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Flashcards in The Liver: Intro to functions Deck (34):
1

Fun facts about the liver

Largest gland and 2nd largest organ

2

What is the biliary tree?

System of ducts to transport bile out of the liver into the duodenum, specifically the common bile duct.

3

Describe the blood supply of the liver

- 75% of supply from hepatic PORTAL vein (from gut)
- 25% of supply from hepatic artery (from aorta)

- central veins of liver lobules drain into hepatic vein and back into vena cava

4

Name the primary cells of the liver, their function and the functional unit

- Hepatocytes (60%): perform most metabolic functions
- Kupffer Cells (30%): Phagocytic activity - remove damaged cells
- Others: Liver endothelial and stellate cells

Functional unit = hepatic lobule - hexagonal plates of hepatocytes around central hepatic vein - at each corner is a triad of branches of portal vein, hep artery + bile duct

5

Describe the passage of blood through the functional unit

Blood enters lob through port vein and hep artery, flows through small channels called sinusoids lined with hepatocytes. Hepatocytes remove toxic substances (eg alcohol) from blood, which exits the lobule through central vein/hepatic venule. Flow of blood is opposite direction to flow of bile. Blood enters oxygen rich (hep artery) but leaves lobule depleted of O2 (term hep venule) as hepatocytes along sinusoid use up the O2.

6

Describe the passage of bile

Bile secreted by hepatocytes -> canalinculi -> small ducts -> large ducts -> anastamose onto common bile duct -> into duodenum via Odii OR cystic duct, if cystic duct -> Gall bladder (stored)

7

How does liver's microstructure support its roles? (3)

- Massive SA for exchange
- Sophisticated separation of blood from bile
- Specific positioning of pumps to achieve specific localisation of materials

8

What do Kupffer cells do?

Kupffer cells - Blood flowing from intestines to liver always picks up bacteria. Kupffer cells cleanse blood as it passes through sinus.

9

What is bile made of?

What are the functions of bile? (3)

Complex fluid = water, electrolytes + mix organic mols. Organic mols = bile acids, cholesterol, bilirubin and phospholipids. Adults prod 400-800ml/day.
- Essential for fat digestion/absorption via emulsification.

- Bile + pancreatic juice neutralises acidic chyme in duodenum, aids digestive enzymes too.

- Also important in elimination of waste products from blood eg. bilirubin + cholesterol.

10

How is bile formed? (2)

Two stages:
1) By hepatocytes into canaliculi-> bile salts, chol, organic subs
2) By epithelial cells lining bile ducts -> water, Na+ and HCO3- secretion (stimulated by SECRETIN)

11

What are the types and causes (4) of gallstones?

Gallstones = precipitated cholesterol, form anywhere in biliary tract
Two types = cholesterol (80%) + pigment (20%)
Caused by:
- High fat diet (inc synth of cholesterol)
- Inflammation of GB epithelium (XS absorption of H2O + bile salts -> cholesterol concentrates)
- More common in women (XS oestrogen/pregnancy/HRT)
- Obesity

12

What are bile acids?

Made in hepatocytes. Derived from cholesterol - cholic and chenodeoxycholic acids. These are conjugated with AA (glycine/taurine) to make it more soluble. Secreted into canaliculi and the intestinal bacteria convert into secondary bile acids (Deoxycholic and lithocholic acid).

13

Describe the enterohepatic circulation of bile acids

95% of bile acids are reabsorbed back into blood from terminal ileum, 5% lost in faeces.
- Bile acids from GB/liver -> duodenum -> terminal ileum -> hepatic portal vein -> liver -> hepatocytes -> Re-secreted in new bile

14

What is bilirubin?

Yellow pigment formed from breakdown of Hb, useless and toxic but made in large quantities so must be eliminated, done so via liver metabolism and excretion into bile.

15

Discuss the path of bilirubin from formation to excretion

- Dead RBCs digested by macrophages
- Fe recycled, globin chains catabolised
- Haeme (porphyrin) converted to free BILIRUBIN
- Released into plasma - bound to albumin
- Free bilirubin absorbed by hepatocytes - conjugated with glucoronic acid
- Major metabolite in faeces (stercobilin) - brown colour
- Urine - yellow urobilin and urobilinogen

Not enough excretion = Jaundice
Too much excretion = hepatitis

16

Describe jaundice and its pathophysiology

Jaundice = XS free/conjugated bilirubin accumulation in ECF -> yellow discolouration of skin/sclera/mucous membranes

- Pre-hepatic/haemolytic - Inc haemolysis -> XS unconj bilirubin, common in neonates.

- Hepatic - prob with hepatocytes, eg from cirrhosis, drugs, virus(Hep) -> XS Un/conj bilirubin. Gilbert's syndrome.

- Post-hepatic (obstructive) - XS conj bilirubin, obstructs passage into duodenum so enters circulation + into urine (v dark). Eg. gallstones, carcinoma of panc/bile ducts.

17

What is Gilbert's syndrome?

Congenital disorder where patients have decreased enzyme that conjugates bilirubin with glucoronic acid leading to inc in unconj bilirubin.

18

What is the Glucose Buffer Solution an what does it involve (Carb metab)? (4)

In terms of carbohydrate metabolism - critical for all animals to maintain [glucose] in blood within narrow range.

