Week 1- Liver disease Diagnosis & Monitoring & drug handling

Question 1

how is liver disease diagnosed?

Answer 1

 Medical history
 Blood tests
 Liver function tests (LFTs)
 Electrolytes
 Full blood count
 Viral screens
 blood clotting
 Imaging
 Ultrasound
 CT scan
 MRI
 Liver biopsy

Question 2

what are the different types of LFTs serum enzyme found during a test?

Answer 2

• Aspartate transaminase (AST)
• Alanine transaminase (ALT)
• Gamma glutamyl transferase (GGT)
• Alkaline phosphatase (ALP)

Question 3

what is Aspartate transaminase (AST)?

Answer 3

 Role in gluconeogenesis - catalyses reversible conversion of aspartate and alpha keto glutarate to oxaloacetate and glutamate
 Reference range – 5-40 IU/L (vary slightly between labs)
 Found in hepatocytes, but also in other tissues including heart, brain and skeletal muscle

Question 4

what is Alanine transaminase (ALT)?

Answer 4

Also role in gluconeogenesis – catalyses reversible transfer of an amino group from L-alanine to alpha ketoglutarate resulting in pyruvate and L-glutamate
 Reference range – 5-30 IU/L
 More specific to liver

Question 5

what kind of levels of ALT and AST will be found in the blood for hepatitis?

Answer 5

Very high levels in acute viral/toxic hepatitis

Question 6

what kind of levels of ALT and AST will be found in the blood for cholestatic jaundice/cirrhosis?

Answer 6

 High levels in cholestatic jaundice/cirrhosis

Question 7

how can the ratio of how much AST/ALT is present determine anything?

Answer 7

helps determine the type of liver disease
Ratio of AST/ALT useful in diagnosing different types of
liver disease eg AST/ALT>2 possibly alcohol injury,
whereas most other liver injuries AST/ALT <1

Question 8

what is Gamma glutamyl transferase (GGT)?

Answer 8

 Catalyses transfer of gamma glutamyl moiety of glutathione to to
an amino acid, peptide or water (forming glutamate)
 Reference range – 5-45 IU/L (vary slightly between labs)
 Very high levels in biliary obstruction, lower increased levels in
chronic alcohol or drug toxicity, hepatitis, cirrhosis, or cholestasis
 Also in kidneys, pancreas, prostate

Question 9

What is alkaline phosphatase (ALP)?

Answer 9

 Removes phosphate groups from nucleotides, proteins and alkaloids
 Reference range – 20-100 IU/L
 Very high levels in biliary obstruction
 Also in bone, intestinal wall, renal tubules, placenta

Question 10

what are some other LFTs components that can be observed for?

Answer 10

• Bilirubin
• Plasma proteins and albumin
• Prothrombin time (PT)
• Urea and ammonia

Question 11

what should be observed for when looking at bilirubin for liver disease?

Answer 11

 Reference range – 0-17mmol/L (vary slightly between labs)
 Jaundice occurs at >35mmol/L can lead to yellow/orange colour in skin
 Reflects depth of jaundice and useful for monitoring disease
progression
 Can measure conjugated/unconjugated can help differentiate what type of liver disease

Question 12

what should be observed for when looking at plasma protein and albumin for liver disease?

Answer 12

 Reference ranges: 60-80g/dL total protein, 35-50g/dL albumin
 Albumin is synthesised solely by the liver
 t1/2 for plasma albumin is 20-26 days would show extended liver damage
 <20g/dl results in oedema

Question 13

what should be observed for when looking at Prothrombin time (PT) for liver disease?

Answer 13

-how long it takes the blood to clot
 Reference range – 10-15 sec
 Increased PT when lack of clotting factors
 If hepatocellular damage – PT is unresponsive to vitamin K
 If cholestasis, increased PT due to deficiency in bile salts responsible for vitamin K absorption so responsive to vitamin K
10 mg i/v for 3 days

Question 14

what should be observed for when looking at plasma protein and albumin for liver disease?

Answer 14

 Reference range for urea: 2.5-7.8 mmol/L
 Reference range for ammonia: 16-60 (M), 11-51 (F) mmol/L
 Urea decreased in liver disease
 Ammonia increased in liver disease – hepatic encephalopathy

Question 15

what LFT components do you look out for to decide if the liver is working?

Answer 15

 Albumin to see if its being produced

 Clotting factors to see if its being produced

Question 16

what LFT components do you look out for to decide if the liver is damaged?

Answer 16

-the different enzymes 
 ALT
 AST
 GGT
 ALT/AST ratio

Question 17

what LFT components do you look out for to decide if the liver is damaged?

Answer 17

 Bilirubin conjugated/ unconjugated
 ALP
 GGT

Question 18

what does liver disease result in effects on?

Answer 18

 on Drug clearance
 on Biotransformation
 on Pharmacokinetics

Question 19

what factors are responsible alteration in the liver for liver disease?

Answer 19

 Intestinal absorption
 Plasma protein binding
 Hepatic extraction ratio
 Liver blood flow
 Portal-systemic shunting
 Biliary excretion
 Enterohepatic circulation
 Renal clearance

Question 20

what are the two stages of metabolism?

