Acute and Chronic Liver Failure Flashcards
1
Q
Describe the hepatic lobule
A
- Roughly hexagonal
- Corners/vertices represent portal triad (hepatic artery proper, common bile duct, portal vein)
- Oxygenated blood from hepatic artery mixes with nutrient-rich blood from portal circulated drained from gut.
- Upon mixing, this blood equilrates and flows across the lobule through a sinuosoidal network before draining into branches of central vein
- This organisation leads to formation of a number of gradients including oxygen, hormones, nutirents and waste products. This gradient and the consequential organisation of relevant metabolic processes has been dubbed ‘metabolic zonation’.
2
Q
Describe the functions of the liver
A
- Detoxification
- Drugs/alcohol
- FAs
- Steroid hormones
- Ammonia → urea
- Environmental toxins/ allergens
- Production of cholesterol - precurso to sex hormones, vitamin D
- Storage of Micronutrients:
- Minerals: Copper, Zinc, Magenisum, iron
- Vitamins: Vitamin A, D, E, K, B12
- Blood sugar balance - Storage of glycogen
- Production of bile:
- Needed for digestion
- GI anti-microbial
- Protein synthesis:
- Blood clotting (prothrombin)
- Cholesterol transport (lipoproteins)
- Immune function (globulins)
- Oncotic pressure (albumin)
- Copper bioavailability (ceruloplasmin)
- Immune system:
- Contains viruses and pathogens
- Maintenance of the hepatic and portal vein immune system
- Metabolism:
- Conversion of T4/T3
- Detoxification of fat
3
Q
Describe the metabolism of the liver in the fasting state
A
- In fasting state, liver is in a net hepatic glucose output mode due to low insulin to glucagon ration. Glucose derived from glycogen and gluconeogenesis
- Gluconeogenic substrates are provided in the form of amino acids (gut and muscle), lactate (muscle), pyruvate (muscle), and glycerol (adipose tissue)
- FAs from adipose tissue lipolysis are also directed to several pathways, e.g. beta-oxidation and TCA cycle. These processes support gluconeogenesis through production of ATP etc. Ketone bodies may also be produced from lipid oxidation and act as an additional energy shuttle b/w liver and other organs.
- Amino acids can also enter TCA cycle as anaplerotic substrates and be utilised for synthesis of proteins. Nitrogen released as result of deamination during amino acid metabolism are disposed of during ureagenesis.
- Urea released from liver, excreted by kidneys
4
Q
Describe the metabolism of the liver in the fed state
A
- During feeding, water soluble nutrients enter portal venous circulation from intestine. At liver, insulin to glucagon ratio elevated leading to net hepatic glucose uptake.
- Glucose may undergo glycolysis, as means of ATP production, or may be stored as glycogen. Amino acids may be oxidised for energy production or used as anaplerotic substrates for the TCA cycle.
- Ingested fats are assembled to form triglycerides from FAs and glycerol. These triglycerides are packaged into chylomicrons, which then enter the lymphatic system. Chylmoicrons drain from the lymphatics to the circulation, and once they reach the liver, are unloaded of remaining FAs and glycerol
- FAs can be used for restoration of energy state, repletion of TCA cycle intermedites, or re-esterified to triglycerides. Trigylcerides can be loaded onto VLDL, which shuttle lipid to other tissues including muscle and adipose depots
5
Q
Define acute liver failure
A
‘Acute’ or ‘Fulminant’ Hepatic failure:
- Sudden onset of liver dysfunction
- Absence of prior liver disease
- Resulting in encephalopathy (brain dysfunction) within 8 weeks of onset
Distinct from acute liver injury:
- Acute injury to liver
- Evidenced by increase in liver enzymes
- Not necessarily affecting synthesis function of liver
- Not complicated by encephalopathy
6
Q
What does encephalopathy indicate?
A
Encephalopathy - Disease in which functioning of brain affected by some agent or condition (e.g. in the case of ALF, this would be a rise in NH3 crossing the blood-brain-barrier)
Encephalopathy: Onset: Disease phenotype and aetiology
Critically impaired liver function
7
Q
Describe initial ALF management
A
- Recognise early
-
Resuscitate
- Involve ITU early, protect airway, correct hypoglycaemia, correct volume depletion, avoid hyponatraemia, low threshold for invasive monitoring, no routine clotting products (tracking coagulopathy important prognostic marker)
-
Give intravenous N-acetyl cysteine (NAC)
- Paracetamol-induced hepatotoxicity - Replenishes glutathione, detoxifies NAPQI (N-acetyl-p-benzoquinone imine)
- Consider empirical antibiotics
- Infection inhibits hepatic regeneration, progression of HE, reduces transplantation rates
- Antibiotics - low threshold, systemic inflammation, evolving HE, severity of hepatic injury, (potential) transplant candidate
- Discuss with expert/transplant centre
8
Q
Describe the clinical management of ALF
A
Multiple organ involvement → Supportive ICU care, has 3 outcomes, transplantation, recovery or death.
