Acute Liver Failure - ALF
Yaakov Maor M.D.
Department of Gastroenterology and Hepatology
Sheba Medical Center, Tel-Hashomer
‫פרשת מקרה‬
‫בן ‪ ,51‬יליד ישראל‬
‫• מנכ"ל חברה נימצא ‪ 6‬חודשים בהודו‬
‫• ‪ 3‬שבועות הרגשה רעה‪ ,‬חוסר תיאבון‪ ,‬בחילות‬
‫• לפני שבועיים שתן כהה ובהמשך צהבת‬
‫• מיומיים "שינוי בהתנהגות" וישנוניות‬
‫• הוטס לארץ ישירות לחדר מיון‬
‫פרשת מקרה‬
‫בבדיקה‪:‬‬
‫• ישנוני אך ניתן להערה‬
‫• דופק ‪ 100‬לדקה‪ ,‬ל"ד ‪ ,100/60‬חום ‪37.3c‬‬
‫• צהבת בולטת בלחמיות ובעור‬
‫• רעד מסוג ‪Flapping Tremor‬‬
‫• ללא סימני מחלת כבד כרונית‬
‫• בטן רכה‪ ,‬הכבד נמוש בקצהו‪ ,‬הטחול אינו מוגדל‬
‫פרשת מקרה‬
:‫בבדיקות מעבדה‬
Bilirubin-15 mg/dL •
ALT-1800 IU/L; AST-1200 IU/L; ALP-220 IU/L •
Glucose-80 mg/dL; Creatinine-1.2 mg/dl •
INR-2.9 •
Hb-12.8 g/dL; WBC-4,300; PLT-133,000 •
pH-7.43; Lactate-21 mg/dL •
Ammonia-90 µg/dL •
Acute Liver Failure
• Definition –
Accurate diagnosis of the syndrome
• Etiology –
Determine prognosis and specific treatment
• Initial resuscitation and treatment
of complications
• Timely transfer to a Transplant Center!!!
Definition
• Rapid development of hepatocellular dysfunction –
Coagulopathy (INR 1.5), Jaundice
• Encephalopathy!!!
• Absence of a prior history of liver disease
(Wilson’s disease, autoimmune hepatitis)
Definition
• Interval between the onset of illness and
ALF <26 weeks (US ALF Study Group)
• Jaundice-to-encephalopathy interval (Prognosis):
- Hyperacute liver failure – Within 7 days
- Acute liver failure – 7 – 21 days
- Subacute liver failure – 21 days – 26 weeks
Etiology
• Viral infection – HAV, HBV (HDV), HCV?, HEV
• Acetaminophen – Predictable, Direct (ETOH)
• Idiosyncratic Hepatotoxicity – Halothane, Anti-TB
• Idiopathic (15-44%) – Occult viral infection?
• Rare: Autoimmune hepatitis, Wilson’s disease,
Budd-Chiari syndrome, Pregnancy related,
Toxins - Amanita Phalloides, Cancer
Etiology
160
Tx. Free survival
140
Transplanted
Transplant-Free
Survival Rate
120
Died Before Tx.
100
80
68%
63%
60
50%
17%
50%
50%
40
Transplant-free survival –
11% (0-25%)
12%
20
25% 0%
13%
AC
AP
Dr
ug
s
HB
V
HA
V
Sh
oc
k
AIH
Wi
lso
Pr
n
eg
na
B.C ncy
.S
yn
d
Ca
nc
er
Ind
Ot
he
ete
r
rm
ina
nt
0
11% 0%
Unfavorable
• Idiopathic
• Drugs (not ACPA)
• HBV (acute on chronic)
• Wilson
•
Etiology-Specific Therapies
• Acetaminophen - N-Acetylcysteine
• Hepatitis B – Lamivudine
• Pregnancy-associated – Urgent delivery
• Budd-Chiari syndrome - Angioplasty
• Amanita Phalloides - Penicillin, Silibinin
‫פרשת מקרה‬
‫• לחולה נימצאו נוגדנים‪Anti HAV IgM :‬‬
‫• אובחנה הפטיטיס ‪ A‬חריפה!‬
Natural History of ALF:
Acute Liver Failure
Acute Hepatitis
Acute Liver
Dysfunction
SIRS
DEATH
‫החייאה וניהול ראשוני – ביחידה לטיפול‬
‫נמרץ‬
‫• ניטור מצב הכרה וסימנים חיוניים‬
‫• החייאת נוזלים ומעקב תפוקת שתן‬
‫• מעקב ומתן גלוקוז ‪ -‬היפוגליקמיה‬
‫• אנזימי כבד‬
‫• מעקב בדיקות דם כולל‪:‬‬
‫• בילירובין‬
‫• גלוקוז‬
‫• קראטינין ואלקטרוליטים‬
‫• ‪ ,INR‬פקטור ‪V‬‬
‫• לקטט‬
‫• גאזים‬
‫• אמוניה עורקית‬
‫• ס‪ .‬ד‬
Encephalopathy – Precipitating Factors
Non-neurological:
• Sepsis and SIRS!
