Liverpud Nephro

1996 Integrated Body Function 536-022: Volume II By Duy Thai
2nd Year Medicine Page 1 of 29
Integrated Body Function

1996
Volume II
CONTENTS
TOPIC PAGE NO.

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PREGNANCY
Before conception
• Even before fertilization has occurred, progesterone and oestrogen secreted by the corpus lutetium (of menstruation)
causes the endometrium to swell.
• Oestrogen causes hypertrophy of the myometrium.
• Progesterone cause growth of the decidual cells, enabling them to store extra glycogen, proteins, lipids and nutrients in
preparation for the conceptus.
Establishment of pregnancy
• The body must cope with enormous amounts of change due to the growing foetus. In effect, the mother's metabolism
must support 2 individuals.
• Physical signs of pregnancy:
• There is cessation of menstruation (amenorrhoea)
• This is brought about by the secretion of human chorionic gonadotropin from the placenta which
keeps the corpus lutetium alive (now called the corpus lutetium of pregnancy) after LH from the
pituitary has diminished.
• Since the corpus lutetium is still active in producing oestrogen and progesterone, sloughing off of the
endometrium is prevented.
• Normal menstruation is due to the removal of oestrogen and progesterone since the corpus lutetium is
no longer active (since there is no LH to keep it alive).
• Morning sickness
• Increased frequency of urination
• The foetus is also producing wastes which is handled by the maternal kidneys. Hence the mother
must worry about her own urine in addition to that of the foetus.
• Also, growth of the foetus puts pressure on the bladder, causing the desire to urinate.
• Increased size of the breasts
• Due to growth of the lactiferous ducts.
• This is promoted by oestrogen
• Darkening of the areolae
• Increased fatigue
• Since the mother must support the metabolism of herself and the foetus, there is an increased demand
on metabolism.
• Physiological adaptations of pregnancy:
• Increased blood volume
• This is due to an increase in plasma volume as a result of fluid retention.
• The increase in blood volume is due more largely to an increase in plasma volume, and hence the
concentration of RBC is reduced leading to apparent anaemia.
• Increased blood volume can also lead to hypertension.
• Increased cardiac output
• Since the metabolic rate of the mother has increased, it is not surprising that there will be an
increased usage of blood.
• An increased oxygen consumption will tend to increase the respiratory rate. This can often lead to
loss of breath because of the extra breathing demands. To make things worse, the growing foetus
pushes up on the diaphragm and hence decreases the chest cavity, making inspiration difficult.
• Increased fluid retention
• This is due to the effects of oestrogen.
• Oestrogen stimulates the release of aldosterone which causes increased salt retention, and
hence increased fluid retention.
• Causes increased plasma volume which predisposes the mother to hypertension.
• Can cause oedema, especially in the feet.
• Enlarged uterus
• This puts pressure on the bladder
• The diaphragm is pushed up and hence decreases the chest cavity.
• Pressure is placed on the GIT causing constipation
• Increased metabolic demands
• Increased heart rate, stroke volume
• Need to eat more to maintain sufficient nutrients
• Increased respiration
• Increase in body temperature.
The placenta
• The placenta has many functions:
• It is the organ of exchange between mother and foetus
• It is an endocrine organ of pregnancy
• It is the substitute for the major foetal systems: cardio-vascular, respiratory, gastrointestinal and urinary
systems.
• The placenta provides oxygenated blood to the foetus via the umbilical veins and removes
deoxygenated blood from the foetus via the umbilical artery.
• Nutrients (and drugs) are also passed onto the foetus via the umbilical veins and foetal nitrogenous
wastes are taken to the maternal blood via the umbilical artery. The foetus cannot excrete nitrogenous
wastes along with its urine into the amnion, otherwise it would poison itself.
Endocrine functions of the placenta

• The endocrine function of the placenta is extremely important in:
• Maintaining the uterine environment
• Regulating foetal function
• Maturation of the foetus
• The major hormones produced by the placenta are:
• Human chorionic gonadotropin (hCG)
• hCG is produced very early by the trophoblastic cells and can be detected in the urine in as little as 8
days after conception. This forms the basis of the pregnancy test.
• hCG has a very similar role to LH. When the pituitary stops producing LH, the corpus lutetium
atrophies. If pregnant, however, hCG takes over LH's role to maintain the corpus lutetium. This
enables progesterone and oestrogen to be secreted thus preventing menstruation.
• The peak secretion oh hCG occurs at approximately 2 months after ovulation, after which it
gradually begins to decline. After 5 weeks, the placenta is capable of producing its own progesterone
and oestrogen, hence hCG is no longer necessary to keep the corpus lutetium alive and so it
involutes. hCG is still being secreted, however.
• hCG, not surprisingly, has effects on the male foetus. It acts on the developing testes and stimulates
the Leydig cells to produce testosterone (just like LH).
• Oestrogen
• The corpus lutetium of pregnancy produces this hormone until about the 5th week. Thereafter, it is
produced by the placenta.
• The major form of the oestrogen produced by the placenta is estriol, which is not a very potent form.
• Oestrogen is not able to be produced intrinsically by the placenta. It requires androgen precursors
from the mother (e.g. DHEA) and precursors from the foetus.
• Oestrogen causes myometrial hypertrophy.
• Oestrogen also stimulates uterine contractions (which is inhibited by progesterone).
• Oestrogen, at parturition, increases the amounts of oxytocin receptors, thus heightening the uterus's
sensitivity to oxytocin.
• Oestrogen is a synergist with progesterone to induce growth of the mammary glands and duct
system.
• Oestrogen leads to the resorption of Na+ (via aldosterone), hence causing increased fluid retention -
risk of hypertension and oedema.
• Oestrogen can also relax the pelvic ligaments to prepare for parturition.
• Progesterone
• Its secretion is the same as that for oestrogen.
• Progesterone is very important for maintaining the health of the uterus. It causes the decidual cells to
become secretory, producing glycogen for the nourishment of the foetus.
• It aids oestrogen in developing the lactiferous duct system of the breasts.
• Progesterone relaxed the uterus, preventing contractions (opposes oestrogen). Hence progesterone
prevents expulsion of the foetus during pregnancy. At parturition, oestrogen levels exceed
progesterone and hence may lead to childbirth.
• Human chorionic somatomammotropin
• Also known as placental lactogen because it has a limited role in initiation of lactation (in animals).
In humans, it is more likely that prolactin, oestrogen and progesterone have a more marked effect.
• It is similar in structure to GH, and hence is also anti-insulin. Anti-insulin effects include:
• Mobilising glucose by reducing their uptake by cells and promoting gluconeogenesis and lipolysis.
• Reducing the mother's sensitivity to insulin.
• By increasing the glucose levels of the mother and decreasing the insulin sensitivity, glucose is given
preferentially to the foetus which, like the adult brain, has a specific requirement for glucose as its
main metabolite.
• A number of minor hormones produced are:
• Relaxin
• This has a role in relaxing the pelvic ligaments but in humans it seems that oestrogen is a more
important initiator of this.
• Corticotroph releasing hormone (CRH)
Labour & parturition

