242 SECTION TWO PHYSIOLOGY
Pathways from Pathways to
motor cortex sensory cortex
Parasympathetic
motor nerves
Sacral Mass
spinal movement
cord
Rectal
distension Sigmoid
colon
Parasympathetic Rectum
motor nerves Anus (contracts)
Somatic motor Internal anal Fig 10.7
nerves sphincter Summary of the defecation reflex.
External anal
sphincter
Osmotic Box 10.1 Summary of the medical and surgical causes
l Fluid enters the bowel if there are large amounts of of constipation
hypertonic substances in the lumen, e.g. purga- Medical Surgical
tives, malabsorption leading to high glucose levels.
The diarrhoea reduces if the patient stops eating Diet Anal fissure
Secretory Lifestyle Carcinoma of the rectum/anus
l There is active secretion and decreased absorption
IBS Carcinoma of the colon
of fluids from the lumen. Causes include: qCa2þ Foreign body
n enterotoxins, e.g. cholera
n hormones, e.g. VIP from a VIPoma Hypothyroidism Pelvic masses
n bile: following ileal resection
n fats: following ileal resection Drugs, i.e. opiates, Post-operative immobility
n laxatives. tricyclic Hirschsprung’s disease
antidepressants
l In secretory diarrhoea stopping food has no effect. (rare in adults)
Inflammatory l In addition, the body needs vitamins, minerals
l Diarrhoea occurs due to mucosal damage and thus and trace elements; deficiency can result in ill
health.
reduced absorption, i.e. infective diarrhoea or
inflammatory bowel disease. l Carbohydrates: present in numerous foods, provide
a rapidly used energy source, but are also converted
Abnormal motility to glycogen in the liver, and if ingested in excess
l Causes include diabetic neuropathy, post-vagotomy quantities will be converted to fat and laid down
in adipose tissue. Carbohydrates provide 4.1 Kcal/g
syndrome, carcinoid, thyrotoxicosis, irritable bowel of energy.
syndrome (IBS) and bowel resection.
l Protein: broken down to amino acids which then form
Constipation (Box 10.1) hormones, enzymes, etc. Of the 20 different amino
acids, 12 can be synthesised in the liver, but 8 are
l Defined as the infrequent or difficult passage of referred to as essential amino acids as they cannot
abnormally hard/firm faeces. be synthesised (isoleucine, leucine, lysine, methio-
nine, phenylalanine, threonine, tryptophan, valine).
l Causes are often divided into medical and surgical. Proteins provide 5.3 Kcal/g of energy.
NUTRITION
Requirements
l The energy requirements of a normal adult are
around 2000–2500 Kcal/day.
l Carbohydrates, proteins and fats supply this energy.
Gastrointestinal system 10 243
l Fats: can be saturated (found in meats, fish and Box 10.3 Summary of the various disorders caused
dairy products) or unsaturated (vegetable); three by vitamin deficiencies
fatty acids are referred to as essential as the body
is unable to synthesise them (linolenic, linoleic and Vitamin Deficiency syndrome
arachidonic acid). Fats have numerous roles
throughout the body: Vitamin A Night blindness, epithelial atrophy
n support of other tissues, e.g. fat around kidneys and infections
n stores fat-soluble vitamins
n forms part of the nerve sheaths Vitamin D Rickets (child) and osteomalacia
n forms part of cell membranes (adults)
n provides 9.3 Kcal/g of energy.
Vitamin E Haemolytic anaemia
l Minerals: include sodium, potassium, calcium,
phosphorus, iron and iodine. They are involved in Vitamin K Clotting disorders
numerous cellular processes (Box 10.2).
Vitamin B1 Beriberi
Box 10.2 Summary of the roles of minerals in Vitamin B2
physiological processes Vitamin B3 Dermatitis and light sensitivity
Vitamin B6
Pellagra
Convulsions, anaemia, vomiting
and skin lesions
Mineral Role Pantothenic Neuropathy
acid
Sodium Main extracellular ion, and is involved
in fluid regulation, muscle contrac-
tion and nerve conduction Biotin Muscle pains and skin lesions
Potassium Main intracellular ion, and is involved Vitamin B12 Pernicious anaemia
in many cellular processes Folic acid Anaemia
Calcium Mineralisation of bone, muscle con- Vitamin C Scurvy
traction and blood clotting
Magnesium Necessary for muscle and nerve
function, also needed for normal
parathyroid hormone secretion
Iron Formation of haem and oxidation of l Vitamins: required in small amounts but defi-
carbohydrates ciency can lead to a variety of clinical conditions
(Box 10.3). Divided into fat-soluble (A, D, E and K)
Iodine Synthesis of thyroid hormones and water-soluble (C and B).
Selenium Part of the enzyme glutathione l Trace elements: include zinc, copper, manganese,
peroxidase and also responsible chromium, cobalt, selenium and molybdenum.
for converting thyroxine to
tri-iodothyronine in liver Regulation
microsomes
l Regulation of eating and food intake is under the
Zinc Involved in numerous metabolic control of two centres in the hypothalamus:
pathways as a cofactor for n hunger or feeding centre: lateral hypothalamus
enzymes, and vital for the n satiety centre: ventromedial hypothalamus.
synthesis of RNA and DNA
l After a meal when the blood glucose is high and the
Phosphorus Forms complexes with calcium to form stomach is distended the satiety centre is inhibited.
bone and is essential in energy- When blood glucose falls the activity within the
requiring processes as part of ATP satiety centre decreases and allows impulses from
the hunger centre to predominate.
Chromium Facilitates the action of insulin
l Lesions in the hunger centre lead to a lack of food
Copper Required for synthesis of haemoglobin intake (aphagia).
and is a component of coenzymes
in the electron transport chain l Lesions in the satiety centre lead to increased food
intake (hyperphagia).
244 SECTION TWO PHYSIOLOGY OSCE scenario 10.2
OSCE SCENARIOS A 32-year-old female is admitted with jaundice
and right upper quadrant pain. Liver function tests
OSCE scenario 10.1 reveal a bilirubin of 112 mmol/L, a markedly raised
alkaline phosphatase and gamma GT. Liver
A 40-year-old male presents with recurrent at- enzymes are normal.
tacks of right upper quadrant pain exacerbated 1. What is jaundice?
by fatty food. His only significant past medical his- 2. At what level of bilirubin is jaundice clinically
tory is a right hemicolectomy 5 years previously for
acute regional ileitis (Crohn’s disease). Investiga- apparent?
tions reveal normal liver function tests but FBC 3. Classify the types of jaundice.
reveals anaemia with a raised MCV. Abdominal 4. What is the most likely cause in this case?
ultrasound scan demonstrates gallstones. 5. Describe the different types of gallstone.
1. Explain the pathophysiology underlying the 6. List the complications of gallstones.
Answers in Appendix page 458
development of gallstones in this patient.
2. What is the cause of the patient’s anaemia?
3. What would be the effects of failing to treat the
anaemia?
4. How would you treat the anaemia?
SECTION TWO PHYSIOLOGY
CHAPTER 11
Urinary system
COMPONENTS RENAL BLOOD SUPPLY
The urinary system is composed of: Renal circulation
l kidneys
l ureters l Renal artery enters the hilum ! branches to form
l bladder interlobar arteries, which ascend between the pyr-
l urethra. amids ! interlobar arteries branch to form arcuate
arteries ! arcuate arteries branch to form interlob-
FUNCTIONS ular arteries ! afferent arteries arise from the
interlobular arteries.
The functions of the urinary system include:
l maintenance of electrolyte balance l Afferent arterioles give rise to glomerular capillaries
l maintenance of fluid balance within Bowman’s capsule ! leave the glomerulus
l maintenance of acid–base balance as the efferent arterioles.
l storage and excretion of urine
l hormone production: renin, erythropoietin, l Efferent arterioles have two distinct courses:
n supply of capillaries to the renal tubules !
1,25-dihydrocholecalciferol. peri-tubular capillaries
n descending vessels called the vasa recta; these
STRUCTURE provide the blood supply to the medulla; the
ascending vasa recta drain into the arcuate
l See Chapter 2 for further anatomical detail of the veins ! interlobar vein ! renal vein.
kidneys, ureter, bladder and urethra.
Regulation of renal blood flow
l Macroscopically the kidney can be divided into:
n outer region: cortex l Total renal blood flow (RBF) is approximately
n inner region: medulla, pelvis. 1.25 L/min or 25% of the cardiac output.
l Medulla is divided into several pyramids that project l Renal blood flow is maintained by intrinsic mecha-
into the pelvis. nisms; it shows very little variation over a range of
arterial pressures; this is termed autoregulation.
l The renal pyramids divide the renal pelvis into two
to three areas known as the major calyces. l Autoregulation fails at systolic blood pressures
< 80 mmHg.
l The functioning portion of the kidney is the nephron;
each nephron consists of a glomerulus; this consists l The mechanisms underlying autoregulation of renal
of a collection of capillaries that are connected to blood flow can be divided into:
afferent (a ¼ arrive) and efferent (e ¼ exit) arterioles. n myogenic: q in pressure due to q in flow
causes distension of the vessels; this elicits
l Each glomerulus is surrounded by epithelium, which smooth muscle contraction and thus q vascu-
forms Bowman’s space. lar resistance and thus Q blood flow.
n metabolic: metabolites from active renal tissue
l The glomerulus is the site of plasma filtration. induce vasodilatation.
l From Bowman’s space the filtrate passes in turn
l Renal blood flow can also be influenced by:
through the proximal convoluted tubules, loop of n humoral factors
Henle, distal convoluted tubule and the collecting n prostaglandins (vasodilatation)
duct. The resulting urine passes through the papilla
in the renal pyramids into the renal pelvis. 245
246 SECTION TWO PHYSIOLOGY
n nitric oxide (vasodilatation) l The fenestrated nature of the endothelium and the
n adrenaline (vasoconstriction) gaps between podocyte processes produce low re-
n noradrenaline (vasoconstriction) sistance to fluid movement.
n angiotensin I (vasoconstriction)
n angiotensin II (vasoconstriction). Glomerular filtration
l Renal nerves:
n sympathetic (vasoconstriction) l The glomerulus is the initial site of urine formation.
n parasympathetic (vasodilatation). l As a result of the factors mentioned above, the kid-
Glomerulus (Fig. 11.1) neys show a high rate of filtration: 120 mL/min.
l The forces governing filtration are identical to filtra-
Microscopic structure
tion forces in peripheral capillaries:
l The endothelium and the epithelium of Bowman’s n hydrostatic pressure
capsule have several features which allow them n osmotic pressure.
to perform the role of filtration:
n the capillary endothelium is perforated by small l Hydrostatic pressure is higher than in normal cap-
pores; it is referred to as a fenestrated capillary; illaries; approximately 50 mmHg; this is generated
it permits the free passage of water and by the high resistance to outflow caused by the
electrolytes efferent arteriole. Pressure within Bowman’s cap-
n negative charge of glycoproteins in the base- sule is approximately 10 mmHg; this leaves a hy-
ment membrane results in greater permeability drostatic pressure of 40 mmHg.
to positively or neutrally charged molecules
than negatively charged molecules l Plasma proteins generate osmotic pressure; they
n the epithelium of Bowman’s capsule contains are not filtered and therefore produce an opposing
specialised cells called podocytes. These cells absorption pressure to the hydrostatic pressure.
do not form a continuous layer, and instead Osmotic pressure is about 25 mmHg; therefore
they are spread over the basement membrane the net filtration pressure is around 15 mmHg.
and pass out processes known as pedicels or
‘foot processes’. This leaves gaps, which allow l As filtration proceeds, the remaining plasma pro-
filtration to occur. teins exert a greater osmotic pressure until it equals
that of the filtration pressure and thus no further re-
l In addition the numerous glomeruli throughout moval of fluid occurs.
the kidney produce a large surface area to allow
filtration. l The fluid that is filtered by the glomerulus is iden-
tical to plasma, apart form the lack of plasma pro-
teins and blood cells; it is often referred to as an
ultrafiltrate.
l The osmolality of the ultrafiltrate is around
300 mosmol/L.
Glomerular P Bowman's
capillary p space
Fenestrated Podocyte
endothelium
Foot
processes
or pedicels
To proximal
convoluted
tubule
Basement
membrane
Fig 11.1
Microscopic structure of the glomerulus.
P ¼ hydrostatic pressure, p ¼ osmotic pressure.
Urinary system 11 247
Proximal convoluted tubule decrease in the osmolality of the ultrafiltrate but
an increase in the osmolality of the surrounding
l The proximal convoluted tubule absorbs 70% of the medullary parenchyma.
filtered sodium; chloride follows by electrostatic l The osmolality of the ultrafiltrate entering the loop
attraction; water follows the absorption of NaCl of Henle is approximately 300 mosmol/L. As fluid
as a result of the osmotic gradient. is removed and ions added in the descending loop
the osmolality increases to around 1200 mosmol/L
l The volume of the ultrafiltrate is decreased but as at the bottom. As the fluid enters the ascending limb
the NaCl solution is isosmotic with the plasma the ions are removed but water remains, as this area is
osmolality of the filtrate reaching the loop of Henle impermeable to water. The osmolality is decreased
is unchanged. as ions are removed; the concentration of the ultra-
filtrate entering the convoluted tubule is about
l The transport of Naþ is an energy-dependent pro- 100 mosmol/L.
cess; it relies on an ATP-dependent pump.
Countercurrent multiplier mechanism
l The proximal tubular cells are particularly vulnera-
ble to ischaemic damage as a result of the energy (Fig. 11.2)
requirements. l The changes in osmolality of the ultrafiltrate as it
Loop of Henle moves through the loop of Henle produce very high
ion concentration within the medulla, providing the
l The descending loop of Henle is permeable to NaCl necessary osmotic pressure for water reabsorption
and water. Due to the high osmolality of the sur- from the collecting ducts.
rounding medulla, water is removed from the ultra- l The mechanism by which the high medullary
filtrate and NaCl is added as ions move down the osmolality is produced is called the countercurrent
concentration gradient between the medulla and multiplier mechanism.
the ultrafiltrate. l The explanation for countercurrrent exchange lies in
its ‘U’ shape and repeated cycles of ion pumping
l The ultrafiltrate in the descending loop of Henle is and fluid movement. This allows fluid to be concen-
concentrated by the passive addition of NaCl from trated several times (osmolality changes from
the medulla and the reduction in volume due to around 300–1200 mosmol/L, which equates to a
the absorption of water. fourfold increase in concentration); this is
l The ascending loop of Henle is responsible for the
active reabsorption of Naþ (which again leads to
passive ClÀ absorption). However, this region is im-
permeable to water; the transport of NaCl leads to a
From PCT To DCT
300
100
Cortex
Na+ Active Medulla
CI– Passive
Fig 11.2
H2O H2O
H2O The osmolality of the fluid entering
the descending loop of Henle is
1200 approximately 300 mosmol/L. The
Flow of fluid descending loop is permeable to
Naþ and ClÀ and H2O, thus there is
osmotic removal of H2O and an
increase in the osmolality due to the
influx of Naþ and ClÀ. In the
ascending limb there is an active
pumping of Naþ (ClÀ following
passively), but this region is
impermeable to water and thus the
fluid becomes more dilute.
248 SECTION TWO PHYSIOLOGY
significantly greater than could be achieved with a l The actions of ADH include:
parallel system. n q water permeability of the distal tubule and
l The ‘U’ shape of the loop of Henle allows solute to collecting ducts
be continuously recycled in order to generate the n q arterial blood pressure by vasoconstriction.
high medullary osmolality.
l The other facet of the countercurrent mechanism is l The secretion of ADH leads to the production of con-
the fact that the vasa recta (medullary blood supply) centrated low-volume urine.
is arranged in a similar ‘U’ shape; this allows the
continuous recycling of solute and prevents the re- l Inhibition (i.e. alcohol), absence (cranial diabetes
moval of solute and resulting decrease in medullary insipidus) or failure to respond to ADH (nephrogenic
osmolality. diabetes insipidus) leads to the production of urine
with a low osmolality and a high volume.
Distal convoluted tubule and
collecting ducts Renin–angiotensin–aldosterone
system (RAS)
l The distal convoluted tubule and the collecting
ducts have two important functions: l The RAS system is a complex interaction of hor-
n water reabsorption mones that influences the ECF volume and also
n Naþ reabsorption. interacts with the vascular system and affects
blood pressure.
l The ultrafiltrate that enters the distal tubule has a
low osmolality and thus water is reabsorbed. Fur- l The juxtaglomerular apparatus in the kidney is a key
ther fluid absorption occurs in the collecting ducts mechanism in monitoring changes in the ECF and
as they descend through the medulla. renal circulation; it is composed of the juxtaglomer-
ular cells of the afferent arteriole and the macula
l The absorption of water in the distal tubule and col- densa cells in the distal tubule that lie in close
lecting ducts leads to a decrease in the volume of association.
urine and an increase in its concentration; there-
fore, under normal circumstances concentrated l Juxtaglomerular cells are specialised smooth mus-
urine of low volume is excreted. cle cells that lie in the wall of the afferent arteriole
and secrete the hormone renin.
l The distal tubule and collecting duct also function to
reabsorb the remaining Naþ. This process is l Renin catalyses the reactions in the RAS system; re-
energy-dependent and requires ATP. A proportion lease from the juxtaglomerular cells is stimulated by:
of the Naþ absorption is under the control of the n decrease in afferent arteriole pressure
hormone aldosterone (see later). n reduction in Naþ, detected by the macula densa
which monitors the Naþ load in the distal tubule
REGULATION OF NAþ AND n stimulation by renal sympathetic nerves.
