ALFDefinitionCaseEvaluation and work-upEtiologiesTreatmentPrognostic criteria

ALFRapid development of severe acute liver injury with impaired

synthetic liver function and encephalopathy in someone with a previously normal liver

* coagulation abnormality (INR > 1.5) and any degree of mental alteration (encephalopathy) in a patient without preexisting cirrhosis and with an illness < 26 weeks duration

Polson J. The Management of Acute Liver Failure. Hepatology 2005;

41, 1179-1197.

ALF: Clinical consequencesCerebral edemaHemodynamic instabilityRenal failureCoagulopathyMetabolic disturbancesSusceptibility to bacterial/fungal infections

ALF : Case39 yo BM transferred from Okinawa with jaundiceHPI: No hx/o prior liver ds. Admitted taking No X-plode

but otherwise no OTC meds. No c/o except pruritus. Denied abd pain, f/ch/sw.

PMH/PSH/FH: negativeSH: occ binge ETOH with 5-10 drinks weekly; no

tobaccoPE: VSS, afebrile. Cheerful, smiling jaundiced BM NAD

HEENT: scleral icterus. lungs CTA; COR RRR, no murmur; abd soft, NT w/o masses or organomegaly; BS nml. Ext w/o CCE

ALF : CaseJan 10

Jan 28

Feb 16

Feb 22

Feb 25

Feb 28

Tot Bili

5.4 7.3 10.3 17.9 24.4 19.6

Dir Bili

2.6 11 15

AlkPhos

262 291 334 260 232 119

ALT 1574 1902 1284 2342 2333 1744

AST 1446 2557 1722 4108 3830 2519

INR 1.1 1.1 1.2 1.5 2.0 2.3

RUQ U/S: normal bile ducts; no focal hepatic abnormality

MRI: normal liver size and contour; no masses, cirrhosis, ascites, or biliary dilation

ALFCourse is influenced by the causeRate of progression of clinical syndrome varies according

to the cause and is inversely related to rapidity of onset of encephalopathy

Survival rate 36% with hyperacute presentation: jaundice to encephalopathy within 1 week (often acetaminophen or hepatitis A or B)

Survival rate 14%: jaundice to encephalopathy > 1 week

ALF: EtiologyCause Treatment

Acetaminophen N-acetylcysteine (NAC)

Hepatitis B virus Entecavir; tenofovir

Herpes simplex virus (HSV) acyclovir

Cytomegalovirus (CMV) gancyclovir

Autoimmune hepatitis (AIH) Steroids; cyclosporine

Pregnancy / acute fatty liver of pregnancy Urgent delivery

ALF : EtiologyCause Treatment

Budd-Chiari syndrome Anticoagulation; angioplasty/stent; shunt

Venoocclusive disease (VOD) Shunt; thrombolysis

Cardiac failure Inotropic support

Septic shock Antibiotics; vasopressors

Wilson disease Albumin dialysis; hemofiltration

Amanita phalloides Penicillin; silibinin

Lymphoma chemotherapy

ALF : Diagnosis / Initial EvaluationINR > 1.5 with altered sensorium = ALFHistory: exposures to viral infection, drugs/toxinsPE: stigmata of chronic liver disease rarely present

* jaundice: not always seen at presentation

* RUQ tenderness: variably present

* mental status exam daily: connect the dotsAdmit to ICU, especially with mental status changesContact Transplant Center/plans for transfer in

appropriate patientsIdentify precise etiology of liver failure

ALF: Initial Laboratory EvaluationPT/INR; chemistry panel; LFT’s; CBCABG; arterial lactate; serum ammoniaBlood type; pregnancy test; HIVAcetaminophen level; drug screenViral hepatitis screen: HAV IgM, HBsAg, HBc IgM;

HEV IgM, HCV Ab; CMV; EBVCeruloplasmin level; 24 hour urinary copperAutoimmune markers: ANA, ASMA, immunoglobulin

levels; LKM-1 Ab (if other markers negative)Consider Liver biopsy: especially for autoimmune

hepatitis, HSV, lymphoma, metastases, Wilson disease

CaseChem panel / CBC normalHepatitis A-E: negativeEBV/ CMV/ HSV negFe 268; TIBC 289, ferritin

> 6400ANA / ASMA / LKM 1

Ab negativeCeruloplasmin 32 (nml)A1AT level nml;

phenotype PiEMHIV neg

Liver biopsy: central and periportal necrosis with mod-severe inflammation (neutrophils/eos) with few plasma cells; periportal fibrosis stage 2/4

