teach me physiology - liver Flashcards
1
Q
bilirubin is produced from what?
A
breakdown of RBCs = haemolysis
2
Q
what are the 2 forms bilirubin exists in?
A
- conjugated (water soluble - can travel in blood without a transport protien bound to it and can be excreted from the body)
- unconjugated (insoluble in water - can only travel in bloodstream bound to albumin and it cannot be directly excreted from the body)
3
Q
what are reticuloendothelial cells? what do they do?
A
macrophages response for the maintenance of the blood, throguh the destruction of old or abnormal cells. they take up RBCs and metabolise the Hb into haem and globin
4
Q
what is globin further broken down into?
A
amino acids which are then recycled
5
Q
what is haem broken down into? what is this catalysed by?
A
iron and biliverdin = catalysed by haem oxygenase
6
Q
what happens to the breakdown products of haem?
A
- iron — recycled
- biliverdin — reduced to create unconjugated bilirubin
7
Q
what enzyme is used in the biliverdin to bilirubin reaction?
A
biliverdin reductase
8
Q
what does unconjugated bilirubin bind to to facilitate its transport to the liver?
A
albumin
9
Q
how does unconjugated bilirubin enter the liver?
A
OATP = organic anion transporting peptide
10
Q
what happens to the unconjugated bilirubin once in the liver?
A
glucaronic acid is added to bilirubin by glucuronyl transferase — forms conjugated bilirubin = soluble
11
Q
conjugated bilirubin is soluble. what does this allow?
A
allows it to be excreted into the duodenum in bile
12
Q
via what is bilirubin excreted from the liver?
A
MRP2 = multi drug resistance-associated protein 2
13
Q
what happens to bilirubin once in ht e colon?
A
colonic bacteria deconjuagte bilirubin and convert it into urobilinogen
14
Q
what happens to 80% of urobilinogen?
A
further oxidised by intestinal bacteria and converted to stercobilin and then excreted through faeces
15
Q
what happens to 20% of urobilinogen?
A
- absorbed into the bloodstream as part of the enterohepatic circulation — it is carried to the liver where some is recycled for bile production, while a small % reaches the kidneys
- here it is oxidised further into urobilin and then excreted into urine
16
Q
what gives faeces its brown colour and urine its yellow colour?
A
brown = stercobilin
yellow = urobilin
17
Q
A
18
Q
the liver plays a central role in maintaining steady blood glucose levels by converting excess glucose into glycogen through a process known as _________
A
glycogenesis
19
Q
when there is bodily demand for glucose, the glycogen can be converted back into glucose through a process known as ___________
A
glycogenolysis.
20
Q
80% of the monosaccharide load absorbed by the SI is comprised of glucose, which is then delivered to the hepatocytes by the what?
A
portal vein
21
Q
fructose and galactose are also absorbed by the SI. what happens to the vast majority?
A
immediately converted into glucose in the liver
22
Q
describe glycogenesis steps
A
glucose —> glucose-6-P —> glucose-1-P —> UDP-glucose —> added to the long glycogen chain within the liver cells —> glycogen
23
Q
what enzyme converts glucose to glucose-6-phosphate in glycogenesis?
A
hexokinase (skeletal muscle) / glucokinase (liver)
24
Q
what enzyme converts glucose-6-P to glucose-1-P to UDO-glucose?
A
glucose-6-P —> glucose-1-P = phosphoglucomutase
glucose-1-P —> UDP-glucose = uridyl transferase
25
glycogensis: finally UDP-glucose is added to the long glycogen chain within the liver cells by ____________, with assistance from ____________
- glycogen synthase
- branching enzyme
26
what is Von Gierke disease?
glucose-6-phosphatase deficiency — body cant break down glycogen
27
what is Cori Disease?
glycogen debranching enzyme deficiency
28
through glycogenolysis, what are yielded from their storage in glycogen?
glucose and glucose-6-phosphate
29
where does glycogenolysis occur?
within the cytosol of the liver and also within the cytosol of skeletal muscle
30
describe the process of glycogenolysis
• the sequence of reactions differs from glycogenesis and is not simply the reverse of it
1. firstly, a molecule of glucose is phosphorylated to remove it from the glycogen chain by glycogen phosphorylase (assisted by de branching enzyme) creating glucose-1-phosphate
2. glucose-1-phosphate is converted to glucose-6-phosphate by phosphoglucomutase
3. glucose-6-P is converted to glucose by glucose-6-phosphatatase
31
in glycogenolysis, glucose-6-P can become glucose or it can also do what?
enter the glycolysis pathway, which culminates int he formation of pyruvate
32
the freed glucose is now ready for transport to other tissues where it will undergo glycolysis to produce __________, which is then converted into __________ before entering the __________
the freed glucose is now ready for transport to other tissues where it will undergo glycolysis to produce pyruvate, which is then converted into acetyl-coA before entering the TCA cycle
33
how does metabolism of glycogen differ between skeletal muscle and the liver?
