Basic Cellular Physiology

The standard model used to understand the cardiac action is the action potential of the ventricular myocyte. The
cardiac action potential has five numbered phases (0-4).
 
Phase 0 – Rapid depolarization phase
 An action potential is triggered once the membrane potential reaches the threshold (approximately -70 mV)
 Fast Na+ channels open and there is a rapid influx of Na+ ions
 Na+ channels automatically inactivate after a few milliseconds
 L-type Ca2+ channels open
 
Phase 1 – Early repolarisation phase
 Commences once Na+ channels inactivate
 Some K+ channels open briefly
 Efflux of K+ and Cl– ions
 
Phase 2 – Plateau phase
 Slow influx of Ca2+ ions via L-type channels that opened in phase 0
 Efflux of K+ ions via delayed rectifier K+ channels
 Plateau sustained by balance between movement of Ca2+ and K+ ions
 
Phase 3 – Rapid repolarisation phase
 L-type Ca2+ channels close
 K+ channels remain open and there is further efflux of K+ ions
 
Phase 4 – Resting phase
 Resting potential restored by Na+/K+ ATPase and Na+/ Ca2+ exchanger
 Resting potential is approximately -90 mV
 Na+ and Ca2+ channels are closed in the resting phase

The velocity of the action potential increases proportionally with the square root of axonal diameter.
The axons with the largest diameter having the fasting conduction velocities.

 The velocity of the action potential also increases if the neuron is myelinated.
The characteristics of cardiac cell types displaying pacemaker behaviour is shown in the table below:
 
 
Inherent
Pacemaker cell Location
rate
 
   
 
Right atrium at junction with superior 60-100
Sinoatrial (SA) node
vena cava BPM
 
   
     
Atrioventricular (AV) Right atrium at posteroinferior area of 40-60 BPM
node interatrial septum  
     
     
Purkinje fibres Throughout the ventricles 20-40 BPM
     
 
Blood flow is tightly matched to metabolic rate in skeletal muscle. This is achieved primary by metabolic
hyperaemia; actively metabolising tissue produces vasoactive substances which cause localised vasodilation. The
identity of these vasodilators is unclear but thought to include K+ efflux secondary to repeated depolarisation, and
metabolites of ATP including adenosine and inorganic phosphates.
 
Capillary recruitment is a consequence of metabolic hyperaemia. In resting muscle the terminal arterioles contract
intermittently and asynchronously so only a third of the muscle is well perfused at any one time. With metabolic
hyperaemia increased arteriole vasodilation causes a higher percentage of capillaries to be well perfused at any one
time. This gives a higher surface area for solute exchange.
 
Sympathetic stimulation constricts feeding arteries so reduces blood flow to the arterioles and muscle.
 
Muscle contraction during exercise pumps blood along the venous system, increasing the pressure difference
between arterioles and venules, and increasing blood flow through the capillaries.
 
Capillary angiogenesis is seen with repetitive muscle use (e.g. endurance training). It is a long-term consequence not
an immediate way of increasing blood flow.

The amount of water in the body varies with a patient’s age, weight, and sex. Total body water (TBW)
accounts for around 60% of an adult male’s total body weight; a normally hydrated 75 kg man will
consist of approximately 45 L of water.

 There are two major fluid compartments in the human body:

1. Intracellular fluid (ICF): This is the water within the cells and accounts for approximately 65% of
total body water (30 L of fluid). This is the matrix in which intracellular organelles are suspended
and chemical reactions take place.

2. Extracellular fluid (ECF): This is the water outside of the cells and accounts for approximately
35% of total body water (15 L of fluid).

 These compartments are separated by the plasma membrane of the cells and differ markedly in terms
of the concentrations of the ions dissolved in them.

 The extracellular fluid is further divided into three other compartments:

 1. Interstitial fluid (ISF): This is the tissue fluid found in the spaces between the cells and accounts
for approximately 65% of the ECF (10 L of fluid).

2. Intravascular fluid: This is the plasma, which is the liquid component of the blood and accounts
for approximately 25% of the ECF (3.5 L of fluid).

3. Transcellular fluid: This is the final 1.5 L of fluid and comprises intraocular fluid, cerebrospinal
fluid, urine in the bladder, joint fluids, and fluid within the lumen of the bowel.

 The barrier between the interstitial fluid and the intravascular fluid consists of the walls of capillaries.

Transcellular fluid is the portion of the total body water that is contained within epithelial
lined spaces. It is the smallest component of the extracellular fluid (ECF), accounting for
approximately 2.5% of the total body water and 5% of the ECF.
 
Examples of transcellular fluids include:
 Intraocular fluid
 Cerebrospinal fluid
 Urine in the bladder
 Joint fluids
 Fluid within the lumen of the bowel
 
Plasma is the intravascular fluid, which is the liquid component of the blood and accounts
for approximately 25% of the ECF.

Third spacing is the unusual accumulation of fluid in the transcellular space. Examples of
third spacing include:
 Pooling of fluids at burn sites
 Ascites
 Pleural effusions
 Fluids leaking from peritoneal cavity e.g. in pancreatitis

The Donnan equilibrium, or Gibbs-Donnan effect, is the name given for the behavioiur of
charged particles near a semi-permeable membrane.
 
It is the state of equilibrium that exists at a semi-permeable membrane when it separates
two solutions containing electrolytes, the ions of some of which are able to permeate the
membrane and some are not. An electrical potential develops between the two sides of the
membrane and the two solutions will have different osmotic pressures.

Osmosis is the passive movement of water across a semi-permeable membrane from regions of low solute
concentration to those of higher solute concentration. The primary mechanism for the movement of water across
these semi-permeable membranes is the creation of osmotic gradients.
 
Fluids can be isotonic, hypotonic or hypertonic:
 Isotonic fluids have the same osmotic potential as plasma
 Hypotonic fluids have a lower osmotic potential than plasma
 Hypertonic fluids have a higher osmotic potential than plasma
 
The ingestion of fluids of differing osmotic potentials has distinct effects on the distribution of water between cells and
the extracellular fluid.
 
If isotonic fluids are ingested the plasma remains at the same concentration. Ions move freely from the plasma into
the interstitial fluid. As the fluid is isotonic no osmotic potential is generated between the interstitial fluid and cells and
the intracellular fluid is unaffected.
 
If hypertonic fluids are ingested the plasma becomes concentrated. Water and ions move freely from the plasma
into the interstitial fluid. The interstitial fluid therefore also becomes more concentrated and the increased osmotic
potential draws water out of the cells. The cells subsequently lose water and shrink and the intracellular fluid
becomes more concentrated.
 
If hypotonic fluids are ingested the plasma becomes diluted and the oncotic pressure is reduced. Water and ions
move freely from the plasma into the interstitial fluid. The interstitial fluid therefore becomes more dilute and the
reduced osmotic potential draws water into the cells. The cells subsequently gain water and swell and the intracellular
fluid becomes more dilute.
 

The sarcomere is defined as being the segment between two neighbouring Z-lines.

 
The I-bands are zones of thin filaments extending from either side of these Z-lines to the start of the thick filament
(myosin).
 
The A-band lies between the I-bands and contains the entire length of a single thick filament (myosin).
 
The H-zone lies at the centre of the sarcomere and is the zone of thick filaments that is not superimposed by thin
filaments. The H-zone serves to hold the myosin filaments in position so that each one is surrounded by six actin
filaments.
 
The M-band (or M-line) is a disc in the middle of the H-zone formed of cross-connecting elements of the
cytoskeleton.

 Myosin is the major constituent of the thick filament. Actin is the major constituent of the thin filament. Thin filaments
consist primarily of actin, tropomyosin and troponin in a ratio of 7:1:1.
Arterioles are small diameter vessels (50-300µm) connecting arteries to capillaries. The walls are
composed of a tunica intima (single layer of squamous endothelium and internal elastic lamina), tunica
media (smooth muscle) and adventitia (connective tissues).

 The function of arterioles is to control blood flow and pressure by constricting or dilating.
Vasoconstriction and dilation can be localised (intrinsic) – matching blood flow to demand within a
single organ - or systemic (extrinsic) – regulating systemic vascular resistance and blood pressure. As the
smallest diameter resistance vessels, arterioles are the main contributor to total systemic vascular
resistance.

 Intrinsic control is via metabolic factors (local metabolite concentration, acid-base state, hypoxia) and
paracrine factors (including NO, histamine, bradykinin, prostaglandins). Systemic control is via
sympathetic stimulation (adrenaline, noradrenaline) and systemic hormones (ADH, Angiotensin).

 Arterioles contain numerous α1 and α2 receptors. Sympathetic stimulation of these receptors causes
vasoconstriction. Arterioles in the skeletal muscle and cardiac muscle circulation also contain β2
receptors. Sympathetic stimulation of these receptors causes vasodilation.

 Arterioles also exhibit spontaneous vasomotion (rhythmic asynchronous constriction and dilatation).

Lymphatic capillaries are found in all tissues except bone, teeth and the central nervous system. They
are larger than blood capillaries (10-50µm and 3-10µm diameter respectively) and are composed of a
single layer of endothelial cells and an incomplete basement membrane. Lymphatic capillaries have no
smooth muscle in their walls, though the larger lymphatic vessels do as the active pumping of lymph
becomes more important proximally.

 Lymphatic capillaries are adapted to be highly permeable. They absorb excess interstitial fluid, leaked
proteins, solutes, bacteria and inflammatory particles. To this end, the edges of the endothelial cells
overlap but are not bound together, forming “flap valves”. Increasing interstitial pressure pushes open
the valve and fluid flows into the capillary. Increasing lymph pressure pushes the valve flaps together,
closing the valve and preventing lymph flowing back to the interstitium.
  

External filaments join the endothelial cells to adjacent structures in the interstitium so an increase in
interstitial volume pulls the valves open to enhance drainage. If this was not the case, increasing
interstitial pressure would cause vessel collapse.

Capillaries are the smallest vessels in the body with a diameter of 3-10µm. They are the site of solute exchange with
interstitial tissues. To this end they have thin walls consisting only of a layer of endothelial cells with a basement
membrane.
 
The continuity of the wall varies with capillary type and this in turn affects permeability:
 
Continuous capillaries
 found in skeletal muscle, myocardium, skin, lungs and connective tissue
 least permeable
 continuous layer of endothelium and basement membrane
 intercellular clefts transmit water and small lipid-insoluble solutes
 
Fenestrated capillaries
 found in kidneys, exocrine glands, intestine and endocrine glands
 specialised for rapid fluid filtration
 endothelium has “windows” or fenestrae bridged by a thin porous membrane through which water, nutrients
and hormones can pass
 basement membrane is intact
 
Discontinuous or Sinusoidal capillaries
 found in spleen, liver and bone marrow
 allow movement of blood cells
 endothelium has gaps > 100nm and an incomplete basement membrane
 
Tight capillaries
 found in central nervous system
 continuous capillaries with adjacent endothelial cells joined by tight junctions forming an impermeable barrier
that prevents the passage of lipid-insoluble solutes and maintains a constant environment for the brain.
 
Pericytes are accessory cells associated with continuous capillaries that wrap around the capillary to envelop part of
the wall. They are thought to regulate vessel structure and diameter and may be a source of fibroblasts.

The flow of fluids through an intravenous cannula can be described by Poiseuille’s Law. It
states that the flow (Q) of fluid is related to a number of factors: the viscosity (n) of the
fluid, the pressure gradient across the tubing (P), and the length (L) and radius (r) of the
tubing:
 
Q = πPr4/8nL
  
The radius of the tubing is very important as doubling the radius of a cannula increases the
flow rate 16 fold (r4). Therefore the larger the intravenous cannula is the greater the flow
rate will be.
 
Fluid viscosity is another important factor. Flow is inversely proportional to the viscosity of
the fluid. Therefore increasing viscosity decreases flow through a cannula. Certain fluids,
for example 5% albumin, have much higher viscosities than others and will therefore take
longer to infuse.
 
The viscosity of blood increases with increasing hematocrit and decreasing temperature.
Warming blood prior to administration increases flow rates and it is for this reason that
fluid warmers are used.
 
Increasing pressure further maximizes flow as described by Poiseuille’s Equation. This can
be achieved by elevating bags of fluids and using pressure bags or pressurized infusion
devices. Both of these strategies will increase pressure gradients and optimize flow rates.
 
An ideal rapid infusion system would consist of the largest diameter and shortest length
tubing possible. Infused fluid should be of the lowest possible viscosity and it should be
delivered under maximum possible pressure.
 
The flow rates and infusion periods of different gauge cannulae is shown in the table
below:
 
GAUGE MAXIMAL FLOW RATE TIME TO INFUSE 1 L OF FLUID

24G (yellow) 13 ml/min 77 min

22G (blue) 31 ml/min 30 min

20G (pink) 67 ml/min 15 min

18G (green) 103 ml/min 10 min

16G (grey) 236 ml/min 4.2 min

14G
270 ml/min 3.7 min
(orange)

Plasma oncotic pressure (πp) is typically 25-30 mmHg. For comparison, interstitial oncotic pressure is
typically 5 mmHg.

 πp is mainly determined by plasma proteins, with 70% of the oncotic pressure being generated by
albumin. The osmotic power of albumin is enhanced by its 17 negative charges which hold Na+ ions in
the plasma and increase the plasma osmotic pressure. This is an example of the Gibbs-Donnan effect.

 If a capillary is highly permeable, protein leak from the plasma to the interstitium will negate the
oncotic pressure of plasma proteins. In this case the influence of π p on fluid movement at the capillary is
negligible. Another way of saying a vessel is highly permeable is the reflection co-efficient is close to 0.

Fluid movement at the capillary bed is described by Starling's equation for fluid filtration.

Filtration forces which promote the movement of fluid out of the capillary (capillary hydrostatic pressure
and interstitial oncotic pressure) are opposed by resorption forces which promote the movement of
fluid into the capillary (interstitial hydrostatic pressure and plasma oncotic pressure). The forces vary
along the length of the capillary bed but overall there is net filtration.

 The formula is often adapted to account for the semi-permeability of the endothelium by the reflection
coefficient (σ), the surface area available (S) and the hydraulic conductance of the wall (Lp) giving:
Volume / min = LpS [(Pc - Pi) - σ(πp – πi)]

The movement of fluid at the capillaries is described by:

 Volume / min = (Pc - Pi) - (πp – πi)

 where

Pc = capillary hydrostatic pressure

Pi = interstitial hydrostatic pressure

 πp = plasma oncotic pressure

πi = interstitial oncotic pressure

 The movement of fluid out of the capillaries into the interstitium is increased by:

 Increased venous pressure (increases Pc )

 Damage to the endothelial wall and protein leak into the interstitium (increases π i, decreases πp)

 Low plasma protein (decreases  πp)

 Accumulation of lactate (water flows out of capillaries through aquaporins down osmotic
gradient)

 Lymphatic obstruction prevents the drainage of interstitial fluid (increases P i ) and reduces the
movement of fluid out of capillaries.

Capillary hydrostatic pressure (Pc) is usually 15-30mmHg. Pc decreases along the length of
the capillary, matching the arteriolar pressure proximally and the venule pressure distally.
The ratio of arteriolar resistance (RA) to venular resistance (RV) determines Pc :
 If RA/RV is high, pressure drop across capillary is low, Pc is close to venule pressure.
 If RA/RV is low, pressure drop across the capillary is high, Pc is close to arteriolar
pressure.

Usually RA/RV is high so Pc  is closer to the venule pressure and therefore more sensitive to
changes in venous pressure than arteriolar pressure.
 
Pc is the main driver for pushing fluid out of the capillary bed into the interstitium. It is also
the most variable of the forces affecting the movement of fluid at the capillary, partly due
to the variation in sympathetic-mediated arteriolar vasoconstriction.

Homeostasis is the property of a system in which variables are regulated so that internal
conditions remain stable and relatively constant. Examples of homeostasis include the
regulation of temperature and pH balance.
 
The two body systems that regulate homeostasis are the nervous and endocrine
systems. The principle mechanism by which homeostasis occurs is via negative
feedback. Negative feedback occurs via receptors, comparators and effectors based upon
a ‘set point’. The ‘set point’ is a narrow range of values within which normal function
occurs.
 
The smooth muscle of the uterus becomes more and more active at the end stages of
pregnancy. This is an example of positive feedback.

Auto-regulation is defined as “the intrinsic ability of an organ to maintain a constant blood flow despite
fluctuations in perfusion pressure”. The renal, coronary and cerebral circulations exhibit exquisite auto-
regulation, ensuring blood flow is maintained to the vital organs. Skeletal muscle has a moderate
capacity to auto-regulate. The cutaneous circulation, however, has little or no auto-regulatory capacity.
In the cutaneous circulation blood flow is primarily controlled by the extrinsic sympathetic nervous
system to regulate body temperature.
The blood-brain barrier (BBB) is a highly selective permeability barrier that separates circulating blood
from the brain extracellular fluid in the central nervous system (CNS).

 The brain is very vulnerable to changes in its environment and the BBB only allows substances that are
necessary for normal function to pass through. It therefore protects the neural tissue from variations in
blood composition, toxins and some pathogens.

 The endothelial cells in the brain capillaries are the site of the BBB. The BBB in adults consists of a
complex cellular system of a highly specialized basal membrane, a large number of pericytes embedded
in the basal membrane and astrocytic feet that surround the endothelial cells.  Whereas the endothelial
cells form the barrier proper, the interaction with adjacent cells seems to be required for the
development of the barrier. 

 The brain endothelial cells differ from endothelial cells from other organs in two important ways and it
is these properties of brain endothelial cells that provide a barrier between the blood and the brain:

1. ‘Tight junctions’ are present between brain endothelial cells.  It is these tight junctions that
prevent paracellular movement of molecules.

2. There are no detectable transendothelial pathways such as intracellular vesicles. 

 The BBB is permeable to:

 Water (freely permeable)

 Non-ionised lipid soluble substances (e.g. barbiturates, ethanol and caffeine)

 The BBB is impermeable to:

 Proteins

 Protein-bound substances (e.g. drugs and hormones)

 Strongly hydrophilic (water soluble) substances (e.g. Na, K)

 Most bacteria, antibodies and antibiotics (which are all too large to cross the BBB)

 Carrier-mediated transport enables molecules with low lipid solubility to traverse the blood-brain
barrier. An example of this is glucose, which enters the brain via the GLUT-1 transport protein.

There are a few sites within the brain that have an incomplete blood-brain barrier.

 These sit in the roof of the 3rd and 4th ventricles and are referred to as the circumventricular organs:

 The subformical organ

 The organum vasculosum

 The median eminence

 The pituitary gland

 The subcommicural organ

 The pineal gland

 The area postrema (vomiting centre)

  The choroid plexus

Metabolic hyperaemia matches local blood flow to local O2 demand. An increase in metabolic rate
increases production of vasoactive metabolites, which act locally on the surrounding arterioles to cause
vasodilation and increase blood supply. A number of vasoactive mediators have been investigated
(including K+, adenosine, CO2, H+, phosphates and H2O2). The mechanism is not clear but it is likely all
these mediators contribute to some extent at different points. What is clear is that specific organs are
more sensitive to specific metabolites:

 in skeletal muscle – K+ and adenosine are the most potent vasodilators

 in the cerebral circulation –K+ and CO2  are the most potent vasodilators

 In most tissues hypoxia also triggers vasodilation. The pulmonary circulation is a special case where
hypoxia causes vasoconstriction with the aim of diverting blood flow towards better perfused alveoli to
improve gas exchange.

Vasopressin (from the posterior pituitary), Angiotensin II (product of Renin-Angiotensin-

Aldosterone system), Endothelin-1 (autacoid produced by vascular endothelium) and
Serotonin (produced by endothelium) are all vasoconstrictors.
 
Atrial Natriuretic Peptide (ANP) is a vasodilator produced by the atria in response to
increased atrial pressure, Angiotensin II and Endothelin-1. ANP causes vascular smooth
muscle relaxation by a G-protein coupled receptor cGMP pathway.

Autacoids are paracrine hormones, released from endothelium in response to local conditions to control
local vasomotor tone and blood flow. There are numerous autacoids including:

 Nitric oxide: potent vasodilator, anti-thrombotic, anti-inflammatory

 Histamine: increases venule permeability and arteriolar dilatation

 Bradykinin: increases venule permeability and arteriolar dilatation

 Prostacyclin (PGI2): potentiates histamine and bradykinin and sensitises nociceptive C fibres

 Leukotriene: increases venule permeability and stimulates leucocyte emigration

 Endothelin-1: potent vasoconstrictor

 Vasopressin is not an autacoid. It is released by the posterior pituitary and amongst other actions acts
on vascular V1 receptors to cause vasoconstriction.

The neurological action potential can be summarized as follows:

 
1. Resting potential: Small subset of potassium channels open, permitting K+ to enter and
exit the cell based on electrochemical forces. There is no net movement of K+ ions.
 
2. Threshold: As a depolarizing stimulus arrives a few Na+ channels open allowing Na+
ions to enter the neuron. The increase in positive ions inside the cell depolarized the
membrane potential and brings it closer to the threshold at which the action potential is
generated (-55mV). Once the threshold of excitation is reached the neuron will fire an
action potential. It is an ‘all or nothing’ phenomenon.
 
3. Depolarisation phase: After the threshold potential is reached additional voltage gated
sodium channels open and Na+ ions rush into the cell. The voltage across the membrane
rapidly reverses and reaches its most positive value.
 
4. Repolarisation phase: At the peak of the action potential, two processes occur
simultaneously. Many of the voltage-gated sodium channels begin to close and more
potassium channels open. This allows positive ions to leave the cell and causes the
membrane potential to shift back towards the resting membrane potential. As the
membrane potential approaches the resting potential the potassium channels are
maximally activated and open.
 
5. Hyperpolarisation phase: The membrane potential then hyperpolarizes beyond the
resting membrane voltage as more potassium channels are open at this point than during
the membranes resting state, allowing more positively charged potassium ions to leave the
cell.
 
6. Recovery: A return to steady state occurs as the additional potassium channels opened
during the action potential close. The membrane potential is now determined by the
subset of potassium channels that are normally open during the membranes resting state.
 

