Week 6 - B - Cirrhosis of the liver(symptoms/management) - ascites/encephalopathy/varices/hepatocelluar ca/transplant/H.R.S

Question 1

What is the pathogenesis of a healthy liver to liver cirrhosis? What is cirrhosis?

Answer 1

Normal healthy liver Insult to hepatocytes -> viral, drug, antibody Increased degree of inflammation to hepatocytes Increased degree of liver fibrosis Cirrhosis Cirrhosis is a chronic disease of the liver marked by degeneration of cells, inflammation, and fibrous thickening of tissue.

Question 2

The final common endpoint for liver disease is cirrhosis of the liver Is cirrhosis of the liver reversible or not? What is seen histologically in liver cirrhosis?

Answer 2

Cirrhosis implies irrversible liver damage It is defined histologically by loss of normal hepatic architecture with bridging bands of fibrosis and nodular regeneration of hepatocytes

Question 3

Cirrhosis is essentially the end point of the chronic liver disease continuum What are different causes of cirrhosis of the liver?

Answer 3

Most often chronic alcohol abuse Can be caused by * Hepatitis B or hepatitis C infection * Genetic disorders * Hepatic vein events * Non-alcholic fatty liver disease * Autoimmunity * Drugs

Question 4

What are different complications of liver cirrhosis?

Answer 4

Portal hypertension (porto-caval anastamoses) Ascites Liver failure Hepatocellular carcinoma

Question 5

What is the blood flow into the liver? - how does this reach the right atrium? What is the normal pressure in the hepatic portal vein?

Answer 5

* O2 blood from hepatic artery + nutrient rich deoxygenated blood from hepatic portal vein * -> Liver sinusoids * -> Central vein of liver lobules * -> Hepatic veins (3) * -> IVC * -> RA of heart Normal hepatic portal vein pressure is very low - approx 5-8mmHg

Question 6

What are the sites of portocaval anastamosis? During portal hypertension, these collateral veins can recieve too large a blood volume leading to dilatation of the veins * What is the clinical sign that there is portal hypertension in each of these anastamoses?

Answer 6

Four collateral pathway Eosophageal and gastric venous plexus - can lead to oesophageal varices and rupture Umbilical venous anastamoses - dliated umbilical/epigastric veins seen as caput medusae Rectal/anal anastamosis - seen as rectal varices

Question 7

Portal hypertension can be caused by things other than liver cirrhosis They are classified according to site of obstruction - prehaptic or intrahepatic List some other causes of portal hypertension

Answer 7

Prehepatic- due to blockage of the protal vein before the liver * Portal vein thrombosis or occlusion secondary to congential portal venous abnormalities Intrahepatic - due to distortion of liver achitecture * pre-sinusoidal - eg shcistosomiasis * postsinusoidal causes include - cirrhosis, alcoholic hepaittis, congenital hepatic fibrosis * Also have budd chairi syndrome and veno-occulsive disease

Question 8

What is the difference between a patient with compensated cirrhosis vs decompensated cirrhosis?

Answer 8

In compensated cirrhosis, the patient may be clinically normal but usually has signs of chronic liver failure In decompensated cirrhosis, there is either Liver failure - acute on chronic * Due to eg Infection, insult, sepsis End stage liver disease - insufficient hepatocytes - run out of liver

Question 9

What are the different signs of decompensated cirrhosis?

Answer 9

Decompensated cirrhosis - features of acute on chronic liver failure * Jaundice * Ascites * encephalopathy * bruising

Question 10

What are the features of compensated liver cirrhosis? (these are features of chronic liver disease)

Answer 10

Leuconychia - white nails from hypoalbuminaemia Caput medusae - due to portal hypertension Gynaecomastia - impaired breakdown of oestrogens Icterus (jaundice) Palmar erythema - impaired breakdown of sex hormones Spider naevia - isolated telangiectasia Finger clubbing Xanthelasma Dupuytren’s contracture Pruritus

Question 11

Is the liver enlarged or small in chronic liver disease? What other organ is often enlarged? Apart from gynaecomastia, what are other features of increased circulatory oestrogens?

Answer 11

Liver is normally enlarged in chronic liver disease - hepatomegaly However in end stage disease it can be small Spleen is often also enlarged Increased circualtory oestrogens - gynaecomastia, testicular atrophy and hair loss

Question 12

What is the general treatment of decompensated cirrhosis?

Answer 12

Remove or treat the underlying cause Look for and treat infection

Question 13

Many different tests involved in diagnosis of cirrhosis What is seen on LFTs? What happens to sodium? What happens to albumin? What is seen on USS? What is seen on coag tests?

Answer 13

* LFTs- ALT and AST raised (ALT greater in chronic liver disease usually, if alcoholic liver disease - AST greater) * Sodium is decreased * Albumin is decreased * USS may show hepatomegaly, splenomegaly, thrombosis, focal lesion or ascites * Coag tests - increased prothrombin time

Question 14

Screening for NAFLD is not recommended How is NAFLD normally diagnosed? What is then carried out in these patients to check for advanced fibrosis?

Answer 14

NAFLD is normally diagnosed as an incidental finding when a patient is getting an ultrasound scan- fatty changed on ultrasound (steatosis on USS shows hyperechogenecity - seen in AFLD and NAFLD)

Carry out an Enhanced Liver Fibrosis (ELF) blood test to check for advanced fibrosis in these patients

Question 15

An Enhanced Liver Fibrosis score of >/=10.51 would indicate advanced liver fibrosis * What would then be carried out to check for cirrhosis in a patient?

Answer 15

Offer patient a transient elastography

Question 16

The diagnosis of liver cirrhosis was traditionally a liver biopsy. This procedure is however associated with adverse effects such as bleeding and pain. * What conditions is cirrhosis screening carried out in? * What is the screening test that is carried out?

Answer 16

Carry out cirrhosis screening using transient elastography (Fibroscan) in: * Known hepatitis B or C * Men drink > 50 units/week or women >35 units/week and have done for several months * Previous alcohol related liver disease

Question 17

How does the transient elastography (fibroscan) work? (used in NAFLD with advanced liver cirrhosis from ELF blood test in cirrhosis screening)

Answer 17

Transient elastography is a non-invasive technique that uses both ultrasound and low-frequency elastic waves to quantify liver fibrosis.

Question 18

If transient elastography confirms stiffness, then cirrhosis is confirmed and it is now important to search for complications What scan should be offered to patients with a new diagnosis of cirrhosis? What scan should be offered on a 6 monthly basis?

Answer 18

NICE recommend doing an upper endoscopy to check for varices in patient’s with a new diagnosis of cirrhosis liver ultrasound every 6 months (+/- alpha-feto protein) to check for hepatocellular cancer

Question 20

In the management of cirrhosis, what is advised for nutrition? What should be avoided?

Answer 20

Good nutrition is vital and small frequent meals/snacks should be encouraged as this reduces fasting gluconeogenesis Avoid alchohol, NSAIDs, sedatives and opiates

Question 21

What is thought to cause the itch that patients may get in chronic liver disease / cirrhosis?

Answer 21

If you have liver disease, you might have higher levels of bile salt accumulating under the skin, which may cause itching. Not everyone with high levels of bile salts feel itchy, and some people feel itchy despite a normal bile salt level. Some people with pruritus have raised histamine levels.

Question 22

What can be given for the treatment of itch in chronic liver disease?

Answer 22

Colestyramine or cholestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption - can be used to treat the excess build up of bile salts that cause itch Chlorphenamine (an anti-histtamine - H1 receptor antagonist) can also be given to try and treat the itch

Question 23

What initial investigation should be carried out for all patients presenting with new ascites? What should be considered in all patients with ascites who deteriorate suddenly?

Answer 23

Every patient with new-onset ascites should undergo a diagnostic paracentesis: Cell count with differential, albumin, and total protein should be measured in the ascitic fluid. Ascitic fluid should also be sent for cytology. Consider spontaneous bacterial peritonitis in all patients with ascites who deteriorate suddenly - abdo pain, fever and ascites

Question 24

What cell count would confirm spontaneous bacterial peritonitis? What is the triple method of management of spontaneous bacterial peritonitis presenting in a patient with ascites?

Answer 24

SBP is confirmed if: Neutrophil count of >250 cells/mm3 OR WCC count >250 cells/ mm3 AND ≥90% polymorphs Management of SBP includes Antibiotic treatment, therapeutic paracetnesis and IV human albumin solution

Question 25

What is given for the management of spontaneous bacterial peritonitis? * Severe? * Mild - ie on routine diagnostic tap?

Answer 25

In management of SBP Severe ie ascites and patient has deteriorating symtpoms - IV piperacillin with tazobactam (Tazocin) Mild - ie routine diagnostic tap - co-trimoxazole PO

Question 26

Which patients are given prophylaxis for ascites and why drug is given?

Answer 26

Give prophylaxis in high risk patients * Very low albumin * Raised PT * Low ascitic albumin * Or those who have had a previous SBP episode Give co-trimoxazole PO (stop prophylaxis on discharge from hospital)

Question 27

What is the treatment of ascites? * What dietary management * Which drug is first line * Which is second line * What is given if these fail?

Answer 27

Ascites mangement * Fluid restrict patient ( * Give spironolactone 1st line to treat ascites * Add frusemide if poor response * Therapeutic paracentesis may be required

Question 28

Encephalopathy - already discussed in acute liver failure lecture What is thought to be the proposed hypothesis behind encephalopathy development? * What builds up? * What does this cause?

Answer 28

Ammonia glutamate/glutamine shuttle - in a healthy liver, ammonia is converted to urea and removed by the kidneys * Damaged liver leads to excess ammonia build up from bacterial breakdown of proteins in the gut * Ammonia passes BBB and astrocytes clear it whilst converting glutamate to glutamine * Excess glutamine can cause cerebral oedema as well as cytoxicity

Question 29

What is the treatment of encephalopathy?

Answer 29

Treat the acute liver failure cause Lactulose is 1st line - promotes excretion of ammonia and promotes metabolisation of ammonia by gut bacteria Rifaxamin can be added for prophylaxis - decreases ureas forming bacteria reducing ammonia production

Question 30

Oeseophageal varices NICE recommend doing an upper endoscopy to check for varices in patient’s with a new diagnosis of cirrhosis What is given for primary prophylaxis? What is given for secondary prophylaxis?

Answer 30

Primary prophylaxis prevents a bleed from occurring Secondary prophylaxis is to prevent a re-bleed from occurring In both cases, the patient is usually given a non-selective Bblocker eg propranolol or carvideolol and endoscopic variceal ligation (endoscopic banding)

Question 31

What is the treatment steps of an oeseophageal variceal haemorrhage? (list all the steps)

Answer 31

Step 1 * ABC resucitation, antibiotics, correct clotting, terlipressin, upper GI endoscoy and endoscopic variceal ligation endoscopy: endoscopic variceal band ligation is superior to endoscopic sclerotherapy. NICE recommend band ligation Sengstaken-Blakemore tube if uncontrolled haemorrhage Transjugular Intrahepatic Portosystemic Shunt (TIPSS) if above measures fail

Question 32

What are the prophylactic intravenous antibiotics for people with cirrhosis who have upper gastrointestinal bleeding?

Answer 32

Bacterial infections occur in about 20% of patients with cirrhosis with upper gastrointestinal bleeding within 48 hours of admission; another 50% will have an infection during their hospital stay. Antibiotic prophylaxis reduces the risk of infection and mortality in this patient group. o Co-trimoxazole 960mg BD for 5 days o Use IV while NBM and convert to oral when able

Question 33

What is the management of acute liver failure?

Answer 33

TREAT THE UNDERLYING CAUSE Intensive care monitoring is mandatory if hepatic encephalopathy presents - tracheal intubation and NG tube to protect airways and avoid aspiration respectively Give IV glucose to prevent hypo Routine blood tests - FBC, Clotting factors (PT/INR), U&Es AVoid hepatoxic drugs and sedatory drugs

Question 34

As hepatocellular carcinoma is a recognised complication of cirrhosis, how is this screened for?

Answer 34

Liver ultrasound every 6 months (+/- alpha-feto protein) to check for hepatocellular cancer

Question 35

A liver transplant is the only definitive treatment for cirrhosis What is the criteria that prompts consideration of liver transplant in acute liver failure? What are the chronic liver failure indications for considering liver transplants?

Answer 35

King’s College Hospital Criteria is used in acute liver failure to predict a poor outcome and prompt consideration for transplantation In chronic liver failure * Events based - eg SBP or refractory variceal bleed * Synthetic LFTs based (bilirubin, albumin, PT) * Quality of life based -itch, lethargy, spontaneous encephalopathy

Question 36

King’s College Hospital Criteria in acute liver failure is used to predict outcomes and prompts consideration for transplantation depeding on the results * What single criteria in paracetamol-induced liver failure would warrant transplant consideration? * What other factors are considered in the King’s College Hospital Critera in acute liver failure?

Answer 36

In paracetamol induced liver failure - Having an arterial pH * Prothrombin time * Creatinine * Bilirubin * Encephalopatthy * Age

Question 37

United Kingdom Model for End-Stage Liver Disease (UKELD) predicts prognosis in chronic liver disease and can be used to prioritize for liver transplantation Takes into consideration INR, creatinine, bilirubin, Na What UKELD score is required for a patient to be listed for elective liver transplant?

Answer 37

PAtient requires a UKELD score of >/= 49 to be listed for elective liver transplants (UKELD score for 1 year mortality of 9% =49) * INR goes up as liver is not able to synthesise clotting factors efficiently * Bilirubin rises as well - causing jaundice * Creatinine (liver produces creatine which is broken down to creatinine in the skeletal muscle) - levels will rise if the liver failure causes renal failure meaning there will be a build up of toxins * Sodium decreases in liver failure

Question 38

Hepatorenal syndrome What is hepatorenal syndrome? When should you suspect hepatorenal syndrome?

Answer 38

Hepatorenal syndrome (often abbreviated HRS) is a life-threatening medical condition that consists of rapid deterioration in kidney function in individuals with cirrhosis or fulminant liver failure. Suspect hepatorenal syndrome in individuals with cirrhosis + ascites + renal failure -> if other causes of renal impairment have been excluded

Question 39

What can liver cirrhosis or less commonly acute liver failure cause that affects the haemodynamics of the splanchnic and systemic circulation?

Answer 39

Cirrhosis or less commonly acute liver failure can affect the haemodynamics of the splanchnic and systemic circulation - Portal hypertension caused by cirrhosis, leads to release of vasodilators eg nitric oxide, by the splanchnic vasculature

Question 40

HRS often occurs spontaneously but what are potential triggers?

Answer 40

Potential triggers include Infection - most classificaly spontaneous bacterial peritonitis or Acute gastrointestinal haemorrhage

Question 41

What is the (widely accepted) pathophysiology for hepatorenal syndrome? (it is known as the underfill theory) (image provides brief explanation for pathogenesis for help)

Answer 41

Splanhnic/systemic vasodilation with renal vasoconstriction * Portal hypertension cause vasoactive mediator release from splanhnic vasculature causing splanchnic / systemic vasodilation * This results in underfilling of the kidneys which is sensed by the juxtaglomerular appratus which then activates the RAAS system. RAAS system tries to cause systemic/renal vasoconstriction * However, the effect of this is insufficient to counteract the mediators of vasodilation in the splanchnic circulation, leading to persistent “underfilling” of the kidney circulation and worsening kidney vasoconstriction, leading to kidney failure

Question 42

Hepatorenal syndrome is classified as either type 1 or type 2 What is the different between the two?

Answer 42

Type 1 hepatorenal syndrome is a rapidly progressive deterioration in circulatory and renal function - very poor prognosis Type 2 hepatorenal syndrome is a more steady deterioration in circulatory and renal function - also a poor prognosis although patients may liver longer

Question 43

The management of hepatorenal syndrome (HRS) is notoriously difficult. What is the ideal treatment however not always able to be carried out?

Answer 43

The ideal treatment is liver transplantation but patients are often too unwell to have surgery and there is a shortage of donors

Question 44

The definitive treatment for hepatorenal syndrome is liver transplantation, and all other therapies can best be described as bridges to transplantation What are the options for treating hepatorenal syndrome other than surgery?

Answer 44

Vasopressin analogues such as terlipressin have a growing evidence supported for their use - they work by causing splanchnic vasoconstriction Terlipressin is given with IV albumin (helps to reduce the renal impairment by causing plasma volume expansion)

Question 45

What is carried out if the terlipressin + albumin fails? How does it work?

Answer 45

A transjugular intrahepatic portosystemic shunt (TIPS) involves the decompression of the high pressures in the portal circulation by placing a small stent between a portal and hepatic vein. * Theoretically, a decrease in portal pressures is thought to reverse the hemodynamic phenomena that ultimately lead to the development of hepatorenal syndrome.

Question 46

What are potential complications of TIPS?

Answer 46

Complications of TIPS for treatment of HRS include the * worsening of hepatic encephalopathy (as the procedure involves the forced creation of a porto-systemic shunt, effectively bypassing the ability of the liver to clear toxins), * inability to achieve adequate reduction in portal pressure, and bleeding