This is a lecture note for 5th semester MBBS students. Lecture notes on hepatology, liver disease, alcoholic liver disease, alcohol-related liver disease, portal hypertension, hepatic encephalopathy, and acute liver failure. Introduction to acute liver failure, causes, approach, and management of acute liver failure .

1. Hepatology lectures for
5th Sem;MBBS
Pratap Sagar Tiwari
MBBS,MD (Medicine),DM (Hepatology)

2. INTRODUCTION
• Until the beginning of the 21st century, hepatitis showing rapid progression was referred to by various
names, including fulminant hepatitis, fulminant hepatic failure, fulminant liver failure, acute hepatic
failure.
• However, ‘‘acute liver failure’’ came to be used predominantly as the most suitable umbrella term,
because it can be assumed to include all of the other disease entities.
• Thus, the Practice Guideline Committee of AASLD published a paper for the MX of ‘‘acute liver failure’’ in
2005.
• Acute liver failure is defined as ‘‘Severe acute liver injury characterized by the
development of HE and coagulation abnormalities, usually characterized by an INR of
≥1.5, in pts without preexisting cirrhosis, and an illness of <26 weeks duration’’.

3. CAUSES OF ALF

4. CLINICAL ASSESSMENT
Cerebral disturbance
Jaundice
HE and/or cerebral oedema
• Early stages: mild and episodic
• Cerebral oedema may occur due to increased intracranial
pressure, causing
❑unequal or abnormally reacting pupils, fixed pupils
❑hypertensive episodes, bradycardia
❑hyperventilation, profuse sweating
❑local or general myoclonus, focal fits or decerebrate posturing
❑Papilloedema occurs rarely and is a late sign.
❑More general symptoms include weakness, nausea and
vomiting.

5. HEPATIC ENCEPHALOPATHY

6. CLINICAL ASSESSMENT
Cerebral disturbance
Jaundice
❑ may not be present at the outset (e.g. in paracetamol overdose).
❑ Fetor hepaticus can be present.
❑ The liver is usually of normal size but later becomes smaller.
❑ Hepatomegaly is unusual and, in the presence of a sudden onset
of ascites, suggests venous outflow obstruction as the cause
(Budd–Chiari syndrome).
❑ Splenomegaly is uncommon and never prominent.
❑ Ascites and oedema are late developments.

8. ADVERSE PROGNOSTIC CRITERIA

9. ADVERSE PROGNOSTIC CRITERIA

10. MANAGEMENT
• Patients should be treated in a ICU .
• Conservative treatment aims to maintain life in the hope that hepatic regeneration
will occur, but early transfer to a specialised transplant unit should always be
considered.
• N-acetylcysteine therapy may improve outcome, particularly in patients with
paracetamol poisoning.
• A number of artificial liver support systems have been developed and evaluated for
use as a bridge to either transplantation or recovery. None, however, has entered
routine clinical use.

12. TOXIC DOSE
• The therapeutic dose of APAP for children <12 years is 15 mg/kg per dose every 4-6 hrs,
(max daily dose 75 mg/kg).
• The therapeutic dose for children 12 years and older and adults is 325-1000 mg per
dose every 4-6 hrs (max daily dose 4 g).
• The minimal toxic dose for an acute ingestion is 150 mg/kg for a child or 10 g for an
adult.
• Virtually all pts who ingest doses in excess of 350 mg/kg develop severe liver toxicity .
Acetaminophen(APAP) Overdosage
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13. • Following ingestion, about 2% of APAP is
excreted in the urine unchanged.
• Over 90% is metabolized via conjugation – 2/3rd
via glucuronidation (urine diphosphate (UDP)
glucuronosyltransferases) and 1/3rd through
sulfation (sulfotransferases). The inactive
nontoxic conjugates are largely excreted in the
urine and bile.
APAP: metabolism
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• The remaining 8% undergoes oxidative conversion via several cytochromes (CYP1A2,
CYP2A6, CYP2E1, CYP3A4) to the highly toxic metabolite N-acetyl-p-benzoquinone
imine (NAPQI) .

