Physiology 16 Flashcards
When is lactate produced during glycolysis?
During the cytosolic phase, excess pyruvate is converted to lactate by lactate dehydrogenase
In what situations does significant conversion of pyruvate to lactate occur?
When pyruvate production exceeds mitochondrial capacity to use it:
- In cells without mitochondria (eg. erythrocytes)
- Increasing anaerobic metabolism
- Rapid increase in metabolic rate
- When glucose metabolism exceeds oxidative capacity of mitochondria
Outline the metabolic pathways for lactate
First lactate is converted back to pyruvate by LDH, then it can:
- Move into mitochondria for use in citric acid cycle
- Be converted to glucose in the liver/kidneys (gluconeogenesis)
- Undergo transamination to alanine in the liver/kidneys
Where is LDH found?
In all cells except pancreatic islet cells
Which tissues are the most active in producing lactate?
Muscles
Erythrocytes
Outline the normal use of lactate in the body
75% is oxidised for use as substrate in the citric acid cycle
25% is transported to the liver where is undergoes gluconeogenesis in the Cori cycle
Outline the Cori Cycle
- Describes the cycle of use of glucose between the muscles and liver, including glycogenolysis and gluconeogenesis
- Gluconeogenesis can only occur in aerobic conditions
- Muscle and sympathetic activity cause glycogenolysis in the muscles, and the glucose produced is glycolysed, producing lactic acid.
- Lactic acid travels to the liver, is converted to pyruvate and then glucose through gluconeogenesis.
- This glucose can then be stored via glycogenesis or transported back to the muscles where it may be used for glycolysis or gylcogenesis depending on level of activity.
How much albumin is produced by the liver per day?
12g
What types of molecules are bound by albumin?
Fatty acids, unconjugated bilirubin, Fe, Cu, bile acids, drugs, toxins
What serum proteins other than albumin are produced by the liver?
What do they transport?
Transferrin - Fe Haemopexin - Haem Transcobalamins - B12 Folate binding protein - Folate Caeruloplasmin - Cu Haptoglobin - Hb Lipoproteins - Triglycerides, cholesterol, bile acids Thyroxine binding globulin - Thyroxine
Which coagulation factors are produced in the liver?
II, VII, IX, X
Why is vitamin K needed for the production of coagulation factors in the liver?
Required for post-translational formation of γ-carboxyglutamyl residues which are essential for physiological activation
What hepatobiliary problems may affect clotting? How is it affected?
PT may be prolonged in conditions that:
- Cause hepatocellular damage (and thus synthetic function)
- Cause cholestasis (and thus reduce absorption of vit K)
What is the liver’s role in production of inhibitors of haemostasis?
Major site of production for:
- Antithrombin III
- Protein C
- Protein S
What are the sources of ammonia in the body?
- Catabolism of protein and nucleic acids
- Production by intestinal flora (from dietary protein and urea)
How is ammonia processed following production?
Absorbed via intestine into portal venous blood
Metabolised in the liver such that almost all ammonia is removed from the blood.
What is a normal systemic blood ammonia level?
In what form is it most abundant?
<35 umol/L
At pH 7.4 it is mostly in its ionised form - the quaternary ammonium ion NH4+
How is ammonia metabolised in the liver?
How is this related to pH regulation?
Conversion to urea and glutamine
H+ released from NH4+ in the process neutralises excess HCO3- produced from amino acid catabolism, thus regulating pH
How is urea excreted?
- Urea is electroneutral
- Transported by facilitated diffusion
- Excreted renally
Where does the urea cycle take place?
What happens in each place?
In the mitochondria and cytosol of hepatocytes, Z1 > Z2 > Z3
The first steps take place in the mitochondria where NH4+ + ornithine -> Citrulline
The next steps take place in the cytosol where Citrulline + aspartate -> Urea + ornithine + fumarate
How much urea is recycled?
