Chronic Liver Disease/cirrhosis Flashcards
there are ____ different types of liver disease
many
chronic liver disease is duration greater than __months with outcome of progression to _____
6, cirrhosis
stage 1 cirrhosis pathology: The activated ______
The activated hepatocytes, kupffer cells and inflammatory cells from inflammation release things (like cytokines) and other products of damaged cells that go on to activate the quiescent Hepatic stellate cell
stage 2 cirrhosis pathology : perivenular fibroblasts (stellate) undergo activation and transdifferentiation to ________. These _______ produce excessive amounts of collagens, downregulate their production of matrix ________, and show an enhanced expression of the physiological inhibitors of the MMPs (_____ and _____).
perivenular fibroblasts undergo activation and transdifferentiation to myofibroblasts. These myofibroblasts produce excessive amounts of collagens, downregulate their production of matrix metalloproteinases (MMPs), and show an enhanced expression of the physiological inhibitors of the MMPs (TIMP1 and TIMP2).
what is stage 1 - chronic liver disease?
causes of chronic liver disease, patient presents with signs and symptoms of the causal disease
what is stage 2 - chronic liver disease?
recurrent inflammation and the process of fibrosis - these are the stigmata of cirrhosis
what is stage 3 - chronic liver disease?
cirrhosis compensation
what is stage 4 - chronic liver disease?
- cirrhosis decompensated
- Get chronic liver failure
- Acute on chronic liver failure
- The patient presents with signs and symptoms of liver failure
what are the common causes of chronic liver disease?
- Alcohol
- Non-alcoholic fatty liver disease
- Hepatitis C
- Primary biliary cirrhosis
- Autoimmune hepatitis
- Hepatitis B - this is not really seen as much in the UK but in the world it is a massive cause of liver disease
what are the uncommon causes of chronic liver disease?
- Haemochromatosis
- Primary Sclerosing Cholangitis - this is an autoimmune disease
- Wilsons Disease
- alpha 1 anti-trypsin
- Budd-Chiari
- Methotrexate
NOTE: there are lots of diseases affecting the liver which are chronic such as ____ or _____ syndrome. However, they are not all chronic liver diseases - this only refers to diseases which can lead to _____ (by activation of _____ and fibrosis)
NOTE: there are lots of diseases affecting the liver which are chronic such as amyloid or rotor syndrome. However, they are not all chronic liver diseases - this only refers to diseases which can lead to cirrhosis (by activation of stellate and fibrosis)
what two main things go wrong in cirrhosis?
- loss of function of hepatocytes
2. malfunction in blood flow and generation of abnormal signalling
histology : the architecture of the cell is disrupted by ___ and ___. the ___ of the liver get smaller
fibrosis and collagen. nodules
which organs does the portal vein drain blood from? 6
the spleen, oesophagus, stomach, pancreas, small and large intestines
portal vein drains the spleen through the ____ ____
splenic vein
portal vein drains the oesophagus through the ____ ____
left gastric branch
portal vein drains the stomach through the ____ ____
left and right gastric
portal vein drains the pancreas through the ____ ____
splenic
portal vein drains the small and large intestines through the ____ ____
inferior and superior mesenteric
The portal vein carries __% of blood to the liver
75%
Hepatic vein flow = ____ml/min
1600
Portal vein flow = ____ ml/min
1200
Hepatic artery flow = __ ml/min
400
Hepatic vein pressure = _mmHg
Portal vein pressure = _mmHg
Hepatic artery pressure = __ mmHg
4,7,100
what are portocaval anastomosis ?
These are places where the portal venous system has communications (anastomosis) with the systemic venous system
what are the 4 collateral pathways?
