Liver

Question 1

What does the liver metabolise?

Answer 1

• carbohydrates
• protein
• aldosterone
• Insulin
• bilirubin
• steroid hormones

DRUGS !!!!!

Question 2

List the 6 main synthetic functions of the liver?

Answer 2

• proteins
• clotting factors
• fibrinogen
• cholesterol
• 25-OH of vitamin D
• glucose from fat and protein

Question 3

What are the 5 main functions of the liver?

Answer 3

• Immunological (Kupffer cells)
• Storage (fat soluble vitamins)
• Glucose homeostasis
• Clearance of drugs/bilirubin/toxins
• Production of bile

Question 4

What are the classes of Liver disease?

Answer 4

Can be:

• Cholestatic
• hepatocellular

They can overlap and both can lead to fibrosis and cirrhosis

Question 5

What is cholestasis liver disease?

Answer 5

• Disruption of bile ducts

Intrahepatic: biliary ductules

Extrahepatic: mechanical obstruction

Ultimately you get impaired biliary excretion and reduced absorption of fatty substances.

Accumulation of bile salts can lead to damage of hepatocytes.

Question 6

What is hepatocellular disease?

Answer 6

• Injury to hepatocytes
• Fatty infiltration (steatosis)
• Inflammation (hepatitis)
• Necrosis

Question 7

what is fibrosis and Cirrhosis?

Answer 7

• Extensive hepatocyte damage (active deposition of collagen = formation of scar tissue = fibrosis)
• Cirrhosis = scar tissue takes over most of the liver.

Question 8

Acute vs. Chronic liver disease

Answer 8

Acute - onset of symptoms does not exceed 6 months.

Acute liver failure - hyperacute, acute or subacute, depending on time from jaundice to encephalopathy.

Chronic - persists for more than 6 months, permanent structural changes following long standing cell damage.

Compensated vs. Decompensated

Question 9

What are the normal bilirubin levels? What’s it function?

Answer 9

• Bilirubin (5-20 micromol/L)
• Product of RBC breakdown
• Attached to albumin
• transformed into a water-soluble conjugate which is excreted via the bile into the intestine.

Jaundice when bilirubin > 50 micromol/L

Question 10

Liver function test

Transaminase enzymes

Answer 10

AST (0-40 iu/L)

ALT (5-30 iu/L)

— Levels increase in viral hepatitis, alcohol related liver injury, drugs, sepsis

Question 11

Liver function tests

ALP and y-GT

Answer 11

Alkaline phosphatase (30-120 iu/L)

y-Glutamyltransferase (5-55 iu/L) = increased by enzyme inducers e.g. alcohol

Question 12

Other tests that can tell us about liver function

Answer 12

• Albumin (35 - 50g/dL) = long half life (20-26 days)
• PT (10-14 secs)/ INR = short half-life (2-3 days)

PT/INR increase in acute and chronic liver disease

Question 13

What is the Child’s Pugh scoring system ? And what does it take into account ?

Answer 13

Used to assess the prognosis of chronic liver disease.

Takes into account:

Bilirubin 
Albumin 
PT/INR
Ascites 
Encephalopathy

Question 14

What are the other investigations needed to assess liver function?

Answer 14

Liver ultrasound 
CT scan 
ERCP and MRCP 
MRI 
Fibroscan 
Liver biopsy 
MELD 

-Never take LFTs in isolation !

Question 15

What is Jaundice? How does it occur ?

Answer 15

Pre-hepatic jaundice - the disruption occurs before the bilirubin has been transported from the blood to the liver (sickle cell anaemia)

Intra-hepatic - disruption occurs inside the liver (Gilbert’s syndrome and cirrhosis)

Post-hepatic - disruption prevents the bile from draining out of the gallbladder (gallstones or tumours)

Question 16

What is ascites?

Answer 16

Accumulation of fluid in the peritoneal cavity = swollen abdomen

• underfill = reduction circulating plasma volume
• overflow = increased plasma volume
• peripheral artery vasodilation

Question 17

Ascites treatment ?

Answer 17

Diuretics:

• spironolactone
• Amiloride
• Furosemide

Fluid/sodium restriction

Paracentesis - drain fluids

Transjugular intrahepatuc portosystemic shuts (TIPS)

Question 18

ASCITES monitoring

Answer 18

Monitor

• electrolytes
• daily weight
• fluid chart
• avoid high Na contents preparation

Question 19

Hepatic encephalopathy

Answer 19

• Neuropsychiatric changes including changes in mood and behaviour, confusion, poor sleep rhythm, delirium and coma.
• due to accumulation of toxins, increased permeability of BBB, increased levels of neurotransmitters.

Question 20

Hepatic encephalopathy treatments

Answer 20

Lactulose
Rifaximin
Metronidazole
Neomycin

Question 21

Variceal bleeding and portal hypertension

Answer 21

Portal hypertension is caused by increased resistance to flow.

