Liver - 3 lecture series overview

Functions of the liver

- Metabolism: carbohydrate, protein, fat, steroid hormones, insulin, aldosterone, bilirubin, DRUGS

- Synthesis: proteins, clotting factors, fibrinogen, cholesterol, 25-OH

vitamin D, gluconeogenesis (from fat/protein)

- Immunological: Kuppfer cells

- Storage: Fat-soluble vitamin A, D, E, K, B12 and Folic acid

- Homeostasis: glucose

- Production of bile: secretion of bile salts and enterohepatic

circulation

- Clearance: Bilirubin, drugs, toxins

Can the liver regenerate ? True or false

True

Why can some patients have liver disease and be unaware?

- Many patients can be asymptomatic until developing hepatic complications

- Often a long time interval between disease occurrence and detection

Liver structure

How is liver disease classified? - understand*

-classified according to both the pattern of damage seen and time course over which damage occurs

- The main patterns of damage can be classified initially as cholestatic or hepatocellular

- These are not distinct entities- overlap occurs

- Both of these can lead to fibrosis and cirrhosis

What is Cholestasis?

- Disruption of bile flow—stagnation of bile in bile ducts - bile fails to flow from hepatocytes to duodenum and is diverted to blood

• Bile salts competes for protein binding sites • Decrease protein binding • Reduce absorption of lipid soluble drugs • Drugs eliminated by biliary route may accumulate

2 types: - Intrahepatic vs extrahepatic

- Intrahepatic—biliary ductules e.g., PBS, drugs, inflammation

- Extrahepatic—mechanical obstruction e.g., inflammation of bile ducts, strictures, gall

stones

- Impaired biliary excretion and reduced absorption of fatty substances

- Accumulation of bile salts can lead to hepatocyte damage

What is Hepatocellular disease?

- Injury to hepatocytes e.g.,, toxins, viruses, drug induced

- Fatty infiltration—steatosis—accumulation of fat within the hepatocyte which can be

micro or macrovesicular

- Cell death—necrosis

What is Fibrosis and Cirrhosis?

Cirrosis - shrivelled up liver

- Persistent, extensive hepatocyte damage—active deposition of collagen formation of scar

tissue—fibrosis

- Disruption of blood flow

- Erratic regeneration and nodules can form

What is the difference between acute and chronic liver disease?

- Acute- history of onset of symptoms does not exceed 6 months

- Acute liver failure (e.g. paracetamol overdose)- hyperacute, acute or subacute depending on time from jaundice to

encephalopathy (brain dysfunction)

- Chronic (e.g. chronic hep B)—persists for more than 6 months, permanent

structural changes following long-standing cell damage

- Compensated (liver is working ) vs decompensated (liver iss unable to carry out its functions listed in the previous card) disease

actute liver failure timeline

How do we interpret LFTs

- Fairly non-specific

- Generally is 2 x ULN considered abnormal

- Liver dysfunction present = usually at least 2 will be deranged

- Trends not isolation—check references ranges and units

- LFTs are not always abnormal even in patients with cirrhosis

- Abnormal LFTs not necessarily due to liver dysfunction

What are the liver function tests (LFTs)?

Bilrubin fact profile - LFTs

• Usual range 5-20micromol/L

• Product of RBC breakdown

• Transported to the liver in the serum attached to albumin

• Transformed into a water-soluble conjugate which is excreted via the bile into the intestine

• Levels increased

• Haemolysis

• Hepatocellular damage • Cholestasis

• Clinical jaundice when Bilirubin greater than 50micromol/L

Conjugated VS unconjugated

Transaminase Enzymes fact profile -LFTs

AST (0-40 iu/L) • Found in liver, heart, skeletal muscle, pancreas, kidney and RBC

ALT (5-30 iu/L) • Often termed 'Liver specific enzyme'

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

Not All patients with liver disease will have raised transaminase enzymes

ALP and γ-GT fact profile - LFTs

Alkaline Phosphatase

• ALP range 30-120 iu/L

• Found in liver, bone, intestine and placenta

• Level increase in cholestasis, infiltrative liver disease, damage to biliary tree