• Hypoglycemia
• Hypoxemia
• Renal failure
Neurological:
• Occult seizures - 33% stage 3 – 4 encephalopathy
• Cerebral edema
Stages of Encephalopathy
• Stage 1 – Affect, insomnia, concentration
• Stage 2 - Drowsiness, disorientation, confusion,
Agitation! Asterixis appears
• Stage 3 - Marked somnolence and incoherence
• Stage 4 - Coma
Encephalopathy - Management
• Quient enviroment!
• Maintain the patient's head at a 30° to
improve jugular venous outflow
• Sedative-hypnotic drugs should be avoided –
Clinical monitoring – Use Propofol!!!
• Treat reversible conditions e.g., hypoglycemia
• Patients encephalopathy stage 3 – 4 – intubation:
- airway protection
-  Intra Cranial Pressure – ICP
Encephalopathy - Management
• Brain CT - Mass, intracranial hemorrhage, and
evidence of brainstem herniation
• Correlation between CT evidence of cerebral edema
ande ICP is imperfect
• Monitor and treat deeply sedated patients with
phenytoin for sub-clinical seizure?
ICP Monitoring
• Most accurate way to detect intracranial hypertension
• Should be limited to specialized units and to patients
awaiting LTS with stage 3 – 4 encephalopathy
• Has not been shown to increase survival
• Aims:
- ICP <20-25 mm Hg
- Cerebral perfusion pressure (CPP) =
Mean Arterial Pressure (MAP) –
Intra Cranial Pressure (ICP) >50-60 mm Hg
ICP Monitoring
• Requires correction of underlying coagulopathy –
Prognostic factor
• Portal of entry for infectious organisms
• Can precipitate intracranial hemorrhage
• Trans-cranial Doppler has not been validated for
ICP monitoring
Treatment of  ICP
• Osmotherapy
Mannitol –
IV bolus of 0.5 to 1 g/kg 20% solution –
May be repeated until plasma osmolarity
reaches 320m Osm/L
• Therapy with mannitol requires preserved renal
function (or hemofiltration)
• Hypertonic NaCl 30% –
Maintain serum Na+ levels of 145-155 mEq/L
Treatment of  ICP
• Hyperventilation - Cerebral vasoconstriction -  CBF
• New therapies:
- N-Acetylcysteine (In non-acetaminophen ALF)
Recently: Patients with early encephalopathy
showed higher spontaneous survival rate
- Mild hypothermia (32C - 34c)  ICP via  CBF
• Not in use !!!
- Lactulose – No proven benefit
- Barbiturate
Coagulopathy
• Avoid plasma/PLT administration:
- Index of hepatic function
- Volume overload
• Indications:
- Bleeding
- Invasive procedures
- Prophylactic: PLT count <20,000; INR >7
• aFVII may be advantageous
Coagulopathy
• Monitor INR q 6-12 h
(Obtain Factor V when INR> 2.5)
Day
INR
2#
3
3#
4
4#
5
Transfer to transplant Center
Infections
• Develop in 80% of patients
• Accounts for 25% of patients who are excluded from
liver transplantation
• Clinical recognition of infection is difficult:
SIRS may occur without infection
• Infection may be without fever/leukocytosis in 30%
• High level of suspicion for infection should
be maintained with a low threshold for
administration of antibiotics!!!