in the skeletal muscle, glucokinase predominates in place of hexokinase during the first steps of glycogenesis
34
what us the key regulatory enzyme in glycogenesis?
glycogen synthase
35
glycogen synthase activity is upregulated by high levels of what?
glucose-6-phosphate
36
what is the key regulatory enzyme in glycogenolysis?
glycogen phosphorylase
37
what is glycogen phosphorylase allosterically inhibited by?
high levels of ATP, glucose-6-P and glucose
38
what act via 2nd messengers to control the rate and direction of glycogen metabolism?
glucagon, adrenaline and insulin
39
how do glucagon and adrenaline influence glycogen synthase and glycogen phosphorylase?
- upregulate adenylate cyclase — converts ATP into cAMP
- activates cAMP-dependent protein kinase
- phosphorylates glycogen synthase and glucose phosphorylase
- phosphorylation leads to deactivation of glycogen synthase and activation of glycogen phosphorylase
40
when are glucagon and adrenaline released?
- released as part of the sympathetic response to stress, adn therefore it follows that the body will need more glucose at this point
- therefore when we need less glycogen (deactivation of synthase) and more free glucose (activation of phosphorylase)
41
what do patients with Von Gierkes disease present with?
lactic acidosis, hypoglycaemia, hyperuricaemia and hepatic enlargement
42
what is gluconeogenesis?
= a metabolic pathway that results in the generation of glucose from non-carbohydrate substrates such as lactate, glycerol and glucogenic amino acids
43
when does gluconeogenesis occur?
around 8 hours of fasting, when liver glycogen stores start to deplete and an alternative source of glucose is required
44
where does gluconeogenesis occur?
mainly in liver and to a lesser extent in the cortex of the kidney
45
what are the 3 main gluconeogenesis precursors?
- lactate from anaerobic glycolysis in exercising muscle and RBCs via the cori cycle
- glycerol released from the breakdown of triglycerides in adipose tissue
- amino acids (mainly alanine)
46
gluconeogenesis vs glycolysis
47
what hormonal control stimulates gluconeogenesis?
stress hormones such as glucagon or cortisol upregulate PEP carboxykinase and fructose 1,6-bisphosphatase in order to stimulate gluconeogenesis
48
what does PEP carboxykinase do?
converts oxaloacetate to phosphoenolpyruvate in gluconeogenesis
49
what hormonal control decreases gluconeogenesis in a fed, high energy state?
gluconeogenesis decreases by inhibiting PEPCK and fructose 1,6-bisphosphatase
50
what are the lipids in the body ? which are composed of fatty acids?
- triglycerides, phospholipids and cholesterol
- former 2 formed from fatty acids, cholesterol isnt
51
what are the functions of the different lipid types?
triglycerides are mainly used as an energy store for times of increased energy demand, whereas cholesterol and phospholipids are used for functions such as the synthesis of the cell membrane and the synthesis of steroid hormones
52
what happens when energy is needed from the fat stored in adipose tissue? (lipolysis)
triglycerides are hydrolysed into fatty acids acids + glycerol by triglyceride lipase
53
what stimulates the hydrolysis of triglycerides?
adrenaline and glucagon
54
what happens when then the fatty acids from lipolysis enter circulation?
the immediately bind to albumin — when conjugated to albumin, the fatty acids are soluble in blood and so can be transported to tissues, including the liver
55
lipolysis: what is glycerol converted to upon entering hepatocytes? what does the product then do?
glycerol-3-phosphate which then enters the glycolysis pathway
56
what happens to the fatty acids in lipolysis?
need to be oxidised and degraded which occurs in the mitochondria via a series of reactions known as beta-oxidation
57
lipolysis: in beta-oxidation, 2 carbon segments are progressively released from the FA chain until what is generated?
acetyl-CoA
58
what are the byproducts of beta oxidation?
NADH and FADH2
59
lipolysis: what does acetyl-CoA then do?
binds immediately with oxaloacetate to form citrate and then enters the TCA cycle to release energy in the form of ATP
60
a large proportion of fatty acid degradation by beta-oxidation occurs in the ___________, but only a small amount is used for __________
- liver
- liver owns metabolism
61
in ketogenesis, what is excess acetyl-CoA converted to>
acetoacetic acid using HMG-CoA as an intermediate, and then transproted to other tissues
62
in ketogenesis, what is acetoacetic acid converted to?
some to beta-hydroxybutyric acid, and small amounts of acetone
63
what is acetoacetic acid?
keto acid
64
acetoacetic acid, together what what 2 other things are known as what?
acetone and beta-hydroxybutryic acid and acetoacetic acid = ketone bodies
65
ketone bodies can travel in the blood to other tissues where they are then used for what?