WATER REABSORPTION
l Renin stimulates the conversion of the plasma
l Three hormones are involved in the control of protein angiotensinogen to angiotensin I; this is then
the extracellular fluid (ECF) volume via their actions converted to angiotensin II in the lungs by the
on Naþ and water absorption; these hormones are: enzyme angiotensin converting enzyme (ACE).
n antidiuretic hormone (ADH or vasopressin)
n renin–angiotensin–aldosterone (RAS) system l Angiotensin II has a number of actions:
n atrial natriuretic hormone. n stimulates arterial vasoconstriction
n stimulates the release of ADH
Antidiuretic hormone n stimulates drinking
n stimulates the release of aldosterone.
l Produced in the supraoptic nucleus in the
hypothalamus; it is then released from the posterior l Aldosterone is released from the adrenal cortex and
pituitary. stimulates the reabsorption of Naþ and water from
the distal tubule and collecting ducts (see Chapter 12
l Stimulation of ADH release is via osmoreceptors in for more details).
the hypothalamus; they detect increases in the
osmolality of the ECF and stimulate drinking. Atrial natriuretic peptide (ANP)
l Other factors that stimulate ADH secretion include: l Released by the heart in response to an increase in
n Q circulating blood volume the ECF—stimulation is via atrial stretch.
n Q arterial pressure
n angiotensin II. l The actions of ANP are:
n increases glomerular filtration
n inhibits reabsorption of Naþ.
Urinary system 11 249
l The actions of ANP lead to increased excretion of ECF Tubular Filtrate
both Naþ and water. HCO3– epithelium
Ion and nutrient reabsorption A HCO3– + H+ H+ + HCO3–
H2CO3
Potassium H2CO3
CA CO2 + H2O
l Active reabsorption of Kþ occurs in the proximal tu-
bule and the ascending loop of Henle in conjunction H2O + CO2
with Naþ and ClÀ transport. By the time it reaches
the distal tubule approximately 90% of the filtered Urine
Kþ has been reabsorbed.
ECF Tubular Filtrate
l The amount of Kþ present in the urine is regulated HCO3– epithelium H+ + HPO42–
by aldosterone.
CO2 HCO3– + H+ H2PO4–
l Aldosterone stimulates the secretion of Kþ into the B
distal tubule and thus into the urine. H2CO3 Urine
CA
Calcium and phosphate
CO2 + H2O
l Calcium and phosphate are actively absorbed in the
proximal tubule and ascending loop of Henle; any ECF Tubular Filtrate
remaining is absorbed in the distal tubule and collect- HCO3– epithelium H+ + NH3
ing duct. Only 1% of the filtered calcium is excreted. NH4+
CO2 NH3
l Absorption in the distal tubule and collecting ducts is HCO3– + H+
controlled by parathormone (PTH) (see Chapter 12).
H2CO3
l PTH stimulates calcium reabsorption and phosphate CA
excretion.
CO2 + H2O
Hydrogen and bicarbonate (Fig. 11.3)
C Urine
l The regulation of Hþ and HCO3À is essential in
maintaining adequate acid–base balance and a Key :-
normal pH.
Active
l The majority of the filtered bicarbonate is reab- secretion
sorbed in the proximal tubule and the loop of
Henle. Passive
diffusion
l Intercalated cells in the distal tubule differ from
proximal tubular cells in that they actively secrete Fig 11.3
ions, namely Hþ, rather than actively absorb
them. Mechanisms for regulation of the pH of extracellular
fluid. Tubular secretion of Hþ leads to reabsorption
l Hþ and HCO3À are generated in the intercalated cells of filtered HCO3À(A). Secreted Hþ can also
by the dissociation of carbonic acid (formed from CO2 protonate filtered phosphates (B) or ammonia (C)
and H2O and catalysed by carbonic anhydrase). and is then excreted.
l Hþ is then transported in the distal tubular lumen and
the HCO3À passively diffuses into the peritubular
bloodstream, thus maintaining electrical neutrality.
l Hþ secretion drives the reaction with HCO3À, this
forms carbonic acid which in turn dissociates to
H2O and CO2; the CO2 diffuses into the tubular cell
and begins the reaction between CO2 and H2O to
produce Hþ and HCO3À.
l These reactions are able to react to changes in
acid–base balance in several ways:
n with a metabolic alkalosis there will be an in-
crease in the filtered HCO3À, thus the HCO3Àwill
swamp the secreted Hþ and will be excreted
250 SECTION TWO PHYSIOLOGY
n with a metabolic acidosis the amount of Measuring GFR
HCO3Àreabsorbed can be increased; this
occurs when the secreted Hþ reacts with l There are a number of mechanisms that can be
other buffers in the urine, and leaves HCO3À used to calculate GFR:
to diffuse into the bloodstream. 1) Inulin clearance: inulin is used as it closely
obeys the following criteria needed of a sub-
Glucose and amino acids stance to measure GFR:
l must be filtered by the glomerulus
l Glucose is filtered by the glomerulus and has an l must not be reabsorbed
identical concentration to plasma. l must not be secreted
l must not be metabolised
l As the concentration of glucose in the ultrafiltrate l this technique is the ‘gold standard’ for
and plasma are identical it cannot be reabsorbed measuring GFR; however, it is not widely
along a concentration gradient; it therefore requires used in clinical practice.
an energy-dependent process. The transport of glu- 2) Creatinine clearance: used in clinical practice as
cose utilises the gradient of Naþ between the ultra- creatinine occurs naturally; production is rela-
filtrate and the plasma; Naþ and glucose bind to a tively constant but a small amount is secreted
carrier protein and the movement of Naþ along the by the tubules; this can be significant at low GFR.
concentration gradient draws the glucose with it. 3) EDTA: has similar kinetics to inulin; it can be
The glucose leaves the cell by a separate cell mem- radioactively labelled and GFR determined
brane transport protein. from subsequent blood tests.
4) Dynamic renography: an estimate of GFR can
l The same mechanism is responsible for the absorp- be made from DTPA and MAG3 scans.
tion of amino acids. 5) Cockroft–Gault equation: this equation can be
used to estimate creatinine clearance, and
l The process occurs in the proximal tubule, and thus GFR:
under normal circumstances leads to the absence
of glucose or amino acids in the urine. Clearance ¼
1:23 ð♂Þ or 1:04 ð♀Þ Â ð140 À ageÞ Â ðweight ½kgÞ
l The uptake mechanism of glucose can be saturated;
in these instances the excess glucose will be lost in Serum creatinine ðmmol=LÞ
the urine (glycosuria); the renal threshold for glucose
absorption is around 11 mmol/L. Glycosuria is one Measuring renal plasma flow
of the main symptoms in diabetes mellitus.
l Measurement of renal plasma flow requires that a
Urea substance be completely removed from the plasma
in a single pass through the kidney.
l Urea is a waste product formed in the liver during
protein metabolism. It is not actively absorbed, l Para-aminohippuric acid (PAH) is used for this test
but as water is drawn out the concentration of urea and is injected into the blood stream; clearance is
in the tubules rises and therefore there is a small then calculated using UV/P.
amount of passive reabsorption as urea moves
down the concentration gradient. l Renal plasma flow is around 650 mL/min.
GLOMERULAR FILTRATION RATE MICTURITION
(GFR) AND RENAL PLASMA FLOW
l Urine is formed at the rate of 1 mL/kg/h.
l The concept of clearance can be used to calculate l Urine is transported from the renal pelvis to the blad-
both GFR and renal plasma flow.
der by the ureters by waves of peristaltic contraction.
l Clearance is a quantitative measure of the rate of l Urine is then stored in the bladder.
removal of a waste product from the blood by the l The pressure within the bladder (intravesical pres-
kidneys; it is calculated from its urinary concentra-
tion, multiplied by the volume per unit time and sure) is around 3 cmH2O. The bladder will fill to a
divided by the plasma concentration: volume of about 200–300 mL of urine before the
desire to urinate is felt. Before this point there is lit-
UV U: urine concentration tle change in intravesical pressure. As the volume
P increases the intravesical pressure rises steeply
Clearance ¼ V: urine volume
P: plasma concentration
Urinary system 11 251
and the desire to urinate increases; at this point the in life it becomes a voluntary response; descending
volume is around 400–450 mL. impulses inhibit parasympathetic fibres and also
l These changes in volume are sensed by stretch stimulate somatic impulses along the pudendal nerve
receptors that send impulses to the spinal cord via which allow contraction of the external sphincter.
the pelvic nerves.
l The nervous control of bladder function is from CLINICAL PHYSIOLOGY
both parasympathetic and sympathetic systems
(Fig. 11.4): Bladder function and spinal injury
n parasympathetic: these run in the sacral out- l A normal bladder has the following innervation:
flow (S2–3) and innervate the bladder (detrusor n L1–2: sympathetic outflow (see above)
muscle) and internal sphincter. Parasympa- n S2–4: parasympathetic (see above)
thetic fibres also run in the pudendal nerve n efferent sensory fibres enter the spinal cord at
and control the external sphincter. They stimu- L1–2 and S2–4.
late micturition by q detrusor contraction
and Q contraction of the internal sphincter l Following spinal injury there are three common
bladder abnormalities, these are:
n sympathetic: these run in the hypogastric n atonic bladder
plexus; they act to inhibit micturition by Q n automatic reflex bladder
detrusor contraction and q contraction of n autonomous bladder.
the internal sphincter.
l Atonic bladder: occurs during the initial phase of
l Therefore, parasympathetic input initiates micturi- spinal shock and may last several weeks; the
tion and sympathetic input inhibits it. following abnormalities are seen:
n bladder wall muscle is relaxed
l Once micturition is initiated the sympathetic im- n sphincter vesicae is contracted
pulses are inhibited by impulses from the brainstem n sphincter urethrae is relaxed
and parasympathetic impulses lead to bladder con- n bladder becomes distended and eventually
traction and relaxation of the internal sphincter. empties by overflow. If the level of the spinal
injury is above L1–2 then the patient is un-
l Voluntary contraction of the abdominal muscles aware of the bladder distension; if the injury
aids bladder emptying. is below L1–2 then the patient is aware of
the distended bladder.
l In the first few years of life micturition is a reflex
occurrence with no voluntary control, however, later l Automatic reflex bladder: this is seen once the
spinal shock has subsided in patients with a spinal
Sympathetic trunk injury above the parasympathetic outflow (S2–4).
The bladder empties reflexly every 3–4 h rather
Inferior hypogastric plexus than by simple distension and overflow.
S2 l Autonomous bladder: occurs if the sacral area of the
S3 spinal cord is damaged. The bladder is flaccid and
its capacity greatly increases; the bladder fills to
S4 capacity and then overflows. Partial emptying can
be performed by compression of the lower abdo-
Bladder Pelvic splanchnic men; however, backpressure leading to vesicoure-
nerve teric reflux and hydronephrosis is unavoidable, and
leads to frequent infections and eventually chronic
Pudendal nerve renal failure.
External HORMONE PRODUCTION
sphincter
of urethra Renin
Urethra l Produced by the juxtaglomerular apparatus in the
kidney.
Fig 11.4
Innervation of the bladder and urethra. l The action of renin is to cleave angiotensin I from
angiotensinogen.
252 SECTION TWO PHYSIOLOGY
l The release of renin is stimulated by: n high altitude
n reduction in renal perfusion n vasoconstriction
n stimulation of the sympathetic nervous system n qlevels of red blood cells degradation
n catecholamine release
n hyponatraemia. products.
l In general these causes result in low tissue PO2; this
Erythropoietin
is the main stimulus for erythropoietin secretion.
l Majority is secreted in the kidney, although small
amounts are made in the spleen and liver. 1a-hydroxylase
l It acts by accelerating differentiation of marrow l 1a-hydroxylase is secreted by the kidney in reponse
stem cells into erythrocytes. toQCa2þ; it converts 25-hydroxycholecalciferol to
1,25-dihydroxycholecalciferol.
l There are numerous stimuli that increase the rate of
erythrocyte production: l 1,25-dihydroxycholecalciferol promotes Ca2þ reab-
n haemorrhage sorption and decreases urinary loss (see Chapter 12
n respiratory disease for further details on calcium homeostasis).
OSCE SCENARIOS OSCE scenario 11.2
OSCE scenario 11.1 A 19-year-old male is admitted to A&E having been
stabbed in the abdomen. On examination he is
A 70-year-old male is 2 days post-repair of a rup- pale, sweating, with a tachycardia of 120 and a
tured abdominal aortic aneurysm. Urine output has systolic blood pressure of 80 mmHg.
been poor, the last 4 h having been 20 mL, 10 mL, 1. What are the grades of haemorrhagic shock?
5 mL and 5 mL per hour, respectively. The patient 2. What is renal blood flow autoregulation and how
has been haemodynamically unstable.
1. How would you define oliguria? is it affected by shock?
3. Describe the hormonal response to shock with
A specimen of urine is sent for examination and
reveals the following results: specific reference to ADH, aldosterone and the
renin–angiotensin system.
Specific gravity > 1020 Answers in Appendix page 459
Urine osmolality > 500 mosmol/L
Urine sodium < 20 mmol/L
Fractional sodium excretion < 1
2. What is the likely cause of the oliguria?
3. What action would you take based on these
results?
Appropriate measures fail to produce a diuresis.
Serum creatinine is now 350 mmol/L and urine
analysis reveals the following:
Specific gravity < 1010
Urine osmolality 290 mosmol/L
Urine sodium > 40 mosmol/L
Fractional sodium excretion > 2
4. What is now the cause of the patient’s renal
dysfunction?
5. What techniques are available for renal
replacement therapy in this patient?
6. What are the absolute indications for renal
replacement therapy?
7. Which mode of renal replacement therapy will
be the most appropriate in this patient?
SECTION TWO PHYSIOLOGY
CHAPTER 12
Endocrine system
INTRODUCTION PITUITARY AND HYPOTHALAMIC
FUNCTION
l The function of the endocrine system is the
secretion of hormones into the circulation and l The hypothalamus lies in the forebrain in the floor
their regulation of cellular responses by bind- of the third ventricle; it is linked to the thalamus
ing to target cells and initiating a particular above and the pituitary below via the hypophyseal
response. stalk.
l Hormones can be divided into: l The pituitary is divided into anterior and posterior.
n steroids: derived from cholesterol n anterior pituitary (adenohypophysis): derived
n peptides from an outpouching of tissue from the oral
n altered amino acids, e.g. thyroid hormones are cavity (ectoderm); it is linked to the hypothala-
composed of two tyrosine residues. mus via the hypophyseal portal system
n posterior pituitary (neurohypophysis): derived
l The secretion of hormones can be stimulated by: from a downgrowth of neural tissue; it is con-
n level of a substance, e.g. glucose and insulin tinuous with the hypothalamus. Nuclei (para-
secretion ventricular and supraoptic) lie within the
n stimulation by another hormone, e.g. TSH hypothalamus and send axons into the poste-
stimulates the thyroid gland to secrete thyroid rior pituitary. These axons are specialised
hormones and release hormones into the bloodstream.
n nervous control, e.g. catecholamines during the
‘fight or flight’ response. Control of pituitary function
l Hormones interact with receptors to exert their Anterior pituitary
effects; there are three main types:
1) Receptors on the cell surface: usually protein l Regulation of hormone secretion from the anterior
or peptide hormones, they initiate conforma- pituitary is by hormones secreted along the hypo-
tional changes in the receptor that leads to physeal tract from the hypothalamus.
the production of second messengers, which
in turn modify the cell’s response. l These releasing or inhibiting hormones act on
2) Cytoplasmic receptors: steroid hormones secretory endocrine cells in the anterior pituitary.
interact with receptors in the cytoplasm (or
nucleus). The receptor–hormone complex l Release of the hormone from the target organ
then enters the nucleus and binds to a spe- is regulated by feedback inhibition, either by the
cific area of DNA and stimulates translation releasing/inhibiting hormone or by the hormone
of a protein product. released from the target organ.
