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home - Liver - Liver Failure - Paracetamol Written by Dr Sebastian Zeki
Knowledge


Assesses the severity of liver dysfunction and its prognostic
significance following haemorrhage

Knows importance of correcting hypovolaemia preventing
complications of GI bleeding and deterioration of liver function and
stopping bleeding

Knows the potential use of blood & clotting factors the role of
antibiotics the use of vasoconstrictors therapeutic endoscopy the
indication for transjugular intra-hepatic portosystemic shunt (TIPS) or
surgical shunt surgery

Aware of the specific complications of bleeding in cirrhotic patients –
including hepatic encephalopathy need for airway protection
nutrition identification of alcohol withdrawal

Skills
Shows proficiency in endoscopy – including emergency endoscopic
techniques of variceal band ligation endoscopic sclerotherapy
injection of cyanoacrylate glues for gastric varices

Can place safely and manage a Sengstaken tube in refractory
variceal bleeding

Can prevent and treat complications including hepatorenal failure
ascites spontaneous bacterial peritonitis and hepatic encephalopathy

Behaviours
Appreciates criteria for referral to specialist centre when appropriate –
such as with bleeding gastric or ectopic varices or consideration of
TIPS

Appreciates need to treat patients using a multi–disciplinary approach
Shows understanding of an empathic approach which may involve


Also....

Knowledge
Knows risks and prognosis of recurrent variceal bleeding in cirrhotic
patients

Aware of role of secondary prophylaxis with either non–selective ?-
blockers endoscopic ligation or both

Skills
Can select suitable endoscopic therapy and perform the appropriate
procedure competently

Behaviours
Appreciates the potential role of other specialists e g interventional
radiologists and nurse specialists

Also...

Knowledge


Understands the mechanisms of biliary metabolism the various
abnormalities that lead to hyperbilirubinaemia and knows and
recognises the causes of the various forms of jaundice

Skills
Selects and interprets appropriate investigations and formulate
management plans

Behaviours
Approaches patients presenting with jaundice in a logical and
methodical manner

Also...
Knowledge


Can define the different types (I and II) of hepatorenal
syndrome(HRS)

Knows the differential diagnosis of different types of renal
failure/impairment in liver disease

Understands the major and minor criteria in diagnosis of HRS and be
able to differentiate between HRS and acute kidney injury

Appreciates the prognostic significance of renal impairment in
patients with chronic liver disease

Knows the options for management and treatment of HRS the role of
colloids and vasoconstrictors as well as renal supportive treatment by
dialysis

Skills
Uses and interprets result of sometimes complex investigations
appropriately

Behaviours
Can judge when to involve other specialists especially nephrologists
radiologists and intensivists

Also...

Knowledge


Understands the pathogenesis of hepatic encephalopathy (HE)
Knows the differential diagnosis of HE including the existence of risk
factors for its causation including metabolic disorders and intracranial
structural disorders (such as subdural haematomas)

Knows factors that may precipitate HE including bleeding electrolyte
disturbance drugs or other organ failure

Knows the various treatment options appropriate for grade of severity

Skills
Can grade the mental state (Glasgow coma score and West Haven
Criteria)

Shows ability to differentiate between acute and acute on chronic liver
injury

Can identify the patient at risk of raised intracranial pressure and
cerebral oedema

Selects and use investigations appropriately and determine timing of
airway protection

Behaviours
Appreciates the role of other specialists and interacts in a
professional manner with intensivists neurologists
neurophysiologists radiologists and other specialists

Makes referral where appropriate to specialist centre for liver
transplantation

Also...

Knowledge


Understands the causes of acute hepatitis including viral druginduced alcohol-induced and auto-immune liver disease

Knows the appropriate plan of investigation and management of
specific diseases including the role of serological investigations and
liver biopsy

Skills
Takes an accurate history from patients with acute liver disease and
performs detailed clinical examination

Utilises investigation in a structured manner
Behaviours
Considers all therapeutic modalities and preparedness to refer to
specialist centre where diagnosis remains in doubt or appropriate
management cannot be performed

Also...

Knowledge
Assessment
Methods GMP
Recognises and knows how to diagnose acute and chronic drug
induced liver injury and dysfunction
SCE 1,2
Aware of methods of diagnosis, role of liver biopsy and therapy
including role of steroids in treatment in selected cases
SCE, CbD 1
Skills
Understands the role of both prescription and recreational drugs and
the aetiology of a wide variety of liver disease and dysfunction often
requiring prompt intervention or involvement of specialist services
SCE, CbD 1,2,3
Has awareness of the range of iatrogenic liver dysfunction SCE, CbD 1,2,3
Behaviours
Able to interact with specialist pharmacy services. Can use yellow
card reporting system of potential adverse effects of drugs.