Arteriovenous anastomoses (AVAs)s are short vessels that connect small arteries and veins. They have a
wide diameter lumen. The walls are thick and muscular which allows AVAs to fully obstruct the vessel
lumen, stopping blood flowing from artery to vein (acting like a sphincter). When the AVAs are open
they provide a low resistance connection between arteries and veins, shunting blood into the superficial
venous plexuses of the limbs. Because of their thick muscular walls, no diffusion of solutes or fluid into
the interstitium occurs.

 AVAs are richly innervated by adrenergic fibres from the temperature-regulation centre of the
hypothalamus. At normal core temperatures there is high sympathetic output, causing vasoconstriction
of the AVAs and blood flows through the capillary networks and deep plexuses. In raised temperatures,
sympathetic output is reduced, causing vasodilation of the AVAs and shunting of blood from artery to
superficial venous plexus. Hot blood runs close to the skin surface and heat is lost to the environment.

 AVAs are a specialised anatomical adaptation and only seen in high numbers in peripheral regions
including the fingers, palms, soles, lips, and pinna of the ear.
 α1-adrenoceptors are widespread in the systemic circulation. Noradrenaline binds to α1-
adrenoceptors which are coupled to a Gq protein (so are G-protein coupled receptors).
 
Downstream signaling involves a complicated cascade but overall:
 PIP2 is converted into IP3 and DAG
 IP3 and DAG increase intracellular calcium levels by opening calcium channels and
releasing calcium from intracellular stores
 Calcium binds to calmodulin which activates myosin light chain kinase (MLCK)
 MLCK phosphorylates myosin and causes contraction

Active transport is the movement of a substance against a concentration gradient i.e. from
a low to a high concentration. If active transport involves the use of chemical energy, for
example from ATP, then it is termed primary active transport. If an electrochemical
gradient is used then it is termed secondary active transport.
 
The sodium-potassium pump, calcium ATPase pump and proton pump all utilize ATP and
are examples of primary active transport. The sodium-calcium co-transporter utilizes an
electrochemical gradient and is an example of secondary active transport.
 
The SGLUT-1 sodium dependant hexose transporter carries glucose and galactose into the
enterocyte. This is an example of secondary active transport.

Coronary muscle has a high basal metabolic rate with oxygen demands 20 times that of
skeletal muscle at rest. A number of adaptations help meet this demand. Coronary muscle
has a greater number of capillaries per mm2 than skeletal muscle (approximately 400 vs
3000 respectively). Oxygen extraction rates are higher in coronary muscle than in skeletal
muscle (approximately 70% vs 25% respectively at rest). Coronary muscle uses fatty acids
as the primary energy whereas skeletal muscle uses glucose.
 
Arterioles in the skeletal muscle and cardiac muscle circulation contain β2 receptors.
Sympathetic stimulation of these receptors causes vasodilation. In both tissues, metabolic
hyperaemia is the primary mechanism of increasing blood flow to meet increased demand.

Nitric oxide (NO) is the main vasodilator produced by endothelial cells.

 NO is synthesised from L-argenine by NO synthase (NOS). There are two forms of NOS.

 cNOS is always active at a basal level. Its activity is calcium dependent. Calcium comes from
intracellular stores and is released by shear stresses acting on the endothelium (i.e. increased
blood flow) or by receptor activation via bradykinin, adenosine or Substance P, amongst others.

 iNOS is calcium independent. Its activity is induced by bacterial endotoxins, interleukins and
cytokines produced in inflammation. In such states, iNOS can be > 1000 more active than cNOS.

Once formed, NO diffuses out of the endothelial cells and either enters the blood stream (where it is
broken down) or enters the adjacent vascular smooth muscle cells by diffusion and triggers a cGMP
signaling pathway ultimately resulting in potent vasodilation. The half-life of NO is a few seconds so it
only exerts effects locally.

 NO also has anti-platelet aggregation effects (anti-thrombotic) and prevents leucocytes adhering to
endothelium (anti-inflammatory).
The myogenic stretch response was first described by Sir William Bayliss in 1902. Increased
blood flow or pressure in a vessel causes vascular myocytes to stretch and activates
membrane channels resulting in depolarisation. Depolarisation activates L-type Calcium
channels leading to an influx of calcium. Increased intracellular calcium causes
vasoconstriction.
 
Excessive constriction is prevented by nitric oxide and endothelium-derived
hyperpolarising factor (EDHF) produced by the sheer stresses the constricted vessel is
exposed to. L-type calcium channel blockers such as amlodipine also inhibit the response.
 
The myogenic stretch response is one of the main mechanisms of auto-regulation;
maintaining a constant blood flow through capillary beds despite fluctuations in arterial
supply.

Blood flow is tightly matched to metabolic rate in skeletal muscle. This is achieved primary
by metabolic hyperaemia; actively metabolising tissue produces vasoactive substances
which cause localised vasodilation. The identity of these vasodilators is unclear but thought
to include K+ efflux secondary to repeated depolarisation, and metabolites of ATP including
adenosine and inorganic phosphates.
 
Capillary recruitment is a consequence of metabolic hyperaemia. In resting muscle the
terminal arterioles contract intermittently and asynchronously so only a third of the muscle
is well perfused at any one time. With metabolic hyperaemia increased arteriole
vasodilation causes a higher percentage of capillaries to be well perfused at any one time.
This gives a higher surface area for solute exchange.
 
Sympathetic stimulation constricts feeding arteries so reduces blood flow to the arterioles
and muscle.
 
Muscle contraction during exercise pumps blood along the venous system, increasing the
pressure difference between arterioles and venules, and increasing blood flow through the
capillaries.
 
Capillary angiogenesis is seen with repetitive muscle use (e.g. endurance training). It is a
long-term consequence not an immediate way of increasing blood flow.

  Function of the endothelium

 Produces autacoids in response to shear stress to regulate local vascular tone

 Secretes both anti-thrombotic and pro-thrombotic factors
 Contains surface enzymes which modify vasoactive peptides in the bloodstream
 Provides a semi-permeable barrier to regulate exchange of substances between blood and
tissue
 Respiratory

The oxygen dissociation curve is a graph that plots the proportion of haemoglobin in its
oxygen-laden saturated form on the vertical axis against the partial pressure of oxygen on
the horizontal axis. The curve is a valuable aid in understanding how the blood carries and
releases oxygen.
 
At high partial pressures of oxygen, haemoglobin binds to oxygen to
form oxyhaemoglobin.  All of the red blood cells are in the form of oxyhaemoglobin when
the blood is fully saturated with oxygen. Each gram of haemoglobin can combine with 1.34
mL of oxygen
 
At low partial pressures of oxygen (e.g. within tissues that are deprived of oxygen),
oxyhaemoglobin releases the oxygen to form haemoglobin.
 
The oxygen dissociation curve has a sigmoid shape because of the co-operative
binding of oxygen to the 4 polypeptide chains. Co-operative binding means that
haemoglobin has a greater ability to bind oxygen after a subunit has already bound
oxygen. Haemoglobin is therefore most attracted to oxygen when 3 of the 4 polypeptide
chains are bound to oxygen.
 
There is often a P50 value expressed on the curve, which is the value that tells us the
partial pressure of oxygen at which the red blood cells are 50% saturated with oxygen. At
an oxygen saturation of 50% the PaO2 is approximately 25 mmHg (3.5k Pa).
 

 Factors affecting the oxygen dissociation curve include:

 
The oxygen dissociation curve can be shifted right or left by a variety of factors. A right
shift indicates decreased oxygen affinity of haemoglobin allowing more oxygen to be
available to the tissues. A left shift indicates increased oxygen affinity of haemoglobin
allowing less oxygen to be available to the tissues.
 
1. pH
A decrease in the pH shifts the curve to the right, while an increase in pH shifts the curve
to the left. This occurs because a higher hydrogen ion concentration causes an alteration
in amino acid residues that stabilises deoxyhaemoglobin in a state (the T state) that has a
lower affinity for oxygen. This rightwards shift is referred to as the Bohr effect.
 
2. Carbon dioxide (CO2):
A decrease in CO2 shifts the curve to the left, while an increase in CO2 shifts the curve to
the right. CO2 affects the curve in two ways. Firstly, accumulation of CO2 causes carbamino
compounds to be generated, which bind to oxygen and form carbaminohaemoglobin.
Carbaminohaemoglobin stabilizes deoxyhaemoglobin in the T state. Secondly,
accumulation of CO2 causes an increase in H+ ion concentrations and a decrease in the pH,
which will shift the curve to the right as explained above.
 
3. Temperature:
An increase in temperature shifts the curve to the right, whilst a decrease in temperature
shifts the curve to the left. Increasing the temperature denatures the bond between
oxygen and haemoglobin, which increases the amount of oxygen and haemoglobin and
decreases the concentration of oxyhaemoglobin. Temperature does not have a dramatic
effect but the effects are noticeable in cases of hypothermia and hyperthermia.
 
4. Organic phosphates:
2,3-Diphosphoglycerate (2,3-DPG) is the main primary organic phosphate. An increase in
2,3-DPG shifts the curve to the right, whilst a decrease in 2,3-DPG shifts the curve to
the left. 2,3-DPG binds to haemoglobin and rearranges it into the T state, which decreases
its affinity for oxygen.
 
A table summarizing these effects is shown below:
 
Factor Decrease Increase
pH Right shift Left shift
CO 2 Left shift Right shift
Temperature Left shift Right shift
2,3-DPG Left shift Right shift
 
The oxygen dissociation curve and the factors affecting it.  ©  Medical Exam Prep

 It is important to have an understanding of lung volumes and definitions of these volumes
in adults.

 
The tidal volume (TV) is the volume of air drawn in and out of the lungs during normal
breathing. The usual volume in a healthy male is 0.5 L.
 
The vital capacity (VC) is the maximum volume of air that can be breathed out following a
maximal inspiration.The usual volume is 4.5 L in a healthy male and 3.5 L in a healthy
female.
 
The residual volume (RV) is the volume of air in the lungs after a maximum expiration. The
usual volume in a healthy male is 1.0 L.
 
The inspiratory reserve volume (IRV) is the maximum volume of air that can be breathed
in at the end of a normal tidal inspiration. The usual volume in a healthy male is 3.0 L.
 
The expiratory reserve volume (ERV) is the maximum volume of air that can be breathed
out at the end of a normal tidal expiration. The usual volume in a healthy male is 1.0 L.
 
Total lung capacity (TLC) is the volume of air in the lungs at the end of a maximal
inspiration. TLC = RV+VC. The usual volume in a healthy male is 5.5 L.
 
Functional residual capacity (FRC) is the volume of air present in the lungs at the end of a
normal expiration. FRC = ERV + RV. The usual volume in a healthy male is 2.0 L.
 

This patient has a history of worsening breathlessness and lung function tests that reveal
a restrictive lung disease pattern. In restrictive lung disease the FEV 1/FVC ratio is usually
normal, i.e. 70% predicted, and the FVC is reduced to < 80% predicted. The FEV1/FVC ratio is
generally normal both the FVC and FEV1 are reduced. The ratio can also be elevated if the
FVC is reduced to a greater degree.
 
Of the options listed in this question only idiopathic pulmonary fibrosis could produce a
restrictive lung disease pattern.
 
Smoking is a risk factor for the development of idiopathic pulmonary fibrosis, especially if
there is a greater than 20-pack-year history.

Obstructive lung disorders are characterised by airway obstruction. Many obstructive diseases of the
lung result from narrowing of the smaller bronchi and larger bronchioles, often because of excessive
contraction of the smooth muscle itself.

 In obstructive lung disorders the FEV1 is generally reduced and the FEV1/FVC ratio is less than 0.7.

 Types of obstructive lung disorders include:

 Chronic obstructive pulmonary disease (COPD)

 Asthma
 Bronchiectasis
 Cystic Fibrosis

 Restrictive lung disorders are characterised by restricted lung expansion. They result in a decreased
lung volume, increased work of breathing, and inadequate ventilation and/or oxygenation.
  In restrictive lung disorders there is a reduction in the FVC and the FEV1. The decline in the FVC is
greater than that of the FEV1, resulting in preservation of the FEV1/FVC ratio (> 80%).

 Types of restrictive lung disorders include:

 Pulmonary fibrosis

 Sarcoidosis

 Pulmonary oedema

 Adult respiratory distress syndrome (ARDS)

 Neuromuscular diseases e.g. muscular dystrophy

 Anatomical e.g. obesity, scoliosis

In restrictive lung disorders the following lung volumes and capacities are reduced:
 Vital capacity (VC)
 Total lung capacity (TLC)
 Inspiratory capacity (IC)
 Residual volume (RV)
 Functional residual capacity (FRC)

In restrictive lung disease the FEV1/FVC ratio is usually normal, i.e. > 0.7, and the FVC is
reduced to < 80% predicted normal.
 
In obstructive lung disease FEV1 is reduced to <80% of normal and FVC is usually reduced
but to a lesser extent than FEV1. The FEV1/FVC ratio is reduced to < 0.7.
 
According to the latest NICE guidelines (2010) airflow obstruction is defined as follows:
 Mild airflow obstruction = an FEV1 of > 80% in the presence of symptoms
 Moderate airflow obstruction = FEV1 of 50-80%
 Severe airflow obstruction = FEV1 of 30-50%
 Very severe airflow obstruction = FEV1 < 30%.
 
Spirometry is a poor predictor of durability and quality of life in COPD but can be used as
part of the assessment of severity
 COPD can only be diagnosed on spirometry if the FEV1 is <80% and FEV1/FVC ratio is < 0.7
  
The following table outlines the affects of obstructive lung disease on the various lung
volumes and capacities:
 

Increased in obstructive lung disease Decreased in obstructive lung disease

Total lung capacity (TLC)

Vital capacity (VC)
Residual volume (RV)
Inspiratory capacity (IC)
Functional residual capacity (FRC)
Inspiratory reserve volume (IRV)
Residual volume/total lung capacity
Expiratory reserve volume (ERV)
(RV/TLC) ratio
 
 
The functional residual capacity (FRC) is the volume of air present in the lungs at the
end of a normal expiration. The usual volume in a healthy male is 2.0 L.
 
At FRC, the opposing elastic recoil forces of the lungs and chest wall are in equilibrium and
there is no exertion by the diaphragm or other respiratory muscles.
 
The FRC is the sum of the expiratory reserve volume (ERV) and the residual volume (RV):
 
 FRC = ERV + RV
 
 The FRC cannot be estimated by spirometry as it includes the residual volume. In order
to measure the RV precisely one of the following methods is needed:
 Nitrogen washout (Fowler’s method)
 Helium dilution technique
 Body plethysmography
 
The FRC is increased by the following:
 Marked airway obstruction (e.g. severe asthma and COPD)
 Loss of elastic recoil (e.g. advanced age and emphysema)
 
The FRC is reduced by the following:
 Abnormally stiff, non-compliant lungs (e.g. restrictive lung disorders such as
pulmonary fibrosis)
 Bilateral paralysis of the diaphragm
 Lying in the supine position

Spirometry is a useful and simple way to measure timed inspired and expired volumes. It is
the gold standard test for diagnosing and monitoring COPD, and is also similarly used in
asthmatic patients.
 
Spirometry is not a good predictor of quality of life in COPD but can be used as part of the
assessment of severity. It is also useful for monitoring disease progression and reviewing
response to treatments.
 
The forced vital capacity (FVC) is the volume of air in the lungs from a maximal
inspiration to a forced maximal expiration.
 
The forced expiratory volume in one second (FEV1) is the volume of air that is expelled in
the first second of a forced expiration.
 
In obstructive lung disease FEV1 is reduced to <80% of normal and FVC is usually reduced
but to a lesser extent than FEV1, with the resulting FEV1/FVC ratio being reduced to <0.7.
 This occurs in conditions when the airways are narrowed, causing obstruction, such as in
asthma, COPD, cystic fibrosis and bronchiectasis.
 
In restrictive lung disease the FVC is reduced to <80% predicted normal and the FEV 1/FVC
ratio is usually normal, i.e. >0.7. The FEV1 is also reduced. This occurs in conditions when
there is a reduced lung volume, such as scoliosis and fibrosing alveolitis.

The normal ranges of vital signs in children depending upon age are shown in the table
below:
 
 
Heart rate Respiratory rate
Age (years)
(beats per minute) (breaths per minute)
<1 110-160 30-40

1-2 100-150 25-35

2-5 95-140 25-30
5-12 80-120 20-25
>12 60-100 15-20

Pre-oxygenation is the administration of oxygen to a patient prior to intubation. It helps to extend the
‘safe apnoea time’. The ‘safe apnoea time’ is defined as the duration of time following cessation of
breathing/ventilation that elapses until arterial desaturation occurs (SaO 2 reaches < 90%).

 The primary mechanism by which pre-oxygenation works is by ‘denitrogenation’ of the lungs, however
maximal pre-oxygenation is achieved when the alveolar, arterial, venous and tissue compartments are
all filled with oxygen. Denitrogenation is achieved using oxygen to wash out the nitrogen contained in
the lungs after breathing room air, resulting in a larger alveolar oxygen reservoir.

 The functional residual capacity (FRC) is the volume of gas that remains in the lungs after a normal
tidal expiration. It is the sum of the residual volume (RV) and the expiratory reserve volume (ERV). One
method of measuring the FRC is the nitrogen washout technique.

 The FRC is the most important store of oxygen in the body. The greater the FRC, the longer apnoea can
be tolerated before critical hypoxia develops. Patients with reduced FRC (e.g. lung disease,
kyphoscoliosis, pregnancy, and obesity) reach critical hypoxia more rapidly. The aim of pre-oxygenation
is to replace nitrogen in the FRC with oxygen.

You review a 60-year-old patient with a history of feeling breathless. He has the following
lung function test results:
 
 FEV1/FVC ratio = 60% predicted
 FEV1 = 45% predicted
 FVC = 75% predicted
 Gas transfer factor = reduced
 Which of the following is the MOST likely cause for these results?

This patient is breathless with an obstructive ventilatory defect and a reduced gas transfer
factor.
 
The gas transfer factor is a measure of gas diffusion across the alveolar membrane into
capillaries. It is dependent upon blood volume, blood flow, surface area of the membrane
and the distribution of ventilation. It is measured by the diffusion of carbon monoxide
(TLCO). The transfer coefficient (KCO) is the TLCO corrected for lung volume.
 
There are numerous causes of a decreased transfer factor including:
 COPD
 Acute asthma
 Anaemia
 Interstitial lung disease
 Pulmonary oedema
 Pneumonia
 Pneumothorax
 Pulmonary vascular disease
 Pneumonectomy
 
Of the causes listed in this question only COPD would cause both an obstructive lung
disease pattern and a reduced gas transfer factor.
 
Normal ventilatory function would be expected in anaemia, whilst pulmonary oedema, and
a pneumothorax would cause an restructive lung disease pattern.
 
Pulmonary haemorrhage would cause a restrictive lung disease pattern and an increased
gas transfer factor.
 

The causes of an increased gas transfer factor include:

 Exercise
 Polycythaemia
 Pulmonary haemorrhage
 Asthma (not during acute attacks)
 Left-to-right shunts
 
Juxtacapillary receptors (J receptors) are sensory cells that are located within the alveolar
walls in juxtaposition to the pulmonary capillaries of the lung.
 
The J receptors are innervated by the vagus nerve and are activated by physical
engorgement of the pulmonary capillaries or increased pulmonary interstitial volume, for
example in the presence of pulmonary oedema, pulmonary embolus, pneumonia and
barotraumas. They may also be stimulated by hyperinflation of the lung.
 
Stimulation of the J receptors causes a reflex increase in breathing rate, and is also thought
to be involved in the sensation of dyspnoea. The reflex response that is produced is
apnoea, followed by rapid breathing, bradycardia, and hypotension.
Dead space is defined as the volume of inhaled air that does not take part in gas exchange.

 The dead space can be further classified into:

 Anatomical dead space: The portion of the airways that conducts gas to the alveoli. No gas
exchange is possible in these spaces

 Alveolar dead space: The sum of the volumes of those alveoli that have little or no blood
flowing through their adjacent capillaries i.e. the alveoli that are ventilated but not perfused.
This is negligible in healthy people but can increase considerably in individuals with lung disease
(pulmonary embolus, pneumonia ) that causes ventilation-perfusion mismatch.

 Physiological dead space: the sum of the anatomical and alveolar dead spaces. The
physiological dead space can account for up to 30% of the tidal volume.

The anatomical dead space can be measured by nitrogen washout test (Fowler’s method). The
physiological dead space can be measured by the Bohr equation.

The infant has a greater metabolic rate and greater oxygen consumption than the adult. This partly
explains the fact that infants and children have higher respiratory rates than adults.

 Neonates preferentially breathe through their nose and their narrow nasal passages are easily blocked
by secretions and may be damaged by a nasogastric tube or a nasally placed endotracheal tube. 50% of
airway resistance in neonates is from the nasal passages.

 The airway is funnel shaped and narrowest at the level of the cricoid cartilage. Here, the epithelium is
loosely bound to the underlying tissue. Trauma to the airway easily results in oedema and one
millimetre of oedema can narrow a baby’s airway by as much as 60%.

 In the adult, the lung and chest wall contribute equally to the total compliance. In the newborn, most of
the impedance to expansion is due to the lung alone, and this is dependent upon the presence of
pulmonary surfactant. Pulmonary surfactant is a mixture if lipids and proteins that is formed and
secreted by type II alveolar pneumocytes. The principal function of pulmonary surfactant is to reduce
the surface tension at the air-water interface in the lung. The lung compliance increases over the first
few weeks of life as fluid is removed from the lung.

 The chest wall is significantly more compliant in infants than it is in adults. As a consequence of this the
functional residual capacity (FRC) in infants is relatively low compared to adults. The compliance of the
infants chest wall leads to prominent sternal recession when the airways become obstructed or lung
compliance decreases.

 The combination of a high metabolic rate and high oxygen consumption with lower lung volumes and
limited respiratory reserve means that infants, and to a lesser degree children, desaturate much more
rapidly than adults. This is a very important consideration during airway procedures, such as
endotracheal intubation.