energy
66
summarise the ketogenesis process
67
when does lipogenesis provide an energy store?
when the body’s energy requirement cannot be met by glucose alone
68
where and when are fatty acids synthesised?
in the cytoplasm of hepatocytes following maximal conversion of glucose to glycogen
69
fatty acid synthesis: what happens to the remaining glucose?
pyruvate via the glycolysis pathway, and transproted into the mitochnrida where it is converted to acetyl-CoA
70
fatty acid synthesis: if not entering the TCA cycle, acetyl-CoA needs to leave the mitochondria and enter the cytosol, but why is this an issue? solution?
because the inner mitochondrial membrane is impermeable to acetyl-CoA and therefore it must transverse the membrane in an altered form = citrate = citrate shuffle
71
in lipogenesis, descirbe how acetyl-CoA is transferred out of the mitochondria and what happens to it
1. acetyl-CoA joins with oxaloacetate to form citrate
2. citrate can cross mitochondrial membrane
3. citrate is then converted back to acetyl-CoA and oxaloacetate within the cytosol
72
lipogenesis: what happens to acetyl-CoA in the cytosol?
- converted to malonyl-CoA by acetyl-CoA carboxylase
- fatty acid synthase then creates an elongated fatty acid chain from the malonyl-CoA molecules, adding 2 carbon atoms for each molecule of malonyl-CoA
- as the malonyl-CoA molecules are added, they lose a carbon atom, creating CO2
73
what do 3 FA combine with to become triglycerides?
glycerol molecule
74
where is VLDL synthesised and what does it do?
- very low density lipoprotein
- synthesised in liver
- transports triglycerides from the liver to their destination in adipose tissue
75
what hormones inhibit lipogenesis?
glucagon and adrenaline
76
negative feedback from what inhibits lipogenesis?
from the presence of lipoprotein
77
what is the main hormone to stimulate lipogenesis?
insulin
78
what cells make glucagon?
alpha cells of islets of langerhans in pancreas
79
what is the role of the liver in protein metabolism?
stores more proteins than other tissues, can rapidly synthesise or degrade proteins, can quickly synthesise and degrade amino acids (unlike most other tissues)
80
how many amino acids does the body need and where do they come from?
- need 20
- can get 10 from diet
81
synthesis of each non-essential amino acid is slightly different, but all occur by a process known as what?
transamination
82
describe transamination
> a precursor alpha-keto acid such as pyruvate is needed
> a donor of the amino group is needed, and this is commonly glutamic acid
> an aminotransferase catalyses the reaction such as alanine transaminase (ALT)
83
what hormones simulate protein synthesis?
insulin and growth hormone
84
give examples of plasma proteins made by the liver
albumin, fibrinogen, clotting factors
85
what do plasma proteins also provide in the blood?
oncotic pressure
86
as vitamin K is fat soluble, what is needed for its digestion and absorption?
bile
hence biliary obstruction —> bleeding as vitamin K dependent clotting factors not made
87
amino acid catabolism
• once the cells of the body have reached their limit of protein storage, the left-over amino acids in the blood are metabolised in the liver, prior to their conversion into _______ or ________
• done through processes of _____________ and ______________, before the __________ generated is cleared in the urea cycle
- lipids or glucose
- transamination and deamination
- ammonia
88
in transamination, what are amino acids converted to? enzyme?
converted too keto acids using an acceptor to accept the amine group
catalysed by aminotransferases such as ALT/AST
89
transamination
amino acid + a-ketoglutarate —>________ + ________
amino acids + oxaloacetate —> _________+_________
amino acid + a-ketoglutarate —> glutamate + keto acid
amino acids + oxaloacetate —> aspartate and keto acid
90
aspartate made from amino acids + oxaloacetate can be further metabolised to what?
aspartate + a-ketoglutarate —> oxaloacetate and glutamate
91
what is the end result of transamination?
the generation of glutamate
92
what happens to the glutamate produced in transamination?
metabolised further by glutamate dehydrogenase — DEAMINATION:
the amine group is removed and rapidly forms ammonia (NH3) and subsequently ammonium (NH4+), alongside a-ketoglutarate
93
what happens to the ammonium and a-ketoglutarate produced in deamination?
• the ammonium is highly toxic and must therefore be removed through the urea cycle
• meanwhile, the a-ketoglutarate can enter the TCA cycle
94
where does the urea cycle occur?
mitochondria and cytoplasm of the hepatocyte
95
describe the urea cycle
• within the mitochondrion, ammonia reacts with ATP and CO2 to generate citrulline from ornithine
• the citrulline then enters the cytoplasm and passes through a series of reactions, consuming aspartate along the way, to generate ornithine
• the ornithine then re-enters the mitochondrion and the cycle repeats
• through this process, the toxic ammonia is converted to harmless urea, which is easily excreted
96
describe vitamin D metabolism
97
what are signs and symptoms of liver disease?
