Transcript Acute Liver Failure

ALF
 Definition
 Case
 Evaluation and work-up
 Etiologies
 Treatment
 Prognostic criteria
ALF
 Rapid 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 consequences
 Cerebral edema
 Hemodynamic instability
 Renal failure
 Coagulopathy
 Metabolic disturbances
 Susceptibility to bacterial/fungal infections
ALF : Case
 39 yo BM transferred from Okinawa with jaundice
 HPI: 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: negative
 SH: occ binge ETOH with 5-10 drinks weekly; no tobacco
 PE: 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 : Case
Jan
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
260
232
AlkP 262
hos
291
334
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
ALF
 Course is influenced by the cause
 Rate 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: Etiology
Cause
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 : Etiology
Cause
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 Evaluation
 INR > 1.5 with altered sensorium = ALF
 History: exposures to viral infection, drugs/toxins
 PE: stigmata of chronic liver disease rarely present
* jaundice: not always seen at presentation
* RUQ tenderness: variably present
* mental status exam daily: connect the dots
 Admit to ICU, especially with mental status changes
 Contact Transplant Center/plans for transfer in appropriate
patients
 Identify precise etiology of liver failure
ALF: Initial Laboratory Evaluation
 PT/INR; chemistry panel; LFT’s; CBC
 ABG; arterial lactate; serum ammonia
 Blood type; pregnancy test; HIV
 Acetaminophen level; drug screen
 Viral hepatitis screen: HAV IgM, HBsAg, HBc IgM;
HEV IgM, HCV Ab; CMV; EBV
 Ceruloplasmin level; 24 hour urinary copper
 Autoimmune markers: ANA, ASMA, immunoglobulin
levels; LKM-1 Ab (if other markers negative)
 Consider Liver biopsy: especially for autoimmune
hepatitis, HSV, lymphoma, metastases, Wilson disease
Case
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Chem panel / CBC normal
Hepatitis A-E: negative
EBV/ CMV/ HSV neg
Fe 268; TIBC 289, ferritin
> 6400
ANA / ASMA / LKM 1 Ab
negative
Ceruloplasmin 32 (nml)
A1AT level nml;
phenotype PiEM
HIV 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/dL
 Start 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 medication
 Med other than APAP rarely causes ALF
 Most common: antibiotics; NSAIDs; anti-convulsants
 No antidote; corticosteroids not indicated (unless
hypersensitivity suspected)
 Combination agents with enhanced toxicity:
* amoxicillin-clavulanate (most common abx causing ALF)
* trimethoprim-sulfamethoxazole
* rifampin-isoniazid
 Diagnosis of exclusion: other causes need to be ruled out
ALF: Drug Induced Hepatotoxicity
 Antibiotics: beta lactams, sulfonamides, dapsone,
ofloxacin, isoniazid, pyrazinamide
 Antivirals: didanosine; efavirenz
 NSAID: diclofenac
 Anti-convulsants: phenytoin
 Others: PTU; metformin; troglitazone; amiodarone;
lisinopril; labetalol; methyldopa; allopurinol;
ketokonazole; disulfiram; halothane;
amphetamine/ecstasy; gemtusumab; imipramine
ALF: Herbal/Dietary Supplements
 Kava kava
 Chaparral
 Skullcap
 Germander
 Pennyroyal
 Jin Bu Huan
 Heliotrope
 Rattleweed
 Comfrey
 Sunnhemp
 Senescio
 Gum thistle
 He Shon Wu
 Ma Huang
ALF : Viral Hepatitis
 HAV – HEV: all can cause ALF; Hep A or B most common
 ALF as part of disseminated viral infection: HSV; CMV;
EBV; VZV; parvovirus B-19; adenovirus; enterovirus
 HAV: < 5% of ALF; often > 40 yo or pre-existing liver ds
 HBV: most common viral cause (8% of ALF); denovo or
reactivation with cytotoxic agents or immunosuppressives
 Reactivation of HBV: HBsAg MUST be checked before
chemo; give nucleoside analogue prophylactically if positive
 Co-infection: HBV/HDV; HCV/HAV; HCV/HBV
 HEV: > 50% ALF in India (also endemic in Mexico, Russia,
Pakistan); high mortality (>25%) in pregnant patients
ALF: HSV Hepatitis
 Rare cause of ALF
 Immunosuppressed or
pregnant pts (third
trimester); reported in
healthy patients
 Skin lesions in < 50%
 Liver biopsy: very helpful
in making diagnosis
 Treatment: acyclovir
ALF: Wilson Disease
 Uncommon cause of ALF (2-3%)
 Fulminant presentation uniformly fatal without OLT
 Typical 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 bx
 Treatment: orthotopic liver transplant
* albumin dialysis; hemofiltration; plasmapheresis
 D-penicillamine NOT recommended in acute presentation
Wilson Ds: Kayser-Fleischer ring
ALF: Autoimmune Hepatitis
 Patients 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 related
 Acute Fatty Liver of
Pregnancy: rapidly
progressive; 3rd trimester
* liver bx: hepatic steatosis
 HELLP: Hemolysis/
Elevated LFT/ Low Plts
 * pre-eclampsia features
common: HTN;proteinuria
 Intrahepatic hemorrhage
and/or hepatic rupture:rare
 Treatment: urgent delivery
* OLT sometimes needed
ALF: Ischemic Hepatitis
 Shock liver: cardiac arrest; sepsis; significant
hypotension/hypovolemia; severe CHF
 Drug induced hypotension/hypoperfusion: long acting
niacin; cocaine; methamphetamines
 Documented hypotension not always found
 Transaminases often > 1000-2000 mg/dL; rapid response
to stabilization of circulatory system
 Simultaneous renal insufficiency and/or muscle necrosis
often found
 Treatment: cardiovascular support; antibiotics
ALF: Budd-Chiari Syndrome
 Hepatic vein obstruction
 Clinical 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 Guidelines
 N-acetylcysteine should be given for non-APAP ALF
 ICU support; treat underlying etiology
 Careful attention to fluid management, hemodynamics,
and metabolic parameters
 Surveillance / treatment of infection
 Maintenance of nutrition
 Recognition / resuscitation of GI bleeding
 Coagulation parameters, CBC, metabolic panels (incl
glucose), and ABG checked frequently
 Daily 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 nonacetaminophen acute liver failure. Gastroenterology 2009; 137:856.
