The Liver Flashcards
Assessing liver function
- Drugs handled differently in the different liver conditions
- Poor information on pharmacokinetics and pharmacodynamics of drugs in liver disease
- Mix of tests, diagnosis and symptoms
Child Pugh score meaning
-prognosis of liver disease
POINTS
-5-6: Class A; 1st year 100%; 2nd year survival 85%
-7-9: Class B; One year survival= 81%; 2nd year survival 57%
-10-15: Class C; 1st year 45%; 2nd year survival 35%
Child Pugh scoring system
1) Bilirubin: 1pt <34; 2pt= 34-50; 3pt >50
2) Serum albumin: 1pt>35; 2pt=28-35; 3 pt=<28
3) INR: 1pt=<1.7; 2pt=1.71-2.2; 3pt=>2.2
4) Ascites: 1pt=none; 2pt=Mild; 3pt= severe
5) Hepatic encephalopathy 1pt=None;2pt GradeI-II; 3pt= Grade–IV
Signs and symptoms
NON SPECIFIC
- Malnutrition
- Peripheral Oedema
- Brusing and bleeding
- Testicular atrophy
- White nail
- Splenomegaly (enlargement of the spleen)
- Fatigue/Malaise
- Abdominal or RUQ pain
- Muscle cramp
- Finger clubbing
Liver Investigations
- Ultra sound (pressure in system)
- CT scan (cysts, masses and fluid in system)
- MRI (structural info- surgery)
- Liver biopsy (tissue sample- hallow needle)
- Venography (pressure ballon in system)
- Doppler (direction and speed in vessels, and identify collateral vessels)
- Fibroscan (stiffness of liver, fibrosis)
- Endoscopy (look for varcies and GI bleed)
- Endoscopic Retrograde Cholangiopancreatography (ERCP- diagnose and treat- use endoscope into the stomach inwhich a dye can be injected, can treat gallstones)
- Percutaneous transhepatic cholangiogramaphy (PTC- contrast medium is injected through needle through the skin, x ray image is used to identify obstructions in bilary tree)
Diagnostic Terms
- Acute (<6 months)
- Chronic (>6 months)
- Compensated (Still have synthetic function)
- Decompensated (Lack of synthetic function)
- Hepatitis (inflammation of the liver- drugs, alcohol, virus- when this is suspected a viral serology is required)
- Fibrosis (Excessive accumulation of scar tissue)
- Cirrhosis (Fibrosis and structural degradation )
- Cholestasis (Reduced excretion of bile salts-INR may be raised due to lack of Vit K absorption, Bilary tree is effected so alkaline phosphate, bilirubin increase common sign is gallstone)
- Mixed pictures are not uncommon especially as a condition progresses
Liver function tests (LFTs)
- Markers of dysfunction rather than function
- Used to monitor progression of liver disease
- Only reflects status at time of test
- Vary between male and female
- Vary with time of day that samples taken
- Do not just measure liver disease as not specific (Problems in other systems e.g. bone disease, haemolysis-high billirubin, ADRs to drugs e.g. penicillins, cholestatic jaundice)
- No single test or combination in uniquely diagnostic
- Only albumin and prothrombin show liver function
- for liver enzymes 2x normal limit is still normal
Which tests Classed as liver function tests
LIVER ENZYMES -Alkaline phosphatase -Aminotransferases: -Aspartate aminotransferase (AST) -Alanine aminotransferase (ALT) -Gamma Glutamyl transferase SYNTHETIC FUNCTION -Bilirubin (urine and serum) -Plasma proteins: Albumin; Ig -Prothrombin time (Clotting studies) \+Suffering form liver disease \+harming themselfs through alcohol \+when starting or monitoring patients on drugs that will effect the liver (phenytoin, phenobarbitone, rifampicin)
Alkaline phosphatase (Alk Phos) -REF RANGE: 30-300 IU/L- higher in children
-Group of isoenzymes found in tissues around the body (Therefore is a non-specific indicators)
-Reference ranges larger for neonates and children-always use correct laboratory reference ranges
-High concentrations in biliary canaliculi, production increased if biliary damage