 Fetal haemoglobin (HbF) is the main oxygen transport protein in the human fetus during the last 7
months of development. It persists in the newborn until roughly 6 months of age. HbF has different
globin chains to adult haemoglobin (Hb). Whereas adult haemoglobin is composed of two alpha and two
beta subunits, fetal haemoglobin is composed of two alpha and two gamma subunits. This change in the
globin chain results in a greater affinity for oxygen and allows the fetus to extract blood from the
maternal circulation. This increased affinity for oxygen means that the oxygen dissociation curve for
fetal haemoglobin is shifted to the left of that of adult haemoglobin.
 Pulmonary surfactant is a mixture if lipids and proteins that is formed and secreted
by type II alveolar pneumocytes.
 
The principal function of pulmonary surfactant is to reduce the surface tension at the
air-water interface in the lung. The proteins and lipids that make up the surfactant have
both hydrophilic and hydrophobic regions. By adsorbing to the air-water interface, with the
hydrophobic tails facing towards the air and the hydrophilic heads facing towards the air
and, the main lipid component of surfactant, dipalmitoylphosphatidylcholine (DPPC),
reduces surface tension.
 
In addition to reducing surface tension pulmonary surfactant is also important for:
 Maintaining structural integrity and alveolar size
 Increasing pulmonary compliance
 Preventing atelectasis
 Keeping the alveoli dry
 Contributing to innate immunity

Carbon monoxide (CO) interferes with the oxygen transport function of the blood by
combining with haemoglobin to form carboxyhaemoglobin (COHb).
 
CO has approximately 240 times the affinity for haemoglobin that oxygen does and for that
reason even small amounts of CO can tie up a large proportion of the haemoglobin in the
blood making it unavailable for oxygen carriage. If this happens the PO 2 of the blood and
haemoglobin concentration will be normal but the oxygen concentration will be grossly
reduced.
 
The presence of COHb also causes the oxygen dissociation curve to be shifted to the left,
interfering with the unloading of oxygen.

The main intrinsic regulator of pulmonary blood flow is the local partial pressure of alveolar oxygen
(pAO2). A low pAO2 causes vasoconstriction of arterioles and visa versa. This is the Hypoxic Pulmonary
Vasoconstriction (HPV) reflex and it facilitates the diversion of blood flow away from poorly ventilated
alveoli and towards well-ventilated alveoli to maximise gaseous exchange. The maximal hypoxic
vasoconstriction occurs at a pAO2 of 70mmHg (at a normal pH). HPV is unique to the pulmonary
circulation. In the systemic circulation hypoxia and hypercarbia cause localised vasodilation and
increased local blood flow.

The mechanism underlying HPV is not fully known but is thought to involve depolarisation via O 2-
sensitive K channels in the vascular smooth muscle membrane, with resultant calcium influx and smooth
muscle contraction.

 A raised pCO2 will also cause localised vasoconstriction. This is a separate mechanism to HPV, which is
independent of pCO2. Acidosis enhances HPV; for a given level of hypoxia, HPV will be greater for a
lower pH.

 The sympathetic nervous system has no major role in controlling pulmonary blood flow. Metabolic
demand also has no role in regulating pulmonary blood flow as alveolar perfusion vastly exceeds
metabolic requirements.
Fetal haemoglobin  (HbF) is the main oxygen transport protein in the human fetus during
the last 7 months of debvelopment. It persists in the newborn until roughly 6 months of
age.
 
HbF has different globin chains to adult haemoglobin (Hb). Whereas adult haemoglobin is
composed of two alpha and two beta subunits, fetal haemoglobin is composed of two
alpha and two gamma subunits. This change in the globin chain results in a greater
affinity for oxygen and allows the fetus to extract blood from the maternal circulation.
 
This increased affinity for oxygen means that the oxygen dissociation curve for fetal
haemoglobin is shifted to the left of that of adult haemoglobin.
 
The curve for myoglobin lies even further to the left than that of fetal haemoglobin and has
a hyperbolic, not sigmoidal, shape. Myoglobin has a very high affinity for oxygen and acts
as an oxygen storage molecule. It only releases oxygen when the partial pressure of oxygen
has fallen considerably. The function of myoglobin is to provide additional oxygen to
muscles during periods of anaerobic respiration.
 

 
Arterial blood gas (ABG) interpretation helps us with the assessment of a patient’s respiratory gas
exchange and acid-base balance. The normal values on an ABG can vary a little between analysers but
broadly speaking are as follows: 

Variable Range

pH 7.35 – 7.45

pO2 10 – 14 kPa

PCO2 4.5 – 6 kPa

HCO3- 22 – 26 mmol/l

Base excess -2 – 2 mmol/l

 In this case the patient’s history should concern you about a possible diagnosis of pulmonary embolus.
The pertinent ABG findings are as follows:

 Mild hypoxia (type 2 respiratory failure)

 Low pH (acidaemia)

 High PCO2

 High bicarbonate

 The combination of acidaemia, a high PCO 2 and a high bicarbonate indicates that this patient has an
acute exacerbation superimposed on a chronic, compensated respiratory acidosis.
 Cardiovascular
A negative deflection after an R wave is called an S wave. This small wave represents depolarization of
the Purkinje fibres. S waves travel in the opposite direction to the R waves because the Purkinje fibres
spread throughout the ventricles from top to bottom and then back up though the walls of the
ventricles.

Q waves can be a normal finding in leads III and aVR. They are pathological if they are greater than half
the height of the subsequent R wave or if they are greater than 0.04 seconds in duration.

T wave inversion can be normal in leads V1, aVL, aVF, aVR and lead III. It can also be normal in lead V2
but only in association with T wave inversion in lead V1.

Cardiac enzymes do not rise in unstable angina and if cardiac markers rise this by
definition becomes a non-ST elevation myocardial infarction (NSTEMI).
 
The ECG can be normal in both unstable angina and NSTEMI.
 
An increased ventricular activation time is indicative of infarcting myocardium. Infarcting
myocardium is slower to conduct electrical impulses and the interval between the start of
the QRS complex and the apex of the R wave may be prolonged.
 A positive troponin indicates the presence of cardiac myocyte necrosis.

 The following table us a guide to the timing of the initial rise, peak and return to normality
of various cardiac enzymes:
 
Marker Initial rise Peak Normal at Notes
Ck-MB = main
Creatine kinase 4-8 hours 18 hours 2-3 days
cardiac isoenyme
Low specificity from
Myloglobin 1-4 hours 6-7 hours 24 hours skeletal muscle
damage
Appears to be most
Troponin I 3-12 hours 24 hours 3-10 days sensitive and
specific
= heart fatty acid
HFABP 1.5 hours 5-10 hours 24 hours
binding protein
Cardiac muscle
LDH 10 hours 24-48 hours 14 days
mainly contains LDH

Central venous pressure (CVP) is the pressure recorded from the right atrium or superior vena cava. The
normal value for CVP is 0-8 cmH2O (0-6 mmHg) in a spontaneously breathing patient.

 CVP should be measured with the patient lying flat at the end of expiration. The tip of the catheter
should be in the junction between the superior vena cava and the right atrium. It is measured by an
electronic transducer that is placed and zeroed at the level of the right atrium (usually in the
4th intercostal space in the mid-axillary line).

 CVP is a useful indicator of right ventricular preload. A volume challenge of 250-500 ml crystalloid
causing an increase in CVP that is not sustained for more than 10 minutes suggests hypovolaemia.

 The CVP waveform has the following appearance:

Cannon a waves are waves that are occasionally seen in the JVP in the presence of certain
arrhythmias. They are caused by contraction of the right atrium against a closed tricuspid
valve.
 
 They can be seen in a variety of conditions including:

 Junctional tachycardia
 Ventricular tachycardia
 Complete heart block

 The components of the CVP are shown in the table below: 

Waveform component Phase of cardiac cycle Mechanical event

a wave End diastole Atrial contraction

Closing and bulging of the

c wave Early systole
tricuspid valve

x descent Mid systole Atrial relaxation

v wave Late systole Systolic filling of the atrium

y descent Early diastole Early ventricular filling

Factors that increase CVP include:

 Hypervolaemia
 Forced exhalation
 Tension pneumothorax
 Heart failure
 Pleural effusion
 Decreased cardiac output
 Cardiac tamponade
 Mechanical ventilation (and PEEP)
 Pulmonary hypertension
 Pulmonary embolism

Factors that decrease CVP include:

 Hypovolaemia
 Deep inhalation
 Distributive shock
 Negative pressure ventilation

In right bundle branch block (RBBB) the right ventricle is not directly activated by impulses travelling
through the right bundle branch. The left ventricle, however, is still activated as normal by the left
bundle branch.

 The right ventricle is activated by impulses travelling through the myocardium across the septum. As
this occurs more slowly than conduction through the bundle of His the QRS complex becomes widened.
 As the left ventricle is activated normally the early part of the QRS complex remains unchanged. The
delayed activation of the right ventricle, however, produces a secondary R wave (R’) in the right
praecordial leads, and a wide, slurred S wave in the lateral leads. It also causes secondary repolarisation
abnormalities, with T wave inversion and ST depression being seen in the right praecordial leads.

 Secondary T wave changes are a normal finding in RBBB. T wave changes are classed as secondary if the
T wave is upright when the terminal portion of the QRS complex is negative and the T wave is inverted
when the terminal portion of the QRS complex is positive. Primary T wave changes occur when these
rules are violated and are consistent with myocardial ischaemia.

 Unlike in the presence of LBBB, the changes of ST-elevation myocardial infarction can usually be clearly
seen in RBBB.

 The diagnostic criteria for RBBB are:

 Broad QRS complex (> 120 ms)

 RSR’ pattern in leads V1-V3 (‘M’ shaped QRS complex)

 Wide, slurred S wave in the lateral leads – I, aVL, V5 and V6 (‘W’ shaped QRS complex)

 A useful mnemonic for distinguishing between the ECG patterns of left bundle branch block (LBBB) and
RBBB is ‘WiLLiaM MaRRoW’:

 WiLLiaM – in LBBB there is a ‘W’ in lead V1 and an ‘M’ wave in lead V6

 MaRRoW – in RBBB there is an ‘M’ wave in lead V1 and a ‘W’ wave in lead V6

 RBBB can be a normal finding in young, healthy people. The pathological causes of RBBB include:

 Ischaemic heart disease

 Rheumatic heart disease
 Right ventricular hypertrophy (cor pulmonale)
 Pulmonary embolus
 Cardiomyopathy
 Myocarditis
 Congenital heart disease (e.g. ASD)
 Degenerative disease of the conduction system

 
In left bundle branch block (LBBB) the left ventricle is not directly activated by impulses travelling
through the left bundle branch. The right ventricle, however, is still activated as normal by the right
bundle branch.

 The left ventricle is activated by impulses travelling through the myocardium across the septum. As this
occurs more slowly than conduction through the bundle of His the QRS complex becomes widened.

 Normally the septum is activated from left to right, which produces small Q waves in the lateral leads. In
the presence of LBBB, however, this septal activation is reversed, which eliminates these normal septal
Q waves.

 The right to left depolarization of produces deep S waves in the right praecordial leads (V1-V3) and tall
R waves in the lateral leads (I, V5 and V6). It also usually causes left axis deviation. As the ventricles are
activated sequentially from right to left, rather than simultaneously, the R wave in the lateral leads is
broad and notched (‘M’ shaped)

 Secondary T wave changes are a normal finding in LBBB. T wave changes are classed as secondary if the
T wave is upright when the terminal portion of the QRS complex is negative and the T wave is inverted
when the terminal portion of the QRS complex is positive. Primary T wave changes occur when these
rules are violated and are consistent with myocardial ischaemia.

 The diagnosis of ST-elevation myocardial infarction can be made in the presence of LBBB by using the
Sgarbossa ECG algorithm.

 The diagnostic criteria for LBBB are:

 Broad QRS complex (> 120 ms)
 Dominant S wave in lead V1
 Broad, monophasic R wave in lateral leads (I, AVL, V5 and V6)
 Prolonged R wave peak time > 60 ms in left praecordial leads (V5-V6)
 Absence of Q waves in lateral leads (I, V5 and V6)

 LBBB, unlike right bundle branch block, is almost always an indication of heart disease. The pathological
causes of LBBB include:

 Ischaemic heart disease

 Anterior myocardial infarction
 Hypertension
 Aortic stenosis
 Dilated cardiomyopathy
 Primary fibrosis of the conducting system (Lenegre’s disease)
 Hyperkalaemia
  Digoxin toxicity

In left posterior fascicular block (LPFB) the posterior portion of the left bundle branch is defective. In
LPFB the cardiac impulses are therefore conducted to the left ventricle via the left anterior fascicle first,
which creates a delay in the activation of the posterior and infero-posterior parts of the left ventricle.

The diagnostic criteria for LPFB are:

 Right axis deviation (> +90 degrees)

 Small R waves with deep S waves in leads I and aVL (‘rS’ complexes)
 Small Q waves with tall R waves in leads II, III and aVF (‘qR’ complexes)
 QRS duration normal or slightly prolonged (80-110 ms)
 Prolonged R wave peak time in aVF > 45 ms
 Increased QRS voltage in limb leads
 No evidence of right ventricular hypertrophy
 No evidence of any other cause of right axis deviation

Under normal circumstances the left bundle branch consists of three fascicles:
 The left anterior fascicle, which supplies the upper and anterior parts of the left ventricle
 The left posterior fascicle, which supplies the posterior and infero-posterior parts of the left
ventricle, and;
 The septal fascicle, which supplies the septal wall

 In left anterior fascicular block (LAFB) the anterior portion of the left bundle branch is defective. In
LAFB the cardiac impulses are therefore conducted to the left ventricle via the left posterior fascicle first,
which creates a delay in the activation of the anterior and upper parts of the left ventricle.

 The diagnostic criteria for LAFB are:

 Left axis deviation (axis usually between -45 and -90 degrees)
 Small Q waves with tall R waves in leads I and aVL (‘qR complexes)
 Small R waves with deep S waves in leads II, III and aVF (‘rS’ complexes)
 QRS duration normal or slightly prolonged (80-110 ms)
 Prolonged R wave peak time in aVL > 45 ms
 Increased QRS voltage in limb leads

Bifascicular block is a conduction abnormality of the heart in which two of the three main fascicles of
the His-Pukinje system are blocked. This can be either:
 Right bundle branch block and left anterior fascicular block (most common pattern) or;
 Right bundle branch block and left posterior fascicular block

 Although it is a sign of extensive conducting system disease, the risk of progression to complete heart
block is relatively low (approximately 1% per year)

 The main causes of bifascicular block are:

 Ischaemic heart disease (approximately 50%)
  Hypertension (approximately 25%)
 Aortic stenosis
 Anterior myocardial infarction
 Primary degenerative disease of the conducting system (Lenegre’s disease)

 No treatment is usually required for asymptomatic patients but a pacemaker is recommended for those
suffering syncope.
 

The second heart sound (S2) is produced by vibrations generated by the closure of
the aortic and pulmonary valves. It corresponds with the end of systole. Splitting during
inspiration is a normal finding.

 
The following conditions are associated with a loud S2:
 Systemic hypertension (loud A2)
 Pulmonary hypertension (loud P2)
 Hyperdynamic states (e.g. tachycardia, fever, thyrotoxicosis)
 Atrial septal defect (loud A2)
 
The following conditions are associated with a soft S2:
 Decreased aortic diastolic pressure (e.g. aortic regurgitation)
 Poorly mobile cusps (e.g. calcification of the aortic valve)
 Aortic root dilatation
 Pulmonary stenosis (soft P2)
 
The following conditions are associated with a widely split S2:
 Deep inspiration
 Right bundle branch block
 Prolonged right ventricular systole (e.g. pulmonary stenosis, P.E.)
 Severe mitral regurgitation
 Atrial septal defect (fixed splitting, doesn't vary with respiration)
 
The following conditions are associated with reversed splitting of S2 (paradoxical
splitting with P2 occurring before A2):
 Deep expiration
 Left bundle branch block
 Prolonged left ventricular systole (e.g. severe aortic stenosis, hypertropic
cardiomyopathy)
 Severe aortic stenosis
 Right ventricular pacing
 Wolff-Parkinson-White (type B)

The first heart sound (S1) is produced by vibrations generated by the closure of the
mitral and tricuspid valves. It corresponds with the end of diastole and the beginning of
ventricular systole and precedes the upstroke of the carotid pulsation.
 
The following conditions are associated with a loud S1:
 Increased transvalvular gradient (e.g. mitral stenosis, tricupsid stenosis)
  Increased force of ventricular contraction (e.g. tachycardia, hyperdynamic states
such as fever and thyrotoxicosis)
 Shortened PR interval (e.g. Wolff-Parkinson-White syndrome)
 Mitral valve prolapse
 Thin individuals
 The following conditions are associated with a soft S1:
 Inappropriate apposition of the AV valves (e.g. mitral regurgitation, tricuspid
regurgitation)
 Prolonged PR interval (e.g. heart block, digoxin toxicity)
 Decreased force of ventricular contraction (e.g. myocarditis, myocardial infarction)
 Increased distance from the heart (e.g. obesity, emphysema, pericardial effusion)
 The following conditions are associated with a split S1:
 Right bundle branch block
 LV pacing
 Ebstein anomaly

The first heart sound best heard at the apex and is due to the closure of the
atrioventricular (mitral and tricuspid) valves. The second heart sound is due to the closure
of the aortic and pulmonary valves.
 
The third heart sound can be physiological in children where it is due to the presence of a
supple ventricle that can undergo rapid filling. When heard in older adults it is often a sign
of increased ventricular filling secondary to disease such as heart failure or mitral
regurgitation.
The 3rd heart sound is a low frequency, brief vibration that occurs in early diastole at the
end of the rapid diastolic filling period of the right or left ventricle. It is associated with
heart failure and may also be a normal finding in children and young adults.
 
The genesis of the 3rd heart sound is controversial. Possible explanations for the third heart
sound include impact of flowing blood against an incompliant ventricle, impact of the
ventricle against the inner chest wall or a sound originating within the ventricular apex due
to sudden limitation of longitudinal expansion.

 The fourth heart sound is due to conditions which cause stiffness of the ventricles. These
include: ventricular hypertrophy, aortic stenosis, ventricular fibrosis and heart failure.
The 4th heart sound is a low-pitched sound that occurs during late diastolic filling of the
ventricle during atrial systole. It is the result if vibrations generated within the ventricles
and its presence usually indicates increased resistance to filling of the left or right ventricle
because of a stiff ventricular wall.
 
The 4th heart sound can be associated with several conditions including the following:
 Ventricular hypertrophy
 Aortic stenosis
 Post-MI ventricular fibrosis
 Hypertrophic cardiomyopathy
 Restrictive cardiomyopathy
  

Mobitz type 1 AV block (also known as Wenkebach block) is a disease of the AV node. It is characterised
by a progressive prolongation of the PR interval until, ultimately, the atrial impulse fails to conduct and a
QRS complex is not generated. The PR interval is shortest in the first beat of the cycle.

 Mobitz type 1 AV block is generally considered to be a benign rhythm that infrequently causes
haemodynamic disturbance and has a low risk of progression to complete heart block. Asymptomatic
patients require no treatment and those that are symptomatic usually respond to the administration of
atropine. Permanent pacing is rarely required.

The QT interval commences at the start of the QRS complex and ends at the endpoint of
the T wave. It represents the duration of time taken for the ventricles to depolarize and
repolarize.  The QT interval is inversely proportional to heart rate.
 
The normal QT interval is less than 440 ms under normal circumstances and tends to be
longer in women. There are numerous causes of a prolonged QT interval including
electrolyte disturbance (hypokalaemia, hypocalcaemia and hypomagnesaemia),
hypothermia, drugs, congenital syndromes and myocardial ischaemia. The QT interval
tends to lengthen during sleep and shorten when awake.
 Digoxin causes a shortened QT interval (the ‘digoxin effect’).

Prolongation of the QT interval is associated with syncope and sudden death, due to
ventricular tachycardia, particularly torsades-des-pointes. It can be caused by the following:

 1. Hereditary syndromes

 Jervell-Lange-Neilsen syndrome (autosomal dominant)
 Romano Ward syndrome (autosomal recessive)
 
2. Metabolic disorders
 Hypothyroidism
 Hypocalcaemia
 Hypokalaemia
 Hypomagnesaemia
 Hypothermia
 
3. Drugs
 Erythromycin
 Quinidine
 Amiodarone
 Tricyclic antidepressants
 Terfenadine
 Sotalol
 Methadone
 Procainamide
 
4. Structural heart problems
 Ischaemic heart disease
 Mitral valve prolapse
 Rheumatic carditis

 
The PR segment commences at the endpoint of the P wave and ends at the start of the QRS
complex. It represents the duration of the conduction of electrical impulses from the AV
node to the bundle branches and Purkinje fibres. The PR segment is isoelectric under
normal circumstances but deviation can occur in the presence of pericarditis and atrial
ischaemia.

The P wave is the first positive deflection on the ECG. It is a small smooth contoured wave
and represents atrial depolarization. Atrial repolarisation is not visible as the amplitude is
too small.
 
The normal P wave is:
 < 120 ms in duration (3 ‘small squares’)
 < 2.5 mm in amplitude in the limb leads
 < 1.5 mm in amplitude in the chest leads
 Positive in lead II and negative in lead aVR

The P wave is 0.08-0.10 seconds in duration. The QRS complex is 0.06-0.10 seconds in
duration. The corrected QT interval is normally less than 0.44 seconds. The corrected QT
interval can be calculated by the QT interval divided by the square root of the RR interval
 
The PR interval is measured from the start of the P wave to the start of the QRS complex.
The PR segment represents the period of time from the end of the P wave to the start of
the QRS complex. The QT interval is measured from the start of the QRS complex to the
end of the T wave. The ST segment is measured from the end of the QRS complex to the
start of the T wave. It is the interval between ventricular depolarization and repolarisation.
The ST interval is measured from the end of the QRS complex to the end of the T wave.
The second wave seen on the ECG is the QRS complex. The QRS complex is a series of 3
deflections that represents ventricular depolarization. It is less than 0.12 seconds in
duration (3 ‘small squares’) under normal circumstances.
 