• We don’t know for sure what triggers the labour process, we can only speculate.
• There are 3 stages of labour:
• Cervical dilatation
• This stage can last up to 12 hours for the first pregnancy, but often reduces in time for later
pregnancies.
• It is characterised by the rupture of the foetal membranes and the expulsion of amniotic fluid.
• Delivery of the baby
• Lasts 1-2 hours
• Afterbirth
• Delivery of the placenta.
• May last 5-20 minutes
• Successful labour is dependent on:
• Maturation of foetal organs
• The lungs must be adequately developed to allow the baby to takes its first breath
• The thermoregulatory systems must be adequate to cope for the shock of the warm uterus to the cold
operating theater (or wherever).
• The baby's GIT must be developed in order to cope with breast milk.
• Ability of the cervix and uterus to remodel.
• Changes in the extracellular matrix of the uterus allows for sufficient dilation to fit the baby's head
through. Prostaglandins may help in facilitating cervical dilation.
• Development of the appropriate uterine contractions
• An increase in oxytocin receptors on the uterus (brought about by oestrogen) allows enhanced
sensitivity for oxytocin to facilitate uterine contractions.
• Oestrogen also induces the formation of gap junctions between smooth muscle cells, enabling
synchronous contractions of the uterus.
Endocrine mediators of parturition

• A number of theory have been put forth to explain what causes the body to suddenly expel the baby:
• The ratio of progesterone:estrogen
• During the early stages of pregnancy, the progesterone levels are greater than oestrogen, hence
progesterone is able to prevent uterine contractions. At parturition, the oestrogen levels rise above
those of progesterone and hence uterine contractions are possible. These events occur in the sheep, it
is not known for certain if they occur in humans.
• Oxytocin
• The increase in oxytocin receptors play a role in the maintenance of labour, i.e. maintaining uterine
contractions, but does not initiate it.
• Prostaglandins
• May be involved in the initiation of labour. Human labour is associated with an increase in
phospholipid metabolism (which provide precursors to prostaglandins)
• The experimental evidence of this is that when prostaglandins are injected, it can cause abortion or
premature delivery.
• Foetal cortisol
• This is important in foetal maturation, especially of the lungs.
• Its levels may act on the uterus to initiate contractions
• Positive reinforcement
• Initial labour contractions and stretching causes positive feedback to increase the force of stretching
and contractions, getting more frequent and powerful. This may be due to the stimulation to produce
more oxytocin.
• Cytokines
• A bacterial infection in the uterus produces cytokines which may force a premature labour.
• In summary, the most likely contributors to the initiation of parturition is the ratio of oestrogen to progesterone, in
addition to the presence of prostaglandins.
• Why do we want to know all this? To answer another baffling question: Why do we get premature births?
Complications of pregnancy
• There are 3 major types:
• Intrauterine growth restriction (IUGR)
• Can lead to cardiovascular disease, diabetes in the adult
• The foetus is small compared to a normal one at that age
• Predisposes the foetus to adult diseases (e.g. hypertension)
• Etiology:
• Unknown
• Maternal smoking
• Foetal infection
• Pre-ecclampsia
• Exercise
• Blood is redistributed from the placenta to the heart, lungs and muscles of the
exercising mother
• Oxygen deprivation of the mother (due to high altitudes) leads to oxygen deprivation of the
foetus
• Pre-term labour
• Premature baby has lots of problems to cope with, the main problem is in the lungs since surfactant is
produced late in foetal life.
• Etiology
• Role of infection
• We must remember that the growing foetus has a unique genetic makeup and it is
amazing that the mother’s immune system does not attack it since technically, it is a
foreign particle.
• Premature rupture of foetal membranes
• Pre-ecclampsia
• Pregnancy specific disorder and only in humans
• Major signs are:
• Hypertension
• Results in weak blood vessels, especially in the brain which can burst, leading to
stroke
• The heart has to pump harder to push blood against a higher pressure system,
therefore heart failure can result
• Proteinuria
• Loss of plasma proteins in the urine since the glomerula capillaries are too leaky.
• As a result, the oncotic pressure of plasma is reduced and fluid will thus tend to
move out of the circulation and into the interstitium
• Generalised oedema
• Intravascular depletion, extravascular accumulation
• A result of a low plasma oncotic pressure and leaky endothelium
• Etiology:
• Unknown
• May be due to improper implantation of the trophoblast, so that the spiral arteries which
provide the blood to the placenta maintain their responsiveness to vasoconstrictor/vasodilator
influences in the maternal circulation. Normally they remain patent no matter what.
• As a result, inadequate blood flow to the placenta leading to hypoxia and lack of nutrients to
the foetus - smaller size foetus.
• The placenta releases metabolic toxins due to a low blood flow.
• These metabolic toxins may be responsible for the circulatory defects.
• The only sure treatment for pre-ecclampsia is deliver of the baby
PERINATAL PHYSIOLOGY
• Antenatal = Prenatal = before birth