• If raised ALP in isolation may be due to other reasons e.g. Paget's disease

γ-Glutamyltransferase

• GGT-(5-55 iu/L)

• Found in liver and biliary epithelial cells, pancreas, kidneys, prostate, intestine

• Level increased by enzyme inducers including alcohol, cholestasis, carcinoma of pancreas & GIT

Albumin and PT fact profile - LFTs

Albumin (35-50 g/dL)

• One of the proteins produced by the liver

• Long half-life (20-26 days)

• Increased level - oedema • Decreased in chronic liver disease

PT (10-14 secs)/INR

• Clotting factors produced by the liver

• Short half-life (2-3 days)

• PT/INR increased in acute and chronic liver disease

What is the Child’s Pugh Scoring System?

-Shows severity of liver disease

What other investigations/scoring systems are used for liver disease?

- Liver ultrasound, CT, MRI

- ERCP and MRCP

- Fibroscan, biopsy

- MELD or UKELD or Lille score -> this is usually used, Child Pugh not really used

What are the signs and symptoms of liver disease? understand why all of these happen

- Jaundice - caused by increase bilirubin

- Ascites

- Unexplained bruising and bleeding

- Varices

- Encephalopathy

- Abdominal pain

- Pale stools and dark urine

- Gynaecomastia

- Fatty stools

- Spider naevi

- Finger clubbing and pruritus

What is jaundice? What are the different types of jaundice ?

- Describes the yellowing of the skin and whites of eyes caused by build-up of bilirubin ( due to red blood cell breakdown) in

the blood and tissues of the body

- Other common signs are pale stools and dark urine

- Pre-hepatic jaundice: disruption occurs before the bilirubin has been transported from

the blood to the liver and is caused by conditions such as sickle-cell anaemia

- Intra-hepatic (hepatocellular) jaundice: disruption occurs inside the liver and caused by

conditions such as Gilbert's Syndrome and cirrhosis

- Post-hepatic (obstructive) jaundice: disruption prevents the bile and bilirubin inside it

from draining out of the gallbladder into the digestive system and caused by conditions

such as gallstones and tumours

What is ascites?

Accumulation of fluid in the peritoneal cavity leading to swollen

abdomen (like those adverts of hungry children looks wise)

How ascites occurs diagram?

Portal hypertension occurs when there is increased resistance to blood flow in the liver (often due to cirrhosis or fibrosis).

This causes increased pressure in the portal vein, leading to:

Splanchnic vasodilation (dilation of abdominal blood vessels).

Increased hydrostatic pressure in capillaries, pushing fluid into the peritoneal cavity.

Reduced effective arterial blood volume, even though total blood volume is high.

2️⃣ RAAS Activation & Fluid Retention

Renin release (kidneys sense low perfusion) → Angiotensin II → Vasoconstriction + Aldosterone & ADH release.

Aldosterone → Sodium & water retention.

ADH → Water reabsorption.

Result: More fluid retention, worsening ascites as excess fluid shifts into the peritoneal cavity

How is ascites treated?

- Diuretic resistant—25-50% mortality within a year

- Consider fluid and/or sodium restriction

- Diuretic therapy includes:

o Aldosterone antagonists e.g., Spironolactone (Potassium sparing diuretic)

o Loop diuretics e.g., furosemide

o Amiloride

- Paracentesis - if diuretics don't work for large volume—need to maintain adequate circulation volume—colloids,

albumin, terlipressin (insert needle and drain while maintain homeostasis)

- Transjugular intrahepatic portosystemic shunting (TIPSS) for more refractory ascites

along with paracentesis

Diagram of Paracentesis

Diagram of TIPPS

Portal hypertension :before the TIPS procedure -PHT causes blood flow to be forced backward, causing veins to enlarge and varices to develop across the oesophagus and stomach from the pressure in the portal vein. The pressure backup also causes the spleen to enlarge.

