2024 KCL MPharm 3 Liver Lecture 1 (copy)

main functions of liver=7

1. metabolisim

   • Carbohydrate • Protein • Fat • Steroid hormones • Insulin • Aldosterone • Bilirubin • Drugs

2. synthesis

   • Proteins (e.g. albumin) • Clotting factors • Fibrinogen • Cholesterol • 25-OH of vitamin D • Gluconeogenesis (generation of glucose from fat and protein)

3. immunological- kpuffer cells-break down rbc

4. storage

   • Fat soluble vitamin A, D, E, K, B12 and Folic acid

5. homestasis- glucose

6. Production of bile

   • Secretion of bile salts

   • Enterohepatic circulation

7. clearance

   • Bilirubin • Drugs • Toxins

liver facts

The liver has a remarkable ability for regeneration

• “Liver Disease” can manifest in a broad spectrum of conditions

• Can range from mild and self limiting to severe with high mortality

• Many patients can be asymptomatic until develop hepatic complications

• Often a long time interval between disease occurrence and detection

• Premature mortality rates from liver disease across England continue to rise and have now reached 20.6 per 100,000 population

Classification of Liver Disease

• Classified according to both the pattern of damage seen and time course over which damage occurs

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

• These are not distinct entities – overlap occurs

• Both of these can lead to fibrosis and cirrhosis

Classification of Liver Disease - Cholestasis

• Disruption of bile flow – stagnation of bile in bile ducts

• Intrahepatic vs. extrahepatic

• Intrahepatic – biliary ductules e.g. PBC (primary biliary cholestasis), drugs, inflammation

• Extrahepatic – mechanical obstruction e.g. inflammation of bile ducts, strictures, gall stones

• Impaired biliary excretion and reduced absorption of fatty substances / and lipophillic drugs

• Accumulation of bile salts can lead to damage of hepatocytes

Classification of Liver Disease – Hepatocellular

• Injury to hepatocytes e.g. toxins, viruses

• Fatty infiltration – steatosis. Accumulation of fat within the hepatocyte. Micro vs. macro vesicular

• Inflammation – Hepatitis. Can be acute or chronic. Can be small vs. widespread

• Cell death - Necrosis

Classification of Liver Disease – Fibrosis and Cirrhosis

1. f0= liver without fibrosis

2. f1= initial fibrosis

3. f2= intermediate fibrosis

4. f3= advanced fibrosis

5. f4= cirrosis

how this happens:

• Persistent, extensive hepatocyte damage - active deposition of collagen formation of scar tissue – fibrosis

• Disruption of blood flow

• Erratic regeneration and nodules can form

• Cirrhosis= a condition in which the liver is scarred and permanently damaged.

Acute vs. Chronic

• Acute – history of 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 (- liver still functioning with the liver damage ) vs. decompensated disease (not able to carry out normal function)

Acute Liver Failure causes=5

• drugs- paracetamol/ statins/ tb drugs

• viral causes- hepatitis a b

• pregnancy related

• vascular

• other

How to Interpret LFTs= liver function tests

• LFTs are fairly non-specific

• Generally if 2 x ULN considered abnormal

• If liver dysfunction – usually at least 2 will be deranged

• Review LFT’s as a trend and not in isolation

• Check reference ranges and units

• LFTs are not always abnormal even in patients with cirrhosis

• Note: abnormal LFTs are not necessarily because of liver dysfunction

Liver Function Tests - Bilirubin

Bilirubin

• Usual range 5-20micromol

• Product of red blood cell 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 increase:

• Haemolysis

• Hepatocellular damage

• Cholestasis

• Clinical jaundice when Bilirubin  50micromol/L

Liver Function Tests – Transaminase Enzymes

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

Liver Function Tests – ALP and γ-GT

Alkaline Phosphatase

• ALP range 30-120 iu/L

• Found in liver, bone, intestine and placenta

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

Other tests

Albumin (35-50 g/dL)

• One of the proteins produced by the liver • Long half-life (20-26 days)

• low 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 high in acute and chronic liver disease

