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Acute Liver Failure
1. Acute Liver Failure
Dr. Anand Naik
IDDCM STUDENT
SAHYADRI
SUPERSPECIALITY
HOSPITAL PUNE
10/05/23
2. Definition:
• Development of
1) Increased liver enzymes
2) Impaired synthetic function (INR of ≥1.5)
3) Altered mental status in a patient without preexisting liver disease.
• Subcategorized based upon how long the patient has been ill,
• (Onset of symptoms to-> development of encephalopathy)
HYPERACUTE
(<7 days)
ACUTE
(7 to 21 days)
SUBACUTE
(>21 days and <26
weeks)
CEREBRAL
EDEMA
RENAL FAILURE
AND PORTAL
HYPERTENSION
Common
Presentation
UpToDate
3. • Underlying liver in patients with ALF before illness is essentially normal
except:
1) Wilson’s disease
2) Hepatitis B reactivation
Acute Liver Failure
Fulminant Hepatic Failure Subfulminant Hepatic Failure
9. Infections(Salient Points)
• Hepatitis B -> Can be primary infection or reactivation
• Hepatitis A -> vaccination available, developing nations
• Hepatitis E -> Endemic & developing countries -> High Mort in Pregnancy
• Hepatitis D -> Co-infection with Hep B
• HSV Hepatitis (1&2) Patients taking steroids, HIV-infected patients,
malignancy,post liver transplant and pregnant patients.
• Herpes Zoster hepatitis in advanced HIV , RASH +/-
• Adenovirus is an acute diarrheal illness with hepatitis
• CMV may have subclinical transaminitis in immunocompetent, ALF in
immunocompromised
• Dengue Hepatitis
10. Drug Induced (Dose Dependant)
• Acitaminophen is most common drug causing ALF in United states.
• Dose dependent and rarely occurs at therapeutic doses.
• Therapeutic Dose- up to four grams per day in a patient without liver disease
• Most cases occur after ingestion of large doses in an attempt to commit
suicide.
• “Therapeutic misadventure“ - when multiple acetaminophen-containing
medications are taken together
• Increased risk in alcoholics and those having pre-existing liver disease,
malnutririon.
• Rumack–Matthew nomogram it plots serum concentration against the time
since ingestion, in order to predict possible liver toxicity, and NAC use. Only
Acute intoxication)
11.
12. • Other Mechanism for Drug induced liver failure are Idiosyncratic reaction
and Hypersensivity(Halothane)
Drug Induced
UpToDate
13. Other causes:
• Hypoperfusion of the liver can result in ischemic hepatitis and acute liver
failure.
• Hypoperfusion may result from systemic hypotension due to causes such as
cardiac dysfunction, sepsis, or drugs
• Acute liver failure may also be seen with Budd-Chiari syndrome (hepatic vein
thrombosis), veno-occlusive disease, or the use of vasoconstricting drugs such
as cocaine and methamphetamine.
• Uncommon Causes:
1)Pregnancy Related ALF (Acute Fatty Liver of Preganacy, HELLP Syndrome)
15. Pathophysiology
Changes in gut microbial flora, small
bowel microbial overgrowth
Increased ammonia
produced in gut
Enterohepatic
circulation
Loss of liver function
Increased circulating
ammonia
Increased circulating
ammonia Ammonia gets converted into Glutamine-> Mito
Dysfunction
Increased intracellular osmolarity of astrocytes->
Hepatic Enceph, Cerebral Edema
Contribution by SYSTEMIC
INFLAMMATORY
RESPONSE/Infection/MODS
Hepatic Encephalopathy
Coagulopathy
Metabolic
Abnormalities
Immunocompromised
18. • Symptoms — Many of the initial symptoms in patients with acute liver failure
are nonspecific
• The presence of hepatic encephalopathy is one of the defining characteristics
●Fatigue/malaise ●Lethargy ●Anorexia ●Nausea and/or vomiting ●Right upper quadrant pain ●Pruritus
●Jaundice ●Abdominal distension
21. 1) Altered mental status
2) Jaundice
3) Right Upper Quadrant abd pain
4) Malaise, Fatigue , nausea & Vominting
Onset <26 weeks
Suspect ALF
Confirm Diagnosis:
1) Liver function Test
2) Prothrombin Time
3) USG/ CT ABDOMEN
DETERMINATION OF ETIOLOGY
22. • A cause for acute liver failure can be established in approximately 60 to 80
percent of patients
1) HISTORY –
-History of alcohol use
-Medication use
-History of depression or prior suicide attempts
-Travel to areas endemic for hepatitis A or E
-Intravenous drug use
-Sexual exposure
-History of blood transfusion
-Hypotension, cardiac failure, a hypercoagulable disorder, oral
contraceptive use, or malignancy -> Ischemia of liver
-Family history of liver disease such as Wilson disease, AIH
DETERMINATION OF ETIOLOGY
25. 9) Arterial blood gas
10) Arterial ammonia
11) Serologic testing for HIV
12) Ceruloplasmin level in patients suspected Wilson disease (+-)
Typical Findings
• Elevated aminotransferase levels
• Elevated bilirubin level (Direct + Indirect)
• Prolonged prothrombin time, resulting in an INR ≥1.5
• Low platelet count (≤150,000/microL), but this is variable and has been associated
with clinically significant portal hypertension.
