Pathophysiology of Acute liver

failure
Pr Haoudar Amal

First Aid and Experimental Medecine

Experimental Medecine
Pathophysiology of Acute liver Failure

S3
2023-2024

www.um6ss.ma
Case study:

A 32-year-old, male,
admitted for suspicion of
pulmonary tuberculosis. Jaundice
A full antituberculosis
treatment was started.
3 days later, he presented Encephalopathy
the following symptoms:

GI bleeding

2
Case study:

Jaundice

Acute liver failure Encephalopathy

Drug toxicity
GI bleeding

3
Introduction:

ALF is a life-threatening critical illness characterized by severe hepatocyte injury that

occurs in less than 26 weeks and can occur in days.

ALF presents with rapid-onset elevation of aminotransferases, altered mental status,

and coagulation abnormalities.

The pathophysiology involves massive hepatocyte necrosis causing cellular swelling and
membrane disruption.

Encephalopathy and cerebral edema may develop, along with multiorgan failure and
death.

The two most common etiologies are drug-induced liver injury and viral hepatitis.

Early management should include consideration for transfer to a transplant center for
potential transplantation
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Learning Objectives:

1-Define ALF

2-Identify the common etiologies of acute liver failure

3- Describe the drug-induced liver injury

4- Define the toxic dose of acetaminophen in a healthy adult

5- Explain the pathophysiology of ALF following an acute toxic

ingestion of acetaminophen

6- Identify the treatment for acute toxic ingestion of

acetaminophen

7- Describe the management of ALF

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1 Liver Anatomy and Physiology:

• Gross Anatomy:

• The liver is located in the upper right-

hand portion of the abdominal cavity,
beneath the diaphragm, and on top of the
stomach, right kidney, and intestines.
• The liver consists of 2 main lobes.
• Both are made up of 8 segments that
consist of 1,000 lobules (small lobes)

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1 Liver anatomy and physiology:

• Gross anatomy:

The lobules are connected to small

ducts (tubes) that connect with
larger ducts to form the common
hepatic duct.
The common hepatic duct
transports the bile made by the
liver cells to the gallbladder and
duodenum via the common bile
duct.

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1 Liver anatomy and physiology:

• Gross anatomy:

• The liver receives the highest proportion of

cardiac output of all the organs in the body:
25% via the portal vein and hepatic artery.

• The portal vein, provides 75% of blood flow to

the liver, it accounts for only 50% of oxygen
delivery given the portal venous blood’s the pressure gradient of blood flow
deoxygenated state after perfusing organs to the liver.
such as the stomach, intestines, spleen, and
pancreas.

• The hepatic artery provides the remaining

25% of liver blood flow and 50% of oxygen
delivery due to its higher oxygen content.

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1 Liver anatomy and physiology:
• Liver functions:
Function Description
Synthesis of glucose and glycogen Regulates blood glucose by producing, storing, and
releasing glucose when needed
Synthesis of cholesterol and proteins Provides support and aids in biosynthesis of hormones
and vitamins

Metabolism of fats, proteins, and carbohydrates Generates energy for homeostatic processes to occur

Metabolism of drugs Cytochrome P450 enzymes in the liver deactivate or

bioactivate drugs to a form that can be used by the body

Detoxification of blood Clears harmful substances in the blood such as bacteria

and toxins

Digestion of food Produces bile to break down fats, vitamins, and minerals

Synthesis of acute phase reactants for Help to surmount and stimulate an immune response

immune support
Processes hemoglobin and stores iron Regulates blood iron concentrations by increasing and
decreasing the storage of iron as needed

Synthesis of coagulation factors and plasma Helps to regulate hemostasis

proteins
Assistance with volume control by blood Reservoir function allows release of blood during
hypovolemia or acute blood loss 9
reservoir function
1 Liver anatomy and physiology:
• Liver functions:

Protein breackdown=deamination=ammonia

Ammonia, a waste product of protein metabolism, is converted to

urea by the liver to be excreted by the kidneys.

Proteines

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2 Assessement of the liver function:

• Lab workup:
•The standard hepatic function panel assesses the following:
✓ Total protein
✓ Bilirubin
✓ Albumin
✓ ALT
✓ AST
✓ AST/ALT ratio
✓ Alkaline phosphatase(ALP)

•Hepatic proteins can be grouped by the type of derangement of liver function they
measure:
• Parameters of liver damage: ALT, AST, AST/ALT ratio, and glutamate
dehydrogenase (GLDH)
• Parameters of biliary disease: gamma-glutamyl transpeptidase
(GGTP), ALP and bilirubin
• Parameters of hepatic synthesis: albumin, cholinesterase, Prothrombine
timeT

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2 Assessement of the liver function:

• Parameters of the liver

damage:
• When hepatocytes are damaged, they release
their enzymes into the circulation
• The magnitude of enzyme level derangement
reflects the severity of liver damage.