Management - General
• ICU admission and supportive treatment
• Timely transfer to a Transplantation Center
• Liver transplantation –
The Only Established & Definitive Treatment
Predictors of Prognosis
Patients with ALF fall into two categories:
• Intensive medical care enables recovery of
hepatic function – Allow time for regeneration!!!
• Require liver transplantation to survive
Predictors of Prognosis
Determinant of prognosis:
• Regeneration
• Liver dysfunction
• Encephalopathy and Brain edema
• Multi-Organ Failure – MOF
Predictors of Prognosis
Avoid the following two scenarios:
• Death of the patient despite intensive medical
care without consideration of transplantation
• Unnecessary liver transplantation when
recovery would have occurred spontaneously –
Surgical mortality, lifelong immunosuppression
Liver Transplantation
• Clinical decision making aided by
prognostic markers
• Before the era of liver transplantation –
<50% survival
• Liver transplantation for ALF –
63% - >70% (Lower than other etiologies)
King’s College Hospital Criteria
ALF secondary to acetaminophen overdose:
• pH <7.30 (irrespective of encephalopathy grade)
or
• Hepatic encephalopathy grade III-IV
• INR >6.5
• Creatinine >3.4 mg/dL
• Arterial Lactate >27 mg/dL
King’s College Hospital Criteria
ALF with other causes:
• INR >6.5 (irrespective of encephalopathy grade)
or any three of the following
(irrespective of encephalopathy grade)
•
•
•
•
•
Age <10 or >40 years
Non-A, non-B hepatitis or drug-induced origin
Duration of jaundice before encephalopathy >7 days
Bilirubin >17.6 mg/dL
INR >3.5
Clichy Criteria
Stage III-IV encephalopathy associated with:
• Factor V level <20% in patients <30 years
• Factor V level <30% of normal in patients >30 years
(Based on cohort of patients with acute hepatitis B)
Predictors of Prognosis
• Model for End-Stage Liver Disease (MELD) Score –
(Bilirubin; INR; Creatinine)
• Elevated Alpha-Fetoprotein
(Indicator of regeneration)
• APACHE II
Liver Transplantation
• Contraindications to transplantation:
- Irreversible brain damage (CPP <40 mm Hg)
- Active extra-hepatic infection
- Multiple-organ failure syndrome – MOF
• Consider living-related liver transplantation
‫פרשת מקרה‬
‫• הוחל טיפול ב‪ 6 N-Acetylcysteine -‬מ"ג לק"ג לשעה‬
‫אבל‪...‬‬
‫•‬
‫•‬
‫•‬
‫•‬
‫מצב הכרה – ישנוני יותר – שלב אנצפלופתי ‪III-II‬‬
‫הונשם ומקבל ‪Propofol‬‬
‫‪ INR‬עלה ל‪ ;6 -‬פקטור ‪15% -V‬‬
‫קראטינין עלה ל‪1.9 mg/dl -‬‬
‫העברה למרכז השתלות‬
Intensive care
Etiology – specific Rx.
Consultation with LTS center
Contraindication for LTS
Yes
No
Transfer to LTS center –
National status one
Re-assess for
recovery or
contraindication for
LTS
No
Liver Transplantation
‫• קשר טלפוני ראשוני‬
Yes
Continue
intensive
support
Ongoing
intensive care
:‫• העברה כאשר‬
II ‫• אנצפלופתיה דרגה‬
,‫ לקטטמיה‬,‫• חמצת‬
‫• היפוגליקמיה‬
‫• קואגולופתיה מטפסת‬
‫פרשת מקרה‬
‫• נוצר קשר עם מרכז השתלות בבלגיה‬
‫• הועבר בהטסה להמתנה להשתלת כבד‬
Experimental Therapy
• Provide a bridge to liver transplantation/
Spontaneous regeneration and recovery
• Auxiliary liver transplantation
• Extracorporeal liver support devices:
- Hemodiadsorption systems
- Bioartificial liver devices
• Nonhuman liver transplantation
• Hepatocyte transplantation