Answer 20

phase I

phase II

Question 21

what is involved in phase I metabolism?

Answer 21

Oxidation eg azathioprine
Reduction eg halothane
Hydrolysis eg atropine, pethidine

Question 22

What is involed in phase II metabolism

Answer 22

Glucuronidation eg paracetamol, morphine
Sulphonation eg steroids
Acetylation eg hydralazine, phenelzine
Methylation eg nicotine

Question 23

what does the rate of extraction from the liver depend on?

Answer 23

blood flow through the liver

Question 24

what is the extraction ratio?

Answer 24

-can be subdivided into 2 high and low

Question 25

for the liver to have a high extraction ratio it depends on what?

Answer 25

clearance depends on hepatic blood flow -drugs involved here undergo high first pass metabolism in the liver close to 1

Question 26

for the liver to have a low extraction ratio it depends on what?

Answer 26

- clearance - depends on metabolising - capacity of liver close to 0

Question 27

what are the rules when modifying drug dosage in liver disease?

Answer 27

no rules so must monitor for clinical and toxic effects

Question 28

how does liver disease affect drug-metabolising enzyes?

Answer 28

 Inhibition and induction of drug-metabolising enzymes are the most frequent and dangerous drug-drug interactions  Liver disease causes reduction in magnitude of interactions due to enzyme inhibition & induction  Monitor effects of drug and plasma concentrations

Question 29

what are the effects of enzyme inhibitors in the Cytochrome P450 system?

Answer 29

can potentially increase the level of drug

Question 30

what are the effects of enzyme inducers in the Cytochrome P450 system?

Answer 30

can potentially decrease the level of drug

Question 31

what LFT enzyme has raised levels in the serum when taking an enzyme inducer?

Answer 31

GGT

Question 32

what kind of drugs will people with liver disease have increased sensitivity for?

Answer 32

 affect clotting/bleeding  affect CNS  Diuretics  constipation

Question 33

how many types of liver disease is there? no. ppl it effects

Answer 33

over 200 types and effects 2million ppl in UK and increasing

Question 34

what are the main causes for liver disease?

Answer 34

Alcohol Obesity Undiagnosed hepatitis infection Drug or other chemical toxicity

Question 35

what are some of the types of liver disease?

Answer 35

- Alcohol-related liver disease - Drug toxicity - Hepatitis (inflammation) - Non-alcoholic fatty liver disease (NAFLD) - Cirrhosis - Cancer - Gallstones stops biles salts from being secreted - Cholangitis - Hemochromatosis (iron overload, inherited) - Wilson’s disease (copper overload, inherited) - Gilbert’s disease (inability to metabolise bilirubin properly)

Question 36

what are the 2 types of liver disease?

Answer 36

acute or chronic

Question 37

what does acute liver disease mean?

Answer 37

- Usually self-limiting - Results in hepatocyte inflammation/damage - Occasionally severe resulting in liver failure - Generally caused by drugs or viruses

Question 38

what does chronic liver disease mean?

Answer 38

-Inflammation present > 6 months - Results in permanent damage with structural changes resulting in cirrhosis leading to loss of function - Most common cause is alcohol abuse

Question 39

what are the different steps in liver disease progressing?

Answer 39

- start off with normal liver then theres damage e.g. alcohol or viral infection or NAFLD - this leads to inflammation and may have a fatty liver - due to inflammation pro-inflammatory cytokines and immune cells causing activation of immune system - resulting in matrix deposition, parenchymal cell death hepaocytes die and angiogenesis - this leads to early fibrosis and this can be resolved to a normal liver by the removal of underlying cuase or anti-fibrotic drug - early fibrosis progresses to late fiborisi/cirrhosis where hepatocytes lose function, disruption to architecture - cirrhosis can lead to liver failure and portal hypertension and eventually needing a liver transplant or cancer process can take 5-50 years

Question 40

what kind of damage can occur that would lead to damage of the liver?

Answer 40

- alcohol - viral infection - NAFLD - autoimmune disorder - cholestatic disorder - metabolic disease

Question 41

can cirrhosis go back to being a healthy liver?

Answer 41

no but there can be regression to early fibrosis

Question 42

what is a fatty liver due to?

Answer 42

obesity | -increase in triglycerides LFTS AND LIVER FAT.

Question 43

what type of cell is increased in appearance in a liver that has advanced fibrosis?

Answer 43

- a lot of hepatic stellate cell - causing lots of extracellular matrix and fibrosis - inflitrating lymphocytes - kupffer cells are activated - sinsoid lumen with increased resistance to blood flow

Question 44

what virus can cause liver disease?

Answer 44

hepatitis

Question 45

what are the different types of hepatitis ?

Answer 45

- Hepatitis A – fecal-oral route, acute inflammation that generally resolves spontaneously, vaccine available - Hepatitis B – body fluids, mother to baby, acute infection that progresses to chronic inflammation, cirrhosis and cancer, vaccine available - Hepatitis C – body fluids, chronic and may progress to cirrhosis and cancer, no vaccine - Hepatitis D – body fluids, requires concomitant infection with -Hepatitis B to survive Hepatitis E – contaminated food and water, usually self-limited - Hepatitis G – body fluids, chronic infection similar to HCV

Question 46

how do drugs cause liver disease?