After the TIPS procedure - The shunt allows the blood to flow normally through the liver to the hepatic vein. This reduces portal hypertension, and allows the veins to shrink to a normal size helping to stop variceal bleeding.

Can patients with an AKI use diuretics

No, diuretics are renally cleared

What side effects of diuretics?

-Hyponatraemia

-Potassium levels altered

What are the cautions associated with ascites? - wHAT SHOULD WE MONITOR

Monitor:

o Daily U&Es—especially sodium, potassium and creatinine

o Daily weight—aim for 0.5-1 kg/day loss

o Fluid chart—note fluid restriction, urine output

o Avoid high sodium preparations

o Complications—dilutional hyponatraemia, hepatic encephalopathy, hepato-renal

syndrome, gynaecomastia, hyperkalaemia, muscle cramps, spontaneous bacterial

peritonitis

What is Spontaneous Bacterial Peritonitis?

- Infection of the ascitic fluid without intra-abdominal source of sepsis (infection of the ascites)

- 75% from gut 25% from skin

- Neutrophil count>250 cells per mm3

- Mortality ~40%

- 1 st line: 3 rd generation cephalosporins, co-amoxiclav, Tazocin

- Prophylaxis: (broad spectrum antimicrobials) Norfloxacin, Ciprofloxacin

What is Hepatic Encephalopathy?

List potential differential diganosis'

- A brain dysfunction caused by liver insufficiency and/or PSS

- Manifests as a wide-spectrum of neurological or psychiatric abnormalities from ranging

from subclinical alterations to coma

- Can occur in either acute or chronic liver disease

- Classifies from grade 1 to 4

- Potentially correctable

- Differential diagnosis = hard to diagnose: hypoglycaemia, alcohol intoxication, withdrawal

- Workable theories: toxin accumulation, increased BBB permeability, increased levels of

neurotransmitters

Grades 1-4 of HE diagram

What are the precipitating factors of HE?

increased protein load, reduced ammonia secretion, electrolyte

imbalance/disturbance, infections, dehydration, drugs

why is HE a problem in liver dysfunction?

Ammonia isn't cleared as well and can travel to the brain = brain dysfunction

How do we get rid of excess ammonia for HE patients

laxatives - lactulose

What are the treatment options for HE?

1. Lactulose (non-absorbable disaccharide)

• Aim for 2-3 soft stools per day

- Promotes growth of beneficial micro-organisms

- Reduces gut protein load

- Lower colonic pH which discourages ammonia producing bacteria (Enemas can be used when patient is constipated)

2. Rifaximin • 550mg twice daily

• Semi-synthetic rifamycin derivative, poorly absorbed (reduced systemic side effects)

• Broad-spectrum with activity against aerobic and anaerobic, gram positive and negative organisms

• Binds to the β-subunit of bacterial DNA-dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis.

• Reduces gut bacteria that would produce ammonia, reduces absorption of ammonia from intestinal lumen

• NOT to be used in acute infection, to be held when patient on broad-spectrum antibiotics

Other options include: • Metronidazole, Neomycin, Sodium benzoate • Dietary protein restriction not recommended

link asterixis to HE

What is Variceal Bleeding and Portal Hypertension?

- Portal hypertension is caused by increased resistance to flow due to:

o Disruption of hepatic architecture

o Compression of hepatic venules by regenerating nodules

- Collateral vessels form and enable blood to bypass the liver

- Variceal bleeding is a serious complication of pHTN (> 12 mmHg) with reduced clotting

factors and vitamin K absorption

- Bleeding varices—mortality 50% index bleed and 30% for subsequent bleeds

Drug options for Variceal Bleeding and Portal Hypertension - mechanisms of treatment not that important for exam

Terlipressin -

• Synthetic analogue of vasopressin which acts on 3 vasopressin receptors. • Greater selectivity for V1 and longer half-life.

