Liver Flashcards
(142 cards)
1
Q
What are the general anatomical features of the liver?
A
- Large, lobulated exocrine and blood-processing gland, with vessels and ducts entering and leaving at the porta.
- Enclosed by a thin Collagen Tissue capsule, mostly covered by mesothelium – provide support
- Collagen tissue of the branching vascular system provides gross support.
Parenchymal cells are supported by fine reticular fibres.
2
Q
What does the blood supply to the liver look like?
A
Organ receives venous and arterial blood – unique – dual blood
* Portal vein – brings food rich blood from the GI tract
* Hepatic artery – bring arterial blood
* Hepatic vein – collects the blood from the liver parenchyma
* Lymphatic system – sewage system of the body
* Hepatic duct - liver produces and secretes bile via the hepatic ducts - bile stored in the gallbladder
Note - Proportion of blood supply – 25% from hepatic artery (oxygenated blood) and 75% from portal vein (rich in nutrients)
3
Q
What does the nerve supply to the liver look like?
A
Sympathetic and Parasympathetic supply to perivascular structures but very little at the sinusoidal level
Cut the nerve supply – liver works pretty well – how do we know this? – liver transplant works well lacking the nerve supply
4
Q
Outline the structure of the liver lobules.
A
Histology of the liver
Hexagonal structure – liver lobule – pattern repeated – surrounded by loose connective tissue (portal tract)
Corners you have the portal triad, which is where the main vessels enter – branch of portal vein, branch of hepatic artery and bile duct
Organization – small channels called sinusoids (surrounded by hepatocytes – cells arranged in perforated plates one cell wide) that start at the portal triad and feed into the portal vein
Path – Blood from HA and PV mix creating highly oxygenated nutrient rich blood moves along the sinusoids towards the portal vein – as the blood moves through the hepatocytes take up, process and release back into the sinusoids – ultimately returns into circulation
5
Q
In general terms, how do hepaotcytes filter the blood in a coordinated manner?
A
Blood flow from the portal triad to the central vein
Flow slows down – allowing for the exchange of molecules with the hepatocytes
Hepatocytes upstream able to sense levels of nutrients, signals to hepatocytes downstream – such that the levels of nutrients are appropriate when entering in the systemic circulation
In between cells you also have bile ducts – flows in the opposite direction toward bile duct into common bile duct, and subsequently stored in the gallbladder
Closer to portal triad – sensing role, further downstream – regulatory function
6
Q
Outline how bloods leaves the liver from the central vein?
A
Blood collected in central veins goes to sublobular veins, then to collecting veins, and
then hepatic veins leaving the liver.
7
Q
What is the liver acinus?
A
Change of perspective – use the portal triad as the central unit – not the central vein
Liver Acinus – comprises a functional unit that puts the portal triad in the centre – based on the position of the triad you have three zones.
These different regions exhibit different metabolic functions – e.g.
1. Zone 1 (periportal) stronger focus on sampling
2. Zone 2 (intermediate) changing the composition
3. Zone 3 (perivenous) blood gets enriched
Low blood sugar – zone 1 detect and send signals downstream – so that downstream hepatocytes break down glycogen releasing glucose
8
Q
Where are stem cells located in the liver?
A
Stem cells – located in the periportal area
Population of undifferentiated cells located near the portal tract – differentiate when there is evidence of liver damage.
8
Q
Outline how the liver sinusoid is organised.
A
Liver sinusoids – channels between portal triad to the central vein that carry blood at low pressure
- Fenestrated endothelial cells gate to the hepatocytes – not tightly attached to hepatocytes creating a space called the space of disse which is where plasma can enter and interact with the hepatocytes (front garden)
- Hepatocytes have microvilli to increase surface area.
- Up and down liver sinusoids – Kupffer cells – surveying - and signal to the rest of the immune system in response to foreign/anitgens
- Stellate cells – store vitamin A - can close the gates of the fenestrated endothelial lining when there is inflammation – unfavorable – increase pressure
Note - Some of this fluid in the space of disse may pass to the periphery of the lobule to be collected as lymph.
9
Q
What are the functions of the sinusoidal wall?
A
Functions of the sinusoidal wall
* Blood cleansing – acts as a filter – plasma only enters
* Hemopoiesis in embryo
* Brings plasma into intimate contact with hepatic cells for metabolic functions
10
Q
What is the main functional cell of the liver?
A
Hepatocytes are the main functional cells of the liver and perform an astonishing number of functions. 80% of the mass of the liver is hepatocytes.
The cells are polygonal in shape and their sides are in contact either with sinusoids (sinusoidal face - microvilli) or neighbouring hepatocytes (lateral faces - low/no microvilli)).
A portion of the lateral faces of hepatocytes is modified to form bile canaliculi.
Hepatocyte nuclei are distinctly round, with one or two prominent nucleoli.
11
Q
What role do stellate cells play in liver cirrhosis?
A
Liver Cirrhosis – disorganized liver structure – hepatocytes no longer receive the nutrients and oxygen – destroyed and replaced by collagen
Alcohol – most common cause of liver disease – activate of Kupffer cells – retrieves White blood cells – activates stellate cell – converts to a fibroblast – that produces collagen – seals the fenestrations – collagen deposition – increase blood pressure in the sinusoids – blood pressure increases enter the portal vein – start of liver cirrhosis
12
Q
In what direction deos bile flow in the liver sinusoids?
A
Bile is produced by hepatocytes – flows in opposite direction into the bile duct via the bile canaliculi
Bile duct is formed by several bile canaliculi – become bigger and bigger to form the common bile duct – drains in towards the ampulla (sphincter of Oddi)
13
Q
How is lymph formed in the liver?
A
Lymph is formed in the space of Disse – flows through the peri-portal lymphatic vessels – drain into the portal triad
14
Q
What are the main veins that form the portal vein?
A
Blood from small intestine (superior mesenteric), large intestine (inferior mesenteric) and spleen – deoxygenated but nutrient rich
15
Q
Bilirubin metabolism - Outline how bilirubin is formed, converted into bile and excreted?
A
Bilirubin – component of bile – break down product of RBC recycling (hemoglobin) – hemolysis
- Unconjugated bilirubin formed from RBC break down
- Transported into the hepatocytes and conjugated with glucuronic acid producing conjugated bilirubin
- Enters the biliary system and released into the small intestine.
