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Gastro nutrition > Liver > Flashcards

Liver Flashcards

1
Q

Outline the functions of the liver

A
  • Metabolism and synthesis
    ◦ Carbohydrate metabolism -
    ‣ glycogen metabolism - up to 100g stored, important in fasting and early starvation response in glycogenlysis but also in high BSL post meal insulin stimulates storage of glucose as glycogen
    ‣ gluconeogenesis - when plasma glucose is low glucose is synthesised from non carbohydrate precursers
    ‣ glycolysis
    ◦ Protein and lipoprotein metabolism -
    ‣ Protein synthesis (albumin, coagulation proteins, carrier proteins)
    ‣ amino acid synthesis and metabolism - deaminiation and transamination allows interchange of non essential amino acids or use of amino acids as a substrate for gluconeogenesis. Ketoacids can also be used for energy
    ‣ protein turnover/breakdown - urea formation with deamination waste
    ◦ Lipid metabolism - energy extraction from beta oxidation of fatty acids, synthesis of cholesterol and phospholipids, production of ketoacids
    ◦ Biotransformation of drugs - phase 1 and 2 reactions
  • Bile production
  • Excretion
    ◦ Bilirubin
    ◦ Urea - protein/amino acid metabolism waste product ammonia removed as urea (Krebs-Henseleit)
  • Storage
    ◦ Vitamins A, D, E, K
    ◦ Iron
    ◦ Copper
    ◦ Glycogen
  • Immune functions
    ◦ Kuppfer cells -
    ‣ phagocytic action of Kuppfer cells especially to ingested bacteria, viruses and parasites
    ‣ Initiation of inflammatory response - unlike other macrophages Kuppfer cells can initiate a pro inflammatory response via cytokine release
    ‣ Filtration of bacteria and degredation of endotoxins
    ◦ Complement synthesis, CRP
  • Haematological functions
    ◦ Haematopoesis in the foetus, continues to produce erythropoetin 10% of total in adults
    ◦ Clotting factor synthesis - fibrinogen, prothrombin, V, VII< IX,X , XI, antithrombin 3, protein C, protein S
    ◦ Thrombopoetin production
    ◦ Blood resevoir - 10% (500mls) normally in the liver but can be up to 1500mLs or 150mls
  • Hormonal/Endocrine
    ◦ Production - Angiotensinogen, Thrombopoetin, Hepcidin, Insulin like growth factor
    ◦ Transport - including production of hormone binding proteins e.g. thyroxine and sex hormone binding proteins
    ◦ Activation - thyroxine is converted to T3 or inactivation of T3 in the liver; Vitamin D intiial activation stages in the liver
    ◦ Inactivation - aldosterone, ADH, oestrogen, half of the insulin before it is even released into the systemic circulation
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2
Q

Outline the metabolic functinos of the liver

A
  • Metabolism and synthesis
    ◦ Carbohydrate metabolism -
    ‣ glycogen metabolism - up to 100g stored, important in fasting and early starvation response in glycogenlysis but also in high BSL post meal insulin stimulates storage of glucose as glycogen
    ‣ gluconeogenesis - when plasma glucose is low glucose is synthesised from non carbohydrate precursers
    ‣ glycolysis
    ◦ Protein and lipoprotein metabolism -
    ‣ Protein synthesis (albumin, coagulation proteins, carrier proteins)
    ‣ amino acid synthesis and metabolism - deaminiation and transamination allows interchange of non essential amino acids or use of amino acids as a substrate for gluconeogenesis. Ketoacids can also be used for energy
    ‣ protein turnover/breakdown - urea formation with deamination waste
    ◦ Lipid metabolism - energy extraction from beta oxidation of fatty acids, synthesis of cholesterol and phospholipids, production of ketoacids
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3
Q

Outline the haematological functions of the liver

A
  • Haematological functions
    ◦ Haematopoesis in the foetus, continues to produce erythropoetin 10% of total in adults
    ◦ Clotting factor synthesis - fibrinogen, prothrombin, V, VII< IX,X , XI, antithrombin 3, protein C, protein S
    ◦ Thrombopoetin production
    ◦ Blood resevoir - 10% (500mls) normally in the liver but can be up to 1500mLs or 150mls
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4
Q

OUtline the immunological functions of the liver

A
  • Immune functions
    ◦ Kuppfer cells -
    ‣ phagocytic action of Kuppfer cells especially to ingested bacteria, viruses and parasites
    ‣ Initiation of inflammatory response - unlike other macrophages Kuppfer cells can initiate a pro inflammatory response via cytokine release
    ‣ Filtration of bacteria and degredation of endotoxins
    ◦ Complement synthesis, CRP
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5
Q

Outline the hormonal functions of the liver

A
  • Hormonal/Endocrine
    ◦ Production - Angiotensinogen, Thrombopoetin, Hepcidin, Insulin like growth factor
    ◦ Transport - including production of hormone binding proteins e.g. thyroxine and sex hormone binding proteins
    ◦ Activation - thyroxine is converted to T3 or inactivation of T3 in the liver; Vitamin D intiial activation stages in the liver
    ◦ Inactivation - aldosterone, ADH, oestrogen, half of the insulin before it is even released into the systemic circulation
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6
Q

Outline the excretory functions of the liver

A

◦ Biotransformation of drugs - phase 1 and 2 reactions
* Bile production
* Excretion
◦ Bilirubin
◦ Urea - protein/amino acid metabolism waste product ammonia removed as urea (Krebs-Henseleit)
* Storage
◦ Vitamins A, D, E, K
◦ Iron
◦ Copper
◦ Glycogen

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7
Q

Outline carbohydrate metabolism in the liver

A

‣ glycogen metabolism - up to 100g stored, important in fasting and early starvation response in glycogenlysis but also in high BSL post meal insulin stimulates storage of glucose as glycogen
‣ gluconeogenesis - when plasma glucose is low glucose is synthesised from non carbohydrate precursers
‣ glycolysis

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8
Q

OUtline protein metabolism in the liver

A

‣ Protein synthesis (albumin, coagulation proteins, carrier proteins)
‣ amino acid synthesis and metabolism - deaminiation and transamination allows interchange of non essential amino acids or use of amino acids as a substrate for gluconeogenesis. Ketoacids can also be used for energy
‣ protein turnover/breakdown - urea formation with deamination waste

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9
Q

Outline lipid metabolism in the liver

A

energy extraction from beta oxidation of fatty acids, synthesis of cholesterol and phospholipids, production of ketoacids

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10
Q

How is nitrogenous waste excreted?

A

Urea through the Krebs cycle

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11
Q

What storage functions does the liver have

A

◦ Vitamins A, D, E, K
◦ Iron
◦ Copper
◦ Glycogen
Blood 500mls

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12
Q

What is the first enzyme in glucolysis

A

Glucokinase

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13
Q

What intermediary in glycolysis is glycogen made from

A

Glucose 6 phosphate

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14
Q

What is lactate formed from

A

pyruvate

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15
Q

What converts pyruvate to Acetyl CoA

A

Pyruvate dehydrogenase
Catalysed by insulin

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16
Q

What can be made from Acetyl CoA

A
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17
Q

How is glycogen made?

A
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18
Q

WHat hormones are produced int he liver

A

Angiotensinogen, Thrombopoetin, Hepcidin, Insulin like growth factor

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19
Q

What transport proteins are made in the liver

A

Albumin
Alpha 1 globulin
Thyroid binding globulin
Sex hormone binding proteins

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20
Q

What hormones are activated in the liver

A

◦ Activation - thyroxine is converted to T3 or inactivation of T3 in the liver; Vitamin D intiial activation stages in the liver

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21
Q

WHat hormones are inactivated in the liver

A

aldosterone, ADH, oestrogen, half of the insulin before it is even released into the systemic circulation

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22
Q

What % of insulin reaches systemic circulation

A

50%
The rest is metabolised in the liver

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23
Q

How much glycogen is stored in the liver

A

100g

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24
Q

What is glycogen

A

‣ Polymer fo glucose residues linked by alpha - 1, 4 - glycosidic bonds

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25
Q

Is the absorption of carbohydrates energy dependent?

A

Yes

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26
Q

How does glucose enter liver cells?

A

◦ Glucose absorption into hepatic cells - non energy dependent, concentration gradient driven, non insulin regulated - via GLUT2 transporter

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27
Q

How is glucose so avidly absorbed by the liver?

A

rapidly phosphorylated (Hexokinase) into glucose 6 phosphate (insulin upregulated) trapping in liver –> biotransformation

This also maintains a constant concentration gradient

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28
Q

What is the primary source of energy for the hepatocyte

A

Fat
Carbohydrates are processed for the benefit of the rest of the body

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29
Q

What role does the liver play in glucose control?

A

‣ Post prandial glycogen synthesis
‣ Post prandial fatty acid synthesis and TG synthesis (for storage of energy - <5% liver mass) from glucose

	‣ Fasting glycogenolysis - main mechanism pre meals of maintaining BSL
		* Other tissues store glucose as glycogen but can only use it themselves as they do not possess glucose 6 phosphatase to recreate glucose for systemic release 
	‣ Gluconeogenesis
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30
Q

How is the liver different to other tissues in its storage of glycogen?

A
  • Other tissues store glucose as glycogen but can only use it themselves as they do not possess glucose 6 phosphatase to recreate glucose for systemic release
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31
Q

What is the enzyme that breaks down glycogen?

A
  • Other tissues store glucose as glycogen but can only use it themselves as they do not possess glucose 6 phosphatase to recreate glucose for systemic release
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32
Q

Glycogen is mainly formed from

A

◦ Lactate
◦ Lesser extent
‣ Pyruvate
‣ Glycerol
‣ Gluconeogenic amino acids
◦ Rarely
‣ Fructose - via triode phosphates
‣ Glucose - 10% of dietary glucose converted to glycogen

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33
Q

Where anatomically in the liver is gluconeogenesis done?

A

◦ Glycogenlysis - phosphorylase converts glycogen to glucose-6-phosphate
‣ Theorised that perivenous hepatocytes are primarily responsible for glycolysis, periportal cells for gluconeogenesis

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34
Q

Where anatomically in the liver is glycogenlysis done

A

◦ Glycogenlysis - phosphorylase converts glycogen to glucose-6-phosphate
‣ Theorised that perivenous hepatocytes are primarily responsible for glycolysis, periportal cells for gluconeogenesis

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35
Q

What can you make glucose out of?

A

◦ Gluconeogenesis - newly synthesised glucose from lactate, pyruvate, amino acids (alanine, glutamine from muscles), and glycerol (lypolysis of fat stores)

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36
Q

What amino acid from muscle can be made into glucose in the liver?

A

◦ Gluconeogenesis - newly synthesised glucose from lactate, pyruvate, amino acids (alanine, glutamine from muscles), and glycerol (lypolysis of fat stores)

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37
Q

What two hormones faciliate gluconeogenesis?