By convention the first deflection in the complex, if it is negative, is called a Q wave. A Q
wave represents the normal left-to-right depolarization of the interventricular septum. A
normal Q wave is:
 < 40 ms wide (1 ‘small square’)
 < 2 mm in amplitude
 < 25% of the depth of the QRS complex
 
Small Q waves are usually normal, but if they exceed the normal criteria listed above they
are termed ‘pathological Q waves’ and can be indicative or an evolving or past myocardial
infarction.
 
The first positive deflection in the complex is called an R wave. This is the largest wave in
the QRS complex and represents depolarization of the thick ventricular walls.
 
A negative deflection after an R wave is called an S wave. This small wave represents
depolarization of the Purkinje fibres. S waves travel in the opposite direction to the R waves
because the Purkinje fibres spread throughout the ventricles from top to bottom and then
back up though the walls of the ventricles.

T wave inversion can be normal in leads V1, aVL, aVR, aVF and lead III. It can also be normal
in lead V2 but only in association with T wave inversion in lead 1 is abnormal.
The ST segment commences at the end of the S wave (the J point) and ends at the
beginning of the T wave. The ST segment is isolelectric under normal circumstances as the
atria are relaxed and the ventricles contracted and there is therefore no visible electrical
activity.
 
The most important causes of ST segment deviation are myocardial ischaemia and
infarction, with ischaemia causing ST depression and infarction causing ST elevation.
 

The ECG segments and intervals are summarized in the table below:
 
  Commences Ends
PR segment End of the P wave Start of the QRS complex
PR interval Start of the P wave Start of the QRS complex
ST segment End of the S wave (J point) Start of the T wave
ST interval End of the QRS complex End of the T wave
QT interval Start of the QRS complex End of the T wave

The table below the answer shows the relationship between the stages of the cardiac cycle,
the ECG and the heart sounds:
 
Stage ECG Heart sounds
3rd heart sound may be
1. Early diastole. Iso-electric line.
heard.
4th heart sound may be
2. Atrial systole. P wave PR interval.
heard.
3. Isovolumetric
QRS complex. 1st heart sound.
ventricular contraction.
4. Ventricular ejection. ST segment. No heart sound.
5. Isovolumetric
Iso-electric line. 2nd heart sound.
ventricular relaxation.

ECG criteria for LVH have good specificity but poor sensitivity for actual left ventricular
hypertrophy. If LVH criteria are present on the ECG then there is a very high probability of
LVH being present.
 
The Sokolow-Lyon index is positive for LVH if the S wave in V1 plus the R wave in V5 or V6 is
greater than 35 mm (7 large squares). The Cornell voltage criteria is positive for LVH if the S
wave in V3 plus the R wave in aVL is greater than 28 mm in men or 20 mm in women. LVH is
also present if the R wave in aVL is greater than 12 mm.
 
ECG criteria for LVH are less reliable for detection in younger patients and should not be
used in patients under the age of 35.
 
ECGs have good specificity for LVH

Echocardiography is the gold standard for diagnosis of LVH.

Cor pulmonale is the enlargement and failure of the right ventricle secondary to respiratory
disease that has caused increased resistance to blood flow in the pulmonary circulation.

 For cor pulomale to occur the mean pulmonary arterial pressure is usually greater than 20 mmHg.
Complete right ventricular failure usually ensues if the mean pulmonary arterial pressure exceeds 40
mmHg.

 The causes of cor pulmonale include:

 COPD and asthma

 Primary pulmonary hypertension
 Recurrent or massive pulmonary embolus
 Obstructive sleep apnoea
 Sarcoidosis

 The diagnostic ECG criteria for right ventricular hypertrophy are as follows:
  Right axis deviation (> +110°)
 Dominant R wave in V1
 Deep S wave in V5 or V6 (> 7 mm deep)
 Normal QRS (excludes RBBB)

The stages of the cardiac cycle are summarised in the following table:
 
Stage Events Valves

Whole heart is relaxed.

Ventricles are expanding
and filling passively with AV valves open.
1. Early diastole.
blood from atria. Semilunar valves closed.
Ventricular presusure is
low and constant.
Atria contract and pump
blood. Final phase of
ventricular filling AV valves open.
2. Atrial systole.
(additional 10-40% of filling Semilunar valves closed.
ventricles). End diastolic
volume (EDV) established.
Ventricular myocytes begin
to contract.
Ventricular pressure
3. Isovolumetric AV valves closed.
increases.
ventricular contraction. Semilunar valves closed.
Ventricular volume is
constant (End diastolic
volume).
Ventricles contract fully.
Ventricular pressure
increases and reaches
maximum.
Ventricular volume
decreases. Aortic pressure
increases and reaches AV valves closed.
4. Ventricular ejection.
maximum. Semilunar valves open.
Ventricular volume
reaches its minimum.
(End systolic volume).
Aortic pressure starts to
fall as blood enters
arteries.
 Ventricles relax.
Ventricular volume is
5. Isovolumetric AV valves closed.
constant (End systolic
ventricular relaxation. Semilunar valves closed.
volume). Atria expand and
are filling.

Pulse pressure is the difference between the systolic and diastolic blood pressure, measured in mmHg. It
represents the force generated by the heart each time it contracts. The usual resting pulse pressure in
healthy adults is approximately 30-40 mmHg.

 Pulse pressure is considered to be abnormally low (narrow) if it is less than 25% of the systolic value.
Causes of a narrow pulse pressure include:

 Reduced cardiac output (e.g. blood loss)

 Aortic stenosis

 Cardiac tamponade

 Congestive cardiac failure

 Pulse pressure is generally considered to be high (wide) if it is greater than 60 mmHg. A resting pulse
pressure greater than 100 mmHg is highly indicative of the presence of a disease state. Causes of a wide
pulse pressure include:

 Atherosclerosis (stiffness of major arteries)

 Aortic regurgitation

 Arteriovenous malformation

 Aortic root aneurysm

 Aortic dissection

 Hyperthyroidism

There are several ways of calculating the QRS axis but the most efficient is the ‘quadrant
method’.
 
The quadrant method works by looking at leads I and aVF. The ‘hexaxial system’ can be
used to look at the relationship between the QRS axis and these two leads:
 
 
The axis of the ECG  © Medical Exam Prep
 
It can be seen that lead I cuts the hexaxial system in half horizontally (at +90 degrees) and
lead AVF cuts the hexaxial system in half vertically (at 0 degrees). Therefore these two leads
can be used to divide the hexaxial system into four quadrants and the QRS axis can be
placed in one of those quadrants:
 
Interpretatio
Lead I Lead AVF Quadrant Axis
n
Positive Positive Lower left 0 to +90 degrees Normal
Possible left
Positive Negative Upper left 0 to -90 degrees
axis deviation
Right axis
Negative Positive Lower right +90 to 180 degrees
deviation
Extreme axis
Negative Negative Upper right -90 to 180 degrees
deviation
 
One limitation of this method is that the QRS axis can be up to -30 degrees into the upper
left quadrant and it still be considered as normal. When the QRS axis is in this region
(between 0 and -30 degrees) it I sometimes referred to as physiological left axis deviation.
One way around this problem is to look closely at the QRS complex in lead II. When the
QRS complex in lead II is positive the axis is generally normal (physiological left axis
deviation) but when the QRS complex in lead II is negative there is left axis deviation
present.

Left axis deviation
Normal (physiological axis deviation)
Left ventricular hypertrophy
Left bundle branch block
Left anterior fascicular block
Inferior myocardial infarction
Wolff-Parkinson-White syndrome
Ostium primum ASD
Right ventricular ectopic rhythm
Right axis deviation
Right heart strain e.g. P.E., COPD
Right ventricular hypertrophy
Right bundle branch block
Left posterior fascicular block
Lateral wall myocardial infarction
Wolff-Parkinson White syndrome
Ostium secundum ASD
 Left ventricular ectopic rhythm
Dextrocardia

On standing blood accumulates in the extremities and venous volume and pressure
become high in the feet and lower limbs. This decreases thoracic venous blood (reduced
venous return) and therefore the central venous pressure decreases. This decreases right
ventricular filling pressure (preload), leading to a decrease in stroke volume via the Frank-
Starling mechanism. Left ventricular stroke volume also falls because of reduced
pulmonary venous return. This causes cardiac output and arterial blood pressure to fall.
 
On standing baroreceptor reflexes are activated and there is a rise in the heart rate and
cardiac contractility and peripheral vasoconstriction occurs. This acts to restore arterial
pressure.
 
Cerebral blood flow remains constant due to the process of autoregulation.

During inspiration, there is an increased venous return to the right atrium due to reduced
intra-pleural pressure. Therefore, during inspiration the filling of the right atrium is
increased.

During expiration lung deflation causes increased flow from the lungs to the left atrium
and left atrial filling is increased.
Wolf-Parkinson-White (WPW) syndrome is a disorder of the electrical conducting system of the heart.
It is caused by the presence of an abnormal electrical conduction pathway, called the bundle of Kent,
between the atria and the ventricles. This bundle of Kent acts as a pre-excitation pathway.

 Electrical signals travelling down the bundle of Kent can stimulate the ventricles, causing premature
contraction. This results in the generation of a type of supraventricular tachycardia referred to as
an atrioventricular re-entrant tachycardia (AVRT). 

 The typical ECG features of WPW in sinus rhythm are:

 Shortened PR (< 120 ms)

  Delta wave (slurring of the initial rise in the QRS complex)

 Widening of the QRS complex (> 110 ms)

 In addition there are two distinct recognisable types of WPW:

 Type A – the delta waves and QRS complexes are predominantly positive in the praecordial
leads with a dominant R wave in V1. The dominant R wave in V1 can be mistaken for RBBB

 Type B – The delta wave and QRS complex are predominantly negative in leads V1 and V2 and
positive in the other praecordial leads, resembling LBBB

The sinoatrial node  (SA node) is the pacemaker of the heart and is the point of origin of
the electrical impulses that are propagated through the heart. The SA node is located in the
right atrium and automatically generates an electrical impulse 60-100 times per minute
under normal conditions.
 
These electrical impulses stimulate the atria to contract and then travel to
the atrioventricular node (AV node), which is located in the inter-atrial septum. Here the
impulse is briefly slowed before continuing down the conduction pathway to the bundle of
His.
 
The bundle of His divides in the septum between the two ventricles into the left and right
bundle branches, which are situated in the left and right ventricular muscle respectively.
Conduction then spreads out via specialized tissue within the venrticular walls known as
Purkinje fibres.
 

The ECG rhythm strip shown in this question is normal sinus rhythm. The rate is approximately 60 beats
per minute and each QRS complex is clearly preceded by a P wave. The segments and intervals are all
normal.

 The heart rate can be calculated from the ECG using a number of different methods and depending
upon the circumstances.
  In most circumstances when there is a regular rhythm the simplest way to calculate the rate is by
counting the number of ‘large squares’ between the ‘spike’ of each complex. These are the R waves and
this is called the ‘R-R interval’. By dividing 300 by this number you will then have calculated the heart
rate.

In this case there are 5 ‘large squares’ between each R wave:

 Rate = 300/5 = 60 beats per minute

 If the rhythm is very fast and there is less than 1 ‘large square’ between each R wave then an
alternative method is to count the number of ‘small squares’ between each consecutive R wave and
then and then divide 1500 by this number.

 Calculation of the rate becomes more difficult if there is an irregular rhythm, such as in atrial fibrillation.
Under these circumstances the rate can be calculated by counting the number of complexes on the
rhythm strip provided across the bottom of the ECG and then multiplying this number by 6. This will give
the average rate over a 10 second period.

 In order to interpret the rate and its relevance it is also important to know what the rate means. In an
adult the rate can be interpreted as follows:

 < 60 beats per minute = bradycardia

 60-100 beats per minute = normal
 > 100 beats per minute = tachycardia

A narrow complex ectopic beat is more likely to have come from above the ventricular
myocardium.
 
Ectopic beats are generally benign and have a very good prognosis if not associated with
underlying structural heart disease or cardiomyopathy. Causes include:
 Abnormal electrolytes e.g. hypokalaemia
 Cardiomyopathy
 Alcohol use
 Caffeine and other stimulants
 Smoking
 
Ectopics can be divided into two groups:
 
 1. Supraventricular (atrial) ectopics
 Arise from above the ventricles and pass through the AV node
 Caused by premature discharge of an atrial ectopic focus
 Produces a normal QRS complex
 Often premature or abnormally shaped P waves
 Usually an incomplete compensatory pause before the next sinus beat
 
2. Ventricular ectopics
 Arise in the ventricles
 Caused by the premature discharge of a ventricular ectopic focus
 Produces a broad QRS complex
 ST segment and T wave usually opposite in polarity to QRS complex
 
Broad complex ectopic beats may be supraventricular in origin if there is a co-existing
bundle branch block.
 Ventricular ectopics after a myocardial infarction are associated with increased mortality.

Einthoven’s Triangle

The limb leads are leads AVR, AVL, AVF, I, II and III. Each of these leads represents a
measured voltage that also has a direction. By combining the magnitude of the measured
voltage and the direction of the voltage a vector is formed.
 
The limb leads AVR, AVL, AVF are also unipolar leads as they only have one associated
electrode. The voltages of these electrodes are very small and have to be ‘augmented’ by
built in amplifiers. The ‘AV’ used in the terminology for these leads therefore stands for
‘Augmented Vector’. For these leads the negative pole is once again the centre of the heart
and the three leads create a triangle with the heart in the middle. The vectors created are
shown below:
 

 
The limb leads I, II and III are called bipolar leads because they have two associated
electrodes. AVR, AVL and AVF make up an equilateral triangle, known as ‘Einthoven’s
Triangle’:
 

 
Information is gathered between these leads to create three more vectors:
 Lead I – information between AVR and AVL
 Lead II – information between AVR and AVF
 Lead III – information between AVL and AVF
 The sum of these vectors is shown below:
 

 
Finally by combining all 6 of these vectors together we create the ‘hexaxial system’, which
gives us a perspective of the view of all six of the limb leads.

It can be difficult to make the diagnosis of myocardial infarction (MI) in the presence of left
bundle branch block or a ventricular paced rhythm. The Sgarbossa criteria can be used as a
method of determining the presence of an MI under these circumstances.
 
The Sgarbossa criteria are:
 > 1 mm concordant ST elevation in leads with a positive QRS complex (5 points)
 > 1 mm concordant ST depression in leads V1-V3 (3 points)
 > 5 mm discordant ST elevation in leads with a negative QRS complex (2 points)
 
Scores > than 3 have a 90% specificity for detecting myocardial infarction.

Blood flow to the brain is described by two equations; CPP = MAP – ICP and CBF = CPP / CVR, where CPP
= Cerebral Perfusion Pressure, MAP = Mean Arterial Pressure, ICP = Intracerebral Pressure, CBF =
Cerebral Blood Flow, CVR = Cerebrovascular resistance.

 Auto-regulation maintains CBF at a relatively constant level, despite the fluctuations in CPP caused by
changes in systemic MAP. The main mechanisms of auto-regulation are:

 myogenic reflexes - at higher pressures the myogenic stretch reflex causes vasoconstriction
which increases CVR and reduces CBF

 metabolic feedback - at lower pressures decreased blood flow allows vasoactive metabolites to
accumulate (primarily CO2 and K+) that cause vasodilation and reduce CVR and increase CBF.

 Outside of the CPP range 60-160mmHg, or in trauma or cerebral disease, auto-regulation is lost and CBF
is dependant on MAP in a linear relationship.
 The autonomic nervous system has a minimal role in auto-regulation.

 Hypothermia reduces CBF by 5% per degree fall in temperature.

Which of the following heart rhythms is demonstrated?

Atrial flutter is a supraventricular tachyarrhythmia caused by a re-entry circuit within the

right atrium. Atrial activity is seen on the ECG as ‘flutter waves’, which occur at a rate of
approximately 300 per minute. These flutter waves have a ‘saw-tooth’ appearance and are
usually best seen in the inferior leads (II, III, and aVF).
 
The ventricular rate is determined by the AV conduction ratio, the commonest being a 2:1
block, which results in a ventricular rate of around 150 per minute. Higher-degree AV
blocks can occur (e.g. 3:1, 4:1 block, or even higher as in this case) and result in lower rate
of ventricular conduction. A variable block may also occur, which results in a variable rate.
Atrial flutter is frequently caused by underlying disease. As it originates in the right atrium
it is most strongly associated with pathology of the right atrium, such as COPD, pulmonary
emobolus, and congenital cardiac conditions.

Which of the following heart rhythms is demonstrated? 

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical
practice. The lifetime risk over the age of 40 years is approximately 25%.
 
The classic ECG features of atrial fibrillation are:
 Irregularly irregular rhythm
 Absent p waves
 Irregular ventricular rate
 Presence of fibrillation waves
 
The atrial impulses are filtered out by the AV node, resulting in the irregularly irregular
rhythm
 
Ashman beats are wide complex QRS complexes, usually with a RBBB morphology, that
follow a short R-R interval preceded by a prolonged R-R interval. These are typically seen in
atrial fibrillation and are considered benign.
 
The disorganized electrical activity in AF usually originates at the root of the pulmonary
veins.
 AF is characterized by an irregularly irregular rhythm with an absence of P waves and an
isoelectric baseline on the ECG. The ventricular rate is variable and the QRS complexes are
usually narrow unless there is a co-existing bundle branch block or accessory pathway.
Fibrillatory waves may be present and can be fine (amplitude < 0.5 mm), or coarse
(amplitude > 0.5 mm).
 

There are many potential causes of atrial fibrillation including:

 Ischaemic heart disease
 Hypertension
 Valvular heart disease
 Electrolyte disturbance (e.g. hypokalaemia)
 Thyrotoxicosis
 Drugs (e.g. sympathomimetics)
 Sepsis
 Alcohol excess

Treatment of Atrial Fibrillation

For patients with a rate-control strategy the first line-drug should be a standard beta-blocker (other than
sotalol), such as bisoprolol, or a rate-limiting calcium channel blocker, such as diltiazem. A resting heart
rate of less than 90 bpm should be targeted for established AF and less than 110 bpm for those with
recent-onset AF.

The use of digoxin is now reserved for patients requiring further rate-control therapy or for patients
with co-existing heart failure.

Amiodarone, sotalol and flecainide are generally used when a rhythm control strategy has been
adopted. Flecainide is generally best avoided in elderly patients with a history of coronary artery
disease.

Which of the following heart rhythms is demonstrated?

A third-degree heart block (complete heart block) is present when there is no relationship
between the P waves and the QRS complexes. In third-degree heart block atrial and
ventricular depolarization arise completely independently and there is a complete absence
of atrioventricular conduction.
 
The patient typically has a severe bradycardia with independent atrial and ventricular rates.
There is a very high risk of ventricular standstill, resulting in syncope if self-terminating, or
asystole and sudden cardiac death if prolonged. Patients with third-degree heart block
require treatment with a permanent implantable pacemaker.
Right atrial enlargement is primarily caused by pulmonary hypertension. The most common causes of
pulmonary hypertension are:

 Chronic lung disease (cor pulmonale)

 Primary pulmonary hypertension
 Tricuspid stenosis
 Congenital heart disease (tetralogy of Fallot, pulmonary stenosis)

Hypertrophy of the right atrial myocardium results in delayed activation of the right atrium and
production of an exaggerated p wave that is tall and narrow.

 The ECG criteria for diagnosing right atrial enlargement (‘p pulmonale’) are as follows:

 P wave amplitude in inferior leads (II,III and AVF) > 2.5 mm, or;

 P wave amplitude in lead V1 and V2 > 1.5 mm

Torsades de pointes is a specific form of polymorphic ventricular tachycardia that occurs in the
presence of prolongation of the QT interval. It has a very characteristic appearance in which the QRS
complex appears to twist around the isoelectric baseline.

A prolonged QT interval reflects prolonged myocyte repolarisation due to ion channel malfunction and
also gives rise to early after-depolarisations (EADs). EADs can manifest as tall U waves, which can cause
premature ventricular contractions (PVCs). Torsades de pointes is initiated when a PVC occurs during the
preceding T wave (‘R on T’ phenomenon)

It can be caused by any cause of prolongation of the QT interval:

  Myocardial infarction
 Electrolyte disturbance e.g. hypokalaemia, hypomagnesaemia and hypocalcaemia
 Congenital e.g. Romano-ward syndrome and Lange-Nielson syndrome
 Drugs e.g. disopyramide, amiodarone, sotalol, terfenadine

The drug treatment of choice for torsades de pointes is IV magnesium sulphate. Magnesium sulphate
acts by decreasing the influx of calcium and lowering the amplitude of EADs.

DC cardioversion is usually kept as a last resort in a haemodynamically stable patient because of the
paroxysmal and recurrent nature of torsades de pointes.

Torsades de pointes can degenerate into ventricular fibrillation and result in sudden cardiac death.

The transfer of blood around the body is determined by pressure gradients. Pressure gradients are
created by the synchronised contraction of the myocardium, which in turn is coordinated by the cardiac
pacemaker and conducting system. 

The table below gives the approximate cardiac pressure in each of the cardiac chambers:

Chamber Pressure (mmHg )

Right atrium 0-4 (varies with respiration)

Right ventricle 25 (systolic), 4 (diastolic)

Pulmonary artery 25 (systolic), 10 (diastolic)

Left atrium 8-10 (varies with respiration)

Left ventricle 120 (systolic), 10 (diastolic)

Aorta 120 (systolic), 80 (diastolic)

 Refer moussa issca book

 Wiggers diagram showing the events of the cardiac cycle and the corresponding chamber values

 Haemorrhage can be classified into four separate classes based on physiological parameters and clinical
signs:

  CLASS I CLASS II CLASS III CLASS IV

Blood loss (mL) Up to 750 750-1500 1500-2000 >2000
Blood loss
Up to 15% 15-30% 30-40% >40%
(% blood volume)
Pulse rate (bpm) <100 100-120 120-140 >140
Systolic BP Normal Normal Decreased Decreased
Pulse pressure Normal (or
Decreased Decreased Decreased
  increased)
Respiratory rate 14-20 20-30 30-40 >40
Urine output (ml/hr) >30 20-30 5-15 Negligible
Anxious, Confused,
CNS/mental status Slightly anxious Mildly anxious
confused lethargic
There are a number of compensatory mechanisms that occur in response to blood loss, including:

 Progressive vasoconstriction of cutaneous, muscle and visceral circulation that preserves the
blood flow to the heart, brain, and kidneys
 Increased heart rate to preserve cardiac output. In most cases the earliest measurable
circulatory sign of shock is tachycardia
 Release of endogenous catecholamines that increase peripheral vascular resistance. This
increases diastolic blood pressure and reduces pulse pressure.