- Conjugated bilirubin converted into urobilinogen by bacterial proteases
- Some urobilinogen is re-absorbed and enters the circulation and excreted by the kidney but most is secreted by the feces
16
Q
Outline the liver’s role in regulating glucose metabolism?
A
Pancreas can regulate glucose via insulin/glucagon release - in harmony with liver
High blood sugar – insulin release – glucose converted to glycogen and gluconeogenesis is inhibited in the liver
Low blood sugar – glucagon released - glycogen catabolized and gluconeogenesis is activated – released into the blood
17
Q
What roles does the liver play in detoxificaiton of the body?
A
Detox organ of the body - Cytochrome p450 system
Toxins go into the liver – steps to produces water soluble product that can then be excreted via the gall bladder or via the kidneys in urine
18
Q
What are the main liver function tests performed?
A
Simple tests to see how healthy the liver is
- Bilirubin – high levels – likely some sort of blockage in the bile ducts – spilling over in the circulation – jaundice
- Aminotransferases - ALT (normally measured) and AST – enzymes within the hepatocytes – when the hepatocytes are dying, they are released into the bloodstream – measure of damage
- GGT and alkaline phosphatase (ALP) – go up when there is damage or blockage of the biliary system – these are released into circulation – note that GGT can also be elevated in response to certain drugs (anti-epileptics) and ALP can come from bone - so if in doubt check both.
- Albumin + clotting factors – synthetic function - liver responsible for their production – Low albumin levels or if prothrombin time decrease (marker of clotting), this indicates that the liver isn’t function properly
19
Q
What is cholestasis and how is it related to jaundice?
A
CHOLESTASIS refers to high levels of bilirubin which then results in jaundice - due to a tumour, gall stones, lesion at the ampulla, etc.
Jaundice – yellowing of the skin and sclera of the eye – due to accumulation bilirubin
20
Q
Are the liver function tests a better reflection of damage or function? Are they sensitive or specific?
A
No blood test for telling you how well the liver is working – markers provide more insight into damage
Not sensitive or specific – can have patients with liver cirrhosis but will have completely normal liver function test
BUT clinically useful AND patterns give clues
21
Q
Do hepatocytes and cells in the bile duct have HLA antigens? What implications does this have for transplantations?
A
Hepatocytes don’t have HLA antigens – consequence liver transplant don’t need to match – need to have the same blood group but not HLA antigens
Bile ducts do have HLA antigens – potential source of liver transplant rejection
22
Q
What is the most common cause of a high bilirubin?
A
Most common cause of high bilirubin – Gilberts (1/20) - agenetic hereditary disorder where slightly higher than normal levels of bilirubin build up inthe blood, causing jaundice
Not always noticeable – jaundice is noticeable at 50 and evident at 100
Causes an isolated rise in bilirubin, all other LFTs is normal
23
Q
How is unconjugated bilirubin transported in the blood?
A
Low solubility in aqueous solutions, so it binds to albumin to be transported to the liver.
24
What does the ALT/AST liver function tests tell us? What can we learn from the ratio of ALT:AST?
Test for damage/hepatocyte integrity
Hepatocyte dies – AST and ALT leak out into the blood – tells you the number of hepatocytes have died
Both have a short half life - hepatocyte death in the last 24 hours (acute) - chronic liver disease these may be normal as there aren't many hepatocytes left.
ALT = 50 (or less) - normal
Ratios
Ratio of AST to ALT is only useful in NAFLD to distinguish the severity
* Healthy liver = equal ratio
* NAFLD (advanced) = AST increases more than ALT - AST is derived from the mitochondria and the higher levels are due to mitochondrial dysfunction.
Alcohol liver disease – AST is always higher than ALT
25
What do ALP and GGT tell us?
ALP and GGT - show damage in bile ducts – don’t tell us that the bile duct cells are dyeing rather that they are irritated.
Hence, if elevated tells us that something is wrong with the bile ducts – stones, autoimmune disease, etc.
Alkaline phosphatase – ALP – liver is the most common cause of raise ALP
Note - ALP can also be derived from bone, intestines and placenta - so check GGT is elevated.
GGT made by liver and biliary system - can also increase in response to alcohol, obesity, phenytoin, carbamazipine (last two - anti-epileptics) - so check ALP
26
In long standing NAFLD cirrhosis, what is potentially the only LFT abnormality that you might see?
NAFLD cirrhosis – quite common that GGT is the only abnormality
Early on in NAFLD ALT is typically also abnormal
27
What does an albumin LFT tell us? When does it normally change in cirrhosis?
Albumin - tells us about the synthetic function of the liver
Important to note that it can also be high in states of dehydration (concentrating) and low due to a state of dilution.
Often normal in cirrhosis until liver failing.
28
What does an prothrombin LFT tell us? Is it better at assessing short or long term changes?
Good marker of synthetic function of the liver.
Very good in acute liver failure - e.g. paracetamol poisoning – prothrombin time becomes very high – very useful test to tell us whether we should transplant someone
Rarely very abnormal in cirrhosis - usually no longer than 20 (normal is 10-12)
29
What condition(s) should you think of if bilirubin is the only abnromal LFT?
Bilirubin only – think gilbert’s or increased hemolysis
30
What condition(s) should you think of if ALT is midly elevated?
ALT mild (50-100) – common
* NAFLD
* HepC
* Alcoholic liver disease including alcoholic hepatitis
31
What condition(s) should you think of if ALT is significantly elevated?
ALT high – hepatitis – can be viral or drug induced damaged
32
What condition(s) should you think of if GGTP is only elevated?
GGTP only – induction – drug + alcohol or inactive cirrhosis (may be the only marker – as number of hepatocytes is low)
Commonly elevated in people that drink to excess (not damage – induction)
33
What condition(s) should you think of if ALP and GGTP are both elevated?
ALP + GGTP – biliary system e.g. stones, pancreatic cancer and primary biliary cholangitis
34
In practise, what happens if a GP has a patient with abnormal LFTs?
Abnormal LFTs triggers Liver Screen, looking at...
* Hepatitis viruses
* Autoantibodies – anti-nuclear Ab, anti-mitochondrial Ab, anti-smooth muscle Ab
* Ferritin – hemochromatosis
* Ceruloplasmin (Wilson’s disease) and alpha-1-antitrypsin – in young people with rare conditions
* Immunoglobulins – auto-immune liver disease
* Ultrasound
35
What role does the liver have in carbohydrate, fat and protein metabolism?