3) Nuclear receptors: thyroid hormone receptors
are found in the nucleus of cells; thyroid hor- Posterior pituitary
mone enters the cell in conjunction with the
receptor and enters the nucleus to exert its l The posterior pituitary stores two hormones, which
effect. are produced by two nuclei in the hypothalamus.
l These two hormones are transported to the ends of
the axons that connect the hypothalamus and the
253
254 SECTION TWO PHYSIOLOGY
posterior pituitary; they are released into the circu- l q Prolactin: hyperprolactinaemia occurs with pitu-
lation following an appropriate stimulus. itary tumours (prolactinoma). Patients present with
galactorrhoea, amenorrhoea, impotence, head-
Anterior pituitary hormones aches and visual field defects. The effects on repro-
ductive function are via its inhibitory effect on GnRH
Adrenocorticotrophic hormone (ACTH) production.
l Secreted in response to corticotrophin-releasing
l TSH: TSH-secreting pituitary tumours can cause
hormone (CRH) from the hypothalamus. hyperthyroidism but they are exceedingly rare.
l Stimulates the release of glucocorticoids from the
l GH: abnormal release of GH results in two disorders,
adrenal cortex; also stimulates the release of depending on the age at which it presents:
b-endorphin and precursors of melanocyte- n q in childhood results in gigantism (see below)
releasing hormone (MSH). n qin adult life results in acromegaly (see below).
Thyroid-stimulating hormone (TSH) l qADH: elevated ADH leads to the syndrome of
l Secreted in response to thyrotrophin-releasing inappropriate antidiuretic hormone (SIADH). The
condition is diagnosed by Q Naþ, Q plasma
hormone (TRH). osmolarity, q urine osmolarity, and urinary Naþ
l Stimulates thyroid secretion. > 30 mmol/L. Causes include:
n tumours, e.g. lung, pancreas, lymphomas
Follicle-stimulating hormone (FSH) and n TB
luteinizing hormone (LH) n lung abscess
l Secreted in response to gonadotrophin-releasing n CNS lesions, e.g. meningitis, abscess, head
injury
hormone (GnRH). n metabolic, e.g. alcohol withdrawal
l Lead to stimulation of the male and female gonads. n drugs, e.g. carbamazepine.
Prolactin Decreased hormone secretion
l Secretion is controlled by the inhibitory action of l Deficiency of pituitary hormones can be isolated or
dopamine. Factors that decrease dopamine lead involve all hormones (panhypopituitarism).
to the release of prolactin. l The effects of individual deficiency include:
Growth hormone (GH) n Q ACTH: results in Addison’s disease (see
l Secretion is stimulated by growth-hormone-releasing below)
hormone (GHRH) and inhibited by growth-hormone- n Q TSH: results in hypothyroidism (see below)
inhibiting hormone (GHIH or somatostatin). n Q FSH and LH: leads to a failure in sexual func-
Posterior pituitary hormones tion and hypogonadism
n Q GH: leads to dwarfism (see below)
Oxytocin n Q ADH: results in diabetes insipidus (cranial),
l Produced by cells in the paraventricular nucleus in
also nephrogenic diabetes insipidus—this
the hypothalamus. occurs due to failure at the cell receptor level
l Secretion is stimulated by sensory stimuli activating in the kidney. A deficiency of ADH leads to
an inability to concentrate urine and the
mechanoreceptors in the breast during suckling. passage of litres of urine (polyuria).
l Also stimulates the ejection of milk and uterine l The causes of pituitary deficiency include:
n rare congenital deficiency, e.g. Kallman syn-
contractions. drome: FSH and LH deficiency
n infection: meningitis and encephalitis
Antidiuretic hormone n pituitary apoplexy: bleeding into a pituitary
l Produced by cells in the supraoptic nucleus in the tumour
n Sheehan’s syndrome: infarction following post-
hypothalamus. partum haemorrhage
l Release is stimulated by sensory input into n cerebral tumours
n radiation
osmoreceptors and cardiac stretch receptors (see n trauma, i.e. frontal skull
section on fluid balance in Chapter 7). n sarcoidosis.
Clinical physiology
Pituitary disorders
Increased hormone secretion
The clinical conditions seen as a result of excess
hormone secretion include:
l q ACTH: Cushing’s disease (see below).
Endocrine system 12 255
THYROID FUNCTION Clinical physiology
Anatomy Antithyroid drugs
l See Chapter 5. The drugs used in the treatment of hyperthyroidism
l Microscopically, the thyroid is composed of follicles; include:
l Thionamides, e.g. carbimazole and propylthiouracil:
these consist of an outer layer of cuboidal epithe-
lium and are filled with colloid. this group of drugs competitively inhibits the
l The follicles are responsible for the production, peroxidase-catalysed reaction (iodide is converted
storage and secretion of thyroid hormone. to iodine). They also block the coupling of the iodo-
l Between follicles lie the parafollicular cells; these tyrosine. Propylthiouracil also inhibits the peripheral
secrete calcitonin (see calcium and phosphate deiodination of T4.
regulation). l Anion inhibitors, e.g. perchlorate: competitively
inhibits the uptake of iodine; discontinued as it
Synthesis of thyroid hormone can cause aplastic anaemia.
l Iodide, e.g. Lugol’s solution: iodide is thought to work
(Fig. 12.1) by blocking the binding of iodine with tyrosine resi-
dues, inhibiting hormone release. It is also thought
l Steps in the synthesis of thyroid hormones to decrease the size and vascularity of the thyroid
include: gland.
n active pumping of iodide ions in from the extra-
cellular space to the follicular epithelium Secretion and transport of thyroid
n iodide ions enter the colloid and are converted hormone
to iodine
n iodine is combined with tyrosine. l Hypothalamus releases thyrotrophin-releasing hor-
mone (TRH). TRH is transported to the endocrine
l Two forms are produced: monoiodotyrosine (1 MT) cells of the anterior pituitary along the hypophyseal
and diiodotyrosine (2 DT); these then combine to tract; this stimulates the release of thyroid-
form the two thyroid hormones: stimulating hormone (TSH).
n triiodothyronine (T3): MT þ DT
n thyroxine (T4): Â 2 DT. l TSH stimulates thyroid hormone production and
secretion.
l More T4 is produced but T3 is more biologically
active. l T3 and T4 have a negative feedback effect on TRH
and TSH.
l Thyroid hormones are stored in the colloid of the
follicle and released into the circulation as needed l Cold stress stimulates thyroid hormone secretion.
(the thyroglobulin is detached).
Plasma Thyroid follicular cell Colloid
I– I– TPO I2
MIT
TG DIT
Tyrosine T3
T4
Lysosomes TG
MIT Fig 12.1
DIT Production of T3 and T4 in the thyroid gland
(IÀ ¼ iodide, I2 ¼ iodine, TPO ¼ thyroid
TG peroxidase, TG ¼ thyroglobulin, MIT ¼
monoiodotyrosine, DIT ¼ diiodotyrosine).
T3 MIT+ DIT
T4 DIT+ DIT
256 SECTION TWO PHYSIOLOGY
l The majority of thyroid hormone in the circula- the TSH receptors and stimulate thyroid
tion is bound to thyroid-binding hormone (TBG); hormone production
however, only the free portion is biologically l solitary toxic adenoma/nodule (Plummer’s
active. disease)
l toxic multinodular goitre
Effects of thyroid hormone l acute phase of thyroiditis—occurs in the early
phase of cell injury and is due to the release
l T3 and T4 cross the cell membrane via diffusion; of large amounts of stored thyroid hormone
most of the T4 is converted to T3 in the cell. l drugs, e.g. amiodarone.
n secondary hyperthyroidism: this includes
l Thyroid hormone then bonds to receptors and causes of hyperthyroidism extrinsic to the
initiates increased DNA transcription and protein thyroid gland:
production. l pituitary/hypothalamic tumour secreting
TSH/TRH; very rare
l The effects of thyroid hormone include: l metastatic thyroid carcinoma: if well dif-
n metabolic: ferentiated, may produce enough thyroid
l q basal metabolic rate: leading to q O2 hormone to produce symptoms of
consumption and q heat production hyperthyroidism
l q absorption of glucose, glycolysis and l choriocarcinoma: this tumour usually pro-
gluconeogenesis duces HCG; however, it can also produce
l q catabolism of fatty acids a substance similar to TSH
l Q cholesterol production l ovarian teratoma: a particular specialised type
l q synthesis and catabolism of protein of teratoma—called struma ovarii—is com-
n cardiac: posed of mature thyroid tissue. This may over-
l q heart rate function and lead to hyperthyroidism.
l Q in peripheral vascular resistance (indirect, The clinical features of hyperthyroidism are shown in
due to increased metabolic rate in tissues) Figure 12.2.
l q in cardiac output and pulse
l q b-receptor production; facilitates activa- Hypothyroidism
tion and increases the response l Hypothyroidism ¼ ‘underactive’ thyroid.
l promotes erythropoiesis l The causes of hypothyroidism include:
n respiratory:
l q ventilatory rate n primary hypothyroidism: this includes diseases
n gastrointestinal: that directly affect the thyroid gland; these
l q motility and secretion include:
n CNS: l autoimmune (atrophic): arises due to micro-
l q CNS activity and alertness somal antibodies that lead to destruction
l normal neuronal function and atrophy of the thyroid gland
n growth and development: l Hashimoto’s thyroiditis: an autoimmune in-
l necessary for normal myelination and flammation of the thyroid gland; microsomal
axonal development autoantibodies are also present. The condi-
l stimulation of skeletal growth tion is associated with atrophy and regener-
l promotes bone mineralization. ation of the thyroid gland; this leads to goitre
formation
Clinical physiology l iodine deficiency
l genetic defects: inherited defects in the
Thyroid disorders enzymes involved in the synthesis of thyroid
hormones, e.g. Pendred’s syndrome
Hyperthyroidism l iatrogenic, e.g. post-thyroidectomy and
l Hyperthyroidism ¼ ‘overactive’ thyroid. -irradiation
l The causes of hyperthyroidism include: l drugs, e.g. lithium
l neoplasia: infiltration and destruction of the
n primary hyperthyroidism: this includes intrinsic gland secondary to a malignant neoplasm.
thyroid diseases:
l Graves’ disease: commonest cause, due to
autoimmune IgG antibodies that bind to
Endocrine system 12 257
Alopecia Eye signs Lid lag
Flushed Lid retraction
Exophthalmos
Sweating Oculomotor palsies
Weight loss
Osteoporosis Tachycardia
Atrial fibrillation
Diarrhoea Hyper-reflexia
Tremor
Thyroid
acropachy
Pretibial
myxoedema
Fig 12.2
Features of hyperthyroidism.
n secondary hypothyroidism: occurs due to l These patients will thus have low T4/T3 levels, but
pituitary or hypothalamic disease: levels of TSH are also low.
l hypopituitarism
l isolated TSH deficiency. CALCIUM AND PHOSPHATE
REGULATION
The clinical features of hypothyroidism are shown in
Figure 12.3. Calcium
Sick euthyroid syndrome l Calcium is absorbed via the gut and is mainly
l Acute illness from any cause can result in a num- excreted in the urine.
ber of abnormalities in the markers of thyroid l Calcium is stored in three ‘pools’:
function without actually affecting thyroid func- n bone: 99% of total body calcium. Osteoclasts
tion, i.e. the patient is euthyroid. These changes break down bone to release Ca2þ (structural
include: bone calcium) and phosphate into the circula-
tion; osteocytes are also able to transfer Ca2þ
n Q binding proteins into the circulation, but do not affect the bone
n Q affinity of binding proteins structure (exchangeable bone calcium)
n Q peripheral conversion of T4 to T3
n Q TSH.
258 SECTION TWO PHYSIOLOGY Dry thin hair
Loss of eyebrows
'Peaches and cream' Deafness
complexion
Bradycardia
Obesity Heart failure
High blood pressure
Hyporeflexia
Cold
peripheries
Constipation Carpal tunnel
syndrome
Myopathy
Oedema
Fig 12.3
Features of hypothyroidism.
n intracellular: Ca2þ is an important mediator of Ca2þ level rises then Naþ permeability
intracellular signals decreases, and the threshold will rise, thus
decreasing nerve and muscle activity
n extracellular: normal levels are between n muscle contraction: excitation–contraction
2.2 and 2.6 mmol/L. Approximately 50% is coupling in muscle (see Chapter 13) requires
protein-bound, only the free fraction is biolog- an influx of calcium
ically active. The extracellular pool is in con- n secretion processes: the products secreted
stant flux with bone, Ca2þ absorbed from from various glands is often triggered by an
the gastrointestinal tract, and excreted in influx of Ca2þ into the cell
the urine. n clotting: Ca2þ is an essential blood-clotting
factor; it acts as a cofactor for several of the
l Calcium is important in a number of cellular clotting factors (see Chapter 20).
processes:
n excitability of nerve and muscle: calcium level Regulation of calcium balance
affects the permeability of the Naþ channel; a
low calcium level will lead to increased perme- l The regulation of calcium is by two hormones
ability and increased Naþ influx, and will thus (parathormone [PTH] and calcitonin) and Vitamin D.
depolarise the cell towards threshold. If the
Endocrine system 12 259
Parathormone l The action of calcitonin is thought to be significant
l PTH is an 84-amino-acid polypeptide released from in periods of hypercalcaemia, and plays little role in
the everyday regulation of Ca2þ.
the parathyroid glands; these are found on the
posterior surface of the thyroid lobes. Regulation of phosphate balance
l A fall in extracellular fluid (ECF) Ca2þ stimulates
the release of PTH. It increases Ca2þ in several ways: l The regulation of phosphate levels occurs in tandem
with Ca2þ regulation.
n stimulates Ca2þ release from bone; the initial
rapid phase of Ca2þ release is due to osteocytes l PTH reduces phosphate levels (decreases renal
mobilising the exchangeable bone calcium. tubular absorption and thus increases urinary loss).
Longer-term release of PTH will stimulate osteo-
clasts to release Ca2þ from the structural bone l 1,25-dihydroxycholecalciferol increases phosphate
pool levels (increases renal tubular absorption).
n increases the rate of Ca2þ uptake from the l Qphosphate stimulates the renal activation of
renal tubules, therefore reducing urinary loss vitamin D to the 1,25 form.
n stimulates urinary phosphate excretion Clinical physiology
n stimulates the rate at which vitamin D is con-
Disorders of calcium and phosphate
verted to the biologically active 1,25 form in balance
the kidney.
Hypoparathyroidism
Vitamin D l Hypoparathyroidism is a rare cause of hypocal-
l Vitamin D is a fat-soluble vitamin, derived from two
caemia.
sources: l Causes include:
n diet: vitamin D2
n skin: UV radiation converts cholesterol to vita- n congenital, e.g. DiGeorge syndrome
min D3. n autoimmune
n iatrogenic: following total thyroidectomy or
l Vitamin D (cholecalciferol) is converted to 1,25-
dihydrocholecalciferol in two stages: parathyroidectomy
n converted to 25-hydroxycholecalciferol in the n hypomagnesaemia: low magnesium levels
liver
n converted to 1,25-dihydroxycholecalciferol (the prevent the release of PTH.
most active form) in the kidney.
Hyperparathyroidism
l PTH and low phosphate levels stimulate the conver- l Hyperparathyroidism is a common cause of hyper-
sion steps for vitamin D.
calcaemia. There are several different types:
l Vitamin D increases plasma Ca2þ by a number of n primary hyperparathyroidism. Causes include:
mechanisms: l single adenoma (> 80%)
n increases the rate of Ca2þ and phosphate l multiple adenomas (< 5%)
uptake from the gut l parathyroid hyperplasia (< 10%)
n increases renal tubular absorption of Ca2þ and l parathyroid carcinoma (rare; < 2%)
phosphate n secondary hyperparathyroidism: with prolonged
n stimulates osteoclastic bone resorption Q Ca2þ the parathyroid glands hypertrophy.
n promotes mineralisation of osteoid. In these instances, e.g. renal failure, the calcium
level will be low or normal, but the PTH level will
Calcitonin be elevated.
l Calcitonin is a 32-amino-acid polypeptide; it is n tertiary hyperparathyroidism: if secondary
hyperparathyroidism develops and the cause
secreted by parafollicular C-cells within the thyroid of the Q Ca2þ is not treated, then tertiary
gland. hyperparathyroidism develops—in this case
l It acts to reduce the rate of Ca2þ release into the the glands produce PTH autonomously and the
ECF by: levels of both Ca2þ and PTH are elevated.
n ectopic PTH: this condition is very rare; it
n decreasing Ca2þ and phosphate reabsorption occurs when tumours, e.g. squamous cell lung
from the renal tubules cancer, produce PTH-related peptide. This is a
141-amino-acid protein that is similar to PTH
n stimulating osteoblasts to mineralise bone and and is thus able to stimulate bone resorption
thus take Ca2þ from the circulation. and calcium release.
