Attending Version:
Acute (“Fulminant”) Liver Failure and Acetaminophen Overdose: created by Dr. Meg
Lieberman
Objectives:
List 5 causes of acute liver failure.
Identify 5 drugs associated with acute liver failure.
Describe the key clinical features of acute liver failure, and their management.
Name two clinical prediction rules that identify patients likely to have poor outcomes.
Identify patients who will require urgent transfer to a liver transplant center.
References:
1. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-Induced Acute Liver Failure: Results of a
United States Multicenter, Prospective Study. Hepatology 2005; 32: 1366.
2. Burns MJ, Friedman SL, Larson AM. Pathophysiology & Diagnosis of Acetaminophen
(Paracetamol) Intoxication. UpToDate2006.
3. Larson, et al. p1367.
4. Rowden AK, Norvell J, Eldridge DL, et al. Acetaminophen Poisoning. Clinics in Laboratory
Medicine 2006; 26:49-55.
5. Larson, et al. p1369.
6. Baquerizo A, Anselmo D, Shackelton C, et al. Phosphorus as an Early Predictive Factor in Patients
with Acute Liver Failure. Transplantation 2003; 75:2007-2014.
7. Larson, et al. p 1369.
8. Blei AT, Selection for Acute Liver Failure: Have We Got it Right? Liver Transplantation 2005;
11: s32-34.
9. Lee WM. Acute Liver Failure in the United States. Seminars in Liver Disease 2003; 23: 217-26.
10. Sass DA, Shakil AO. Fulminant Hepatic Failure. Liver Transplantation 2005: 600.
Overview:
Acute Liver Failure = Coagulopathy & encephalopathy in patient without history of cirrhosis.
Acetaminophen overdose most common cause: 51% of cases in 2003, and becoming more common
(only 28% in 1998). (1)
(2)
Acute Ingestions: Rumack-Matthews nomogram
Subacute ingestions (>24 hrs. prior): AST & ALT also taken into account, along with APAP level,
reported amount ingested (generally>7.5 gms), and risk factors for hepatotoxicity.
NAC proven beneficial even in “late” setting, when transaminases high and APAP undetectable.
Chronic overdose: NAC indicated at any time if APAP detectable in serum or transaminases
elevated. (May even be indicated with suggestive history alone.) Mortality rate = Acute OD’s (3)
NAC – mechanisms of action: 1. Functions as GSH precursor; increases its synthesis so NAPQI
binds to it instead of hepatocytes
2. Increases sulfation of APAP to nontoxic metabolites
3. May reverse formation of NAPQI
4. Multiple other salutory effects (4)
Most efficacious if given within 8 hrs. of ingestion, but never too late to be useful.
Duration of treatment: 20-hr. IV protocol (Europe & Canada >20 yrs.) now FDA approved:
150 mg/kg bolus over 15 min 50 mg/kg over 4hrs.--> 100 mg/kg over remaining 16 hrs.
Ingestions > 10 hrs. prior, &/or with transaminase elevations: Continue NAC until LFT’s
improving & INR <1.5. Caution is advised prior to discontinuing therapy in: alcoholics, the
malnourished, pregnancy, and those with markedly elevated (>300ug/ml) 4 hour serum levels.
Prognostic Indicators in Acetaminophen Toxicity and Acute Liver Failure
Kings College Criteria for transplantation:
Sensitivity low (26%) but specificity 92% (5)
Hyperphosphatemia:
On admission predicts poor outcome
(a surrogate for renal failure, or
an actual marker of regeneration?)
Creatinine > 3.5, plus
INR > 6-7, plus
Hepatic encephalopathy > Stage III
(drowsy or agitated/aggressive)
OR: Serum pH < 7.30
> 5 mg/dL  0% survival
2.5-5 “
 45% “
< 2.5
“  74% “
if PO4 is adequately repleted
(otherwise only 24%) (6)
APACHE Score>20 (APAP only): More sensitive than KCH criteria (68%); similar specificity (87%)
(7)
Other candidates: Lactate, AFP, MELD criteria ( both PPV & NPV lower than when used in setting
of chronic liver failure) & many others. (8)
AdditionalCauses of Acute Liver Failure
Viral: HAV, HBV (+/- HDV), HEV (pregnancy), HSV, CMV, EBV, HVZ, adenovirus,
hemorrhagic fever virus
Drugs: Idiosyncratic: Halothane, INH, rifampicin, valproate, NSAID’s, disulfuram, et al.