• Perinatal = the period just before and after birth
• Neonatal = period after birth
Stages of pregnancy
• There are 3 stages of pregnancy
• Early pregnancy
• 1st 2 weeks after conception
• The foetus at this time is not susceptible to teratogens (chemicals inducing malformations)
• The foetus is susceptible to chromosomal abnormalities
• Some environmental disturbances can interfere with implantation
• Embryonic period
• Weeks 3 -8
• This is the time where the foetus is most susceptible to teratogens
• By 1 month, all organ systems are present in the foetus, although they are not fully mature yet
• Foetal period
• Weeks 9+
• Exponential growth phase
• Disturbances at this time lead to
• Physiological defects
• Minor morphological abnormalities
• Note: if you get a disease while the foetal organ systems are still developing, the effect would be an
organ malformation. If the organs are already developed, a disturbance will leads to physiological
(functional) defects
Factors affecting foetal growth

• Genetic factors
• Number of pregnancies
• Maternal nutritional status
• Oxygenation (effects of altitude)
• Placental function to provide nutrients to the foetus
• Smoking
• Alcohol
• Drugs
• Infectious agents
• Environmental chemicals/radiation
Amniotic fluid
• The normal volume of amniotic fluid is between 500 - 1000 ml
• Amniotic fluid is important for:
• Normal foetal growth (maintains buoyancy to lower the effective weight of the foetus in utero)
• Normal foetal lung development
• Shock absorber
• Allows for foetal movements to take place
• Determinants of amniotic fluid volume:
• Foetal urine
• Lung liquid
• Nasopharyngeal and buccal secretions
• Fluxes across skin and umbilical cord
• It is important to note that the fluid is dynamic: it is continuously being absorbed and secreted
• Removal of fluid
• Foetal swallows the fluid to keep the gut patent
• Foetus breathes the fluid in to keep the lungs patent
• Intramembranous and transmembranous reabsorption
• Intramembranous means the fluid is reabsorbed back into the foetal circulation
• Transmembranous means the fluid is reabsorbed back into the maternal circulation
Foetal kidney’s
• Produces some of the amniotic fluid
• Produces growth factors
• Important for foetal development, especially lung maturation
• Regulates foetal blood pressure
• Fluid and electrolyte homeostasis
• Acid base balance
Foetal swallowing
• Foetal swallowing is episodic and the foetus has no control over it
• The swallowed fluids are
• Amniotic fluid
• Lung fluid
• Oronasal fluid
• If the foetus is in stress, it will defecate a substance call meconium
• Birth is a stressful time for both mother and foetus.
• That is why some foetuses are born stained yellow, due to the meconium in the amniotic fluid. Nothing is
wrong though
• During birth, all foetal swallowing ceases to prevent meconium from being ingested
• If the foetus doesn’t swallow, you will get immature gut development
• An important side point: the foetal and neonatal gut is sterile and so there are no bacteria living there. In the
adult, the gut bacteria are important for many things, one of which is to produce vitamin K. The foetus thus
must rely on the vitamin K stored in its liver via maternal vitamin K. If the mother has a vitamin K deficiency,
so will the foetus. Hemorrhage in the foetus will thus be life threatening because the foetus does not have many
clotting factors.
Oligohydramnios
• Decreased amniotic fluid due to
• Renal dysfunction
• Placental dysfunction
• Increased loss of fluid
• Consequences are that the foetus does no get the necessary exercise to develop its muscles in utero. The foetus may also
be squashed, leading to deformity.
Polyhydramnios
• Increased amniotic fluid due to:
• Increased production
• Decreased loss
• May lead to rupture of the foetal membranes and a premature birth
Foetal respiratory system

• The foetal lungs is not an organ of exchange in utero and so it is functionally useless (except to contribute to amniotic
fluid)
• The foetal lung liquid is produced by the pulmonary epithelium and is important in keeping the lungs patent to maintain
their volume.
• In utero, the respiratory muscles contract to practice breathing movements. This is important for:
• Developing the respiratory muscles
• Developing the respiratory center in the brainstem
• If the foetus does not practice breathing in utero, immature development of the respiratory muscles and
respiratory center may be a cause of SIDS.
• During labour, the lung liquid is reabsorbed by the pulmonary epithelium and some is also squashed out of the lungs
during the pressures in the birth canal.
• The production of surfactant occurs late in foetal development and so premature births have a risk of causing foetal
asphyxiation because the alveoli collapse and can’t be kept open - respiratory distress syndrome (RDS)
• When born, the hypoxia and hypercapnia of the foetus triggers its breathing center in the brain and so the foetus begins
to take its first breath.
• It is important that if the mother is sedated, the foetus will be also, and so it may not be able to breathe due to
respiratory muscular depression and CNS depression
Cardiovascular system
• There are 4 unique shunts in the foetal circulation which close shortly after birth:
• Umbilical circulation
• Provides oxygenated blood from the mother to foetus via umbilical vein
• Removes deoxygenated blood and wastes form the foetus and takes them to the mother via the paired
umbilical arteries
• Foramen ovale
• An opening between the right and left atria.
• Blood entering the right atrium will enter the right ventricle when the right atrium contracts. However,
the foramen ovale also allows blood to pass directly to the left atrium.
• In adults, the right atrium pumps blood into the pulmonary arteries to be oxygenated by the lungs.
However, in the foetus, the lungs are non functional. Why then do we get blood being pumped into the
right ventricle - isn’t that a waste? The answer is that the right ventricle needs blood in it to contract,
even though there is no functional benefit in utero. If the ventricle does not contract, its development
is impaired and so when born, the right ventricle will be weak due to lack of exercise in utero.
• Ductus arteriosis
• Blood in the right ventricle gets pumped into the pulmonary trunk.
• The blood in the pulmonary trunk is unable to enter the lungs and so the ductus arteriosis allows the
blood to bypass the lungs and enter directly into the aorta.
• Ductus venosus
• Since the foetal gut is non functioning, the liver does not need to process any gut nutrients or wastes
from the foetus.
• The ductus venosus allows nutrients from the umbilical vein (maternal blood) to bypass the liver and
enter directly into the foetal IVC.
RENAL FAILURE I: CHRONIC
Kidney function
• The kidney has 3 major roles:
• Excretory function
• Synthetic function
• Endocrine function
• The synthetic and endocrine functions of the kidney are generally concerned with metabolic functions.
• To understand kidney failure, we must have a sound knowledge of normal kidney function.
Synthetic and hormonal function

