What does the liver act as an interface between?
- Bloodstream and the gastrointestinal tract
> Receives around 25% of the resting cardiac output
Low Blood pressure (portal vein = 9 mm.Hg; hepatic vein = 0 mm.Hg)
Low vascular resistance
Stores around 450 mL of blood and can expand
List 4 ways the liver acts as an interface between bloodstream and gastrointestinal tract.
- Filters blood
- Stores and releases metabolites
- Production of bile and coagulation factors
- Metabolises vitamins and hormones
Hepatocytes are secretory epithelial cells specialised for exchanging solutes between …..
- The Space of Disse and the bile canaliculi
> Hepatocytes possess microvilli to increase surface area for exchange from blood
> Hepatocytes are able to uptake, metabolise and excrete a wide range of solutes using both the Multidrug-resistance-associated proteins (MRP) and Organic Anion Transporters (OAT).
List three ways the liver is involved in transportation/production of lipids
- Lipoprotein synthesis, secretion and reuptake
- Chylomicron processing
- Bile Salt production
The liver is a master regulator of whole body metabolism
- Describe cholesterol metabolism. Where do statins work?
- Inhibit HMG-CoA reductase which is the enzyme responsible for converting HMG-Co-A into Mevalonate
Describe Enterohepatic circulation.
- Key note: Primary/seecondary bile salts recycled partially absorbed and enter portal circulation back to the liver.
- Primary bile salts conjugated with glycine or taurine to form bile salts.
- In recycling secondary bile acids can be reconjugated with glycine or taurine and re-enter the bile pool.
How is the liver involved in protein metabolism?
Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors- which drug effects this process?
- Warfarin
- Vitamin K is essential for proteins in the cascade that require calcium binding to function. Warfarin acts on this cycle to reduce coagulation, thin the blood.
What are the 3 main roles of the liver in carbohydrate metabolism?
- Regulation of blood glucose by glycogen synthesis and breakdown
- Gluconeogenesis
- Conversion of carbohydrate and proteins into fatty acid and triglyceride
> Controlled by insulin, glucagon, circulating catecholamines and the sympathetic nervous system
Insulin promotes anabolism (building up) and storage. What are the main effects on:
- Skeletal muscle
- Liver
- Adipose tissue
Glucagon controls catabolism and gluconeogenesis:
- Skeletal muscle
- Liver
- Adipose tissue
Give a brief overview of the cori cycle.
- Lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, then returns to the muscles and is cyclically metabolised back to lactate.
The liver’s response to fasting:
1- What happens in the earliest response to fasting (first 6 hours)?
2- After the first 24 hours what process begins?
3- In the protein conservation phase, (10 days) after extended fasting what supplies the CNS?
1- In the post-absorptive stage the CNS and other tissues preferentially use glucose broken down from glycogen stores- glycogenolysis
2- Gluconeogenic phase: Gluconeogenesis. Protein catabolism in order to supply glucose to the CNS whilst other tissues use fat and ketones.
3- Ketones are used instead of glucose for CNS, gluconeogenesis is reduced for proteins and fatty acids used fuel all other tissues
Liver can produce ketones as an alternative to glucose to fuel metabolism during periods of fasting. All of the bodies cells can use these.
1- The presence of which hormone prevents ketone production?
2- What will too much ketone production do to the blood?
3- Why is diabetic ketoacidosis a medical emergency?
1- Insulin. In absence of insulin and maintained presence of glucagon, the body will release free fatty acids from adipocytes which can be rapidly converted to ketone bodies in liver.
2- Acidify it- ketoacidosis
3- Ketones acidify the bloodstream – leading to vomiting, and with concurrent hyperglycaemia triggering an increase in urine output, patients can rapidly become dehydrated and can fall into a coma.
Liver oxidation of fatty acids during fasting releases what?
- Release ketone bodies during fasting
Describe the metabolism of Bilirubin.
How does the liver play a role in Iron homeostasis?
1- Which protein is an iron exporter?
> On which cells is it present?
- Ferroportin
> Intestinal cells absorbing iron,
> Erythrocyte-recycling
> macrophages
> Iron-storing hepatocytes
1- Which hormone is an iron-regulating peptide made in the liver?
2- How does it act to regulate plasma iron?
3- In the case of low serum iron, will the liver compensate by releasing high or low levels of hepcidin?
1- Hepcidin
2- Hepcidin acts by binding to and inactivating the sole cellular iron exporter, ferroportin.
3- Low levels
What happens when things go wrong in the liver?
- Damage E.g hepatitis, alcohol liver damage, leading to cirrhosis
> Stellate cells can be activated by lots of things: cytokines NKT cells, oxidative stress, hepatocytes and many other
Describe the contributing factors and stages leading to ascites. (1) What does liver cirrhosis cause?
- Liver cirrhosis = stellate cell to assume a myofibroblast-like phenotype - causes them to deposit collagen inSpace of Disse and contract- leading to compression of sinusoidal capillaries – increasing resistance to blood flow into hepatic vein.
- Deposition of collagen also blocks fenestrations in sinusoidal capillaries – reducing albumin’s movement from hepatocytes into circulation (hypoalbuminemia)
= The increased resistance to flow trigger sinusoidal capillary and portal hypertension
Describe the contributing factors and stages leading to ascites. (2) How is portal hypertension worsened?
- Build up of pressure in the splanchnic circulation triggers greater nitric oxide production – elicits vasodilatation of upstream splanchnic arterioles– increasing blood flow into splanchnic circulation.
= Increasing portal hypertension and greater volume of blood within the splanchnic veins, leading to fluid build up.
Describe the contributing factors and stages leading to ascites. (3) Explain the issue surrounding Increase/Decrease of peritoneal fluid volume.
1- Reduction in plasma albumin content of blood
- Sinusoidal and portal hypertension which both increase fluid filtration of plasma across hepatic and intestinal capillaries (Starling’s Forces). = ↑Peritoneal fluid volume
2- This ↓ Blood Volume
↓mean arterial pressure
↓sinusoidal and intestinal pressure
= Can’t maintain increase in Peritoneal fluid volume = preventing further filtration.
3- BUT…
↑ Blood Volume
= mean arterial pressure
= sinusoidal and intestinal pressure
↑ Peritoneal fluid volume
> Therefore to support large-scale filtration into the peritoneum we also need to expand the blood volume to allow fluid to be redistributed from the blood into the peritoneum without affecting arterial blood pressure.
Describe the contributing factors and stages leading to ascites. (4)
1- What causes a reduction of blood reaching IVC?
2- What does ↓Blood pressure in vena cava cause?
1- Pooling of blood in splanchnic circulations
- Higher resistance of blood flow through sinusoids to hepatic vein
2- Reduction of blood reaching IVC triggers reduced firing of the cardiopulmonary baroreceptors
> The body interprets this as a fall in blood volume and acts to expand the blood volume.
> In reality the blood volume hasn’t changed, it is just abnormally distributed due to its increased pooling in the sphlanchnic circulation.
Describe the contributing factors and stages leading to ascites. (4) What does reduced firing of cardiopulmonary baroreceptors result in?
- Triggers increased sympathetic outflow to kidneys – increasing Na+ reabsorption and activation of renin-Angiotensin II-Aldosterone system (via secretion of renin from afferent arterioles).
- Angiotensin II and Aldosterone increase the blood volume by stimulating an increase in Na+ content of the blood (via increase dietary intake and reducing urine Na+ losses) and increasing feelings of thirst.
> Blood volume continues to expand = ASCITES