Also....

Knowledge


Understands the causes and pathophysiology of acute liver failure
Can plan appropriate investigation evaluate prognosis and construct
a detailed management plan

Identifies those potentially suitable for emergency liver transplantation
Skills
Develops ability to make accurate evaluation of patients with liver
failure at the stage of initial presentation

Can deliver management plan appropriately evaluate changes in
patient’s condition and react accordingly

Utilises the range of medical interventions necessary to support
critically ill patients

Behaviours
Demonstrates ability to identify patients at risk of developing acute
liver failure and understand the criteria for referral to specialist centres

Works collaboratively with nurses and all ITU staff as well as
colleagues in other clinical disciplines to deliver the highest standard
of clinical care

Communicates effectively and relates with empathy to family and
close friends of patients

Paracetamol

Plasma paracetamol conc High risk treatment line Normal treatment line 12 24 100 200 Time (hours) Acute alcohol ingestion — NOT a risk factor; may even be protective by competing with paracetamol for CYP2E1 with less NAPQI produced.Chronic alcohol ingestion — Increases CYP2E1 activity + depletes glutathione levels.-----Single overdose —Chronic alcoholics do NOT appear to be at increased risk compared to nonalcoholics for developing hepatotoxicity following a SINGLE overdose of paracetamol and management need not be altered for this patient group.-----Multiple overdoses — Chronic alcoholics with multiple overdoses are at risk as1. Alcohol induces CYP2E1, with more paracetamol shunted through the CYP2E1 pathway and so NAPQI forms2. More likely depleted in glutathione from chronic malnourishment3. Chronic alcoholics may also have a decreased capacity to synthesize a mitochondrial glutathione transport protein, thus enhancing susceptibility of mitochondria to NAPQI. Prognostic factors: if fulfilled and have liver transplantation-66 % 1-year survival ratePatients with a blood pH of <7.3 that fails to correct with fluid resuscitation PT > 100sSerum creatinine concentration > 300umol/litreGrade III or IV encephalopathy. N-acetylcysteine (NAC) EfficacySerious hepatotoxicity rare if NAC given 8-10 hours post paracetamol od, regardless of the initial serum [paracetamol]Efficacy dec 8 hours post ingestionDeath v. unlikely if NAC given prior to ALT rise- Normal LFT’s at treatment initiation predicts survival.Late administration may still be beneficial Chronic liver disease (non EtOH)— Can still induce cyt P450 so no increased risk.Medications altering CYP2E1 activity include anticonvulsants (eg, carbamazepine, phenobarbital, and phenytoin) and antiTB drugs (eg, isoniazid and rifampin).Trimethoprim-sulfamethoxazole and zidovudine compete for glucuronidation pathways with shunting down CYP2E1 path and NAPQI produced.Nutritional status — Glucuronidation depends on hepatic carbohydrate reserves.Genetics — Relevance of cytochrome isoenzymes polymorphisms unknownImpaired glucuronidation secondary to Gilbert's syndrome enhances toxicity.Age — Children < 5 y less susceptible to toxicity as more glutathione.Tobacco — contains CYP1A2 inducers and increases oxidative metabolism.It is an independent risk factor for mortality following paracetamol overdose independent of the amount of tobacco consumed.Mortality was greatest in smokers who also drink alcohol.Pattern of use — Accidental poisoning more likely to present late therefore worse prognosis Without treatment: a)Those with serum [paracetamol]s above the line joining 200 mcg/mL at 4 hours and 25 mcg/mL at 16 hours ("probable hepatic toxicity") have 60 % incidence of severe hepatotoxicity (AST > 1000 IU/L) + mortality rate- 5 %. b) Untreated patients with serum [paracetamol]s above the line joining 300 mcg/mL at 4 hours and 37.5 mcg/mL at 16 hours ("high hepatic toxicity") have a 90 % incidence of severe hepatotoxicity and a mortality rate of up to 24 %. Indications For NAC :-[Paracetamol] above the "possible hepatic toxicity" line of the Rumack-Matthew nomogram.-A single ingestion of > 150 mg/kg (or 7.5 g in an adult) and paracetamol levels N/A for 8 hours post ingestion.-Patients with an unknown time of ingestion and a serum [paracetamol] >10 mcg/mL.