Carbohydrates
* Glucose metabolism: storage and release: glycogenesis, glycogenolysis, gluconeogenesis,
Lipids
* Fatty acid metabolism & synthesis of lipoproteins
Protein
* Protein synthesis: albumin, transport proteins, proteases, clotting factors, acute phase proteins
* Converts ammonia to urea
36
What role does the liver play in xenobiotic metabolism?
Liver plays an important role in drug metabolism, sometimes called xenobiotic metabolism, as it biotransforms less polar compounds into more polar compounds (water soluble) that can be excreted more easily.
Important to note that the kidney also plays a role in drug metabolism.
37
Drug metabolism - What processes take place in phase 1 and 2 reactions?
Phase 1 reactions – oxidation or hydrolysis - detoxification (can also activate drugs)
Phase 2 reactions – glutathione conjugation, sulphation, acetylation and glucuronidation - increased solubility
Note - Phase 3 is also possible - secretion (into bile) that is ATP mediated.
38
Outline how paracetamol is metabolised by the liver.
Paracetamol metabolism – most common cause of acute liver failure
Normally metabolised by the liver via conjugation with glucuronidation or sulphation
But another pathway is also present...
Paracetamol can be converted into (P450 – isoenzyme 2E1) NAPQI (toxic)
NAPQI needs to react with glutathione in order to form non-toxic products.
If glutathione is used up we get acute hepatocyte death – treatment is a NAC as it is a glutathione donor in order to increase levels
39
What is the definition of acute liver failure?
Definition: loss of liver function that occurs quickly in days or weeks in a person with NO pre-existing liver disease
Main causes are...
* Paracetamol
* Viral Hep B and A
* Drug Reactions
40
What are some early and later signs of acute liver failure?
**Early non-specific**; malaise, nausea, vomiting, abdominal pains, dehydration.
**Later stages** - fully developed syndrome manifests with acidosis, profound hypoglycaemia, coagulopathy and encephalopathy leading to coma. renal failure, multi-organ failure
Treatment outcome depends when they arrive into hospital
41
In general terms, outline the pathophysiology taking place in liver cirrhosis?
Pathophysiology of cirrhosis – scarring of the liver
Cirrhosis - Development of fibrotic tissue that disrupts the hepatic architecture coupled with disorganised hepatocyte regeneration.
Leads to nodules of hepatocytes surrounded by fibrosis - disrupting normal hepatocyte functioning.
Timeline...
* Sustained damage in the liver
* Activation of kuppfer cells
* Inflammatory cells come in destroying the hepatocytes
* Stellate cell activation which then start producing collagen.
* Fenestrations of the endothelial cells close up
* Increases the pressure in the sinusoids
* Pressure gradient is transmitted back into the portal vein, leading to portal hypertension.
42
What are the complications associated with liver cirrhosis?
Liver cirrhosis - portal hypertention leading to...
* Bleeding from varices
* Encephalopathy (flapping tremor, confusion, foetor hepaticus)
* Ascites
Ultimately leading to liver failure.
43
What biochemical changes do we see in liver failure?
Liver failure...
* low albumin
* prolonged PT
* low urea
* high ammonia
44
What is the treatment for end-stage liver disease?
Treatment of end stage liver disease –liver transplantation
Alcohol abstinence for 6 months important
45
How does portal hypertension result in esophageal varices?
Portal hypertension – high pressure in portal vein
Blood from the mesenteric system cannot go smoothly through the liver, so the blood takes a diversion via the coronary vein
This then results in the formation of collaterals (in the oesophagus and stomach), in order to allow the blood to return into systemic circulation.
Problematic as these varices can burst
46
What are the two main causes of fatty liver disease?
Fatty liver disease – excessive accumulation of fat
Two main causes
a) Alcohol
b) Metabolic syndrome – obesity and type 2 diabetes
47
How is alcohol metabolised by the liver? How does it result in fatty liver disease?
Alcohol metabolism
Alcohol converted into acetaldehyde (ALDH), which is converted into acetate, ultimately leading to acetyl CoA formation.
Results in high levels of oxidative stress (free radical production) and fatty acid formation (enhanced lipolysis, FFA release and esterification of FFA)
The end result is steatosis - macrovesicular with large droplets of fat accumulating within the hepatocyte.
48
What is the alcohol flush response? What causes it?
Alcohol flush syndrome - deficiency in ALDH-2 resulting in an accumulation of acetaldehyde – toxic
49
What histological mark points towards Alcoholic fatty liver?
Mallory’s hyaline bodies
50
What is MASLD?
Metabolic dysfunction associated liver disease (MASLD) - replaced NAFLD
Histological appearance is very similar to ALD.
But patients have **Metabolic Syndrome** - abdominal obesity, serum triglycerides, cholesterol, high BP and high blood sugar – any 3 of these used for metabolic syndrome diagnosis.
51
Who is most likely to suffer from MASLD?
MASLD - tightly linked to obesity and type 2 diabetes
Only a subgroup of MASLD patients have a normal BMI but have a genetic predisposition
52
Outline how MASLD can progress in disease severity?
52
Outline the underlying pathophysiology of MASLD.
In MASLD we see...
* Insulin resistance - peripheral and hepatic
* Dysregulated fatty acid metabolism - leading ROS production/oxidative stress by mitochondria
Inceased ROS can drive...
* Cell death
* Activate stellate cells - leading to fibrosis
* Drive an inflammatory response
53
Does adipose tissue secrete cytokines and hormones?
Adipose tissue is a physiological reservoir of hormones and cytokines
* Pro-inflamatory ( leptin, TNFa, IL-6 etc) - Leptin is raised in NAFL and correlated with degree of steatosis.
* Anti-inflammatory - adiponectin
**Visceral fat** rather than subcutaneous is responsible for secreting these cytokines.
54
What are the clinical features of MASLD?
* Can be asymptomatic
* Abnormal liver biochemistry on routine check up
* RUQ abdominal pain
* Fatigue
* Hepatomegaly
* Acanthosis nigricans (children) - skin condition that causes a dark discoloration in body folds and creases
55
How is a diagnosis for MASLD made?