14. • NAPQI is a highly reactive that can act as an
oxidant.
• Normally, it is rapidly metabolized by
conjugation to intracellular glutathione (GSH)
forming a nontoxic APAP-GSH conjugate .
• Subsequent processing leads to its urinary excretion as mercapturic acid and cysteine
conjugates.
• However, under conditions where the supply of NAPQI exceeds the amount of available
glutathione, the former covalently binds hepatocellular proteins, initiating hepatocyte
necrosis.
APAP: metabolism
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15. Pts often have few signs/symptoms within 1st 24 hrs, but may develop N/V, and malaise.
Lab studies are usually Normal
24-72 hrs : Pts may develop abdominal pain or liver tenderness and elevations in serum
AST, ALT, PT, and bilirubin.
Acetaminophen(APAP) Overdosage: manifestations
STAGE 1
STAGE 2
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16. 72–96 hrs, the most severe abnormalities occur –HE, coagulopathy, hyperbilirubinemia (median 4.5
mg/dL), renal dysfunction, and lactic acidosis.
Marked AT elevations (median ∼4,100 IU/L) .
During this stage, death most often occurs from cerebral herniation or from MOF.
Acetaminophen(APAP) Overdosage: manifestations
STAGE 3
4d-2 wks — Pts who survive enter a recovery phase.
Symptoms and lab values may not normalize for several wks.
STAGE 4
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17. N-Acetylcysteine for Acetaminophen Overdose
• The use of an antidote may decrease hepatic injury and reverse ALF in
specific circumstances.
• NAC remains the treatment of choice for APAP overdose.
• The administration of NAC replenishes glutathione, thereby detoxifying
NAPQI.
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18. Extra note : GI DECONTAMINATION
• Adult patients who present soon after a potentially toxic ingestion of
APAP (single dose ≥7.5 g) are likely to benefit from gastrointestinal
decontamination.
• We suggest treatment with activated charcoal (AC), 1 g/kg (maximum
dose 50 g) by mouth in all patients who present within four hours of a
known or suspected acetaminophen ingestion, unless there are
contraindications to its administration.
• Note: Charcoal should be withheld in patients who are sedated and may
not be able to protect their airway, unless endotracheal intubation is
performed first.
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19. Mushroom poisoning
• ALF from ingestion of the mushrooms of the genus Amanita (A. phalloides,
A. verna, and A. virosa) .
• Three medium sized mushrooms (50 g) contain sufficient toxin, α-amanitin
and phalloidin, to cause ALF; the toxins are heat stable and not degraded
by cooking.
• The phallotoxin causes damage to the enterocyte cell membrane.
• The a-amanintin toxin (amatoxin) is dose dependent and responsible for
hepatic injury by disrupting hepatocyte messenger RNA synthesis.
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20. Mushroom Poisoning: Course of poisoning
• Following ingestion, a 6–12-hour asymptomatic phase evolves into three
clinical phases.
• The gastrointestinal phase (phase 1; 12–24 hours), consists of diarrhea,
vomiting, and abdominal pain.
• During the hepatotoxic phase (phase 2: 24–48 hours) signs of liver
damage occur and the disease may progress to the third clinical phase
(4– 7 days), during which ALF, hepatorenal syndrome, hemorrhage,
convulsions, coma, and death occur.
• Mortality approaches 10–30% .
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21. Mushroom Poisoning
• A combination of penicillin (300,000-1,000,000 U/kg/day, or 250
mg/kg/day iv) and silibinin (20-50 mg/ kg/day iv) has been used as a
specific antidote in those with evidence of liver injury due to Amanita
poisoning.
• These agents are hypothesized to interrupt the enterohepatic circulation of toxins and also to compete
at the hepatocyte membrane for transmembrane transport.
• Because of the rarity of this cause of ALF, the benefits of this regimen remain unproven.
In ALF pts with known or suspected mushroom poisoning, consider administration of
penicillin G and N-acetylcysteine (III). AASLD 2011
Pts with ALF secondary to mushroom poisoning should be listed for transplantation, as
this procedure is often the only lifesaving option (III).AASLD 2011
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22. END OF SLDIES