Administer in bolus doses 1-2mg every 4-6hours (continue until haemostasis achieved)

• Monitor - Blood pressure, sodium, potassium, fluid balance • Side-effects include headaches, abdominal cramps, ischaemia (monitor extremities)

Somatostatin and Analogues:

• Inhibits splanchnic vasodilatation - decrease of splanchnic hypervolaemia. • Results in decreased arterial blood supply leading to reduction in pressure in the portal circulation.

treatment options for Variceal Bleeding and Portal Hypertension - mechanisms of treatment not that important for exam - not that important extra info

-Band litigation - superior to sclerotherapy in terms of re-bleeding and mortality

-Sclerotherapy - Injection of sclerosants ("glue") e.g. cyanoacrylate

-Balloon Tamponade - temporary, Mechanical "pressure" over bleeding points, hig rates of re-bleeding when deflated

Variceal Bleed and portal -HTN - generate a question from this

- Infection is common after a upper GI bleed in cirrhotic

patients

- Major cause of mortality and morbidity

- All patients should receive broad-spectrum antibiotic

prophylaxis

- 6RCTs- antibiotic vs placebo

- 7 days antibiotic decreases mortality—IB broad-spectrum

Tazocin or meropenem/ciprofloxacin for penicillin allergic

patients

What can we use for secondary prophylaxis of portal hypertension?

-Non-selective beta-blocker: • Propranolol • Carvedilol

• Splanchnic vasoconstriction (beta2 blockade)

• Cardiac output results in reduced portal pressures (beta1 blockade)

• Beta-blockers:

• Prevent re-bleeding

• Increase surviva

• Role of Nitrates • Problems with tolerability • Dose titration and monitoring

What is Spider naevi

- Central red arteriole surrounded by radial pattern of thin capillaries

- Raised oestrogen—pregnant women, HRT, OCP

- Hepatic disease—failure to metabolise oestrogen

Pruritus slide - slide 49

Lecture 2

What are the causes of liver disease?

-Alcohol

• Viral infections - Hepatitis (A, B, C, D, E)

• Inherited and metabolic disorders

• Immune disease of the liver

• Vascular abnormalities

• Non-alcoholic fatty liver disease (NAFLD)

• Drugs and toxins

• Cancer

• Biliary tract disorders

• Infections

• Other

how many mls is a unit of alcohol

8ml

Effects on alcohol on the body

Everything bro

Short term:

• Decreased respiratory rate • GI disturbances • Impaired judgement • Loss of consciousness • Impotence • Acute poisoning • Complexion/ effect on appearance • Unintentional injuries

Long term effects:

• Liver disease • Cancer (several types) • Pancreatitis • GI ulceration • Osteoporosis • Infertility • Heart disease • Stroke • Increased BP • Obesity • Dementia

How is alcohol metabolised?

- Alcohol is oxidised to acetaldehyde via alcohol dehydrogenase

- Acetaldehyde is most important to liver damage

- Dehydrogenase metabolises acetaldehyde which is metabolised to water, fatty acids

and CO2

- Higher alcohol intake increases CYP450 2E1 oxidising system which metabolises

alcohol to unstable free radicals

What is Steatosis?

- Fatty acid accumulation in the liver

- Reversible

- Disrupts metabolic pathways causing large lipid accumulation damaging hepatocytes

-usually has minimal effect on liver function

-Liver is scanned to see fatty acid accumulation

What is Steatohepatitis? Acute Alcoholic Hepatitis (AAH)

- Accumulation of fat and hepatocyte injury with fibrosis

- Caused by many things e.g.: Oxidative stress, acetaldehyde accumulation and altered protein function

-Usually improves with abstinence although proportion patients will develop cirrhosis despite abstinence

What is fibrosis/cirrhosis?

• Inflammation - fibrogenesis + collagen deposition

• Mechanism activation unclear but thought to include direct injury by free radicals plus expression inflammatory cytokines

• Patient may exhibit signs of decompensation including encephalopathy, ascites, coagulopathy

• Proportion patients will go onto develop HCC

• Abstinence key to management

Who is susceptible to liver damage?