Case
 N-acetylcysteine started immed on arrival NMCSD
 Member transferred to Scripps Green for ALF and listed
for liver transplant
 Repeat liver biopsy: massive hepatocyte necrosis with
scattered plasma cells
 Corticosteroids started for possible atypical fulminant
autoimmune hepatitis
ALF: CNS Effects
 Cerebral 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 IV
Degrees of Encephalopathy:
 Grade I: changes in behavior with minimal change in level
of consciousness
 Grade II: gross disorientation, drowsiness, possibly
asterixis, inappropriate behavior
 Grade III: marked confusion, incoherent speech, sleeping
most of the time but arousable to vocal stimuli
 Grade 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 Encephalopathy
 Intubate trachea for airway protection
 Sedation: propofol preferable (reduced cerebral blood flow)
 Raise head of bed to 30 degrees; avoid stimulation
 Seizures: control with phenytoin
* prophylactic phenytoin: no proven benefit
 ICP 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 ICP
 ICP should be maintained below 20-25 mm Hg
* Cranial perfusion pressure maintained above 50-60 mm Hg
 Mannitol: 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 only
 Corticosteroids: no benefit in ALF pts with elevated ICP
 Hypothermia (32-34 deg C): may prevent/control ICH; more
studies are needed; potential deleterious effects
ALF: Infection/Coagulopathy
 Infection risk: bacterial/fungal; sepsis
* prophylactic antibiotics may be considered but no
controlled trials to confirm benefit
* surveillance for infection critical if not on antibiotics
 Coagulopathy: platelets often < 100K due to consumption
* FFP indicated for bleeding and procedures (with high INR)
* Vitamin K 5-10 mg SC should be given
 Platelet transfusion: if low platelet count and active bleeding
* platelet counts > 10K often well tolerated w/o bleeding
* transfuse for invasive procedures and plt count < 50K
 Recombinant activated Factor VIIa: effective temporary
correction of coagulopathy before procedures
ALF: GI Bleeding
 GI bleed: well recognized complication of ALF
 Large 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; shock
 H2 Blockers proven effective for prophylaxis of GI bleed
 PPI’s: almost certainly effective but unproven
 Recommendation: 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 / ARF
 Preservation of renal function imperative
 Fluid resuscitation for intravascular volume deficits
 Hypotension due to low SVR: PA catheter helpful
 Colloid (albumin) preferable to crystalloid (saline); all
solutions should contain dextrose
 Inotropic or pressor support: maintain MAP 50-60 mm Hg
* epi/norepinephrine or dopamine; NOT vasopressin
 ARF: 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 Concerns
 Metabolic derangements common in ALF
 Alkalosis and acidosis: treat underlying cause
 Hypoglycemia: Continuous IV glucose infusion
 Phosphate, magnesium, potassium: often low; replete
 Nutrition 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 Transplant
 OLT: only definitive therapy for patients who cannot
regenerate sufficient hepatocyte mass to sustain life
 Pre-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 Factors
 Cause 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 Criteria
 Acetaminophen 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 Criteria
 King’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-II
 Age
 History of severe organ
 Rectal temperature
insufficiency or
immunocompromised
 Glasgow coma scale
 A-a gradient
 Arterial ph
 Heart rate
 Respiratory rate
 Serum sodium
 Serum potassium
 Serum creatinine
 Hematocrit
 WBC
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 Pearls
 INR > 1.5 with mental status changes = ALF
 N-acetylcysteine for all patients with ALF
 Avoid all supplements, herbals, OTC meds (unless
physician advised)
 Zero APAP level does not r/o acetaminophen related ALF
 Contact Transplant Center ASAP and transfer appropriate
patients
 ICU transfer for any patient with ALF
 Questions ?