• The true tests of liver function are PT and albumin

• Albumin is synthesized exclusively in the liver and can be used as a
general measure of hepatic synthetic function.
• Clotting factors are largely synthesized in the liver; abnormalities of
coagulation can be a marker of hepatic synthetic dysfunction.

• The others only signify altered function and do not correlate with
overall synthetic activity of the liver

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2 Etiology of ALF:

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4 Pathophysiology:

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:
Drug-induced liver injury is quite common and can be caused by several classes of
drugs.

Can occur with over-the-counter medications, herbs, supplements:

Antibiotics Acetaminophen NSAIDs Antiepileptic Antituberculosis

Acetaminophen overdose (accidental or intentional) remains the most common

cause of drug-induced liver injury

Recognition and removal of the offending agent as quickly as possible can help
prevent the progression to hepatitis or liver failure.

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:

Most common cause of acute liver failure (ALF) in the US and UK

At-risk populations:
• Limited literacy
• Heavy APAP use
• APAP/opioid combination use

Significant number of overdoses are unintentional:

• Failure to recognize APAP contents in medication
• Incorrect understanding of dosing directions
Early identification of overdose is associated with low mortality
rates.

Development of ALF:
• Associated with 28% mortality
• One-third of cases with ALF require liver transplantation.

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:
Acetaminophen Pharmacokinetics :

•APAP is quickly absorbed via the GI tract.

•Therapeutic dose serum concentrations peak after 0.5–2 hours.
•In overdose:
• Serum concentrations peak within 4 hours.
• Can be > 4 hours if taken with drugs that delay gastric
emptying
•Therapeutic dose:
• Children: 10–15 mg/kg every 4–6 hours
• Adults: 325–1,000 mg every 4–6 hours (maximum: 4 g a
day)
•Toxic dose (single ingestion):
• > 250 mg/kg or > 12 g over a 24-hour period
• Note: lower dose threshold for alcoholics/anticonvulsant
users
• Ingestion of > 350 mg/kg likely to result in severe
livery toxicity if untreated
• Severe livery toxicity: peak AST or ALT> 1,000 IU/L 17
4 Pathophysiology:

• Acetaminophen induced acute liver

failure:
Normal metabolism

•About 90% is metabolized in

the liver to sulfate and glucuronide
→ excreted in urine

•Remaining undergoes oxidation

via hepatic cytochrome P450
And produces the toxic
metabolite N-acetyl-p-
benzoquinone-imine (NAPQI)

• NAPQI is normally detoxified

by glutathione →
nontoxic cysteine
• Excreted in urine

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:

•At therapeutic doses of APAP:

• NAPQI pathway is relatively
underutilized.
• NAPQI metabolites are
rapidly conjugated to
nontoxic compounds.

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:
•At toxic doses:

• Primary hepatic metabolism pathways become oversaturated.

• ↑ APAP metabolism via cytochrome P450→↑ NAPQI production

• ↑ NAPQI depletes glutathione levels and saturate

the elimination pathways

• ↑ Free NAPQI binds with hepatic macromolecules → produce

NAPQI-protein adducts (irreversible process) → ↑ oxidative
stress
→ hepatocellular necrosis

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:

Mecanisms of
hepatotoxicity

Toxic
metabolite
Alteration of
Mitochodrial immune
dysfunction system

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:

Potential mechanism overlaps of drugs may occur as mixed hepatocellular and

cholestatic changes occur.
Potential mechanisms of how drugs cause liver cell injury:

•Drug disrupts calcium homeostasis: actin fibrils disassemble → cell membrane blebbing
→ cell lysis

•Immune response activation:

• Cytochrome P450 enzyme binds with the drug, producing non-functioning adducts.
• Adducts reach the cell surface → cytolytic T cells
• and cytokines attack the adducts as targets

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:
•Drug activation of apoptotic pathways: Stimulation of death receptors(tumor
necrosis factor (TNF) receptor
•Results in programmed cell death

•Mitochondrial disruption:
• ↓ Adenosine triphosphate (ATP) levels; ↑ lactate, and reactive oxygen
species
• lipid peroxidation → cell injury Failed free fatty acid metabolism
• → triglyceride accumulation (steatosis)
Potential mechanisms of how drugs affect the biliary excretion pathway:

•Bile duct damage:

• Toxic metabolites (excreted in bile) damage bile-duct epithelium
• → cholestasis
• Protracted cholestasis leads to vanishing bile duct syndrome

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4 Pathophysiology:

• Acetaminophen induced acute liver failure:

• Possible pathophysiology of drug-induced liver injury:

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure:

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4 Pathophysiology:

• Acetaminophen induced acute liver

failure: Pathogenesis of brain edema in ALF
ALF

Alteration of
Hyperammonia Pro-inflammatory state
BBB

Accumulation Cerebral
Glutamine vasodilation

Astrocyte swelling Oxidative stress

↑ cell calcium

Vasogenic Cytotoxic ↑CBF

edema edema

Cerebral edema
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5 Clinical presentation:

• Acetaminophen induced acute liver:

The clinical course of APAP poisoning is often divided into 4 stages that are
classified according to duration since time of ingestion.

