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Flashcards in lecture 16 Deck (37):
1

What does the normal liver look like?

- reddish brown in colour
- 1.5kg
- in the right upper part of the abdomen attached to the undersurface of the diaphragm
- hidden by the ribcage
- smooth anterior surface

2

What are the major vessels in the liver?

- hepatic portal vein (from intestines)
- common bile duct (to intestines, stored temporarily in the gall bladder, released e.g. when eating a fatty meal)
- hepatic artery (from abdominal aorta)
- blood in portal vein and hepatic artery returns to heart via the inferior vena cava

3

What happens to the major vessels when they enter the liver?

- ensheathed in connective tissue that extends from the porta hepatis (entry point) (aka hilum)
- also contains lymphatics and nerves
- portal tract
- structures divide
- portal vein/hepatic artery branches = sinusoids

4

What are the specialised cells of the liver?

Cell types by percentage of total liver cells
- hepatocytes - 60%
- cholagiocytes (BEC) - 4.5%
- endothelial cells - 21%
- kupffer cells - 8.5%
- hepatic stellate cells - 5.5%
- pit cells (NK cells) - <1%

By relative volume of liver mass
- hepatocytes - 80%
- non-hepatocytes - 6%
- extracellular space - 14%

5

What are the functions of hepatocytes?

Metabolic
- glucose homeostasis
-- glycogen storage
-- glycogenolysis and gluconeogenesis

- lipid metabolism
-- uptake of fatty acids, conversion to triglycerides and secretion of lipoproteins

Synthetic
- most plasma proteins - albumin
- clotting factors - almost all and natural anticoagulants (Antithrombin III and protein C & S)
- complement and other acute phase reactants
- specific binding proteins e.g. Fe, Cu, Vit A
- cholesterol

Storage
- glycogen, triglycerides, lipid soluble vitamins, Fe, Cu

Catabolic
- endogenous substances – hormones and serum proteins
- detoxification of foreign compounds e.g. drugs, industrial chemicals, bacterial products
- activation of drugs and foreign compounds
- removal of ammonia via urea synthesis

Excretory
- bile formation and excretion into the gut – bilirubin, IgA, bile acids, cholesterol, elimination of environmental toxins, carcinogens and drugs and their metabolites

6

What is the structure of hepatocytes? How do they fit in their environment?

- liver cell plates are like bricks laid out one on top of the other – a wall, muralium
- hexagonal bricks - 8 faces: 6 facing each other, attached firmly with (?) studs (attached firmly like lego)
- groove between large face, sealed with tight junctions but where the bile drains through
- forms continuous network which drains out to the bile tracts
- biliary canaliculus
- surfaces facing sinusoids are covered with microvilli for increased absorption and secretion function (SA)

7

What is the structure of sinusoids?

- lined by endothelial cells which have little grooves/holes in them called fenestrae (.15microns) to allow the free access of plasma and small products (certain particles and proteins) to hepatocytes = sieve plates
- kupffer cells (macrophages) on inside of sinusoid --> trap particular matter passing through the blood stream from the gut, including toxins, endotoxins and so on, clear the blood before it goes back via circulation to the heart

8

What is inside the space between the endothelium of the sinusoids and the hepatocytes?

- space of Disse
- collagen fibres called reticulum (important in fibrosis and chronic liver disease)
- hepatic stellate cells in sinusoidal space, between hepatocytes, contain lipids which store vitamin A (unknown why)

9

What do we see when we look at the 3D arrangement of liver cells?

- hepatocytes are organised in single cell thick walls (called liver cell plates)
- separated by sinusoids in space that separate the labyrinth of hepatocytes (called lakuning?)
- portal vein penetrates limiting plate and then gives off branches
- bile duct attaches to limiting plate and biliary canaliculi drain into it (canal of Hering)

10

Where are liver stem cells located?

canals of Hering

11

How much blood goes through the liver?

1L/min in portal vein
500mL/min in hepatic artery
- so 1.5L/min; massive blood flow

12

What does a normal portal tract lack?

inflammatory cells

13

How do we describe the structure of a liver?

- lobule and acinus with zones 1, 2 and 3
- 3 portal tracts around each 'lobule'
- according to the lobular model, the liver is divided into 1- to 2mm hexagonal lobules oriented around the terminal tributaries of the hepatic vein, with portal tracts at the periphery of the lobule
- in the acinar model (more according to function), triangular shaped, bases are formed by the penetrating septal venules from the portal vein extending out of the portal tracts
- in the acinus the parenchyma is divided into three zones, zone 1 being the closest to the vascular supply, zone 3 abutting the terminal hepatic venule and most remote from the afferent blood supply, zone 2 intermediate

14

Why is zonation of the parenchyma an important concept?