-Levels slightly raised in hepatocellular damage
-Levels greatly increased in biliary obstruction
-Other isoenzymes of Alk Phos in
+Osteoblasts- raised in pages disease, osteomalacia, bony metastases
+Kidney, intestine and placenta (Alk Phos also raised in hypoparathyroidism, pregnancy)
-Drug therapy- e.g. rifampicin, phenytoin, erythromycin, carbamazepine
Alanine transaminases (AST and ALT)
- AST= Aspartate Transaminase ref range 0-40 IU/L (non-specific but reliable)
- ALT= Alanine Transaminase ref range 0-40 IU/L (greater specificity for liver)
- Found in heart, liver, skeletal muscle, kidney, erythrocytes, pancreas, lung (ALT less so)
- Levels may be raised following MI shock, haemolysis (cell lysing)
- Patients with cirrhosis may have normal or only slightly raised enzyme levels
- In chronic liver disease however, a rise may not occur due to reduced production
- Raised ALT may indicate acute hepatitis (+++), Cirrhosis-only raised if continual inflammation (++/+) cholestatic jaundice (++) may also be raised in shock, highest levels in paracetamol toxicity
- In hepitis C cells die by apoptosis, these cells must produce less enzymes so sensitivity is decreased
- In alcohol injury AST levels are higher the ALT
- Drugs e.g. rifampicin, erythromycin, isoniazid
Gamma glutamyl Transferase (GGT)- ref range 0-50 IU/L
- Enzyme found in endoplasmic reticulum in hepatobiliary tract (Also in kidney, pancreas, intestine, prostate)
- Released in all types of liver dysfunction
- Synthesis increase in response to prolonged alcohol intake (Up to 20x)
- Or may be raised by enzyme inducing drugs e.g. phenytoin, carbamazepine, rifampicin (2x-5x)
- Levels also elevated in cholestasis, liver and pancreatic disease, MI and diabetes (fatty liver) (x3)
Bilirubin: range 2-20 mcmol/L
- Jaundice (yellowing of skin caused by bilirubin)
- Usually >50mcmol/L in adults (>80mcmol/L neonates)
- Classification based on cause of raised bilirubin
- Levels rise characteristically in cholestasis
- May be raised in acute liver failure due to inability of hepatocytes to conjugate
- In chronic decompensated cirrhotic patients bilirubin may be normal
Classification of Jaundice- Pre hepatic
- Usually caused by haemolysis- sickle cell
- Levels rarely exceed 85-100 mcmol/L as unconjugated form
- Excess production of unconjugated bilirubin
- Not excretable in urine
- Urine colour normal
- Risk of gallstones
Classification of Jaundice- Intra-hepatic jaundice
\+Causes -Acute viral hepatitis -Drug induced liver injury -Alcoholic hepatitis -Primary biliary cirrhosis- autoimmune disease, destruction of bile ducts- increased bile= choleostasis -Pregnancy -Intrahepatic cholestasis -Acute fatty liver -Congenital hyperbilirubinaemia \+Accumulation of bilirubin in liver, mainly conjugated, water soluble \+Excreted in urine, causing darkening
Classification of Jaundice- Post hepatic Jaundice
-Obstruction of extrahepatic bile ducts caused by: \+Congenital biliary atresia \+Gallstone \+Structures (often biliary surgery) \+Tumours (often head of pancreas) -Excess bilirubin is conjugated -Darkening of urine
Albumin: ref range 35-50 g/L
- Major protein synthesised in the liver
- Marker of synthetic capacity of liver
- Long half life (20 days)- Indicator of chronic disease
- Hypoalbuminaemia leads to peripheral oedema and ascites due to loss of oncotic pressure (osmotic pressure exerted by proteins)
- Fluid retention may lower albumin concentration
- Affects transport of protein bound drugs and Ca, this means there effects can go on for longer
- Malnutrition, Malabsorption and nephrotic syndrome also reduce serum albumin
- Albumin synthesis depressed in inflammatory states- increased protein demand (burns, trauma, sepsis)