Diagnosis...
* Chronic elevation of serum aminotransferases
Note - other elevations also possible - GGT, elevated blood glucose, HOMA-IR (how much insulin needed to regulate blood sugar), total cholesterol and triglycerides
* Exclusion of other liver diseases
* Imaging studies (USSA/CT/MRI) : cannot easily distinguish steatosis from NASH or other liver diseases - Fatty changes detected if > 1/3 of liver involved.
* Liver biopsy is diagnostic and should be performed if diagnostic doubt exists mainly to exclude Autoimmune CAH.
56
What is the treatment for MALSD?
Number 1 - **weight reduction** – 1.5kg/week max weight loss
* Diet – low in carbohydrates and saturated fats – increased free radical production – Diet rich in polyunsaturated fat and fibre
* Exercise – improves insulin sensitivity
Other things to consider...
* Coffee is good – strong anti-oxidant effect
* Anti-obesity agents - orlistat (decrease lipid uptake) or sibutramine (appetite regulation)
* Cannabinoid receptor antagonists - improve lipid metabolism
* Bariatric surgery
* Insulin Sensitizers – metformin – insulin sensitizwer
* Antioxidants – Vitamin E – in theory might work but in practise is more difficult
57
What are 6 principal roles performed by the liver?
Largest solid organ
* Nutrient metabolism
* Drug Metabolism
* Protein synthesis
* Secretion - e.g. Bile
* Storage
* Immunological function
58
Apart from hepatocytes, what are some other cells present in the liver?
* Cholangiocytes – cells that line the bile duct - modificaiton of bile
* Sinusoidal cells – endothelial (transfer of subtances to hepatocytes) and Kupffer cells (specialized tissue macrophages)
* Perisinusoidal cells - stellate cells
59
Outline the flow of bile from the canaliculus to the duodenum.
* Bile Canaliculus
* Bile ducts
* Right and left hepatic ducts
* Stored in gallbladder
* Cystic ducts
* Common bile duct
* Enters the duodenum at the ampulla of vater
60
Outline the roles of the liver in nutrient metabolism - Carbohydrates, Fats and proteins.
Carbohydrate
* Fed State – insulin high / glucagon low - hepatic glucose uptake – glycogen deposition in hepatocytes.
* Fasting – insulin low/ Glucagon high - glycogen breakdown in periportal area and gluconeogenesis from lactate, pyruvate, amino acids and glycerol
Lipids
* Bile digests lipids in the gut - take up as chylomicrons - travel to the liver
* Chylomicrons metabolised by lipoprotein lipase into cholesterol, phospholipids, triglycerides and free fatty
Proteins
* Catabolism of circulating proteins/peptides
* Interconversion of amino acids
* Deamination of amino-acids allowing gluconeogenesis
* Synthesis of non-essential amino acids
* Catabolism of hepatic proteins in fasted state for fuel
* Protein synthesis
61
What role does the liver play in ammonia metabolism?
Ammonia/ium – toxic needs to be removed
* Most comes from the gut and travels to the liver
* But also produced from amino acid metabolism
Both are converted to urea so that it can be removed – urea cycle
Problems with the urea cycle – presents as encephalopathy
62
What role does the liver play in protein synthesis?
Protein synthesis
* Main protein is albumin – makes over 55% of circulating proteins (holds fluid in the circulation)
* Transport proteins (caeruloplasmin – Cu and transferrin - Fe)
* Ferritin (storing iron)
* Protease inhibitors (alpha-1 antitrypsin)
* CRP
* AFP
* Complement
* Coagulation factors - Fibrinogen, II, V, VII, IX and X - Note that factor 8 is made by the endothelial cells rather than the hepatocytes
63
What components make up bile?
Composed of…
* Bile acids primary (made in liver) and secondary (absorbed) - Allow digestion of dietary fats through emulsification
* Phospholipids
* Cholesterol
* Conjugated drugs
* Electrolytes: Na+, Cl-, HCO3- and copper
* Bilirubin
64
What vitamins and minerals are stored by the liver? What important vitamin is modified by the liver
Vitamins
* Vitamin A, D and B12 are stored in large amounts
* Small amounts of Vitamin K and folate are rapidly depleted with decreased dietary intake
* Metabolises cholecalciferol vitamin D3 → activated 25-(OH) vitamin D - 25 hydroxylation
Mineral
* Iron stored in ferritin and haemosiderin (iron-storage complex)
* Copper
65
What immunological function does the liver perform?
* “Firewall” filtering all blood from gut
* Kupffer cells phagocytose pathogens from gut
* Supply of important chemokines:
1. Interleukins – between WBCs
2. Tumour necrosis factor – pro-inflammatory
* Priming T cell responses
66
What are the causes of liver cirrhosis?
1. **Viral infection** – chronic infection – common cause worldwide - Hepatitis B and C
2. **Alcohol, toxin and drugs** – most common
3. **Non Alcoholic Steato-Hepatitis (MASLD)** – metabolic fatty liver disease – obesity
4. Immune-mediated disorders
* Autoimmune hepatitis
* Primary biliary cholangitis
* Primary sclerosing cholangitis – associated with IBD
5. Cholestatic liver disease
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)
6. Inherited disease – hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency
67
What are the stages of that lead up to cirrhosis?
1. Simple steatosis
2. Steatohepatitis - inflammation
3. Fibrosis - In its initial stages, fibrosis is thought to be reversible to some degree, but in the late stages it is felt to be irreversible.
4. Cirrhosis - distortion of hepatic architecture and the formation of regenerative nodules. It is traditionally believed to be an irreversible condition.
5. Hepatocellular carcinoma
68
Outline the role of stellate cells in the development of cirrhosis.
1. Liver injury
2. Hepatocyte becomes injured releasing factors
3. Drives an inflammatory response
4. Stimulates stellate cells and kupffer cells
5. Stellate convert into myofibroblasts and start to make collagen
6. Blocks of the fenestrations increasing portal blood pressure and deprives hepatocytes of oxygen and nutrients leading to dysfunction.
69
What are the consequences of increased sinusoidal resistance?
1. Portal hypertension - Portosystemic collaterals - forming varices that are at higher risk of bleeding
2. Reduced venous return to the heart - drives Na+ retention and vasocontriction - increased cardiac output - increasing portal hypertension further.