• Coombs Positive Anemia- AIH
• Coombs Negative Anemia- Wilsons
26.
27.
28. • Neuroimaging (head CT or magnetic resonance imaging [MRI])-
1) Evidence of cerebral edema
2) Decrease in the size of the ventricles
3) Flattening of cerebral convolutions
4) Attenuation of the signal intensity of brain parenchyma
• An electroencephalogram may reveal seizure activity, even in the absence of
clinical signs of seizures.
• USG Abdomen & Doppler/Abdominal computed tomography (CT)
-> Size , increased in Budd Chiari syndrome , Malignant Infiltration, alcohol
-> Presence of Portal Hypertension may indicate Subacute pathology
29. • Liver biopsy - Our practice is to obtain a liver biopsy in patients with acute
liver failure of indeterminate etiology who are hemodynamically stable
with low bleeding risk.
-> STRONGEST INDICATION -> EXCLUDE MALIGNANT INFILTRATION/
ALCOHOLIC HEPATITIS IN PATIENTS POSTED FOR LIVER TRANSPLANT.
• Other characteristic findings in Liver Biopsy
1) Wilson’s disease-> Interface hepatitis
2) Acute FLP-> Fatty Infiltration
3) Budd Chiari Syndrome-> Venous sinusoidal congestion
31. General Management
• Patients with acute liver failure should be managed in centers with an active
liver transplantation program and expertise in caring for these patients since
only 40% patients recover on own.
• Hemodynamic management
1) Intravascular volume depletion -> due to drceased oral intake and extra
vascular fluid shift -> Normal saline , Normal Saline + 75 meq Bicorbonate (if
patient acidotic, Dextrose containing fluid prevents hypoglycaemia.
However, it is important to avoid overhydration since it may worsen
cerebral edema
-The goal is to maintain a mean arterial pressure of at least 75 mmHg or a
cerebral perfusion pressure of at least 50 to 60 mmHg.
-Noradrenaline (1st choice) -> Vasopressin may be added
-If hypotension/ shock persist even after-> trial of hydrocortisone (since
these patients have adrenal insufficiency)
32. 2) N-acetyl cysteine-
-Used for the treatment of acetaminophen toxicity, but it may be beneficial in
other forms of acute liver failure.
33. • Dose of n-acetyl cysteine
1) Loading dose -> 150mg/kg
2) Maintainance dose-> 100mg/kg within 24 hours , until INR <2
NO ROLE OF L-ORNITHINE L-ASPARTATE(Acharya SK et al)
NO ROLE OF BRANCHED CHAIN AMINO ACIDS (Gluud L et al)
AIRWAY MANAGEMENT->
• Intubate if grade 3 encephalopathy
• Sedation if needed propofol(antiseizure activity), fentanyl
34. 3) Bleeding prevention-
-Balanced Hemostatic Compromise, INR might not be a good indicator of coagulopathy.
- Prophylactic administration of fresh frozen plasma is not recommended since it has
not been shown to influence mortality in a small randomized trial
- Because the most common site of bleeding is the gastrointestinal tract, patients should
receive stress ulcer prophylaxis with an H2 blocker or proton pump inhibitor.
- Vitamin K injection 10mg iv/oral to patients suspected of having nutritional deficiency.