A

‣ Facilitated by glucagon
* Enhances alanine transport across hepatocytes membrane
* Enhances pyruvate transport across mitochondrial membrane
‣ Cortisol
* Increased peripheral proteolysis —> increased plasma concentrations of amino acids —> promoting gluconeogenesis

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38
Q

How does glucagon cause gluconeogeneis?

A

‣ Facilitated by glucagon
* Enhances alanine transport across hepatocytes membrane
* Enhances pyruvate transport across mitochondrial membrane
‣ Cortisol
* Increased peripheral proteolysis —> increased plasma concentrations of amino acids —> promoting gluconeogenesis

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39
Q

How does cortisol affect BSL

A

‣ Facilitated by glucagon
* Enhances alanine transport across hepatocytes membrane
* Enhances pyruvate transport across mitochondrial membrane
‣ Cortisol
* Increased peripheral proteolysis —> increased plasma concentrations of amino acids —> promoting gluconeogenesis

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40
Q

Define glycolysis

A

breakdown of glucose to carbon dioxide and water with production of energy

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41
Q

What is the Emden Meyehoff pathway?

A

◦ Cleavage of glucose to trioses —> pyruvic acid + lactic acid (Embden-Meyerhof pathway)

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42
Q

How is pyruvate converted to Acetic acid?

A

‣ Pyruvic acid —> citric acid cycle by conversion to acetic acid via loss of one molecule of CO2

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43
Q

Citric acid cycle generates how much ATP per acetic acid>

A

‣ Citric acid cycle generates 12 molecules of ATP for every molecule of acetic acid

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44
Q

How many molecules of ATP are produced from aerobic breakdown of glucose

A

‣ 38 molecules of ATP

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45
Q

What step of glucose production can be diverted to fat production

A

Acetyl CoA can be used for TG and lipogesis

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46
Q

Where do amino acids and fat enter the energy producing pathway

A

Pyruvate

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47
Q

With is the hexose monophosphate shunt?

A

◦ Oxidation and decarboxylation of glucose—> pentose (hexose monophosphate shunt)
‣ Pentose phosphate pathway involves production of NADPH (nicotinamide adenine dinucleotide phosphate)
‣ 2 NADPHmolecules and ribose-5-phosphate are produced from 1 glucose molecule
‣ NADPH required for microsomal and mitochondrial hydroxylation fo steroid hormones and bio transformation of drugs

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48
Q

What is produced from the hexose monophosphate shunt?

A

NADPH required for hydroxylation and biotransformation of drugs

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49
Q

Net energy gain from glycolysis only

A

3 molecules

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50
Q

How much energy is stored as fat in the liver?

A

600kcal

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51
Q

Fat contains how much energy pre gram

A

7kcal per gram

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52
Q

Glycogen has what kcal per gram

A

4 kcal per gram
Then stored in a hydrated form making it less energy efficient than fat for storage

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53
Q

Fatty acids water soluble? How do they move in the bloodstream? Half life?

A

‣ Not especially water soluble, bound to albumin, short half life <5 minutes

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54
Q

Why are free fatty acids in large volumes not good?

A

producing oxidative stress and interfere with biosynthesis in endoplasmic reticulum of cells –> therefore not the ideal substrate to transport in large quantities

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55
Q

Why despite the side effects of free fatty acids are they allowed to circulate?

A

Immediately usable metabolic fuel

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56
Q

How is fat transported other than as FFA?

A

◦ Packaged as triglycerides to allow transport - 3 FFA and a glycerol backbone, similar energy density to FFA
‣ Insoluble, packaged in VLDLs and chylomicrons
‣ Endothelial lipases release FFA locally

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57
Q

How are free fatty acids mobilised from TG?

A

◦ Packaged as triglycerides to allow transport - 3 FFA and a glycerol backbone, similar energy density to FFA
‣ Insoluble, packaged in VLDLs and chylomicrons
‣ Endothelial lipases release FFA locally

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58
Q

How many FFA are in a TG?

A

◦ Packaged as triglycerides to allow transport - 3 FFA and a glycerol backbone, similar energy density to FFA
‣ Insoluble, packaged in VLDLs and chylomicrons
‣ Endothelial lipases release FFA locally

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59
Q

How are TG transported?

A

◦ Packaged as triglycerides to allow transport - 3 FFA and a glycerol backbone, similar energy density to FFA
‣ Insoluble, packaged in VLDLs and chylomicrons
‣ Endothelial lipases release FFA locally

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60
Q

3 main roles of lipid metabolism in the liver?

A

Lipid breakdown for energy
Lipid synthesis for fat storage
Lipid processing

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61
Q

What is the preferential fuel for the liver?

A

FFA i.e. fat

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62
Q

How are FFA converted to energy?

A

‣ Beta oxidation
* Free fatty acid conversion to acetyl CoA occurs rapidly in the liver (hepatocytes mitochondria)
* Excess acetyl CoA is converted to ace to acetic acid - highly soluble and transportable to other tissues —> converted back to acetyl CoA peripherally for energy
‣ Partial oxidation of fatty acids to ketone bodies which is alternative ot TG production providing metabolic fuel between meals

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63
Q

What is beta oxidation?

A

‣ Beta oxidation
* Free fatty acid conversion to acetyl CoA occurs rapidly in the liver (hepatocytes mitochondria)
* Excess acetyl CoA is converted to ace to acetic acid - highly soluble and transportable to other tissues —> converted back to acetyl CoA peripherally for energy
‣ Partial oxidation of fatty acids to ketone bodies which is alternative ot TG production providing metabolic fuel between meals

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64
Q

What are ketone bodies

A

‣ Partial oxidation of fatty acids to ketone bodies which is alternative ot TG production providing metabolic fuel between meals

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65
Q

What is the process that forms TG from FFA called?

A

Esterification

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66
Q

Excess glucose is converted into fat how?

A

‣ Synthesis of fatty acids from excess glucose —> converted to triacylglycerol and very low density lipoproteins (VLDL)
* Triglyceride storage in fat deposits is the most efficient method of energy storage
◦ Either in the liver itself (can lead to pathological changes) or transported as VLDL to peripheral sites

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67
Q

Where does cholesterol come from?

A
  • Origin - from diet, also synthesised in the liver, adrenal cortex and skin from Acetyl CoA
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68
Q

Where can cholesterol by synthesised in the body?

A
  • Origin - from diet, also synthesised in the liver, adrenal cortex and skin from Acetyl CoA
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69
Q

What is the fate of cholesterol?

A

◦ Hydroxymethylglutaryl CoA
◦ 80% of cholesterol synthesised in the liver is converted to bile
◦ Remainder of cholesterol is
‣ Transported in blood by lipoproteins —>used by cells to form membranes and intracellular structures
‣ Precursor to steroid hormones

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70
Q

What are the uses of cholesterol?

A

◦ Hydroxymethylglutaryl CoA
◦ 80% of cholesterol synthesised in the liver is converted to bile
◦ Remainder of cholesterol is
‣ Transported in blood by lipoproteins —>used by cells to form membranes and intracellular structures
‣ Precursor to steroid hormones

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71
Q

What are synthesised in the liver that allow transport of fat

A

Apoliproteins

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72
Q

How is lipid transported in the blood stream

A

‣ Apoliproteins synthesised in the liver involved in packaging cholesterol and TG as low density lipoprotein, VLDL and HDL
* Phospholipids transported by lipoproteins —> used to form cell membranes and intracellular structures

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73
Q

What enzyme breaks down fat in the periphery

A

‣ Lipoprotein fragments return to liver post peripheral degredation of VLDL by lipoprotein lipases at adipocytes and tissue surfaces where they are absorbed by endocytosis then either
* Hydrolysed into FFA and released unchanged or as ketones
* Hydrolysed into free fatty acids and burned by hepatocytes as metabolic fuel sources
* Hepatic fat storage as TG

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74
Q

What is the fate of fat peripherally

A

‣ Lipoprotein fragments return to liver post peripheral degredation of VLDL by lipoprotein lipases at adipocytes and tissue surfaces where they are absorbed by endocytosis then either
* Hydrolysed into FFA and released unchanged or as ketones
* Hydrolysed into free fatty acids and burned by hepatocytes as metabolic fuel sources
* Hepatic fat storage as TG

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75
Q

What is the fate of TG after absorption from the diet

A
  • Triglycerides absorbed from the diet
    ◦ 50% hydrolysed to glycerol and fatty acids
    ◦ 40% partially hydrolysed to monoglycerides
  • Fate after absorption
    ◦ Short chain fatty acids (<12 carbon atoms) transported directly to the liver via portal vein without re-esterification
    ◦ Longer chain fatty acids are re-esteritifed after absorption, then covered with phospholipid and protein layers to form chylomicrons
    ‣ Lipoprotein lipases hydrolyse the chylomicrons —>free fatty acids —> adipocyte storeage or metabolised within body tissues for energy
    ◦ Absorption into the liver via receptor mediated endocytosis
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76
Q

What differentiates whether a fat is resterified post absorption

A
  • Triglycerides absorbed from the diet
    ◦ 50% hydrolysed to glycerol and fatty acids
    ◦ 40% partially hydrolysed to monoglycerides
  • Fate after absorption
    ◦ Short chain fatty acids (<12 carbon atoms) transported directly to the liver via portal vein without re-esterification
    ◦ Longer chain fatty acids are re-esteritifed after absorption, then covered with phospholipid and protein layers to form chylomicrons
    ‣ Lipoprotein lipases hydrolyse the chylomicrons —>free fatty acids —> adipocyte storeage or metabolised within body tissues for energy
    ◦ Absorption into the liver via receptor mediated endocytosis
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77
Q

What breaks down chylomicrons?

A
  • Triglycerides absorbed from the diet
    ◦ 50% hydrolysed to glycerol and fatty acids
    ◦ 40% partially hydrolysed to monoglycerides
  • Fate after absorption
    ◦ Short chain fatty acids (<12 carbon atoms) transported directly to the liver via portal vein without re-esterification
    ◦ Longer chain fatty acids are re-esteritifed after absorption, then covered with phospholipid and protein layers to form chylomicrons
    ‣ Lipoprotein lipases hydrolyse the chylomicrons —>free fatty acids —> adipocyte storeage or metabolised within body tissues for energy
    ◦ Absorption into the liver via receptor mediated endocytosis
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78
Q

How are chylomicrons absorbed in the liver?