Dose-related: Acetaminophen, sulfonamides, tetracycline, ecstasy, cocaine
Currently available statins and thiazolidinediones have NOT been implicated!
Toxins (also dose related): Amanita phylloides, Bacillus cereus toxin, CCl4, yellow
Phosphorus
Herbs: Chaparral, germander, kava, ginseng
Vascular: Right heart failure, Budd-Chiari syndrome, portal vein thrombosis, “shock liver,”
heat stroke
Metabolic: Wilson’s Disease, acute fatty liver of pregnancy, HELLP, Reye’s syndrome,
autoimmune, malignancy, adult-onset Still’s disease
Undetermined: Still accounts for 20% (9)
Lab Workup: CBC, Chem 10 (phosphate), LFT’s, coags, acetaminophen level, urine tox screen,
lactate, hepatitis serologies, ammonia, free copper, (ceruloplasmin=acute phase
reactant; may be normal).
Imaging: Ultrasound if biliary process suspected; CT if malignancy a concern
Care is largely supportive: NAC may be useful in non-acetaminophen induced ALF; trial is
ongoing. (10)
Efforts to develop an “artificial liver” have not yet proven fruitful.
Nutrition: Enteral feeding preferred; no need to restrict protein
Hepatic Encephalopathy: Lactulose is still backbone of Tx; concern for renal failure with neomycin
Coagulopathy: FFP indicated only if active bleeding, or if a procedure is anticipated.
High risk for infection, especially SBP; low threshold to perform paracentesis
Hepatorenal syndrome; dialysis indicated if transplant candidate
Questions:
A) Which patients are likely to require > 20 hours of NAC?
1. The cachectic elderly lady brought in by family concerned by her lethargy. AST=145, ALT=252,
Acetaminophen level = 0. A large half-empty bottle of Tylenol is in her medicine cabinet.
2. The alcoholic waitress who takes a gram of Tylenol once or twice daily for her aches &
pains, and comes in to your E.R. complaining of nausea and vomiting. LFT’s are normal and
acetaminophen level is in the therapeutic range.
3. The 22 year old man who was convinced to come to the E.R. by his girlfriend after admitting to
her that he took a hundred extra-strength Tylenol capsules the day before.
4. The sobbing teenage girl who was at the mall with her boyfriend until 6 hours ago, & now has a
toxic APAP level.
a.
b.
c.
d.
e.
1, 2, 3
1, 3
2, 4
4
all of the above
Answer: b
1. Elevated transaminases suggest subacute or chronic toxicity. Many, if not most, of these patients
worsen initially, and require protracted courses of NAC.
2. Acetaminophen toxicity is not likely. If nausea and vomiting were due to acetaminophen
toxicity either her acetaminophen level or her transaminases would be elevated.
3. Subacute or chronic overdoses are more likely to result in hepatotoxicity and require protracted
NAC therapy.
4. This is likely an acute overdose.
B) Who is likely to require urgent transfer to a liver transplant center?
1.
2.
3.
4.
a.
b.
c.
d.
e.
Young man with INR 6.5, creatinine 1.9, pH 7.32 and stage III hepatic encephalopathy
40 year old woman with a phosphate of 5.2
Acetaminophen overdose with an APACHE score of 18
52 year old man with INR 2.0, creatinine 2.5, pH of 7.29
1,2,3
1,3
2,4
4
all of the above
Answer: c
1. Does not meet all three of the KCC, and pH isn’t low enough to trump them.
2. Hyperphosphatemia alone is a poor prognostic indicator
3. APACHE score needs to be > 20
4. Meets KCC criteria on the basis of pH alone (< 7.30)
Case Study
HPI : A 62 year old woman presented to the E.R. complaining of epigastric and RUQ pain. The pain
began 5 days ago & gradually increased. It was constant, severe, and exacerbated by deep inspiration.
She also reported nausea, anorexia, fatigue, night sweats and chills, but denied fever, vomiting,
diarrhea, melena, hematochezia and weight loss.
PMH: Rheumatoid Arthritis
MEDS: Prednisone 5 mg po daily
P/S: Rare Etoh
Spinal stenosis
Prevacid 30 mg. po daily
40 PYH Tobacco
COPD
Levothyroxine 0.125 mg. po daily
(quit 1988)
Hypothyroidism
Naproxen 500 mg. po bid
FHx : N/C
Physical Exam: Appeared stated age, normal habitus, and in no acute distress.