- Eosophageal and gastric venous plexus
- Umbilical vein from the left portal vein to the epigastric venous system
- Retroperitoneal collateral vessels
- The hemorrhoidal venous plexus
In cases of ____ _____ these anastomoses may become engorged, dilated or varicosed and subsequently rupture
portal hypertension
portal hypertension is a:
- portal vein pressure above the normal range of __-__ mmHg
or
- a hepatic vein pressure gradient greater than _ mmHg
5-8 mmHg
a hepatic vein pressure gradient greater than 5mmHg
Portal hypertension represents an increase of the _____ pressure within the portal vein or its tributaries
hydrostatic
what are the two causes of portal hypertension in liver disease
- increased resistance to flow
2. increased portal venous inflow
Portal hypertension can be caused by things other than cirrhosis so PH can be classified according to the___ ___ ____
site of obstruction
what prehepatic causes can lead to portal hypertension? 2
- portal venous thrombosis or occlusion secondary to congenital portal venous abnormalities
what are the tow types of intrahepatic obstruction?2
- presinusoidal
2. postsinusoidal
give examples of the presinusoidal causes of portal hypertension. 2
schistomiasis
non-cirrhotic portal hypertension
give examples of the postsinusoidal causes of portal hypertension. 3
cirrhosis, alcoholic hepatitis, congenital hepatic fibrosis
what posthepatic causes can lead to portal hypertension? 2
budd chiari syndrome and veno-occlusive disease
circulation changes in liver disease: what do the low albumin levels signal to the kidneys?
that there is low plasma volume
circulation changes in liver disease: the low plasma volume stimulates the kidneys to produce ___ and by the ___- system - get ____ production
This stimulates the kidneys to produce renin and by the RAAS system - get aldosterone production
the aldosterone produced by the RAAS system cannot be _____ by the liver so we get increased ___ reabsorption from the ___, ____, and the ___
This aldosterone cannot be metabolised by the liver so get increased sodium reabsorption from the urine, sweat, and the gut
which other hormones increasee in liver disease?
endothelin and oestrogen
The increase in angiotensin II, aldosterone, SNS and ADH (vasopressin) means that the kidneys are _____ as they are all _______
The increase in angiotensin II, aldosterone, SNS and ADH (vasopressin) means that the kidneys are squeezed as they are all vasoconstrictors
what is the effect of the vasoconstrictors on the kidneys?
leads to sodium retention, potassium loss and water retention
what can the loss of K do?
make you feel very unwell
what is the function of ADH?
stops you peeing out water and is also a vasoconstrictor
adh keeps more water in the body and basically____ the sodium so you get more sodium retentio
keeps more water in the body and basically dilutes the sodium so you get more sodium retentio
the vasoconstrictor hormones can all cause renal ____ but renal ________ are also produced to vasodilate the kidneys
failure, prostaglandins
what is the effect of NSAIDS on the renal prostaglandins?
they inhibit them and cause renal failure
liver disease is not associated with cancer, true/false ?
false - associated with hepatic carcinogenesis
hepatic carcinogenesis: Cirrhosis leads to recurrent hepatocyte ___ so you get cells trying to _______. This leads to cellular _____ and recurrent ___ copying. This means that mutations are more common because of the ____ of DNA being copied but also because of the _____ environment that they are copying in - lots of ____ ____ and ____
Cirrhosis leads to recurrent hepatocyte death so you get cells trying to regenerate. This leads to cellular hyperplasia and recurrent DNA copying. This means than mutations are more common because of the volume of DNA being copied but also because of the mitogenic environment that they are copying in - lots of oxidative stress and toxins
what is a mitogenic environment?
a toxic environment where there is lots of oxidative stress and toxins
hepatic carcinogenesis : why do you get inflammation
This is because there is deregulation in cell-cycle control and so more cells are surviving - they would normally be killed via apoptosis if this was in a non stressful environment
You get DNA damage - from ROS,RNS, and adaducts
what are the causes of hepatic carcinogenesis ?
HBV DNA integration
what do histological slides of hepatic carcinogenesis look like? 3
All the cells are really jumbled up.
The nuclei are much bigger and
the cytoplasm is smaller
what are the two categories of cirrhosis?
compensated and decompensated
in compensated cirrhosis They will be clinically ____ and often it is an ______ finding on ___ or ____ tests for something else
They will be clinically normal and often it is an incidental finding on imaging or lab tests for something else
what happens in decompensated cirrhosis?
the patient has liver failure
what two categories of decompensated cirrhosis is there?