260 SECTION TWO PHYSIOLOGY
Vitamin D deficiency l Causes include:
l A lack of vitamin D leads to inadequate mineralisa- n excess PTH—primary and tertiary hyperpara-
thyroidism, ectopic PTH secretion
tion of bone; in adults this leads to osteomalacia, in n excess vitamin D
children it leads to rickets. n sarcoidosis
l Causes of vitamin D deficiency include: n milk–alkali syndrome (excess calcium intake)
n drugs, e.g. thiazide diuretics
n dietary insufficiency: particularly common in n malignancy:
vegans l solid tumour with lytic bony metastases, e.g.
carcinoma of the breast, carcinoma of the
n lack of sunlight: common in elderly patients and bronchus
Asian women l solid tumour with humoral mediation, e.g.
inappropriate PTH secretion with carcinoma
n malabsorption: particularly after gastric sur- of the bronchus, carcinoma of the kidney
gery, coeliac disease and disorders of bile salt l multiple myeloma
production n hyperthyroidism
n Addison’s disease
n renal disease: leads to inadequate conversion n prolonged immobilisation
to the active form 1,25-dihydroxycholecalciferol n Paget’s disease of bone
n familial hypocalciuric hypercalcaemia.
n hepatic failure
n Vitamin-D-resistant rickets: a familial condition Hypophosphataemia
l Hypophosphataemia results in:
with hypophosphataemia, phosphaturia and
rickets. n confusion
n convulsions
Hypocalcaemia n muscle weakness: acute hypophosphataemia
l Hypocalcaemia results in symptoms related to neu-
can lead to significant diaphragmatic weakness
romuscular irritability, e.g. paraesthesia, numbness, and delay weaning from a ventilator in patients
cramps and tetany. Neuropsychiatric disturbances in the intensive treatment unit
may also occur, e.g. anxiety and psychosis. n left shift of oxyhaemoglobin curve: this results
l Specific signs include Chovstek’s sign and Trous- in decreased oxygen delivery to tissues and is
seau’s sign. due to the reduction in 2,3-DPG.
l ECG may show a prolonged QT interval. l Causes include:
l Causes include: n hyperparathyroidism: PTH reduces renal tubule
absorption
n hypoalbuminaemia n vitamin D deficiency: vitamin D stimulates gut
n hypomagnesaemia and tubular absorption of phosphate
n hypophosphataemia n total parenteral nutrition (TPN): refeeding
n hypoparathyroidism with carbohydrate after fasting can result in
n acute pancreatitis hypophosphataemia
n rhabdomyolysis n diabetic ketoacidosis
n sepsis n alcohol withdrawal
n massive transfusion (due to citrate binding) n acute liver failure
n post-thyroid surgery n paracetamol overdose: phosphaturia.
n vitamin D deficiency
n osteoblastic metastases Hyperphosphataemia
n hypoventilation with respiratory alkalosis and l Hyperphosphataemia is usually asymptomatic and
reduction in ionised plasma calcium no treatment is required.
n drugs, e.g. diuretics, aminoglycocides, l Causes include:
bisphosphonates, calcitonin. n chronic renal failure: causes itching, hyper-
parathyroidism and deposition of calcium in
Hypercalcaemia the joints and around vessels
l Hypercalcaemia is more common than hypocal-
n tumour lysis: occurs following radio- or chemo-
caemia therapy
l Symptoms can be remembered by the rhyme,
n myeloma.
‘stones, bones, abdominal groans and psychiatric
overtones’, i.e. renal stones, bone pain, abdominal pain
(due to peptic ulceration in some cases) and
depression.
l ECG may show a reduced QT interval.
Endocrine system 12 261
ADRENAL FUNCTION Cortex
l The adrenal glands are located at the upper poles of Synthesis and excretion
both kidneys (see Chapter 2).
l Cholesterol is converted to pregnenolone in mito-
l They consist of an outer cortex and an inner chondria; this provides the basic structure for the
medulla. formation of all other steroid hormones.
l The cortex secretes steroid-based hormones and is l Conversion products of pregnenolone are shown in
subdivided into three sections: Figure 12.4.
n zona glomerulosa: mineralocorticoids
n zona fasciculata: glucocorticoids l Adrenal steroids are broken down by the liver and
n zona reticularis: sex hormones. excreted via the kidneys and in faeces.
l The medulla is part of the sympathetic nervous Actions of the adrenal cortex hormones
system; it contains chromaffin cells; these are
specialised sympathetic post-ganglionic neurons. Aldosterone
l Aldosterone is a mineralocorticoid.
l Nerve fibres from the splanchnic nerves innervate l Mineralocorticoids function to regulate ECF volume
the medulla; these release acetylcholine, which
stimulates hormone release. by altering the rate of Naþ reabsorption.
l Glucocorticoids have a mild mineralocorticoid
l The chromaffin cells release a variety of hormones
when stimulated to do so; they are stored in action.
granules and exit the cells into the circulation l Aldosterone secretion is stimulated by a number of
via exocytosis.
factors:
l The adrenal medulla produces: n renin–angiotensin system: a reduction in the
n epinephrine (adrenaline) ECF volume, blood pressure or Naþ concentra-
n norepinephrine (noradrenaline) tion in plasma (detected by the juxtaglomerular
n dopamine apparatus) will lead to an increase in the secre-
n b-hydroxylase (enzyme involved in catechol- tion of renin from the juxtaglomerular cells; this
amine synthesis) leads to the production of angiotensin II, which
n ATP stimulates the release of aldosterone
n opioid peptides (metenkephalin and leuen- n q Kþ in plasma
kephalin). n ACTH (does not play a role in the normal regu-
lation of aldosterone release).
I7.OH pregnenolone Cholesterol
ACTH control
Testosterone I7.OH progesterone
II Deoxycortisol Pregnenolone
Oestradiol Cortisol Progesterone
Corticosterone
Aldosterone
Under renin-angiotensin
control
Fig 12.4
Scheme for the production of adrenal cortical hormones.
262 SECTION TWO PHYSIOLOGY
l The actions of aldosterone include: mediators such as prostaglandins, leukotri-
n stimulation of the reabsorption of Naþ from the enes and platelet activating factor (PAF)
distal convoluted tubule in the kidney n immunosuppressive effects: the immunosup-
n secretion of Kþ into the distal convoluted tubule pressive effects of the glucocorticoids include:
n secretion of Hþ into the distal convoluted tubule. l Q T-cell number and function
l Q B-cell clonal expansion
Cortisol l Q basophils and eosinophils
l The zona fasciculata releases several glucocorticoid l inhibit complement
n mineralocorticoid: the glucocorticoid hormones
hormones: cortisol or hydrocortisone (the main have very mild mineralocorticoid activity
glucocorticoid), corticosterone and cortisone. n permissive effects: this relates to the normal
l Cortisol is bound to a specific binding protein called function of other hormones in the face of
transcortin (75%); approximately 15% is bound to normal cortisol levels; they include:
albumin and only 10% is active or free. l vascular reactivity to catecholamines
l Cortisol secretion is stimulated by a number of l activity of aldosterone on renal tubules
factors: l activity of ADH on the collecting ducts
l gluconeogenesis
n ACTH: released from the anterior pituitary (pro- l increases the effect of T3 in maintaining
moted by CRH released from the hypothala- body temperature
mus); it binds to receptors in the adrenal l facilitates the action of growth hormone.
glands and stimulates the release of cortisol.
Cortisol levels then inhibit CRH and ACTH Androgens
release (negative feedback) l The zona reticularis produces sex steroids: andro-
n circadian rhythm: cortisol levels are higher first gens in men, and oestrogen and progesterone in
thing in the morning (7–8 am) and fall to a women; the amount is insignificant in comparison
lower level in the middle of the night (1–2 am) with the amount produced by the testes/ovaries.
l Secretion is stimulated by ACTH released from the
n stress hypothalamus.
n trauma
n burns Medulla
n infection
n exercise l The adrenal medulla acts as an extension of the
n hypoglycaemia. sympathetic nervous system. It contains chromaffin
l The actions of cortisol include: cells that resemble the post-ganglionic cells in the
n metabolic effects: the metabolic effects of cortisol sympathetic nervous system. They do not possess
axons but are similar in the fact that they release
generally oppose those of insulin; they include: a number of neurotransmitters from intracellular
l breakdown of protein to amino acids vesicles once stimulated.
l amino acids are then converted to glucose
l The main hormones secreted by the adrenal me-
(gluconeogenesis) dulla are epinephrine (adrenaline) and norepineph-
l storage of glucose as glycogen rine (noradrenaline); they are synthesised from the
l lipolysis: mobilises free fatty acids and glyc- amino acid tyrosine
erol; these are then converted to glucose in l Epinephrine and norepinephrine released from the
the liver adrenal medulla bind to a-receptors (mainly norepi-
n cardiovascular effects: cortisol is necessary for nephrine) and b-receptors (mainly epinephrine).
vasopressors, e.g. epinephrine, to increase Binding to these receptors leads to the production
vascular tone. In the absence of cortisol, blood of second messengers such as cAMP; these second
vessels become unresponsive to the effects of messengers lead to further intracellular reactions
catecholamines that ultimately alter cell function.
n CNS: cortisol produces euphoria
n anti-inflammatory effects: the glucocorticoids l The adrenal hormones are rapidly inactivated once
have profound anti-inflammatory actions, released, by the enzymes catechol-O-methyl-
which include: transferase and monoamine oxidase, present in
l Q immunocompetent cells and macrophages the liver and kidney.
l stimulate synthesis of lipocortin in leukocytes.
This protein inhibits phospholipase A2 and
thus prevents formation of inflammatory
Endocrine system 12 263
Box 12.1 Efficacy of norepinephrine (noradrenaline) n mineralocorticoid deficiency: there is increased
and epinephrine (adrenaline) in various physiological urinary Naþ loss leading to dehydration, Q
processes Naþ, Q blood pressure, Kþ retention leading
to hyperkalaemia, and Hþ retention leading
Norepinephrine > Epinephrine > to metabolic acidosis
epinephrine norepinephrine
n glucocorticoid deficiency: this leads to nonspe-
qgluconeogenesis (a1) qglycogenolysis (b2) cific symptoms such as weight loss, anorexia
and lethargy. Hypoglycaemia may occur during
Qinsulin secretion (a2) qlipolysis (b3) fasting, and there is reduced resistance to
trauma and infection.
Vasoconstriction:qBP qinsulin secretion (b2)
(a1) Hyperaldosteronism
qglucagon secretion l Excess secretion of aldosterone may be primary or
qtone in GI sphincters (b2)
(a1) secondary.
qKþ uptake by l Primary hyperaldosteronism:
Bronchoconstriction (a1) muscle (b2)
n a very rare cause of q blood pressure (< 1%);
qheart rate (b1) it is caused by adrenal adenomas in 60–70%
arteriolar tone in skeletal (Conn’s syndrome) and bilateral hyperplasia
in 20–30%.
muscle (b2)
qcardiac contractility l Secondary hyperaldosteronism:
n results from excess secretion of renin, this
(b1) stimulates angiotensin II and thus aldosterone;
bronchodilatation (b2) causes include:
l renal artery stenosis
The effects of epinephrine and norepinephrine are l congestive cardiac failure
shown in Box 12.1. l cirrhosis.
Clinical physiology l The effects of excess aldosterone secretion
include:
Disorders of adrenal function n Naþ and water retention, leading to q blood
pressure
Addison’s disease n renal Kþ loss, leading to hypokalaemia
l Addison’s disease is caused by destruction of the ad- n renal Hþ loss, leading to metabolic alkalosis.
renal cortex; this produces a reduction in mineralocor- Cushing’s disease/syndrome
ticoid, glucocorticoid and sex-hormone production. l Cushing’s disease/syndrome is due to excess glu-
l The causes of Addison’s disease include:
cocorticoid; this can occur in several situations:
n primary hypoadrenalism: caused by destruction n ACTH-dependent: there is increased ACTH,
of the adrenal cortex; causes include: which stimulates glucocorticoid secretion.
l autoimmune (> 80%) The ACTH may be from the pituitary (Cushing’s
l TB (20%) disease) or by ectopic secretion from a tumour
l haemorrhage, e.g. Waterhouse–Friderichsen n ACTH independent: this is caused by an excess
syndrome in meningococcal septicaemia of glucocorticoid with suppression of ACTH; this
l malignant infiltration can result from:
l drugs l adrenal adenoma
l adrenal carcinoma
n secondary hypoadrenalism: due to pituitary dis- l glucocorticoid administration.
ease and the resulting decrease in ACTH secre-
tion; production of mineralocorticoids is not l The clinical features of Cushing’s syndrome are
affected as stimulation is via angiotensin II; shown in Figure 12.6.
sex hormone secretion is also independent of
pituitary function. l The main effects of raised glucocorticoids include:
n hyperglycaemia
l The clinical features of Addison’s disease are n muscle wasting due to protein breakdown
shown in Figure 12.5. n osteoporosis
n striae (stretch marks)
l The clinical features of Addison’s disease are
mainly due to the deficiencies in mineralocorticoid
and glucocorticoid:
264 SECTION TWO PHYSIOLOGY Weight loss
Constipation
Buccal
pigmentation
Postural
low blood
pressure
Pigmentation
of scars
Loss of body
hair
Fig 12.5
Features of Addison’s disease.
n weight gain, partly due to a stimulation of ap- secretion; this has the effect of driving the unused
petite but also due to abnormal fat deposition cortisol precursors into the androgenic hormone
in the face (moon face) and back (buffalo synthetic pathways.
hump) l The clinical effects depend on the sex of the
affected individual:
n q blood pressure, due to fluid retention from
the mineralocorticoid activity of cortisol n male: there is rapid growth in childhood and
early sexual development (precocious puberty);
n hirsutism and acne, due to the androgenic due to early fusion of the epiphysis, these
properties of cortisol. patients are often shorter than average
Adrenogenital syndrome n female: there is masculinisation of the external
l Also known as congenital adrenal hyperplasia genitalia with hypertrophy of the clitoris, a male
body shape and hair distribution.
(CAH), it results from genetic deficiencies in
the enzymes in the synthesis of cortisol. Phaeochromocytoma
The commonest defect affects the enzyme 21- l A rare condition characterised by oversecretion of
hydroxylase.
l The lack of this enzyme leads to a decrease in cor- catecholamines (epinephrine and norepinephrine)
tisol secretion and as a result increases in ACTH from the adrenal medulla.
Plethora Endocrine system 12 265
'moon face'
Acne
High blood 'Buffalo
pressure hump'
Poor wound Centripetal
healing obesity
Bruising
Thin skin
Striae Proximal
Osteoporosis myopathy
Oedema
Fig 12.6
Features of Cushing’s syndrome.
l A tumour of the chromaffin cells causes the con- l GH is released in a pulsatile manner and demon-
dition: 10% are malignant, 10% are multiple strates a circadian rhythm, with elevation in secre-
and 10% arise outside of the adrenal medulla tion during periods of deep sleep.
(‘rule of 10s’).
l Hypoglycaemia is a potent stimulator of GH secre-
l The effects of the increased circulating catechol- tion; it stimulates GHRH release and inhibits
amines include: somatostatin secretion.
n palpitations and arrhythmias
n tremors l A number of other stimuli promote GH secretion:
n sweating and flushing n anxiety
n q blood pressure (episodic) n pain
n hyperglycaemia (episodic). n hypothermia
n haemorrhage
Growth hormone n trauma
n fever
l Human growth hormone (hGH) is the main form of n exercise.
growth hormone; it is a large protein composed
of 191 amino acids. l The effects of GH can be divided into those predo-
minating in childhood and adolescence, and those
l Secretion is stimulated by growth hormone releas- that predominate in adulthood:
ing hormone (GHRH) released by the hypothalamus n childhood and adolescence: GH stimulates
and inhibited by somatostatin. skeletal growth by stimulating mitosis in
the cartilage cells in the epiphyseal plates
266 SECTION TWO PHYSIOLOGY
at the ends of the long bones; this process is n insulin (secreted by b-cells)
aided by insulin-like growth factors (IGFs) n glucagon (secreted by a-cells)
that encourage matrix secretion from carti- n somatostatin (secreted by d-cells).
lage cells
n adulthood: after fusion of the epiphyseal plates, Insulin
GH no longer has any influence on skeletal
growth; however, it still has an important role l Insulin is a small peptide consisting of 91
in a number of metabolic functions: amino acids; it is derived from the precursor
l qglycogenolysis proinsulin.
l Qglucose uptake by cells
l promotes amino acid uptake into cells l Proinsulin undergoes cleavage to form insulin.
l promotes protein synthesis l Insulin is stored within granules in b-cells and is
l qlipolysis and release of free fatty acids
secreted into the circulation by exocytosis.
(FFAs) l Insulin has a short half-life in the circulation
l QLDL cholesterol.