-Hepatotoxicity (from mildly elevated aminotransferases to fulminant hepatic failure) and a history of excessive paracetamol ingestion.-Staggered doses, have risk factors for paracetamol-induced hepatotoxicity, and a serum [paracetamol] >10 mcg/mL. Management of Hepatic Failure—Administer NAC until death/recovery with INR <2.0.Do not reverse PT unless bleeding- is good for monitoring.Give vitamin K for coagulopathy; a lack of response suggests a poor prognosis whereas an improved PT suggests viable liver tissue.Consider the need for liver transplantation — GI decontamination —Activated charcoal (AC) if< 2 hours post ingestion.It is useful > 2 hrs if delayed absorption.Give as a single oral dose at 1g/kg.It adsorbs paracetamol, reducing its absorption by 50-90 %.It can also reduce (NAC) absorption by 39 %,but amount of NAC absorbed is still well above the amount required to detoxify paracetamol. Clinical Manifestations CYP2E1, CYP1A2, CYP3A4 subfamilies In normal paracetamol metabolism, paracetamol gets converted to glucuronide and sulfate and a tiny bit into NAPQI which is conveted to cysteine and mercapturic acid to make it non-toxic.In paracetamol overdose, the first two pathways get saturated, so NAPQI is overproduced, and there’s not enough glutathione to detoxify it -NAC increases glutathione stores, combines directly with NAPQI as a glutathione substitute, and enhances nontoxic sulfate conjugation . -NAC has powerful antiinflamm-tory and antioxidant effects (as a modifier of cytokine production and a free radical scavenger) that may limit secondary paracetamol-induced tissue injury.-NAC also has inotropic and vasodilating effects, which improve microcirculatory blood flow and oxygen delivery to vital organs. Stopping NACCan stop if ALT normal + can’t detect paracetamolALT rises 12-24 hrs post ingestion.Side effects: nausea, flushing, urticaria, broncho-pasm, angioedema, fever, chills, hypotension, hemolysis, and, rarely, cardiovascular collapse.Anaphylaxis occurs within 1 hour of dosing Duration and route of administration —Oral and I.V. regimens = similar efficacy if given within 10 hours72-hour oral NAC regimen is more effective than the 20-hour I.V. regimen in reducing acute hepatotoxicity when treatment is delayed > 10 hours probably as oral is a bigger dose Oral administration —10 or 20 % (solution)SE’s: Vomiting (common)/ diarrhea and maculo-papular rash. I.V. administration —Loading dose: 150 mg/kg in 200 mL of 5 % dextrose over 60mThen 50 mg/kg in 500 mL of 5 % dextrose over 4hThen 100 mg/kg in 1 L of 5 % dextrose given over next 16hr.I.V. rather than oral if: Vomiting; Cant absorb; Acute liver failure; pregnant, (get higher serum level so transplacental clearance. Methods of NAC Administration Paracetamol Overdose Risk Factors for hepatotoxicity Irreversible NAPQI-protein adducts on hepatic macromolecules.Lipid peroxidation and mitochondrial injury likely play a role in the progression of hepatocellular injury. Causes oxidative injury and hepatocellular centrilobular necrosis. Cytokine release from hepato-cytes may initiate a secondary inflammatory response from Kupffer cells and other inflammatory cells, extending the zone of hepatic injury. Stage III (72 to 96 hours) —LFTs peakARF (due to ATN) occurs in 25 % with significant hepatotoxicity and in >50 % of those with frank hepatic failure.Stage IV (4 days to 2 weeks) — Recovery phase(if survive stage 3)Labs may not normalize for several weeks. Histologic recovery may take up to 3mHistologic changes in the liver vary from cytolysis to centrilobular necrosis (zone III- greatest [CYP2E1] and therefore maximal production of NAPQI) Stage I (0.5 to 24 hours) — Nausea, vomiting, diaphoresis, pallor, lethargy, and malaise.Some asymptomatic; Labs normal.Stage II (24 to 72 hours) — Labs: hepatotoxicity and, occasionally, nephrotoxicity.Stage I symptoms usually resolve.Of those developing hepatic injury, 50% get ALT elevation in < 24 hours and all have elevations by 36 hours.Develop RUQ pain, with hepatomegaly.Elevations of prothrombin time (PT) and total bilirubin, oliguria, and renal function abnormalities become evident. Written by Dr Sebastian Zeki Cysteine and mercaptopuric acid conjugates (non-toxic) glutathione NAC N-acetly-p-benzo-quinone imine (NAPQI) (TOXIC) P450 (2E1) sulfate moiety (Non-toxic) Acetaminophen conjugation glucuronide moiety (Non-toxic) conjugation

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