- Normal albumin levels lower in pregnancy
Clotting factors INR range (0.9-1.2)
- Liver synthesis Vit K dependant clotting factors II,V, VII, IX and X
- Prothrombin time (PT- time taken for clot to form) becomes abnormal when 80% of liver synthesising capacity is lost
- May be due to reduced absorption Vit K or reduced liver synthesis of clotting factors
- Clotting factors have short life, sensitive marker of loss of liver function
- Failure to absorb Vit K absorption (Chronic cholestasis, fat malabsorption) supplementation
- Caution with NSAID
Drug induced Liver injury
- Acute reactions and from long term use
- 2% of jaundice patients
- 50% of acute Liver Injury Patients
- Hepatocellular, cholestatic, mixed presentations
- Direct hepatotoxicity e.g. paracetamol or idiosyncratic drug reactions
- Steatosis (Abnormal retention of fat)
- Oral contraceptives
- Risk factors: age, other medications, poor renal function, previous liver injury
Drug handling in liver failure
-Issues of drug absorption
+Cholestasis- reduce absorption of fat soluble drugs
+Ascites
-Issues of altered distribution
+Ascites- changes water soluble drugs
+Lack of albumin- protein bound drugs phenytoin
-Metabolism
+Lack of function- increased half-lives
-Elimination
- Reduction of first pass metabolism (Varacies, portal HTN)- propanolol and morphine
Side effects to consider in Liver disease
- Hepatotoxicity-
- Biliary effects-
- Bleeding risk - no NSAIDs
- GI- SSRI and NSAID cause bleeding (liver disease random clotting factor release)
- Neurological- mask encepthalopgy
- Electrolyte disturbances- bad in ascites due to shift of fluid
- Fluid accumulation
- Renal- more susceptably to kidney decline
Prescribing in liver failure
- Keep number of medicines to a minimum
- Small doses
- Avoid modified release preparations
- Short half life
- Plan to monitor for side effects of drugs and consider side effects when choosing an agent
- NO NSAID (fluid retention, bleeding and increased kidney injury)
- Check SPCs- Bioavailability, protein binding etc
Signs and symptoms- specific vs non-specific: SPECIFIC
JAUNDICE
- Jaundice
- high levels of bilirubin occur in acute hepatitis or cirrhosis
- this is not an indication of liver function gilberts syndrome is a begin condition and LF is not effected
- In people with dark skin, it can still be seen to sclera of eye and gums
Signs and symptoms- specific vs non-specific: SPECIFIC
PALE AND DARK STOOLS
- Pale stool and dark urine
- sign of obstructive jaudince water soluble conjugated bilirubin cannot be excreted through faeces so increases renal elimination through urine
Signs and symptoms- specific vs non-specific: SPECIFIC
steatorrhoea
Steatorrhoea
- fat in poo, bile salt defficiency which means less fat is absorbed from the gut
- Orlistat causes this
- Reduction is fat soluble vitamins including K
Signs and symptoms- specific vs non-specific: SPECIFIC
SPIDER NAEVI
-Spider Naevi
(vascular changes and long term liver disease)
Signs and symptoms- specific vs non-specific: SPECIFIC
HEPATIC ENCEPHALOPATHY
-Hepatic Encephalopathy -Severe, caused by toxic substances
e,g, ammonia, fatty acids and nitrogen based comounds
act as false neurotransmitter
-This increases when liver cannot clear them OR if the circulation bypass liver
-Symptoms: aggression; confusion; poor concentration; coma
-This is graded in terms of severity- this can be tested by asking them to hold there arms out straight. If they have the disorder the arms will flap
+It is termed liver flap
Signs and symptoms- specific vs non-specific: SPECIFIC
DUPUYTENS CONTRACTURE
- Dupuytens contracture
- fixed forward contracture of a finger, with a fibrous link-
- starts as nodules and they join together to form cords of tissue