 Numerous vasoactive hormones are released including histamine, bradykinin, beta endorphins,
prostanoids and cytokines

The mean arterial pressure (MAP) is defined as the average arterial pressure during a
single cardiac cycle. It normally lies within the range of 65 and 110 mmHg and needs to be
a minimum of 65 mmHg for adequate organ perfusion to occur. It is considered a better
indicator of vital organ perfusion than systolic blood pressure.
 
MAP can be calculated by non-invasive means using one of the following equations:
 
MAP =  [(2 x diastolic BP) + systolic BP] / 3 or;
 
MAP = diastolic BP + [(systolic BP – diastolic BP) / 3]
 
 Diastole counts roughly twice as much as systole because 2/3 of the cardiac output is
spent in diastole.
 
MAP is determined by the cardiac output (CO), systemic vascular resistance (SVR), and the
central venous pressure (CVP), according to the following relationship:
 
MAP = (CO x SVR) + CVP
 
 Because the CVP is generally close to zero and does not significantly impact on the end
result of the equation, this relationship is often simplified to:
 
MAP = CO x SVR
 Endocrine
Parathyroid hormone (PTH) is a polypeptide containing 84 amino acids. It is the principal controller of
free calcium in the body.

 PTH is synthesized by and released from the chief cells of the four parathyroid glands that are located
immediately behind the thyroid gland.

 PTH is released in response to the following stimuli:

 Decreased plasma calcium concentration

 Increased plasma phosphate concentration (indirectly by binding to plasma calcium and
reducing the calcium concentration)

 PTH release is inhibited by the following factors:

 Normal/increased plasma calcium concentration

 Hypomagnesaemia

 The main actions of PTH are:

 Increases plasma calcium concentration

 Decreases plasma phosphate concentration
 Increases osteoclastic activity (increasing calcium and phosphate resorption from bone)
 Increases renal tubular reabsorption of calcium
 Decreases renal phosphate reabsorption
 Increases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (via
stimulation of 1-alpha hydroxylase)
 Increases calcium and phosphate absorption in the small intestine (indirectly via increased
1,25-dihydroxycholecalciferol)

 
   Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down and
releases proteins, such as myoglobin, that are harmful to kidneys and can cause renal
failure. It is not uncommon for patients with rhabdomyolysis to be cared for in a high
dependency or intensive care setting. Rhabdomyolysis causes hyperphosphataemia and
hypocalcaemia therefore a reduction in ionized calcium levels.

Addison’s disease, hyperthyroidism, thiazide diuretics and lithium all have a tendency to
cause hypercalcaemia.
 
Other causes of hypocalcaemia include: ( FRESH PT H2 )
 Fluoride poisoning
 Renal failure
 EDTA infusions
 Sepsis
 Hypovitaminosis D
 Pancreatitis
 Tumour lysis syndrome
 Hypoparathyroidism
 Hypomagnasaemia

Insulin is a peptide hormone produced by the beta-cells of the islets of Langerhans in the pancreas.

The beta-cells first synthesize a biologically inactive precursor called preproinsulin. This is then
converted to proinsulin by signal peptidases, which remove a signal peptide from the N-terminus. Finally
proinsulin is converted to the biologically active hormone insulin by the removal of the C-peptide.

The most potent stimulus for the release of insulin from the beta-cells is the presence of increased
glucose levels. The release of insulin reduces glucose concentrations back to normal and acts as
a negative feedback. Insulin has a short half-life in the circulation of around 5-10 minutes and is rapidly
broken down by the liver and kidneys.

 Other factors that stimulate insulin release include: ( CP CABS G5 )

 Cholecystokinin
 Parasympathetic stimulation (via acetylcholine)
  Cortisol
 Amino acids (arginine and leucine)
 Beta-adrenergic stimulation
 Secretin
 Gastrin
 Glucagon
 Growth hormone
 Glucagon-like peptide 1 (GLP-1)
 Gastric inhibitory polypeptide (GIP)

 Factors that inhibit insulin release include:

 Reduced blood glucose
 Fasting
 Alpha-adrenergic stimulation
 Somatostatin
 Leptin

Insulin is an anabolic hormone that has a variety of actions. These can be broadly divided
into:
 Carbohydrate metabolism
 Protein metabolism
 Lipid metabolism
 
These effects are summarized in the table below:
 
Type of metabolism Effects
Promotes glucose uptake (most prominently in
muscle and adipose tissue)
Promotes glycogen storage
Carbohydrate metabolism Stimulates glycolysis
Increases glycogenesis
Decreases glycogenolysis
Decreases gluconeogenesis
Accelerates net formation of protein
Stimulates amino acid uptake
Protein metabolism Stimulates protein synthesis
Inhibits protein degradation
Inhibits amino acid conversion to glucose
Inhibits lipolysis by lipase
Lipid metabolism
Stimulates liopgenesis

Calcitonin is a 32 amino acid polypeptide that is primarily synthesized and released by the

parafollicular cells (C-cells) of the thyroid gland. Its main role is to reduce the plasma calcium
concentration, therefore opposing the effects of parathyroid hormone.
  Secretion of calcitonin is stimulated by:

 Increased plasma calcium concentration

 Gastrin
 Pentagastrin

 The main actions of calcitonin are:

 Inhibition of osteoclastic activity (decreasing calcium and phosphate resorption from bone)
 Stimulation of osteoblastic activity
 Decreases renal calcium reabsorption
 Decreases renal phosphate reabsorption

Glucagon is a peptide hormone that is produced and secreted by alpha cells of the
islets of Langerhans, which are located in the endocrine portion of the pancreas. The
main physiological role of glucagon is to stimulate hepatic glucose output, thereby leading
to increases in glycaemia. It provides the major counter-regulatory mechanism to insulin in
maintaining glucose homeostasis.
 
Hypoglycaemia is the principal stimulus for the secretion of glucagon, which then
stimulates:
 Glycogenolysis
 Lipolysis
 Gluconeogenesis
 
The secretion of glucagon is stimulated by:
 Hypoglyacemia (principal stimulus)
 Adrenaline
 Cholecystokinin
 Arginine
 Alanine
 Acetylcholine
 
The secretion of glucagon is inhibited by:
 Insulin
 Somatostatin
 Increased free fatty acids
 Increased urea production
 
Glycogenolysis is the breakdown of glycogen to glucose-6-phosphate and glucose. This
provides energy for muscle contraction and allows glycogen to broken down to release
glucose into the bloodstream.
 
Lipolysis is the breakdown of lipids and involves hydrolysis of triglycerides into glycerol
and free fatty acids. It makes fatty acids available for oxidation.
 
Gluconeogenesis is a metabolic pathway that results in the biosynthesis of new glucose
from non-carbohydrate substrates.
 
Glycolysis is the metabolic pathway that converts glucose into pyruvate. The free energy
released by this process is used to form ATP and NADH. Glycolysis is inhibited by glucagon
and glycolysis and gluconeogenesis are reciprocally regulated so that when one cell
pathway is activated the other is inactive and vice versa.
 Cushing’s syndrome.
 The most common cause of Cushing’s syndrome is the iatrogenic administration of
corticosteroids. 

The endogenous causes of Cushing’s syndrome include:

 Pituitary adenoma (Cushing’s disease)
 Ectopic corticotropin syndrome e.g. small cell carcinoma of the lung
 Adrenal adenoma
 Adrenal carcinoma
 Adrenal hyperplasia

The clinical features of Cushing’s disease include:

 Truncal obesity and weight gain
 Supraclavicular fat pads
 Buffalo hump
 Facial fullness and plethora (‘moon facies’)
 Proximal muscle weakness and wasting
 Diabetes mellitus or impaired glucose tolerance
 Hypertension (that can be difficult to control)
 Skin atrophy and easy bruising
 Hirsutism
 Acne
 Osteoporosis
 Depression
 
Elevated androgen levels tend to cause amenorrhoea or oligomenorrhoea, as opposed to
menorrhagia. Excess androgen levels can also cause infertility in women of childbearing
age.
 
Patients with Cushing’s syndrome are generally hypertensive due to cortisol enhancing the
vasoconstrictive effect of endogenous adrenaline.
 
Cortisol levels vary throughout the day and are usually highest at 0900 hrs and lowest
during sleep at 2400 hrs. In Cushing’s syndrome there is loss of the diurnal variation of the
cortisol levels and levels are higher throughout the entire 24-hour period. Levels may be
within normal range in the morning but high at midnight, when they are usually
suppressed.
 
The presence of Cushing’s syndrome can be confirmed by either a dexamethasone
suppression test of 24-hour urinary free cortisol collection.
 24-hour urinary fee cortisol collection can confirm the presence of Cushing’s syndrome but
in order to confirm Cushing’s disease, a pituitary adenoma MRI or CT imaging of the
pituitary gland are necessary.

 ACTH levels are typically elevated.

 
A bitemporal hemianopia may be present due to the pituitary adenoma compressing the
optic chiasm.
 Hyperglycaemia, caused by insulin resistance, is a common feature. This insulin resistance
can cause skin changes such as acanthosis nigricans in the axilla and around the neck.

Although a combination of hypokalaemia, a high normal sodium level and resistant

hypertension often points to a diagnosis of Conn’s syndrome, these blood results can also
be present in Cushing’s syndrome. The numerous other history and examination features
consistent with a diagnosis of Cushing’s syndrome, therefore make it a more likely
underlying diagnosis in this case.
 
Renal artery stenosis could also be suspected in a case of refractory hypertension, however
a deterioration in renal function would be expected on a full dose of an ACE inhibitor such
as ramipril. In this case the patient’s renal function is entirely normal.
 
Phaecochromoctyoma is associated with clinical features such as headache, palpitations,
tremor and sweating. The hypertension tends to be paroxysmal. In the absence of these
features a diagnosis of phaeochromocytoma is unlikely.

Glucocorticoids, such as cortisol, are released in response to hypoglycaemia and have a

number of effects on glucose regulation. These include:
 Inhibition of glucose uptake
 Promotion of gluconeogenesis
 Promotion of glycogen production
 Promotion of glycogen storage ( in liver )
 Promotion of lipoylsis (free fatty acids and glycerol are used in preference to
glucose)

Diabetes insipidus is the inability to produce concentrated urine. It is characterised by the presence of
excessive thirst, polyuria and polydipsia. There are two distinct types of diabetes insipidus:

1. Cranial (central) diabetes insipidus and;

2. Nephrogenic diabetes insipidus

 Cranial diabetes insipidus is caused by a deficiency of vasopressin (anti-diuretic hormone). Patients with
cranial diabetes insipidus can have a urine output as high as 10-15 litres per 24 hours but adequate fluid
intake allows most patients to maintain normonatraemia. 30% of cases are idiopathic and a further 30%
are secondary to head injuries. Other causes include neurosurgery, brain tumours, meningitis,
granulomatous disease (e.g. sarcoidosis) and drugs, such as naloxone and phenytoin. A very rare
inherited form also exists that is associated with diabetes mellitus, optic atrophy, nerve deafness and
bladder atonia.

 Nephrogenic diabetes insipidus is caused by renal resistance to the action of vasopressin. As with
cranial diabetes insipidus urine output is markedly elevated. Serum sodium levels can be maintained by
secondary polydipsia or can be elevated. Causes of nephrogenic diabetes insipidus include chronic renal
disease, metabolic disorders (e.g. hypercalcaemia and hypokalaemia) and drugs, including long-term
lithium usage and demeclocycline.

 The water deprivation test, also known as the fluid deprivation test, is the best test to determine if a
patient has diabetes insipidus as opposed to another cause of polydipsia. It also helps to distinguish
cranial from nephrogenic diabetes insipidus. Patients are deprived of water intake for up to 8 hours and
weight, urine volume, urine osmolality and serum osmolality are all measured. 2 micrograms of IM
desmopressin is administered at the end of the 8 hours and further measurements are made at 16
hours.

 Results are interpreted as follows:

Urine osmolality after fluid Urine osmolality after IM

deprivation desmopressin

Cranial diabetes insipidus < 300 mosmol/kg > 800 mosmol/kg

Nephrogenic diabetes insipidus < 300 mosmol/kg < 300 mosmol/kg

Primary polydipsia > 800 mosmol/kg > 800 mosmol/kg

The following table summarizes the effects of thyroid hormones on different systems:
 
System Effects
Increased basal metabolic rate
Increased oxygen consumption
Increased heat production
Increased absorption of glucose
Metabolic Increased glycolysis
Increased gluconeogenesis
Increased catabolism of fatty acids
Decreased cholesterol production
Increased synthesis and catabolism of proteins
Increased heart rate
Increased cardiac output
Increased beta-receptor production
Cardiovascular
Promotion of erythropoiesis
Decreased peripheral vascular resistance
(indirect due to increased metabolic rate in tissues)
Respiratory Increased ventilatory rate
Increased motility
Gastrointestinal
Increased secretion
Increased CNS activity
Central nervous system
Increased alertness
Necessary for normal myelination and axonal
development
Growth and development
Stimulation of skeletal growth
Promotion of bone mineralization

The thyroid hormones, triiodothyronine (T 3) and thyroxine (T4), have a complex relationship with glucose
regulation. Low concentrations of T3 and T4 tend to have an anabolic effects and reduce plasma glucose
concentrations whereas high concentrations tend to be catabolic and induce hyperglycaemia.

 The effects of the thyroid hormones on glucose regulation include:

 Promotion of glucose uptake into cells
 Stimulation of glycogenolysis
 Stimulation of gluconeogenesis
 Increased absorption of glucose from the gastrointestinal tract
 Enhances rate of insulin-dependent glycogenesis
 Thyroid-stimulating hormone (TSH) is a glycoprotein hormone synthesized and secreted by thyrotrope
cells in the anterior pituitary gland. It is secreted in response to the release of thyrotropin-releasing
hormone (TRH) from the hypothalamus. Somatostatin, which is also produced in the hypothalamus, has
the opposite effect to TRH and inhibits the release of TSH.

 TSH acts to regulate the endocrine function of the thyroid gland. The thyroid
hormones, triiodothyronine (T3) and thyroxine (T4) have a negative feedback effect on TRH and TSH.
When concentrations of the thyroid hormones are high, the production of TRH and TSH is decreased.
Conversely, when concentrations are low, production is increased.

Thyrotropin-releasing hormone (TRH) is an important peptide hormone that is produced by cells within
the paraventricular nucleus (PVN) of the hypothalamus. It is released at the median eminence from
neurosecretory terminals of these neurons into the hypothalamo-hypophyseal portal system. It is
released in response to low levels of secretion of thyroid-stimulating hormone (TSH).

 The hypothalamo-hypophyseal portal system carries the TRH to the anterior pituitary, where it
stimulates thyrotropes to secrete TSH. TSH in turn stimulates thyroid hormone production and
secretion. TRH also stimulates the release of prolactin from the anterior pituitary.

Primary hyperparathyroidism is the third commonest endocrine disorder and the commonest cause of
hypercalcaemia. It most commonly occurs in women between the ages of 50 and 60.

 The commonest cause of primary hyperparathyroidism is a solitary adenoma of the parathyroid gland
(approximately 85% of cases). Other causes include:

 Multiglandular parathyroid hyperplasia

 Parathyroid carcinoma (rare)

 Ectopic adenomas (e.g. in thymus)

 Drugs (e.g. thiazide diuretics and lithium)

 Primary hyperparathyroidism can be asymptomatic or may present with features of hypercalcaemia

such as polyuria, polydipsia, renal stones, constipation, bone and joint pain, and psychiatric problems . It
is the most common cause of hypercalcaemia in the UK

 Investigations in patients with primary hyperparathyroidism will usually reveal elevated PTH, elevated
calcium and low phosphate levels.

 Secondary hyperparathyroidism occurs secondary to chronic hypocalcaemia and is most often seen in
patients with chronic kidney disease or vitamin D deficiency. Chronic hypocalcaemia results in
hyperplasia of all four parathyroid glands. Investigations will reveal elevated PTH and low or low-normal
calcium. Phosphate levels are usually raised if secondary to chronic renal failure. Serum alkaline
phosphatase will also be elevated.

The clinical features are those of hypocalcaemia including:

 Pins and needles in extremities and around mouth
 Convulsions
 Arrhythmias and prolongation of QT interval
 Generalised malaise and tiredness
 Hyperactive deep tendon reflexes
 Latent tetany (positive Chvostek and Trousseau signs)
 Psychiatric effects including depression and psychosis
 Tertiary hyperparathyroidism is seen in patients with long-term secondary hyperparathyroidism in
which autonomous hypersecretion of PTH develops causing hypercalcaemia. A change occurs in the ‘set-
point’ of the calcium sensing mechanism to hypercalcaemic levels. It is almost exclusively seen in
patients with chronic renal disease undergoing dialysis. Investigations will reveal elevated PTH, elevated
calcium and low phosphate levels if secondary to chronic renal failure. Serum alkaline phosphatase will
also be elevated.

 A summary of the biochemical findings in the different types of hyperparathyroidism is shown below: 

Primary Secondary Tertiary

 
Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism

PTH Elevated Elevated Elevated

Calcium Elevated Low or low-normal Elevated

Phosphate Lowered Raised in CRF Lowered in CRF

The thyroid hormones, triiodothyronine (T3) and its precursor thyroxine (T4) are tyrosine-based

hormones produced by the follicular cells of the thyroid gland. They are primarily responsible for the
regulation of metabolism. Both of the thyroid hormones are partially composed of iodine and iodine
deficiency results in decreased production of both T 3 and T4.

 T3 and T4 are released in response to the secretion of thyroid-stimulating hormone (TSH) from

the anterior pituitary gland. TSH itself is secreted in response to the release of thyrotropin-releasing
hormone (TRH) from the hypothalamus.

 T3 and T4 have a negative feedback effect on TRH and TSH. When concentrations of the thyroid
hormones are high, the production of TRH and TSH is decreased. Conversely, when concentrations are
low, production is increased.

 Most of the thyroid hormones circulating in the blood are bound to transport proteins and only a very
small fraction is free (unbound). For this reason measuring the concentration of free thyroid hormones
is of great diagnostic value. Only the free portion of the thyroid hormones is biologically active and
measurement of total thyroid hormone levels can be misleading

 The thyroid hormones, triiodothyronine (T 3) and thyroxine (T4), have a complex relationship with
glucose regulation. Low concentrations of T3 and T4 tend to have an anabolic effects and reduce plasma
glucose concentrations whereas high concentrations tend to be catabolic and induce hyperglycaemia.

The effects of the thyroid hormones on glucose regulation include:

 Promotion of glucose uptake into cells

 Stimulation of glycogenolysis
 Stimulation of gluconeogenesis
 Increased absorption of glucose from the gastrointestinal tract
 Enhances rate of insulin-dependent glycogenesis
The relative percentages of bound and unbound thyroid hormones are shown in the table below:

Type Percentage

Bound to thyroid-binding globulin 70%

Bound to albumin 15-20%

Bound to transthyretin 10-15%

Free T3 0.3%

Free T4 0.03%

The major form of thyroid hormone circulating in the blood is T 4, which has a longer biological half-life
than T3 (the ratio of T4:T3 is approximately 20:1).

 T3 and T4 cross the cell membrane via diffusion and once inside the cell T4 is converted by deiodinases
into T3, which is 3- to 5-fold more active than T 4.

The normal ranges for thyroid function tests as per the British Thyroid Foundation are:

Test From To Units

TSH 0.4 4.0 mU/L

FT3 3.5 7.8 pmol/L

FT4 9.0 25.0 pmol/L

A high TSH level with a low FT4 level indicates hypothyroidism. A low TSH level with a high FT4 level and
a high FT3 level indicates hyperthyroidism. An abnormal TSH level together with a normal FT4 level
indicates that the patient may be at risk of developing a thyroid disorder. A low TSH level together with
a low T4 level can indicate a disorder of the pituitary gland.

Addison’s disease is caused by underproduction of the steroid hormones by the adrenal glands.
Glucocorticoid, mineralocorticoid and sex steroid production are all affected. Automimmune adrenalitis
is the commonest cause and this accounts for approximately 70-80% of cases.

 It is more common in women than men and most commonly occurs between the ages of 30 and 50.

 The clinical features of Addison’s disease include:

 Weakness and lethargy

 Hypotension (notably orthostatic hypotension)
 Nausea and vomiting
 Weight loss
 Reduced axillary and pubic hair
 Depression
 Hyperpigmentation (palmar creases, buccal mucosa and exposed areas more commonly
affected)
  The classical biochemical features of Addison’s disease are as follows:

 Increased ACTH levels (rise in an attempt to stimulate the adrenal glands)

 Hyponatraemia
 Hypoglycaemia
 Hyperkalaemia
 Hypercalcaemia
 Metabolic acidosis
 Elevated blood urea nitrogen (BUN) and creatinine

 An ACTH level of greater than 80ng/l in the presence of a low or normal serum cortisol level is highly
suggestive of primary hypoadrenalism. Hyponatraemia causes a raised serum renin level.

 Random cortisol measurements have a low sensitivity for detecting Addison’s disease due to the diurnal
variation of cortisol secretion.

Addison’s disease is associated with an increased incidence of the following conditions:

 Type I diabetes mellitus (not type II)

 Hashimoto’s thyroiditis
 Grave’s disease
 Premature ovarian failure
 Pernicious anaemia
 Vitiligo
 Alopecia

 Management should be by an Endocrinologist. Typically patients require hydrcortisone, fludrocortisone

and dehydropiandrosterone. Some patients also require thyroxine if there is hypothalamic-pituitary
disease present. Treatment is life-long and patients should carry a steroid card and a MedicAlert
bracelet and be aware of the possibility of Addisonian crisis.