1. Glycogenesis (G6P->Glycogen) (insulin)
- Liver stores 80g of glycogen when XS glucose after meal

2. Glycogenolysis (Glycogen->G6P) (Glucagon + adrenaline)
- Decrease in blood glucose so liver returns glucose to blood

3. Glycolysis (G6P->Pyruvic acid)
- Releases energy to form ATP/NADH (anaerobic respiration)

4. Gluconeogenesis (Pyruvic acid->G6P)
- Glucose made from TGs/AAs/Lactate when liver glycogen reserve exhausted

19

Describe fat metabolism in the liver (4)

1. TGs oxidised in hepatocytes, often dietary. Enter TCA cycle to release energy and converted to ketone bodies.

2. Lipoproteins transported to blood made in liver (chylomicrons, VLDL, IDL, LDL & HDL).

3. XS Carbs/proteins converted to FA/TGs stored in adipose

4. Synthesis of cholesterol & phospholipids, 80% cholesterol -> bile salts, rest transported with lipoproteins - used by cells to form membranes, steroid hormones etc.

20

Describe protein metabolism in the liver

- Deamination/transamination of AAs -> glucose + lipids

- Synthesis of non-essential AAs

- Synthesis of nearly all plasma proteins (90%) eg. albumin (fall in chronic liver disease)

- Synthesis of urea which removes ammonia from body

21

What substances are toxic to the body that the liver must get rid of?

- Bilirubin
- Ammonia
- Hormones eg. all steroid hormones (androgens, oestrogens, cortisol, aldosterone, throxine) are catabolised in the liver
- Drugs + exogenous toxins (aspirin, paracetamol, ethanol)

22

What are the phases of biotransformation/detox for drugs/hormones?

Not all drugs use both phases

Phase 1 (primarily oxidation/reduction)
- Occurs in SER, catalysed by cytochrome enzymes -> makes substrate into POLAR compound

Phase 2 (conjugation) - trueDETOXIFICATION
- Make it water soluble by conjugating with eg. glucuronyl, acetyl, methyl, glycyl, sulphate, glutamate...

Phase 3 - elimination into blood/bile via ATPase pumps

23

How is paracetamol detoxified?

3 pathways:
- Glucoronidation (45-55%)

- Sulfation (20-30%)

- N-Hydroxylation & dehydration -> interm product NAPQI is TOXIC -> detoxified by GLUTATHIONE (GSH) conjugation (

24

What happens in paracetamol overdose and what is the treatment?

Paracetamol has a narrow therapeutic index and accidental/deliberate overdose is common. But the liver has limited capacity of these enzymes and stores of glutathione (needed to detoxify).

In OD: The liver enzymes are saturated and glutathione stores rapidly depleted -> liver necrosis + damage to kidney by toxic metabolites.

Treatment: infusion of N-acetyl cysteine (precursor to glutathione).

25

What is the paracetamol 2 phase effect of overdose?

Damage is not immediate and patients can wake up feeling fine, asymptomatic for 24 hours and don't seek help until it's too late for effective treatment.

26

How is ethanol metabolised?

Alcohol cannot be stored so needs to be oxidised in the liver where enzymes are found to initiate the process and then enters normal metabolic pathways + metabolised like fat.

1. Ethanol -> acetaldehyde -> produces XS NADH, which is...
- used in rxn: Pyruvic acid -> LACTIC ACID -> acidosis!
- reducing agent in LIPOGENESIS -> overweight!
- ETC to synth ATP - inhibits normal ox of fats in TCA, fats accumulate -> ketone bodies OR lipids into blood -> heart attack!

XS Acetaldehyde = TOXIC to liver -> HEPATITIS + CIRRHOSIS!

27

What happens to the excess acetaldehyde?

Converted to acetate by ALDH2 -> released harmlessly to circulation

* 50% asians have deficiency in ALDH2 -> Alcohol flush reaction

28

What problems can be caused by alcohol in regards to the liver? (4)

- Fatty liver
- Alcoholic hepatitis
- Alcoholic cirrhosis -> lead to gynecomastia
- Reduced regenerative ability

29

Briefly discuss liver regeneration and advantage of it

Adult hepatocytes are long lived and normally don't undergo cell division. After partial hepatectomy or in response to toxic injury, they rapidly proliferate - this stops once the original MASS of liver is established.

Allows for use of partial livers from living donors for transplantation + does not involve stem cells or progenitor cells but mature functioning liver cells.

30

What are the pathways involved in liver regeneration?

- Growth factor mediated pathway -> most important HGF (hepatocyte GF) and TGFa (transforming GF alpha).

- Cytokine signalling pathway using IL-6 via TNFa binding to its receptor on Kupffer cells

31

What are important blood clotting factors?

Vitamin K is essential for formation of:
- Prothrombin
- Factors II, VII, IX, X

Fibrinogen also important

32

What does the liver store?

- Stellates store fat-soluble Vit D, E, K, A - Liver dysfunction -> fat malabsorption -> vitamin deficiency

- VitB12 (deficiency = pernicious anaemia)

- folate, required in pregnancy

- Iron as ferritin (blood-Fe buffer)

33

What are Liver Function Tests used for? (4)

- Screen for liver infections eg. hepatitis
- Monitor prog of a disease + treatment eg. alcoholic/viral hep
- Measure severity of disease, eg. cirrhosis
- Monitor side effects of meds

34

What are the most common LFTs?

- Alanine aminotransferase (ALT) - hepatitis / alcohol
- Aspartate aminotransferase (AST) - hepatitis / alcohol

- Alkaline phosphatase (ALP) - obstructs bile flow
- Gamma glutamyl transferase (GGT) - obstructs bile flow
- Bilirubin - jaundice
- Albumin - decreased in chronic liver disease/malnutrition
- Clotting studies (prothrombin time) - low factors = prothrombin time longer