellular insufficiency in ALF results in the
accumulation of ammonia in peripheral tissues,
particularly brain and muscle, which detoxify
ammonia by synthesizing glutamine from glutamate.
• In turn, glutamine released into blood is taken up by
the intestines, liberating ammonia, or cleared by the
kidneys.
• The capacity of renal excretion of glutamine in ALF is
adversely affected by renal dysfunction, which
often accompanies ALF.
(From Vaquero J, Chung C, Cahil M, Blei AT. Pathogenesis of hepatic encephalopathy in acute liver failure. Semin
Liver Dis 2003;23:259–269.)
Zakin/boyer

Astrocyte swelling in the pathogenesis of cerebral edema in
ALF: mechanisms of cell swelling and compensation.
Intracerebral concentrations of ammonia are
detoxified by the amidation of glutamate to
glutamine, a reaction catalyzed by glutamine
synthetase.
Glutamine, an osmotically active solute,
increases astrocyte cell volume, which may be
attenuated by two mechanisms, exporting ions
(minor pathway) or organic osmolytes (major
pathway).
Zakin/boyer

Cerebral Edema
• Astrocyte swelling results from an increase in intracellular osmolarity
(cytotoxic edema), which ensues with the accumulation of glutamine, in
turn derived by the addition of ammonia to glutamate via glutamine
synthetase.
Neurons normally adapt to increased intracellular osmolarity and cell volume by
increasing export of endogenous organic osmolytes such as myoinositol.
The compensation of accumulating glutamine by exporting endogenous osmolytes
from astrocytes also explains why patients with HALF frequently develop CE while
those with SALF are relatively protected because pts with the former condition appear
not to have time for compensation to occur.

Intracranial Hypertension and Cerebral Edema
• The adult cranium is a rigid compartment with low compliance.
• Increased blood volume (cerebral hyperemia) and cerebral swelling
(edema) quickly result in intracranial HTN.
• ALF results in “compromised” autoregulation: the normal response of
cerebral blood flow to remain constant during variation in MAP.
• Furthermore, regional variation in blood flow results in hyperperfusion of some areas and hypoperfusion of others,
resulting in cerebral ischemia.
• Disruption of the blood–brain barrier allows toxins to more freely enter the CSF [1,2].
• The development of the SIRS is a/w progression of HE in ALF, as the weakened blood–
brain barrier allows an influx of inflammatory cytokines [3,4].
1. Wendon J, Lee W. Encephalopathy and cerebral edema in the setting of acute liver failure: pathogenesis and management. Neurocrit Care 2008;9:97–102.
2. Bernal W, Hall C, Karvellas CJ, et al. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 2007;46:1844–52.
3. Rolando N, Wade J, Davalos M, et al. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000; 32(4):734–9.
4. Jalan R, Rose C. Hypothermia in acute liver failure. Metab Brain Dis 2004;19:215–21.

• In addition, the disturbance of central pathways (i.e., glutamatergic,
serotonergic, noradrenegeric), activation of G–aminobutyric acid (GABA)
receptors, production of false neurotransmitters, and altered cerebral
energy metabolism likely contribute [1].
1. Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 2002;17:221–7.
Hepatc encephalopathy and cerebral edema

Altered neurotransmitter system
• The two neurotransmitter systems that appear to be most adversely
affected in ALF are the γ-aminobutyric acid (GABA) and the glutamatergic
systems.
• Increased circulating endogenous ligands for GABA receptors have been
detected in pts with ALF, and ammonia increases the affinity of such
ligands for this receptor.
• Intracellular concentrations of glutamate, the major excitatory
neurotransmitter of the brain, are decreased in ALF.
• Diminished glutamate concentrations probably result from increased
consumption rather than decreased production because glutamate is used
to detoxify ammonia within astrocytes.

HE, Cerebral Edema & Intracranial Hypertension
• Complete neurologic recovery usually follows normalization of liver
function whether spontaneous or following LT.
• However, severe cerebral ischemia, which results from cerebral edema,
intracranial HTN, or arterial hypotension with hypoperfusion may
result in permanent neurologic disability.
• Risk factors for developing CE in pts with ALF include hyperacute
compared with SALF, S ammonia concentrations >150-200 μmol/L,
and high-grade HE(Grade 3 or Grade 4), although the relationship
between ammonia concentration and ICP is not linear.
• The need for vasopressors and RRT and the presence of infection
and/or SIRS also predict the progression of HE and cerebral edema.