- If this cord shortens the finger contracts
Signs and symptoms- specific vs non-specific: SPECIFIC
PRUITUS
- Pruritus
- High conc of bile salt in the skin, this is when bilirubin is above 50
- This causes a central itch
- opiate antagonists , antihistamines are both treatments
Signs and symptoms- specific vs non-specific: SPECIFIC
LEUCONYCHIA TOTALIS
- Leuconychia totalis
- white nail, is from a lack of albumin and is not just shown in liver dysfunction e.g. congenital disorders where there is poor protein absorption or renal
- Sulphonamides also can cause this
Signs and symptoms- specific vs non-specific: SPECIFIC
HEPATOMGEALY
- Abdominal signs
- Hepatomegaly
- enlargement of the liver may disappear as hepatocytes are destroyed and replaced with fibrous tissue
Signs and symptoms- specific vs non-specific: SPECIFIC
Palmar erythema
- Reding of palms, hands and soles of feet
- Can occur in pregnancy, RA and other conditions
Signs and symptoms- specific vs non-specific: SPECIFIC
ASCITES
- This is excess fluid in the peritoneal cavity
- Large amounts can be uncomfortable and effects breathing
- This comes from increased portal pressure, lack of albumin and over activity of RAAS
- Liver failure leads to salt and water retention, this decreases renal blood flow and GFR,
- Excess reabsorbtion of sodium and water leads to increase in renin and aldosterone
- This is then exacerbated by the liver which cannot metabolised aldosterone or vasopressin
- Hypoalbumaemia lowers the collidal osmotic pressure and encourages oedema formation and contributes to poor renal blood flow
Signs and symptoms- specific vs non-specific: SPECIFIC
GYNAECOMASTIA
- Increase in male breast tissue
- This occurs from reduce oestrogen metabolism
- This can be an indication that drug metabolism is also impaired
- Spironolactone can also cause this as a side effect
Signs and symptoms- specific vs non-specific: SPECIFIC
OESOPHAGEAL AND GASTRIC VARICES
- Portal HTN is an increase in BP in the portal venous system
- Vessels from stomach, spleen and pancreas merge into this system
- This then branches through the liver
- The hepatic venous pressure gradient approx the gradient pressure between the portal vein and the inferior vena cava
- This quantifies the degree of portal HTN
- A normal value is between 1-5mmHg
- Portal HTN is stated to be present when this value is above 6
- Above a value of 10, this is now clinically significant and oesophageal varies may develop
- At above 12 the patient may be at risk of varieal bleeding and the development of ascites
- This increase in pressure can increase for a number of reasons: pressure on the portal vein because of a tumor; disorganised blood flow through the liver due to cirrhosis: thrombosis of hepatic vein (due Budd-chari syndrome)
- Portal HTN can be pre-hepatic; intra-hepatic or post-hepatic
- Oesophageal and gastric varices can burst due to portal HTN, these are abnormally dilated collateral vessels
- The porto-systemic collateral circulation in stomach or oesophagus rises due to increase HTN this allows blood to bypass vessels
- Higher mortality 30% die;
- Reduction is 1st pass metabolism so drugs can have a greater effect on the body- dont use these drugs
Splenomegaly
- Patients with portal HTN may have an enlarged spleen
- This is because it may get congested due to increase iun pressure
Back to structure
- Hepatocytes can regenerate if injured and life span is around 5 months
- Will always be liver enzymes released from cells
- Most drug injury occurs in area 3 of the acinus- where ALT and AST release
- Alkaline phosphate occurs in cells around bile ducts, so we would except an increase in bilirubin to indicate problem with bilary tree rather than hepatic problem