VS: T 37.2 HR 105 R 16
BP 92/50
HEENT: NCAT, anicteric, MM moist
NECK: Supple, w/o adenopathy or JVD
THORAX: CTA
CV: RRR, S1S2 no m/g/r
BACK: No CVAT
ABDOMEN: Obese, non-distended, with marked tenderness of epigastrum & RUQ, no rebound.
Bowel sounds normally active
EXT: without clubbing, cyanosis or edema
RECTAL: Nl sphincter tone, heme negative
NEURO: A&O x 3, appropriate, nonfocal
Labs: Hgb. 12.7 WBC 10.7 Plt. 297
INR 1.2 PTT 30.7
BUN 25 Creatinine 1.8 AST 1659 ALT 1386 Alk Phos. 650 Bili. 2.0/1.9
Electrolytes, amylase & lipase were normal
Abdominal 3-way: normal
EKG: normal
What is your initial diagnosis and management plan?
She was admitted and treated presumptively for acute cholecystitis with IV fluids, levofloxacin,
metronidazole, stress dose hydrocortisone, famotidine and meperidine.
What further studies would you want to obtain?
Abdominal ultrasound: small stone in gallbladder neck, otherwise unremarkable.
CT abdomen & pelvis (non-contrast): focal mural thickening in gastric antrum with possible
luminal constriction, adjacent peripancreatic inflammation, and several small retroperitoneal lymph
nodes. Liver unremarkable.
Now what?
EGD revealed a hiatal hernia and edematous gastric folds without discrete masses or ulceration.
Duodenum appeared normal.
ERCP: intra and extrahepatic biliary anatomy. Cystic duct filled freely; pancreatogram was
unremarkable.
The third hospital day her abdominal pain worsened and watery, blood-streaked stools, dyspnea, and
mild hypoxia developed. Her abdomen became more distended, and she had scleral icterus. AST was
5564, ALT 2979 and Tbili 4.3. WBC was 1.2 , Hgb. 10.7 and Plts. 127. PT and PTT were moderately
elevated. Tests for hepatitis B surface antigen, hepatitis B core antibody, hepatitis A IgM and hepatitis
C antibody were negative.
IV fluids and antibiotics were continued. Biopsy of the gastric mucosa revealed only mild chronic
inflammation. Review of the peripheral-blood smear showed a normochromic, normocytic anemia;
neutropenia with toxic granulation, and a mild thrombocytopenia. Tapering of the dose of IV
corticosteroids was begun.
On the fourth hospital day, progressive metabolic acidosis and hypotension developed, with worsening
hypoxemia, and the patient was transferred to the intensive care unit and intubated. She became
lethargic and difficult to arouse. Her serum transaminases continued to rise, and progressive renal
insufficiency and markedly elevated PY and PTT developed. Intravenous bicarbonate, vasopressor
medications, empirical acetylcysteine, and blood products were given, and the patient was transferred
to a tertiary care hospital.
She remained hypotensive despite receiving vasopressors. She became stuporous, and her neurologic
examination revealed hyperreflexia and clonus. She had a firm, distended abdomen and scattered
ecchymoses. At the referral hospital, the patient’s son revealed that she had begun taking an unknown
herbal remedy for her rheumatoid arthritis two weeks before the onset of her illness. Aslicylate and
acetaminophen levels were undetectable. Repeated abdominal ultrasonography revealed a
heterogeneous liver parenchyma, ascites, and a thickened edematous gallbladder with sludge and small
stones but no biliary dilatation.
Despite the use of supportive care, the encephalopathy, coagulopathy, hypotension, and acidosis
progressed, and the patient was not deemed to be a suitable candidate for liver transplantation. On the
fifth hospital day, asystole occurred and she could not be resuscitated. At the time of her death, her
hepatic failure was thought to be a consequence of exposure to some herbal toxin or the Budd-Chiari
syndrome.
At autopsy, her liver was congested and had extensive cholestasis. Microscopic review demonstrated
widespread necrosis and hemorrhage, as well as viral inclusions consistent with the presence of
fulminant herpetic hepatitis. On the day after her death, tests for IgM and IgG antibodies against HSV
were determined to be positive.
Adapted from: Bliss SJ, Moseley RH, Del Valle J, et al. A Window of Opportunity. NEJM 2003;
349:1848-53.