Child’s Pugh Scoring System

• point system based on ascites, bilirubin, albumin, INR

• class a b c. c being worst/ severe

  a being none

Other Investigations/Scoring Systems

• Liver Ultrasound

• CT scan

• ERCP and MRCP

• MRI

• Fibroscan

• Liver Biopsy

• Calculate MELD or UKELD

Signs/Symptoms of Liver Disease

•Jaundice

•Ascites

•Unexplained bruising and bleeding

•Varices

• Encephalopathy

•Abdominal pain

• Pale stools and dark urine

•Gynaecomastia

• Fatty stools

• Spider naevi

• Finger clubbing and pruritus

Jaundice (hyperbilirubinaemia)

• Jaundice is a term used to describe the yellowing of the skin and the whites of the eyes.

• It is caused by a build-up of bilirubin in the blood and tissues of the body.

• Common signs of jaundice are:

  - Yellowing of the skin, eyes and mucus membrane

  - Pale-coloured stools (faeces)

  - Dark-coloured urine

different types of jaundice

• Pre-hepatic jaundice

  • The disruption occurs before the bilirubin has been transported from the blood to the liver. This is caused by conditions such as sickle cell anaemia

• Intra-hepatic jaundice (also known as hepatocellular jaundice)

  • The disruption occurs inside the liver. This is caused by conditions such as Gilberts Syndrome and cirrhosis

• Post-hepatic jaundice (also known as obstructive jaundice)

  • The disruption prevents the bile (and the bilirubin inside it) from draining out of the gallbladder into the digestive system. This is caused by conditions such as gallstones or tumours

Ascites

• Accumulation of fluid in the peritoneal cavity leading to swollen abdomen

• basically happens from cirrhosis- leading to increased blood volume

Ascites- treatment

Diuretics therapy includes:

• ➢Aldosterone antagonists (spironolactone) - first line

➢Loop diuretics (furosemide) - added next

➢Amiloride

•some patients are Diuretic resistant – 25-50% mortality within a year

• Consider fluid and/or sodium restriction

• Paracentesis for large volume. may be needed - drain it out

Need to maintain adequate circulating volume – colloids, albumin, terlipressin

• Transjugular intrahepatic portosystemic shunting (TIPSS) for more refractory ascites (along with paracentesis)

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.

Cautions with Ascites- what to monitor=4

Monitor:

1. Daily U&Es – especially sodium, potassium, and creatinine (electrolytes )

2. Daily weight – aim for 0.5-1kg/day loss → how to know if the diuretics are effective/ if not losing weight= not working

3. Fluid chart – note fluid restriction, urine output - fluid restrictions may need to be put in

4. Avoid high sodium preparations (e.g. soluble preparations)

• Complications – dilutional hyponatraemia, Hepatic Encephalopathy (HE), HepatoRenal Syndrome (HRS), gynaecomastia, hyperkalaemia, muscle cramps, Spontaneous Bacterial Peritonitis (SBP)

Spontaneous Bacterial Peritonitis- SBP

• Infection of the ascitic fluid without intra-abdominal source of sepsis

• 75% from gut, 25% from skin

• Neutrophil count > 250 cells per mm3

• Mortality rate is ~40%

• 3rd gen cephalosporins, Co-amoxiclav, Tazocin

• Norfloxacin / Ciprofloxacin as prophylaxis

HEPATIC ENCEPHALOPATHY

• Brain dysfunction caused by liver insufficiency and/ or PSS

• can. occur in acute or chronic liver disease

• classified into 4 grades 1-4

• potentially correctable

• differential diagnosis: hypoglycaemia, alcohol intoxication, withdrawal

• number of workable theories-

  1. accumulation of toxins

  2. increased BBB permeability

  3. increased levels of neurotransmitters

Precipitating factors of HE= 6 ( what can cause it)

1. • Increased protein load

2. • Reduced ammonia excretion

3. • Electrolyte imbalance/disturbance

4. • Infections

5. • Dehydration

6. • Drugs- opoids/ benzodiazepams. or stopped taking drugs they needed to take

ammonia cycle

• protein broken down

• produces ammonia

• ammonia transferred to urea

• urea excreted from body

astrexis - in patients with HE

helps diagnose

• flapping terror elicited by attempted dorsiflexion of the wrist with the forearm fixed