30% of urea produced is hydrolysed in the colon, producing ammonia which is reabsorbed and converted back to urea in the liver
How is ammonia metabolised other that via urea production?
Where does this take place?
Coversion to glutamine by glutamine synthetase in perivenular (Z3) hepatocytes (scavenger cells).
This is a high affinity system, thus damage to these cells produces hyperammonaemia
What type of immune cells reside in the liver?
Kupffer cells
NK cells
NKT cells
What is the mean turnover rate for Kupffer cells?
21 days - 14 months
Outline the role of the liver in humoral immunity
Key role in IgA transport and clearance
IgA synthesised in the gut and transported to the liver -> secreted in bile thus reaching the lumen
Aside from the liver, which other tissues take up urea from the blood?
Skeletal muscle and brain
What is the cardia of the stomach?
Area adjacent to the oesophagus
What is the fundus of the stomach?
the area superior to the cardia. Dome shaped and may contain gastric bubble
What is the body of the stomach?
The main part
What is the antrum of the stomach?
The widest part of the distal stomach. Possesses a thick, mucular wall.
What is the pylorus?
The funnel-shaped most distal part of the stomach ending in the pyloric sphincter, through which chyme passes into the proximal duodenum
What are the muscular layers of the stomach?
[from outside in]
- Serosa
- Smooth muscle layer (longitudinal, circular and oblique)
- Submucosa
- Muscularis mucosae
- Mucosa (lamina propria and columnar epithelium)
What are the gastric rugae?
Longitudinal irregular folds of mucosa and submucosa more prominent in the proximal stomach. They flatten out as the stomach fills.
Outline the parasympathetic innervation of the stomach
Para (vagus):
- Sensory - pain/distension
- Secretomotor
- Motor - tone/peristalsis
Symp (splanchnic nerves):
- Sensory - pain/distension
- Motor - inhibit motility
How is the enteric nerve supply arranged?
Two layers within the wall:
- Myenteric (Auerbach’s) plexus - between longitudinal and circular muscle layers. Regulates motility and sphincter function.
- Submucosal (Meissner’s) plexus - in submucosa. Regulates epithelial and submucosal blood vessels.
What are the principle neurotransmitters involved in GI function?
Stimulatory:
-ACh
Inhibitory:
- Adrenaline
- NANC (non-adrenergic non-cholinergic) neurotransmitters eg. substance P, vasoactive intestinal peptide (VIP), NO
What is the structure of the gastric mucosa?
Columnar epithelium forming deep gastric pits (100 per mm^2) which connect to and convey secretions from two or three tubular glands to the stomach lumen
What are the important cells of the gastric mucosa?
Mucus neck cells:
- situated at openings of gastric pits
- secrete mucus
Chief cells:
- Found at base of glands
- Secrete pepsinogen
- Possess extensive RER and apical secretory granules
- Most concentrated in body of stomach
Parietal / Oxyntic cells:
- Pyramidal in shape
- Secrete HCl and IF
- Possess extensive apical canalicular system which maximises SA for acid secretion
- Numerous mitochondria (for acid production)
- Most concentrated in fundus and body
G cells:
- Entero-endocrine cells
- Produce gastrin and secrete into blood
- Most concentrated in antrum
D cells:
- Entero-endocrine cells
- Produce somatostatin and secrete into blood
- Respond to gastric acidity
Summarise the functions of the stomach
- Temporary storage of ingested contents
- Mechanical breakdown of food
- Chemical digestion and breakdown of protein
- Secretion of IF for B12 absorption
- Regulation of chyme output into duodenum
Outline the function of the stomach as a temporary storage area
- Converts episodic input of food into more continuous output of chyme
- Highly distensible, with minimal increase in intragastric pressure up to a volume of 1L
- When empty has volume of 50ml
- Maximum capacity ~4L
What are the mechanisms by which the stomach distends to accommodate food input?