Stage I (first 24 hours):

• Nausea
• and vomiting malaise
• May be asymptomatic
• Laboratory studies are usually normal.
Stage II (24–72 hours):
• Ongoing hepatic necrosis results in transaminases by 36 hours
• RUQ pain and hepatomegaly occur.
• Prothrombin time (PT) and total bilirubin
• Oliguria and abnormal creatinine may occur

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5 Clinical presentation:

• Acetaminophen induced acute liver:

Stage III (72–96 hours):

• Liver function abnormalities peak.
• Stage I symptoms return with jaundice confusion, and bleeding
diathesis
• Severe hepatotoxicity:
• ALT, AST > 10,000 IU/L
• Prolonged PT/INR
• Lactic acidosis
• Bilirubin > 4 mg/dL
• Possibly complicated with ALF, renal failure and pancreatitis
• Death often occurs due to multiorgan failure.

Stage IV (4 days to 2 weeks):

• If stage III is survived, cases enter a recovery phase.
• Recovery is typically complete by week 1 (longer if severely ill).
• Symptoms and laboratory values can take weeks to return to normal.
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5 Clinical presentation:

• Acetaminophen induced acute liver:

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6 Management:

• Acetaminophen induced acute liver:

• General recommendations
•Main treatment: cessation of the offending drug

•Serial laboratories until the LFTs return to normal

•Monitor for complications:

• Hypoglycemia
• Monitor level of consciousness
• Prevent gastrointestinal bleeding with a proton pump inhibitor
• Infection
• Multi-organ failure

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6 Management:

• Acetaminophen induced acute liver:

• Specific therapy: N-acetylcysteine
(NAC)

▪ Antidote for APAP

▪ Given to all individuals at risk for hepatotoxicity
▪ Repletes glutathione stores and subsequently
decreases NAPQI production
▪ Indications for NAC:
• History of APAP ingestion and evidence of any liver
injury
• Unclear time of ingestion and serum drug level of > 10
µg/mL
• Suspected single dose of > 7.5 g or 150 mg/kg
• > 24 hours after ingestion with evidence of liver injury
▪ If given within 8 hours, serious hepatotoxicity is prevented
and death is rare.
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6 Management:

• Acetaminophen induced acute liver:

•Treatment protocol and duration:

• Can vary based on individual case a clinical judgment
• Cases are generally treated for 20–72 hours.
•Available in oral and IV forms
• In general, both are acceptable.
• Use IV for:
• Cases with intractable vomiting
• Hepatic failure
• Contraindications to oral: pancreatitis, ileus, bowel obstruction

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6 Management:

• Acetaminophen induced acute liver:

•Supportive care

•Transplantation

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7 Other causes:

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7 Other causes of ALF:

Viral hepatitis:

▪ Infection from a virus causing an acute inflammatory

reaction in the liver
▪ Presents with jaundice, fever and hepatomegaly
but ALT/AST are usually > 1,000 in cases of viral
hepatitis.
▪ Further differentiation can be established by detecting
viral antigens and antibodies in the serum.
▪ Treatment is based on etiology.
▪ For certain hepatitis types, prevention is achieved
by vaccin.

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7 Other causes of ALF:

Autoimmune hepatitis:

•An ALF that presents with fatigue jaundice, hepatomegaly, and RUQ
tenderness.
•Drug-induced hepatitis must be ruled out using the history and a
laboratory evaluation.
•The presence of the anti-smooth muscle antibody is a
strong indicator of autoimmune hepatitis
•Treatment is with immunosuppressants such as steroids

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7 Other causes of ALF:

▪ Hemorrhagic shock

▪ Low cardiac output Ischemic liver

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Take home message:

▪ Acute liver failure is defined by:

1.No prior liver disease ▪ Depending on the cause, acute
2. New-onset hepatic encephalopathy, liver failure can sometimes be
jaundice,and coagulopathy reversed with treatment. In many
3. Elevated transaminases situations, though, a liver
4. Illness duration < 26 weeks transplant may be the only cure.
▪ common etiologies for acute
liver failure:
1. Drug induced liver failure such
acetaminophen
2. Viral hepatitis
3. Autoimmune hepatitis
4. Shock/ischemic liver
▪ ALF can lead to multiorgan failure
and death

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Bibliographie:

• Rumack BH: Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin

Toxicol 2002; 40: pp. 3-20
• Brain edema in acute liver failure. A window to the pathogenesis of hepatic
encephalopathy. DOI: 10.1016/S1665-2681(19)32153-2

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