- acute on chronic
2. end-stage liver disease
give three examples of acute on chronic decompensated liver cirrhosis?
insult
- systemic inflammatory response syndrome
- infections
with decompensated cirrhosis acute-on-chronic you can potnetially get the person back to _____ state
compensated
what happens in end stage liver disease?
you don’t have enough functioning hepatocytes so basically run out of liver
what are the signs of compensated liver disease ? 7
- Spider naevi - more worrying if man has it
- Palmer erythema
- Clubbing
- Gynaecomastia
- Hepatomegaly
- Splenomegaly
- They may also have no symptoms
what are the signs of decompensated liver disease ? 4
- Jaundice
- Ascites
- Encephalopathy
- Easy bruising
los of liver functio which leads to decreased urea synthesis which leads to increased blood ammonia leads to ……?
encephalopathy
decreased hormonal detoxification leads to increased circulatory oestrogens which leads to …..? 3
- gynaecomastia
- testicular atrophy
- hari loss
decreased albumin synthesis leads to ______
ascites
altered liver structure:
- get decreased blood circulation leading to
- shunting leading to
- undetoxified blood anaemia which leads to
- hepatic coma which leads to
……..?
PORTAL HYPERTENSION
impaired bile circulation leads to ____
jaundice
pathogenesis of ascites :
1. you get ______ through portal hypertension which leads to increased production and sensitivity of ______, resistance to_______
2. This leads to _____ ______ vasodilation - this causes the activation of arterial ______s so get increased HR, ___
3. This causes activation of ___-
Causing renal vasoconstriction leading to ___ and ___ retention
shunting; vasodilators; vasoconstrictors; splanchnic arteriolar; baroreceptors; CO; RAAS; sodium and water
how is ascites diagnosed clinically ?
through shifting dullness and ultrasound - the dark bits
Ascites is a marker for ___ ____
poor prognosis
what may develop if you get translocated infection of ascites ?
spontaneous bacterial peritonitis
Do a __ in all cases of ascites and a cell count - the neutrophil will be > ___ cells/mm3
tap
encephalopathy: This is a mental confusion due to failure of the liver to clear ____ waste (as ____) so it builds up in the circulation and passes to the brain, where _____ clear it (by processes involving the conversion of glutamate to _____). The excess ____ causes an osmotic imbalance and a shift of fluid ___ these cells - hence cerebral ____ which - ______ the astrocytes.
This is a mental confusion due to failure of the liver to clear nitrogenous waste (as ammonia) so it builds up in the circulation and passes to the brain, where astrocytes clear it (by processes involving the conversion of glutamate to glutamine). The excess glutamine causes an osmotic imbalance and a shift of fluid into these cells - hence cerebral oedema which compresses the astrocytes.
how is a diagnosis of encephalopathy made? 3
Flap confusion
Any neurology
Alcohol withdrawal
where can you get variceal bleeding?
Can get oesophageal, gastric, rectal and ectopic
what are the complications of cirrhosis ?
- ascites
- encephalopathy
- variceal bleeding
- liver failure
- gut oedema
what is the variceal bleeding caused by?
portal hypertension
which signs tell you about pressure in the varices 4
- High HVPG (Hepatic venous pressure gradient)
- Variceal size
- Red colour signs - wall thickness
- Liver failure - increased HVPG
what is the HVPG a measure of ?
the difference in pressure between the portal vein and the IVC
1/__ of varices bleed. __-___% stop and ___-___% rebleed.
1/3rd of varices bleed. 40-60% stop and 70-80% rebleed.
what does gut oedema cause?
poor absorption
In Cirrhosis the blood supply is effectively b_____ the liver and so drugs are not being _____
In Cirrhosis the blood supply is effectively bypassing the liver and so drugs are not being metabolised
give some examples of drugs that are highly metabolised by the liver? 3 and what does this mean for these drugs in cirrhosis
GTN, phenytoin, calcium blockers
need to be giving lower doses
If the IV dose of a drug in the BNF or something is much ____ than the oral dose you know that it is heavily ______ by the liver so should be weary of these in liver disease
If the IV dose of a drug in the BNF or something is much smaller than the oral dose you know that it is heavily metabolised by the liver so should be weary of these in liver disease
give examples of drugs where the enzymes becomes saturated and cannnot metabolise anymore ? 2
alcohol and phenytoin
why are NSAIDs a bad idea in liver disease?