The following are the characteristic features of an Addisonian crisis:

 Pain in legs and abdomen
 Vomiting and dehydration
 Hypotension
 Confusion and psychosis
 Fever
 Convulsions
 Hypoglycaemia
 Hyponatraemia
 Hyperkalaemia
 Hypercalcaemia
 Eosinophilia
 Metabolic acidosis

Broadly speaking hormones can be divided into three different classes based on their
chemical composition, amines, peptides (and proteins), and steroids. Amines are derived
from single amino acids (e.g. tyrosine), peptide hormones consist of peptides (or proteins),
and steroid hormones are converted from their parent compound, cholesterol.
 
Some notable examples of each of these three classes of hormone are shown in the table
below:
 

Type of hormone Examples

Adrenocorticotropic hormone (ACTH)
Prolactin
Vasopressin
Oxytocin
Peptide hormone
Glucagon
Insulin
Somatostatin
Cholecystokinin
Adrenaline (epinephrine)
Amine hormone Noradrenaline (norepinephrine)
Dopamine
Glucocorticoids (e.g. cortisol)
Mineralocorticoids (e.g. aldosterone)
Steroid hormone Androgens
Oestrogens
Progestogens

Osteoclasts are a type of bone cell that breaks down bone tissue. This is a critical function in the
maintenance, repair and remodeling of bones. The osteoclast disassembles and digests the composite of
hydrated protein and mineral at a molecular level by secreting acid and a collagenase. This process is
known as bone resorption and also helps to regulate the plasma calcium concentration.

 Osteoclastic activity is controlled by a number of hormones:

 1,25-dihydroxycholecalciferol increases osteoclastic activity

 Parathyroid hormone increases osteoclastic activity
 Calcitonin inhibits osteoclastic activity

 Bisphosphonates are a class of drug that slow down and prevent bone damage. They are osteoclast
inihibitors.

The sites of production and main effects of the hormones produced by the hypothalamus
is shown in the table below:

Hormone Site of production Effects

Parvocellular neurosecretory
Corticotropin-releasing Stimulates ACTH
cells of the paraventricular
hormone (CRH) production form the
nucleus
  anterior pituitary
 
Parvocellular neurosecretory Stimulates TSH and
Thyrotropin-releasing
cells of the paraventricular prolactin release from
hormone (TRH)
nucleus anterior pituitary
Inhibits prolactin
Dopamine nucleus of the
Dopamine release from the
arcuate nucleus
anterior pituitary
Growth-hormone-releasing Neuroendocrine neurons of Stimulates GH release
 from the anterior
hormone (GHRH) the arcuate nucleus
pituitary
Stimulates FSH and LH
Gonadotropin-releasing Neuroendocrine cells of the
release from the
hormone (GnRH) preoptic area
anterior pituitary
Somatostatin Inhibits GH and TSH
Neuroendocrine cells of the
  release from the
periventricular area
  anterior pituitary
Magnocellular and Increases permeability
parvocellular neurosecretory to water of cells in the
Vasopressin cells of the paraventricular distal tubule and
nucleus and supraoptic collecting duct in the
nucleus kidney
Magnocellular and
parvocellular neurosecretory Lactation via the milk
cells of the paraventricular letdown reflex and
Oxytocin
nucleus and magnocellular stimulation of uterine
cells of the supraoptic contraction
nucleus

Vasopressin, which is also known as antidiuretic hormone (ADH), is a peptide hormone

that regulates the body’s retention of water.
 
It is derived from a prohormone precursor in the hypothalamus and then transported via
axons to the posterior pituitary, where it is stored in vesicles.
 
There are several mechanisms that regulate the secretion of vasopressin from the
posterior pituitary:
 
1. Increased osmolality of the plasma: Hypothalamic osmoreceptors sense an
increase in osmolality and stimulate vasopressin release.
2. Hypovolaemia: This results in decreased atrial pressure that is detected by stretch
receptors in the atrial walls and large veins (cardiopulmonary baroreceptors). Atrial
receptor firing normally inhibits vasopressin release but when stretched the firing
decreases and vasopressin release is stimulated.
3. Hypotension: This decreases baroreceptor firing, which leads to enhanced
sympathetic activity and increased vasopressin release.
4. Angiotensin II: An increase in angiotensin II stimulates angiotensin II receptors in
the hypothalamus to increase vasopressin production.
 
Vasopressin has two principal sites of action:
 
1. The kidney: The primary function of vasopressin is to regulate the volume of the
extracellular fluid. It acts on the renal collecting ducts via V2 receptors to increase
 permeability to water (via a camp-dependent mechanism). This results in decreased urine
formation, an increase in blood volume and a resultant increase in arterial pressure.
2. Blood vessels: A secondary function of vasopressin is vasoconstriction. Vasopressin
binds to V1 receptors on vascular smooth muscle to cause vasoconstriction (via the
IP3signal transduction pathway). This results in an increase in arterial pressure.

Assuming normal glomerular filtration rates, about 10 g of calcium is filtered at the

glomerulus per day and only 100-200 mg of calcium is excreted in urine (i.e. 98-99% of
filtered calcium is resorbed).
 
Of this filtered calcium:
 60-70% is resorbed at the proximal convoluted tubule. The majority of calcium
resorption (80%) is by passive diffusion via a paracellular route. A smaller proportion (20%)
is via an active transcellular route involving transporters.
 There is no movement of calcium at the descending Loop of Henle.
 20-30% is resorbed at the ascending Loop of Henle, mainly by a paracellular route
driven by an electrical gradient created by the Na.K.2Cl transporters and ROMK potassium
channels.
 10% is resorbed at the distal convoluted tubule exclusively by a transcelluler route
involving apical calcium channels and a basolateral active Na.Ca antiporter.
 5% is resorbed at the collecting duct.
 
The terminal nephron may only reabsorb 5-10% of filtered calcium but it is the main site of
regulation of calcium excretion as it is here that PTH exerts it's effect.

The following hormones are released from the anterior pituitary:

 Adrenocorticotropic hormone (ACTH)
 Thyroid-stimulating hormone (TSH)
 Follicle-stimulating hormone (FSH)
 Luteinizing hormone (LH)
 Growth hormone (GH)
 Prolactin
 
The following hormones are released from the posterior pituitary:
 Antidiuretic hormone (ADH), also known as vasopressin
 Oxytocin
The adrenal glands, also known as the suprarenal glands, are endocrine glands situated just above the
kidneys. Each gland has an inner adrenal medulla and an outer adrenal cortex. The adrenal cortex is
further subdivided into three layers; the zona glomerulosa, zona fasciculata, and zona reticularis.

 The sites of production and main effects of the hormones produced by the adrenal glands are shown in
the table below: 

Site of production Hormone

Zona glomerulosa Aldosterone

Cortisol

Zona fasciculata Corticosterone

11-deoxycorticosterone

Dehydroepiandrosterone (DHEA)

Zona reticularis DHEA-sulfate (DHEA-S)

Androstenedione

Adrenaline (epinephrine)

Adrenal medulla Noradrenaline (norepinephrine)

Dopamine

Microscopic view of the layers of the adrenal gland

Approximately 99% of the body’s calcium is stored in bones, but it is also present in some cells (most
notably muscle cells) and in the blood. The normal adult diet contains about 25 mmol of calcium per
day, of which only about 5 mmol is absorbed by the body.

 Calcium is essential for a number of important functions including:

 Formation of bone and teeth

 Muscle contraction
 Blood clotting
 Normal heart rhythm
 Enzymatic reactions
 Intracellular signaling
 Nerve conduction

 The total plasma calcium concentration is in the range if 2.2-2.5 mmol/l (note that there is some slight
variation between laboratories). The usual range for ionized calcium is 1.3-1.5 mmol/l.

 The amount of total calcium in the blood varies with the plasma albumin level, which is the main carrier
of protein-bound calcium in the blood. The biological effect of calcium is, however, determined by the
amount of ionized calcium. It is therefore the plasma ionized calcium level, which is tightly regulated to
remain within tight limits by homeostasis.

 Calcium in the plasma is:

 Approximately 50% unbound in its ionized form

 Approximately 40% bound to albumin
 Approximately 10% bound to other plasma proteins

In order to compensate for the albumin dependent variation of total calcium a correction
can be performed in which 0.1 mmol/l is added to the calcium concentration for every
4 g/l that albumin is below 40 g/l. Similarly 0.1 mmol/l is subtracted from the calcium
concentration for every 4 g/l that albumin is above 40 g/l.
 
This correction is approximate and does not replace measurement of unionized calcium
concentration. Special care should be taken in cases where the measured albumin is less
than 20 g/l as albumin measurement can be inaccurate below this level.
PTH is released from the four parathyroid glands in response to low levels of ionised Ca 2+ in the plasma.
It acts on the kidney to increase serum calcium by several mechanisms:

 It increases calcium resorption at the distal convoluted tubule (primarily via calcium
channels and a Ca.Na antiporter which is magnesium dependent)
  It decreases phosphate resorption at the proximal convoluted tubule. Phosphate and
calcium form hydroxyapatite crystals in solution. If less phosphate is available to form
crystals, there is more serum ionised calcium available. The kidney is the only organ where
calcium levels can be raised whilst phosphate levels are reduced
 It increases the action of 1α-hydroxylase which catalyses 25(OH)Vit D (Calcifediol) to
1,25(OH)2Vit D (Calcitriol). Calcitriol has minor effects on the kidney itself - increasing both
phosphate and calcium resorption - but its major effect is to increase bone resorption to
release calcium and phosphate
 A minor effect is to decrease HCO3-  resorption which creates a mild acidosis. Plasma
proteins release Ca2+ to take up H+, so more ionised Ca2+ is available in the serum

The pituitary gland is an endocrine gland that is roughly the size of a pea. It is a protrusion
off the bottom of the hypothalamus at the base of the brain and is divided into anterior
and posterior parts.
 
The anterior pituitary (adenohypophysis) is linked to the hypothalamus via the
hypophyseal portal system. Hormone secretion from the anterior pituitary is regulated by
hormones secreted along the hypophyseal tract from the hypothalamus that act on the
secretory endocrine cells within it.
 
The posterior pituitary (neurohypophysis) is functionally connected to the hypothalamus
by the median eminence via a small tube called the pituitary stalk. Nuclei that lie within the
hypothalamus and send axons into the posterior pituitary. These axons are specialized and
release hormones into the bloodstream.
 

 
The anatomical position of the pituitary gland (from Gray’s Anatomy)
 
The following hormones are released from the anterior pituitary:
 Adrenocorticotropic hormone (ACTH)
 Thyroid-stimulating hormone (TSH)
 Follicle-stimulating hormone (FSH)
 Luteinizing hormone (LH)
 Growth hormone (GH)
 Prolactin
 
The following hormones are released from the posterior pituitary:
 Antidiuretic hormone (ADH), also known as vasopressin
 Oxytocin

In an elderly patient with this history of gradual decline with hyperglycaemia, thirst, recent
infection and very high blood sugars the most likely diagnosis is hyperosmolar
hyperglycaemic state (HHS). This lady has 1+ ketones in her urine, which is likely to be
secondary to vomiting and only a mild acidosis. HHS is a life threatening illness with an
approximately 50% mortality. It typically presents with hyperglycaemia, dehydration,
reduced mental status and electrolyte imbalance. 50% of patients are hypernatraemic.
 
The serum osmolality can be calculated by 2 (K+ + Na+) + urea + glucose. In this case 2 (3.2 +
154) + 17.6 + 32 = 364 mmol/l. Patients with HHS typically have a high serum osmolality >
350 mmol/l.
 
Her metformin should be stopped, not increased, due to the risk of metformin associated
lactic acidosis (MALA). An insulin IV infusion should also be commenced in this case.
 
The risk of thromboembolism is very high in patients with HHS and low molecular weight
heparin should be routinely given. In patients such as this with a serum osmolality greater
than 350 mmol/l full heparinisation should be considered.

The release of catecholamines is stimulated when the plasma glucose concentration falls
below 4 mmol/l.
 
The effects of catecholamines on glucose metabolism include:
 Stimulation of glycogenolysis
 Inhibition of insulin secretion
 Promotion of glucagon secretion
 Promotion of lipoylsis (free fatty acids and glycerol are used in preference to
glucose)

Corticotropin-releasing hormone  (CRH) is a peptide hormone and neurotransmitter. It is

produced by cells within the paraventricular nucleus (PVN) of the hypothalamus and is
released at the median eminence from neurosecretory terminals of these neurons into
the hypothalamo-hypophyseal portal system. CRH is secreted in response to stress.
 
The hypothalamo-hypophyseal portal system carries the CRH to the anterior pituitary,
where it stimulates corticotropes to secrete adrenocorticotropic hormone (ACTH). ACTH
subsequently stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids, and
DHEA.
 
Excessive secretion of CRH leads to an increase in the size and number of corticotropes in
the anterior pituitary, and may result in the formation of a corticotrope tumour that
produces excessive amounts of ACTH.
 The following cause an increase in thyroid binding globulin (TBG) levels and subsequently
increase total T4 levels:
 Oestrogens
 Pregnancy
 Chronic liver disease
 Acute intermittent porphyria
 
The following cause a decrease in TBG levels and subsequently decrease total T4 levels:
 Acromegaly
 Protein loss (nephritic syndrome and malabsorption)
 Androgens
 Steroids

T3 and T4 are over 95% protein bound and this is predominantly to thyroid binding globulin (TBG). TBG
levels are generally unaltered in primary hypothyroidism and thyrotoxicosis, and conditions that alter
TBG levels tend to change total T3 and T4 levels but not free T3 and T4 levels.

 The following can increase TBG levels:

 Pregnancy
 Oestrogens including OCP and HRT
 Heroin and methodone
 Phenothiazines
 Hepatitis

 The following can decrease TBG levels:

 Nephrotic syndrome
 Sodium valproate
 Phenytoin
 Androgens
 Testosterone
 Prednisolone
 High doses of aspirin

 Congenital TBG abnormalities also exist than can cause either an increase or a decrease in TBG levels.

Dopamine  is an important amine hormone and neurotrasmitter that is a derivative of the amino acid
tyrosine. It is produced in a variety of locations within the human body, both inside and outside of the
central nervous system. Sites of dopamine production include the adrenal medulla, dopamine neurons
of the arcuate nucleus within the hypothalamus, the substantia nigra, and several others.

 The tuberoinfundibular pathway refers to the population of dopamine neurons in the arcuate nucleus

in the tubeal region of the hypothalamus. Dopamine is released at the median eminence from
neurosecretory terminals of these neurons into the hypothalamo-hypophyseal portal system.

 It is released in response to high levels of secretion of prolactin and the main function of dopamine
released from the hypopthalamus is to inhibit prolactin release from the anterior pituitary. Other
important functions within the brain include the modulation of motor-control centers and activating the
reward centers.
 Dopamine-secreting cells are also found in other parts of the body where most of its actions are
paracrine (acting on nearby cells).

Adrenocorticotropic hormone (ACTH) is a peptide hormone produced and secreted by

the anterior pituitary (adenohypophysis). It is released in response to the
hormone corticotropin-releasing hormone (CRH) being released from the hypothalamus.
 
ACTH release binds to cell surface ACTH receptors in the zona fasciculata of the adrenal
cortex and stimulates the secretion of cortisol.
 
ACTH also stimulates the release of beta-endorphin and precursor of melanoctye-releasing
hormone (MRH).
 Gastrointestinal
The gastrointestinal hormones are released into the bloodstream and they pass through the liver
unaltered.

 Gastrin is a peptide hormone that stimulates the production of gastric acid by the parietal cells of the
stomach and aids in gastric motility. It is released by G-cells in the pyloric antrum of the stomach, the
duodenum, and the pancreas.

 It is released in response to vagal stimulation, hypercalcaemia, stomach distension and the presence of
partially digested proteins, in particular amino acids. Its release is inhibited by the presence of acid and
somatostatin.

 Gastrin binds to cholecytsokinin B receptors to stimulate the release of histamine in enterochromaffin-

like cells and induces the insertion of K+/H+ ATPase pumps in the apical membrane of parietal cells.

 Cholecystokinin (CCK) is a peptide hormone that is produced and released by the I-cells in the
duodenum. It is an important hormonal regulator of the digestive process. CCK cells are concentrated in
the proximal small intestine and the hormone is secreted into the blood upon the ingestion of food. The
most potent stimuli for the production of CCK is the presence of partially digested fats and proteins in
the duodenum.

 The main physiological actions of CCK are:

 Stimulates the delivery of digestive enzymes from the pancreas into the small intestine
 Stimulates contraction of the gallbladder and relaxation of the sphincter of Oddi, resulting in
the delivery of bile into the duodenum
 Inhibits gastric emptying and decreases gastric acid secretion
 Induction of satiety

Secretin is produced by the S-cells in the mucosa of the duodenum and jejunum.
 Secretin is released in response to the following stimuli:
 Increased acidity within the duodenum (following the release of the stomach contents into
the small intestine)
  Presence of fatty acids.

 The main function of secretin is to increase bicarbonate ion production and release from the exocrine
pancreas, bile ducts and from the Brunner’s glands in the duodenum. The bicarbonate ions act to
neutralize the acid and establish a pH conducive to the action of other digestive enzymes.

 Other functions of secretin include:

 Enhances the effects of cholecystokinin

 Stimulates insulin release from pancreas following ingestion of glucose
 Stimulates glucagon release
 Stimulates pepsinogen release from the pancreas
 Stimulates pepsin release
 Stimulates pancreatic polypeptide release
 Stimulates somatostatin release

Gastrin is a peptide hormone that stimulates the secretion of gastric acid from the gastric
parietal cells of the stomach and aids in gastric motility. It is released by G-cells in the
pyloric antrum of the stomach, the duodenum and the pancreas.
 

Gastrin is released in response to the following stimuli:

 Vagal stimulation (mediated by gastrin-releasing peptide)
 Distension of the stomach
 Presence of partially digested proteins (particularly amino acids)
 Hypercalcaemia
 
The release of gastrin is inhibited by:
 The presence of acid (low antral pH)
 Somatostatin.
 

The main actions of gastrin are:

 Increases HCl secretion
 Increases pepsinogen secretion
 Increases intrinsic factor secretion
 Increases gastric motility
 Stimulates parietal cell maturation

The main actions of gastrin are as follows:

 Stimulation of gastric parietal cells to secrete hydrochloric acid
 Stimulation of ECL cells to release histamine
 Stimulation of gastric parietal cell maturation and fundal growth
 Causes gastric chief cells to secrete pepsinogen
 Increases antral muscle mobility and promotes stomach contractions
 Slows the rate of gastric emptying
 Induces pancreatic secretions
 Induces emptying of the gallbladder
 
The following table summarises the factors that situmlate and inhibit the release of gastrin:
 
 
Stimulate the release of gastrin Inhibit the release of gastrin
 
The presence of acid (primarily HCl)
 
Distension of the gastic antrum
Somatastatin
 
 
Vagal stimulation
Secretin
 
 
Presence of partially digested proteins in
Gastroinhibitory peptide (GIP)
the
 
stomach (most notably amino acids)
Vasoactive intestinal peptide (VIP)
 
 
Hypercalcaemia (via calcium-sensing
Glucagon
receptors)
 
Calcitonin
 

The following table summarises the cell types found in the stomach and shows the
substance each cell type secretes and the function of the secretion:
 
Cell type Substance secreted Function of secretion

Kills microbes and activates

Parietal cells Hydrochloric acid
pepsinogen

Binds to vitamin B12 and facilitates it’s

Parietal cells Intrinsic factor
absorption

Chief cells Pepsinogen Protein digestion

Chief cells Gastric lipase Fat digestion

G-cells Gastrin Stimulates gastric acid secretion

Enterochromaffin-like cells (ECL

Histamine Stimulates gastric acid secretion
cells)

Mucous and
Mucous-neck cells Protects stomach epithelium from acid
bicarbonate

D-cells Somatostatin Inhibits gastric acid secretion

Enterochromaffin-like cells (ECL cells) are a type of neuroendocrine cell founds in the
gastric glands of the gastric mucosa beneath the epithelium. They are most commonly
found in the vicinity of the gastric parietal cells.
 
The main function of the ECL cells is the production of histamine, which in turn stimulates
the production of gastric acid from the parietal cells.

Pepsinogen is a proenzyme that is released by the gastric chief cells in the stomach wall. Upon mixing
with the hydrochloric acid present in the gastric acid, it is converted to pepsin. Pepsin breaks down
proteins into smaller peptides and thereby aids protein digestion.

Gastric lipase, which is also referred to as LIPF, is an acidic lipase secreted by gastric chief cells that are
generally located deep in the mucosal layer of the stomach lining. It is an enzymatic protein that is
responsible for the digestion of fats in the stomach.

D-cells, or delta-cells, are somatostatin-producing cells that are found in the pyloric antrum, the
duodenum, and the pancreatic islets. In the stomach, somatostatin acts directly on the acid-producing
parietal cells via a G-protein coupled to inhibit gastric acid secretion. Somatostatin can also indirectly
decrease gastric acid secretion by inhibiting the release of other hormones, including gastrin, secretin
and histamine, thereby slowing the digestive process.

Amylase is secreted by the acinar cells of the parotid and submandibular glands. Amylase starts the
digestion of starch before food is even swallowed and works an at optimal pH of 7.4

The gastric chief cells are a type of cell situated in the stomach that are responsible for the secretion of
pepsinogen and gastric lipase. Gastric chief cells are generally located deep in the mucosal layer of the
stomach lining. They work in conjunction with the gastric parietal cells, which release gastric acid and
convert pepsinogen to pepsin. Their main function is to aid in the digestion of fats and proteins.

 The gastric chief cells are activated in response to the following stimuli:

 Acetylcholine via parasympathetic activity (primary mechanism)

 Decrease in pH (mediated by activation of gastric parietal cells)
 Secretin release from S-cells in the duodenum (via the presence of acid in the duodenum)

Gastric mucous-neck cells, which are also referred to as foveolar cells, are cells that line the
gastric mucosa and are found in the necks of the gastric pits.
 
These cells produce mucous and bicarbonate, which together prevent the stomach
digesting itself. The mucous allows the acid at pH 4 to penetrate the lining, but below pH 4
the acid cannot penetrate the mucous. This process is referred to as viscous fingering.
 