3. Portal hypertension + fluid retention - resulting in ascites - fluid accumulation in the peritoneal cavity.
4. Portal hypertension - back pressure results in spleen enlargement
5. Portal hypertension - Less blood going to the liver - less ammonia/ammonium is processed - hepatic encephalopathy
70
What is the difference between compensated and decompensated liver cirrhosis?
Cirrhosis is classified as compensated or decompensated.
Compensated cirrhosis is where the liver is coping with the damage and maintaining its important functions - carry on with daily life without restriction.
In decompensated cirrhosis, the liver is not able to perform all its functions adequately - impacts daily life
71
What are the some physical features of compensated and decompensated liver cirrhosis?
Compensated - Xanthelasmas, Spider naevi, gyno, liver enlargement, clubbing, xanthamos and purpura (skin hemorrhages)
Decompensated - **Jaundice**, **neurological** (encephalopathy, disorientation, drowsy, hepatic flap - hand tremor), **ascites**, dilated veins in abdomen (**variceal bleeding**) and oedema.
72
How to diagnose fibrosis/cirrhosis?
1. Elastography – most widely used tool for determining fibrosis – non-invasive, fast and user friendly - Fibroscan
2. Liver biopsy – gold standard – cons = sampling error and morbidity (risky)
3. Serum markers – widely available and non-invasive - non-specific and not good at determining the intermediate stages of fibrosis
73
What serum markers are we looking for when diagnosing cirrhosis?
Serum markers
* Albumin - liver not function albumin will drop - longer half-life making it useful in cirrhosis
* Prothrombin time – prothrombin time will increase as there is a decrease in coagulation factors - associated with more advanced disease
* Bilirubin – increased in end stage cirrhosis due to decrease clearance
* Platelets – decreased in cirrhosis, splenomegaly – increase consumption, decreased thrombopoietin
74
Detoxification - What does a failure in clearing bilirubin and NH3/NH4+ result in?
* Failure to clear bilirubin in bile results in jaundice (product of RBC breakdown)
* Colon by-products contain toxins need to be cleared by the liver (e.g. NH3/NH4+) – if there is reduced capacity this will continue to circulate causing problems around the body – e.g. encephalopathy (symptoms drowsy/confused)
75
Protein synthesis - What does decreased production of clotting factors and albumin result in?
* **Decreased clotting factors** – increases in prothrombin time
Note that the liver also produces clotting inhibitors so it is the balance between clotting factors and inhibitors that determine clotting time.
Clotting factors have a low half life (average 6 hours) - change in clotting can therefor be noticed quickly
* **Failure to produce albumin** – disrupted fluid balance (oedema) and impaired binding of drugs
Albumin – longer half-life – lasts weeks – liver injury doesn’t immediately result in reductions
76
Energy storage - What does a failure to store or release glucose result in? What does inadequete use of proteins result in?
Liver plays important roles in energy storage and utilization
* Failure to store or release glucose – resulting in hypoglycaemia
* Inadequate use of proteins – results in a catabolic state leading to muscle wasting – sarcopenia
77
What is the difference between acute and chronic liver failure?
Different definitions:
Acute - 2-3 months
Chronic - More than 2-3 months - In reality most chronic liver disease occurs over years
Different causes and presentations
Acute liver failure – progresses rapidly – significantly morality if it is not addressed – but luckily the cases are quite low in comparison to chronic cases
78
What is the definition of acute liver failure? What LFTs associated with acute liver injury, severe acute liver injury and acute liver failure?
Acute liver failure - Rapid onset (less than 2-3 months) + no underlying chronic liver disease
* Acute liver injury (most common) – damage to hepatocytes – causing a high ALT
* Severe acute liver injury (uncommon) – high ALT + jaundice/coagulopathy
* Acute liver failure – rare – high ALT + jaundice/coagulopathy and encephalopathy
79
What is the main cause of acute liver failure?
Most common cause paracetamol
Used for suicide attempts – account for 80-90% of cases of acute liver failure in Scotland
80
Apart from paracetamol overdose, what are examples of less common causes of acute liver failure?
**Other drugs**
- Antibiotics – TB
- Antiepileptics
- Herbal remedies – important to ask about in history
- Ecstasy
**Viral Infections**
- Hepatitis B – most likely to cause ALF – A and E can occasionally – treatments available – important to recognize
- EBV or CMV
**Autoimmune hepatitis** – treatments available – important to recognize
**Seronegative hepatitis** – no causative agent identified
81
What are examples of rare causes of acute liver failure?
Rare
* **Vascular** – Budd-Chiari – thrombosis of the hepatic vein (block outflow – causing damage)
* **Metabolic disease** – Wilsons (accumulation of copper in the liver – teens/20s)
* **Acute fatty liver of pregnancy**
* **Cancer** – very severe infiltration with multiple metastases
* **Ischemia** as a result of hypotension
* **Toxins** – Amanita phalloides mushroom and carbon tetrachloride (industrial exposure)
82
What is the treatment for paracetamol overdose?
N-Acetyl Cysteine as it increases glutathione stores - antidote to paracetamol overdose which causes glutathione depletion
Glutathione is important as it mops up free radicals/reduce oxidative stress
83
How do we try to correct prothrombin time in ALF?
Provide Vitamin K
Vitamin K is required for clotting factor synthesis – 2, 7, 9 and 10
Futhermore, dietary deficiency of vitamin K makes the liver function appear worse than it actually is, so replacement is introduced to ensure that vitamin K deficiency is not masking as liver dysfunction and provides the liver with the best opportunity to do its job.
Alternatively...
We can give patients fresh frozen plasma - blood product containing clotting factors.
Avoid giving FFP as it will prevent us from being able to monitor liver function – only given if patient has significant bleed that needs to be treated
84
What criteria do we use to help inform judge whether someone will recover from paracetamol induced ALF?
1. PT> 100
2. Anuric or creatinine over 300
3. Grade 3-4 encephalopathy
Liver is very unlikely to recover if all these criteria are met - more likely to survive with a transplant
85
What criteria do we use to help us decide the prognosis for non-paracetamol ALF?
Prognosis in non-paracetamol ALF – 3/5 unlikely to recover spontaneously
* Age – very young or slightly older – do worse
* Etiology – Drug or seronegative less likely to recover vs. acute viral Hep more likely to recover
* PT > 50 or INR > 3.5 – bad sign
* Bilirubin over 300 – bad sign
* Time from jaundice to encephalopathy less than 7 days – not good
86
How do paracetamol and non-paracetamol induced ALF differ in terms of timing?