A

◦ Absorption into the liver via receptor mediated endocytosis

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79
Q

Summarise the role of the liver in lipid metabolism

A
  • Lipid breakdown for energy extraction
    ◦ Beta oxidation - free fatty acid conversion to acetyl CoA which proceed through the Kreb’s cycle; or alternatively stored as acetic acid to transport energy to peripheral tissues to undergo conversion back to Acetyl CoA for energy utilisation
  • Lipid synthesis
    ◦ Synthesis of fatty acids from excess glucose —> conversion to triglycerides integrated into VLDL for peripheral fat storage
    ◦ Cholesterol synthesis - either cholesterol ingested or synthesised in the liver or adrenal cortex from acetyl CoA is converted to bile, used as a precursor for hormones or transported to peripheral tissues in lipoproteins for use in cell membranes or intracellular structure
  • Lipid processing
    ◦ Apoliprotein synthesis to facilitate transport and redistribution of body lipid
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80
Q

What are the roles of the liver in protein metabolism

A

Catrabolism
Amino acid metabolism and storage
Urea synthesis

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81
Q

Where does ammonia come from in the body?>

A

Amines
Nucleic acids (proteins)
Amino acids
Glutamate

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82
Q

What is glutamine

A

A product from ammonia

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83
Q

Draw the urea cycle

A
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84
Q

What is the overall reaction of the urea cycle

A
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85
Q

Show how ammonia becomes urea

A
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86
Q

What are amino acids removed from the liver for?

A

Gluconeogenesis
Protein synthesis
Interconversion of amino acids for re-release for utilisation by peripheral tissues
Breaking down for removal of nitrogen as urea via deamination or oxidation into metabolic fuel and ammonia

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87
Q

How do proteins and amino acids enter liver cells?

A

◦ endocytosis of large circulating proteins into Kupffer cells (macrophages of reticuloendothelial system) –> degraded into amino acids and peptides by lyososomes and re-released
◦ Hepatocyte uptake of released amino acids and direct uptake of some proteins e.g. lipoproteins via receptor mediated endocytosis

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88
Q

What proteins are made by the liver?

A

Albumin
Globulins including complement
Clottign factors

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89
Q

Albumin made per day

A

120-300mg/kg per day

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90
Q

What regulates albumin production

A

◦ Regulated by nutritional status, endocrine balance, plasma oncotic pressure

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91
Q

What is the half life of albumin

A

20 days
Poor marker of acute processes

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92
Q

What are 3 examples of alpha globulins

A

‣ Haptoglobin
‣ Alpha 1 anti trypsin - serine protease inhibitor protecting the body from damaging enzymes released by activated inflammatory cells e.g. neutrophil elastase
‣ Alpha 2 macroglobulin
‣ Antithrombin 3
‣ Ceruloplasmin transporting copper
‣ Thyroxin binding globulin

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93
Q

What are 3 examples of beta globulin

A

transferrin binding iron in its ferric form,sex hormone binding globulin binding androgen ad oestrogen

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94
Q

What protein transports basic drugs?

A

Alpha 1 acid glycoprotein

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95
Q

What protein transport acidic drugs

A

Albumin

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96
Q

What clotting factors are produced by the liver

A

◦ Vitamin K dependent clotting factors - 2, 7, 9,10 - vitamin K cofactor catalysed gamma carboxylation required for synthesis
◦ Vitamin K independent factors - 5, 8, 11, 12, 13
◦ Fibrinogen
◦ Protein C, S antithrombin 3

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97
Q

When an amino acid is degraded to a fuel substrate what i this called

A

Oxoacid carbon skeleton

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98
Q

What is the remannt post urea removal used for in amino acid degredation

A

Energy in citric acid cycle
Transformed into another maino acid
Substrate for gluconeogenesis

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99
Q

Which amino acids are able to directly produce energy post deamination?

A

glutamate oxidation to alpha ketoglutarate whcih directly enters citric acid cycle

glycine oxidation to glyoxylate

serine deaminiation to pyruvate

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100
Q

When oxidative deamination is not possible what other process may occur in degredation of an amino acid?

A

TransaminationD

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101
Q

Describe when transamination is perofrmed

A

When no dedicated deamination to usable substrate amino group transfered to a keto acid leaving behind an oxoacid and creating a new amino acid that is amenable to deaminiation (usually glutamate)

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102
Q

What are keto acids used for?

A

‣ Keto acids can be transformed into non essential amino acids by transaminaation taking amino groups from one amino acid transferring it to a keto acid to form anew amino acid

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103
Q

Transamination producets include

A

‣ Producing acetyl CoA, oxoglutarate, succinyl COA, oxaloacetate and fumurate —> all which enter the citric acid cycle
‣ This gets rids of lots of unwanted amino acids, but generates lots of ammonia, and ammonium

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104
Q

Where are amino acids metabolised

A
  • Amino acid path
    ◦ Arginine,histidine, lysine, methionine, threonine, tryptophan, phenylalanine degraded in the liver primarily
    ◦ Aspartic acid, glutamic acid, glycine, proline, alanine metabolised in BOTH hepatic and muscle tissue
  • Oxidative deamination of amino acids that are no longer required liberating energy —> produces urea
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105
Q

Creatinine synthesis is done where? How?

A
  • Syntheised in the liver from methionine, glycine and arginine
  • Muscles phosphorylation creating to form phosphocreatine —> backup energy store for ATP production
  • Creatinine is formed from phosphocreatine and is excreted at a relatively constant rate
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106
Q

Where does creatinine come from?

A
  • Syntheised in the liver from methionine, glycine and arginine
  • Muscles phosphorylation creating to form phosphocreatine —> backup energy store for ATP production
  • Creatinine is formed from phosphocreatine and is excreted at a relatively constant rate
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107
Q

Why is creatinine released from muscle cells

A
  • Syntheised in the liver from methionine, glycine and arginine
  • Muscles phosphorylation creating to form phosphocreatine —> backup energy store for ATP production
  • Creatinine is formed from phosphocreatine and is excreted at a relatively constant rate
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108
Q

How does the liver function in the immune system?

A
  • Filter for bacterial and other antigens from the GIT via the portal system
    ◦ Kupffer cells (macrophages) attached tot eh endothelium in the liver phagocytoses substances mediating infection, inflammation e.g.bacteria, viruses, endotoxins, immune complexes, denatured albumin, thrombin, fibrin-fibrinogen complexes
    ◦ Antigens degraded without antibodies as little lymphoid tissue - prevents adverse immune reactions as antigens never reach antibody producing sites
  • Kupffer cells secrete interleukins, tumour necrosis factor, collagenases, lysosomal hydrolases
    ◦ This can be prompted by endotoxin exposure
  • Plasma proteins such as complement are produced in the liver
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109
Q

What is the in situ macrophage of the liver

A

Kupffer cells

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110
Q

What is the function of Kupffer cells?

A
  • Filter for bacterial and other antigens from the GIT via the portal system
    ◦ Kupffer cells (macrophages) attached tot eh endothelium in the liver phagocytoses substances mediating infection, inflammation e.g.bacteria, viruses, endotoxins, immune complexes, denatured albumin, thrombin, fibrin-fibrinogen complexes
    ◦ Antigens degraded without antibodies as little lymphoid tissue - prevents adverse immune reactions as antigens never reach antibody producing sites
  • Kupffer cells secrete interleukins, tumour necrosis factor, collagenases, lysosomal hydrolases
    ◦ This can be prompted by endotoxin exposure
  • Plasma proteins such as complement are produced in the liver
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111
Q

What is the reticuloendothelial system composed of

A

Tissue macrophages and monocytes distributed in areas of high blood vessel permeability allow for significant filtering of blood to occur

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112
Q

Give examples of tissue macrophages

A
  • Tissue macrophages in this system include
    ◦ Kuppfer cells lining hepatic sinusoids
    ◦ Macrophages lining sinusoids of the bone marrow and spleen
    ◦ Pulmonary alveolar macrophages
    ◦ Macrophages in lymph nodes
    ◦ Microglial cells in CNS
    ◦ Osteoclasts in bone
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113
Q

What is the function of the reticuloendothelial system

A

◦ Antigen prcessing and presentation via Class 2 MHC proteins
◦ Phagocytosis of bacteria, cellular debris
◦ Removal of bacteria, old RBC, other debri
◦ Secretions of cytokines

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114
Q

What storage function does the liver have

A
  • Glycogen
  • Triglycerides
  • Vitamins A, D E, K, riboflavin, nicotinamide, pyridoxine, folic acid, B12
    ◦ Vitamin D storage sufficient for 4 months
    ◦ Vitamin A storage for 10 months
    ◦ B12 for 1 year
  • Iron - excess iron take up with apoferritin to form ferritin
  • Copper
  • Blood
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115
Q

What vitamins in particular are stored in the liver

A
  • Glycogen
  • Triglycerides
  • Vitamins A, D E, K, riboflavin, nicotinamide, pyridoxine, folic acid, B12
    ◦ Vitamin D storage sufficient for 4 months
    ◦ Vitamin A storage for 10 months
    ◦ B12 for 1 year
  • Iron - excess iron take up with apoferritin to form ferritin
  • Copper
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116
Q

How does the liver respond to shocked state

A
  • BV 450mL-500mLs (30mL per 100g of liver tissue) half (250-350mLs) of which can be mobilised
  • Portal blood can bypass sinusoids as blood shunted from portal venules to hepatic venules by relaxation of hepatic venules sphincters
  • Catecholamines mobilise blood from sinusoids
  • Hepatic o pliable is higher at high venous pressures than low venous pressures buffering against high volumes
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117
Q

What role does the liver have in acid base

A
  • Can be either a signficant net producer or consumer of hydrogen ions
  • Carbon doxide production from complete oxidation of substrates
    ◦ Liver uses 20% of the bodies oxygen consumption
    ◦ Produces 20% of the bodies CO2
  • Metabolism of acid anions
    ◦ Endogenous - lactate and ketoacids
    ‣ Metabolism consumes the H+ produced when lactate was originally produced in muscles or other locations
    ◦ Exogenous - citrate, acetate, gluconate
    ‣ Metabolism of these where a H+ was not adminsitered with them results in H+ consumption resulting in net proudction of a bicarbonate anion
  • Amino acid metabolism
    ◦ Incomplete metabolism –> net fixed acid production
    ‣ E.g. sulphuric acid from metabolism of methionine, cysteine
    ◦ Overally amino acid metabolism results in average net production of 50mmol/day of fixed acid which is 70% of daily net fixed acid production
  • Metabolism of ammonium
    ◦ Conversion of NH4+ to urea results in equivalent production of H+
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118
Q

Liver uses what % of total body oxygen?

A

20%

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119
Q

What acid anions does the liver process?