Answer 46

-Hepatocytes become temporarily inflamed or permanently damaged by drugs/medicines - Some drugs require overdose to cause liver damage eg paracetamol - Others may cause damage even when appropriately prescribed eg Statins Some common antibiotics eg amoxicillin, tetracycline Methotrexate - Some natural products can also cause liver damage Herbal remedies eg kava kava High doses of vitamin A Some wild mushrooms

Question 47

how does alcohol cause liver disease?

Answer 47

-Most common cause of liver disease/cirrhosis - Directly toxic to liver cells - Alcohol causes inflammation which progresses to fatty liver and eventually fibrosis - Fibrosis alters structure and blood flow leading to portal hypertension and eventual liver failure - Damage occurs >40g/d in men and >20g/d in women (1 unit = 9g)

Question 48

what are the uk alcohol guidelines?

Answer 48

``` UK Alcohol guidelines: • <14 units per week • Don’t save them up • Spread over at least 3 days • No alcohol in pregnancy ```

Question 49

what is cholestatis? cause?

Answer 49

lack of bile - Due to hepatocytes: Failure of bile production and secretion Causes include hepatitis from viruses, alcohol, drugs Pregnancy Due to bile duct: Failure of outflow via bile ducts due to obstruction Gallstones, carcinoma, cholangitis (progressive scarring of bile ducts)

Question 50

what are some symptoms of acute liver disease?

Answer 50

- Possibly asymptomatic - Generalised malaise - Anorexia - Fever-due to inflammation - Possibly jaundice (later) yellow colour

Question 51

what are the symptoms of chronic liver disease?

Answer 51

- Fatigue and weakness - Loss of weight - Nausea/vomiting - Loss of appetite - Cachexia – wasting of muscle in arms and legs - Abdominal swelling - Right upper quadrant abdominal pain and tenderness - Jaundice - Bleeding from gums/nose and easy bruising

Question 52

what are the symptoms of chronic disease?

Answer 52

Could be specific depending on type of disease eg gallstones upper abdominal pain and vomiting after greasy meal Individuals with cirrhosis develop progressive symptoms as liver fails - Inability to metabolise waste as liver fails - Failure to produce proteins required for body function eg clotting - Symptoms include easy bruising, gynecomastia, impotence, confusion, ascites, portal hypertension, oesophageal varices

Question 53

what are some signs and complications of liver disease?

Answer 53

``` Jaundice Ascites Portal hypertension and oesophageal varices Hepatic encephalopathy Hematological changes Circulatory changes Skin changes Endocrine abnormalities Renal failure – due to reduced renal blood flow ```

Question 54

what is jaundice? cause?

Answer 54

Yellow discolouration of skin & mucous membranes (sclera) Causes: bilirubin build up -Haemolysis (haemolytic jaundice) RBC are breaking down liver not getting rid of haem so build up of bilirubin Hepatocellular damage (hepatic jaundice) hepatocyte build up - Cholestasis (obstructive jaundice) bile from liver being made but not being moved due to obstruction in bile duct

Question 55

what is portal hypertension? cause

Answer 55

-where there's a back pressure because of resistance of blood flow due to cirrhosis, because of fibrosis that's happening so there resistance of blood flow in the liver leading to back pressure in portal vein -high blood pressure pushes blood into the surrounding blood vessles including thin walled veins in oesophagus close to the surface. -If pressure too high, they can rupture and bleed – uncontrolled bleeding leads to shock and death

Question 56

what is ascites? cause

Answer 56

``` Abnormal accumulation of fluid in the peritoneal cavity due to pressure imbalance between inside the circulation (high) and outside, in this case the peritoneal cavity (low) Causes: Portal hypertension Low plasma albumin Salt and water retention by kidneys eg secondary hyperaldosteronism ```

Question 57

whats Hepatic encephaloathy?

Answer 57

- Neurological abnormality caused by build up of substances (mainly ammonia) normally metabolised by liver in the blood and crosses blood brain barrier - Can be associated with cirrhosis, or acute liver failure or portal-systemic bypass of liver - Results in altered mental state, fetor hepaticus, asterixis, drowsiness, confusion, coma Due to ammonia & nitrogenous substances from gut by-passing liver & crossing BBB Precipitated by: Dehydration, hypovolaemia, GI bleed, CNS drugs, alcohol, ↑ dietary protein, constipation

Question 58

what is Wernicke encephalopathy?

Answer 58

due to deficiency of thiamine, with decreased mental function. Occurs in chronic alcohol abuse

Question 59

what are some hematogical changes during liver disease?

Answer 59

``` Anaemia Effects on iron homeostasis Splenomegaly from portal hypertension Alcohol toxic to bone marrow etc Reduction in clotting factor synthesis Bleeding and bruising Reduction in clotting factor synthesis ```

Question 60

what are some circulatory and skin changes during liver disease?

Answer 60

``` Circulatory: Palmar erythema Spider naevi Finger clubbing Skin: Pruritis ```