Management : AASLD 2011
• Intracranial pressure (ICP) monitoring is recommended in ALF pts with
high grade HE, in centers with expertise in ICP monitoring, in pts
awaiting and undergoing LT (III).
• In the absence of ICP monitoring, frequent (hourly) neurological
evaluation is recommended to identify early evidence of intracranial
hypertension (III).
• In early stages of HE, lactulose may be used either orally or rectally to
effect a bowel purge, but should not be administered to the point of
diarrhea, and may interfere with the surgical field by increasing bowel
distention during LT (III).

• Pts who progress to high-grade HE (grade III or IV) should undergo
endotracheal intubation (III).
• In the event of intracranial HTN, a mannitol bolus (0.5-1.0 gm/kg body
weight) is recommended as first-line therapy; however, the prophylactic
administration of mannitol is not recommended (II-2).
• In ALF pts at highest risk for cerebral edema (S ammonia >150 μM, grade
3/4 HE, acute renal failure, requiring vasopressors to maintain MAP), the
prophylactic induction of hypernatremia with hypertonic saline to a
sodium level of 145-155 mEq/L is recommended (I).

• Short-acting barbiturates and the induction of hypothermia to a core
body temperature of 34-35°C may be considered for intracranial HTN
refractory to osmotic agents as a bridge to LT(II-3).
• Seizure activity should be treated with phenytoin and benzodiazepines
with short half-lives. Prophylactic phenytoin is not recommended (III).
• Corticosteroids should not be used to control elevated intracranial
pressure in pts with ALF (I).

• First-line therapy includes increasing blood osmolality with mannitol
boluses (0.5 to 1 g/kg body weight), which draws water from swollen
astrocytes back into the intravascular space.
• However, mannitol is ineffective in returning ICP to an acceptably low
level (<25 mm Hg) in individuals with severe intracranial HTN (>40-60
mm Hg), and initial improvements in ICP usually wane, necessitating
multiple doses, which can result in hyperosmolality (>320 mOsm/L).
• Mannitol will transiently expand circulating blood volume and increase
CVP, as well as ICP.
• In pts with renal failure this may result in a paradoxical increase in ICP.
• Ultimately, mannitol administration may bridge a pt with ALF to OLT but
does not provide definitive therapy.
Management : USE OF MANNITOL

Management of Cerebral Edema in ALF: SUMMARY
Zakin/boyer

Cardiovascular Consequences
• The initial CV hallmark of ALF is a hyperdynamic state, characterized by an increased
CO and decreased SVR.
Final Stage
Hemodynamic Collapse
Falling CO
Peripheral Vasodilation
• MAP is maintained by the increase in CO in early ALF but drops once CO succumbs
to intravascular volume depletion, arrhythmias, or myocardial depression.
Tissue hypoxia at the microcirculatory
level is frequent with consequent lactic
acidosis.

Cardiovascular Derangements: management
• ALF dramatically alters systemic hemodynamics, with the primary hemodynamic abnormality being
systemic arterial vasodilation due to reduced precapillary sphincter tone, similarly to sepsis.
• Volume status in a hypotensive pt with ALF can be difficult to assess.
• A normal saline challenge guided by changes in CVP should be administered
before vasopressors are considered.
• In hypotensive pts who do not respond to volume resuscitation, vasopressors
should be titrated to achieve a MAP of >75 mm Hg and cerebral perfusion
pressure (CPP) of 60-80 mm Hg.
• Vasopressin and its analogues potentiate the vasoconstricting effect of
norepinephrine, allowing reduction in the infusion rate of norepinephrine, but
controversy about its potential to increase ICP in pts with ALF replaces it to a
secondary role.
• Persistently hypotensive pts with ALF despite use of vasopressors should be
evaluated for adrenal insufficiency, which occurs frequently in pts with ALF
and correlates with the severity of illness.

Pulmonary Consequences
• As ICP rises, hyperventilation often progresses, and the development of sudden, severe
hyperventilation may precede sudden respiratory arrest.
Initial pulmonary presentation of ALF Central hyperventilation with a respiratory alkalosis
• V/P mismatch within the lungs
• Volume overload
• Left ventricular failure
• Intrapulmonary arteriovenous shunting,
• Increased pulmonary capillary permeability
• Pneumonia
Initially, oxygenation is relatively
preserved in pts with ALF, but
progressive hypoxemia supervenes
• Pulmonary edema in the presence of a normal pulmonary capillary wedge pressure suggests the
development of ARDS, which can also emerge as the pulmonary component of the SIRS.