A
  • Can be either a signficant net producer or consumer of hydrogen ions
  • Carbon doxide production from complete oxidation of substrates
    ◦ Liver uses 20% of the bodies oxygen consumption
    ◦ Produces 20% of the bodies CO2
  • Metabolism of acid anions
    ◦ Endogenous - lactate and ketoacids
    ‣ Metabolism consumes the H+ produced when lactate was originally produced in muscles or other locations
    ◦ Exogenous - citrate, acetate, gluconate
    ‣ Metabolism of these where a H+ was not adminsitered with them results in H+ consumption resulting in net proudction of a bicarbonate anion
  • Amino acid metabolism
    ◦ Incomplete metabolism –> net fixed acid production
    ‣ E.g. sulphuric acid from metabolism of methionine, cysteine
    ◦ Overally amino acid metabolism results in average net production of 50mmol/day of fixed acid which is 70% of daily net fixed acid production
  • Metabolism of ammonium
    ◦ Conversion of NH4+ to urea results in equivalent production of H+
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120
Q

AMino acid metabolism results in how much acid production

A
  • Can be either a signficant net producer or consumer of hydrogen ions
  • Carbon doxide production from complete oxidation of substrates
    ◦ Liver uses 20% of the bodies oxygen consumption
    ◦ Produces 20% of the bodies CO2
  • Metabolism of acid anions
    ◦ Endogenous - lactate and ketoacids
    ‣ Metabolism consumes the H+ produced when lactate was originally produced in muscles or other locations
    ◦ Exogenous - citrate, acetate, gluconate
    ‣ Metabolism of these where a H+ was not adminsitered with them results in H+ consumption resulting in net proudction of a bicarbonate anion
  • Amino acid metabolism
    ◦ Incomplete metabolism –> net fixed acid production
    ‣ E.g. sulphuric acid from metabolism of methionine, cysteine
    ◦ Overally amino acid metabolism results in average net production of 50mmol/day of fixed acid which is 70% of daily net fixed acid production
  • Metabolism of ammonium
    ◦ Conversion of NH4+ to urea results in equivalent production of H+
121
Q

Outline how the liver is involved in metabolism of fat, carbs and protein

A

Carbohydrate metabolism summary
* Blood glucose level regulation
◦ Energy storage - up to 100g of glucose can be stored through glycogen formation and storage of glucose which is stimulated by insulin in response to elevated portal blood sugar levels.
◦ Glycogenlysis + gluconeogenesis in response to low BSL levels - glucose released from glycogen breakdown but also glucose is synthesised from muscle derived amino acids (alanine,glutamine) and glycerol from lypolsyis of peripheral fat stores
* Energy production
◦ Catabolism via glycolysis with net energy gain of 38 ATP from aerobic breakdown of glucose to pyruvate and subsequent citric acid cycle processsing
* Oxidation and decarboxylation of glucose to pentose producing NADPH for steroid hormone processing and bio transformation of drugs

Lipid summary
* Lipid breakdown for energy extraction
◦ Beta oxidation - free fatty acid conversion to acetyl CoA which proceed through the Kreb’s cycle; or alternatively stored as acetic acid to transport energy to peripheral tissues to undergo conversion back to Acetyl CoA for energy utilisation
* Lipid synthesis
◦ Synthesis of fatty acids from excess glucose —> conversion to triglycerides integrated into VLDL for peripheral fat storage
◦ Cholesterol synthesis - either cholesterol ingested or synthesised in the liver or adrenal cortex from acetyl CoA is converted to bile, used as a precursor for hormones or transported to peripheral tissues in lipoproteins for use in cell membranes or intracellular structure
* Lipid processing
◦ Apoliprotein synthesis to facilitate transport and redistribution of body lipid

Protein metabolism summary
* Protein synthesis - the dominant site of protein synthesis for all major protein groups aside from immunoglobulins
◦ Albumin synthesis - key transport protein for acidic drugs and intrinsic hormones + electrolytes; the dominant source of intravascular plasma oncotic pressure
◦ Globulin protein synthesis
‣ Alpha globulins including haptoglobin for plasma free haemoglobin binding, serine protease inhibitors e.g. alpha 1 anti trypsin
‣ Beta globulins - transferrin binding and transferring iron in its ferric form
‣ Complement synthesis
◦ Clotting factors - vitaminK dependent clotting factors + independent factors
* Amino acid synthesis and metabolism
◦ Oxidative deamination forming energy and urea from surplus amino acids - remaining keto acid can be transformed by transamination to another amino acid, used as a substrate for gluconeogenesis or utilised in the citric acid cycle
* Nitrogenous waste excretion from protein degredation i.e. urea
◦ Surplus ammonia is toxic thus converted to urea for kidney excretion

122
Q

How does ammonia enter the urea cycle?

A

Note that the reverse reaction to produce glutamine can be performed consuming 2 NH4+

123
Q

What amino acid substrates are involved in reactions causing the production of ammonia as a result of transamination

A
124
Q

Where does ammonia come from? Why is it a problem>?

A
  • a toxic metabolite of protein and purine synthesis which mainly causes neurological dysfunction and cerebral oedema
125
Q

Is ammonia polar or non polar?

A

Non polar
Therefore abel to diffuse through lipid bilayers

126
Q

WHat are some characteristics of ammonia

A
  • Ammonia, NH3 is non-polar and can diffuse through lipid bilayers
    ◦ It has a pungent/sharp odour
    ◦ In low concentrations has high toxicity when inhaled causes pulmonary oedmea/ARDS
    ◦ Immediate blistering contact with skin
    ◦ Supports combustion by donation hydrgoen to oxygen
127
Q

Why is ammonia toxic to surfaces it contacts?

A
  • Ammonia, NH3 is non-polar and can diffuse through lipid bilayers
    ◦ It has a pungent/sharp odour
    ◦ In low concentrations has high toxicity when inhaled causes pulmonary oedmea/ARDS
    ◦ Immediate blistering contact with skin
    ◦ Supports combustion by donation hydrgoen to oxygen
128
Q

What is the pKa of ammonia? What form is it mostly in therefre?

A
  • 98% exists in ionised form (ammonium, NH4+) at physiological pH, which is less lipid-soluble and is trapped in water compartments
    ◦ NH3 (gas) + H+ ⇌ NH4+
    ◦ pKa 9, confined to extracellualr body water with a Vd 0.4L/kg
129
Q

What is the Vd of ammonia

A
  • 98% exists in ionised form (ammonium, NH4+) at physiological pH, which is less lipid-soluble and is trapped in water compartments
    ◦ NH3 (gas) + H+ ⇌ NH4+
    ◦ pKa 9, confined to extracellualr body water with a Vd 0.4L/kg
130
Q

What is the half life of ammonia

A

1-4 minutes

131
Q

Where is ammonia metabolised

A

Liver and skeletal muscle mainlyW

132
Q

What is the baseline concentration of ammonia

A

11-30 micromol/L

133
Q

How much ammonia does the liver process per day

A

150mmol

134
Q

Where does ammonia come from

A
  • Intestine
    ◦ Primarily from gut bacteria urea hydrolysis/urea splitting in colon –> main source for the liver
    ◦ Metabolism of glutamine by enterocytes leading to recirculation
    ◦ Dietary sources - miniscule
  • Amino acid metabolism in the liver and skeletal muscle
    ◦ Glutamine from peripheral tissues is exported to the liver via circulation where metabolism releases ammonia
    ◦ Skeletal muscle when resting is a net absorbed of ammonia but exercising muscle produce ammonia
    ◦ The liver itself deamination of amino acids - dietary or endogenous in origin
  • Purine nucleotide cycle in skeletal muscle and brain
  • Renal tubular synthesis (from glutamine) - small percentage of ammonia release - 70% of ammonia produced in kidney is returned to blod stream
  • Liver - deaminiation of amino acids (mainly glutamine)
135
Q

What is the main source of ammonia from the liver?

A

Metabolised of glutamine in the liver –> deamination

Glutamine is released from peripheral tissues for liver and renal processing

136
Q

What % of renal tubular processing of glutamine reaches systemic ciruclation

A
  • Renal tubular synthesis (from glutamine) - small percentage of ammonia release - 70% of ammonia produced in kidney is returned to blod stream
  • Liver - deaminiation of amino acids (mainly glutamine)
137
Q

How is the intestine involved in ammonia

A
  • Intestine
    ◦ Primarily from gut bacteria urea hydrolysis/urea splitting in colon –> main source for the liver
    ◦ Metabolism of glutamine by enterocytes leading to recirculation
    ◦ Dietary sources - miniscule
138
Q

Skeletal muscle has what relationship to ammonia?

A

◦ Skeletal muscle when resting is a net absorbed of ammonia but exercising muscle produce ammonia
* Purine nucleotide cycle in skeletal muscle and brain

139
Q

Illustrate how glutamine is produced

A
140
Q

How does ammonia travel in the blood

A
  • Circulating pure ammonia
  • Circulating glutamine as a form of interorgan ammonia transport (by far the most important, quantitatively) - and represents 50% of circulating amino acids. Alanine is a less important circulating ammonia pathway
141
Q

What is the most abundant circulating amino acid

A
  • Circulating pure ammonia
  • Circulating glutamine as a form of interorgan ammonia transport (by far the most important, quantitatively) - and represents 50% of circulating amino acids. Alanine is a less important circulating ammonia pathway
142
Q

How is urea formed

A
  • Ammonia and CO2 are combined to form urea, (NH2)2CO, in an enzyme cycle which recycles ornithine
143
Q

What is the extraction ratio for ammonia from the circulation in the liver?

A

92% first pass extraction ratio

144
Q

WHere does the urea cycle occur? WHy?

A
  • Only hepatocytes possess the full set of enzymes to complete these reactions - in particular oxidative deamination requring glutamate and water as substrates (glutamate dehydrogenase can transform glutamate into alpha ketoglutarate releasing ammonia)
145
Q

How much urea is made per day

A

420mmol

146
Q

Where is urea eliminated

A

the kidneys mostly
13-30% enterohepatic recirculation

147
Q

How are urea and the gut associated?

A
  • Some (~13-30%) undergoes enterohepatic recirculation where urea is excreted into the gut, hydrolysed back into ammonia by gut organisms, is reabsorbed into the portal blood and returns to the liver.
148
Q

How much ammonia is excreted unchanged in the kidney?

A
  • Some tiny fraction of ammonia 10-100mmol is eliminated as ammonium ions, and some as gaseous ammonia
    ◦ glutamine enters peritubular cells of PCT –> 80% from peritubular capillaries, 20% from filtrate reabsorbed. Deaminated via glutaminase which has increased activity in acidosis. HCO3 reabsorbed, NH4 excreted.
    ◦ Ammonium cycling with 80% reabsorbed TAL of LOH but then diffuses down concentration gradient into collecting duct
149
Q

Describe the handling of ammonia in the kidney

A
  • Some tiny fraction of ammonia 10-100mmol is eliminated as ammonium ions, and some as gaseous ammonia
    ◦ glutamine enters peritubular cells of PCT –> 80% from peritubular capillaries, 20% from filtrate reabsorbed. Deaminated via glutaminase which has increased activity in acidosis. HCO3 reabsorbed, NH4 excreted.
    ◦ Ammonium cycling with 80% reabsorbed TAL of LOH but then diffuses down concentration gradient into collecting duct
150
Q

How is muscle an ammonia clearance organ?