9
Q
Why are patients with cirrhosis at risk of bacterial infections? Describe spontaneous bacterial peritonitis
A
Multiple factors:
- Liver dysfunction
- Portosystemic shunting
- Gut dysbiosis
- Increased bacterial translocation
- Cirrhosis- associated immune dysfunction
- Genetic factors
Spontaneous bacterial peritonitis:
- Bacterial infection of ascitic fluid w/o any intra-abdominal surgically treatable source of infection
- Prevalence: All patients with cirrhossi and ascites at risk
- 1.5-3.5% in outpatients; 10% hospitalised
- Prognosis: Mortality exceeded 90% when first described, but goes down to 20% with early diagnosis and treatment
10
Q
How is SBP managed?
A
- IV antibiotics - tazocin
- IV albumin
- Significantly decreases incidence of type-1 hepatorenal syndrome and reduced mortality
- 1.5g/kg at diagnosis and 1g/kg on Day 3
- Ensure patients discharged on secondary prophylaxis
- Ciprofloxacin 500mg od or rifaximin or septrin
- PPIs may increase risk of SBP - stopped in those with ascites w/o indication
11
Q
What are the clinical consequences of liver failure?
A
Manifestations of failure of liver to perform functions:
- Abnormal blood clotting
- Jaundice - uncommon unless subacute liver failure
- Low glucose
- High blood lactate
- Impaired renal function (indirect effect)
- Acidosis
- Hyperammonaemia - lethargy, stupor, confusion, agitation, flapping tremor, coma
- Infections (immune dysfunction)
12
Q
Describe the prognosis of end-stage liver disease
A
- Child-Pugh score
- Developed to assess surgical risk in those with cirrhosis
- Model for End-stage Liver Disease (MELD) score
- Developed to assess mortality in those undergoing TIPSS
- Serum creatinine, INR, bilirubin
- UK model for End-stage Liver Disease (UKELD) score
- Developed to allow risk stratification for purpose of listing for liver transplantation in UK
- Serum creatinine, INR, bilirubin, sodium
13
Q
Describe the aetiology of ALF
A
- > 50% caused by paracetamol overdose
- Liver injury can be drug induced, with drugs causing this being paracetamol, NSAIDs, amiodarone, anabolic steroids, chlorpromaxine, phenytoin, herbs, erythromycin, augmentic, haloathane, statins etc.
- <50% non-paracetamol related
- This could be as follows:
- Indeterminate
- DILI
- Pregnancy
- Viral
- Ischemia
- Malignancy
- Budd-Chiari
- Wilsons
- Other or unknown
- This could be as follows:
14
Q
What are the risk factors for ALF?
A
- Hepatotoxic drugs
- Contaminated food/water (enteric viruses - Hep A and E)
- Travel history
- Blood borne virus risks (Hep B)
- High risk sexual activity
- Tattoos/piercing with unclean equipment
- Recreational drug use (mushrooms, ecstasy)- Shared paraphernalia
- Threshold for liver injury reduced if underlying liver disease
15
Q
Describe the pathophysiology of ALF
A
- Damage to hepatocytes causing sudden increase in liver tests
- Caused by acute inflammation of liver (hepatitis), of any cause, hypoxaemia, immune-mediated liver damage
- Usually manifests as increase in aminotransferases (ALT and AST)
- Intracellular enzymes
- Released by disruption/death of hepatocytes
- If ongoing necrosis of hepatocytes and loss of critical liver cell mass, ALF may occur as liver can’t perform its functions, and this can lead to multiorgan dysfunction
16
Q
Describe the role of ammonia in hepatic encephalopathy
A
- Brain dysfunction caused by build up, or shunting of, ammonia.
- Can be more subtle when due to CLF rather than ALF (minimal HE)
- Poor concentration, personality and mood change, sleep disturbance, confusion, disorientation, flapping tremor, altered conscious level.
- In contrast to ALF, HE in CLF more likely to be precipitated by constipation (increases absorption of ammonia), infections, bleeding, kidney dysfunction, medications.
- In CLF HE does not usually cause raised intracranial pressure
Hepatic encephalopathy is:
- Sudden decrease in urea-cycle metabolism
- Accumulation of ammonia - product of protein catabolism from gut/muscle - in systemic circulation
- NH3 crosses blood-brain barrier
- Normally detoxified in cerberal astrocytes to glutamine
- Accumulation of glutamine has osmotic effect leading to influx of water and astrocyte swelling
- Glutamine shuttled via transporters (SNAT 5/SNAT 1) to presynaptic neurones and converted to GABA or glutamate before release into inhibitory or excitatory synaptic cleft, respectively, and subsequently scavenged by astrocytic reuptake transporters (EAAT 1/2)
- Can lead to raised intracranial pressure in acute liver failure
17
Q
Describe the grading of hepatic encephalopathy
A
Grade 1:
- Trivial lack awareness
- Euphoria or anxiety
- Short attention span
- Impaired performance of addition
Grade 2:
- Lethargy or apathy
- Minimal disorientation of time or place
- Subtle personality changes
- Inappropriate behaviour
- Lethargy or apathy
Grade 3:
- Somnolence to semi-stupor but responsive to verbal stimuli
- Confusion
- Fross disorentiation
Grade 4:
- Coma (unresponsive to verbal or noxious stimuli)
18
Q
Describe the clinical presentation of ALF
A
Symptoms/signs:
- RU quadrant pain
- Nausea/vomiting
- Malaise (general sense of unwellness)
- Sweet smelling/musty breath (fetor)
- Disorientation, confusion, agitation, sleepiness, flapping tremore (features of encephalopathy
Manifestations of failure of liver to perform functions:
- Abnormal blood clotting
- Jaundice - uncommon unless subacute liver failure
- Low glucose
- High blood lactate
- Impaired renal function (indirect effect)
- Acidosis
- Hyperammonaemia - lethargy, stupor, confusion, agitation, flapping tremor, coma
- Infections (immune dysfunction)
19
Q
How is ALF investigated?
A
- Massive transaminitis: ALT or AST >1000
- Drugs (paracetamol)
- Viruses
- Ischaemia
- Autoimmune hepatitis
- NOT alcohol
- Liver enzymes indicate severity of hepatocellular damage but do not tell us about synthetic function of liver, do not have prognostic value
- Standard blood tests
- FBC, U and Es
- LFTs, GGT, blood clotting
- Glucose
- In unwell/unstable patient
- ABG
- Blood cultures
20
Q
Compare ALF and CLF, the aetiology of acute and chronichepatitis and thier outcomes
A
ALF:
- Fulminant hepatic failure
- Subacute liver failure
- Period of hepatocellular injury lasting <6 motnhs
Aetiology of Acute hepatitis:
- Enteric viruses Hep A and E
- CMV, EBV, HSV, Adenovirus
- Hep B adult acquired
- Acute HCV is rare
- Most drug related causes
- Acute alcoholic hepatitis
- Vascular/ischaemic
Outcome of Acute hepatitis:
- Self-limited - resolution
- ALF if severe
CLF:
- Decompensated liver cirrhosis
- Period of hepatocellular injury lasting >6 months
Aetiology of Chronic hepatitis:
- Parenteral viruses (chronic HCV - this is rare tho), maternal/childhood acquired HCV)
- Methotrexate, amiodrone, methyldopa
- Haemochromatosis
- MAFLD
- Alcohol-related steatohepatitis
- PBC
- PSC
Outcome of Chronic hepatitis:
- Resolution if cause treated/resolved/removed
- Progressive fibrosis - cirrhosis - chronic liver failure if cause persits/persisting hepatitis
21
Q
What are the effects of decompensated liver failure?
A
- Ascites
- Jaundice
- Variceal bleeding
- Heaptic encehalopathy
- Infection
- Kidney injury
22
Q
Describe the pathogenesis of encephalopathy in cirrhosis
A
- Change in microbiota with worsening liver disease severity and cognitive performance
- Paucity of autochthonous floral bacter that have pathological species overrepresented, creating dysbiosis.
- Changes gut ammonia metabolism, contributes to colonic inflammation, portal circulation endotoxemia, increased inflammatory burden in presence of portal hypertensive enteropahty, and impaired intestinal mucosal barrier
23
Q
When does paracetamol cause liver toxicity?
A
When used in supra-therapeutic doses:
- Degree of liver injury dose-dependent
- Caution in dosing with those with low body weight or significant underlying liver disease
NAPQI begins to be produced, this causes mitochondrial dysfunction, increased free radicals, oxidative stress
24
Q
Describe paracetamol metabolism
A
Paracetamol can be conjugated with sulphate or glucuronide or is broken down into NAPQI by cytochrome P450 2E1
NAPQI is toxic metabolite produced from paracetamol metabolism when the other 2 pathways become oversaturated. NAPQI is converted into nontoxic metabolites by glutathione, which is regnerated by N-acetylcysteine.
25
Who are the high risk groups that can be affected by increased paracetamol toxicity?
- High doses
- Chronic alcohol consumption
- Certain prescription drugs (anti-seizure, opioids) and OTC substances (dietary supplements)
- Advanced age
- Malnutrition
- Chronic liver disease
26
Describe the first line management in relation to paracetamol overdose
Patients whose plasma-paracetamol concentrations are on or above treatment line should be treated with acetylcysteine by IV infusion
27
Describe variceal band ligation treatment
- Non- cardioselative beta blockers (e.g. propranlol) reduce portal pressure, used to treat larger varices (primary prophylaxis0 and where varices have bled (secondary prophylaxis)
- TIPSS (transjugular intrahepatic portosystemic shunt) can be inserted to shuhnt blood, reduce portal pressure in variceal blleding when there’s failure of endoscopic therapy