- FFP in patients with active bleeding/ before invasive procedure (10 mL/kg and one
unit of single-donor platelets, based on INR and platelet count)
- Thrombocytopenia <50000 platelets with bleeding, invasive procedure , <10000
without bleeding
35. 4) Infection surveillance and prevention-
- Patients are immunocompromised,most common sites of infection are the
respiratory tract, the urinary tract, and the blood.
- Localizing signs of infection, such as fever and sputum production, are
frequently absent.
- Guidelines from the AASLD(American Association for the Study of Liver
Diseases) and EASL(European Association for the Study of the Liver) suggest
that all patients (including those without signs of infection) should have routine
urine, sputum, and blood cultures, as well as chest radiographs to detect
bacterial or fungal infection.
- The role of prophylactic antibiotics is controversial. While a randomized trial
with 59 patients with acute liver failure who were not infected at entry found
that prophylactic antibiotics reduced the rate of infection, a survival benefit
was not seen
36. -If the decision is made to provide empiric broad spectrum antibiotic coverage,
nephrotoxic antibiotics, particularly the aminoglycosides, and hepatotoxic
antibiotics should be avoided.
-We often use piperacillin/tazobactam or a fluoroquinolone. In addition,
surveillance cultures are not needed in patients receiving antibiotic prophylaxis.
5) Nutrition –
-To prevent protein catabolism, severe protein restrictions should be avoided; a
daily intake of 60 grams of protein is reasonable for most patients with acute
liver failure.(25-30kcal/kg , 1.2gm protein/kg)
-In patients with grade I or II encephalopathy- Oral/enteral
-grade III or IV - Enteral feeding
-Placement of a nasogastric tube can increase intracranial pressure (because of
gagging) and should generally be performed only in patients who are intubated
and sedated
If adequate enteral feeding cannot be provided, parenetral should be initiated.
UpToDate
37. • Sedation should be avoided in general since
1) Clearing of sedatives is hampered
2) Sedatives may mask features of encephalopathy/ cerebral edema.
3) If at all used , ultrashort acting benzodiazepines to be used for agitation and
+-Propofol infusion
• Unhelpful treatments UpToDate
TREATMENT TRIAL
Glucocorticoids, which increase the risk of sepsis Steroid use in acute liver failure. Karkhanis J, Verna EC
, Hepatology. 2014 Feb;
Hepatic regeneration therapy using insulin
and GLUCAGON
Treatment of fulminant hepatic failure with insulin
and glucagon. A randomized, controlled trial. Woolf
GM, Redeker AG
Dig Dis Sci. 1991;36(1):92.
Charcoal hemoperfusion Controlled trials of charcoal hemoperfusion and
prognostic factors in fulminant hepatic failure.
O'Grady JG, Gimson AE
Gastroenterology. 1988;94
38. TREATMENT OF THE UNDERLYING CAUSE
Acetaminophen
toxicity
Hepatitis B
infection
Mushroom
poisoning
Budd-Chiari
syndrome
Herpes simplex virus
infection
Wilson disease
Autoimmune
hepatitis
Acute fatty liver
of pregnancy
CAUSE NOT KNOWN
N-acetylcysteine
(<8HOURS)
Anti-vial
Entacavir/tenofovir
Activated
charcoal
transjugular intrahepatic
portosystemic shunt
placement, surgical
decompression, or
thrombolysis
Acyclovir
Liver
transplant,plasma
exchange for
copper removal
Glucocorticoids+- delivery once the
mother has been
stabilized
N-acetylcysteine
39. COMPLICATIONS
1)Metabolic abnormalities
- Respiratory Alkalosis- Hyperventilation
- Metabolic alkalosis- Hypoalbuminic alkalosis-> may contribute to hepatic
encephalopathy by facilitating ammonia entry into the brain by promoting the
conversion of ammonium (NH4+), a charged particle that cannot cross the
blood-brain barrier, into ammonia (NH3).
-Metabolic Acidosis- circulatory failure, lactate buildup -> met acidosis
-Hypokalemia (diuretic therapy and increased sympathetic tone,)
-Hyponatremia (SIADH)
-Hypoglycemia
On the average, a decrease in plasma albumin concentration of 1 g/dl produces an
increase in "standard" bicarbonate of 3.4 mM/liter, and an apparent base excess of
+3.7 meq/liter; it also reduces the value of the normal anion gap by about 3
meq/liter.
40. 2)Hepatic encephalopathy
-Lactulose is commonly used in patients with hepatic encephalopathy due to
chronic liver disease, its use in acute liver failure is controversial.