A
  • Brain, skeletal and cardiac muscle non hepatic amino acid metabolism - transamination
    ◦ Amino acids transminated into carbon skeletons to feed TCA cycle producing alpha ketoglutarate and glutamine/alanine which the muscle exports back to the liver
    ◦ This consumes ammonia in vast quantities so muscle becomes an ammonia clearance organ
151
Q

How do muscles use amino acids for energy? is there any waste product?

A
  • Brain, skeletal and cardiac muscle non hepatic amino acid metabolism - transamination
    ◦ Amino acids transminated into carbon skeletons to feed TCA cycle producing alpha ketoglutarate and glutamine/alanine which the muscle exports back to the liver
    ◦ This consumes ammonia in vast quantities so muscle becomes an ammonia clearance organ
152
Q

Glutamine is important in the body why?

A

◦ Make amino acids back out of ammonia reversing deaminiation usually happens thorugh glutamate dehydrogenase adn glutamine synthase
‣ Glutamate dehydrogenase catalyses the pathway in both direction
◦ Glutamine is the most abundant amino acid in the body - 1/3 of glutamine syntheiss is extrahepatic
‣ And this is the main form in which ammonium is usually transported in the body
◦ This does not however excrete the ammonia, and is not a source of fuel without the re-release of ammonia
◦ It does however allow transport of ammonia in non toxic form back to the lvier for processing

153
Q

What enzymes allow ammonia to be attached back to amino acids? Why is this important?

A

◦ Make amino acids back out of ammonia reversing deaminiation usually happens thorugh glutamate dehydrogenase adn glutamine synthase
‣ Glutamate dehydrogenase catalyses the pathway in both direction
◦ Glutamine is the most abundant amino acid in the body - 1/3 of glutamine syntheiss is extrahepatic
‣ And this is the main form in which ammonium is usually transported in the body
◦ This does not however excrete the ammonia, and is not a source of fuel without the re-release of ammonia
◦ It does however allow transport of ammonia in non toxic form back to the lvier for processing

154
Q

What is the purine nucleotide cycle?

A

Fumarate and malate metabolic substrates produced and plugged into citric acid cycle
* Many tissues have necessary enzymes but brain and muscle most important

155
Q

Describe the processes by which urea enterohepatic recycling occurs

A
156
Q

What to processes occur in the catabolism of protein

A

Deamination
Transamination

157
Q

Deamination of proteins involves…

A

◦ oxidative deaminiation in liver removing amino group to create a ketoacid and ammonia which enters the urea cycle (requiring 3 ATP

158
Q

Transamination is performed to produce? What byproducts are there?

A

◦ transamination where amino group transferred by aminotransferases to another amino acid or ketoacid to produce
‣ ketoacids (enter citric acid cycle producing ATP or get converted to glucose or fatty acids)
‣ amino groups entering the urea cycle

159
Q

What is a toxic concentration of ammonia

A

> `1microg/mL

160
Q

How does ammonia first get processed to enter the urea cycle

A

‣ Nitrogenous end of ammonia (2x ammonia) combines with carbon dioxide in liver cell mitochondria forming carbomoyl phosphate (NH2)2-CO

161
Q

What is the first product produced to enter the urea cycle?

A

Carbamoyl phosphate

162
Q

How much energy si required to process ammonia for the urea cycle

A

Urea cycle an energy dependent process utilising 3 ATP molecules per urea molecule synthesised

163
Q

What is carbamoyl phosphate?

A

‣ Nitrogenous end of ammonia (2x ammonia) combines with carbon dioxide in liver cell mitochondria forming carbomoyl phosphate (NH2)2-CO

164
Q

What does carbamoyl phosphate react with?

A

Ornithine to produce citrulline

165
Q

What is combined to form citrulline in the urea cycle?

A

Ornithine and carbamyl phosphate

166
Q

What is the fate of citrulline in the urea cycle?

A

‣ Citrulline reacts with aspartate —>arginine

167
Q

What is the fate of arginine in the urea cycle?

A

‣ Arginine hydrolysed —> ornithine, water, urea

168
Q

What is the fate of ornithine in the urea cycle

A

Combines with carbamyl phosphate to produce citrulline

169
Q

What combines with citrulline to form arginosuccinate in the urea cycle?

A

Aspartate

170
Q

What role does aspartate have in the urea cycle?

A

combines with citrulline to form arginosuccinate

171
Q

What is produced from arginosuccinate to make arginine?

A

Fumarate

172
Q

Draw the urea cycle

A
173
Q

Draw the overall reaction of the urea cycle

A
174
Q

Is urea polar or non polar

A

non polar

175
Q

What is the chemical formula of urea

A

CH4N20

176
Q

How much urea is excreted in the intestine

A

10-30% - 15% on average

177
Q

Why does urea move into the intestine

A

Passive diffusino down concentration gradient

178
Q

What are urease splitting organism?

A

◦ Urease splitting organisms (E.coli, Clostridium, Klebsiella, Proteus, Providencia and Morganella ) then produce ammonia and CO2 –> reabsorption fo ammonia intop splanchnic circulation and transport back to the lvier with 90% clearance

179
Q

How much of filtered urea is excreted

A

60%

180
Q

What is the baseline concentration of urea

A

5mmol/L

181
Q

What happens to urea in the PCT

A

◦ 50% is then reabsorbed in the proximal tubule
‣ This is a passive process (solute drag) - 40% - paracellualrly
‣ More water is reabsorbed than urea –> As the result, urea is concentrated by about 50% (7.5mmol/L)

182
Q

How does urea move out of the tubule in the PCT? What % moves out? WHat does this leave behind?

A

◦ 50% is then reabsorbed in the proximal tubule
‣ This is a passive process (solute drag) - 40% - paracellualrly
‣ More water is reabsorbed than urea –> As the result, urea is concentrated by about 50% (7.5mmol/L)

183
Q

What happens to urea in the thin descending LOH

A

◦ In the thin descending limb, urea is concentrated signficantly
‣ Some urea is added to the fluid by UT-A2 transport proteins from ascending vasa recta; urea permeability out is low and water permeability high resulting in water reabsorption and urea concentration by 30-40 times –> 150-200mmol/L

184
Q

What happens to urea in the ascending LOH

A

‣ Thin ascending - urea permeability higher,. water permeability low, urea therefore diffuses out into the medullary intersitium, where it is captured by the vasa recta and recirculates; however even more enters the thin ascending limb from the collecting duct increasing concentration by 20-25% between the bend and the ned of the thin ascneding limb.
‣ In the thick ascending limb, some urea may diffuse back out into the medullary interstitium
‣ In the inner medulla, urea is recycled by countercurrent exchange and a high urea concentration is maintained to facilitate osmotic recovery of water from the tubular fluid

185
Q

What happens to urea in the distal neprhon

A

‣ The recovery of water via aquaporins in the collecting duct further concentrates the urea in the lumen
‣ Terminal collecting duct *(deep medullary interstitium) urea concentration can be up to 100 times greater than plasma
‣ Here, urea permeability is increased, allowing urea diffusion into the inner medulla –> via UTA transporters
‣ Reuptake of urea from the terminal collecting duct is a part of urea recycling and helps maintain high urea concentration in the renal medulla driving reabsorption of water elsewhere in the tubule

186
Q

How does urea move out of the lumen into the medulla in the distal nephron?

A

‣ The recovery of water via aquaporins in the collecting duct further concentrates the urea in the lumen
‣ Terminal collecting duct *(deep medullary interstitium) urea concentration can be up to 100 times greater than plasma
‣ Here, urea permeability is increased, allowing urea diffusion into the inner medulla –> via UTA transporters
‣ Reuptake of urea from the terminal collecting duct is a part of urea recycling and helps maintain high urea concentration in the renal medulla driving reabsorption of water elsewhere in the tubule

187
Q

How does lactulose work

A

Metabolised by gut bacteria and increases osmolality of the tool and water content preventing reabsotion

Also a metabolic substrate for bacteria diverting metabolism to production of non nitrgoenous metabolites

188
Q

Half-life of lactulose? Duration of effect

A

2 hours
Duration of effect 4-8 hours

189
Q

WHat is lactulose chemically?

A

Disaccharide of glucose and fructose
Cannot be absorbed

190
Q

Why might urea levels be raised?

A

Increased exogenous administration
Increased urea synthesis
Increased catabolism
Decreased clearance due to either increased reabsorption or decreased renal clearance

191
Q

Why might there be increased urea synthesis?

A

◦ High protein diet
◦ GI haemorrhage - as enteric organisms break down proteins in blood into amino acids which are reasborbed with a large protein load processed by the liver
◦ Paraenteral oversupplementation of amino acids - TPN
◦ Glycine intoxication in TURP syndrome
◦ Gastric bypass
◦ Multiple myeloma

192
Q

Causes of increased catabolism?

A

◦ Corticosteriods
◦ Trauma
◦ Burns
◦ Major surgery
◦ Starvation

193
Q

Increased urea reabsorption

A

‣ Hypovolaemia - CCF, renal artery stenosis
‣ actual hypovolaemia
‣ Tetracyclkine therapy
‣ Post renal obstruction

194
Q

Why might urea levels be low

A

In liver impairment urea may fail to be produced from ammonia resulting in ammonia accumulation
* Liver failure - acute, chronic, portosystemic shunt
* Drugs and toxins - valproate, carbamazapine, topiramate, salicylates, rifampicin, hepatotoxic drugs
* Metabolic errors

195
Q

What are the physiological implications of a high urea?

A
  • Inhibits Na/K/2Cl cotransporter in red blood cells at levels 45mmol/L and above
    ◦ Involved in regulation of cell volume and K levels ‘
  • Inhibition of enzyme function
    ◦ Xanthine oxidase directly involved in reducing intracellular macromolecular crowding
  • Nitric oxide synthase inhibition opposing vasodilation
  • Carbamoylation of proteins - changing their function
196
Q

Symptoms of elevated urea?