(5–10 min); it is rapidly broken down by the liver
Clinical physiology and kidney.
l A number of factors are able to influence the secre-
Disorders of growth hormone tion of insulin; the level of glucose is the most potent
secretion stimulus.
l Increased glucose stimulates insulin release from
Gigantism the b-cells; this decreases glucose concentration
l Caused by growth hormone hypersecretion prior to in the plasma and acts as a negative feedback.
l Other regulators of insulin secretion include:
epiphyseal fusion; there is increased growth, partic-
ularly of the limbs—this results in the condition of n fatty acids (þ)
gigantism. n ketone bodies (þ)
n parasympathetic stimulation (þ)
Acromegaly n amino acids, i.e. arginine, leucine (þ)
l In this condition there is also hypersecretion of n gastrin, cholecystokinin (CCK), secretin, gastric
growth hormone, but it occurs in adult life after inhibitory polypeptide (GIP) (þ)
epiphyseal fusion. n prostaglandins (þ)
l Hypersecretion of growth hormone in adult life is n drugs, e.g. sulphonylureas (þ)
called acromegaly, and results from a pituitary n sympathetic stimulation (À)
tumour. n dopamine (À)
l The symptoms and signs of acromegaly can be n serotonin (À)
divided into those produced by the tumour and n somatostatin (À).
those produced by the growth hormone excess l Insulin is an anabolic hormone; it has a variety of
(see Fig. 12.7). actions, which can be divided into:
n carbohydrate metabolism
ENDOCRINE FUNCTION OF THE n protein metabolism
PANCREAS n lipid metabolism.
l The exocrine role of the pancreas has been dis- Carbohydrate metabolism
cussed in Chapter 10.
l Promotes glucose uptake, except in brain cells;
l Exocrine secretions are produced in the pancreatic these are freely permeable to glucose.
acini and then discharged into the ductal system;
the endocrine secretions are produced in the islets l Promotes glycogen storage via q glycogenesis
of Langerhans. and Q glycogenolysis; this allows glucose storage
in the post-prandial period. Liver glycogen is con-
l The islets of Langerhans are highly vascular and are verted to glucose and is able to maintain plasma
innervated by the sympathetic and parasympathetic glucose levels. Muscle glycogen acts as an energy
nervous system. store. Muscle lacks the phosphatase enzyme
necessary to release free glucose and thus muscle
l Three main hormones produced in the islet of glycogen can only be used in the muscle cells for
Langerhans play a role in the regulation of plasma glycolysis.
glucose levels:
l Stimulates the use of glucose (glycolysis).
Prominent Endocrine system 12 267
supra-orbital
Visual field
ridge defects
Broad nose
Heart failure Large tongue
High blood
pressure Carpal tunnel
syndrome
Galactorrhoea
'Spade-like'
Thick 'greasy' hands
skin
Oedema
Protein metabolism Fig 12.7
Features of acromegaly.
l Stimulates amino acid uptake.
l Stimulates protein synthesis. l The actions of glucagons can be divided into those
l Inhibits protein degradation. affecting carbohydrate metabolism and those
l Inhibits amino acid conversion to glucose. affecting lipid metabolism.
Lipid metabolism Carbohydrate metabolism
l Inhibits lipolysis by lipase. l q Glycogenolysis.
l Stimulates lipogenesis. l q Gluconeogenesis.
l Glucose sparing by preferential oxidation of fatty
Glucagon
acids; this produces ketones, i.e. acetone, aceto-
l Glucagon is a catabolic hormone. It is a 29-amino- acetate, b-hydroxybutyrate.
acid polypeptide and is released from the a-cells of
the pancreas; like insulin it has a short half-life in Lipid metabolism
the circulation (approximately 5 min).
l Stimulates lipase activity to increase plasma FFAs
and glycerol.
268 SECTION TWO PHYSIOLOGY
Somatostatin Clinical physiology
l Somatostatin is released by d-cells in the pancreas. Disorders of the endocrine pancreas
l Secretion is stimulated by:
Diabetes mellitus
n q plasma glucose l Diabetes mellitus encompasses a number of condi-
n q plasma amino acids
n q plasma glycerol. tions in which there is either a lack of insulin or a
l The effects of somatostatin include: relative resistance to its effects.
n inhibits the release of insulin and glucagons The causes of diabetes mellitus include:
n Q gastrointestinal motility, secretion and l Primary:
absorption. n type I insulin-dependent diabetes mellitus (IDDM)
n type II non-insulin-dependent diabetes mellitus
Effects of other hormones on glucose
regulation (NIDDM).
l Secondary:
Glucocorticoids
n pancreatic disease:
l Released in response to hypoglycaemia, the effects l pancreatitis
include: l pancreatic cancer
n anti-insulin: inhibit glucose uptake l pancreatectomy
n promote lipolysis: FFAs and glycerol are used in l cystic fibrosis
preference to glucose
n promote gluconeogenesis n antagonists to insulin:
n promote glycogen production. l acromegaly (GH)
l Cushing’s syndrome (glucocorticoids)
Growth hormone l hyperthyroidism (thyroid hormone)
l phaeochromocytoma (catecholamines)
l Released in times of fasting, the effects include: l glucagonoma (glucagon)
n anti-insulin: inhibits glucose uptake
n promotes lipolysis n drugs, e.g. corticosteroids, thiazide diuretics
n stimulates glycogenolysis. n liver disease
n genetic syndromes, e.g. Down’s syndrome,
Thyroid hormone
Friedreich’s ataxia
l The role of thyroid hormone is complex: at low n insulin receptor abnormalities, e.g. congenital
concentrations it is anabolic and reduces plasma
glucose; at high concentrations it is catabolic lipodystrophy
and induces hyperglycaemia. l Diabetes mellitus has a number of complications,
l The effects of thyroid hormone include: these can be divided into:
n qglycogenolysis
n qgluconeogenesis Acute
n qabsorption of glucose from the gastrointesti- l Hypoglycaemia: very common complication of insu-
nal tract
n quptake of glucose into cells lin therapy in patients with diabetes; symptoms
n enhances the rate of insulin-dependent usually develop when blood glucose falls
glycogenesis. < 3 mmol/L. Symptoms include sweating, tremor
and palpitations (adrenergic symptoms); in patients
Catecholamines with long-standing disease these warning signs
may not be present.
l Release of catecholamines is stimulated when the l Diabetic ketoacidosis (DKA): occurs when the body
plasma glucose falls below 4 mmol/L, their effects produces ketones in an uncontrolled manner. Glu-
include: cose is not taken up into cells and is lost in the
n qglycogenolysis urine, producing an osmotic diuresis. The abnormal
n enhance glycogen secretion glucose handling is associated with increased lipol-
n inhibit insulin secretion ysis, which leads to increased circulating levels of
n lipolysis (FFAs and glycerol metabolised in fatty acids; these are converted to acetyl-CoA and
preference to glucose). then to ketones. The ketones lead to a severe met-
abolic acidosis and dehydration due to nausea and
vomiting.
l Hyperglycaemic hyperosmolar non-ketotic coma
(HONK): occurs in the absence of ketosis; it is
Endocrine system 12 269
typically seen in patients with NIDDM. The patients l Somatostatinoma: a very rare tumour derived from
present with severe dehydration and a decreased the d-cells of the pancreas; they cause diabetes
level of consciousness with a very high plasma mellitus, cholelithiasis and steatorrhoea.
glucose level.
l Lactic acidosis: occurs in patients on biguanide Hormonal response to trauma/
therapy; it rarely occurs nowadays as long as the surgery
dosage is not exceeded and is not used in patients
where it can accumulate, i.e. renal or hepatic l The body responds to a variety of noxious stimuli
failure. such as pain, infection, trauma and surgery.
Chronic l This response aims to limit the injuring process
l Macrovascular and allow the body to heal; this involves a variety
of hormonal changes that alter the metabolism
n Diabetes mellitus is a risk factor in the develop- of carbohydrates, proteins and fats, and also
ment of atherosclerosis. This tends to be wide- involves stimulating the immune and clotting
spread and more severe as it tends to affect systems.
vessels distally (thus making bypass surgery
technically harder). l There are four systems involved in the body’s
response to injury:
n Disorders caused by atherosclerosis are all 1) Sympathetic nervous system: this response is
increased in diabetics, i.e. ischaemic heart dis- the initial phase of a response to injury and oc-
ease (IHD), stroke, myocardial infarction (MI) curs at the time of injury. It prepares the body
and peripheral vascular disease. for action, i.e. ‘fight or flight’; the release of
epinephrine and norepinephrine has a number
l Microvascular of effects:
n Small blood vessels are predominantly af- l blood is redistributed to non-essential
fected; this has its greatest effect at three sites: organs, thus supplying more to the heart,
l eye: diabetic retinopathy skeletal muscle and brain
l kidney: diabetic nephropathy l q glucose: provides energy
l nerves: diabetic neuropathy. l q lipolysis: provides energy
l q ketone production: provides energy
Pancreatic endocrine tumours l inhibition of non-essential visceral func-
tions, e.g. bowel peristalsis.
Tumours can arise in the endocrine cells of the pan- 2) Acute phase system: the acute phase
creas. When these are ‘functioning’ and secrete ex- response refers to the cytokine and inflam-
cess hormone they can lead to clinical syndromes; matory mediator production that occurs
examples include: following tissue injury; this has local and
l Insulinoma: 75% of endocrine tumours; they are de- systemic effects:
l local effects: this involves the rapid influx of
rived from b-cells; the classic presentation is with inflammatory cells such as neutrophils and
‘Whipple’s triad’ – hypoglycaemic symptoms during macrophages (see below) into the wound;
fasting, a reduced blood sugar during these periods, these release a variety of cytokines such
and relief with intravenous glucose; 10% are as IL-1, 2, 6, TNF-a, and interferons and in-
malignant. flammatory mediators such as the prosta-
l Gastrinoma (Zollinger–Ellison syndrome): arise glandins, histamine, serotonin, etc. These
from pancreatic G-cells; malignant in > 50% mediators aim to limit tissue injury by pro-
of cases; the excess gastrin leads to gastric ducing vasodilatation, increased vascular
hypersecretion, diarrhoea and widespread peptic permeability, attraction and migration of
ulceration. neutrophils, fibroblasts and endothelial
l Vipomas: associated with excess secretion of VIP cells, and stimulation of the clotting system
(vasoactive intestinal peptide); they lead to severe and complement cascade
watery diarrhoea, Q Kþ, and achlorhydria (absence l systemic effects: the cytokine cascade as-
of HCl in the stomach). sociated with local injury is usually limited
l Glucagonoma: a rare cause of secondary diabetes to the area of injury; however, if the insult
mellitus; other symptoms include anaemia, weight is severe, it may lead to cytokines spilling
loss and a characteristic rash called necrolytic
migratory erythema; the tumour arises from the
a-cells; 75% are malignant.
270 SECTION TWO PHYSIOLOGY
into the circulation; this produces systemic l nitric oxide (NO): produces vasodilatation; this
effects such as: may lead to hypotension. NO also increases
l tachypnoea the number of antigen-presenting cells
l fever
l tachycardia l endothelins: these oppose the action of NO
l increased vascular permeability (Q blood and produce vasoconstriction
pressure) l platelet-activating factor (PAF): released in
l vasodilatation (Q blood pressure) response to cytokines such as IL-1 and
l immune cell activation TNF-a. The main effect is to stimulate plate-
l increased leukocyte adhesion let aggregation and produce vasoconstriction
l effects on glucose metabolism (see
l prostaglandins: reduce platelet aggregation
below). and cause vasodilatation.
3) Endocrine response: a variety of hormones are
l The changes associated with trauma and surgery
involved in the response to tissue injury; these lead to wide-ranging local and systemic changes
are shown in Box 12.2. and production of numerous cytokines and humoral
4) Vascular endothelium: the endothelium should mediators; together they produce a number of
be considered as an organ in its own right. The clinical changes:
response to trauma has both local and n hypovolaemia: this type of fluid loss is re-
systemic effects: ferred to as ‘third space’ loss; the vasodilata-
l increased adhesion molecule expression: tion and increased vascular permeability lead
to fluid being sequestered in the interstitial
this action attracts cells such as neutrophils space
to destroy bacteria and digest foreign bod- n renal changes: following injury there is reduced
ies; however, enzymes released and produc- excretion of free water and sodium; this con-
tion of free radicals can lead to additional tinues for about 24 h and is due to the release
tissue damage of aldosterone and ADH
Box 12.2 Summary of the action of various hormones in the body’s response to trauma
Hormone Action
ACTH Stimulates glucocorticoid release and potentiates the actions of catecholamines on the heart
Glucocorticoids Protein ! glucose, glucose ! glycogen. Inhibits insulin and stimulates gluconeogenesis,
Aldosterone decreases vascular permeability, potentiates catecholamine-induced vasoconstriction,
anti-inflammatory (suppresses prostaglandin synthesis), immunosuppressant (inhibits
secretion of IL-2)
Stimulates reabsorption of Naþ (water follows by osmosis; this leads to a reduced urine volume)
and secretion of Kþ
ADH Increased water absorption from the collecting ducts, vasoconstriction (particularly splanchnic),
and stimulates glycogenolysis and gluconeogenesis
Insulin Low in the ebb phase (due to Q b-cell sensitivity to glucose levels; glucagon inhibits its secretion
and cortisol reduces its peripheral action), levels increase in the flow phase but hyperglycaemia
remains due to continued resistance
Glucagon Stimulates glycogenolysis, gluconeogenesis, ketogenesis, and lipolysis
Thyroxine See Sick euthyroid syndrome, p. 257
Serotonin Causes vasoconstriction, bronchoconstriction, q heart rate and contractility, and stimulates
platelet aggregation
Histamine Causes vasodilatation and q vascular permeability
Growth hormone Stimulates protein synthesis, lipolysis and glycogenolysis
Endocrine system 12 271
n fever: injury (even in the absence of infection) is glycogen; this is stimulated by catechol-
associated with a rise in temperature; this is amines and glucocorticoids (insulin resis-
due to changes in the thermoregulatory set tance prevents cell uptake). After 24 h the
point in the hypothalamus by IL-1 glycogen is exhausted and the hyperglycae-
mia is maintained by gluconeogenesis
n haematological changes: there is a leukocyto- l lipids: lipolysis is stimulated by catechol-
sis; albumin levels fall due to decreased amines, the sympathetic nervous system,
production and loss into injured tissue. The co- cortisol and growth hormone. They provide
agulation system is activated. This is primarily the primary source of energy for all tissues
to reduce bleeding after the injury; however, it (leaving the brain and blood cells to utilise
leads to a state of hypercoagulability and an in- glucose)
creased risk of deep vein thrombosis (DVT) l proteins: the demand for amino acids is met
by skeletal muscle breakdown; the greater
n electrolyte and acid–base changes: the electro- the insult the greater the breakdown and
lyte changes include QNaþ (due to dilution nitrogen loss. The amino acids are used in
from retained water), qKþ (as a result of cell gluconeogenesis and synthesis of acute
death and tissue injury), metabolic alkalosis phase proteins.
(the absorption of Naþ stimulated by ADH leads l Respiratory changes: there is increased respiratory
to Kþ and Hþ excretion) and metabolic acidosis drive that leads to a respiratory alkalosis (due to Q
(this occurs with more severe injuries with P aCO2); in addition, the systemic effects of the
hypotension, poor perfusion and consequent cytokine release and immune cell activation can
anaerobic metabolism). lead to ARDS and severe hypoxia. The metabolic
alkalosis created by Hþ excretion affects the oxygen
l Metabolic changes: the altered metabolism seen dissociation curve, making it harder for O2 to dissoci-
after trauma or surgery can be divided into two ate into tissues—thus exacerbating hypoxia.
phases: the ebb phase and the flow phase: l Cardiac changes: the cardiac output increases
n the ebb phase is the initial response to injury and dramatically following injury.
is a phase of reduced energy expenditure and l Immune system changes: there are a variety of
metabolic rate that lasts for approximately 24 h defects in the immune system that occur following
n the flow phase follows: this is a catabolic phase trauma:
with increased metabolic rate, hyperglycaemia, n cell-mediated immunity
negative nitrogen balance and increased O2 n antigen presentation
consumption. The flow phase has significant n neutrophil function
effects on the metabolism of carbohydrates, n opsonisation of bacteria.
lipids and proteins:
l carbohydrates: hyperglycaemia is seen
post-injury due to mobilisation of liver
OSCE SCENARIOS OSCE scenario 12.2
OSCE scenario 12.1 A 40-year-old male presents to his GP with inter-
mittent headaches, palpitations, sweating, anxiety
A 32-year-old female is admitted with suspected and intermittent chest pains. Examination reveals
acute appendicitis. She is sweating, agitated, con- a blood pressure of 180/110 mmHg.
fused and complaining of palpitations. Her symp- 1. What endocrine condition do you need to
toms do not fit with a straightforward diagnosis of
acute appendicitis. Examination reveals a temper- consider? Explain the condition.
ature of 40 C and a tachycardia of 140 with an 2. How could you confirm the diagnosis?
irregularly irregular pulse. You check her thyroid 3. What measures would you take to prepare the
function, which reveals an elevated T3 and T4 with
suppressed TSH. patient for surgery?