Collateral vessels form enabling the blood to bypass the liver

Question 22

Variceal bleeding treatments

Answer 22

Terlipressin (potent splanchnic vasoconstrictor)

Somatostatin and analogues (causes selective vasoconstriction and reduces portal pressure on the portal blood flow).

Endoscopic (band ligation/ sclerotherapy/ballon tamponade)

Question 23

What is spider Naevi ?

Answer 23

Central red arteriole, representing the body of the spider.

Cause: failure to metabolise oestrogen

Question 24

What is Pruritus? (Caused by liver disease)

Answer 24

Severe itching of the skin

Question 25

What are the Factors effecting drug handling in liver disease?

Answer 25

- Patient factors (such as LFTs) - Drug factors (PK/PD/side effects) - Therapeutic effect Child-Pugh scoring system is used to make recommendations in drug SPCs.

Question 26

Increased bilirubin effect on drugs

Answer 26

- Reduces absorption for highly lipophilic drugs = reduced clinical effect. - Biliary clearance will be reduced = this may affect drugs which are cleared by biliary system e.g. digoxin. - Competition for protein binding sites (potential displacement of drug = enhancing clinical effect) such as warfarin and phenytoin.

Question 27

Decreased albumin effect on drugs

Answer 27

Decreased protein binding = | Highly protein bound drugs - increase in "free" drug available to act = increased clinical effect.

Question 28

INR/PT effect on drugs

Answer 28

Dose adjustment if prothrombin time > 130% normal

Question 29

Effect of liver disease on metabolism

Answer 29

High extraction ratio drugs = drugs that are highly first-pass metabolised. Reduced hepatic blood flow = increased bioavailability

Question 30

What are the caused of reduced hepatic blood flow?

Answer 30

``` Cirrhosis Portal vein thrombosis Cardiac failure Shock ( reduced BP) Portal systemic shunting ```

Question 31

Pharmacodynamic

Answer 31

Patients may be at risk of:
 - Increased toxicity - Exaggerated response - Reduced response

Question 32

Route of administration for liver disease

Answer 32

Oral – generally preferred Avoid modified release and long-acting preparations Avoid IM if coagulopathy Topical preparations – consider transdermal absorption Topical preparations – may cause irritation PR – consider presence varices/bleeding

Question 33

Risk factors which may pre-dispose drug induced liver disease

Answer 33

- Gender (tends to be more common in females) - Age - Genetics - Concurrent diseases e.g. obesity, diabetes, co-infection with HIV - Polypharmacy

Question 34

Intrinsic drug induced liver disease

Answer 34

``` Predictable Reproducible Dose dependent Tend to occur rapidly e.g. within hours Tend to cause necrosis, acute liver failure E.g. paracetamol overdose ```

Question 35

Idiosyncratic drug induced liver disease

Answer 35

Not predictable Not reproducible Not dose dependent Tend to take longer to occur – weeks to months Can result from metabolic idiosyncrasy or immunoallergic reaction Can cause any type of liver injury e.g. increased LFTs, jaundice, fever, rash, eosinophilia E.g. NSAIDS (metabolic), carbamazepine (immunoallegic)

Question 36

Drugs that can cause liver disease

Answer 36

Cholestasis – OCP, warfarin, azathioprine ALF – allopurinol, NSAIDS, MDMA Steatosis – amiodarone, steroids, TPN Fibrosis and Cirrhosis – methotrexate Vascular disorders – OCP, azathioprine

Question 37

Symptoms of alcohol withdrawal

Answer 37

``` Marked tremor Fear and delusions Restlessness and agitation Fever Rapid pulse Dehydration Seizures Delirium tremens ```

Question 38

Alcohol withdrawal treatment

Answer 38

combination sedatives and vitamin supplementation – Chlordiazepoxide + Pabrinex - Benzos can be given e.g. Diazepam - Shorter acting, e.g. Oxazepam or lorazepam, more suitable in patients with hepatic impairment

Question 39

Acute Alcoholic Hepatitis treatments

Answer 39

- Prednisolone 40mg OD for at least 5-7 days. Problem: increased risk infection and GI bleeding - Pentoxifylline (Oxpentifylline) Non-selective phosphodiesterase inhibitor which inhibits TNFα. - Other anti-TNF agents – Infliximab, Etanercept

Question 40

Management of Alcoholic Cirrhosis

Answer 40

- Diuretics for ascites - Propanolol for portal hypertension - Vitamin K for coagulopathy - Antibiotics for spontaneous bacterial peritonitis - Lactulose for hepatic encephalopathy (+ avoidance precipitants)

Question 41

How to achieve abstinence?

Answer 41

Abstinence can be achieved by: Psychological treatments Pharmacological treatments Combination of both Agents available: - Acamprosate - Disulfiram (Antabuse) - Naltrexone

Question 42

key points

Answer 42

- Patients may present at any stage 
– need to understand degree underlying dysfunction - Abstinence is key 
 - Appropriate use of benzodiazepines in management of withdrawal - For AAH 
– in severe cases Prednisolone treatment should be used but stopped after 7 days if no fall in bilirubin