• Gluconeogenic:
• The kidney is one of only 2 organs in the body capable of complete gluconeogenesis, the other being the liver.
This is because both these organs have the enzyme glucose-6-phosphatase which is capable of hydrolysing
glucose-6-P to glucose. (Muscle, is capable of incomplete gluconeogenesis. It lacks this enzyme and hence it
stops at glucose-6-P. This can then be used by the muscle via glycolysis. The liver produces glucose for use by
the body, not for itself).
• Renin:
• The kidney produces renin, which has a role in blood pressure regulation and water retention.
• Renin initiates the renin-angiotensin-aldosterone cascade. It is produced when there is decreased perfusion
pressure to the kidneys (indicative of a low BP) which initially result in a decreased GFR. (Remember
GFR=125ml/min) As a result, there is a decreased amount of Na+ reaching the macula densa and triggers the
secretion of renin from the myoepithelial cells of the JGA.
• Renin catalyzes the conversion of angiotensinogen to angiotensin I (AI). AI is converted to AII by angiotensin
converting enzyme (ACE).
• AII has widespread effects. It causes constriction of the efferent arteriole (and possibly generalised
vasoconstriction). This leads to increased back pressure and a decreased RBF, resulting in an increased GFR
(due to an increased filtration fraction). Hence, the kidney has compensated for the decreased GFR.
• AII also stimulates the zona glomerulosa of the adrenal cortex to produce aldosterone. Aldosterone causes
increased salt retention (and hence water retention) in the distal nephron and increased K secretion. Hence
leading to an increased plasma volume, compensating for the suspected low BP.
• Erythropoetin
• Erythropoetin is produced by the kidney when it detects a low oxygen saturation in the blood. Erythropoetin
regulates bone marrow function and increases the rate of RBC formation.
• Vitamin D
• Vitamin D is converted to its most potent form by the kidney. Vit D produced by the skin due to exposure with
UV is hydroxylated in the 25 position by the liver. This then is hydroxylated in the 1 position by the kidney
(stimulated by PTH) to produce 1,25dihydroxyVitD (1,25DHVitD). This active form is considered to be a
steroid hormone.
• Active VitD main action is to increase Ca reabsorption in the gut. It also causes bone resorption and
increased phosphate excretion by reducing phosphate reabsorption.
• All these effects are synergistic with those of PTH to try and increase plasma calcium. PTH is released
when the level of ionised Ca is reduced in plasma.
• In the kidney, 60% of Ca is reabsorbed passively in the proximal tubule. The rest is reabsorbed in the
distal nephron. It is here where the actions of PTH and VitD act.
• It is understandable that when Ca is reabsorbed, phosphate is excreted. It both Ca and phosphate were
to be reabsorbed, then they will react in the plasma to form CaPO4. Since it is the free, ionised form of
Ca which is detected, the body will still think that there is a Ca deficiency and hence increase PTH,
leading to increased bone resorption - bone disease.
• Why is Ca homeostasis important? Apart from being a major constituent of bone, it is also important
in blood clotting and muscular contraction. It is also important in excitable tissues. Ca can bind to
membrane ion channels and inhibit the transport of key electrolytes like Na+ and K+. Hypercalcemia
results in depressed neuromuscular activity whilst hypocalcemia results in increased excitability of
nerve and muscle.
• Medullary hypotensive factor
• This hormone, produced by the medulla, may have a role in reducing blood pressure (opposite to renin).
Excretory function
• Aldosterone, ADH and ANP affect the reabsorption of Na+ and water.
• Aldosterone increases collecting duct sodium reabsorption and K+ secretion.
• ADH causes the collecting duct to become permeable to water by inducing the formation of aquaporins.
• ANP is produced by the heart atria and has a role in preventing sodium reabsorption. It is released in states of
hypernatremia.
• The kidney has a tight regulation on K+ since its plasma levels are an indication of acid base balance. An acidosis will
result in K+ retention because in the distal tubule, Na+ is reabsorbed in exchange for K+ or H+, depending on which is in
excess. In acidosis, H+ is in excess, so H+ is exchanged instead of K+. Hyperkalemia, can result in nerve and muscle
excitability because the resting membrane potential is dependent on intracellular K+ to be 140 mmol and extracellular to
be 4 mmol. If there is excess K+ extracellulary, the resting membrane potential would be increased closer towards
threshold, making the cell more excitable.
• H+ is mostly produced as a product from animal protein metabolism. Removal of excess H+ by the kidneys is important
to prevent an acidosis.
• Ca2+ and PO4.
• Ionised Ca2+ is filtered at the glomerulus and 60% is reabsorbed in the proximal tubules in co-transport with
Na+. Hence an increased Na+ load will result in more Ca2+ reabsorbed along with it. In the distal nephron,
reabsorption of Ca2+ is facilitated by PTH and Vit D (see previous section).
• PO4 is freely filterable at the glomerulus and most of it is reabsorbed in the proximal tubule only. Hence the
level of PO4 excretion is dependent on GFR. A decreased GFR leads to decreased PO4 excretion (hence PO4
retention). The PO4 retention can react will Ca and lead to a decrease in free ionised Ca2+, prompting a
condition of hypocalcemia.
• Urea
• A breakdown product of proteins, urea itself is not toxic. It acts as an indicator. An increased urea will indicate
and increase in other breakdown products of protein in the plasma. It is these other products which exert the
toxic effects.
Consequences of Chronic renal failure