1. What is the most likely diagnosis? Answers in Appendix page 461
2. What may precipitate the condition?
3. How is the condition managed?
SECTION TWO PHYSIOLOGY
CHAPTER 13
Nervous and locomotor
systems
INTRODUCTION n the initiation and co-ordination of movement
and muscle contraction
Components
n higher functions such as thought, memory and
l The nervous system is composed of two components: the ability to learn.
n central
n peripheral: sensory and motor. CENTRAL NERVOUS SYSTEM
l The nervous system can also be divided into somatic Cerebral blood flow (Fig. 13.1)
and autonomic:
n somatic: supplies the skin and muscles l Blood flow to the brain is via the internal carotid and
n autonomic: supplies glands, sphincters and the vertebral arteries; they anastomose to form a
smooth muscles within blood vessels etc. circle of arteries that supply the brain: the circle
of Willis.
l The central nervous system (CNS) is composed of
the brain and spinal cord; it is composed of numer- l The control of cerebral blood flow is maintained
ous specialised cells called neurons. within very close limits. The brain is particularly
sensitive to ischaemia, with loss of conscious-
l The neurons are supported by neuroglia (or glial ness occurring within 5 s of the interruption of
cells); these are cells that have a variety of ancillary cerebral circulation, and irreversible damage
functions including: within 2–3 min.
n astrocytes: form the ‘blood–brain barrier’
n microglia: perform a phagocytic role in the CNS l The brain receives approximately 10–15% of the
n oligodendroglia: produce myelin. cardiac output.
l The CNS is organised into two distinct areas: l Cerebral blood flow is controlled by three mechanisms:
n grey matter: contains the neuronal cell bodies n autoregulation: myogenic or metabolic
n white matter: contains the axon of the neurons. n neural
n local.
l The peripheral nervous system consists of the cra-
nial and spinal nerves and the autonomic nervous Autoregulation
system and their associated ganglia. They link the
CNS with sensory receptors (e.g. pain receptors) Myogenic
and effectors (i.e. muscles). l The brain will maintain a remarkably similar
Functions cerebral blood flow over a wide range of blood
pressures: this is known as autoregulation.
l The functions of the nervous system include: l Myogenic autoregulation occurs when the cerebral
n the interpretation of sensory input such as blood vessels constrict or dilate to maintain
touch, temperature, proprioception and pain adequate cerebral perfusion.
n interpretation of electrical impulses from the l When the blood pressure rises the vessels constrict
special senses leading to our ability to taste, thus decreasing flow; when the blood pressure falls
smell, hear and see the cerebral vessels dilate in order to increase flow.
272
Nervous and locomotor systems 13 273
CBV CVR l Myogenic autoregulation can be impaired by a
CBF number of factors, such as:
Cerebral Blood Flow (CBF) n hypoxia
Cerebral Blood Volume (CBV) n ischaemia
n trauma
0 60 160 n cerebral haemorrhage
n tumour
Cerebral Perfusion Pressure (CPP) n infection.
Fig 13.1 Metabolic
l The activity of certain areas of the brain will differ
Graph illustrating control of cerebral blood flow
(CBF). The range of autoregulation is at a CPP of depending on the task being performed; as a con-
60–160 mmHg. Flow is maintained by changes in sequence these areas will require additional blood
the cerebrovascular resistance (CVR) with increasing flow.
vasoconstriction at high CPP and vasodilatation at l The increased activity results in a decrease in P aO2
low CPP. The effect of CVR can also be seen to affect and increase in P aCO2 and Hþ, the changes result-
cerebral blood volume (CBV): vasodilatation ing in local vasodilatation of cerebral blood vessels
increasing CBV and vasoconstriction decreasing it. and thus increased perfusion.
l Autoregulation has a limit to which it can compen- Neural control of cerebral blood flow
sate. At a cerebral perfusion pressure (CPP; see
below) of around 50 mmHg the dilatation of cerebral l The cerebral circulation does receive some sympa-
vessels will fail to maintain flow and at a CPP of thetic vasoconstrictor and parasympathetic vasodi-
150–160 mmHg the cerebral vessels will begin to fail lator innervation, but their effect is very weak and
to regulate flow—indeed, at this point they become their precise role, if any, is unclear.
abnormally permeable, causing cerebral oedema.
Local control of cerebral blood flow
l These same mechanisms are responsible for main-
taining cerebral flow in patients with head injuries. l Cerebral blood flow is sensitive to changes in the
arterial P aO2 and P aCO2.
l In patients with severe head injuries the amount of
perfusion the brain is receiving is dependent upon l Increases in P aCO2 are associated with an increase
the intracranial pressure resisting flow within the in CBF due to marked cerebral vasodilatation; how-
cranial cavity: ever, just as hypercapnia results in vasodilatation
then a fall in P aCO2 (hypocapnia) results in cerebral
Cerebral perfusion pressure ðCPPÞ vasoconstriction.
¼ mean arterial pressure ðMAPÞ
À intracranial pressure ðICPÞ l The effect that CO2 has on cerebral blood flow is
particularly important in head injury patients; main-
l When CPP falls below 50 mmHg then cerebral taining a low–normal CO2 prevents increases in ICP
ischaemia results; when it falls below 30 mmHg due to cerebral vasodilatation. Equally it must be re-
then death occurs. membered that overzealous ventilation to low CO2
levels can be equally detrimental due to vasocon-
l These changes occurring during cerebral autoregu- striction and consequent cerebral ischaemia.
lation can be seen in Figure 13.1:
n autoregulation occurs over the range l The effect of changes in P aO2 is not as marked;
50–150 mmHg hypoxia only has a significant effect when it falls be-
n to maintain flow over this range you can see low 8 kPa. Below this level then CBF may increase
from the graph that CVR (cerebral vascular dramatically.
resistance) falls as CPP falls; this reflects the
vasodilatation of cerebral vessels l Increases in P aO2 can cause mild cerebral vaso-
n as the CPP rises then CVR increases; this re- constriction; indeed hyperbaric oxygen therapy
flects the vasoconstriction of cerebral vessels can reduce CBF by 20–30%.
n as the CVR varies so does the CBV (cerebral
blood volume); as vessels vasodilatate the CBV l These normal responses to PaO2 and P aCO2 can be
rises, and as CVR increases the CBV decreases. affected by a number of factors, such as:
n head injury
n cerebral haemorrhage
n shock
n hypoxia.
274 SECTION TWO PHYSIOLOGY
CEREBROSPINAL FLUID l The CSF circulates around the subarachnoid space
and is reabsorbed back into the circulation via the
l Cerebrospinal fluid (CSF) lies in the subarachnoid arachnoid villi; these drain into the venous sinuses.
space; the total volume is 130–150 mL (40 mL in
the cerebral ventricles and 100 mL around the l The arachnoid villi may become blocked by blood
spinal cord). following a subarachnoid haemorrhage and prevent
reabsorption of CSF; this results in hydrocephalus.
l The rate of production of CSF is approximately
500 mL/day. l A small amount of CSF is also absorbed by spinal
villi in the lumbar region.
l The normal CSF pressure is approximately 0.5–1 kPa;
obstruction to the flow of CSF leads to an increase l CSF has two main functions:
in this pressure, i.e. hydrocephalus. n hydraulic ‘cushion’: serves to protect the brain
from violent movements of the head
l CSF is produced by the choroid plexus in the lateral, n provides a stable ionic environment for cerebral
third and fourth ventricles. function.
l CSF flows from the lateral ventricles to the third BLOOD–BRAIN BARRIER (Fig. 13.2)
ventricle via the interventricular foramina; it then
flows to the fourth ventricle via the cerebral aque- l Lipid-soluble molecules are able to pass freely from
duct. From the fourth ventricle CSF flows into the the blood into the interstitial space of the brain; how-
subarachnoid space via the foramen of Luschka ever, ions are unable to pass freely into the brain.
(lateral) and the foramen of Magendie (midline).
Capillary Astrocyte foot process
lumen Basement membrane
Tight junction
A
Transcellular Astrocyte foot process Lipid soluble transport, e.g.
Adsorbtive transcytosis,
e.g. albumin CO2, O2, alcohol,
anaesthetic agents
Transcellular Capillary Basement membrane Fig 13.2
Receptor mediated lumen
transcytosis, e.g. insulin Carriers (transport proteins) The blood–brain barrier.
Tight junction e.g. glucose, amino acids A Longitudinal section through
B a capillary in the brain. The capillaries
have tight cell-to-cell junctions and
the astrocytes project foot processes
to cover the capillary basement
membrane. B Transverse section
through a capillary in the brain,
showing methods of transport across
the blood–brain barrier.
Nervous and locomotor systems 13 275
This enables the brain to maintain the ionic environ- l It is legally regarded as being equivalent to the more
ment within very tight limits, thus allowing the opti- traditional mode of death, i.e. cessation of respira-
mal environment for neuronal communication. tory and cardiac activity.
l The blood–brain barrier also prevents the release of
neurotransmitters from neurons into the peripheral l The diagnosis of brainstem death is important for
circulation. several reasons:
l The blood–brain barrier is formed by the structure of n withdrawal of treatment
the capillaries. Rather than the freely permeable n assessment for suitability for organ donation.
fenestrated capillaries found in other tissues, the
cerebral capillaries have very tight cell-to-cell junc- l The diagnosis of brainstem death must first satisfy
tions in the endothelium. In addition, the end-feet of several preconditions and exclusions before the
astrocytes cover the basement membrane. appropriate tests can be performed.
l Specific functions provided by the blood–brain
barrier are: Preconditions for the diagnosis
of brainstem death
n tight junctions restrict penetration of water-
soluble substances l There are four preconditions:
n the patient must be in a coma
n lipid-soluble molecules such as CO2, O2, hor- n there must be a known cause for the patient’s
mones, anaesthetics and alcohol (that’s why coma
we get drunk!) can pass freely across the bar- n this cause must be known to be irreversible
rier via the lipid membranes of the capillary n the patient must be dependent on a ventilator.
endothelium
Exclusion criteria for the diagnosis
n the endothelium contains transport proteins of brainstem death
(carriers) for nutrients such as sugars and
amino acids l There are a number of exclusion criteria:
n no residual drug effects from narcotics, hyp-
n certain proteins, e.g. insulin and albumin, may notics, tranquillisers, muscle relaxants, alcohol
be transported by endocytosis and transcytosis and illicit drugs
n core body temperature must be > 35 C
n an ‘efflux pump’ extrudes unwanted lipid n no circulatory, metabolic or endocrine abnormal-
soluble molecules back into the blood. ity disturbance that may contribute to the coma.
l The blood–brain barrier is not continuous and in Brainstem death tests
some areas consists of fenestrated capillaries.
These areas lie in the midline and include: l The UK brainstem death criteria tests seven areas.
n third and fourth ventricles: allows drugs and All must be absent for the diagnosis to be made.
noxious chemicals to trigger the chemorecep-
tor area in the floor of the fourth ventricle; this l The tests include:
in turn triggers the vomiting centre. In addition 1) No pupillary response to light, direct or consen-
angiotensin II passes to the vasomotor centre in sual: this reflex involves cranial nerves II and III.
this region to increase sympathetic outflow and 2) Absent corneal reflex—normally would result
causes vasoconstriction of peripheral vessels in blinking; this reflex involves cranial nerves
n posterior lobe of pituitary: allows the release of V and VI.
oxytocin and antidiuretic hormone (ADH) into 3) No motor response in the cranial nerve distribu-
the circulation tion to stimuli in any somatic area, e.g. supra-
n hypothalamus: this allows the release of releas- orbital or nailbed pressure leading to a grimace.
ing or inhibitory hormones into the portal– 4) No gag reflex: back of the throat is stimulated
hypophyseal tract. with a catheter; this reflex tests cranial nerves
IX and X.
BRAINSTEM DEATH 5) No cough reflex: no response to bronchial
stimulation with a suction catheter; this reflex
l The brainstem provides the capacity for con- tests cranial nerves IX and X.
sciousness. 6) No vestibulo-ocular reflex: head is flexed to
30 and 50 mL of ice-cold water is injected
l The cerebral hemispheres provide the content of over 1 min into each external auditory meatus;
consciousness.
l Brainstem death is a condition in which the heart
and lungs function, but there is no cerebral activity.
276 SECTION TWO PHYSIOLOGY
there should be no eye movements; this reflex Intracranial pressure (ICP; mmHg) Herniation
tests cranial nerves III, VI and VIII.
7) Apnoea test: the patient is preoxygenated with 100
100% O2 for 10 min; P aCO2 is allowed to rise
to 5 kPa (before testing); the patient is discon- 80
nected from the ventilator and O2 is insufflated
at 6 L/min; P aCO2 is allowed to rise to 6.5 kPa; 60
there should be NO respiratory effort.
l There are several other caveats to the brainstem 40
death tests:
n performed on two occasions 20
n performed by two doctors Decompensation
n one must be a consultant
n must be competent in the field, e.g. ITU or 0
neurology
n must have > 5 years’ experience Intracranial volume (arbitrary units)
n must not be part of the transplant team.
l The time of death is legally defined as the time at Fig 13.3
which the first set of brainstem tests were performed. Pressure–volume curve for intracranial pressure (ICP).
The compensatory properties of the intracranial
SPACE-OCCUPYING LESIONS contents follow a pressure–volume exponential curve.
AND RAISED INTRACRANIAL Increased volume of any of the three components
PRESSURE (i.e. brain, CSF, blood) can be accommodated up to
a certain point without any change in intracranial
l Space-occupying lesions (SOLs) result from a pressure. Once a critical volume is reached,
variety of causes, and may be focal or diffuse. decompensation occurs, i.e. blood and CSF have been
pushed from the cranial cavity and ICP increases
l Focal SOLs include: exponentially to the point of herniation.
n tumour
n aneurysm l The removal of blood and CSF can accommodate a
n blood or haematoma SOL of approximately 100–150 mL; after this com-
n granuloma pensatory point the ICP will increase rapidly.
n tuberculoma
n cyst l Raised ICP has a number of consequences:
n abscess. n hydrocephalus: an increase in ICP may result in
the interruption of CSF flow; this is most com-
l Diffuse SOLs result from either vasodilatation or monly seen with posterior fossa lesions leading
oedema. to compression of the cerebral aqueduct and
fourth ventricle
l The consequences of intracranial SOLs include: n cerebral ischaemia: remember that CPP ¼
n raised intracranial pressure MAP À ICP. Any rise in ICP will eventually exceed
n intracranial shift and herniation autoregulation and lead to cerebral ischaemia
n hydrocephalus. n brain shift and herniation: as ICP increases the
risk of herniation increases; this occurs at
Raised intracranial pressure (ICP) specific sites (Fig. 13.4):
l transtentorial: the lesion lies within one
(Fig. 13.3) hemisphere; leads to herniation of the
medial part of the temporal lobe over the
l The skull is a rigid container in which brain, CSF and tentorium cerebelli
blood are the only contents; it therefore follows that l tonsillar: caused by a lesion in the posterior
ICP ¼ VCSF þ VBrain þ VBlood. fossa; the lowest part of the cerebellum
pushes down into the foramen magnum
l This formula is the basis for the Monroe–Kellie and compresses the medulla
hypothesis, which states that the ICP will increase l subfalcial: caused by a lesion in one
if the volume of one component is increased; the hemisphere; leads to the herniation of the
increase in ICP can only be compensated for by a cingulate gyrus under the falx cerebri
decrease in one or both of the other components.
l Normal ICP in the supine position is 0–10 mmHg.
Cingulate Nervous and locomotor systems 13 277
Lateral gyrus Falx cerebri
Sub-falcine
ventricle herniation
Expanding
Parahippocampal lesion
gyrus
Skull
Dura Collapse of Fig 13.4
ventricle
Tentorium Diagram illustrating the possible
cerebelli Transtentorial consequences of an expanding
Midbrain herniation lesion, i.e. haematoma, on one
Pons side of the brain. Diencephalic
Cerebellar tonsil herniation is caused by generalised
Cerebellum herniation into brain swelling.
Medulla foramen magnum
l diencephalic: generalised brain swelling; n cerebral peduncles: contralateral hemiparesis
leads to the midbrain herniating through (transtentorial)
the tentorium; this is termed coning
n posterior cerebral artery: cortical blindness
n systemic effects: the systemic effects of (transtentorial)
raised ICP are thought to occur due to auto-
nomic imbalance, hypothalamic overactivity n cerebral aqueduct: hydrocephalus (transtentorial)
(due to compression) and ischaemia of the n compression of cardio/respiratory centres in
vasomotor area; the effects include:
l Cushing’s response: Q respiratory rate, the medulla: death (tonsillar)
bradycardia and hypertension n reticular activating system: coma (all types)
l neurogenic pulmonary oedema n anterior cerebral artery: infarction (subfalcial)
l Cushing’s ulcers n distortion of the midbrain and tearing of vessels:
l preterminal events include bilateral pupil
constriction followed by dilation, tachycardia, death (all types).
Q respiratory rate, and hypotension.