Intrinsic factor is essential for the absorption of the small amounts of vitamin B12 normally present in
the diet from the terminal ileum. The parietal cells of the stomach produce intrinsic factor and following
a gastrectomy, the absorption of vitamin B12 will be markedly reduced and a deficiency state will exist.

Achlorhydria is an autoimmune disease of the gastric parietal cells, which results in

inadequate production of gastric acid. The damaged parietal cells are unable to produce
 the required amount of gastric acid. This leads to an increase in gastric pH, impaired food
digestion and an increased risk of gastroenteritis.
 
The gastric parietal cells are epithelial cells situated in the stomach that are responsible for
the secretion of hydrochloric acid and intrinsic factor. These cells are located in the gastric
glands in the lining of the fundus and the body of the stomach.
 
The gastric parietal cells secrete hydrochloric acid in response to the following three
stimuli:
 Histamine stimulating H2 histamine receptors (most significant contribution)
 Acetylcholine via parasympathetic activity stimulating M3 receptors
 Gastrin stimulating CCK2 receptors
 
The gastric parietal cells also produce intrinsic factor, which is required for the absorption
of vitamin B12.

The following factors promote gastric emptying:

 Increased food volume in the stomach
 Gastrin
 Motilin
 Parasympathetic innervation (via the vagus nerve)
 Prokinetics such as metoclopramide and erythromycin
 
The following factors inhibit gastric emptying:
 Duodenal distension
 Cholecystokinin
 Secretin
 Somatostatin
 Vasoactive intestinal peptide (VIP)
 Gastric inhibitory peptide (GIP)
 Sympathetic innervation (via the coeliac plexus)
 Pregnancy (via increased progesterone levels)
 
Proteins empty fastest and fats slowest

Saliva is a watery substance produced in the mouth that is secreted by the salivary glands.
It is hypotonic and contains a mixture of both inorganic and organic constituents. The
constitution depends upon which gland is secreting and whether it is resting or being
stimulated.
 
Saliva maintains the pH of the mouth, contributes to the digestion of food and to the
maintenance of oral hygiene. It helps to dissolve food molecules so that they can react with
gustatory receptors to give the sensation of taste. It also eases swallowing and begins the
early part of digestion of polysaccharides. It protects the oral cavity by coating the teeth
with a protein that acts as a protective barrier.
 
Three pairs of salivary glands secrete saliva during mastication:
 Parotid glands: these produce 25% of the saliva. Parotid saliva is watery, lacks
mucus and contains amylase and IgA.
 Submandibular glands: these produce 70% of the saliva. Submandibular saliva is a
more viscous saliva that is mixed serous and mucosal.
 Sublingual glands: these produce a relatively small amount (5%) of saliva that
contains mucoproteins.
 
Formation of saliva within the salivary glands is a two-step process:
1. Isotonic fluid of similar composition to the extracellular fluid (ECF) is secreted by the
acinar component of the salivary gland.
2. The isotonic fluid is modified as it moves along the duct. Sodium and chloride are
removed and potassium and bicarbonate are added via ATP transport proteins.
 
During low rates of secretion the saliva is dilute as there is ample time for ductal
modification.  During high rates of secretion the bicarbonate, sodium and chloride content
increases and the saliva becomes more concentrated.
 
The secretion of saliva is controlled by the autonomic nervous system. The reflex is
stimulated by the salivary nuclei in the medulla. Secretion of saliva is stimulated by:
 Stimulation of mechanoreceptors and chemoreceptors in the mouth
 Stimulation of higher CNS centres e.g. via the smell of food

Adults are recommended a daily intake of 1,000 to 1,300 milligrams of calcium each day. Women are at
greater risk of developing osteoporosis as they age, and have calcium requirements that are slightly
higher than men's.
The foods that are highest in calcium include:
 Dairy products e.g. milk, cheese and butter
 Green vegetables e.g. broccoli, spinach, green beans
 Whole grain foods e.g. bread, rice, cereals
 Bony fish e.g. sardines, salmon
 Eggs
 Nuts

 The foods that are lowest in calcium include:

 Fruits e.g. kiwi fruit, raspberries, oranges, papaya
 Meats such as chicken and pork
 Carrots

Urobilinogen is a colourless by-product of bilirubin reduction that is formed in the

intestines by the action of bacteria in bilirubin. This occurs independently of the
hepatocytes.
 
Hepatocytes are a type of cell situated in the main parenchymal tissue of the liver and
make up 70-85% of the live’s mass.
 
 The main functions of the hepatocytes include:
 Protein synthesis
 Protein storage
 Transformation of carbohydrates
 Synthesis of cholesterol, bile salts and phospholipids
 Initiation of formation and secretion of bile
 Detoxification, modification, and excretion of exogenous and endogenous
substances

Gastric acid is a digestive fluid that is formed in the stomach. The stomach secretes approximately 2-3 L
per day. It has a pH in the region of 1.5-3.5 and is involved in tissue breakdown, the conversion of
pepsinogen to active pepsin, and the formation of soluble salts with calcium and iron. It also acts as an
immune mechanism by killing micro-organisms.

 Gastric acid contains:

 Water
 Hydrochloric acid
 Pepsinogen
 Mucous
 Intrinsic factor

 Gastric acid is secreted by the parietal cells in the proximal 2/3 (body) of the stomach. The hydrogen ion
concentration in parietal cell secretions is roughly 1-2 million times higher than in blood. Chloride is
secreted against both a concentration and electric gradient and the ability of the partietal cell to secrete
acid is dependent on active transport.

 The secretion of gastric acid occurs as follows:

 1. The H+/K+ ATPase (proton pump) located in the cannalicular membrane is vital to gastric acid
secretion. Hydrogen ions are generated within the parietal cell from the dissociation of water. The
hydroxyl ions formed in this process rapidly combine with carbon dioxide to form bicarbonate ion. This
reaction is cataylsed by carbonic anhydrase.

 2. Bicarbonate is transported out of the basolateral membrane in exchange for chloride. The outflow of
bicarbonate into blood results in a slight elevation of blood pH known as the ‘alkaline tide’. This process
serves to maintain intracellular pH in the parietal cell. Chloride and potassium ions are transported into
the lumen of the cannaliculi by conductance channels.

 3. Hydrogen ions arew pumped out of the cell, into the lumen, in exchange for potassium through the
action of the proton pump; potassium is thus effectively recycled.

 4. The accumulation of osmotically-active hydrogen ions in the cannaliculi generates an osmotic
gradient across the membrane that results in the outward diffusion of water.

Bile is produced continuously by the liver and stored and concentrated in the gallbladder.
Approximately 400 to 800 ml of bile is produced in any given 24 hour period.
 
Bile plays a role in the following:
 The breakdown of fats into fatty acids
 The elimination of waste products
 Cholesterol homeostasis
 
The secretion of bile is principally controlled by the enteric hormones cholecystokinin and
secretin. These are released when chyme from an undigested meal enters the small
intestine and they have the following role in the secretion and flow of bile:
 Cholecystokinin: stimulates contraction of the gallbladder and common bile duct,
delivering bile to the gut
 Secretin: stimulates biliary duct cells to secrete bicarbonate and water, which
expands the volume of bile and increases its flow into the intestine
 
Bile acids are amphipathic, containing a hydrophobic and hydrophilic region. The
amphipathic natures of bile acids allows them to carry out the following important
functions:
 Emulsification of lipid aggregates: increasing the surface area of fat and making it
amenable to digestion by lipases
 Solubilisation and transport of lipids: solubilises lipids by forming lipid aggregates
called micelles that remain supspended in water

A somatostatinoma is a malignant tumour of the D-cells of the endocrine pancreas that produces
somatostatin. Increased levels of somatostatin inhibit pancreatic and gastrointestinal hormones.

 Somatostatin has the following effects on hormones:

 Inhibits growth hormone release from anterior pituitary

 Inhibits thyroid-stimulating hormone release from anterior pituitary
 Suppresses the release of several gastrointestinal hormones (including gastrin, CCK,
secretin, motilin, VIP and GIP)
 Reduces the rate of gastric emptying
 Inhibits insulin and glucagon release from the pancreas
 Suppresses the exocrine secretory action of the pancreas

 Somatostatinomas are associated with the following clinical features:

 Diabetes mellitus via inhibition of insulin secretion
 Steatorrhoea via inhibition of CCK and secretin
 Gallstones via inhibition of CCK
 Hypochlorhydria via inhibition of gastrin, which normally stimulates gastric acid secretion

Swallowing is initiated by sensory impulses transmitted by stimulation of tactile receptors

on the fauces, tonsils, soft palate, base of tongue and posterior pharyngeal wall.
 
Sensory impulses are transmitted to the swallowing centre in the brainstem by cranial
nerves VII, IX and X. The efferent (motor) function is mediated by cranial nerves IX, X and
XII.
 
Broadly speaking swallowing can be divided into three phases:
 
1. The oral phase:
The oral phase of swallowing is voluntary. The food is chewed and mixed with saliva to
forma a soft consistency called a food bolus. The bolus is pushed against the roof of the
 mouth by the tongue, which forces it into the oropharynx and then subsequently into the
pharynx.
 
2. The pharyngeal phase:
The pharyngeal phase of swallowing is involuntary. The vocal cords are closed by the
lateral cricoarytenoid and oblique interarytenoid muscles, which prevents food from
entering the airway. This also initiates a wave of contraction (peristalsis) that pushes the
food through the upper oesophageal sphincter. Respiration is inhibited at this stage to
prevent food inadvertently entering the respiratory system.
 
3. The oesophageal phase:
The wave of peristalsis continues into the oesophagus and propels food into the stomach.
If the food fails to enter the stomach then the resulting distension of the oesophagus
initiates a secondary peristaltic wave.

The sequence of events that occur during the act of vomiting are as follows:
1. Reverse peristalsis against a closed glottis
2. Relaxation of the pyloric sphincter
3. Forced inspiration against a closed glottis
4. Forceful contractions of the stomach
5. The lower and upper oesophageal sphincters are closed
6. The lower and upper oesophageal sphincters are open
The pancreas releases the following enzymes:
 Chymotrypsinogen
 Trypsinogen
 Proelastase
 Procarboxypeptidase
 Amylase
 Lipase
 Phospholipase A2
 Cholesterol esterase
 Renal
Aldosterone is a steroid hormone produced in the zona glomerulosa of the adrenal cortex. It is the
main mineralocorticoid hormone and plays a central role in the regulation of blood pressure.

 Aldosterone is released in response to:

 Increased angiotensin II levels

 Increased potassium levels
 Increased ACTH levels

 The main actions of aldosterone are:

 Reabsorption of Na+ from the distal convoluted tubule

 Reabsorption of water from the distal convoluted tubule (follows Na +)
 Reabsorption of Cl– from the distal convoluted tubule
 Secretion of K+ into the distal convoluted tubule
 Secretion of H+ into the distal convoluted tubule

1,25-dihydroxycholecalciferol (also known as calcitriol) is the hormonally active metabolite of vitamin

D. Its actions increase the plasma concentration of calcium and phosphate.

 The synthesis of 1,25-dihydroxycholecalciferol starts in the epidermal layer of the skin, where 7-
dehydrocholesterol is converted to cholecalciferol in the presence of UVB radiation.

 Cholecalciferol is then hydroxylated in the endoplasmic reticulum of liver hepatocytes by 25-

hydroxylase to become 25-hydroxycholecalciferol (calcifediol).
 Finally 25-hydroxycholecalciferol is hydroxylated in the kidney by 1-alpha-hydroxylase to become1,25-
dihydroxycholecalciferol. 1-alpha-hydroxylase is stimulated by parathyroid hormone or
hypophosphataemia and serves as the major control point in the production of 1,25-
dihydroxycholecalciferol. 

Vitamin D is metabolized in the kidney to its active form 1,25-dihydroxycholecalciferol.

The main actions of 1,25-dihydroxycholecalciferol are:

 Increases calcium and phosphate absorption in the small intestine

 Increases renal calcium reabsorption
 Increases renal phosphate reabsorption
 Increases osteoclastic activity (increasing calcium and phosphate resorption from bone)
 Inhibits 1-alpha-hydroxylase activity in the kidneys (negative feedback)

 
During the first two years of life both renal blood flow and glomerular filtration are low due
to high renal vascular resistance. Tubular function is immature until around 8 months and
as a consequence infants below this age are unable to excrete a large sodium load.
 
The body surface area (BSA) to weight ratio decreases with increasing age and small
children, with a high ratio, lose fluid and heat more rapidly and are more prone to
dehydration and hypothermia. At birth the head accounts for 19% of BSA, but this falls to
9% by the age of 15 years.
 
Children also have a larger proportion of extracellular fluid than adults (40% of body weight
compared to around 20% in adults).
 
Normal urine output in adults is 0.5-1 ml/kg/hour but in children it is higher at 1-2
ml/kg/hour.

Parathyroid hormone (PTH) is a polypeptide containing 84 amino acids. It is the principal controller of
free calcium in the body.

 The main actions of parathyroid hormone are:

 Increases plasma calcium concentration

 Decreases plasma phosphate concentration
 Increases osteoclastic activity (increasing calcium and phosphate resorption from bone)
 Increases renal tubular reabsorption of calcium
 Decreases renal phosphate reabsorption
 Increases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (via
stimulation of 1-alpha hydroxylase)
 Increases calcium and phosphate absorption in the small intestine (indirectly via increased
1,25-dihydroxycholecalciferol)
Calcitonin is a 32 amino acid polypeptide that is primarily synthesized and released by the
parafollicular cells (C-cells) of the thyroid gland. Its main role is to reduce the plasma calcium
concentration, therefore opposing the effects of parathyroid hormone.

Secretion of calcitonin is stimulated by:

 Increased plasma calcium concentration

 Gastrin
 Pentagastrin

The main actions of calcitonin are:

 Inhibition of osteoclastic activity (decreasing calcium and phosphate resorption from bone)
 Stimulation of osteoblastic activity
 Decreases renal calcium reabsorption
 Decreases renal phosphate reabsorption

The following table summarises some common causes of the various different acid-base
disorders:
Acid-base disorder
Respiratory alkalosis
Respiratory acidosis
Metabolic alkalosis
Causes
Hyperventilation (e.g. anxiety)
Pulmonary embolism
CNS disorders (e.g. CVA, SAH, encephalitis)
Altitude
Pregnancy
Early stages of aspirin overdose
COPD
Life-threatening asthma
Pulmonary oedema
Sedative drug overdose (e.g. opiates, benzodiazepines)
Neuromuscular disease
Obesity
Vomiting
Potassium depletion (e.g. diuretic usage)
Cushing’s syndrome
Conn’s syndrome

Lactic acidosis (e.g. hypoxaemia, shock, sepsis, infarction)

Ketoacidosis (e.g. diabetes, starvation, alcohol excess)
Metabolic acidosis
Renal failure
(with raised anion gap)
Poisoning (e.g. late stages of aspirin overdose, methanol, ethylene
glycol)

Renal tubular acidosis

Metabolic acidosis Diarrhoea
(with normal anion gap) Ammonium chloride ingestion
Adrenal insufficiency
 
Renin is an enzyme that plays an important role in the renin-angiotensin-aldosterone system (RAAS).
Through this it helps to regulate the mean arterial blood pressure.

 It is released from juxtaglomerular cells that are situated in the afferent arterioles of the kidney in
response to the following stimuli:

 Decreased arterial blood pressure (reduced renal perfusion)

 Decreased sodium load delivered to the distal tubule of the kidney
 Sympathetic nervous system stimulation

 The main action of renin is to cleave the peptide bond between the leucine and valine residues on
angiotensinogen, converting it to angiotensin I. This activates the RAAS and eventually causes an
increase in mean arterial blood pressure and restoration of renal perfusion.

 The juxtaglomerular apparatus © Medical Exam Prep

The juxtaglomerular apparatus (JGA) is located in the renal cortex, where the distal convoluted tubule
(DCT) lies next to the afferent and efferent arterioles of it's own glomerulus.

 The JGA consists of:

1. Macula densa cells – tall, densely clustered epithelial cells of the DCT

2. Juxtaglomerular cells – smooth muscle fibres in the walls of the afferent arteriole which synthesise
and release renin

3. Extraglomerular mesangial cells – the function of which is unclear but is proposed to be structural

The anatomical structure of the JGA facilitates a feedback loop (tubuloglomerular feedback) between
the glomerulus at the start of the nephron and the DCT near the end of the nephron. Changes in tubular
 fluid composition at the DCT result in adjustments to glomerular blood flow to regulate glomerular
filtration rate (GFR). This is intrinsic auto-regulation.

 The macula densa can be considered a sensor; monitoring the sodium content of tubular fluid arriving
at the DCT. High sodium levels are taken to reflect a high GFR (increased flow rates mean reduced time
for absorption in the preceding tubule). The response is vasoconstriction of the afferent arterioles to
reduce renal blood flow and GFR. The underlying mechanism is not known but it is proposed that
increased sodium at the DCT results in greater uptake by the macula densa cells, which is followed by
water through osmosis. The resultant swelling of the cells causes an ATP leak, ATP is converted to
adenosine, and adenosine binds to receptors on the afferent arteriole causing vasoconstriction and
decreased GFR.

 Conversely low sodium levels at the macula densa triggers a signalling cascade that ultimately results in
increased PGE2, which acts on juxtaglomerular cells to trigger renin release and activate the renin-
angiotensin-aldosterone pathway.

Electrolytes are substances that dissociate in solution and have the ability to conduct an electrical
current. These substances are located in the extracellular and intracellular fluid. Within the extracellular
fluid, the major cation is sodium and the major anion is chloride. Within the intracellular fluid the major
cation is potassium and the major anion is phosphate. These electrolytes play an important role in
maintaining homeostasis.

The anion gap represents the concentration of all the unmeasured anions in the plasma. It
is the difference between the primary measured cations and the primary measured anions
in the serum. It can be calculated using the following formula:
 
Anion gap = [Na+] – [(Cl-) + (HCO3-)]
 
The reference range varies depending upon which methodology is used to make the
measurement but is usually 8 to 16 mmol/L.
 
Generally speaking the value of K+ is low relative to other three ions and has little effect on
the equation. An alternative formula, which includes K+ is sometimes used, particularly by
Nephrologists. In Renal units the K+ covers a wider range and therefore has a greater effect
on the measured anion gap. In these circumstances an alternative formula is used:
 
Anion gap = [(Na+) + (K+)] – [(Cl-) +(HCO3-)]
 
 
A high anion gap metabolic acidosis usually occurs as a consequence of the accumulation
of organic acid or the impaired excretion of H+ ions. The mnemonic CAT MUDPILES is a
useful way of remembering the causes of a high anion gap metabolic acidosis:
 Carbon monoxide
 Alcoholic ketoacidosis
 Toluene, Toxins
 Metformin, Methanol
 Uraemia
 Diabetic ketoacidosis
 Propylene glycol, Paracetamol,Phenformin,Paraladehyde
 Iron, Isoniazid
 Lactic acidosis
 Ethylene glycol
 Salicylates, Starvation
 
A normal anion gap metabolic acidosis usually results from the loss of HCO3- ions from the
extracellular fluid. The mnemonic CAGE is a useful way of remembering the causes of a
normal anion gap metabolic acidosis:
 Chloride excess
 Acetazolamide, Addison’s disease
 Gastrointestinal causes (diarrhoea, vomiting, fistulae)
 Extra (Renal tubular acidosis)
 
A low anion gap is very rare indeed and if present is usually due to some sort of analytical
error. When genuinely present it can be caused by a decrease in unmeasured anions (e.g.
low albumin) or by an increase in unmeasured cations (e.g. IgG paraprotein in multiple
myeloma or hypercalcaemia).

Arterial blood gas (ABG) interpretation helps us with the assessment of a patient’s
respiratory gas exchange and acid-base balance. The normal values on an ABG can vary a
little between analysers but broadly speaking are as follows:
 
Variable Range
pH 7.35 – 7.45
pO2 10 – 14 kPa
PCO2 4.5 – 6 kPa
HCO3- 22 – 26 mmol/l
Base excess -2 – 2 mmol/l
 
 
In this case the patient’s history should alert us to the possibility of a diagnosis of diabetic
ketoacidosis (DKA). The pertinent ABG findings are as follows:
 Normal PO2
 Lowered pH (acidaemia)
 Low PCO2
 Low bicarbonate
 Raised lactate
 
The anion gap represents the concentration of all the unmeasured anions in the plasma. It
is the difference between the primary measured cations and the primary measured anions
in the serum. It can be calculated using the following formula:
 
Anion gap = [Na+] – [Cl-] – [HCO3-]
 
 The reference range varies depending upon which methodology is used to make the
measurement but is usually 8 to 16 mmol/L.
 

 
 
She is likely to have a type B lactic acidosis secondary to diabetic ketoacidosis. Some causes
of type A and type B lactic acidosis are shown below:
  
Cohen & Woods classification
Type A lactic acidosis ( GLASS C2R2S2) Type B lactic acidosis

Generalised convulsions Sepsis (non-hypoxic sepsis)

Left ventricular failure Thiamine deficiency
Asphyxia Inborn errors of metabolism
Shock (including septic shock) Renal failure
Severe anaemia Liver failure
Cardiac arrest Alcoholic ketoacidosis
CO poisoning Diabetic ketoacidosis
Respiratory failure Cyanide poisoning
Regional hypoperfusion Biguanide poisoning
Severe asthma and COPD Methanol poisoning
Sprinting
Refer moussa issca

Lactic acidosis is defined as a pH <7.35 and a lactate >5 mmol/L. It is a common finding in
critically ill patients and is often associated with other serious underlying pathologies.
 
There are major adverse consequences of severe acidaemia, which affect all body systems,
and there is an associated increased mortality in critically ill patients with a raised lactate.
The mortality associated with lactic acidosis despite full supportive treatment remains at
60-90%.
 
Acquired lactic acidosis is classified into two subtypes:
 Type A is due to tissue hypoxia
 Type B is due to non-hypoxic processes affecting the production and elimination of
lactate
 
Lactic acidosis can be extreme after a seizure but usually resolves spontaneously within a
few hours.
 
Left ventricular failure typically results in tissue hypoperfusion and a type A lactic acidosis.

The anion gap is raised in lactic acidosis. The normal range for the anion gap is 8-16
mmol/L. There is generally a large base deficit (> - 5 mmol/L).