-One concern with the use of lactulose is that it may lead to bowel distension
that could result in technical difficulties during liver transplantation.
-We do not routinely treat patients with acute liver failure with lactulose.
-Continuous renal replacement therapy (CRRT) has been used successfully to
remove ammonia and/or manage fluid balance in patients with acute liver
failure
UpToDate
41. - Role of Neomycin/Rifaximin in ALF is controversial.
- We do not use rifaximin for the treatment of hepatic encephalopathy in
patients with acute liver failure.UpToDate
42. 3) Cerebral edema-
-Present in 25 to 35 percent of those with grade III encephalopathy and in
approximately 75 percent of those with grade IV encephalopathy.
-The consequences of cerebral edema include intracranial pressure (ICP)
elevation, brain ischemia and hypoxia, and brainstem herniation, which are
the most common causes of death in acute liver failure.
-Methods to prevent ICP elevation include minimizing patient
agitation/stimulation, elevating the head of the patient's bed, maintaining
optimal fluid balance, and prophylactic administration of hypertonic saline.
-Patients should be placed in an environment with minimal sensory
stimulation since stimulation can raise ICP.
- Nasogastric tube placement can cause gagging and thus should generally be
performed only in patients who are intubated and sedated.
43. -Maintain serum sodium levels of 145 to 155 mEq/L or standard treatment
alone.
- Patients with an elevated ICP, the goals of therapy are to reduce the ICP to
below 20 to 25 mmHg and to maintain cerebral perfusion pressure above 50
to 60 mmHg(normal 60-80)
A bolus of mannitol (0.5 to 1.0
g/kg) is typically the first-line
therapy for patients with an
elevated ICP. Two additional
boluses may be given ( maintain
plasma osmolality <320)
3% NS , useful PREVENTING
raised ICP however not
useful once ICP is already
increased.
Hyperventilation
-Transient Effect
-Decreasing the PaCO2 to 25 to
30 mmHg via hyperventilation
restores cerebrovascular
autoregulation
If other measures to treat severe ICP
elevation fail, a barbiturate coma
should be induced
with pentobarbital or thiopental.
- 3 to 5 mg/kg intravenously
NO ROLE OF GLUCOCORTICOIDS
-EXPERIMENTAL THERPAY-
1)HYPOTHERMIA INDUCTION
2)ROLE OF INDOMETHACIN
44. Role of ICP/Neuromonitering in ALF?
• Non invasive monitering -> Serial CT, Transcranial Doppler, Pupilometry -> No
role (Kandiah PA, Olson JC, Subramanian RM. Emerging strategies for the treatment of patients with acute hepatic failure. Curr Opin Crit
Care. 2016 Apr;22(2):142-51. doi: 10.1097/MCC.0000000000000291. PMID: 26849251.)
• Owing to high bleeding risk and unproven role-> routine invasive ICP
monitering is not advised in all patients of ALF.
• There may be a role of ICP monitering in patients with ALF with Grade ¾
enceph, pupillary abnormality and very high levels of ammonia (>150mcmol/L)
which could lead to herniation ( Rosen DR, Magee GA. Who should undergo ICP monitering in acute liver failure A
consise clinical review . PulmCCM J)
45.
46. 4)Seizures –
-Seizure activity in patients with acute liver failure is common but may be difficult
to detect if patients are intubated and receiving paralytics.
-If patient is intubated/sedated->use sedatives with anti-seizure activity
-If without sedation -> Daily EEGs to monitor for seizure activity
-Seizure should be treated promptly because seizure activity increases ICP and
may cause cerebral hypoxia.
-Phenytoin , short acting benxodiazepines can be used.
-No role of prophylactic anti convulsants.
5) Acute kidney injury
- Fluid challenge-> norad to maintain bp
- Avoid nephrotoxic drugs/contrast
-CRRT>Intermittent hemodialysis (citrate anticoagulation with calcium
monitering)
48. • The decision to proceed with liver transplantation depends upon the probability
of spontaneous hepatic recovery.
• The goal is to differentiate patients who are likely to benefit from liver
transplantation from those who are likely to recover spontaneously.
• In the United States and Europe, patients with acute liver failure who require
transplantation are given the highest priority on the transplantation list.
• It is important to determine if the patient has contraindications to
transplantation.