POST-OPERATIVE CONFUSION
l The clinical manifestations of raised ICP include:
n headache l One of the commonest complications occurring in
n nausea and vomiting elderly patients.
n papilloedema
n decreased conscious level. l The symptoms can include:
n clouding of consciousness
l The clinical manifestations of cerebral herniation n restlessness
include: n abnormalities of perception
n oculomotor nerve compression: ipsilateral pupil n incoherent speech
dilation (transtentorial) n agitation
n violence
n pulling out lines, catheters, drains, etc.
278 SECTION TWO PHYSIOLOGY
l There are numerous factors that predispose to or n presence of nursing staff in a well-lit environment
cause post-operative confusion; these include: n low-dose sedation, e.g. haloperidol
n dehydration n physical restraint—only if patient at risk of
n electrolyte abnormalities
n hypoxia harming self or others.
n infection
n drugs PERIPHERAL NERVOUS
n uraemia SYSTEM (PNS)
n hypoglycaemia
n pre-existing psychiatric disorder or dementia Conduction and transmission
n alcohol and drug with withdrawal (particularly
in young patients) Action potentials (Fig. 13.5)
n urinary retention
n pain and anxiety l Action potentials are the method by which nerves
n cerebrovascular accident (CVA) send information; they are electrical signals and
n head injury (especially in trauma patients) are described as ‘all-or-nothing’.
n sleep deprivation
n ITU syndrome: pain, fear and sleep deprivation l Axons have a resting membrane potential with
can lead to visual and auditory hallucinations respect to the extracellular environment; this is
and inability to differentiate reality from fantasy. approximately À70 mV.
l Post-operative confusion is an important complica- l As stimuli attempt to activate an action potential
tion with many serious underlying causes; a full man- the membrane potential is decreased towards a
agement plan must be formulated and the cause ‘threshold’; stimuli below this threshold will not
sought. Appropriate management should include: result in an action potential and are described as
n history and examination subthreshold. If the stimulus is large enough to
n FBC, U&E, LFT, glucose, ABG decrease the membrane potential above the thresh-
n ECG old then this will result in an action potential.
n sepsis screen: blood cultures, chest X-ray,
sputum, midstream urine, wound swab. l The action potential, once initiated, begins with a
rapid depolarisation and a reversal of the mem-
l If a specific cause is found then this must be brane potential to around 50 mV; this occurs in a
corrected, e.g. hypoxia, urinary retention; however, few tenths of a millisecond.
non-specific treatment may include:
n eliminate drugs likely to cause or increase the l Following depolarisation is repolarisation: this is
confusional state where the cell returns to the normal resting membrane
potential; the repolarisation may initially be more neg-
ative than the resting potential—hyperpolarisation.
l During the action potential the cell has an ‘absolute’
refractory period in which no further action potential
+50
Depolarisation
0
0
Membrane potential (mV) 5 Time (ms)
Membrane permeabilityRepolarisation Na Depolarisation
or conductance (arbitrary units)
Threshold
–70 Resting Repolarisation
membrane K
A Subthreshold potential 0
Fig 13.5 stimulus Time (ms)
0 24
Suprathreshold B
stimulus
A Graph illustrating the theory of the ‘all-or-nothing’ response to electrical stimuli. B The ion flows responsible
for depolarisation and repolarisation of a nerve.
Nervous and locomotor systems 13 279
can be generated. During repolarisation then a ‘rel- generated at these points as the myelin acts to
ative’ refractory period exists; an action potential insulate the intervening sections; thus, the ac-
can be stimulated but will need a stimulus of greater tion potential jumps between the gaps. This is
magnitude than the initial stimulus. referred to as saltatory conduction (Fig. 13.6).
l Action potentials self-propagate: once the cell is A classification of nerve fibres is shown in Table 13.1.
stimulated the signal will propagate along all cells.
l The intra- and extracellular concentrations of Naþ Synaptic transmission
and Kþ differ:
l When an action potential reaches the end of an axon
n Naþ concentration is greater extracellularly and it must be transmitted to the next adjacent nerve;
thus tends to diffuse into the cell, both along the gap between neurons is known as the synapse.
this concentration gradient and due to the neg-
ative membrane potential l Transmission of the signal relies on the release of
neurotransmitters; these then affect the adjacent
n Kþ has a greater concentration intracellularly nerve chemically to initiate another action potential.
and thus tends to diffuse out of the cell.
l The action potential travels along the presynaptic
l The change in permeability of the cell to Naþ and Kþ nerve. The axon terminates in an expanded end; this
during an action potential is due to conformational is called the terminal bouton.
changes in voltage-controlled ion channels by the
initial stimulus depolarising the cell membrane. l Inside the bouton are numerous membrane-bound
vesicles containing neurotransmitters.
l The initial depolarisation is due to the rapid influx of
Naþ as the Naþ channel opens; at the same time l The transmission of the action potential occurs by:
the Kþ channel also opens and Kþ is released into n the action potential depolarises the presynaptic
the extracellular environment. membrane by opening voltage-gated Ca2þ
channels
l The Naþ channel activates much faster than the Kþ n Ca2þ enters the axon down an electrochemical
channel. This explains the rapid influx of Naþ; the and concentration gradient
channel also closes much faster; the Kþ channel n the increase in Ca2þ results in the vesicles fus-
remains open over a longer period than the Naþ ing with the presynaptic membrane and releas-
channel and is responsible for repolarisation as ing neurotransmitters into the synaptic cleft
Kþ is released and the membrane potential falls n the neurotransmitters then bind with receptors
back to its negative value. on the post-synaptic membrane
n binding of neurotransmitters initiates second-
Propagation of action potentials ary signals within the cell and opens ion chan-
nels, thus generating a depolarising current
l The action potential results in the inside of the cell n the transmitter is released from the receptor and
being positive in respect to the extracellular envi- is broken down by specific breakdown pathways.
ronment; this is the opposite of the normal negative
resting membrane potential; as a result the action Neurotransmitters
potential travels from positive to negative.
l Neurotransmitters are chemicals that are responsi-
l The action potential is unidirectional and sets up ble for the transmission of action potentials across
local currents that result in the propagation of the the synapse.
action potential across the whole membrane; the
action potential is unidirectional due to the refrac- l The main neurotransmitters include:
tory nature of the membrane, preventing further n acetylcholine (ACh): this is an excitatory trans-
depolarisation. mitter; it is present in the brain, spinal cord,
autonomic nerves and the PNS. It is broken
l The conduction velocity of action potentials is deter- down to acetate and choline by the enzyme
mined by two factors: acetylcholinesterase
n axon diameter: the greater the diameter the n amines: this group includes catecholamines
higher the conduction velocity; this effect is (adrenaline, noradrenaline, and dopamine),
due to the increase in myelin causing a 5-hydroxytryptamine (serotonin) and histamine.
decrease in electrical resistance The catecholamines are formed from the amino
n myelination: myelinated cells have a much faster acid tyrosine. Two enzymes degrade catechol-
conduction velocity in comparison with unmy- amines: monoamine oxidase breaks down trans-
elinated cells (50–100 m/s vs 1 m/s); this effect mitter taken up by the presynaptic neuron; and
is due to the gaps between the myelin sheath catechol-O-methyl transferase breaks down cat-
that surrounds nerves. These gaps are called echolamines taken up by the postsynaptic neuron
the nodes of Ranvier. Action potentials are only
280 SECTION TWO PHYSIOLOGY
Action potential jumps from node to node
Axon
Myelin sheath Node of Ranvier
Transverse
section
Schwann cell membrane Schwann cell
forms myelin sheath nucleus
Axon Axon Fig 13.6
membrane
Action potential conduction in a
myelinated nerve fibre (saltatory
conduction).
Table 13.1 Different types of nerve fibre, showing Pain and sensation
functions, conduction velocities and diameters
l Pain is defined as an unpleasant sensory and emo-
Type Function Conduction Diameter tional experience associated with actual or potential
velocity (m/s) (mm) tissue damage.
Aa Motor 100 15–20 l Pain can be classified into:
5–10 n nociceptive: somatic and visceral
proprioception 3–6 n referred
2–5 n neuropathic
Ab Touch and 50 n psychogenic.
pressure 3
0.5–1 l Nociceptive and referred pain are the commonest
Ag Muscle spindles 30 types of pain encountered in the surgical patient.
Ad Pain, 20 l Somatic pain is defined as pain that originates from
temperature the skin, muscles, bones and joints; it tends to be
and touch sharp in nature and is well localised.
B Autonomic 10 l Visceral pain is due to ischaemia, inflammation and
stretching or contraction (colic) of smooth muscle in
C Pain 1 hollow viscera; it is poorly localised.
n amino acids: several amino acids act as neuro- l Referred pain occurs when damage to an internal
transmitters; these include: organ is associated with pain in a particular
l glycine: inhibitory skin region; this occurs as the organ in question
l glutamate: excitatory or inhibitory (can be shares the same dermatomal innervation as the
converted to GABA) region the pain is felt. Examples of referred pain
l aspartate: excitatory include:
n MI and angina: pain may be referred to the
n peptides: examples of peptide transmitters neck, jaw, shoulder and left arm
include: n spleen: haemoperitoneum leads to left-sided
l substance P: involved in the transmission of diaphragmatic irritation and left shoulder tip
pain sensation pain (Kehr’s sign)
l endorphins: inhibit pain pathways.
Nervous and locomotor systems 13 281
n appendix: central abdominal pain in the T10 release of inflammatory substances, i.e. prosta-
dermatome is the initial sign until peritoneal ir- glandins, histamine, serotonin, bradykinin and
ritation localises the pain to the right iliac fossa substance P. These substances lead to electrical
impulses that are transmitted along sensory
n gall bladder: cholecystitis can lead to irritation nerves.
of the right hemidiaphragm and right shoulder l Transmission of pain sensation is along Ad and C
tip pain (Boas’ sign). fibres to the spinal cord; here they synapse in
lamina I and III in the dorsal horn.
l Pain can also be classified according to the speed of l The sensation of pain is then transmitted along
onset; soft-tissue injury is associated with a sudden the spinal cord where it is modulated before
sharp pain that lasts for a few seconds and is finally being perceived in the sensory areas
followed by a longer-lasting dull throbbing pain. of the brain.
Peripheral nerves differ in their diameter and l Modulation of pain involves the ‘gate control theory’
conduction velocity; this explains the different pain of Melzack & Wall: this theory proposes that pain
sensations: impulses received in the dorsal horn can be modu-
n Ad fibres: these are myelinated nerves; as a lated by other descending spinal inputs. These
result they have a high conduction speed and include inhibitory inputs from the periaqueductal
diameter. They are responsible for the sharp grey matter and nucleus raphe magnus (both re-
initial pain leasing serotonin) and the locus coeruleus (releases
n C fibres: these are unmyelinated nerves and noradrenaline) (Fig. 13.7). In addition there is the
thus have a smaller diameter and lower con- release of the naturally occurring enkephalins and
duction velocity. They are responsible for the endorphins.
longer-lasting dull pain.
Drug modulation of pain
l Pain transmission can be divided into:
n transduction l There are numerous forms of analgesia used in
n transmission current surgical practice; each acts on different
n modulation elements in the chain of pain sensation.
n perception.
l Transduction involves the production of electrical
impulses; following tissue damage there is the
Descending inputs
Periaqueductal Enkephalin-releasing
grey matter hormone
+
Pons
and Nucleus
mid- raphe magnus
brain
Serotonin
Locus - Iº afferent
coeruleus neuron
-
Noradrenaline
(Norepinephrine)
Relay neurone Pain sensation
= Opioid receptors Fig 13.7
Descending inputs modulating
pain sensation.
282 SECTION TWO PHYSIOLOGY
l The provision of analgesia is particularly useful in AUTONOMIC NERVOUS SYSTEM
the surgical patient; the effects of inadequate (ANS) (Fig. 13.8)
analgesia include:
n respiratory: l The autonomic nervous system is involved in the
l q chest wall splinting control of visceral organs, smooth muscle and
l Q tidal volume secretory glands.
l Q vital capacity
l Q functional residual capacity (FRC) l It is principally involved in maintaining the internal
l difficulty coughing, and retention of environment by regulating cardiac, respiratory and
secretions, leading to atelectasis and digestive functions.
pneumonia
n cardiovascular: l The efferent neurons of the ANS have a two-neuron
l pain increases BP and heart rate, thus plac- arrangement. This differs from somatic nerves. The
ing increased strain on the heart cell body of the first neuron lies in the brainstem or
n immobilisation and increased risk of spinal cord (preganglionic); the second neuron is
thromboembolism located in the periphery in an autonomic ganglion
n ileus (post-ganglionic).
n urinary retention
n stress response l The ANS can be divided into two specific functional
n psychological stress. groups:
n sympathetic
l Transduction: drugs like paracetamol and n parasympathetic.
NSAIDs inhibit prostaglandin production. Prosta-
glandins are involved in sensitising nociceptive Sympathetic nervous system
receptors in injured tissues to the effects of noci-
ceptive compounds such as bradykinin and sub- l Sympathetic neurons:
stance P. n located in the thoracic and upper 2–3 lumbar
segments of the spinal cord
l Transmission: Ad and C fibres are involved in the n preganglionic neurons lie in the lateral horn of
transmission of pain sensation. Local anaesthetics the spinal grey matter
can be used to prevent the conduction of action po- n preganglionic axons leave via the ventral root of
tentials in these nerve fibres. Ab fibres are involved the spine to join the spinal nerve (see Chapter 4)
in inhibiting transmission to higher centres; stimu- n post-ganglionic neurons have their cell bodies
lation can thus provide analgesia. This is the basis either in the sympathetic chain (see Chapter 4)
for TENS (transcutaneous electrical nerve stimula- or in a named plexus along the aorta, i.e. coeliac,
tor) machines. superior and inferior mesenteric.
l Modulation: opioids are potent analgesics. They l Spinal nerves are connected to the sympathetic
produce their effect by combining with opioid re- chain by two small branches: the lateral white ra-
ceptors in the spinal cord and higher centres. The mus communicantes (myelinated), and the medial
analgesic effect of opioids is due to: grey ramus communicantes (unmyelinated).
n combining with receptors in higher centres
such as the periaqueductal grey matter l The sympathetic innervation of the head and
and nucleus raphe magnus; here they stimu- neck is via preganglionic neurons synapsing with
late descending inhibitory inputs to pain post-ganglionic bodies within the sympathetic
perception chain; the post-ganglionic neurons then leave
n binding to opioid receptors in the dorsal horn via the grey rami communicantes to join the
and inhibiting pain transmission; this action is spinal nerve.
believed to be related to hyperpolarising the
cell and thus decreasing the chance of propa- l The sympathetic innervation of the abdominal and
gating the pain impulse pelvic organs differs from that of the head and neck.
n inhibiting the release of substance P. Preganglionic neurons pass straight through the
sympathetic chain to their individual plexuses and
l Perception: pain perception can be influenced synapse with post-ganglionic cell bodies within
by factors such as fear, anxiety, depression, the plexus.
and activation of the ‘fight or flight’ mechanism.
l The neurotransmitter of the sympathetic nervous
system is noradrenaline (except sweat glands;
these are innervated by cholinergic fibres).
Nervous and locomotor systems 13 283
Spinal Spinal
cord cord
Sympathetic Head and neck Ciliary muscle 1 Oculomotor nerve
chain Sphincter pupillae
Dilator pupillae
Blood vessels Lacrimal gland 2 Facial nerve
Sweat glands Nasal glands
Muscles of hairs nerve
Submandibular gland 3
Sublingual gland Vagupshnareryvnegeal
Superior cervical ganglion Parotid gland
Cervicothoracic ganglion Oesophagus Glosso
4
Respiratory tract Cardiac branches
Cardiac branches
Coeliac Oesophagus Respiratory tract
ganglion Gut from
stomach to colon Gut from stomach
to colon
Renal Liver, biliary tract
ganglion Pancreas Liver, biliary system
Kidney, ureter Pancreas
Bladder
Hind gut
Pelvic ganglion Reproductive tract
Bladder Pelvic splanchnic S2
Urethra
nerve S3
Hind gut
5 S4
Uterus, uterine tubes
Erectile tissue
AB
Fig 13.8
A Layout of the sympathetic nervous system. B The parasympathetic nervous system: 1 ¼ ciliary ganglion,
2 ¼ sphenopalative ganglion, 3 ¼ submandibular ganglion, 4 ¼ otic ganglion, 5 ¼ pelvic ganglion.