Pulmonary Complications and Ventilatory Support
• A major decision in the treatment of a pt with ALF is the timing of
endotracheal intubation.
• The indications for intubation include airway protection, provision of
respiratory support, and management of intracranial hypertension.
• A less quantifiable indication is extreme agitation, which risks
exacerbating intracranial HTN. The airway should be secured by
endotracheal intubation after Grade 3 HE has been reached.
• For neuromuscular blockade, the nondepolarizing agent cisatracurium
may be preferable to the depolarizing agent succinylcholine, which
causes muscle contraction, which in turn increases ICP.
• Metabolism of cisatracurium is also independent of renal and hepatic function.
Patients who progress to high-grade hepatic encephalopathy (grade III or IV) should
undergo endotracheal intubation (III). AASLD 2011

Renal and Electrolyte Disturbances
• AKI occurs in 40% to 80% of pts with ALF, and is more common in pts
with APAP-induced ALF.
Zakin/boyer

• Severe fluid and electrolyte abnormalities always accompany ALF.
• Hyponatraemia is also relatively common in pts with ALF, especially
hyperacute cases. Free water retention occurs early, resulting in dilutional
hyponatremia, which can contribute to cerebral edema, mandating
immediate correction.
• Hypokalemia accompanies hyponatremia, due to GI losses, diuretics, and
alkalosis.
• Hypokalemic alkalosis occurs early in the course of ALF, whereas
hyperkalemic acidosis dominates the late stages.
• The former condition requires iv infusion of K, whereas the latter
mandates HD.
Renal and Electrolyte Disturbances…..continue

Extra note:
• In Alkalosis, the blood PH is too high, so inorder to counter that, the
intracellullar H ions go out of the cells into the blood, using the H-K pump,
pushing K into the cells, and as such decreasing the serum K levels (vice
versa in Acidosis)
• Each unit of packed red cells for transfusion contains approximately 3 mg
citrate. This amount of citrate is normally rapidly (within 5 minutes) cleared
from blood by the liver.
• However, among the very sick patients who require multiple units of
donated blood products, this process of liver elimination is compromised.
Additionally, of course, the citrate dose is very high.
• These two factors determine that citrate accumulates in blood of those
receiving massive transfusion where it chelates (binds to) circulating
ionized calcium, thereby reducing plasma iCa concentration.

Hyponatremia : Management
• In general, the degree of hyponatremia is proportional to the severity of liver
failure.
• Data reported that 32% of cases with paracetamol induced ALF had serum
sodium <130 mmol/L [1,2].
• There is a correlation between serum sodium and ICP. Infusion of hypertonic
saline to maintain S Na between 145-155 mmol/L compared with standard of
care resulted in reduced ICP. A decrease in vasopressor requirement was also
observed during the first 36 h of infusion [3].
• These data suggest that hyponatraemia should be avoided, and maintaining
relative hypernatraemia with infusion of hypertonic saline can prevent raised
ICP. However, S Na levels>150 mmol/L may be A/W cell damage and should be
avoided. [EASL17]
1. Schneeweiss B, Pammer J, Ratheiser K, Schneider B, Madl C, Kramer L, et al. Energy metabolism in acute hepatic failure. Gastroenterology 1993;105:1515–1521.
2. O’Riordan A, Brummell Z, Sizer E, Auzinger G, Heaton N, O’Grady JG, et al. Acute kidney injury in patients admitted to a liver intensive therapy unit with paracetamol-induced hepatotoxicity. Nephrol Dial
Transplant 2011;26:3501–3508.
3. Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2004;39:464–470.

• Fluid resuscitation and hypertonic saline infusions should be targeted to
maintain sodium at 140–145 mmol/L. [EASL17]
• Rapid change in sodium levels should also be avoided and correction
should be correlated to the rate of drop, which should not exceed 10
mmol/L per 24 h [1].
• RRT can also be utilised to correct hyponatraemia, facilitate fluid balance
and control of acidosis [2].
The target serum Na is 145-155 mmol/L, which has been a/w a reduced incidence of cerebral edema.
Judicious use of hypertonic saline may facilitate correction of hyponatremia and has not been
associated with pontine myelinolysis, in contrast to its use in pts with CLD and hyponatremia.
Once renal failure sets in, severe hyponatremia is best treated in conjunction with renal replacement
therapy. [ZAKIM N BOYER]
Hyponatremia : Management
1. Klinck J, McNeill L, Di Angelantonio E, Menon DK. Predictors and outcome impact of perioperative serum sodium changes in a high-risk population. Br J Anaesth 2015;114:615–622.
2. Bagshaw SM, Bellomo R, Devarajan P, Johnson C, Karvellas CJ, Kutsiogiannis DJ, et al. Review article: Renal support in critical illness. Can J Anaesth 2010;57:999–1013.