ALF : Acetaminophen (APAP)Most frequent cause of severe hepatotoxicity in the U.S.Severe hepatotoxicity is dose related, often > 10 gms APAP ALT/AST very high, often > 2000 mg/dLStart N-acetylcysteine (NAC) as soon as possible (oral or

IV)Lower doses APAP (< 4 grams) can rarely cause ALF in

certain clinical situations:

* malnourished patient

* underlying liver disease (ETOH)

ALF: APAP Nomogram

Do not use nomogram to exclude APAP toxicity

Give NAC even if APAP suspected but level is low or zero (multiple doses over time or altered metabolism)

Give NAC even if history unavailable/incomplete

NAC still of value > 48h from ingestion

ALF: Amanita phalloides

No available blood test to make diagnosis

Suspect if: N/V/D, abdominal cramps within 24 hours of ingestion

Consider gastric lavage and activated charcoal via NG

Low survival without OLT; list pts for OLT immediately

PCN G and silymarin (milk thistle): accepted antidotes despite no controlled trials

NAC should be given as well for suspected ALF from mushroom ingestion

ALF: Drug Induced Hepatotoxicity

Idiosyncratic toxicity within 6 months starting medicationMed other than APAP rarely causes ALFMost common: antibiotics; NSAIDs; anti-convulsantsNo antidote; corticosteroids not indicated (unless

hypersensitivity suspected)Combination agents with enhanced toxicity:

* amoxicillin-clavulanate (most common abx causing ALF)

* trimethoprim-sulfamethoxazole

* rifampin-isoniazidDiagnosis of exclusion: other causes need to be ruled out

ALF: Drug Induced Hepatotoxicity

Antibiotics: beta lactams, sulfonamides, dapsone, ofloxacin, isoniazid, pyrazinamide

Antivirals: didanosine; efavirenzNSAID: diclofenacAnti-convulsants: phenytoinOthers: PTU; metformin; troglitazone; amiodarone;

lisinopril; labetalol; methyldopa; allopurinol; ketokonazole; disulfiram; halothane; amphetamine/ecstasy; gemtusumab; imipramine

ALF: Herbal/Dietary SupplementsKava kavaSkullcapPennyroyalHeliotropeComfreySenescioHe Shon Wu

ChaparralGermanderJin Bu HuanRattleweedSunnhempGum thistleMa Huang

ALF : Viral HepatitisHAV – HEV: all can cause ALF; Hep A or B most commonALF as part of disseminated viral infection: HSV; CMV;

EBV; VZV; parvovirus B-19; adenovirus; enterovirusHAV: < 5% of ALF; often > 40 yo or pre-existing liver dsHBV: most common viral cause (8% of ALF); denovo or

reactivation with cytotoxic agents or immunosuppressivesReactivation of HBV: HBsAg MUST be checked before

chemo; give nucleoside analogue prophylactically if positiveCo-infection: HBV/HDV; HCV/HAV; HCV/HBVHEV: > 50% ALF in India (also endemic in Mexico, Russia,

Pakistan); high mortality (>25%) in pregnant patients

ALF: HSV Hepatitis

Rare cause of ALFImmunosuppressed or

pregnant pts (third trimester); reported in healthy patients

Skin lesions in < 50%Liver biopsy: very helpful

in making diagnosisTreatment: acyclovir

ALF: Wilson DiseaseUncommon cause of ALF (2-3%)Fulminant presentation uniformly fatal without OLTTypical scenario: young pt with abrupt onset hemolytic

anemia and jaundice (Tbili often > 20 mg/dL); low alk phos (Tbili/AP ratio > 2.0 consistent with Wilson ds)

Kayser-Fleischer rings present in only 50%Ceruloplasmin level low; can be normal in 15%Diagnosis: high urinary copper and hepatic copper on liver bxTreatment: orthotopic liver transplant

* albumin dialysis; hemofiltration; plasmapheresisD-penicillamine NOT recommended in acute presentation

Wilson Ds: Kayser-Fleischer ring

ALF: Autoimmune HepatitisPatients often have

unrecognised pre-existing chronic liver disease

Typical pt: young female with other autoimmune d/o

Auto-antibodies may be absent (15%)