2 vagal reflexes:
- ‘Receptive relaxation’ of smooth muscle as a response to oesophageal stretch receptors
- ‘Adaptive relaxation’ due to presence of food in proximal stomach.
- Involve release of VIP and NO
What forms the lower oesophageal sphincter (LOS)?
What is its opening pressure?
- Physiological sphincter
- Formed by tonic contraction of lowest 2-4cm of oesophagus
- Opening pressure of 15-25 mmHg above gastric pressure.
Whas factors affect LOS tone?
Increase tone:
- Gastrin
- Cholinergic stimulation
- Metoclopramide, prochlorperazine, cyclizine
- Suxamethonium
Decrease tone:
- Swallowing
- Antimuscarinics
- Dopamine
- Alcohol
- Opioids
- Thiopentone
- Oestrogen, progesterone (ie, pregnancy)
Other than LOS tone, what factors contribute to reducing risk of reflux?
- Acute angle of gastrooesophageal junction
- Passage of oesophagus through crura of diaphragm
Explain the electrophysiological generation of gastrointestinal motility
- SM cells have a transmembrane potential which fluctuates between -40 and -70 mV. This oscillation constitutes the basic electrical rhythm (BER) or ‘slow wave’. This determines the maximum rate of contraction.
- When threshold potential of -40 mV reached -> depolarisation (‘spike’ / ‘burst activity’) and SM contraction
- Gap junctions between SM cells enable sychronous contraction and syncytial function.
- BER is generated in the longitudinal muscle of the greater curve in the stomach with a rate of 3/min.
How is strength of GI smooth muscle contraction modulated?
Factors eg. vagal stimulation and gastrin secretion cause reduction in transmembrane potential (ie. towards 0), increasing frequency and amplitude of spike potentials and increased motility
Factors eg. sympathetic stimulation cause hyperpolarisation and thus decreased frequency and amplitude of spike potentials and reduce motility.
Outline gastric activity in the ‘fed state’
- Tonic contractions of proximal stomach (up to 6 mins each) exert a steady pressure on gastric contents which are gradually squeezed distally. No slow-wave activity at this point.
- Vigorous contractions of distal stomach ‘grinds’ contents with gastric juices forming an acidic ‘chyme’
- The antrum, pylorus and pyloric sphincter contract together, causing retropulsion and turbulence which shears particles and increases mixing
What size food particles may pass into the duodenum?
<1mm diameter
Outline gastrointestinal motility in the fasted state
- ‘Migratory motor complexes’ (MMCs) start in the antrum every 90-120 mins, progressing along the bowel at 6-8 cm/min
- Likely occur to move indigestible contents such as fibre
- Strength of MMC contractions increased by motilin, released from the duodenum
What is the pH of gastric juice?
How much is produced per day?
pH 1-1.5
Around 2L per day produced
Summarise the structure and function of gastric parietal cells
Parietal cells secrete HCl and IF into the gastric gland space
They have extensive apical canaliculi which increase SA for secretion of H+ ions via H+/K+ ATPase.
They have numerous mitochondria
Receptors for gastrin, ACh and H2 on basolateral membrane. These serve to stimulate acid secretion by activating second-messenger systems
What factors increase gastric acid secretion via gastrin?
Distension of stomach body
Presence of amino acids and peptides
What factors inhibit gastric acid secretion?
Low gastric pH Vagotomy Somatostatin H2 antagonists PPIs
What are the functions of gastric acid?
- Facilitates protein breakdown
- Activates pepsinogen -> pepsin and creates optimal conditions for activity
- Improves Ca2+ and Fe solubility
- Antimicrobial action
Outline the process of production and secretion of gastric acid
Carbonic acid dissociates -> H+ + HCO3- within parietal cells
H+ exchanged for K+ from the gastric lumen
HCO3- exchanged for Cl- at the basolateral membrane
Cl- is then transported across the apical membrane along with K+ ions