• Hypophosphatemia also occurs commonly, and results from a shift of
phosphate from the extracellular to the intracellular compartment in response
to glucose infusions and possibly due to use in ATP synthesis by regenerating
hepatocytes.
• Hypophosphatemia is a favourable prognostic sign and appears to be
associated with liver regeneration [1].
• In the presence of oliguric renal failure, however, hyperkalemia and
hyperphosphatemia usually develop and requires RRT.
• Finally, hypocalcemia can complicate the transfusion of large amounts of
citrated blood products.
• Hypocalcemia and hypomagnesemia may present concurrently and interfere
with the correction of hypokalemia; these abnormalities should be corrected
by iv replacement.
Renal and Electrolyte Disturbances
1. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology 2002;36:659–665.

Extra note: Mg & K
• One possible explanation is put forth in a 2007 JASN article by Huang
and Kuo. In this paper, the authors suggest that magnesium regulates
the activity of ROMK, the renal outer medullary potassium channel,
providing a rationale for how low Mg levels lead to low K levels.
ROMK is the inwardly rectifying K channel on the apical surface of the
distal nephron which is required for the backleak of K+. When there is
high intracellular Mg2+, it will block the ROMK channel pore and
prevent K+ from effluxing. Conversely, a low intracellular Mg2+ would
allow for high ROMK efflux activity and therefore result in K+ wasting.
The authors are cautious to state that additional factors (e.g., high
aldosterone levels, increased Na uptake, etc) may also be required to
result in clinically significant renal K+ losses.

Acid – base changes
• Respiratory alkalosis is due to hyperventilation, probably related to direct
stimulation of the respiratory centre by unknown toxic substances.
• Respiratory acidosis can be caused by elevated ICP and respiratory depression,
or pulmonary complications.
• Acidosis, increased circulating lactate and reduced bicarbonate are common
features in pts with hyperacute and acute ALF, and are multifactorial in
pathogenesis, with increased systemic production and reduced hepatic
clearance reported [1,2,3].
• Lactic acidosis develops in about half of the pts reaching stage 3 coma. It is related to inadequate tissue perfusion due to
hypotension and hypoxaemia.
• Both acidosis and increased lactate have been proposed as prognostic markers
in APAP induced ALF. It is likely they are also applicable in other forms of
hyperacute liver failure. RRT was utilised in the majority of pts where lactate
was identified as an additional possible prognostic marker [4], and therefore
RRT should not be discouraged when managing patients with ALF.
1. Levy B, Perez P, Gibot S, Gerard A. Increased muscle-to-serum lactate gradient predicts progression towards septic shock in septic patients. Intensive Care Med 2010;36:1703–1709.
2. Clemmesen O, Ott P, Larsen FS. Splanchnic metabolism in acute liver failure and sepsis. Curr Opin Crit Care 2004;10:152–155.
3. Murphy ND, Kodakat SK, Wendon JA, Jooste CA, Muiesan P, Rela M, et al. Liver and intestinal lactate metabolism in patients with acute hepatic failure undergoing liver transplantation. Crit Care Med
2001;29:2111–2118.
4. [130] Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002;359:558–563.

Management of Acute Kidney Injury
• The development of AKI is a marker of poor prognosis and greatly
complicates fluid and electrolyte, hemodynamic, and ventilator
management of the patient with ALF.
• Once oliguria develops, continuous renal replacement therapy (CRRT)
should be considered. Hemofiltration techniques minimize hypotension,
rapid fluid shifts, and plasma osmolality changes, and thereby decrease
the risk of cerebral edema as compared with intermittent hemodialysis.

Hematologic Disturbances
• Although disturbed hemostasis comprises a part of the definition of ALF, it would be
inaccurate to conclude that elevated INR represents an assessment of the bleeding
risk.
• Procoagulant and anticoagulant proteins decrease in parallel in ALF, and appear to
generally maintain balanced hemostasis, similar to the case in cirrhosis.
• Consequently, spontaneous, clinically significant bleeding is
uncommon in patients with ALF (approx 5%), and very rarely
contributes to death.
• When bleeding in pts with ALF occurs, the origin is most often
from a mucosal (capillary-type) source, such as the gastric,
pulmonary, or genitourinary systems, and rarely necessitates
transfusion.

Abnormal Parameters of Coagulation in ALF
The degree of hypofibrinogenemia reflects the severity of the DIC, and is most severe in ALF complicated by sepsis.
Zakin/boyer