Paracetamol causes **hyperacute** liver failure
* Rapid progression of coagulopathy over hours, rather than days
* Usually encephalopathy in less than 1 week
Non-paracetamol ALF (other causes) usually more gradual onset
* Progression over several weeks
87
In general terms, how is ALF managed?
Identify and treat underlying cause
* NAC for paracetamol
* Antivirals for hepatitis B
* Steroids for autoimmune hepatitis
Supportive care
Close monitoring (especially paracetamol)
Liver transplantation if appropriate
88
How do we define chronic liver failure?
Less well-defined terminology - liver disease that has been present (normally) over many years.
We see impaired hepatocyte function..
* jaundice
* coagulopathy
* low albumin
ALT can be normal - low number of total hepatocytes - so ALT rise is not significant
89
Complications associated with chronic liver failure?
1. Shunting of blood from portal circulation to systemic circulation – via varices - risk of bleeding.
2. Hepatic encephalopathy – blood is not being filtered by the liver - removal of toxins is not taking place – NH3 is not being cleared
3. Ascites - low albumin (low oncotic pressure), portal hypertension and renal hypoperfusion (increases RAAS)
90
Apart from chronic liver disease, what are some other causes of encephalopathy?
Encephalopathy can also occur in response to other events...
1. Constipation - increased transmit time – more time for toxins to be produced by bacteria – shunting or impaired liver function for that to be significant.
2. Drugs (opiates and sedatives) increases sensitivity of the brain
3. Dehydration
4. Any infections
5. GI bleeding
91
What are the causes of chronic liver failure?
Basically any cause of liver cirrhosis
* **Alcohol**
* **Non-alcoholic fatty liver disease**
* Hepatitis B or C
* Haemochromatosis
* Wilson’s disease
* Primary biliary cholangitis
* Primary sclerosing cholangitis
* Autoimmune hepatitis
92
In general terms, how is chronic liver failure managed?
* Identify and treat underlying cause
1. Abstinence for alcohol - diazepam (alcohol withdrawal) and vitamin B (thiamine) to protect brain
2. Antivirals for hepatitis B/C
3. Steroids for autoimmune hepatitis
* No treatment for jaundice
* Low salt diet and diuretics for ascites
* Laxatives and antbiotics for encephalopathy
* Liver transplantation if appropriate
93
How can we reduce the risk of bleeding from varices in chronic liver disease?
Treatment with beta-blocker to reduce pressure / risk of bleeding
94
Summary of the main effects of liver cirrhosis.
* Reduced synthetic capacity - Albumin, Clotting factors, Protein (muscle)
* Reduced clearance of waste products - Jaundice and Encephalopathy
* Portal Hypertension - Ascites, Varices and Splenomegaly
95
General terms, what is the structure of a virus particle?
Viruses - require host cell machinary to replicate and survive
Structure:
* Single stranded or double stranded DNA or RNA
* Single stranded – can be + or – stranded
* DNA or RNA within a virus-encoded protein coat (nucleocapsid)
* Sometime an outer-most host cell membrane-derived envelope - those that have an envelope are more sensitive to detergents
* Viruses receptors and glycoproteins on the outside - determine species and tissue specificity
* Matrix proteins – can be viral proteins or human proteins
96
What does hepatitis mean?
Hepatitis means inflammation of the liver - can be caused by numerous things - like excessive alcohol intake and viral infection.
97
What are the clinical symptoms of hepatitis?
98
What biochemical and serological tests do we perform on someone with suspected hepatitis?
Biochemical tests on blood – liver enzymes, other liver proteins (albumin and prothrombin), and bilirubin - normal LFTs basically
Serological and molecular tests
- **ELISA** – test for viral antigens and anti-viral antibodies
- **Molecular assays** - PCR looking for viral RNA and DNA + sequencing can also be performed to find out more about the genotypes and resistance to specific drugs
- Liver biopsy – done later down the line
99
How can you group the hepatitis viruses (A-E) in terms of transmission?
**Hepatitis B, C and D**
* Are transmitted parenterally (not via the gut) – sexual contact, blood and blood products
* Often cause chronic diseases - virus is not eliminated after the initial infection and stays around.
* Treatments are available for Hep C and B – drugs are particularly good for hep C – treat up to 90% of patients with Hep C
* Envelope viruses
**Hepatitis A and E**
* Transmitted fecal-orally
* Fecal-oral viruses do not have an envelope – need to be more resistant to the environment
Note - Hep D – can only infect someone that is hep B positive
100
What can you tell me about hepatitis A incubation period, who it primarily affects, mode of transmission, onset, impact on liver function, mortality, chronicity and treatment?
**Incubation** - All Hepatitis viruses typically have a long incubation time - Hep A – 10-50 day incubation period
**Primarily affects** - children and young adults
**Mode of transmission** - fecal-orally - contaminated water infects food (vegetables or shellfish) - ingested
**Onset** - abrupt onset, commonly with pyrexia (fever)
**Liver** - results in high LFTs (1000s units/per ml of blood)
**Morality** - Fatality rate is relatively high – acute liver failure – increasing age morality goes up – e.g. over 50 mortality increases above 2%
**Chronicity** - resolves spontaneously (without chronicity – ie, no carrier state) followed by life-long immunity
**Treatment** - Prevention - Inactivated virus vaccine and immunoglobulins. Treatment is supportive
101
How is IgM, IgG and RNA use to track the course of hepatitis A infection?
Antibodies are useful for diagnosis – Have more antibodies than viral proteins/particles in the blood during an infection.
* IgM presents - indicates recent infeciton
* IgG present - indicates HAV infection (or vaccine response) and detectable by onset of symptoms/signs
* HepA RNA in blood - present at the onset of symptoms/signs
Patients may be infective before they have symptoms and antibodies in their blood
102
Where is hepatitis A most prevelant around the world?
Distribution of hepatitis viruses
Hep A – sub-Saharan Africa, India and south-east Asia
103
What are the outcomes for Hepatitis A infection in adults and children?