• Intake (threshold) • Consumption patterns • Dependency • Genetics • Gender • BMI • Race • Environmental influences e.g. chronic viral disease

What drugs are used to treat ALD?

- Sedatives and vitamin supplementation (drinking alocohol = patients are not eating as much = lacking vitamins)

- Chlordiazepoxide and Pabrinex (Lorazepam- (double check this drug choice))

- Withdrawal Protocol

- Lorazepam = shorter half-life easier to manage symptoms

Why is Chlordiazepoxide used?

- A benzodiazepine = long-half life (decreased chance of abuse), sedative and anti-convulsant

- Slower onset = low dependence

- Lorazepam better in hepatic impairment

- Highly lipophilic and extensive liver metabolism = in cirrhosis = higher active drug in

system

Why is Pabrinex used? Thiamine, ascorbic acid, nicotinamide, pyridoxine

- Malnourished - vitamin supplementation

- High in carbs, low in proteins

- IM not given due to clotting factor risk (coagulopathic) = high risk of bleeding

Why is Prednisolone (steroid) used?

- For inflammation 5-7 days then 1 month if works but stopped after 7 days if no fall in bilirubin

- Increased risk infection and GI bleed

-PPI can be prescribed with it (Low dose PPI - double check dose)

-Supplement calcium and vit d for bone health

SE:

-Immunosuppressed

-Appetite increase

-Weight gain

-Drastic mood fluctuations

-Agitation

-Tapered dose necessary

How can abstinence be acheieved and What are the abstinence drugs ?

Abstinence can be achieved by:

• Psychological treatments

• Pharmacological treatments

• Combination of both

Drugs: Abstinence aids

- Acamprosate = taurine derivate stimulates GABA neurotransmission, crosses BBB, no

hepatic excretion, no sedative effect

- Disulfiram = reduces alcohol consumption, irreversibly inhibits dehydrogenase

- Naltrexone = opiate antagonist = reduce alcohol craving

Symptoms of Acute Alcoholic Hepatitis?

- Jaundice and liver failure

- Reversible

- Fever, large liver, leucocytosis, ascites

- High creatinine too (renal pressure to excrete)

-Transplant is an option if patient is abstinent

LFT results for liver disease

• Raised AST, WCC, neutrophil count, Bilirubin and INR

-There are different s

Why do we no longer use Clormethiazole ?

- respiratory depression, addiction/dependence

Liver disease and clotting factors?

not being made as well

Other pharmacological management includes:

• Diuretics for ascites • Propranolol for portal hypertension • Vitamin K for coagulopathy • Antibiotics for spontaneous bacterial peritonitis (SBP) • Lactulose for hepatic encephalopathy (+ avoidance precipitants)4

-Transplantation

Describe how alcohol dependece occurs and the effects of abrupt withdrawal - condense these notes

1️⃣ Neurotransmitter Effects & Dependence

Alcohol affects GABA, glutamate, dopamine, and opioid systems.

β-endorphins released during alcohol consumption stimulate dopamine, reinforcing pleasurable effects and dependence.

Alcohol enhances GABAergic inhibition, but chronic use leads to GABA receptor downregulation as the body adapts.

Glutamate (excitatory) is inhibited at low doses, but chronic use upregulates NMDA receptors to compensate.

2️⃣ Withdrawal & CNS Hyperactivity

Chronic alcohol use causes GABA-glutamate imbalance.

Sudden alcohol withdrawal removes inhibition, leading to excess glutamate activity and CNS hyperexcitability.

This can result in withdrawal seizures, tremors, and agitation.

Lecture 3

What to consider about drugs in liver disease?