- gradient of activity displayed by many hepatic enzymes, and the zonal distribution of certain types of hepatic injury
- zone 1 closest to blood therefore oxygen
- zone 3 prone to anoxia (e.g. when in shock, cardiac arrest)

15

What are the contents of a hepatocyte?

- large amounts of ER where breakdown and detoxification of compounds and so on occurs
- rough ER where protein synthesis occurs
- smooth ER with lots of glycogen

16

What happens if you give an animal/patient a drug (e.g. phenobarbital) for a long period of time?

- proliferation/hypertrophy of ER --> demand for work
- hepatocyte starts to look pale due to increase of smooth ER (as opposed to blueish because of large amounts of RNA on rough ER)
- cells are much bigger --> lobule is bigger

17

What is the difference between zone 1 and zone 3?

zone 1 vs zone 3:
- carbohydrates: gluconeogenesis vs glycolysis
- proteins: albumin synthesis, fibrinogen synthesis vs same
- cytochrome P450: + vs ++
-- after phenobarbital: +/- vs ++++++
- glutathione ++ vs - (means that zone 3 is not good at dealing with new reactive oxygen species, quickly leads to necrosis)
- alcohol dehydrogenase + vs ++
- oxygen supply: +++ vs +
- urea synthesis/carbamoylphosphate synthetase: +++ vs -
- HMG CoA reductase: ++ vs -
- cholesterol 7 alpha-hydroxylase: - vs ++
- bile formation:
-- bile-salt dependent: ++ vs -
-- non-bile-salt dependent: - vs ++

- zone 3 hepatocytes are prone to toxic, alcoholic and anoxic injury

18

What happens when you perform a hepatectomy?

- normally only 1 in 1000 hepatocytes is in mitosis
- long-lived cells - 50 to 150 days
- stable cell population
- if you remove two thirds of the liver the animal will live
- in rat:
- within 18 hours 30% of the parenchymal cells are dividing
- ductal and littoral cells divide later (~36 hours)
- after 3 days return to normal levels of mitosis
- takes 6 weeks, maybe 2 or 3 months in humans
- shape won't be the same

19

What are kupffer cells?

- stretched across sinusoids
- resident macrophages
- trap all the particulate matter and endotoxins passing in the blood stream from the gut to cleanse it
- remove degenerate blood cells
- important part of the defence system of the body
- become activated from a small quiescent cell
- big filopodia
- happens in response to endotoxins (bacterial products of gram negative organisms in the gut) or cytokines
- goes into action by phagocytosing bactera that are covered with certain opsins
- bacteria get incorportated into lysosomes that kill the bacteria
- activated kupffer cells will release a number of agents e.g. cytokines and eicosanoids, TNF, IL-1, prostaglandins, reactive oxygen species (can damage/kill hepatocytes)

20

What are stellate cells?

- cells in the space of disse
- have long processes that wrap around the sinusoids
- large
- filled with lipid that stores vitamin A
- minor contractile function
- can control blood flow through the liver
- cells that form the reticulin framework: collagen I, IV
- (whereas in the portal tracts fibroblasts produce lots of type I collagen)
- when activated by the kupffer cells start secreting proteinases that breakdown the extracellular matrix

21

What happens when Kupffer cells are activated?

- activated Kupffer cells secrete multiple cytokines
- PDGF and TNF cause HSC (hepatic stellate cell) to proliferate and become contractile
- contraction is stimulated ET-1 and fibrogenesis by TGF-beta
- chemotaxis of activated HSC is promoted by PDGF and MCP-1
- become like myofibroblasts

22

What happens to HSCs during liver injury?

- activated and change in phenotype
- activated by kupffer cell factors
- normally compact shape, non-proliferative, cells in contact with BM

initiation of activation
- cell spreading
- cytokine receptor expression
- matrix disruption via collegenase secretion
- retinol release

- start producing type I, hard collagen (normally Type III, IV)

perpetuation of activation
- proliferation in response to mitogens (e.g. PDGF)
- enhance collagen synthesis via TGF-beta
- replacement of BM by Type I collagen, leading to further activation
- narrow the sinusoids thereby increasing vascular resistance
- portal hypertension

23

What is the end of very severe liver disease?

- cirrhosis
- maybe hepatocellular carcinoma

24

What is cirrhosis?