49. • As a general rule, the most important factors for predicting the outcome in
acute liver failure are
1) Degree of encephalopathy
2) Age
3) Cause of the acute liver failure
• Patients younger than 10 or older than 40 years of age may have a lower
likelihood of spontaneous recovery compared with patients between these
ages.
50. • The transplant free survival rate was ≥50 percent in patients with acute
liver failure due to acetaminophen, hepatitis A, ischemia, or pregnancy-
related acute liver failure.
• <25 percent for those whose liver failure was due to hepatitis B,
autoimmune hepatitis, Wilson disease, Budd-Chiari syndrome, cancer, or
an indeterminate cause.
• INR and arterial ammonia levels, have been used to predict the probability
of recovery, but their predictive accuracy has not been well established.
52. • Several models have been developed
1) The King's College Criteria
2) Model for End-Stage Liver Disease (MELD) score (Chronic>Acute)
3) Sequential Organ Failure Assessment (SOFA score)
4) The Clichy criteria (Encephalopathy and low Factor V levels)
5) Acute Liver Failure Study Group (ALFSG) index
53. • King's College Criteria-
-The King's College Criteria were developed in a cohort of 588 patients with
acute liver failure who were managed medically between 1973 and 1985.
-Most commonly used and best validated criteria
-Not used in
1) Case of pregnancy related complications leading to liver failure
2) Acute Budd Chiari syndrome
3) Wilsons Disease
4) Trauma
5) Pediatric liver failure
( EASL advocates transplant fro patients with ALF from Budd chiari syndrome
& Wilsons disease associated with any grade of encephalopathy)
54. Refer the patient for
Liver transplant if –
(these patients will have
high mortality without
transplant)
55. • Model for End-stage Liver Disease (MELD) score
(Initially used for predicting 3 month mortaility of post TIPS patients)
-Uses a patient's laboratory values for
1) Serum bilirubin
2) Serum creatinine
3) International normalized ratio
- Score ranges from 6-40 (The higher the number, the more likely you are to
receive a liver from a deceased donor when an organ becomes available)
-Higher the MELD score, poorer is the prognosis and more should the patient
prioritised for liver transplant.
• Addition of Sodium to MELD score increases transplant priority in 12% of
patients. (MELD Na – MELD + 1.59 (135-Na mEq/L)
56. Kings college criteria Vs MELD criteria
• In a study of 91 patients with non-acetaminophen-related acute liver failure,
the MELD score was compared with the King's College Criteria.
• The King's College Criteria had a sensitivity and specificity for mortality of
88 and 71 percent, respectively. Similar results were obtained when a MELD
score of 32 or higher was used to predict mortality (sensitivity of 79 percent
and specificity of 71 percent).
57. • Clichy-Villejuif Criteria
- Encephalopathy + Factor V level <20% in age <30 years
OR
Factor V level <30% in age >30 years
58. Liver support
• A number of approaches to perform the functions of the liver in an attempt to delay
or obviate the need for liver transplantation in patients with acute liver failure
continue to be studied.
1) Artificial hepatic assist devices
2) Auxiliary liver transplantation
3) High Volume Plasma Exchange
4) MARS
Artificial hepatic assist devices
Non-cell-based systems
1) Plasmapheresis
2) Plasma exchange
3) Albumin dialysis
4) Charcoal-based hem-
adsorption
Bioartificial liver support
systems
(Encorporates
hepatocytes or hepatic tissue)
59.
60. Auxiliary liver transplantation
• Auxiliary liver transplantation involves placement of a reduced-size liver
graft adjacent to the patient's native liver known as auxiliary heterotopic
liver transplantation.
OR
• Hepatic bed after a portion of the native liver has been removed known as
auxiliary orthotopic liver transplantation.
• A potential advantage is that this procedure may support the patient while
the native liver regenerates, obviating the need for chronic
immunosuppression
• While auxiliary liver transplantation shows promise, the procedure is
technically difficult, and has not been adequately evaluated in controlled
clinical trials.
61. It is an
exchange of 8-
12 L or 15% of
ideal body
weight with
fresh-frozen
plasma
62. Molecular Absorbent Recirculating System
• It is an extracorporeal hepatic support
system that integrates the mechanisms
of dialysis, ultrafiltration, and
adsorption.
• Removes water soluble as well as
albumin bound toxins.
• MARS exploits the usage of three
different circuits
1) Blood circuit that utilizes
hemodialyser
2) Albumin circuit that contains an
anionic exchange column
3) Activated charcoal adsorber