• Pharmacokinetic properties (F, Vd, Cl) • Pharmacodynamic properties • Side-effect profile • Therapeutic Index • Route of administration

Resources to guide treatment

BNF/SPC recommendations

What does bilurubin tell us

- Drug absorption for highly lipophilic drugs = reduced absorption

- Biliary clearance - reduced

- Enterohepatic recirculation = reduced exposure and therapeutic effect

- Competition for protein binding = displace drug

What do Transaminase Enzymes, ALP and γ-GT tell us? - i don't understand this ngl gang

1️⃣ Transaminase Enzymes (AST & ALT) – Liver Cell (Hepatocellular) Damage

AST (Aspartate Aminotransferase) & ALT (Alanine Aminotransferase) are markers of liver cell injury.

No direct link between AST/ALT levels and drug concentration (AUC).

Drug-induced liver injury (DILI) can cause elevated AST/ALT.

2️⃣ Alkaline Phosphatase (ALP) & γ-Glutamyltransferase (γ-GT) – Cholestasis & Bile Flow Issues

ALP & γ-GT are markers of cholestasis (bile flow obstruction).

Some drugs cause cholestasis, which can reduce drug absorption.

Enzyme-inducing drugs (e.g., anticonvulsants, alcohol) can elevate γ-GT without liver damage.

What do Albumin and INR tell us?

1️⃣ Albumin & Liver Synthetic Function

Albumin is made by the liver → Low albumin = Reduced liver function.

The International Normalized Ratio (INR) measures blood clotting ability → High INR = Impaired liver function.

Both indicate reduced liver synthetic capacity, common in liver disease.

2️⃣ Effects on Drug Binding & Clinical Impact

Albumin binds many drugs; low albumin = less protein binding.

Highly protein-bound drugs (e.g., Phenytoin) have more "free" drug in circulation → Increased drug effect/toxicity.

3️⃣ Therapeutic Drug Monitoring (TDM) & Dose Adjustments

Low albumin can cause misinterpretation of TDM results (total drug levels may seem normal, but active free drug is higher).

If prothrombin time > 130% of normal, a dose adjustment may be needed for drugs affected by liver metabolism

What is the pharmacokinetics in liver disease?

- Reduced absorption

- Reduced protein binding

- Ascites

- Portal systemic shunting

- Reduced metabolism

- Cholestasis = reduced elimination

- Increase half-life and toxicity with repeat dosing

What are high extraction ratio drugs and low extraction drugs, how do they effect bioavailability?

drugs that are highly first-pass metabolised

- High 1 st pass = hepatic blood flow in liver disease reduced so bioavailability increases

- Low extraction drugs = bioavailability not affected

When is hepatic blood flow reduced

- Cirrhosis

- Portal vein thrombosis

- Cardiac failure

- Shock (low BP)

- Portal systemic shunting

What does hepatic cell mass show us

= functional capacity of the liver

Drug cautions

- Sedation

- GI ulceration - risk of bleedin in coagulopathy

- Constipation

- Clotting effect (interfere or have adverse effect on)

- Fluid retention

- Narrow Therapeutic index

Administration prefrences

- Oral preferred

- Avoid modified release and long acting preparations, if patient doesnt get on well with the drug, they have to deal with SE's for long

- Avoid IM in coagulopathy

- Topical may irritate but can be considered

What to consider for drugs for liver disease

• Is drug highly metabolised in liver? • What is the route of elimination? • What is it side-effect profile? • Consider hepatic blood flow and synthetic function • Be aware of potential renal impairment • Where possible - TDM • Think about route of administration • Titrate to patient response

Risk factors which may pre-dispose to drug induced liver diseas (DILD)

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

Intrinsic vs. Idiosyncratic reactions

Intrinsic

• Predictable

• Reproducible

• Dose dependent

• Tend to occur rapidly e.g. within hours

• Tend to cause necrosis, acute liver failure

• E.g. paracetamol overdose

Idiosyncratic

• 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)

Types of DILD and associated drugs:

- Cholestasis = warfarin, azathioprine

- ALF = allopurinol, NSAIDs

- Steatosis = amiodarone, steroids, TPN

- Fibrosis cirrhosis = methotrexate

- Vascular = azathioprine