- bleeding
- oedema and ascites
- GI bleeds — varices due to portal hypertension
- fetor hepaticus
- jaundice
- hepatic encephalopathy
98
why do you get oedema in liver failure?
liver synthesis almost all of the body’s plasma proteins, without which the oncotic pressure of the blood falls, and fluid leaks out of the blood vessels into the extracellular space, leading to oedema
99
why do you get ascites in liver failure?
cirrhosis increases resistance to the flow of blood which causes portal hypertension. the hypertension in the portal vein leads to more fluid leaking out of the portal vein contributing to ascites
100
what is fetor hepaticus?
faecal/sweet smelling breath — late sign. due to thiols (sulphur containing compounds) and acetone in the breath. thiols accumulate in the blood as portal vein hypertension leads to porto systemic shunting, meaning some thiols absorbed by the gut escape first pass metabolism. raised acetone levels are due to an increase in fatty acid breakdown as a response to impaired gluconeogenesis and glycgoen storage
101
what leads to hepatic encephalopathy?
102
what is one of the major contributors to the hyperglycaemia seen diabetic patients?
gluconeogenesis
103
how can alcohol cause hypoglycaemia?
- alcohol abuse alters the NAD+/NADH ratio, leading to excess NADH
- ths inhibits fatty acid oxidation that provides ATP and favours the pyruvate to lactate reaction, deleting the pyruvate for gluconeogenesis and causing hypoglycaemia
- this leads to hepatic glycogen depletion combined with alcohol-mediated inhibition of gluconeogenesis and is common in malnourished alcohol abusers
104
what are the 3 categories of jaundice?
- pre-hepatic
- hepatic
- post-hepatic
105
what causes pre-hepatic jaundice?
increased haemolysis — results in the increased presence of unconjugated bilirubin in the blood as the liver is unable to conjugate it all at the same rate.
106
what causes increased haemolysis?
- tropical disease eg. malaria, yellow fever
- genetic disorders eg. sickle cell anaemia, Gilbert’s syndrome
- haemolytic anaemias
107
what causes hepatic jaundice?
liver impairment (eg. viral hepatitis, hepatotoxic drugs like paracetamol overdose, alcohol abuse) — causes decreased ability of the liver to conjugate bilirubin, resulting in the presence of conjugated and unconjugated bilirubin in the blood
108
what causes post-hepatic jaundice?
blockage of bile ducts (eg. gallstones, hepatic/pancreatic tumours) — results in backflow of conjugated bilirubin into the blood as it cannot move past the obstruction
109
what is Gilbert’s syndrome?
an inherited disorder where there is hyperbilirubinaemia due to a fault in the UGT1A1 gene leading to a deficiency in UDP-gluconoryltransferase — this faulty gene results in slower conjugation of bilirubin in the liver and so it builds up in the bloodstream instead of being excreted through the biliary ducts
when well, patients are usually asymptomatic and have normal bilirubin levels. however, under physiological stressors such as illness, alcohol base and extreme exercise, patients can become markedly jaundiced
110
what is glucose converted to in glycolysis?
2 molecuels of pyruvate, 2 H atoms, 2 H20 molecules
high energy intermediates, ATP and NADH are also synthesised
111
what happens to the pyruvate made in glycolysis?
proceeds to the link reaction which makes acetyl-CoA — acetyl-CoA then goes to TCA cycle
112
is glycolysis an aerobic or anaerobic process?
anaerobic
113
where do the electrons required for ATP to pass down the electron transport chain come from?
come from electron carriers such as NADH and FADH2 = produced in TCA cycle
114
describe the link reaction
pyruvate from glycolysis is decarboxylated to form acetyl-CoA by the pyruvate decarboxylase complex - this acetyl-coa then enters the cycle
115
what does each TCA cycle produce?
> 2 molecules of CO2
> 3 molecules of NADH
> 3 H+
> 1 FADH2
> 1 GTP
116
• each molecule of glucose produces __ molecules of pyruvate, which in turn produce __ molecules of acetyl-CoA
• therefore each molecule of glucose produces _____ the net output of each cycle
• each molecule of glucose produces 2 molecules of pyruvate, which in turn produce 2 molecules of acetyl-CoA
• therefore each molecule of glucose produces double the net output of each cycle
117
how do products of the TCA cycle regulate it?
provide -ve feedback on the enzymes that catalyse it. for example, NADH inhibits the majority of enzymes in the cycle
118
how does citrate regulate the TCA cycle?
inhibits phosphofructokinase = a key enzyme in glycolysis. this reduces the rate of production of pyruvate and therefore acetyl-CoA
119
how does calcium regulate the TCA cycle?
accelerates the TCA cycle by stimulating the link reaction