Children is typically subclinical and asymptomatic
A lot rarer in adults – usually gets jaundice = icteric disease + higher fatality rate
104
What can you tell me about hepatitis B incubation period, who it primarily affects, mode of transmission, onset, impact on liver function, mortality, chronicity and treatment?
**Incubation** - All Hepatitis viruses typically have a long incubation time - Hep B – 60-90 day incubation period
**Primarily affects** - babies and young adults
**Mode of transmission** - parenteral, vertical (mom to fetous in pragnancy) and sexual
**Onset** - insidious onset (gradual) and apyrexial
**Liver** - Virus remains in hepatocytes for life and may re-active under immunosuppression
**Morality** - Up to 2% fatality rate in icteric cases.
**Chronicity** - Chronic infection* (carrier state) develops in 5-10% of adults (but >95% of neonates) and is associated with hepatocellular cancer.
**Treatment** - Prevention - HepB vaccine and immunoglobulins. Treatment is Interferon alpha OR antivirals.
Vaccine (Hepatitis surface antigen) is effective – 95-98% - good but not perfect for healthcare providers – means that you have 2-5% of non-responders
105
What are we looking for when testing for hepatitis B infection?
Suspect someone has HepB infection:
1. Draw blood and check for Hep B surface antigen for Hep B surface antigen antibody
2. Core antigen (HBcAg) and the E antigen (HBeAg) – other antigens that can be tested - also look for antibodies against these antigens
106
When and how long can HBsAg be detected for? In what percentage of cases to levels of HBsAg persist?
Typically levels rise 1 month following exposure
Surface antigen can hang around for months – once antibodies raised, the surface antigens are removed, and symptoms typically disappears
Antibodies against the core and E antigen can also be raised – Anti-HBc and AntiHBe - indicates that you probably have a high viral load.
In 5-10% we get chronic infection and surface antigen persists – used to test for chronic infection - Level of E antigen can be used to differentiate between high and low infectivity
107
Where is hepatitis B prevelant in the world?
Sub-Saharan Africa, South east Asia, Russia
108
How do outcomes from Hep B infection differ between newborn/infants, young children and teenagers/adults?
**Newborns and young children** – infection is severe and have a high rate of chronic infection
**Adults/teenagers** – recovery rates are much higher and rates of chronic infection are a lot lower
109
What can you tell me about hepatitis C incubation period, who it primarily affects, mode of transmission, onset, impact on liver function, mortality, chronicity and treatment?
**Incubation** - All Hepatitis viruses typically have a long incubation time - Hep C – average 50 day incubation period
**Primarily affects** - adults
**Mode of transmission** - parenteral - sexual
**Onset** - Acute phase very often completely asymptomatic
**Liver** - Chronic infection (carrier state) is associated with hepatocellular cancer
**Morality** - Up to 1% fatality rate in icteric (jaundice) cases
**Chronicity** - Chronic infection established in 70-90% of cases
**Treatment** - Interferon alpha together with ribavirin (not commonly used) OR **direct-acting antivirals (DAAs)** such as protease inhibitors (eg, boceprevir, telaprevir) and/or polymerase inhibitors (sofosbuvir).
DAAs are really good, make condition largely curable, but is expensive.
No vaccine available.
110
What serological test do we use to track HepC infections?
Serological tests
1. Test anti-HepC antibodies
2. Hepatitis C antigen and PCR tests also available (used to quantify viral load)
3. SNP IL28B – helped for prognosis – not used anymore
111
Where is hepatitis C prevelant across the world?
Distribution is occurs everywhere.
112
What do you need to remeber about hepatitis D infection? How do you get infected by HepD?
Defective virus that needs HBV for replication
How do you get HepD?
- Co-infection with HBV – injectable drug users – causes severe acute disease and is associated with low levels of chronicity
- Super-infection – someone that has HepB that is then super-infected by HepD – causes Hep D chronic infection + high risk of severe chronic liver disease
HBV vaccination provides indirect protection against HDV
113
What does the prevelance of HepD look like?
Specific countries with high prevelance.
114
What can you tell me about hepatitis E incubation period, mode of transmission, onset, impact on liver function, mortality, chronicity and treatment?
Scotland – HepE most common hepatitis virus - most common genotype 3 - transmission via pork.
Several genotypes – 1 and 2 (spread between humans), 3 and 4 (zoonosis)
**Incubation** - All Hepatitis viruses typically have a long incubation time - Hep E – average 40 day incubation period
**Mode of transmission** - faecal-oral transmission
**Morality** - overall fatality rate is 1%-3% (but 15%- 25% in pregnant women)
**Chronicity** - no chronicity identified (except in the immunocompromised)
**Treatment** - No specific treatment – normally supportive (treat symptoms) sometimes we use ribavirin (in chronic infection)
115
How do we test for HepE?
Look at IgG and IgM antibodies for HepE presence + qPCR to test viral load
116
Where is HepE most prevelant across the globe?
Distribution is much higher in the developed countries.
117
What are some other viral causes of hepatitis?
Once we have tested for Hep B, C and E (common in the UK) we move on to the others
1. After Hep – EBV (very common – >90%) and CMV are the most common causes
2. HSV (90% of people have this – lays dormant)
3. Rubella – very rare in UK and Europe – vaccinate with MMR
Others - Enteroviruses and yellow fever virus
118
How does alcohol influence paracetamol metabolism?
Competition between acetaminophen and alcohol in the liver
* Acutely taken together – might be protective
* Long term alcoholism – lowers glutathione – lower dose of paracetamol needed
119
What are the two main causes of acute liver failure?
Paracetamol overdose
Viral hepatitis - A and **B (main)**
120
What is jaundice? At what point is it visible?
Yellowish pigmentation of the skin, membranes and sclera (conjuctival membrane)
Jaundice (Jaune) = yellow
Visible at bilirubin level >35umol/L
121
How much bile is produced per day? What does bile consist of?
Bile produced by liver hepatocytes - 500-1500 mls/day
Bile consists of: water, bile salts (solubilise and absorption of lipids), cholesterol and bilirubin
122
Where does bilirubin come form in the body?
Bilirubin - it is a breakdown product of haem
25—400mg bilirubin daily
70-90% from haemoglobin
Rest comes from myoglobin
123
Explain what this diagram is showing.