• Chronic renal failure is mostly untreatable and is due to as yet unknown toxins in the body.
• Symptoms of chronic renal failure as not evident until much later, when the disease has progressed extensively.
• Excretory functions are affected:
• There may be excessive salt and water excretion due to the reabsorptive functions of the kidney being impaired.
This leads to polyuria and dehydration.
• If instead, the GFR is so low as to retain water and electrolytes, oedema would result and increase in plasma
volume leading to hypertension, ultimately leading to cardiac failure.
• Nitrogenous wastes:
• There is a rise in plasma creatine and urea but these don't cause the toxicity - unknown toxins do.
• Potassium:
• Hyperkalemia leading to enhanced excitability of nerve and muscle cells. Especially toxic to the heart where it
would lead to cardiac arrhythmia.
• Hydrogen:
• An acidosis would ensue, and hence and increased need for air to blow off excess CO2 (i.e. hyperventilation)
• Ca and PO4 & Vitamin D:
• Reduced production of active VitD prevents Ca from being absorbed from the gut and Ca retention in the
kidneys. Hence there will be a decreased plasma Ca and hence a resultant hyper parathyroidism. This causes
bone disease since they are being broken down.
• Decrease Ca also stuffs ups the clotting mechanism, hence bleeding must be controlled.
• Drugs:
• Normally, the kidney is able to detoxify and excrete drugs. Kidney failure prevents this occurring and hence
you get a buildup of potentially toxic drugs.
• Erythropoetin:
• Kidney is unable to produce this and hence you get anaemia with a resultant lack of energy. Therefore you fell
lethargic.
• Renin:
• If the kidney is not producing this, there will be a failure to reabsorb fluids, leading to decreased blood volume
and hypotension.
Management of chronic renal failure

• The first thing to try and do is find out the cause and treat it. This is often not possible, hence we must manage the
symptoms.
• Must maintain salt and water balance and keep hydrated.
• Diet: eat less protein rich foods to reduce the nitrogen load
• Control hyper or hypotension
• Prevent and detect infections of the urinary tract. This is particularly important in the female because their urethra is not
long.
• Detect and treat electrolyte imbalances
• Treat other complications such as:
• Bone disease
• Anaemia
• Bleeding
• Possible treatment: dialysis or kidney transplant.
RENAL FAILURE II: ACUTE
• Problems when the kidney fail are:

• Na+ and water hypertension
• Hyperkalemia
• Acidosis
• What is the differences between chronic and acute renal failure?
• Chronic:
• The whole body is involved to try and compensate.
• The disease is usually unrecoverable
• Acute:
• The compensatory mechanisms occur intra-renal, and hence the rest of the body is spared.
• Patients often recover.
• Causes of acute renal failure

• Pre-renal failure (circulatory)
• This is often due to prolonged hypovolemia.
• In an attempt to autoregulate (via TGF, myogenic response), the kidneys produce renin in response to
the decreased GFR. Renin causes the production of AII which constricts the efferent arteriole, causing
GFR to increase. Also dilation of the afferent arteriole due to myogenic response or maybe to NO.
• If, however, hypotension still results, any excessive AII would cause constriction of the afferent
arteriole as well as efferent, and this reduces overall blood flow to the kidney. Prostaglandins
produced by the kidney can dilate the arterioles a bit to maintain some blood flow but eventually, the
low blood flow will cause necrosis.
• Renal failure (intra-renal)
• The most common condition is acute tubular necrosis. Other causes can be due to toxic agents.
• Acute tubular necrosis:
• As the tubular cells are deprived of oxygen, they start to get big holes in them. Often this will
lead to blood in the urine and extensive K in the urine. Remember K is usually reabsorbed
and only a small amount is normally secreted. The K lives inside the tubular cells, and if you
get rupture of the cells, the K will leak out and into the urine.
• Since the tubular cells are damaged, they are unable to perform their role as modifiers, hence
urine composition tends towards being the same as plasma.
• There is decreased urine output since the great big holes in the tubular cells cause persistent
leakage of water.
• The tubular cells are able to recover if the underlying condition is treated (i.e. decreased
blood flow to the kidneys). It takes approx. 2 weeks for the tissues to regenerate.
• Another cause of tubular cell damage apart from necrosis is poisoning by toxins. An example is if you
get muscle damage. This releases large amounts of myoglobin . The kidney filters myoglobin but little
does the kidney know- the myoglobin eats away at the tubular cells, causing renal failure.
• Post renal failure (obstructive)
• This is due to blockage of the urinary tract. The blockage needs to be bilateral because the body can
function quite happily with only one kidney functioning normally.
• The easiest way, if you don't want to obstruct 2 kidneys is to kill two birds with a single stone. i.e.
obstruct the urethra. This is often due to prostatic cancer in the male or cervical cancer in the female.
• Often, there is anuria (no urine). In other conditions, such as in acute nephrotic syndrome, there may
be oliguria (little urine).
NEPHROTIC SYNDROME
Review of the filtration barrier