Parasympathetic nervous system organ they innervate; an example would be the
enteric nervous system (see Chapter 10). Here
l Preganglionic neurons lie in cranial nerve nuclei neurons contribute to two plexuses, the myenteric
within the brainstem; the parasympathetic output and submucosal. These are found within the bowel
is derived from the oculomotor, facial, glossophar- wall itself.
yngeal and vagus nerves; this provides innervation l The neurotransmitter of the parasympathetic
to the head, neck and abdomen. nervous system is acetylcholine.
l The pelvic viscera are innervated by preganglionic Functions of the autonomic nervous
neurons derived from the S2–4 spinal roots. system
l The parasympathetic nervous system feeds into five l The effects of the autonomic nervous system are
ganglia before being distributed to the structures it summarised below.
innervates; these ganglia are:
n oculomotor (III) nerve ! ciliary ganglion l Sympathetic system:
n facial (VI) nerve ! sphenopalatine ganglion n constricts pupils
and submandibular ganglion n reduces salivary secretions
n glossopharyngeal (IX) nerve ! otic ganglion n reduces lacrimal secretions
n S2–4 ! pelvic splanchnic nerve ! pelvic n increases heart rate (tachycardia)
ganglion. n increases the contractility of the heart
n bronchodilation
l The cell bodies of postganglionic neurons lie in
ganglia that are found in close proximity to the
284 SECTION TWO PHYSIOLOGY
n decreases GI motility slow, sustained contractions and resist fatigue
n increases sweat gland secretion well. They rely on aerobic metabolism and
n contraction of erector pili muscles in the skin. contain myoglobin
l Parasympathetic system: n type II or fast twitch:
n dilates pupils l type IIa or fast oxidative fibres, e.g. calf
n increases salivary secretion
n increases lacrimal secretion muscles: they rely on aerobic metabolism
n decreases heart rate (bradycardia) and contain myoglobin; they have moderate
n decreases the contractility of the heart resistance to fatigue
n bronchoconstriction l type IIb or fast glycolytic fibres, e.g. extraocu-
n increases GI motility. lar muscle: do not contain myoglobin and thus
appear white; they contain a large amount of
LOCOMOTOR SYSTEM glycogen and rely on anaerobic metabolism.
Skeletal muscle physiology Sliding filament hypothesis (Fig. 13.9)
Structure of skeletal muscle l Muscle contraction is known to occur by the actin
and myosin filaments sliding past each other: the
l Muscles are composed of a number of muscle sliding filament theory.
fibres; these are grouped together to form bundles
called fasciculi. l The process of muscle contraction occurs, as the head
section of myosin is able to form cross-links with actin.
l The muscle fibres are composed of numerous fila-
mentous bundles called myofibrils. l When ATP binds to the head section of myosin it dis-
sociates from its binding site on the actin filament.
l The myofibrils contain the contractile proteins actin
and myosin; under a microscope muscle has a l The ATP is hydrolysed and changes the angle of the
striated appearance due to the arrangement of myosin head (relative to its tail); as the ATP has
actin and myosin: been hydrolysed the myosin is again able to bind
n the dark bands or A bands are composed of the to the actin filament.
thicker myosin filaments
n the light bands or I bands are composed of the l The release of phosphate from the myosin head re-
thinner actin filaments stores the angle and moves the actin filament along
n the I band is divided by the Z line; the space the myosin filament; this is called the power stroke.
between Z lines is called a sarcomere
n at the Z lines the membrane of the muscle cell l ATP will bind to myosin and start the process again.
(sarcolemma) forms narrow tubes that traverse l Creatine phosphate is present in very high concen-
the sarcomere; these are called the T-tubules.
trations within muscle and provides sufficient
l The myosin filaments consist of a long tail and a energy reserves for the above processes to take
head section; the head has a binding site for ATP. place. The enzyme creatine kinase catalyses the
transfer of the phosphate group from creatine
l The actin filaments contain three different proteins: phosphate to ADP, thus replenishing ATP stores.
n actin: a thin contractile protein, arranged in a
double-stranded helix Excitation contraction coupling
n tropomyosin: lies in the groove between the
actin filaments l Skeletal muscle only contracts if it receives an
n troponin: lies at regular intervals along the fil- excitatory impulse from a motor nerve (see below).
ament, attached to both actin and tropomyosin;
it also has binding sites for Ca2þ and is involved l An action potential is conducted down the motor
in the regulation of contraction. Troponin and nerve and activates an electrical signal to be con-
tropomyosin block the myosin-binding site on ducted across the sarcolemma; this impulse is con-
actin. ducted deep within the cell by the invaginations in
the sarcolemma (T-tubules).
Skeletal muscle classification
l Depolarisation of the cell leads to the release of
l Skeletal muscle is classified according to the speed Ca2þ from the sarcoplasmic reticulum within
of contraction: the cell. The rise in Ca2þ activates contraction
n type I or slow twitch: act as postural muscles, by binding to troponin on the thin filaments; this
e.g. in the back; they are designed to perform leads to a conformational change and removes
troponin and tropomyosin from the myosin binding
site on actin.
l As the cell repolarises the Ca2þ is actively pumped
back into the sarcoplasmic reticulum.
Nervous and locomotor systems 13 285
ATP Actin
ATP Myosin
ATP binds to myosin
head-group
Dissociation from actin
ADP
ADP Pi Hydrolysis of ATP leads
to change in head angle
and binding to actin
Release of Pi changes
angle of myosin head
ADP Pi group and 'pushes' the
actin filament forwards;
this is called the
'power stroke' Fig 13.9
Molecular events involved in
contraction of skeletal muscle.
l The Ca2þ is removed from the troponin and thus end-plate. It is separated from the axon terminal
the troponin and tropomyosin block the myosin of the motor neuron by a gap; this is called the
binding site. neuromuscular cleft.
l Transfer of the action potential from the motor neu-
Neuromuscular transmission ron to the muscle is very similar to nerve conduction
described above:
l Muscles are supplied by nerves from the spinal
cord, known as a motor neurons; they innervate n action potential depolarises the terminal axon
the muscle directly and lie in the anterior horn of of the motor neuron
the spinal cord grey matter.
n axon membrane becomes more permeable
l a motor neurons are myelinated and conduct action to Ca2þ
potentials to the muscle fibre surface; here they form
a modified synapse called the neuromuscular junction. n the rise in Ca2þ stimulates secretory vesicles to
fuse with the cell membrane and release
l The motor neurons lose their myelin sheath and acetylcholine (ACh) into the neuromuscular cleft
terminate in grooves in the muscle known as
synaptic gutters; this is known as the motor n the ACh binds to receptors on the muscle fibres;
this leads to the opening of ion channels, in turn
286 SECTION TWO PHYSIOLOGY
leading to the influx of Naþ and Kþ and depo- inhibition). This reduces resistance to contrac-
larisation of the cell; this is called the end-plate tion of the stretched muscle.
potential l The anterior horn also contains g motor neurons
n an action potential is initiated when the thresh- (innervate the contractile ends of the muscle spin-
old is reached; this leads to the impulse being dle). Activation of g motor neurons leads to contrac-
propagated across the plasma membrane tion of the ends of the muscle spindle; this lowers
n acetylcholine is released from the receptor and the threshold for action potential generation, and
the muscle cell repolarises and is broken down thus increases the sensitivity to stretch stimuli ap-
by acetylcholinesterase. plied to the muscle. This reflex is called the gamma
reflex loop.
LOCOMOTION l The stretch reflex and gamma reflex are important
for a number of reasons:
Spinal cord reflexes n the control of voluntary activity: the muscle
spindle is able to contract with muscle fibres
l Reflex: involuntary, stereotyped response as a and thus maintain sensory output
result of a sensory stimulus. n control of muscle tone: the stretch reflex resists
passive changes in muscle length; this is par-
l The reflex pathways consist of an afferent neuron ticularly important in the maintenance of body
that conveys impulses from a sensory receptor, posture, i.e. antigravity muscles of the neck,
and an efferent neuron that runs from the brain to trunk and legs.
the effector organ, i.e. muscle. l The stretch reflex is the physiological basis under-
lying tendon reflexes in clinical examination:
Muscle stretch reflex (Fig. 13.10) n biceps reflex: C5–6
n brachioradialis reflex: C5–6
l Simplest reflex: it is monosynaptic and consists of n triceps reflex: C6–7
the afferent input from stretch receptors in skeletal n quadriceps reflex: L3–4
muscle and the efferent output to the stretched n achilles tendon reflex: S1–2.
muscle.
Golgi tendon organ reflex
l The sensory organ for the stretch reflex is the mus-
cle spindle: this consists of intrafusal muscle fibres l The golgi tendons are another stretch receptor.
which lie in parallel to the skeletal muscle fibres. They are located in the tendon of muscles and
There are two types of intrafusal muscle fibre: are sensitive to tension.
n nuclear bag fibres
n nuclear chain fibres. l The reflex they are involved in is an inhibitory
response. It involves:
l The muscle spindle is divided into three regions: a n afferent impulse acting on a motor neurons that
contractile region at either end and a receptor supply the contracting muscle
region in the centre. n reduction in the level of active contraction
(via inhibitory interneurons)
l The contractile regions are supplied by g motor n the reflex is protective and limits muscle/
neurons from the anterior horn of the spinal cord. tendon stretch.
l The chain of events in the stretch reflex is as Withdrawal reflex (Fig. 13.11)
follows:
n muscle spindle is stretched: this causes the l This is a more complex reflex; it is polysynaptic.
receptor region to depolarise; this generates l The withdrawal or flexor reflex is a response to
an action potential in the afferent nerve
(Ia afferent) painful or noxious stimuli.
n the afferent impulse enters the spinal cord via l The afferent input is from pain receptors; these
the dorsal horn and synapses with an a motor
neuron that supplies the stretched muscle synapse with several efferent neurons:
n the action potential in the a motor neuron n a motor neurons: this results in stimulation of
signals the muscle to contract to oppose the flexors in the limb in which the painful stimulus
stretch was experienced, thus withdrawing the
n the afferent impulse also synapses with inhibi- affected limb
tory neurons that synapse with a motor neurons n inhibitory signals are passed to a motor
that supply antagonist muscles (reciprocal neurons in the opposing extensor muscles
Alpha motor Nervous and locomotor systems 13 287
neuron
Ia afferent
Intrafusal muscle fibre
Quadriceps muscle
Patellar tendon
Knee flexor
muscles
A Inhibitory interneuron
Ia afferent neuron Extrafusal
muscle fibres
Intrafusal
muscle fibre
Alpha motor neuron
Gamma motor neuron
B
Fig 13.10
A Quadriceps stretch reflex: striking the patellar tendon produces knee extension. Reciprocal innervation
leads to inhibition of the knee flexors. B The gamma reflex loop.
n this pattern is reversed in the opposing limb: Control of locomotion
flexor muscles are inhibited and extensor mus-
cles are stimulated; this is called the crossed l A number of areas in the brain are involved in the
extensor reflex. It enables us to balance or push control of movement; these include:
away from a noxious stimuli, e.g. if you stand n cerebral cortex
on a sharp object and pull away your foot, n brainstem
the reflex will lead to extension of the contra- n cerebellum
lateral limb to maintain balance. n basal ganglia.
288 SECTION TWO PHYSIOLOGY
Lumbar cord
Interneuron
Cutaneous afferent
neuron
Quadriceps Alpha motor neurons
muscle
Knee flexor
muscles
Fig 13.11
The flexor (withdrawal) reflex and crossed extensor reflex.
l Control of movement by these centres can be via des- Brainstem
cending pathways that synapse with the spinal motor
neurons, or via inputs into the motor area of the cere- l There are four descending inputs from the brain-
bral cortex from the cerebellum and basal ganglia. stem; these are:
1) The rubrospinal tract: originates in the red
Cerebral cortex nucleus and primarily innervates distal limb
muscles.
l The motor area of the cerebral cortex lies in the 2) The tectospinal tract: fibres arise in the supe-
frontal lobe immediately anterior to the central rior colliculus of the midbrain; it receives
sulcus; this area is called the precentral gyrus. inputs from the visual cortex and is believed
to control reflex activity in response to visual
l Descending pathways leave this area to supply stimuli.
spinal motor neurons: 3) The vestibulospinal tract: originates in the ves-
n corticobulbar tracts: supply the motor portions tibular nuclei; it supplies muscles of the ipsilat-
of the cranial nerves eral side of the body. It innervates muscles
n corticospinal tracts: supply the spinal motor concerned with balance and posture in re-
neurons; they are concerned with voluntary sponse to inputs from the vestibular apparatus.
movements. 4) The reticulospinal tract: fibres are derived from
the pons and medulla; they supply muscles
l The descending fibres from the cerebral cortex on the ipsilateral side of the body and are impor-
cross the midline and innervate the opposite side tant in maintaining posture and muscle tone.
of the body, i.e. the left hemisphere supplies the
right (contralateral side).
Nervous and locomotor systems 13 289
Cerebellum l Bones contain four main cell types; these are:
n osteoprogenitor cells: undifferentiated cells
l There are no descending pathways from the cere- n osteoblasts: these cells secrete the organic matrix
bellum; they influence movement via inputs directly of bone; they are also involved in mineralisation
to the motor cortex. n osteocytes: mature cells; they are trapped in
gaps (lacunae) after they deposit matrix. They
l The cerebellum receives information from the are involved in calcium homeostasis as they
vestibular apparatus, visual system, corticospinal are able to transport Ca2þ from the bone
tracts and peripheral proprioceptors. interior to the extracellular environment
n osteoclasts: these cells are responsible for the
l The cerebellum collates information from these absorption of bone; this is via the release of
sources, and is important in maintaining balance lytic enzymes, i.e. collagenase, acid phospha-
and producing smooth, co-ordinated movements. tase. These cells are considered part of the
mononuclear macrophage system.
Basal ganglia
Bone formation and reabsorption
l The basal ganglia have no descending tracts; they
receive information from the substantia nigra, the l Bone is not an inert tissue; it is constantly remodel-
thalamus and the motor cortex. ling in order to cope with changes in the demands
placed upon it.
l The basal ganglia appear to be involved in the ini-
tiation of movement, ensuring that body posture is l 5–10% of the bone mass is recycled each week;
appropriate for a particular movement and eliminat- this can be much greater in those undertaking
ing unwanted movements. strenuous activity. During immobility then bone
mass can be rapidly lost—disuse osteoporosis.
BONE PHYSIOLOGY
l Remodelling of bone is a two-stage process:
l Bone is a type of connective tissue. It has an organic n osteoclastic reabsorption of bone
and inorganic component. n osteoblastic phase in which new bone is laid
down.
l The organic component is referred to as osteoid;
this consists of collagen I, keratan sulfate, hyaluro- l The control of bone remodelling is not completely
nic acid and glycoproteins. understood (particularly at a cellular level);
however, a number of hormones are known to be
l The inorganic component contains complexes of involved, including:
calcium and phosphate (hydroxyapatite); it also n parathyroid hormone
contains calcium carbonate, fluoride, magnesium n calcitonin
and sodium ions. n thyroxine
n oestrogen
l Bone has four main functions; these are: n vitamin D.
n mechanical support
n locomotion (by means of joints)
n calcium and phosphate homeostasis
n haemopoiesis.
290 SECTION TWO PHYSIOLOGY OSCE scenario 13.2
OSCE SCENARIOS A 55-year-old male presents to a pain clinic with a
long history of lumbar back pain that has become
OSCE scenario 13.1 more severe recently. There is no history of sciat-
ica and there is no neurological deficit on exami-
An 18-year-old male is admitted to A&E following nation. Paracetamol has been of no benefit.
an assault. He has severe head injuries. His 1. Why is paracetamol unlikely to have been of
GCS is 6.
1. How is brain injury classified? benefit?
2. Describe the mechanism of compensation for He is commenced on ibuprofen.
2. Why is this more likely to be of benefit than
an acute rise in intracranial pressure. paracetamol?
The patient is transferred to ITU and you are called Treatment with ibuprofen brings about little
because the intracranial pressure (ICP) has risen improvement and he is treated with a TENS
acutely. machine.
3. Describe the possible management options. 3. What is the mechanism of action of TENS?
TENS provides initial improvement but the
benefit is slowly lost. He is treated by facet
joint injections with local anaesthetic and
steroid.
4. What is the purpose of the local anaesthetic
injection and what is the mechanism of action of
local anaesthetics?
Facet joint injections with steroid fail to give
lasting relief and he is commenced on
oramorph.
5. What is the mechanism of action of oramorph
and what side-effects might be expected?
Answers in Appendix page 462
SECTION III
PATHOLOGY
14 Cellular injury 293
15 Disorders of growth, morphogenesis and differentiation 311
16 Inflammation 319
17 Thrombosis, embolism and infarction 325
18 Neoplasia 331
19 Immunology 343
20 Haemopoietic and lymphoreticular system 355
21 Basic microbiology 373
22 System-specific pathology 400
The words you are searching are inside this book. To get more targeted content, please make full-text search by clicking here.
BASIC SCIENCE FOR THE MRCS
Discover the best professional documents and content resources in AnyFlip Document Base.
Search
BASIC SCIENCE FOR THE MRCS
- 1 - 50
- 51 - 100
- 101 - 150
- 151 - 200
- 201 - 250
- 251 - 300
- 301 - 350
- 351 - 400
- 401 - 450
- 451 - 500
- 501 - 522
Pages: