Liver Disease Flashcards
General functions of the liver?
Synthesis (bilirubin, cholesterol, clotting proteins, proteins)
Metabolism (drugs, proteins, carbs, bilirubin)
Immune response (Kupffer cells)
Homeostasis (glucose)
Storage (fat soluble vitamins)
Overview of liver disease
Can manifest in broad spectrum of conditions
- Ranges mild to severe
- Delayed disease occurrence and diagnosis: most of the time asymptomatic until severe loss of function (can operate at 30-40% function) “decompensated liver disease”
Brief structure of the liver
Large right lobe, smaller left lobe
Biliary ducts running through joining liver to gallbladder, small intestine, pancreas, etc.
Classifications of liver disease
Dependent on time course and pattern of disease
1) Cholestatic
2) Hepatocellular
One often leads to the other and can result in fibrosis, thus cirrhosis
What is cholestatic liver disease?
Block in the biliary flow (bile salts)
Can cause impaired absorption of fats and malabsorption
Accumulation of bile salts can lead to hepatocellular damage
1) Intrahepatic: biliary ductules blocked within liver
due to drug (paracetamol), autoimmune conditions
2) Extrahepatic: mechanical block in bile/pancreatic duct
due to gallstones, strictures in UC/CD)
What is hepatocellular disease?
Damage to the hepatocytes
Can be caused by steatosis (fatty liver disease)
- fat deposited in hepatocytes can cause cell death and cause inflammation
Causes hepatitis (inflammation)
- acute: such as paracetamol overdose
- chronic: ongoing constant inflammation
- can be small or widespread and lead to necrosis
What does hepatocyte necrosis appear as on scans?
Shrunken liver
What classifies disease as chronic?
> 6 months
Causes permanent structural changes
- progression from compensated and decompensated liver disease
What is fibrosis and cirrhosis?
Caused by toxins, drugs, disease
Fibrosis
- persistent hepatocyte damage
- leads to deposition of collagen to cause scarring of the liver tissue
- can cause disruption in blood flow
- Erratic regeneration and formation of nodules
Cirrhosis
- extensive scarring leading to reduced liver function
What is decompensated liver disease?
What is compensated liver disease?
Compensated: liver compensates for damage and is still is able to perform daily functions (until around 30% left)
Decompensated: Extensive damage affecting ability for daily functions of the liver
What is measured in the liver function tests? (6)
Bilirubin Albumin PT/INR (prothrombin time/INR) Transaminase enzymes (AST, ALP) gamma-glutamyltransferase (GGT) Alkaline phosphatase (ALP)
At least 2 must deviate from the norm to classify liver dysfunction
What is the normal range for bilirubin?
5 - 20 umol/L
Why is bilirubin measured?
Transported to liver, attached to albumin
Waste product due to RBC breakdown (performed in hepatocytes)
- conjugated and excreted via bile into intestine (found in faeces)
Increased levels indicate haemolysis/ hepatocellular damage/ cholestasis
- > 50umol/L = jaundice
What serum level is indicative of jaundice?
What are the symptoms?
Over 50umol/L (build up)
Yellowing of skin and whites of nails/eyes/palms
Pale coloured stools and dark urine
What are the normal serum levels for AST and ALT?
Why might these be raised?
AST: 0-40iu/L
ALT: 30-50iu/L
Not all patients will have raised transaminase enzymes (if functioning has reduced severely, no enzymes will be synthesised at all) but high levels will indicate inflammation
What are the normal serum levels for ALP?
Why might these be raised?
30-120iu/L
- increased levels due to cholestasis, infiltrative liver disease or damage to the biliary tree
If ALP is raised in isolation, why might this be?
Paget’s disease
What are the normal serum levels for GGT?
Why might these be raised?
30-55iu/L
Increased due to inducers (such as alcohol), cholestasis, carcinoma of pancreas and GIT
What drug can cause increased levels of GGT?
Phenytoin
What are the normal serum levels for albumin?
In liver disease, will these be raised or reduced?
35-50g/dL
Reduced
- oedema (no maintenance of oncotic pressure within cardiovascular system)
- chronic liver disease
- alcoholic patients (malnourished: reduced production)
Will the PT/INR increase/decrease due to liver disease?
Increased
- less clotting factors synthesised (risk of haemorrhage and bleeding)
What is the scoring system used to classify and assess chronic liver disease/cirrhosis?
What does it consider?
What cautions are there with using this?
Child’s Pugh Score: gives a prognosis of the disease and mortality rate (classes A, B, C)
Considers signs and symptoms, such as jaundice, encephalopathy, ascites, albumin, INR
Drug dosing is based on Child’s Pugh score, however no pharmacokinetic/pharmacodynamic data is provided (not developed to predict drug handling- cannot be used to predict the course of the drug according to liver class)
Upon diagnosis of chronic liver disease, what further investigations need to be done?
LFTs
Child’s Pugh Scoring System
Others such as:
- Ultrasounds (nodular/smooth)
- CT/MRI
- Fibroscans
- ERCP/MRCP (visualise biliary ducts)
- liver biopsy (gold standard but invasive)
- MELD (model for end stage liver disease- similar to Child’s Pugh)
What are Fibroscans?
Probe pushes air into the liver
- measures how quickly air pushes into the liver
- indicates the stiffness of the liver (advanced scarring, cirrhosis)
Signs and symptoms of liver disease (10)
Encephalopathy
Jaundice
Ascites
Varices (collateral vein formation)
Spider naevi
Bruising/bleeding
Pale stools/dark urine (kidneys begin to accommodate)
Gynecomastia (no liver breakdown of hormones such as oestrogen)
Fatty stools
Finger clubbing and pruritus (build up of bile salts, “intractable pruritus lead to transplant)
3 main types of jaundice?
pre-hepatic jaundice
intra-hepatic jaundice
post-hepatic jaundice
different stages of obstruction
What is ascites?
Reduced oncotic pressure across CVS and increased hydrostatic pressure due to portal hypertension
Oedema occurs as water seeps into extracellular space
Accumulation of fluid in the peritoneal cavity, leading to swollen abdomen
How is ascites treated?
MEDICATION
1) Spironolactone (K+ sparing diuretic)
2) Amiloride
3) Addition of furosemide
OTHER
Fluid/sodium restriction in diet
Paracentesis (needles to drain fluid mechanically)
- Caution: losing volume too fast can cause BP to collapse (simultaneously infuse albumin/colloids/terlipressin)
What does terlipressin do?
Vasoconstriction to maintain blood pressure
If drug treatment is inadequate to treat ascites, what else can be done?
TIPS: Transjugular hepatic portosystemic shunting
- for ascites that do not recede/recur after paracentesis
Reduce portal hypertension as a shunt is inserted (false pathway) to redirect blood flow to where it should go, not through varices
Prevents use of varies and risk of bursting
What monitoring would need to be done for patients with ascites?
Daily weight (aim for gradual weight loss) Fluid chart (fluid restriction, urine output) Daily U&E's (Na, K, Cr) Avoiding high Na concentrations in IV preparations
Can impair some drug absorption in advanced disease
What are some complications that can arise from ascites?
Hepatic encephalopathy Hyponatremia Hyperkalaemia Gynecomastia Muscle cramps Hepatorenal syndrome Spontaneous bacterial peritonitis
What is spontaneous bacterial peritonitis?
Acute bacterial infection of ascitic fluid (without intra-abdominal source of sepsis)
- diagnosed from fluid sample (no. neutrophils)
- treated with cephalosporins, co-amoxiclav, tazocin
What is hepatic encephalopathy?
Acute/chronic liver disease
Neuropsychiatric changes e.g. confusion, mood, behaviour, sleep
Due to build up of toxins, namely ammonia from gut breakdown (not excreted)
- increased permeability across BBB
TEST: Asterixis
Precipitating factors of hepatic encephalopathy
Reduced excretion of ammonia
Drugs (opioids, alcohol)
Electrolyte disturbance
Infection
What is asterixis?
Test for encephalopathy
- Flapping tremor when wrist is extended is a distinguishable feature
- Indicates abnormal motor functions
What treatments are used to treat hepatic encephalopathy?
1) Lactulose, phosphate enemas
- Laxatives remove ammonia and acidifies contents of gut (converted to ammonium- easier to excrete)
- aim for 2-3 loose stools/day
2) Rifaximin
- Antibiotic to kill the gut flora metabolising and producing ammonia
- others less used include metronidazole, neomycin, sodium benzoate
Reduced dietary protein is NOT recommended (most patients are malnourished anyway)
What is variceal bleeding and how do they form?
Complication of Portal hypertension
- Stiffer liver and compression of hepatic venules by regenerating nodules
Formation of weak collateral vessels to enable the passage of blood
- Already decreased clotting factors and vitamin K absorption
- Can lead to blood in stools, coughing up blood and collapsing (blood pressure decreases)
What treatments are currently used for variceal bleeding?
1) Terlipressin
- Analogue of vasopressin (prodrug)
- Vasoconstriction (splanchnic vein)
- Maintains pressure in the kidneys (hypertension leads to dilation in splanchnic vein and a back flow, leading to reduced flow to kidneys and can cause hepatorenal syndrome)
- Bolus injection every 4-6h until haemostasis is achieved
- s/e: abdominal cramps, headaches, ischaemia, blue fingers/toes
2) Somatostatin and analogues
- Selective splanchnic vasoconstriction
- Controversy over being no better than a placebo
3) GOLD standard: Endoscopic procedures
- Band Ligation
- Sclerotherapy (glue- gastric varices)
- Balloon Tamponade (temp. measure)
4) Antibiotics
- All patients must be on prophylaxis as infection risk is high after upper GI bleed
- Ciprofloxacin or other broad spectrum
5) TIPS
Then once haemodynamically stable: non-selective beta blockers (propranolol, carvedilol) for secondary prophylaxis
What is spider naevi?
Failure to metabolise oestrogen
- central arteriole with capillaries branching out in radial pattern
What treatments can be given for Pruritus? (9)
Cholestyramine (binds to bile- caution as may bind to other medications: separate doses)
UDCA (ursodeoxycholic acid)
Chlorpheniramine, hydroxyzine (antihistamines: sedation can mask encephalopathy)
Loratidine, cetirizine (non sedating antihistamines)
Calamine lotion
Ondansetron (last line)
Rifampicin (lower dose than TB)
Naltrexone, naloxone
Sertraline
Does bilirubin affect drug handling in prescribing patients with liver disease? (4)
Do drug doses need to be adjusted?
1) Reduced absorption of lipophilic drugs (no solubilisation)
2) Reduced biliary clearance e.g. digoxin build up
3) Reduced enterohepatic recirculation e.g. contraceptives that must undergo liver metabolism
4) Competition for protein binding can lead to increased free drug- toxicity e.g. theophylline
Adjustments should be considered when at high bilirubin levels - >100micromol/L
Do transaminase enzymes, ALP and GGT affect drug handling in prescribing for patients with liver disease?
Patients monitored until reaches high concentrations
- change medication to observe whether it is drug induced
- transaminase enzymes: drug induced spikes
- GGT and ALP: drug induced as can cause cholestasis which reduce absorption (e.g. co-amoxiclav) OR cause some drugs can be enzyme inducers causing GGT elevation
Remember severe cirrhosis - no enzymes made so concentrations can be very low
Does albumin affect drug handling in prescribing for patients with liver disease?
Low albumin/high INR indicate impaired synthetic function
- Lower doses with close monitoring
- Low albumin can mean reduced protein binding
- Significant for highly protein bound drugs e.g. phenytoin (enhances clinical effect)
Does PT/INR affect drug handling in prescribing for patients with liver disease?
Low albumin/high INR indicate impaired synthetic function
- Dose adjustment if PT is >130% normal (and close monitoring)
At what point is drug handling generally effected?
At advanced disease (capacity of liver is so great it can compensate, even in cirrhotic patients)
- liver blood flow and functional cell mass affects drug handling
- difficult to predict
Classes of drugs based on metabolism?
High extraction ratio drugs
Low extraction ratio drugs
What are high extraction ratio drugs?
- High first pass metabolism
- Dependent on hepatic blood flow
- Reduced flow, higher bioavailability
E.g. phenytoin, warfarin
What are low extraction ratio drugs?
- Bioavailability not affected by hepatic blood flow EXCEPT highly protein bound drugs
- Low intrinsic clearance
E.g. propranolol, lidocaine
What is formed after drugs undergo liver metabolism?
Inactive soluble compounds for elimination
Pharmacologically active compounds
in what disease states will hepatic blood flow be impaired? (5)
Cirrhosis Heart failure Portal Vein Thrombosis Shock Portal systemic shunting
Reduce frequency of dosing
What drugs need to be cautioned in particular in liver disease?
Those with side effect profiles affecting:
- sedation
- encephalopathy
- GI ulceration
- constipation (can lead to encephalopathy)
- clotting
- fluid retention and electrolyte imbalance
- TDM drugs (narrow range/hepatotoxic/nephrotoxic)
What routes of administration should be avoided in cirrhotic patients?
- Modified release
- Intramuscular (if coagulopathy)
- Topical preparations (little fat, malnourished so prone to dry/cracked skin, unpredictable absorption)
- Enemas etc. if rectal varices present (esp in constipation)
What is DILD?
Drug induced liver disease
Examples of conditions caused by DILD?
1) Fibrosis/cirrhosis
2) Steatosis
3) Cholestasis
4) Acute liver failure
5) Vascular disorders
In DILD, what examples of drugs cause cholestasis?
Warfarin
Azathioprine
Oral contraceptives
In DILD, what examples of drugs cause acute liver failure?
Allopurinol
MDMA
NSAIDs
In DILD, what examples of drugs cause Fibrosis/Cirrhosis?
Methotrexate
In DILD, what examples of drugs cause steatosis?
Amiodarone
Steroids
Total parenteral nutrition
In DILD, what examples of drugs cause vascular disorders?
Oral contraceptive pill
Azathioprine
Does liver disease mean that hepatotoxicity is more likely?
No, however effects will be worse due to reduced hepatic liver reserve
- always take liver history
- methotrexate, cytotoxic and sodium valproate should be avoided
Difference between idiosyncratic and intrinsic reactions
INTRINSIC
- e.g. paracetamol overdose
- predictable PK (prognosis)
- Dose dependent
- occurs within hours
- Causes necrosis and liver failure
IDIOSYNCRATIC
- e.g. NSAIDS
- unpredictable
- occurs over longer time
- can cause any types of liver injury