- liver diffusely replaced by nodules of hepatocytes separated by anastomosing sheets of fibrous tissue (septa)
- loss of normal lobular architecture
- portal tracts and central veins are irregularly spaced in the regenerative nodules or are embedded in the fibrous septa
- normal liver becomes hard, scarred
- macronodular - >3mm nodules
- micronodular - <3mm nodules
- mixed

25

What are the effects of cirrhosis?

- portal hypertension
- hepatocellular failures
- hyperestrinism - males unable to breakdown normal female hormones, abnormal oestrogen levels
- hepatocellular carcinoma (HCC)

26

What are the consequences of portal hypertension?

- splenomegaly - hyperplenism (anaemia, leukopaenia, thrombocytopaenia)
- oesophageal varices, caput medusae (serum out into peritoneal cavity)
- ascites
- veins from stomach, GIT, spleen form portal veins so if blood is not going through it causes increased pressure in these veins ( superior mesenteric, inferior mesenteric, splenic, short gastric)
- blood tries to find other pathways to get back to the heart
- varices around the oesophagus
- testicular atrophy, development of breasts in male

27

What happens as a consequence of hepatocellular failure?

- inability to excrete bilirubin causing jaundice
- reduced albumin synthesis leads to reduced intravascular osmotic pressure leading to peripheral oedema and ascites
- decreased synthesis of clotting factors – haemorrhagic tendency
- deficient ammonia metabolism – hepatic encephalopathy (coma)
- renal failure – hepatorenal syndrome

28

What is hyperestrinism? Consequences?

- due to inability to breakdown oestrogens
- testicular atrophy
- gynaecomastia
- altered hair distribution in males
- spider naevi

29

What is hepatocellular carcinoma?

- complicates 10-30% of all cirrhotics
- depending on cause of cirrhosis
- higher in hepatitis B and C, hereditary haemochromatosis, alpha-1-antitrypsin deficiency

30

What are the pathways to end stage liver disease?

- necrosis, cholestasis (back up of toxic bile acids):
1. liver failure
2. recovery
3. chronic disease --> scarring --> cirrhosis

31

What are types of liver injury?

- toxic
- metabolic (enzyme deficiencies?)
- infectious
- immunological
- cholestatic
- circulatory
- neoplastic

32

What is drug and toxin-induced liver disease?

- wide range of patterns of liver injury are observed in response to the large range of pharmaceutical and environmental chemicals
- genetic variability a critical factor influencing susceptibility to drug induced liver injury
- injury may result from
-- direct toxicity or conversion to an active metabolite/toxin – dose dependent and predictable
-- through immune or idiosyncratic mechanisms – unpredictable

33

What is toxic liver injury?

- direct toxic action of chemical agents characterised by zonal necrosis
- usually zone 3 because highest concentrations of cytochrome P450 are located in this zone
- resulting in conversion of the toxin to a reactive metabolite in high concentrations in this zone
- zone 1 can survive even if zone 3/2 die
- can be caused by very high levels of paracetamol

34

What is the hepatotoxicity Ethanol (EtOH) ?

Progression to cirrhosis:
- 10-25% of heavy drinkers
- 260gm/day x 30 years - 100%
- 160gm/day x 15 years - 25%
- 80gm/day - ? safe
- 20gm/day - some women

35

How is EtOH metabolised?

- 90% to acetaldehyde and acetate by alcohol dehydrogenase
- smaller metabolic pathway – microsomal ethanol oxidising system (MEOS) located in SER (CP450)
- accumulation of fat in the liver is seen in all chronic alcoholics
- EtOH leads to increased lipolysis (increased delivery of FFA to liver), in hepatocytes EtOH leads to increased fatty acid synthesis, decreased mitochondrial oxidation of fatty acids, increased production of TG, decreased release of lipoproteins from liver cells

36

What is the alcoholic liver disease spectrum?

- steatosis (fatty liver) – all chronic alcoholics
- steatohepatitis (alcoholic hepatitis) ~ 25%
- cirrhosis (micronodular cirrhosis) ~10%

37

What is steatohepatitis?

Characterised histologically by:
- steatosis
- zone 3 ballooning (hydropic swelling of hepatocytes) and presence of Mallory bodies
- Zone 3 spotty necrosis and inflammation (clusters of neutrophils and mononuclear cells)
- zone 3 activation of HSC with perisinusoidal collagen deposition and central perivenous fibrosis with or without obliteration of central veins
- fibrosis progressing to micronodular cirrhosis