• The glomerular capillaries differ from capillaries elsewhere in many ways:
• The glomerular capillary has many large fenesrations, making it much more permeable than a normal capillary.
• The glomerular capillary is within the arterial system, and hence is subject to high perfusion pressures. In
contrast, normal capillaries lie between an arteriole and venule, and hence are subject to a large pressure drop.
• The differences in perfusion pressures mean that fluid movement in the glomerulus is often largely by bulk
flow, whereas there is very little fluid movement out of a normal capillary (any fluid movement is due to
oncotic pressures).
• Since there is lots of fluid lost from a glomerular capillary, there is a large increase in oncotic pressure as we
move along the capillary. In a normal capillary there is no change in oncotic pressures.
• If we analyse the forces responsible for filtration at the glomerulus, the oncotic pressure plays a very large role. At the
start of the glomerular capillary, oncotic pressure is small. At the end, since there has been lots of fluid filtered out, the
oncotic pressure rises and hence net filtration stops.
• What makes up the filtration barrier?
• There are classically 3 visible layers but a 4th one can be considered.
• The fenestrated endothelial cells
• The large fenestrations act as a sieve to stop large molecules (usually proteins) from passing
through. A molecular weight <2000 is freely filterable, >60,000 has a very difficult time
getting through.
• The basement membrane
• This is layer has many negative charges related to it, hence any molecules which have a
negative charge will tend to be repelled, despite their size
• Visceral epithelium (podocytes)
• These podocytes are capable of squeezing the capillary, forcing more fluids out (maybe).
• The 4th layer is considered to be a layer of unfilterable proteins which have been blocked by the fenestrations
and aggregate on the luminal surface of the endothelium.
Normal filtration
• Normally, the filtration of serum albumin is 0.01. Say the concentration of albumin in plasma is 40g/l. That means 0.4g/l
of albumin is filtered. If 144L of fluid is filtered per day, then the amount of albumin filtered per day is (144 x 0.4)=60g
per day. Obviously, none of this is excreted otherwise we won't have much albumin left in our circulation.
• The proximal tubule cells actively reabsorb the albumin once they get caught in the brush border of the PCT. The cells
then endocytose the albumin and break them down, releasing the amino acids into the circulation.
• If the net loss of albumin exceeds the synthetic capacity of the liver, then there will be less in the plasma.
Abnormal filtration: nephrotic syndrome

• Nephrotic syndrome is characterised by proteinuria and generalized oedema.
• If the plasma albumin is low, the liver will try and produce more. If the loss is too great the liver won't be able to produce
enough in time and hence there will be low plasma albumin. Since albumin is the most important circulating protein
holding fluid in the circulation, fluid will tend to leak out of the circulation and into the interstitium, producing oedema.
• Since the fluid has come from the circulation, there is a decreased plasma volume and hence hypotension will
develop. This leads to a decrease in BP and hence compensatory mechanisms arise. Renin is secreted and
causes increased salt and water retention to try and correct the low plasma volume. Hence there would be a low
plasma volume This may work, but what will happen? The newly acquired fluid in the plasma will just leak out
into the interstitium along with the rest of the fluid, hence the compensatory mechanisms will just make things
worse. (Note that oedema due to fluid shift from the circulation results in decreased BP. If it is due to excess
salt and water retention, this would lead to hypervolemia and the excess fluid would tend to distribute itself
evenly between the interstitium and plasma.)
• 2L of fluid retention is necessary before oedema starts to become visible.
• The location of oedema can tell us what may be wrong:
• Swelling in the ankles indicate cardiac failure since there is a build up of venous blood which tends to collect at
the feet and cause oedema there. (due to increased CVP).
• Generalised swelling indicates nephrotic syndrome because albumin circulates everywhere and hence fluid loss
from the circulation can occur anywhere.
• Swelling in the abdominal cavity indicates a liver disease due to increase in portal venous pressure.
Symptoms (other than oedema)

• Since the liver must start to produce more albumin, its synthetic role increases. Albumin is not the only protein produced.
Globulins and lipoproteins also start to be produced in excess. The increased lipoproteins results in increased plasma
cholesterol levels.
• If the protein in the urine is albumin, then we have what is known as selective proteinuria.
• If there is severe damage to the filtration barrier (e.g. widening of the fenestrations, loss of BM charge), the all proteins
will be able to pass into the urine. Hence the urine protein concentration will be the same as that of plasma.
MALABSORPTION
Types of malabsorption syndrome

• Failure of digestion:
• A generalised failure to digest nutrients, mainly due to lack of pancreatic enzymes.
• Specific defect in digestion:
• An example would be a lack of a specific digestive enzyme such as lactase. This leads to a deficiency of
lactose digestion.
• Generalised absorptive defect:
• Problems with the intestinal mucosa.
• Specific absorptive defect:
• e.g. Lack of a specific amino acid transporter in the gut.
• Decreased transit time:
• The normal transit time is 4hrs. Any less means too fast a transit time leading to inefficient absorption.
• Decreased surface area:
• A decrease in surface area will hinder greatly the absorptive capabilities of the gut. It can be due to surgical
removal of part of the small intestine or damage to microvilli (coeliac disease).
• Bacterial overgrowth:
• Normally, the small intestine is protected from bacteria is the colon by:
• Ileocaecal valve
• High acidity from the stomach
• Forward flow of gut contents
Various defects due to:

• Digestion: due to enzyme defects
• Delivery: insufficient or lack of bile acids
• Membrane: lack of carrier proteins facilitating absorption
• Mucosal cells: damage leads to a decrease in surface area for absorption
• Blood supply: blockage leads to mucosal cell atrophy and inability of nutrients to travel from gut to liver.
• Lymphatic supply: blockage leads to defect in fat absorption via the lacteals
Enzyme defects
• Salivary amylase is not essential for the initial breakdown of carbohydrates in the mouth.
• Gastric enzymes:
• The main one is pepsin
• Pepsin only works in the stomach because it requires an acidic environment (pH < 5) for its
activation from its inactive precursor (pepsinogen).
• There are no major digestive problems if this enzyme is not present. However, the protein breakdown
products produced by the actions of this enzyme play an important role in activating CCK release in
the duodenum.
• Pancreatic enzymes:
• The pancreas is the most important organ of digestion. It produces most of the digestive enzymes.
• Proteases:
• The main ones are trypsin and chymotrypsin.
• These are activated in the GIT via enterokinase. If they were to be activated in the pancreas,
autodigestion would occur.
• Trypsinogen, once cleaved to trypsin, can act itself as a cleavage enzyme.
• Like pepsin, there is enough membrane proteases in the gut to facilitate protein digestion should there
be a lack of these proteases.
• Amylases:
• Breaks down the alpha 1-4 glycosidic links in long chain polysaccharides.
• Limit dextrinases:
• Breaks down the alpha 1-6 gycosidic links.
• Dissaccharidases:
• Breaks down disaccharides into their constituent monosaccharides.
• Once again, the above 3 enzymes are not essential for digestion, since the membrane bound enzymes in the
GIT are sufficient to handle CHO digestion in the absence of these enzymes.
• Lipases:
• Unlike the other enzymes, a deficiency in this enzyme is detrimental, since there are no other
intestinal lipases to act as backup. Hence, pancreatic damage will usually manifest itself as a fat
digestion problem, even though all enzyme types are affected.
• Bile Acids:
• These are important in the digestion of fats but not essential.
• Bile acids act to emulsify the fats by allowing the fat to be broken up into smaller particles (micelles), thus
keeping them in solution so the pancreatic enzymes can act on them. However, they are not necessary because
once the fats have been broken up by a small extent into MAG and fatty acids by lipase, the free fatty acids are
able to act as emulsifying agents in place of bile acids.
• Bile acids are essential however for the absorption of fat soluble vitamins in the terminal ileum.
Lipase deficiency
• Leads to steatorrhoea (fatty faeces).
• Wasting due to poor calorie intake.
• Fat soluble vitamin deficiency:
• Vitamin D: low Ca
• Vitamin K: poor blood coagulation
• Vitamin A: night blindness
• Tests done for absorption give a normal result however. This is because these tests are usually done by giving glucose,
amino acid or fatty acid doses. Digestion is not required because there is no need to digest these substances any further.
Absorption is also fine because there is nothing wrong with the absorptive mechanism. The problem lies in the
digestion of fats to fatty acids.
Generalised intestinal defect

• This is often a result of Coeliac disease.
• Coeliac disease is an allergic response to gluten protein found in wheat. This causes autodigestion of the villi
of the gut, resulting in less surface area for absorption.
• You get malabsorption of all substances.
• Fats:
• We notice malabsorption of fats first because they are the most difficult to digest and absorb.
• Amino acids
• Deficiency in amino acids (especially essential ones) leads to a severe restriction on protein
production by the body. Muscle starts to be degraded to provide amino acids required for the
synthesis of more important structures.
• Glucose
• Defect in glucose leads to similar symptoms of diabetes.
• Iron
• Iron deficiency anaemia results
• Calcium
• There is normal production of vitamin D (which stimulates the increased absorption of Ca from the
gut) but since the intestinal mucosal cells are damages, no Ca is able to be absorbed.
• People may present with different symptoms, depending on the time course of the disease - e.g. iron deficiency, bone
disease, steatorrhoea, but the underlying problem may be identical for all symptoms.
Specific enzyme defect

• We take the example of lactase deficiency, illustrating the common condition of lactose intolerance.
• Lactose intolerance is not a major problem for adults because we can get our nutrients elsewhere. The only problem
would be diarrhoea and excess flatus.
• In infants, it poses a serious problem because milk (containing lactose) is their main nutrient source. The gut is unable
to break lactose down into glucose and galactose and hence the lactose stays in the gut. This causes an osmotic effect,
pulling water, Na+ and K+ into the gut and causing diarrhoea. The infant will thus be unable to grow properly.
• Excess flatus is due to the bacteria in the colon having a feast on the undigested lactose entering the colon.
Lack of surface area

• This can be due to damage caused by disease eating away at the villi.
• Severe starvation can also cause reduction in surface area because the body destroys the villi in order to provide amino
acids for synthesis of more important proteins.
• Bowel resection can cause a reduction but we can still survive with only 1-2 m of bowel left.
• A fistula
• A fistula is when you bypass the small intestine. e.g. a gastro-ileal or gastro-colic fistula. In this case, you
won't get proper mixing of the enzymes with the food at the appropriate time, and hence not a normal
digestive process.
• You also won't get neutralisation of the acidic chyme leaving the stomach, and hence most digestive enzymes
won't work (since they work in alkaline conditions).
Specific absorptive defects

• Iron:
• Iron levels in the body are unregulated by homeostatic means. Hence, excess iron in the body is just deposited
in tissues. The only regulation is in its absorption from the gut.
• Normally 10% of iron in the diet is absorbed to replace that lost by bleeding (mainly). If there is an iron
deficiency, the body will increase its iron absorption from the gut.
• Excess iron cause haemachromatosis - excess iron deposited in organs. Excess iron in the adrenal glands and
liver cause damage. Excess iron in the pancreas causes damage to the islet cells, leading to diabetes.
• Vitamin B12:
• Vitamin B12 is important in the DNA synthesis (hence cell division) of RBC.
• Vitamin B12 is principally an animal product, hence strict vegans have a danger of being deficient.
• Intrinsic factor (produced in conjunction with acid by the oxyntic cells) is essential for the absorption of B12
in the terminal ileum.
• Since intrinsic factor is produced in conjunction with acid, a test indicating a low acidity in the
stomach would most likely mean low intrinsic factor release.
• Since B12 is absorbed in the terminal ileum, loss of the terminal ileum (due to disease, surgery, fistula) will
cause impairment of B12 absorption, among other numerous things.
• Overpopulation of bacteria in the small intestine will lead to a B12 deficiency because the bacteria digest the
B12.
• The liver has a 1 year store of B12, so any deficiency will not manifest itself for a while.
• Amino acids:
• This is due to a defect in the co-transporter with Na+.
• If the defect is in one of the transporters for essential amino acids, then the body will be unable to synthesise
important proteins normally.
Clinical presentation: symptoms & signs