Extra note
• Disturbed hemostasis in pts with ALF results from decreased coagulation factor synthesis, increased
factor consumption, and quantitative as well as qualitative platelet dysfunction.
• The presence of DIC consumes coagulation factors and should be suspected in a pt with
microangiopathic hemolytic anemia, increased fibrinogen degradation products and fibrin D-dimer
levels, and decreased fibrinogen levels.
• Platelet defects, both qualitative and quantitative, are likely to compound the bleeding diathesis of
ALF. Platelets from pts with ALF exhibit poor adhesion and aggregation, especially in the setting of
renal failure.
• Thrombocytopenia commonly accompanies ALF and probably results more from increased
consumption rather than decreased production because thrombopoietin concentrations correlate
poorly with platelet count.
• Abnormal fibrinolysis accompanies ALF, but its contribution to a bleeding tendency remains unclear
because decreases in liver-derived profibrinolytic proteins are offset by increases in endothelial-
derived profibrinolytic proteins; a similar balance has been observed for antifibrinolytic proteins.
• Finally, endothelial cell injury and activation, which occurs as part of the SIRS in ALF, also contributes
to abnormal hemostasis.
• In summary, abnormal hemostasis occurs in ALF, but mechanisms are complex and incompletely
defined. Generally, a precarious state of balanced hemostasis remains, which may be upset by an
appropriate trigger, such as infection.

Bleeding: management
• Pts with mild-mod coagulopathy and absence of bleeding do not require
specific intervention.
• The administration of vit K will ensure that deficiency does not
contribute to the bleeding diathesis.
• The use of FFP in pts with severe, but asymptomatic, coagulopathy
remains controversial and is usually discouraged because few data
document efficacy in bleeding prevention, overzealous infusion of FFP
may result in volume overload, a small but definite risk of transfusion-
related ALI exists, and the practice obscures important prognostic
information regarding trends in the PT.

• A more common clinical situation involves the pt with ALF who requires
an invasive procedure, such as the placement of a central venous
catheter or ICP monitor.
• Although indications in the specific setting of ALF are not available, it
seems reasonable to target plasma fibrinogen levels 1.5–2 g/L by
infusing fibrinogen concentrate at an initial dose of 25–50 mg/kg body
weight, and a platelet count >60,000/ll [1].
• The role of additional supportive therapies such as tranexamic acid
should also be considered in this context.
• An appropriate level of haemoglobin is usually agreed to be greater than
7 g/dl.[EASL17].
1. Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, Filipescu DC, et al. Management of severe perioperative bleeding: guidelines from the European Society of
Anaesthesiology. Eur J Anaesthesiol 2013;30:270–382.
Replacement therapy for thrombocytopenia and/or prolonged PT is recommended
only in the setting of hemorrhage or prior to invasive procedures (III). AASLD 2011

• Disseminated intravascular coagulation usually does not require specific
intervention unless it is severe and accompanied by obvious bleeding;
limited studies have shown that heparin may be used to treat DIC in pts
with ALF, but the potential bleeding risks limit enthusiasm for this
treatment.
• Gastrointestinal bleeding in a pt with ALF usually results from superficial
gastric erosions and stress ulcers, which should be prophylaxed by the
use of H2 receptor antagonists or proton pump inhibitors.
Pts with ALF in the ICU should receive prophylaxis with histamine-2 (H2) blocking
agents or PPI (or sucralfate as a second-line agent) for acid-related GIB associated
with stress (I). AASLD 2011

Breakdown of Host Immune Defenses
• Abnormalities in immune defense in pts with ALF greatly ↑ the
susceptibility to infection, a major trigger of MOSF, intracranial HTN, &
death.
• More than 80% of pts with ALF have bacteriologic evidence of infection
at some point during their illness. [ZAKIM/BOYER]
• Natural host barriers are breached by the process of caring for any
critically ill pt. Abnormal antibacterial defenses further contribute to the
susceptibility to infection, such as depressed complement
concentrations, impaired opsonization of bacteria, and decreased
neutrophil chemotaxis and superoxide production.
• Clinically, pneumonia, septicemia, and UTI are the MC types of infection
encountered in pts with ALF.

Factors Contributing to Infection in ALF
ZAKIM N BOYER

Management of infections
• Prevention of infection is thus an important objective of the medical MX
of ALF, and general guidelines to avoid nosocomial transmission of
organisms should be strictly enforced.
• Daily blood and urine cultures should be sent especially early in the
course of ALF to obtain antibiotic sensitivities in case of future infection.
In a large, retrospective, controlled study of 1551 ALF pts from the U.S. A LF Study Group registry, 600
pts (39%) received prophylactic antibiotics and 951 did not.[1]
Antimicrobial prophylaxis did not reduce the incidence of bloodstream infection or mortality within 21
days of ALF.
• Given that the findings of controlled studies are inconclusive, consensus
recommends antimicrobial prophylaxis (extended-spectrum β-lactam agent) in the
presence of multiorgan dysfunction, high-grade coma, or AKI or in the setting of
listing for LT, and antifungals if pts become/remain septic after 5 days in the ICU.
1. Karvellas CJ, et al: Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin Gastroenterol Hepatol 12(11):1942–1949.e1, 2014.