• put pressure on fingers-push them back- when stop hands go back and forth

• indication that they’ve got HE

treatment 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

• β-Binds to the 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- malnutrition

Variceal Bleeding &Portal Hypertension

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

  • disruption of hepatic architecture

  • compression of hepatic venules by regenerating nodules

• Collateral vessels form – enable blood to bypass the liver

• • Variceal bleed is a serious complication of pHTN(>12mmHg) with less clotting factors/vitamin K absorption

• Bleeding varices – mortality 50% index bleed and 30% for subsequent bleeds

Terlipressin- for varicella bleed

• Synthetic analogue of vasopressin which acts on 3 vasopressin receptors.

• Greater selectivity for V1 and longer half-life.

• V1a – very potent splanchnic vasoconstriction (also liver gluconeogenesis, platelet aggregation and release of factor VIII).

• Biphasic action:

  • Immediate vasoconstriction effect

  • Prolonged effect with transformation of terlipressin in-vivo to lysine vasopressin

• 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- VB

• Octreotide is an analogue of somatostatin

• Hormone involved in blood vessel tone in the GI tract

• Inhibits splanchnic vasodilatation – decrease of splanchnic hypervolaemia.

• Results in decreased arterial blood supply leading to reduction in pressure in the portal circulation.

• Generally unimpressive data for somatostatin and it’s analogues vs. placebo in variceal bleeds

Analysis 21 RCTs showed no significant difference as regards to:

• Mortality

• Failure to stop bleeding/re-bleeding Analysis 21 RCTs

• Showed improvement in initial haemostasis

• SIGN guidelines (BSG endorsed) - Terlipressin

theory they might work-21 randomised controlled trials- said compared to placebo they don’t really show any difference

Endoscopic Procedures- band ligation- VE

• tie band around where bleed is and it stops the bleed

• Meta-analysis showed band ligation superior to sclerotherapy in terms of re-bleeding and mortality

• OV haemorrhage – band ligation recommended

• Technical difficulties

• Complications – oesophageal ulceration

Endoscopic Procedures

Sclerotherapy- VE

• Injection of sclerosants (“glue”) e.g. cyanoacrylate

• More complications - oesophageal ulceration, sepsis

• GV haemorrhage – sclerotherapy recommended

Endoscopic Procedures

Balloon Tamponade- VE

Temporary measure (< 24 hours)

• Several different types e.g. Sengstaken- Blakemore tube

• Mechanical “pressure” over bleeding points

• Highly effective when deployed, but high rates re-bleed when deflated

• High complication rates e.g. oesophageal ulceration

Variceal Bleed & Portal Hypertension

• Infection common after upper GI bleed in cirrhotic patients (20% pts within 48hrs)

• Major cause mortality and morbidity

• All patients should receive broad-spectrum antibiotic prophylaxis

• 6 RCTs – Antibiotics Vs. placebo

• 7 days antibiotics decreases mortality – IV broad spectrum antibiotic (e.g. tazocin) or meropenem/ciprofloxacin for penicillin allergic patients.

Secondary Prophylaxis- VE

• 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 survival

• Role of Nitrates - not used s/e not great not tolerated

• Problems with tolerability

• Dose titration and monitoring

Spider Naevi

• Name stems from appearance, which is characterized by a central red arteriole, representing the body of the spider, surrounded by a radial pattern of thin-walled capillaries, resembling legs

• Raised oestrogen – pregnant women, HRT, OCP

• Hepatic Disease – failure to metabolise oestrogen

Pruritus- itching

• Colestyramine - interacts with a lot of drugs

• UDCA (ursodeoxycholic acid)

• Chlorpheniramine, Hydroxyzine (sedating antihistamine)

• Loratadine, cetirizine (non-sedating antihistamine)

• Calamine lotion, Menthol 2% in Aq cream

• Rifampicin

• Ondansetron

• Naltrexone, Naloxone

• Sertraline