Liver biopsy: severe hepatocellular necrosis with plasma cells

Treatment: steroids * list for OLT immediately

ALF: Pregnancy relatedAcute Fatty Liver of

Pregnancy: rapidly progressive; 3rd trimester

* liver bx: hepatic steatosisHELLP: Hemolysis/

Elevated LFT/ Low Plts* pre-eclampsia features

common: HTN;proteinuriaIntrahepatic hemorrhage

and/or hepatic rupture:rareTreatment: urgent delivery

* OLT sometimes needed

ALF: Ischemic HepatitisShock liver: cardiac arrest; sepsis; significant

hypotension/hypovolemia; severe CHFDrug induced hypotension/hypoperfusion: long acting

niacin; cocaine; methamphetaminesDocumented hypotension not always foundTransaminases often > 1000-2000 mg/dL; rapid response

to stabilization of circulatory systemSimultaneous renal insufficiency and/or muscle necrosis

often foundTreatment: cardiovascular support; antibiotics

ALF: Budd-Chiari SyndromeHepatic vein obstructionClinical presentation:

abdominal pain; ascites; striking hepatomegaly

Diagnosis: CT; Dopplar U/S; MR venography

Treatment:anticoagulation; angioplasty w/ stent; TIPS

* OLT (with ALF)Exclude underlying

malignancy prior to OLT

ALF: General Treatment GuidelinesN-acetylcysteine should be given for non-APAP ALF ICU support; treat underlying etiologyCareful attention to fluid management, hemodynamics,

and metabolic parametersSurveillance / treatment of infectionMaintenance of nutritionRecognition / resuscitation of GI bleedingCoagulation parameters, CBC, metabolic panels (incl

glucose), and ABG checked frequentlyDaily LFT

N-acetylcysteine in ALF Placebo controlled trial in 173 patients with ALF due to

non-APAP cause (Hep B; drug induced liver injury; autoimmune hepatitis; indeterminate)

Significantly higher OLT free survival (40 vs 27%) in patients given NAC

Benefit confined to patients with early stage encephalopathy

Lee WM. IV NAC improves OLT-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009; 137:856.

Case

N-acetylcysteine started immed on arrival NMCSDMember transferred to Scripps Green for ALF and listed

for liver transplantRepeat liver biopsy: massive hepatocyte necrosis with

scattered plasma cellsCorticosteroids started for possible atypical fulminant

autoimmune hepatitis

ALF: CNS EffectsCerebral edema and intracranial hypertension (ICH): most

serious complications of ALF * mechanism unclear: osmotic disturbances, loss of

cerebrovascular autoregulation; increased ammonia * related to severity of encephalopathy: 70% in grade IVDegrees of Encephalopathy:Grade I: changes in behavior with minimal change in

level of consciousnessGrade II: gross disorientation, drowsiness, possibly

asterixis, inappropriate behaviorGrade III: marked confusion, incoherent speech, sleeping

most of the time but arousable to vocal stimuliGrade IV: comatose, unresponsive to pain, decorticate or

decerebrate posturing

Grade I-II Encephalopathy

Management: Grade I-II encephalopathy

* ICU admission; frequent MS checks

* Consider transfer to liver transplant facility and listing for OLT

* Head CT to r/o hemorrhage/other causes of MS changes

* avoid sedation; avoid stimulation

* agitation: short acting benzodiazepines (small doses)

* lactulose: no difference in outcome; concern for gaseous abdominal distension which may impact OLT

Grade III-IV EncephalopathyIntubate trachea for airway protectionSedation: propofol preferable (reduced cerebral blood flow)Raise head of bed to 30 degrees; avoid stimulationSeizures: control with phenytoin

* prophylactic phenytoin: no proven benefitICP monitoring for early recognition of cerebral edema

* Cushing’s triad not uniformly present; CT unreliable

* Goal: maintain neuro integrity/survival while awaiting donor organ or recovery of functioning hepatocyte mass

* complication rate 3.8% (infection and bleeding)

* Factor VIIa may reduce bleeding risk

ALF: Treatment of Elevated ICPICP should be maintained below 20-25 mm Hg

* Cranial perfusion pressure maintained above 50-60 mm HgMannitol: effective in decreasing cerebral edema

* associated with improved survival (bolus 0.5-1 g/kg IV)Hyperventilation: indicated to acutely lower ICP via

vasoconstriction and decreased cerebral blood flow

* prophylactic hyperventilation not recommended Barbiturates: thiopental or phenobarbital

* effectively decreases ICP; severely elevated ICP onlyCorticosteroids: no benefit in ALF pts with elevated ICPHypothermia (32-34 deg C): may prevent/control ICH;

more studies are needed; potential deleterious effects

ALF: Infection/CoagulopathyInfection risk: bacterial/fungal; sepsis

* prophylactic antibiotics may be considered but no controlled trials to confirm benefit

* surveillance for infection critical if not on antibioticsCoagulopathy: platelets often < 100K due to consumption

* FFP indicated for bleeding and procedures (with high INR)

* Vitamin K 5-10 mg SC should be givenPlatelet transfusion: if low platelet count and active bleeding