bad idea for the kidneys because they inhibit prostaglandins which are responsible for saving the kidneys from being squeezed to death
in liver disease there are less ___ in the plasma so you have to be careful when doing drug level tests as they may be artificially ___ because the amount of bound drug is low whereas the unbound may be really high. You need to measure the amount of ____ drug in liver disease
proteins, low , free
NSAIDS mean that renal PGE synthesis is decreased and what does this lead to
further sodium retention and risk of hepato-renal syndrome
Cirrhosis ___ _____are increased with nsaids
Cirrhosis peptic ulcers are increased with nsaids
WHAt else do NSAIDS cause? 4
Asthma; hypertension; diarrhoea/colitis; CHF
If someone is going to be on NSAIDS or a COX-2 inhibitor for a couple of weeks what should they be co-prescribed with?
a proton pump inhibitor
opiates cause more ____ pretending to be neurotransmitters and disrutping normal pathways
amines
what are patients with liver disease more prone to with opiates?
sedation
what is the first phase of drug metabolism?
CYP450 biotransformation
first phase drug metabolism : affected ___ and is useful for ___ soluble drugs
This is affected early and is useful for fat soluble drugs
what is the second phase of drug metabolism?
conjugation
2nd phase drug metabolism : affected ___
late
in liver disease we want drugs that are metabolised ___
late
give examples of drugs which have a reduced metabolism in liver disease. 6
opiates ; benzodiazepines; chlormethiazole; cyclosporin; metronidazole; calcium blockers
paracetamol is converted to ____ and _____ with the byproduct ____________-
sulphates and glucoronides, N-acetyl- p- benzoquinoneimine
N-acetyl-p-benzoquinoneimine which is a ____ ____ intermediate which causes hepatic _____
N-acetyl-p-benzoquinoneimine which is a highly reactive intermediate which causes hepatic necrosis
in normal people why does the N-acetyl-p-benzoquinoneimine not cause problems
because it is inactivated by glutathione
what happens in paracetamol toxicity
the glutathione stores run out and the N-acetyl-p-benzoquinoneimine can cause necrosis
what enzymes converts paracetamol to N-acetyl-p-benzoquinoneimine?
P4502E1
what are the features of liver disease which mean that paracetamol is more toxic ? 2
- they have reduced glutathione stores
- increased p4502e1
Infusion of _____(analogue) prevents paracetamol causing further problems
metathione
Paracetamol is metabolised by CYP2a1 and _____ blocks the paracetamol binding to this receptor
alcohol
alcohol also ___ the presence of p450 2a1 _____ meaning that you get late paracetamol ____
increases, receptors, toxicity
bad _____ can also deplete your glutathione stores
glutathione
for pain relief in liver disease paracetamol __g ___ ____ . do not exceed __g and avoid ____ use
1g twice daily , 3g, prolonged
what is the amount of codeine that is allowed to be given to liver disease patients?
30 mg
what drug should be avoided in liver disease?
NSAIDs
drug induced liver disease probably has a ____ component
genetic
which drugs can induce hepatitis? 2
amoxicillin and clavulanic acid
Hys law is where a drug is at high risk of causing fatal liver injury
ALT/AST > __ x ULN
And bilirubin > __mg/dl
5, 3
drug induced liver disease is more common in men, tru/false?
false
why is frusemide not used in liver disease?
Reduced intra-vascular volume
Worsens hypokalaemia, hypomagnesaemia
why is thiazide not used in liver disease?
hypokalaemia , hypomagnesaemia
which diuretic is given in liver disease?
spironolactone
with spironolactone aim to los __kg/ day - why
1
if you lose weight faster than this the kidneys will struggle so can take a long time to get rid of the fluid build up
for sedation in liver disease patients use phase ___ metabolism ________ in __ doses. Give examples of these drugs 3
II, benzodiazepines, small
lorazepam; oxazepam; lormetazepam
which antibiotics are avoided because they are nephrotoxic
aminoglycosides
which antibiotics are avoided because they are epileptogenic
quinolones
which antibiotic has reduced metabolism in liver disease
metronidazole
what are the main areas of management in liver disease?
- remove or treat the underlying cause
- look for and treat infection
- avoid NaCl retention
- think about nutrition - very important
An energy intake of ___ - ____kcal/kg and a protein intake of ___ -___g/kg are recommended.
An energy intake of 35-40 kcal/kg and a protein intake of 1.2-1.5g/kg are recommended.
why is nutrition control necessary in liver disease?
Low threshold to switch to gluconeogenesis and lipolysis and catabolism
what is recommended to reduce gluconeogenesis and muscle catabolism
small frequent meals and snacks
when is fasting often a problem ? and what is done to solve this
Overnight. They are often given an NG tube
what does vitamin B thiaminc do?
(cofactor in the metabolism of alcohol) mandatory in excess alcohol intake
what are two common complications of ppoor intake and absorption of calcium, vitamin D, malnutrition and steroid use
Osteoporosis and osteomalacia
Fat soluble vitamin deficiency may occur in ___ and ___. Monitor levels and supplement if necessary.
Fat soluble vitamin deficiency may occur in PSC and PBC.
treatment os ____ ____ ____ in ascites is urgent
SBP
which vitamins and minerals often need to be supplemented in liver disease
- vitamin B thiamine
- calcium- 2000g
vitamine D - 20 micrograms
in ascites ____ is given to treat vascular instability
terlipressin
what other drugs are given in ascites?
spironolactone
in new ascites you should escalate spironolactone whereas in recurrent ascites you should give stepwise increments of spironolactone and _____ ____
loop diuretic
what needs to be measured in ascites especially after a dose change of paracentesis
U and E
paracentesis gives ____ ___ but has risks of ____,____,_____
Rapid relief but there is risk of infection, encephalopathy and hypovolaemia
with TIPSS for treatment of ascites
- __% of patients who receive this will have no ascites so will be off diuretics
- __% will have ascites but that can be controlled using diuretics
- __% see no improvement
60% of patients who receive this will have no ascites so will be off diuretics
30% will have ascites but that can be controlled using diuretics
10% see no improvement
what is a final option for ascites
transplant
for treatment of encephalopathy you should loos for a cause such as ___, ____, _____, ____ ____
nfection, metabolic, drugs, liver failure
what is the drug used for encephalopathy which clears the gut/reduces transit time (by pulling water from the body to the colon
lactulose
what other part of treatment is important for encephalopathy
nutrition
why is a carbohydrate contaning late evening snack recommended in encephalopathy treatment ?
this increases the carbohydrate oxidation and decreases lipid and protein oxidation rate and hence improves nitrogen balance and reduces fasting periods overnight.
why do you regularly endoscope patients with cirrhosis ?
to check for varices
what are the treatment options for varices?
beta blockers
- variceal ligation
- balloon tamponade
- scleropathy
- TIPSS
B blockers for variceal treatment should be non selective true/false?
true
what are the treatment steps in acute variceal bleeding? 4
- resuscitate until haemo dynamically stable -
- Correct clotting abnormalities with vitamin K, FFp and platelets rtansfusion
- Start IVI of terlipressin
- TIPSS or transection/shunt surgery
what are the complications of scleropathy?
can get scleroulcers
success rate of balloon tamponade is ___ -__ % what are the complications (2)
80-90%
- aspiration and perforation
what should be done for secondary prophylaxis of variceal bleeding? 3
- Variceal band ligation
- B blockers
- Also increased risk of clotting so patients will be on anticoagulation
what is the risk with TIPSS in variceal bleeding?
there is a risk of encephalopathy
transplantation can be given based on :
- events e.g. ___ - _____ and _____
- liver function e.g. ____, ___ and ___ time
- QoL = ____, ____ and spontaneous ______
Can be given based on events
- Ascites -resistant or spontaneous bacterial peritonitis
- Variceal bleed
Liver function based
- bilirubin , albuin, prothrombin time
QoL based
- Itchy, lethargy and spontaneous encephalopathy
Transplant carries risks so you need to make sure the patient has a _% risk of dying from doing nothing before you transplant
10
Need a UKELD score of > or = ___ to be listed for elective transplant unless what?? (2)
49
They have a variant syndrome
or have hepatocellular carcinoma
what are the examples of variant syndromes ? 7
Diuretic resistant ascites Hepatopulmonary syndrome Chronic hepatic encephalopathy Intractable pruritus Polycystic liver disease Familial amyloidosis Primary hyperlipidaemia