A
  • Cardiovascular - pericardial rub, pericardial effusion
  • Neuro - encephalopathy, peripheral neuropathy
  • Endocrine - improved glycaemic control
  • GI - nausea and vomiting
  • Platelet dysfunction
  • Misc
    ◦ Mixed metabolic acidosis
    ◦ Uraemic foetor, frost, pruritis, nail atrophy and sallow skin
197
Q

How is bilirubin produced?>

A
  • Haemoglobin broken down in reticuloendothelial system (spleen)
    ◦ 85% of bilirubin comes from haemoglobin, 15% from other haem containing compounds e.g. myoglobin
  • Haem broken down into
    ◦ Haem
    ◦ Globin —> broken down into constituent amino acids
  • Haem unit broken down via haem oxygenase and NADPH-cytochrome P450
    ◦ Iron—> re-utilised and bound to transferrin for transfer to bone marrow
    ◦ Small amounts of carbon monoxide excreted via lungs
    ◦ Porphyrin ring —> Biliverdin via oxidation in macrophages of the spleen
  • Biliverdin reductase converts (reduces) this to unconjugated (indirect) bilirubin (insoluble)
198
Q

How is bilirubin metabolised

A
  • Bilirubin bound to serum albumin and transported to the liver
  • Hepatocytes uptake bilirubin - 2 binding proteins involved
  • Conjugation inside hepatocytes via UDP (uridine disphosphate)-glucoronosyl transferase with glucoronides —> water soluble conjugated bilirubin
  • Conjugate bilirubin secreted in bile into the small intestine
199
Q

How is bilirubin transported in the blood

A

ALbumin

200
Q

Bilirubin clearance

A
  • Conjugated bilirubin reabsorbed in the small intestine - enterohepatic recycling as resecreted by the liver into the intestine
  • Conjugated bilirubin broken down by bacteria to
    ◦ Urobilinogen —> enters enterohepatic circulation but its reuptake is not as complete as conjugated bilirubin and excreted in urine
    ◦ Urobilinogen may be converted further by oxidation to urobilin and stercobilin which are excreted in faeces
201
Q

Outline the impact of intrahepatic disease on bilirubin metabolism

A
  • Failure of bilirubin conjugation due to intrahepatic disease —> blood unconjugated bilirubin levels high
  • Because it is unconjugated none is filtered by the glomerulus
  • The degree of hepatocellular dysfunction and the aetiology may effect the degree to which pure hepatocytes dysfunction occurs or some biliary duct disruption leading to a mixed picture of conjugated and unconjugated
202
Q

Outline the impact of post hepatic disease obstruction on bilirubin

A
  • Obstruction of bile drainage results in back pressure on hepatocytes and release of conjugated bilirubin into systemic circulation
  • High conjugated levels peripherally in blood —> as it’s water soluble it is found in the urine with a ositive dipstick
  • Faeces becomes pale in colour due to failure of bilirubin and its metabolites to reach the intestine
203
Q

Define bile

A

exocrine secretion of hepatocytes into the gut lumen via hepatic and bile ducts

204
Q

What membrane of hepatocytes is bile secreted from? Into what tract?

A
  • Bile is created at the tiny apical membrane of the hepatocytes that forms the biliary canaliculi.
205
Q

What % of bile goes into the gallbladder?

A

◦ Bile then undergoes extensive modification in the bile ducts.
◦ About 90% of the bile produced during the day comes to rest in the gallbladder before being released to work its magic on some ingested fats, and while it waits the gallbladder also slowly works to modify its composition

206
Q

What % of cholesterol metabolism becomes bile acids?

A

80%

207
Q

What is the substrate from which bille acids are produced?

A

cholesterol

208
Q

What is a bile acid chemically

A

Carboxylic acid incorporated inot a sterol ring

209
Q

Outline the steps in the production of bile acids

A

◦ Cholesterol is converted to cholic acid and chenodeoxycholic acid by oxidation and excreted into canaliculi by hepatocytes (primary bile salts)
◦ Passes into the gallbladder where it s concentrated to 1/5 of its volume
◦ In the gut bacterial action result in secondary bile acids —> deoxycholic acid and lithocholic acid
◦ These conjugate with taurine and glycine to form bile salts with Na and K
◦ Bile salts are more water soluble and less lipid soluble limiting passive absorption

210
Q

What are the primary bile salts?

A

◦ Cholesterol is converted to cholic acid and chenodeoxycholic acid by oxidation and excreted into canaliculi by hepatocytes (primary bile salts)
◦ Passes into the gallbladder where it s concentrated to 1/5 of its volume
◦ In the gut bacterial action result in secondary bile acids —> deoxycholic acid and lithocholic acid
◦ These conjugate with taurine and glycine to form bile salts with Na and K
◦ Bile salts are more water soluble and less lipid soluble limiting passive absorption

211
Q

What are the secondary bile salts? How do they get produced?

A

◦ Cholesterol is converted to cholic acid and chenodeoxycholic acid by oxidation and excreted into canaliculi by hepatocytes (primary bile salts)
◦ Passes into the gallbladder where it s concentrated to 1/5 of its volume
◦ In the gut bacterial action result in secondary bile acids —> deoxycholic acid and lithocholic acid
◦ These conjugate with taurine and glycine to form bile salts with Na and K
◦ Bile salts are more water soluble and less lipid soluble limiting passive absorption

212
Q

What level of concentration occurs in the gallbladder

A

1/5 of volume
5-10x concentration
Although lots of ions are also reclaimed

213
Q

How much bile is produced per day

A

1L

214
Q

How much bile salt is made per day

A

0.5g per day

215
Q

What is the mass of the total pool of bile salts?

A

2.5-3g

216
Q

How many times do bile salts circulate

A

2-3x per meal for 3x meals per day

217
Q

Where are bile salts reabsorbed

A

95% in terminal ileum

218
Q

How are bile salts reabsorbed

A

Apical sodium dependent bile transporter

219
Q

Describe the circulation of bile salts after excretion from the pancreatic duct

A
  • 95% reabsorbed at terminal ileum by apical sodium dependent bile transporter
    ◦ Carried to the liver in portal circulation bound to plasma proteins —> reabsorbed into hepatocytes
    ◦ Recirculation called enterohepatic recirculation —> re-secreted into bile ducts via active transport
    ◦ Enterohepatic recirculation important in maintaining a low hepatic bile acid production requirement - production is subject to feedback inhibition by reabsorbed bile acids
220
Q

What does bile salt dependent bile secretion refer to?

A

Due to osmotic effects of bile salts on water it moves out into the canaliculi post secretion

221
Q

What does bile salt independent bile secretion refer to

A

is due to the osmotic effects of other organic molecules such as glutathione, bilirubin, bicarbonate and organic conjugates

222
Q

How does fluid get into the canaliculi from hepatocytes?

A

Bile salt dependent bile secretion - osmotic effects of bile salts

Bile salt INDEPENDENT bile secretion due to the osmotic effects of other organic molecules such as glutathione, bilirubin, bicarbonate and organic conjugates

Transported via aquaporins via osmotic forces and through tight junctions

223
Q

What modification to bile occurs in the bile ducts themselves?

A
  • In the bile ducts, more fluid (~40%) is added and the bile is alkalinised
224
Q

What is the composition of bile?

A
  • Water 95% - transported into bile via aquarporins via mostly osmotic forces as well as thorugh tight junctions
  • 5% organic and inorganic solutes
    ◦ Electrolytes - similar to plasma, more alkaline (pH 8) –> becomes more acidic (pH5-6) and concentrated in gallbladder
    ◦ Protein <1g/L -
    ‣ Passively filtered - albumin, apoliproteins, Haptoglobin, ceruloplasmin
    ‣ Secreted - cholecystokinin, amylase, epidermal growth factor, IgA, IgG, IgM
    ◦ Bilirubin - otherwise known as bile pigment 1-2mmol/L
    ‣ bilirubin content of bile is therefore high (1000-2000 μmol/L), usually at least ten times higher (and up to a hundred times higher) than in blood
    ◦ Bile salts - bile acids are steriod compounds produced in the liver from cholesterol
    ‣ 3-45mmol/L - total pool 3g
    ◦ Lipids - cholesterol and phospholipids
    ‣ Cholesterol 2.5-8mmol/L and lipids 20g/L
225
Q

What is the electrolyte composition of bile?

A
  • 5% organic and inorganic solutes
    ◦ Electrolytes - similar to plasma, more alkaline (pH 8) –> becomes more acidic (pH5-6) and concentrated in gallbladder
226
Q

What is the pH of bile?

A

◦ Electrolytes - similar to plasma, more alkaline (pH 8) –> becomes more acidic (pH5-6) and concentrated in gallbladder

227
Q

What other than electrolytes ad water is in bile?

A

◦ Protein <1g/L -
‣ Passively filtered - albumin, apoliproteins, Haptoglobin, ceruloplasmin
‣ Secreted - cholecystokinin, amylase, epidermal growth factor, IgA, IgG, IgM
◦ Bilirubin - otherwise known as bile pigment 1-2mmol/L
‣ bilirubin content of bile is therefore high (1000-2000 μmol/L), usually at least ten times higher (and up to a hundred times higher) than in blood
◦ Bile salts - bile acids are steriod compounds produced in the liver from cholesterol
‣ 3-45mmol/L - total pool 3g
◦ Lipids - cholesterol and phospholipids
‣ Cholesterol 2.5-8mmol/L and lipids 20g/L

228
Q

WHat protein is in bile?

A

◦ Protein <1g/L -
‣ Passively filtered - albumin, apoliproteins, Haptoglobin, ceruloplasmin
‣ Secreted - cholecystokinin, amylase, epidermal growth factor, IgA, IgG, IgM
◦ Bilirubin - otherwise known as bile pigment 1-2mmol/L
‣ bilirubin content of bile is therefore high (1000-2000 μmol/L), usually at least ten times higher (and up to a hundred times higher) than in blood
◦ Bile salts - bile acids are steriod compounds produced in the liver from cholesterol
‣ 3-45mmol/L - total pool 3g
◦ Lipids - cholesterol and phospholipids
‣ Cholesterol 2.5-8mmol/L and lipids 20g/L

229
Q

What is bile pigment

A

Bilirubin

230
Q

What is the function of bile

A

Emulsificatino of fat for lipase action and absorption

  • The micelles make contact with enterocytes which absorb the lipid contents including fat soluble vitamins
    ◦ Absorption of fat soluble vitamins A, D, E, K
  • Excretory function
    ◦ Excreting cholesterol and bilirubin - main mechanism
    ◦ Lipid soluble xenobiotic secretino
  • Immune function - IgA and IgG
  • Growth stimulus - trophic stimuli to enterocytes
231
Q

What solubility characteritic do bile salts have?