The renin-angiotensin-aldosterone system (RAAS) is a hormonal system that is

responsible for the regulation of the arterial blood pressure and of the concentration
of sodium in the plasma.
 
The system is activated by either a fall the plasma sodium level or reduced renal perfusion.
This causes the juxtaglomerular cells that are situated in the afferent arterioles of the
kidney to release renin.
 
 Angiotensinogen is an alpha-2-globulin that is produced and released into the circulation
primarily by the liver. Renin cleaves the peptide bond between the leucine and valine
residues on angiotensinogen, converting it to angiotensin I.
 
Angiotensin I is then converted to angiotensin II by the removal of two C-terminal residues
by the enzyme angiotensin-converting enzyme (ACE). This primarily occurs in the lungs,
although it does also occur to a lesser degree in endothelial cells and renal epithelial cells.
Angiotensin II is the main bioactive product of the RAAS.
 
The main actions of angiotensin II are:
 Vasoconstriction of vascular smooth muscle (resulting in increased blood pressure)
 Vasoconstriction of the efferent arteriole of the glomerulus (resulting in an
increased filtration fraction and preserved glomerular filtration rate)
 Stimulation of aldosterone release from the zona glomerulosa of the adrenal cortex
 Stimulation of anti-diuretic hormone (vasopressin) release from the posterior
pituitary
 Stimulation of thirst via the hypothalamus
 Acts on the Na+/H+ exchanger in the proximal tubule of the kidney to stimulate
Na+ reabsorption and H+ excretion
 Angiotensin II will therefore have the following effects on renal measurements:
 Decreased renal plasma flow
 Increased filtration fraction
 Increased glomerular filtration rate

 Angiotensin II is part of the renin-angiotensin-aldosterone (RAA) loop, which ultimately aims to increase
blood volume and blood pressure. Hypotension, sympathetic stimulation or hyponatraemia trigger the
release of renin from the renal juxtaglomerular apparatus. renin cleaves angiotensinogen (a circulating
protein produced by the liver) into angiotensin I. Angiotensin I is cleaved by ACE (an enzyme produced
by the lungs) to give angiotensin II, a peptide hormone.
 Angiotensin II has multiple sites of action and effects including:
 Widespread peripheral vasoconstriction causing an increase in systemic vascular resistance
 Acts at the nephron to cause efferent arteriole constriction which maintains the glomerular
filtration rate in times of reduced renal flow
  Acts at the proximal convoluted tubule to increase sodium resorption, which drives water
resorption by osmosis
 Acts at the adrenal gland to cause Aldosterone release
 Acts at the hypothalamus to activate the thirst centre
 Acts at the hypothalamus to stimulate ADH release

Angiotensinogen is an alpha-2-globulin that is produced and released into the

circulation primarily by the liver. It is converted into angiotensin I by the action of renin,
which cleaves the peptide bond between the leucine and valine residues on
angiotensinogen.
 
Plasma angiotensinogen levels are increased by:
 Increased corticosteroid levels
 Increased thyroid hormone levels
 Increased oestrogen levels
 Increased angiotensin II levels

The kidney is unique in that it is the only vascular network to have two capillary beds. Having arterioles
both supplying and draining the glomerular capillaries maintains higher hydrostatic pressures at the
glomerulus to maximise filtration. A second capillary network at the tubules allows secretion and
absorption at the tubules and plays an important role in concentrating urine.

The non-drug causes of hyperkalaemia include: ( RTA BRACER )

 Renal failure
 Tumour lysis syndrome
 Addison’s disease (adrenal insufficiency)
 Burns and trauma
 Renal tubular acidosis (type 4)
 Acidosis
 Congenital adrenal hyperplasia
 Excess potassium supplementation
 Rhabdomyolysis

 Drugs that can cause hyperkalaemia include: (A BANDS )

 ACE inhibitors
 Beta-blockers
 Angiotensin receptor blockers
 NSAIDs
 Digoxin
 Suxamethonium

 Causes of hypokalaemia include: ( HARD EGG BITCH )

 Hypomagnesaemia
 Alkalosis
 Renal artery stenosis
 Drugs e.g. diuretics and insulin
 Excessive liquorice ingestion
 Gastrointestinal loss e.g. diarrhoea
 Gitelman’s syndrome
 Bartter’s syndrome
 Inadequate dietary intake
 Renal tubular acidosis (types 1 and 2)
 Conn’s syndrome
 Hypokalaemic periodic paralysis
 

Bartter’s syndrome is a rare inherited defect in the ascending limb of the loop of Henle. It is
characterized by a hypokalaemic alkalosis with normal to low blood pressure.

 Type 1 and 2 renal tubular acidosis both cause hypokalaemia whereas type 4 renal tubular acidosis
causes hyperkalaemia.

 Gitelman’s syndrome is a rare inherited defect of the distal convoluted tubule of the kidney. It causes a
metabolic alkalosis with hypokalaemia and hypomagnesaemia.

 Excessive liquorice ingestion can cause hypermineralocorticoidism and result in hypokalaemia.

Fluid entering the loop of Henle has an osmolality of approximately 300 mOsm, and the main solute is
sodium. The thin descending loop is permeable to water but has no solute transporters. As the loop
descends into the medulla, the peritubular fluid is increasingly concentrated, so water leaves the tubule
by osmosis. The tubular fluid equalises to the osmolality of the peritubular fluid, to a maximum of
approximately 1200 mOsm in a long medullary loop of Henle and 600 mOsm in a short cortical loop of
Henle.

 The thin ascending limb allows passive movement of sodium, chloride and urea down their
concentration gradients, so urea enters the tubule and sodium and chloride leave.

 The thick ascending limb is impermeable to water but actively transports sodium, potassium and
chloride out of the tubular fluid. The osmolality of the tubular fluid falls compared to the surrounding
peritubular fluid. Water cannot follow by osmosis because this limb is impermeable. The result is that
tubular fluid leaving the loop of Henle has an osmolality of approximately 100 mOsm, lower than that of
the fluid entering the loop, and the main solute is now urea.

 
Filtration rates are much greater at the glomerulus than in any other capillary network in the body
because:

 The anatomical arrangement of the glomeruli maximises the surface area available for
filtration
 The arrangement of the arterioles results in high hydrostatic pressures and facilitates
filtration
 The filtration membrane is highly permeable (relative to other capillary beds)

 The glomerular filtration membrane consists of three layers:

1. Fenestrated capillary endothelium with relatively large pores which allow free movement of
plasma proteins and solutes but restrict movement of blood cells

2. Basement membrane, which is more selective and contains negatively charged glycoproteins
but still allows free passage of water, nutrients and ions

Filtration slits formed by the foot processes of podocytes (specialised cells of the visceral epithelium
layer of the capsule) which are the finest filter and restrict movement of plasma proteins but still allow
free movement of ions and nutrients.
Vasoconstriction of the afferent arteriole of the glomerulus will decrease renal plasma flow
and decrease the glomerular filtration rate. It will have no effect, however, on the filtration
fraction itself.
 
The following table summarises the effects that various haemodynamic changes on the
glomerulus have on common renal measurements:
 
Renal plasma Filtration Glomerular filtration
Haemodynamic change
flow fraction rate
Vasoconstriction of afferent
Decreased No effect Decreased
arteriole
Vasodilatation of afferent
Increased No effect Increased
arteriole
Vasoconstriction of efferent
Decreased Increased Increased
arteriole
Vasodilatation of efferent
Increased Decreased Decreased
arteriole
 

GFR can be estimated by:

 GFR = (UCr x V) / PCr

 Where:

UCr = urine concentration of creatinine

PCr = plasma concentration of creatinine

V = rate of urine flow

 In this case GFR = (20 x 2) / 0.25 = 160 ml/min

 Creatinine is used to estimate GFR because it is an organic base naturally produced by muscle
breakdown, it is freely filtered at the glomerulus, it is not resorbed from the nephron, it is not produced
by the kidney, it is not toxic and it doesn't alter GFR. In reality a small volume (10-15%) is secreted into
 the tubule, which affects the accuracy of the calculation. Other formulas have been derived to more
accurately predict GFR, including the Cockcroft-Gault calculation, which corrects for age and weight.

Glomerular filtration is a passive process which depends upon the net hydrostatic
pressure acting across the glomerular capillaries, countered by the oncotic pressure, and
also influenced by the intrinsic permeability of the glomerulus.
 
The mean values for GFR in healthy young adults are 130ml/min/1.73m 2 (men) and
120ml/min/1.73m2 (women). The GFR declines with age after the age of 40 at a rate of
approximately 1 ml/min/year.
 
Creatinine clearance can be calculated by the equation:
 
Creatinine clearance = (Urine creatinine x Urine volume x 1000)
  (Plasma creatinine x 24 x 60)( ml/min)
 
The Cockcroft and Gault formula is as follows:
 
GFR (ml/min) = (140 – age in years) x weight (kg) x 1.23 (men) or 1.04 (women)
Urine creatinine (mmol/l)
 
 
The Cockcroft and Gault formula overestimates creatinine in obese patients as their
endogenous creatinine production will be less than that predicted by overall body weight.

The filtration fraction (FF) is the percentage of the plasma (not blood) delivered to the
glomerulus that is filtered through the glomerulus to become ultrafiltrate. In health 15-20%
of plasma is filtered to become ultrafiltrate (i.e. FF = 15-20%).
 
It can be calculated by:
 
FF = GFR / RPF
 
Where:
 GFR is the glomerular filtration rate (ml/min) i.e. the amount of ultrafiltrate
produced per minute.
 RPF is the renal plasma flow (ml/min) i.e. the volume of plasma passing through the
glomerulus per minute
 
RPF is subtly different to renal blood flow (RBF), which is the volume of blood flowing
through the glomerulus per minute. RPF = RBF x (1-Haematocrit).
 
Afferent arteriole constriction decreases RBF and RPF, and thus decreases the pressure
across the glomerulus and GFR. However as both RPF and GFR decrease equally, FF
remains constant.
 
Efferent arteriole constriction doesn't affect RBF or RPF but increases the pressure across
the glomerulus to increase GFR. As RPF remains steady but GFR increases, FF increases.
 
Decreased plasma protein (e.g. hypoalbuminaemia) has no impact on RPF but decreases
the oncotic pressure in glomerular vessels so GFR increases. As RPF remains steady but
GFR increases, FF increases.

The glomerular filtration membrane is composed of the fenestrated capillary endothelium, the
basement membrane and the filtration slits formed by foot processes of podocytes (the epithelial cells
of the renal corpuscle). The passage of substances across this membrane depends on molecular size and
electrical charge.
 
Molecules < 7,000 Daltons in size are freely filtered (dissolved electrolytes and solutes such as urea,
glucose, amino acids and creatinine).
 
Molecules > 70,000 Daltons in size are not filtered at all (most plasma proteins, platelets and blood
cells).
 
The filtration of molecules between 7,000 and 70,000 Daltons varies according to their size and charge.
The basement membrane contains negatively charged glycoproteins which repel negative molecules,
hence negatively charged molecules (most plasma proteins) are less readily filtered than positively
charged molecules. Most negative molecules > 50,000 Daltons are not filtered. This includes albumin
which is negatively charged and 60-65,000 Daltons in size.
 
Unconjugated bilirubin is not filtered as it is insoluble so strongly bound to albumin in plasma.
Conjugated bilirubin is soluble and passes freely through the filtration membrane.

The mechanisms of sodium resorption and excretion by the nephron are complex, with numerous
transporters and channels involved, influenced by hormonal regulatory mechanisms and the osmolality
of plasma, tubular and peritubular fluids. In general sodium resorption is driven by electrochemical
gradients established by ATP-ase pumps. The movement of Na is often used to co-transport other
solutes and provides the main osmotic drive for the passive movement of water in the tubules.
 
As a basic overview:
 Sodium is freely filtered at the glomerulus so the ultrafiltrate is isotonic with the plasma.
 65% of filtered sodium is resorbed at the proximal convoluted tubule.
 Na.K.ATP-ase pumps on the basolateral membrane set up a chemical gradient (primary active
transport). This gradient then drives sodium resorption from the lumen by Na.Solute symporters
and Na.H anti-porters.
 A further 20% of filtered sodium is resorbed at the Loop of Henle, mainly by the Na.K.2Cl (triple)
transporter on the ascending limb. This is also driven by ATP-ase and is an example of primary
transport.
 A further 5-10% of filtered sodium is resorbed at the distal convoluted tubule. Again a
basolateral Na.K.ATP-ase pump sets up a chemical gradient, driving a Na.Cl symporter on the
luminal membrane.
 Sodium transport in the collecting duct is via an epithelial sodium channel (ENaC). Resorption
through the channel is driven by a chemical gradient established by a Na.K.ATP-ase transporter
on the basolateral membrane.
 Aldosterone is a steroid hormone that enters the cells of the collecting duct and binds to
cytoplasmic receptors to stimulate the transcription of mRNA encoding ENaC and Na.K
transporters, thus increasing sodium resorption at this site.
 Sodium transporters in the Loop of Henle and distal convoluted tubule are load dependent – i.e.
the more sodium in the plasma, the higher the transport rate (until maximum rate of transport
or Tmax is reached). This is an example of positive feedback.
  In the Loop of Henle, load-dependent sodium transport contributes to establishing the
medullary concentration gradient in the peritubular fluid; tubular fluid arriving at the ascending
limb is highly concentrated so large amounts of sodium are actively transported out of the
tubule.
 As tubular fluid ascends the limb it becomes less concentrated and less sodium transport out of
the tubule occurs.

The cells of each section of the nephron have different morphologies, reflecting the differences in their
function.

 The proximal convoluted tubule is where the majority of solute resorption occurs and this resorption is
driven by ATP-dependant transporters. Cells are cuboidal with abundant mitochondria to provide energy
and multiple microvilli (a brush border) to increase surface area.

 The descending loop of Henle has flat cells with few microvilli and few mitochondria, reflecting that in
this segment there is the movement of water by osmosis and no solute transport.

 The ascending thick loop of Henle has cuboidal cells which are impermeable to water and contain
plentiful mitochondria providing energy to Na.K.2Cl transporters. These measures contribute to the
formation of the medullary concentration gradient and countercurrent multiplication.

 The distal convoluted tubule allows variable resorption and secretion to fine-control urine composition.
Mitochondria provide energy for membrane transporters. There are few microvilli.

 The collecting duct allows the final adjustments in urine concentration. The upper collecting duct is
lined by columnar epithelium, which transitions into urothelium in the lower duct.  Aquaporin channels
are present in the cell membranes to allow the transcellular movement of water. The number of
aquaporin channels is controlled by ADH.

Erythropoietin is a glycoprotein hormone that is responsible for the control of

erythropoiesis (red cell production). It is produced by interstitial fibroblasts in the kidney
and also in perisinusoidal cells in the liver.
 
Hypoxia stimulates the production and secretion of erythropoietin in the kidney.
Erythropoietin has two main effects on red blood cells:
1. It stimulates stem cells in the bone marrow to increase the production of red blood
cells
2. It targets red blood cell progenitors and precursors in the bone marrow and
protects them from apoptosis
 
The resultant increase in red cell mass results in increased oxygen carrying capacity and
increased oxygen delivery.

ANP is a peptide hormone released from cardiac myocytes in response to stretching of the
atria. ANP plays a key role in regulating fluid volume and sodium/potassium homeostasis
by a number of mechanisms with the ultimate aim of increasing fluid losses.
 
 ANP acts to:
 Vasodilate afferent arterioles and vasoconstrict efferent arterioles in the
glomerulus, which increases renal blood flow and glomerular filtration
 Inhibit aldosterone secretion from adrenal glands
 Inhibits renin secretion from juxtaglomerular cells
 Inhibits sodium resorption at the collecting duct
 Inhibits the release of ADH
 Inhibits the action of ADH at the collecting duct
 Cause systemic vasodilatation

ADH acts on the collecting duct to increase water resorption and reduce fluid losses in urine.

 ADH release is triggered by:

 Increased plasma osmolality - activates osmoreceptors in the supraoptic nucleus of the
hypothalamus to cause ADH synthesis and release
 Low blood pressure - activates baroreceptors in the aortic arch and carotid sinuses (monitor
high pressure circulation) which feedback to supraoptic nucleus
 Low blood volume - activates barorecptors in the left atrium and pulmonary vessels
(monitor low pressure circulation) which feedback to supraoptic nucleus
 Angiotensin II
 Nicotine
 Sleep
 Fright
 Exercise

 ADH release is inhibited by alcohol (which partly explains the diuretic effect of alcohol) and increased
levels of ANP/BNP.

ADH plays a key role in water and electrolyte balance. It is released in response to numerous factors but
the main driving forces are increased plasma osmolality or decreased blood pressure. ADH acts on the
kidneys and the peripheral vasculature to increase plasma volume and blood pressure.

 ADH acts on peripheral V1 receptors to cause widespread vasoconstriction.

 In the kidney, ADH binds to V2 receptors in the terminal distal convoluted tubule and collecting duct to
increase transcription and insertion of aquaporins in the cells lining the lumen. Aquaporins are water
channels that allow the passive diffusion of water out of the tubule into the interstitial fluid by osmosis,
so reducing losses in urine.

 ADH also increases the permeability of the distal collecting duct (the portion within the inner medulla)
to urea. More urea moves out of the tubule into the peritubular fluid and contributes to the
countercurrent multiplier to improve the concentrating power of the Loop of Henle. 

Overall, in the presence of ADH there is increased urea and water resorption resulting in small volumes
of concentrated urine. In the absence of ADH there limited urea and water resorption resulting in large
volumes of dilute urine.

The kidneys receive 20-25% of the cardiac output. This equates to 1-1.2 L per minute.
Weight for weight this is approximately six times what the brain receives and five times
what the heart receives.
 
Organ % of cardiac output
Liver 28%
Kidneys 22%
Skeletal muscle 16%
Brain 14%
Skin 9%
Heart 5%
Rest of body 6%
 
Blood flow is not evenly distributed throughout the kidney. The metabolically active
medulla receives 10% of renal blood flow while the less active cortex receives 90%. This
counter-intuitive arrangement of blood flow, inversely proportionate to metabolic demand,
provides the high hydrostatic pressures needed to maintain filtration at the glomerulus.
125 ml of plasma is filtered per minute at the glomerulus. This equates to 180 L of plasma
filtered per day. Considering urine output is typically 1-2 L per day, it becomes apparent
how significant resorption along the nephron is.

Glucose resorption
Glucose is freely filtered at the glomerulus and no active excretion occurs at any point along the
nephron. Glucose resorption occurs exclusively in the proximal convoluted tubule via Na.Glu co-
transporters driven by the electrochemical gradient for sodium, so is an example of secondary active
transport.
The resorption of glucose is limited by the number of glucose carriers present in the proximal
convoluted tubule. When these carriers are working at maximum capacity, the transport maximum or
Tmax is reached, and any excess glucose will appear in the urine. The Tmax for glucose is approx
16mmol/L. However glucose actually appears in the urine before Tmax is reached. The level at which
glucose starts to appear is called the renal threshold and is approx 10mmol/L (still much higher than
plasma glucose concentrations in health). This effect is called splay. It may be due to heterogenous
nephron function and length, for example nephrons with shorter proximal tubules may not resorb as
much glucose as nephrons with longer proximal tubules.

Calcium resorption
Assuming normal glomerular filtration rates, about 10 g of calcium is filtered at the glomerulus per day
and only 100-200 mg of calcium is excreted in urine (i.e. 98-99% of filtered calcium is resorbed).

Of this filtered calcium:

 60-70% is resorbed at the proximal convoluted tubule. The majority of calcium resorption (80%)
is by passive diffusion via a paracellular route. A smaller proportion (20%) is via an active
transcellular route involving transporters.

 There is no movement of calcium at the descending Loop of Henle.

 20-30% is resorbed at the ascending Loop of Henle, mainly by a paracellular route driven by an
electrical gradient created by the Na.K.2Cl transporters and ROMK potassium channels.

 10% is resorbed at the distal convoluted tubule exclusively by a transcelluler route involving
apical calcium channels and a basolateral active Na.Ca antiporter.

 5% is resorbed at the collecting duct.

The terminal nephron may only reabsorb 5-10% of filtered calcium but it is the main site of regulation of
calcium excretion as it is here that PTH exerts it's effect.

The renal corpuscle is the first part of the nephron and is the portion where the plasma undergoes
filtration. It is composed of a glomerulus and the Bowman’s capsule. Each kidney usually contains
approximately 1 million nephrons (0.8-1.5 million).

The glomerulus consists of a network of capillaries that are located between the afferent arteriole,
which brings blood to the glomerulus, and the efferent arteriole, which drains blood way from it. The
diameter of the efferent arteriole is smaller than the afferent arteriole, increasing the hydrostatic
pressure within the glomerulus.

The Bowman’s capsule is a double-walled epithelial cup, which surrounds the glomerulus. The inner
visceral layer is formed by specialised cells, called podocytes, that wrap around capillaries and leave slits
between them called filtration slits. The area between these two layers is called the capsular space.

The cells that form the outer edges of the glomerulus form close attachments with the cells of the inner
surface of the Bowman’s capsule. These cells together form a filtration membrane that enables water
and solutes to pass through the first wall of the Bowman’s capsule into the capsular space. This fluid is
known as the glomerular filtrate and passes into the renal tubule.

The order in which blood flows at the nephron? 

Afferent arteriole→Glomerular capillary→Efferent arteriole→Peritubular capillary→Vasa recta

Renal systems of infants and adults

During the first two years of life both renal blood flow and glomerular filtration are low due to high renal
vascular resistance. Tubular function is immature until around 8 months and as a consequence infants
below this age are unable to excrete a large sodium load.
The body surface area (BSA) to weight ratio decreases with increasing age and small children, with a
high ratio, lose fluid and heat more rapidly and are more prone to dehydration and hypothermia. At
birth the head accounts for 19% of BSA, but this falls to 9% by the age of 15 years.

Children also have a larger proportion of extracellular fluid than adults (40% of body weight compared
to around 20% in adults).

Normal urine output in adults is 0.5-1 ml/kg/hour but in children it is higher at 1-2 ml/kg/hour.