Algorithm for the prevention and treatment of
infection in pts with ALF.
ZAKIM N BOYER

(From Rolando N, et al. Management of infection in acute liver failure. In: Lee WM, Williams R, editors. Acute liver failure. Cambridge, United Kingdom:
Cambridge University Press, 1997: 158-171.)
ZAKIM N BOYER

Gastrointestinal Consequences
• Nausea and vomiting occur frequently early in the course of ALF, while an
ileus may develop in later stages.
• The cause of ileus is often multifactorial, and includes electrolyte and
acidbase disturbances, sepsis, and the use of narcotics to control
agitation.
• Although pancreatic enzyme levels are elevated in a third of pts, clinically significant
pancreatitis occurs infrequently.
• GI bleeding from mucosal petechial lesions can also occur, especially in
the setting of thrombocytopenia, DIC, and sepsis.

Management of Nutrition
• ALF is a catabolic state characterized by negative nitrogen balance,
muscle wasting, and aminoaciduria.
• Although the clinical value of nutritional support in ALF has not been
carefully studied, protein-calorie malnutrition adversely affects the
immune system, thereby increasing susceptibility to infections, and
impairs wound healing, suggesting that repletion may decrease the risk of
infection and improve the outcome of LT, respectively.
• The enteral route is preferred for nutritional support in critically ill pts.
• Protein at approximately 40 g/day should be administered initially. and
the dose should be modified on the basis of an assessment of the
metabolic state. Indeed Liver failure is a catabolic state; there is no need
to restrict protein. [easl 2017]

Managing Hypoglycemia
• Hypoglycaemia is found in 40% of pts with ALF. It may be persistent and intractable.
Plasma insulin levels are high due to reduced hepatic uptake; gluconeogenesis is
reduced in the failing liver.
• Hypoglycaemia can cause rapid neurological deterioration and death. Blood glucose
levels <60 mg/dL should be treated with a continuous infusion of 5 or 10% dextrose.
Enteral feedings should be initiated early unless CI.
• The frequency of hypoglycaemia requiring RX is increased in pts with paracetamol
induced ALF and AKI (55%) compared with pts without AKI (22%) [1,2] due to failure
of compensatory renal gluconeogenesis .
• The C/F of hypoglycaemia may be confused with developing HE. Therefore, frequent
monitoring of blood glucose is required in pts with ALF, especially hyperacute cases,
where ‘‘BMstix” monitoring should be undertaken every 2 h.
• Rapid boluses of conc glucose may induce large osmotic shifts in intravascular and
cerebral compartments and should be avoided, but may be necessary to treat critical
hypoglycaemia.
1. Craig DG, Bates CM, Davidson JS, Martin KG, Hayes PC, Simpson KJ. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced
hepatotoxicity. Br J Clin Pharmacol 2012;73:285–294.
2. Sheen CL, Dillon JF, Bateman DN, Simpson KJ, MacDonald TM. Paracetamolrelated deaths in Scotland, 1994–2000. Br J Clin Pharmacol 2002;54:430–432.

• Many studies have suggested that decreased levels of branched-chain
amino acids (BCAAs) contribute to HE, forming the basis for the
administration of BCAAs.
• Although numerous studies have evaluated the utility of BCAAs as a
treatment of HE in cirrhosis, the results remain inconclusive. Thus the
routine use of BCAA-supplemented feeds or infusions in the
management of ALF cannot be advocated.
• The initial caloric goal for the pt with ALF is approximately 35-40 kcal/d,
preferably by the enteral route.
Management of Nutrition

Main organ specific complications in ALF
EASL 2017

Initial Evaluation of ALF
HISTORY PHYSICAL EXAMINATION
Medications
Alcohol consumption
Mushrooms
Medical History: prodrome,
psychiatric
Pregnancy( in females )
Travel History
Vital Signs
Mental Status
Size of liver
Rash/ oropharyngeal lesions
Stigmata of CLD

Extra note
• As Altered mental status is an integral part of defining ALF , so Once a patient’s mental status begins to deteriorate,
one may lose the opportunity to obtain vital information that could guide management, including the
administration of life-saving antidotes, so history should also be obtained from family members.
• Therefore, on initial contact, a careful drug ingestion history should be obtained and should include prescription
medications, herbal remedies, over-the-counter medications. The details of dose ingested, amount and timing of
last dose, duration of medication/ herbal usage, and ingredients of nonprescription medications can be invaluable.
• Confounding conditions, such as alcohol use, malnutrition, and drug-drug interactions, must be considered.
• Although by definition ALF occurs in a patient with a previously normal liver, chronic liver disease may manifest
itself initially as acute liver.
• A complete physical examination is a necessity, and mental status should be thoroughly and frequently assessed.
• A history of cirrhosis or the presence of its stigmata (i.e., spider angiomas, palmar erythema, or splenomegaly)
suggests underlying chronic liver disease, which has a different course and prognosis.
• Abdominal tenderness may or may not be localized to the right upper quadrant.
• In the setting of infiltrative disease or hepatic outflow obstruction, hepatomegaly may be present. However, if
there has been significant hepatocyte loss, the liver will not be palpable or percussable, which is an ominous
prognostic sign.
• Jaundice may be absent until later in the course, particularly in the setting of microvesicular fatty injury.