A

◦ Bile salts are amphipathic - hydrophobic on one end and hydrophilic on the other, enabling them to surround dietary lipid breaking large globules into a suspension of multiple small fat droplets called micelles

232
Q

How do bile salts emulsify fat

A

◦ Bile salts are amphipathic - hydrophobic on one end and hydrophilic on the other, enabling them to surround dietary lipid breaking large globules into a suspension of multiple small fat droplets called micelles
‣ Bile salts act with monoglycerides and phospholipids to do this
‣ This action occurs becasue there is a decrease in surface tension in the fat particles caused by these substances

233
Q

How does fat get absorbed

A

◦ These micelles enable pancreatic lipase to act on the dietary lipid in the core, and micelles transported to the brush border where lipids diffuse out of the micelle and across the lipid membrane of the enterocytes
◦ Absorption of dietary fat is reduced to 50% with excess lost in stools in absence of bile salts

234
Q

How important is bile production to fat absorption

A

◦ These micelles enable pancreatic lipase to act on the dietary lipid in the core, and micelles transported to the brush border where lipids diffuse out of the micelle and across the lipid membrane of the enterocytes
◦ Absorption of dietary fat is reduced to 50% with excess lost in stools in absence of bile salts

235
Q

What other than facilitating dietary absorption of fat does bile do?

A
  • The micelles make contact with enterocytes which absorb the lipid contents including fat soluble vitamins
    ◦ Absorption of fat soluble vitamins A, D, E, K
  • Excretory function
    ◦ Excreting cholesterol and bilirubin - main mechanism
    ◦ Lipid soluble xenobiotic secretino
  • Immune function - IgA and IgG
  • Growth stimulus - trophic stimuli to enterocytes
236
Q

How is a bile acid different to a bile salt?

A

Bile acids are insoluble fatty (sterol) acids
Bile salts are soluble ionised fatty (sterol) acids

237
Q

How does liver failure impact drug absorption and bioavailability

A
  • Decreased first pass metabolism as discussed under metabolism will also be reflected in increased oral bioavailability of drugs especially those with high hepatic clearance - this occurs due to both increased intrahepatic shunting with disease as well as reduced intrinsic metabolic potential and therefore reduced hepatic extraction
238
Q

How does liver failure influence drug distribution

A
  • Drug transport
    ◦ High bilirubin levels may displace drugs from albumin resulting in lower total drug levels altering drug monitoring mechanisms
    ◦ Low drug transport proteins due to failure of transport protein synthesis e.g. albumin will increase free fraction and reduce total drug levels
  • Increased total body water as part of chronic liver disease
    ◦ Increased volume of distribution
239
Q

How does drug metabolism and excretion get impacted by liver failure

A

The liver is one of the primary sites of drug metabolism and clearance and like any organ its clearance is a manifestation of both the blood flow to the organ and the efficiency of irreversible drug extraction (hepatic extraction ratio)
* Drug metabolism occurs via 3 phases and its compromise reduces hepatic extraction ratio and therefore clearance
◦ Phase 1 reactions - Non synthetic, non specific reactions converting parent drug to a more polar metabolite by introducing or unmasking a functional group. Involve largely cytochrome p450 enzyme reactions within the hepatocyte’s endoplasmic reticulum e.g. oxidation, reduction and hydrolysis. These reactions often inactivate drugs, but may also activate or enhance their action and by increasing their polarisation they are more likely to be renally cleared
‣ Liver failure will reduce this process resulting in prolongation of drugs inactivated by this process, or failure of action of drugs which require activation via this process
◦ Phase 2 reactions - Conjugation reactions the most common of which is glucoronidation e.g. of morphine orpropofol
‣ Many phase 1 metabolites go on to have phase 2 reactions which generally inactivate them a major exception being morphine 6 gluronide; although some phase 2 reactions have no preceding phase 1 reaction
‣ Liver failure reduces this process leading to prolongationof mechanism of action or longer half lives of drugs with reduced clearance
◦ Drug metabolism also occurs via plasma esterases and peptidases that are live rproudced prolonging the clearance of suxamethonium and other drugs metabolised in plasma
* Synergistic mechanism with reduced liver blood flow and increased intrahepatic shunting will reduce hepatic clearance
◦ This will also reduce first pass metabolism therefore for orally administered medications with high hepatic clearance there will be a proportional significant increase in bioavailability
* Phase 3 - ATP dependent drug excretion into bile often against a concentration gradient
◦ Reduction in this process will prolong half life by reducing clearance e.g. steroid based muscle relaxants
◦ Enterohepatic recirculation of drugs will be decreased

240
Q

Describe phase 1 reactions in the liver for metabolism? How does liver failure affect these reactions?

A

◦ Phase 1 reactions - Non synthetic, non specific reactions converting parent drug to a more polar metabolite by introducing or unmasking a functional group. Involve largely cytochrome p450 enzyme reactions within the hepatocyte’s endoplasmic reticulum e.g. oxidation, reduction and hydrolysis. These reactions often inactivate drugs, but may also activate or enhance their action and by increasing their polarisation they are more likely to be renally cleared
‣ Liver failure will reduce this process resulting in prolongation of drugs inactivated by this process, or failure of action of drugs which require activation via this process

241
Q

How does liver failure impact phase 2 reactions for drug metabolism

A

◦ Phase 2 reactions - Conjugation reactions the most common of which is glucoronidation e.g. of morphine orpropofol
‣ Many phase 1 metabolites go on to have phase 2 reactions which generally inactivate them a major exception being morphine 6 gluronide; although some phase 2 reactions have no preceding phase 1 reaction
‣ Liver failure reduces this process leading to prolongationof mechanism of action or longer half lives of drugs with reduced clearance
◦ Drug metabolism also occurs via plasma esterases and peptidases that are live rproudced prolonging the clearance of suxamethonium and other drugs metabolised in plasma

242
Q

What factors influence drug metabolism in liver failure other than enzyme availability

A
  • Synergistic mechanism with reduced liver blood flow and increased intrahepatic shunting will reduce hepatic clearance
    ◦ This will also reduce first pass metabolism therefore for orally administered medications with high hepatic clearance there will be a proportional significant increase in bioavailability
243
Q

How much does the liver weigh?

A

1500-1800g

244
Q

What are the 2 surfaces of the liver anatomically

A

◦ 2 surfaces the diaphragmatic and the visceral
‣ Diaphragmatic - convex and smooth, covered in peritoneum, everywhere realted to the diaphragm lungs and pleura. Superiorly also related to the pericardium
‣ Visceral surface
* Concave, irregular, impressed with shapes of organs beneat
* H shaped patter of structures
◦ Porta hepatis is the cross bar of the H - it is the right a left hepatic ducts, the right and left branches of the hepatic artery and portal vein
* Gallbladder and IVC on the right of the H
* Lesser omentuand ligamentum teres on the left of the H

245
Q

Describe the diaphragmatic surface of the liver

A

◦ 2 surfaces the diaphragmatic and the visceral
‣ Diaphragmatic - convex and smooth, covered in peritoneum, everywhere realted to the diaphragm lungs and pleura. Superiorly also related to the pericardium
‣ Visceral surface
* Concave, irregular, impressed with shapes of organs beneat
* H shaped patter of structures
◦ Porta hepatis is the cross bar of the H - it is the right a left hepatic ducts, the right and left branches of the hepatic artery and portal vein
* Gallbladder and IVC on the right of the H
* Lesser omentuand ligamentum teres on the left of the H

246
Q

Describe what is meant by the visceral surface of the liver

A

◦ 2 surfaces the diaphragmatic and the visceral
‣ Diaphragmatic - convex and smooth, covered in peritoneum, everywhere realted to the diaphragm lungs and pleura. Superiorly also related to the pericardium
‣ Visceral surface
* Concave, irregular, impressed with shapes of organs beneat
* H shaped patter of structures
◦ Porta hepatis is the cross bar of the H - it is the right a left hepatic ducts, the right and left branches of the hepatic artery and portal vein
* Gallbladder and IVC on the right of the H
* Lesser omentuand ligamentum teres on the left of the H

247
Q

What cell types does the liver consist of?

A
  • Consists of hepatocytes (70%), cholangiocytes (15%) and Kupffer cells (15%)
248
Q

Based on blood supply how many lobes are there to the liver?

A

4

249
Q

What are the structural units of the liver called

A

1-2mm units called hepatic lobules

250
Q

Describe the structure of a hepatic lobule

A
  • Each lobule has a central hepatic vein and peripheral portal tracts (portal vein, biliary ductule, hepatic arteriole), connected by hepatic sinusoids.
  • A lump of tissue, hexagonal in cross-section, filled with hepatocytes
  • Terminal vein, running down the centre
  • Portal tracts, running along the corners, which contain:
    ◦ Interlobular hepatic artery, around the corners
    ◦ Interlobular portal veins, around the corners
    ◦ Biliary ductules
    ◦ Lymphatic vessels
    ◦ Nerves
251
Q

What exists within a portal tract

A

◦ Interlobular hepatic artery, around the corners
◦ Interlobular portal veins, around the corners
◦ Biliary ductules
◦ Lymphatic vessels
◦ Nerves

252
Q

What is different between a hepatic sinusoid and a regular cpiallary

A

‣ near absent discontinuous basement membrane with multiple endothelial fenestrations - only prevents cells from entering space of disse
‣ slightly larger diametre than most cpaillaries
‣ hepatocyte microvilli - on the basal surface, apical surface onto canaliculi
‣ Space of Disse - perisinusoidal space between endothelial layer of sinusoid and hepatocytes filled with blood plasma and microvilli
‣ Lined with Kupffer cells descended from monocytes in the lumen of sinusoids -
* phagocytosing bacteria translocating into circulation, foreign particles, sensecent blood cells, heparin, blood proteins, immune complexes
* Metabolism of iron, bilirubin
* Secretion and synthesis of complement, pyrogens, lymphokines, LK and interferon
‣ Hepatic stellate cells - regulatory proteins and can function as APC, storage of vitamin A and TG storage, contractile functions and fibroblast like functions

253
Q

What is a hepatic stellate cell?

A

‣ Hepatic stellate cells - regulatory proteins and can function as APC, storage of vitamin A and TG storage, contractile functions and fibroblast like functions

254
Q

What characteristics does the basement membrane have in hepatic sinusoids

A

‣ near absent discontinuous basement membrane with multiple endothelial fenestrations - only prevents cells from entering space of disse

255
Q

What is the function of Kupffer cells

A

‣ Lined with Kupffer cells descended from monocytes in the lumen of sinusoids -
* phagocytosing bacteria translocating into circulation, foreign particles, sensecent blood cells, heparin, blood proteins, immune complexes
* Metabolism of iron, bilirubin
* Secretion and synthesis of complement, pyrogens, lymphokines, LK and interferon

256
Q

What is the area called between sinusoidal endothelium and hepatocytes? Why is it there?