Most of the bilirubin comes from hemoglobin and myoglobin - break down product is called unconjugated bilirubin (not water soluble) – needs to transported with albumin
Liver takes up unconjugated bilirubin – processed in the liver – becomes conjugated (glucuronic acid) making it water soluble – excreted into bile
Enterohepatic reabsorption – bacteria process it, allowing for reabsorption
Bilirubin in the colon gets processed even further forming stercobilin – makes stool go brown
124
How could you categorize the three types of jaundice?
Different types of jaundice
* Pre-hepatic – before liver – high levels of RBC breakdown (hemolysis)
* Hepatic – in the liver
* Post-hepatic – after the liver
125
What happens in pre-hepatic jaundice? What are two causes?
* Increased bilirubin production
* Exceeds ability of liver to conjugate
* As water insoluble, does not enter urine
Causes
* Increased haemolysis
* Glucoronyl transferase deficiency (Gilbert’s), 10% of the population
126
What happens in hepatic jaundice? What are some causes?
Hepatic - something happening in the liver – can’t uptake unconjugated or conjugate it due to hepatocyte damage – mix rise of conjugated and unconjugated bilirubin
Causes...
* **Viruses** – hepatitis, CMV, EBV
* Drugs: paracetamol, anti-TB,
* **Alcohol**
* Cirrhosis, autoimmune diseases
* Sepsis
* Right heart failure
127
What is post-hepatic jaundice? How does it present?
Obstructive jaundice - outflow of conjugated bilirubin is blocked
Presentation
1. Pale stool - lack of stercobilirubin
2. Dark urine - some bilirubin excreted via the kidneys
3. Itch - bile salts end up in skin
128
How can we further classify post-hepatic jaundice?
* Within lumen of bile ducts– gallstones - most common.
* Within the wall – tumour of the bile duct – cholangiocarcinoma
* External compression – pancreatic cancer
129
What are the different types of malignancy that can cause post-hepatic jaundice?
* Hilar of the liver or distal cholangiocarcinoma
* Compression from nodes (patient with colorectal cancer or lymphoma) – hilar lymphadenopathy
* Pancreatic tumours
* Ampullary tumours
130
What surgical procedure can be undertaken if someone presents with a distal cholangiocarcinoma, ampullary tumour or pancreatic tumours?
Whipples Procedure - Taking out the gall bladder, distal bile duct, duodenum and part of the stomach
High complication rate
131
How is endoscopic retrograde cholangiopancreatography (ERCP) used in the treatment of post-hepatic jaundice?
1. Sometimes we can't resect liver mets or lung mets – so an endoscope can be used to place a stent into the common bile duct to prevent blockage and improve symptoms.
2. Benign disease – if gall stones are present in the common bile duct we can also do an ERCP – inflate balloon above the stone and pull it out
132
If someone presents with jaundice, what things should we be thinking of during the history?
1. Features of obstructive jaundice: pale stools, dark urine and itch
2. Features of cancer: weight loss, loss of appetite
3. Recent travel - hepatitis or viral illness
4. Family or personal history
5. Autoimmune disease
6. IV drug users
7. Drug history + alcohol
133
If someone presents with jaundice, what things should we be looking for during an examination?
Signs of liver disease
* Peripheral stigmata - finger clubbing, palmar erythema, dupuytren’s, sclera for jaundice, Virchow’s nodes, spider naevi, gynaecomastia
* Hepatomegaly
* Splenomegaly
* Ascites
* Palpable gallbladder
134
If someone presents with jaundice, what investigations are we performing?
1. **Hematology** – full blood count (anemic – possible cancer?) and abnormal clotting
2. **LFTs** – raised bilirubin with ALP > ALT/AST = obstructive vs. ALT/AST > ALP = liver disease
3. **Liver screen** – hep screen, autoimmune, electrolyte abnormalities
4. **Imaging** – Ultrasound – investigation of jaundice – good to tell you if it is a post-hepatic cause or not – if it is a blockage you see intrahepatic ducts become dilated (not the case for hepatic or pre-hepatic causes), look for gallstones and maybe see the pancreas (difficult)
5. **CT abdomen** useful for cancers or **MRI** (MRCP) of bile duct useful for gallstones
6. **Tissue biopsy** might be needed
135
How is jaundice managed?
**Management**
* Treat the symptoms
* Analgesia – pain
* Fluids
* Antibiotics if there is an infection
* Vitamin K (clotting) and chlorphenamine (treat itch)
**Treat cause**
* Prehepatic – stop hemolytic process
* Hepatic – Anti-virals, halt cirrhosis, etc.
* Obstructive – ERCP/stenting, surgery and palliation
136
Outline the structure of the biliary system.
1. Common hepatic duct (left and right branches)
2. Cystic ducts (to/from gall bladder)
3. Common bile duct - forms part of portal triad
Blood supply - Cystic artery – comes from the right hepatic artery
137
Are gallstones common? Are the normally symptomatic or asymptomatic? Who is it most likely to affect?
* 10 to 20 % of adult population
* 80 % asymptomatic (silent gallstones)
* Who - Fair, fat, female, fertile and forthy
138
What symptoms do patients with gallstones normally present with?
Presentation
* Right upper quadrant pain, epigastric pain
* Colicky pain (comes, builds and eases) but can be constant
* Nausea and vomiting
* Dyspepsia
Ultrasound – wall of gall-bladder is thick (inflammation – cholecystitis) and gall stone (blob)
139
What are the different ways that gallstones may clinically present?
Clinic presentation
1. **Biliary colic** - fatty food followed by pain – right sides colicky pain 30-60 minutes after eating – most common presentation – gall stones getting trapped in the narrowing (Hartman's pouch) resulting in spasms and colicky pain
2. **Acute cholecystitis** – inflammation of the gall bladder and sometimes infection – pain may start colicky but becomes constant + temperature – treatment with antibiotics – sometimes emergency operations to remove gall bladder
3. **Obstructive jaundice** – gall stones entering the bile duct causing jaundice – ERCP – drag down gall stone into duodenum
4. **Acute pancreatitis** – acute inflammation – pressure changes in the pancreatic duct – causes back pressure
140
What is the management for gallstones?
1. Pain killers
2. Antibiotics (infection)
3. Percutaneous drainage (people not fit for general anesthetic – ask radiology to stick a drain in)
4. ERCP (removal of gall stones)
5. Surgery - e.g. Laparoscopic cholecystectomy