Laboratory Studies
Haematology
CBC: white blood cells, hb, platelets
Coagulation panel: prothrombin time/INR,
factor V
Blood group
Biochemical
Serum chemistries: sodium, potassium, urea,
creatinine, calcium, magnesium, phosphate,
glucose
Hepatic panel: AST, ALT, alk phos, albumin,
total protein, total bilirubin
Arterial blood gas
Virology
Hepatitis B surface antigen and IgM
anticore
Hepatitis A (IgM) antibody
Hepatitis C antibody, HCV RNA
IgM hepatitis E antibody
Hepatitis D antibody if hepatitis B +
HSV, CMV, EBV PCR (if history of
immunosuppression)
Human immunodeficiency virus (if
considering transplantation)
Autoimmune markers
Antinuclear antibody (ANA)
Antismooth - muscle antibody (SMA)
Antiliver/ kidney microsome 1 (ALKM1)
Immunoglobulins

Investigations
Toxicology
Paracetamol level
Blood alcohol
Urine drug screen
Miscellaneous
Urine copper
Pregnancy test
Microbiology
Blood culture, aerobic and anaerobic
Urine culture and microscopy
Sputum culture and microscopy
Other studies
• Chest X - ray

Abdominal ultrasound is used to assess for vasculature patency and mass lesions.
Hepatic nodularity is commonly seen in the acute setting, reflecting regenerative
nodules rather than cirrhosis .
CT scanning of abdomen will show a reduction in liver size but correlation of liver
size with survival is imprecise.
Electroencephalogram ( EEG )
• Continuous EEG recording shows slowing of cortical activity and up to 50% of pts
with ALF to have subclinical seizure/ epileptiform activity. This is not recognized
clinically without EEG because the pt is usually paralysed and ventilated.
• EEG monitoring is controversial since prophylactic phenytoin is of unproven
value.
• With increasing drowsiness, evolution in eeg is seen as increasing amplitude and
decreasing frequency and with furthur in stupor to comatose pt, triphasic waves
and then delta waves do appear and with increasing severity, there is slowly
decreasing of amplitude with little frequency changes and then no cerebral
activity finally in deep comatose.

Non - contrast computed tomography of the brain is insensitive for
detecting intracranial hypertension but may help rule out other pathology,
such as haemorrhage.
Liver Biopsy
• The use of diagnostic liver biopsy remains controversial.
• Biopsy may be indicated if metastatic disease, lymphoma, or other
infiltrative process is suspected or autoimmune hepatitis.
• The presence of severe coagulopathy makes percutaneous biopsy
impossible; therefore, tissue must be obtained via the transjugular route.
• It is rare, however, that a liver biopsy will help elucidate a diagnosis and
the histologic findings do not generally alter the treatment course.

Liver transplant and prognostic indices
• The most common technique is orthotopic transplantation, in which the
native liver is removed and replaced by the donor organ in the same
anatomic position as the original liver.
Auxiliary transplantation uses a partial left or right lobe from the donor which acts as
temporary support for the recipient's injured liver, which remains in place. Once the
native liver recovers, immunosuppression is withdrawn and the graft is either surgically
removed or is allowed to atrophy naturally.

Orthotopic Liver Transplantation
• LT remains the definitive RX for pts with severe ALF, and clearly improves
both short-term and longterm survival in pts with G3/4 HE, especially in
pts with non–APAP-induced ALF.[1]
• Because APAP-ALF overdose usually resolves spontaneously with the early
administration of NAC, only approx 10% of affected individuals undergo
OLT for this indication in the US compared with 30-50% with ALF from
other causes.[2]
• In addition, pts with ALF due to APAP often have psychosocial barriers to
OLT, such as substance abuse and a history of suicidal behavior. [3]
• However, those that do go on to receive an OLT have outcomes similar to
those of non-APAP ALF and cirrhotic pts.[4]
1. Liou IW, Larson AM: Role of liver transplantation in acute liver failure. Semin Liver Dis 28(2):201–209, 2008.
2. Lee WM: Etiologies of acute liver failure. Semin Liver Dis 28(2):142–152, 2008.
3. Larson AM, et al: Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 42(6):1364–1372, 2005.
4. Karvellas CJ, et al: Medical and psychiatric outcomes for patients transplanted for acetaminophen-induced acute liver failure: a casecontrol study. Liver Int 30(6):826–833, 2010.

• The challenge remains to identify pts with a high risk of death with
medical MX and a high probability of survival with LT.
• It is equally important to decide when not to proceed with LT. Pts
with a poor prognosis for neurologic recovery, such as those with a
sustained increase in ICP >40 mm Hg or a ↓ in CPP <40 mm Hg, may
not benefit from LT even if it is technically successful. [ZAKIM]
• The presence of septicemia or advanced multiorgan failure is also a
contraindication to LT.
Ref: Sleisenger

Extra note
• Normal intracranial pressure
• ICP is generally measured in mm Hg to allow for comparison with
MAP and to enable quick calculation of CPP. It is normally 7-15 mm
Hg in adults who are supine, with pressures over 20 mm Hg
considered pathological and pressures over 15 mm Hg considered
abnormal.
• Note that ICP is positional, with elevation of the head resulting in
lower values. A standing adult generally has an ICP of -10 mm Hg but
never less than -15 mm Hg.

OLT in the US
• Patients with ALF listed for OLT in the US receive priority above all pts
with cirrhosis according to the rules of the United Network for Organ
Sharing, so-called status 1A priority.
• Status 1A criteria include a life expectancy without LT of <7 days, onset
of HE< 8 wks of the first symptom of liver injury, care within an icu, and
absence of preexisting liver disease.
• Objective criteria include being at least 18 yrs old, and at least one of the
following: ventilator dependence, receiving RRT, or INR >2.0.

• Many liver transplant centers have reported average survival after transplant
for ALF of approx 65%.[1,2,3,4]
• In one of the largest studies[5] a number of variables were evaluated as
predictors of outcome after LT in 100 pts with ALF. In pts with ALF unrelated to
APAP (n = 79), an elevated S creatinine level predicted poor outcome, as did
G3 or G4 HE (80% survival for those with G1/2 vs. 56% for those with G3/4).
The major hindrance however, will likely remain the amount of time required to evaluate a potential donor, which
often requires several days. Auxiliary LT, in which a donor liver (whole or partial) is heterotopically implanted below
the native liver to provide support while regeneration of the native liver occurs, has also been explored in pts with
ALF.
Withdrawal of immunosuppression after regeneration of the native liver causes rejection and atrophy of the
donated liver, and obviates the need for long-term immunosuppression.
1. Liou IW, Larson AM: Role of liver transplantation in acute liver failure. Semin Liver Dis 28(2):201–209, 2008.
2. Ascher NL, et al: Liver transplantation for fulminant hepatic failure. Arch Surg 128(6):677–682, 1993.
3. Bismuth H, et al: Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience. Ann Surg 222(2):109–119, 1995.
4. Bismuth H, et al: Liver transplantation in Europe for patients with acute liver failure. Semin Liver Dis 16(4):415–425, 1996.
5. Devlin J, et al: Pretransplantation clinical status and outcome of emergency transplantation for acute liver failure. Hepatology 21(4): 1018–1024, 1995.

Assessment of Prognosis: When to Initiate OLT Evaluation
• Pts with ALF have one of three outcomes: spontaneous recovery, LT, or death.
• As of October 2015, the U.S. ALFStudy Group registry of more than 2200 pts recorded
that approximately 43% spontaneously recovered, 24% underwent LT (of whom 14%
died), and 33% died without LT.
• The overall survival, with or without LT and for all major causes, has steadily improved
with time, and is currently 65% in the U.S. ALFStudy Group registry.
• The ability to predict which pt with ALF will recover spontaneously with medical MX
and which will succumb without LT remains a question of paramount importance.
Although LT offers hope of survival from ALF, the decision to perform a transplant
introduces the need for lifelong immunosuppression, an operative mortality of up to
30%, and the use of a scarce resource.[1]
• Thus universal LT for ALF cannot be endorsed. Although mortality from all causes of
ALF parallels the depth of HE(>80% mortality for G3 or G4 HE), spontaneous recovery
occasionally follows even the deepest hepatic coma[2]; thus more accurate predictors
of outcome are needed.
1. Lake JR, Sussman NL: Determining prognosis in patients with fulminant hepatic failure: when you absolutely, positively have to know the answer. Hepatology 21(3):879–882, 1995.
2. Karvountzis GG, et al: Long term follow-up studies of patients surviving fulminant viral hepatitis. Gastroenterology 67(5):870–877, 1974.

Acute Liver Failure: Pathogenesis and Management

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