A

‣ Space of Disse - perisinusoidal space between endothelial layer of sinusoid and hepatocytes filled with blood plasma and microvilli

  • Space of Disse is the narrow (500-1000nm) space that contains hepatocyte microvilli, hepatocyte precursor stem cells and hepatic stellate cells.
    ◦ From the space of Disse, filtered blood plasma flows through interstitial lymphatic channels into the thoracic duct, where hepatic lymph contributes ~50% of the total flow
257
Q

Where is a Kupffer cell in the liver

A

Within the hepatic sinsuoids

258
Q

Where are the microvilli orientated on hepatocytes

A

Within the space of Disse facing the sinusoid

259
Q

What is a periportal limiting plate

A
  • Periportal limiting plate, the ring of connective tissue and the adjacent row of hepatocytes that surround each portal tract.
260
Q

What is the space of Mall

A
  • Space of Mall, a space between the other wall of the portal tract and the hepatocytes, where the formation of hepatic lymph occurs
261
Q

Where is hepatic lymph formed?

A
  • Space of Mall, a space between the other wall of the portal tract and the hepatocytes, where the formation of hepatic lymph occurs
  • Space of Disse is the narrow (500-1000nm) space that contains hepatocyte microvilli, hepatocyte precursor stem cells and hepatic stellate cells.
    ◦ From the space of Disse, filtered blood plasma flows through interstitial lymphatic channels into the thoracic duct, where hepatic lymph contributes ~50% of the total flow
262
Q

What are the functional zones of the liver

A
  • Zones - dividing the liver into elliptical acinus with a terminal branch of the hepatic vein at either end with two portal triads at the midpoint of the gflattenedsides. Blood flows from the portal triad towards the terminal vein - the further the hepatocyte is from the portal triad the lower the O2 tension
    ◦ Zone 1 - closest to portal triads, best oxygenated. Does energy consuming processes e.g. gluconeogenesis and beta oxygenation of fatty acids
    ◦ Zone 2 - intermediate areas
    ◦ Zone 3 - closest to terminal vein, lowest O2 tension, least energy consuming processes e.g. drug metabolism and glycolysis. Centrilobular necrosis refers to this zone owing to the distance from the triad and most susceptable to hypoxic injury as well as the site affected by drug toxic metabolites
263
Q

What is the pressure in a hepatic sinusoid?

A

2-4mmHg

264
Q

What % of lymph is from the liver

A

50%

265
Q

What is the area hepatocytes secrete bile into?

A

Canaliculi

266
Q

What are the characterersitics of canaliculi?

A

◦ Narrow channels between hepatocytes (i.e. walls consist of hepatocytes) - basically just clefts in the adjacent walls of hepatocytes, like gutters running between neighbouring houses
◦ Normally 1-2 μ in width; also occasionally referred to as “bile capillaries”

267
Q

What joins canaliculi to ductules?

A
  • Canals of Hering:
    ◦ Short channels between biliary canaliculi and biliary ductules, lined by a combination of hepatocytes and cholangiocytes
268
Q

What do canaliculi drain into as the next order of biliary drainage?

A

Ductules

269
Q

What are characteristics of bile ductules

A
  • Terminal cholangioles, occasionally called “bile ductules”
    ◦ The first tubular structure entirely lined by cholangiocytes
    ◦ The finest ramification of the biliary tree, less than 15 μm in diameter
270
Q

What do bile ductules drain into? Where do they run?

A
  • Interlobular ducts
    ◦ Cholangiocyte-lined tubes, 15–100 μm in diameter
    ◦ Run along portal tracts
271
Q

After interlobular ducts what are the major drainage vessels for bile?

A
  • Septal ducts
    ◦ Originate from the confluence of interlobular ducts
    ◦ 100–300 μm in diameter
  • Area ducts
    ◦ 300–400 μm in diameter; structurally just a larger version of septal ducts
  • Segmental ducts
    ◦ 400–800 μm in diameter, draining a segment of the liver
  • Hepatic ducts
    ◦ Larger than 800 μm; regarded as being a part of the extrahepatic biliary tree
272
Q

How are cholangiocytes different to hepatocytes structurally?

A
  • Cuboidal (in small ducts) or columnal (in large ones)
  • Smaller than hepatocytes, 6 to 15 μm in diameter
  • Distinct apical and basal membrane properties
  • Joined by tight junctions
  • Apical membrane possesses microvilli
273
Q

What are the functions of cholangiocytes?

A
  • Apical membrane secretes bile
  • Modification of secreted bile takes place:
    ◦ Alkalinisation of bile by exchanging chloride for bicarbonate
    ◦ Concentration of bile by reabsorbing water
  • The reabsorption of other organic molecules (glucose, amino acids, etc) takes place here mainly to reclaim nutrients that would otherwise be lost
274
Q

How does cirrhosis impact liver function

A

Altered liver function
* Disturbed carbohydrate metabolism
◦ Hyperglycaemia chronically
◦ Hypoglycaemia acutely
* Decreased protein synthesis
◦ Clotting abnormalities
◦ Hypoalbuminaemia - altered protein binding and fluid redistribution
* Altered drug metabolism
◦ Slower clearance systemically
◦ Higher amounts of systemic drug delivery if high first pass metabolism usually from oral route
◦ Reduced delivery of prodrug active metabolites if dependent on same
* Inadequate clearance of ammonia and nitrogenous waste

275
Q

How does cirrhosis impact liver blood flow? What impact does this have?

A
  • Increased resistance to flow due to fibrosis obstructing sinusoids increasing portal vein pressure (normally 5-10mmHg) and hypertension is when >12mmHg
  • Portal vein hypertension causes
    ◦ Ascites - transudative fluid loss into peritoneal cavity which poses infection risk
    ◦ Splenomegaly - backflow into splenic vein with increased platelet and red cell removal
    ◦ Portocaval anastomoses - high portal veinous pressure opens collateral vessels with systemic circulation causing dilation and engorgement leading to varices(oesophageal/rectal/caput medusae)
276
Q

What causes a reduction in albumin levels?

A

◦ Failure of synthetic function - and has prognostic relevance in liver disease (Child Pugh score)
◦ Starvation, protein malnutrition - preserve scarce amino acids
◦ Stress and critical illness - as other protein production is prioritised
◦ Protein loss via nephrotic syndrome
◦ In the context of dehydration albumin level may appear normal

277
Q

What is the half life of albumin

A

30- days

278
Q

What clotting factors are not produced by the liver

A

Factor 3 - tissue factor
Factor 4 - calcium
Factor 8 - antihaemophilic factor from vascular endothelium
Platelets
vWF

279
Q

What is a normal PT

A

11-15 seconds

280
Q

Normal aPTT

A

30-40 seconds

281
Q

What impact does liver idsease have on clotting function

A

◦ Decreased clotting function by decreased synthesis of clotting factors and decreased clearance of tPA
◦ Increased clotting function by decreased synthesis of antithrombotic factors (eg. proteins C and S)

282
Q

What clotting factors have short half lives?

A

2, 5, 7, 10 all <24 hours

283
Q

Acute liver failure affects clotting how?

A
  • Acute liver failure typically results in the loss of clotting protein synthesis and as 2/5/7/10 have half lives <24 hours demonstrate acute changes
    ◦ Normal - 8, 11, tPA (increased because of reduced hepatic clearance)
    ◦ Reduced in early liver failure - Vitamin K factors (2/7/9/10), 5, platelets with increased destruction in spleen and reduced thrombopoetin
    ◦ Reduced in severe end stage/fulminant liver failure - fibrinogen, protein C and S, antithrombin,
284
Q

What clotting factors are unaffected by liver failurw

A
  • Acute liver failure typically results in the loss of clotting protein synthesis and as 2/5/7/10 have half lives <24 hours demonstrate acute changes
    ◦ Normal - 8, 11, tPA (increased because of reduced hepatic clearance)
    ◦ Reduced in early liver failure - Vitamin K factors (2/7/9/10), 5, platelets with increased destruction in spleen and reduced thrombopoetin
    ◦ Reduced in severe end stage/fulminant liver failure - fibrinogen, protein C and S, antithrombin,
285
Q

How does liver disease affect intrinsic pathway clotting? What impact does this have on clotting measurements

A
286
Q

How does liver disease impact vitamin K dependent factors? How does this affect measurement?

A
287
Q

How does liver disease impact fibrinogen? How does this impact measurement of clotting?

A
288
Q

How does reduced liver function impact anticoagulant production? What impact does this have on clotting measurement?

A
289
Q

How does liver dysfunction impact fibrinolysis?

A
290
Q

How is glucose impacted by the liver and its function?

A
  • Glucose is the dominant form of metabolic fuel in human cellular energy production
    ◦ Normal value is 5mmol/L, up to 10 following a meal
    ◦ The liver stores glucose as glycogen and triglycerides, and is able to mobilise glucose into the bloodstream as needed
  • Hypoglycaemia is often associated with acute liver failure - blood glucose can drop over hours or minutes
  • In chronic liver failure, hyperglycaemia is often seen, due to decreased hepatic insulin clearance and increased peripheral insulin resistance
  • Extrahepatic influences on glucose include nutrition (eg. glucagon depleted in starvation), diabetes, medications (eg. insulin, exogenous IV glucose), skeletal muscle glycogen and renal gluconeogenesis.
291
Q

What is a normal ammonia level

A

11-32 micromol/L

292
Q

What does a raised ammonia reflect

A
  • A raised ammonia level suggests poor metabolic liver function, a dysfunction of urea cycle enzymes, altered gut organisms, or increased protein turnover/catabolism/uptake
293
Q

What is AST? What relevance does it have to hepatic function?

A
  • Aspartate aminotransferase (AST)
    ◦ Ubiquitous enzyme which converts oxaloacetate into aspartate.
    ◦ Found in many extrahepatic tissues, including cardiac and skeletal muscle
    ◦ An early but nonspecific biomarker of hepatocellular injury
294
Q

What is ALT? What relevance does it have to liver function?

A

◦ Kreb cycle enzyme found in hepatocytes cytosol ; half life 50 hrs
◦ Released later, after AST, in hepatocellular injury

295
Q

What is GGT? What relevance does it have to liver failure?

A

◦ ​​​​Induceable microsomal enzyme; transfers γ-glutamyl off glutathione
◦ Found in numerous tissues (renal tubules, liver, biliary tract, pancreas (minimal in bone)) - in hepatocytes surrounding biliary canaliculi
◦ Disproportionate rise in comparison to ALP suggests ETOH
◦ A highly non-specific marker of biliary tract disease

296
Q

What is ALP? What relevance does it have to liver function?

A
  • Alkaline phosphatase (ALP)
    ◦ A hydrolase which removes the phosphate group from various molecules
    ◦ Found in all tissues (eg. kidney, bone, small intestine, leukocytes and the placenta) as well as biliary canalicular membrane of hepatocyte
    ◦ A non-specific marker of biliary tract stress when >3x ULN
297
Q

What is LDH? What relevance does it have to liver function

A
  • Lactate dehydrogenase (LDH)
    ◦ C​​​​atalyses the conversion of lactate acid to pyruvate
    ◦ Found in essentially all cells
    ◦ A non-specific marker of liver damage
298
Q
A

Gastro nutrition (7 decks)

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