* platelet counts > 10K often well tolerated w/o bleeding

* transfuse for invasive procedures and plt count < 50KRecombinant activated Factor VIIa: effective temporary

correction of coagulopathy before procedures

ALF: GI BleedingGI bleed: well recognized complication of ALFLarge prospective multi-center cohort study: mechanical

ventilation and coagulopathy were only significant risk factors for bleeding in critically ill pts (ref 123)

* other RF’s: hepatic and renal failure; sepsis; shockH2 Blockers proven effective for prophylaxis of GI bleed PPI’s: almost certainly effective but unprovenRecommendation: patients with ALF in the ICU should

receive prophylaxis with H2 blockers or PPIs (or sucralfate as second line agent) for acid related GI bleeding associated with stress

ALF: Hemodynamics / ARFPreservation of renal function imperativeFluid resuscitation for intravascular volume deficitsHypotension due to low SVR: PA catheter helpfulColloid (albumin) preferable to crystalloid (saline); all

solutions should contain dextroseInotropic or pressor support: maintain MAP 50-60 mm Hg

* epi/norepinephrine or dopamine; NOT vasopressinARF: may be due to dehydration, HRS, or ATN

* maintain adequate hemodynamics; treat infection ASAP

* avoid nephrotoxins (NSAID; aminoglycosides); use IV contrast with caution

* CVVHD if dialysis needed (better than intermittent)

ALF: Metabolic ConcernsMetabolic derangements common in ALFAlkalosis and acidosis: treat underlying causeHypoglycemia: Continuous IV glucose infusionPhosphate, magnesium, potassium: often low; repleteNutrition very important: initiate enteral feeds early

* 60 gram protein diet

* branched chain amino acids: no benefit

* parenteral route for nutrition if enteral feeds contraindicated

ALF: Orthotopic Liver TransplantOLT: only definitive therapy for patients who cannot

regenerate sufficient hepatocyte mass to sustain lifePre-transplant era ALF survival rate < 15%Post-transplant era ALF survival rate: > 60%Spontaneous survival rate approx. 40%; post-OLT

survival 80-90%Liver support systems: no proven benefit

* sorbent systems (charcoal; adherent particles in column) detoxify but offer no hepatocyte replacement

* transient improvement in encephalopathy but no improvement in hepatic function or survival benefit

ALF: Prognostic FactorsCause of ALF: most significant predictor of outcome

* APAP, Hepatitis A, shock liver, pregnancy related with > 50% OLT free survival

* all others < 20% OLT free survival Degree of encephalopathy: Grade I-II with 65-70%

spontaneous recovery; Grade III-IV < 20%Age: > 40 yo or < 10 yo have worse outcome

ALF: King’s College CriteriaAcetaminophen induced ALF: * arterial pH < 7.3 OR * PT > 100 sec (INR > 6.5) + serum creatinine > 3.4 mg/dL

+ Grade III-IV encephalopathy

Non-acetaminophen induced ALF: * PT > 100 sec (INR > 6.5) OR * any 3 of the following: : drug toxicity : indeterminate cause : age < 10 or > 40 years old : jaundice to coma interval > 7 days : PT > 50 sec (INR > 3.5) : serum bilirubin > 17.5 mg/dL

ALF: Prognostic CriteriaKing’s College criteria: specificity > 90%, sensitivity

69%Meta-analysis compared King’s criteria, pH < 7.3 alone,

and APACHE-II scores

* King’s criteria and pH < 7.3 alone very specific for predicting poor outcome but sensitivity low

* APACHE-II score > 15 with specificity 92% and better sensitivity 81%

MELD: Model for End stage Liver Disease

* useful to predict mortality in patients with cirrhosis

* not applicable in patients with ALF

APACHE-IIAgeRectal temperatureHeart rateRespiratory rateSerum sodiumSerum potassiumSerum creatinineHematocritWBC

History of severe organ insufficiency or immunocompromised

Glasgow coma scaleA-a gradientArterial ph

ALF: Case

Liver function declined despite supportive measures and high dose corticosteroids

Member listed > 2 weeks for liver transplant however no compatible liver was offered

GI bleed occurred followed by asystolic arrest with member expiring after unsuccessful rescucitation

Final analysis: drug induced liver injury (N.O. X-plode vs another supplement?) most likely

ALF with indeterminate cause in 15% of cases

ALF: Clinical PearlsINR > 1.5 with mental status changes = ALFN-acetylcysteine for all patients with ALFAvoid all supplements, herbals, OTC meds (unless

physician advised)Zero APAP level does not r/o acetaminophen related ALFContact Transplant Center ASAP and transfer appropriate

patientsICU transfer for any patient with ALFQuestions ?