• Malnutrition, weight loss, lethargy:
• Due to failure of nutrient absorption.
• Insufficient calorie intake.
• Lack of proteins and amino acids for synthesis of bodily proteins, e.g. in muscle, leading to muscle wasting -
weakness.
• Anaemia results in fatigue and lethargy.
• Stools:
• Diarrhoea due to excess fluid in the bowel as a result of undigested osmotically active particles.
• Steatorrhoea is fatty faeces due to failure to absorb lipids.
• Steatorrhoea can also indicate a low Ca reabsorption because the unabsorbed fatty acids react with Ca to form
an insoluble precipitate in the gut, thus preventing Ca to be absorbed.
• Presence of undigested food.
• Flatus:
• Bacterial overgrowth and bacteria having a feast from the undigested food reaching them. The products of
bacterial digestion give rise to human flatus.
• Anaemia:
• Vitamin B12 deficiency - macrocytic RBC
• Iron deficiency - microcytic, hypochromic
• Lack of proteins in the diet necessary for globin synthesis
• Folate deficiency.
• Purpura:
• Spots under the skin due to weak capillaries. This is a result of protein lack.
• Bleeding disorder:
• Lack of Vitamin K for production of clotting factors.
• Lack of Ca which is an important co-factor in the clotting mechanism.
• Bone disease:
• Low Ca reabsorption.
• Decreased intestinal absorption

• Decreased vitamin D
• Due to liver/kidney failure which are responsible for the hydroxylation of Vit D to its active
form.
• Lack of vitamin D receptors.
• Decreased absorption in the terminal ileum due to removal of the terminal ileum of lack of
bile acids.
• As a result of low plasma Ca, the body secretes more PTH which attempts to increase Ca absorption from the
gut (which, however is defective). PTH also increases the reabsorption of Ca from the kidney tubules and the
resorption of bone - leading to bone disease if prolonged.
• Tetany:
• Low plasma Ca causes increased excitability of nerve and muscle cells because normally, Ca binds to
membrane ion channels and tones down their action. A low Ca will cause increased activity of these channels.
• Night blindness:
• Lack of vitamin A. Vitamin A is an important part of retinal, an essential photoreceptive pigment in the retina.
• Peripheral neuropathy:
• The inability to conduct nerve impulses properly due to lack of vitamin B12 and folate, which, apart from
being important growth factors for RBC, are also important for growth and development of nerves.
LIVER FAILURE I
Location of the liver

• The liver receives all blood coming from the GIT.
• Therefore all the absorptive products from the GIT entering the portal venous system must pass through the liver before
going to the systemic circulation.
• The liver modifies any substance it receives form the portal blood (e.g. drugs, toxins from bacteria).
• 1st class liver drug metabolism means that certain drugs are 100% broken down by the liver.
Liver circulation
• Portal blood enters the liver via the portal veins which then breaks up into sinusoids. The sinusoids are wedged in
between liver hepatocytes, with the space between sinusoid and hepatocyte known as the space of Disse.
• Sinusoids are very leaky capillaries, able to let all plasma constituents through (that includes the plasma proteins) to
bathe the hepatocytes. Only RBC cannot pass through the fenestrations of the sinusoids. Thus, the liver is in contact
with everything in the plasma and hence is able to modify substances in the plasma effectively.
• Sinusoids empty into the central vein which joins the hepatic vein. This then empties into the systemic circulation via
the IVC.
• Bile canaliculi join the form the left and right hepatic ducts which then join up to become the common bile duct. If the
opening of the common bile duct is closed (via the sphincter of Oddi), the bile gets re-routed to the cystic duct,
emptying into the gall bladder.
Metabolic functions of the liver

• Carbohydrate metabolism:
• The liver is the main site of glucose storage, delivery and gluconeogenesis.
• In liver disease, the blood glucose is very low because there is no storage of glycogen and the liver is unable to
synthesise glucose from proteins via gluconeogenesis.
• Protein metabolism:
• The liver is a major site of transamination
• The carbon skeletons from amino acids can be used to synthesise fats, carbohydrates or different amino acids.
• The liver is the only site of urea formation, which then heads off to the kidney to be excreted.
• Fats:
• Liver produces lipoproteins which transport fats and carbohydrate to other cells in the body.
• The liver metabolises cholesterol, forming bile acids.
Detoxification role
• Absorbed products reaching the liver via the portal blood can either be conjugated or metabolised by the liver.
• Drugs, toxins and waste products are usually conjugated to detoxify them, nutrients are metabolised.
• Conjugation means to make a lipid soluble substance water soluble. Lipid soluble substances are delivered to the liver
bound to plasma proteins (usually albumin). In the liver, these substances are conjugated and then released into the
circulation (now water soluble) to be excreted by the kidney.
• If a toxic lipid soluble substance is not conjugated before being released into the circulation, it will be able to pass
through the blood brain barrier and cause neurological impairment.
• Waste products, e.g. bilirubin is conjugated and then released into the bile to be excreted via faeces or urine.
Storage role
• This is not of major concern in liver disease.
• The liver stores:
• Glycogen
• Fats
• Vitamin B12
• Copper
• Iron (as ferritin)
Synthetic role of the liver

• This is very significant in liver disease.
• The liver produces almost all of the circulating plasma proteins:
• Albumin:
• Albumin is important in maintaining blood volume by exerting an osmotic pressure, thus keeping
fluid inside the blood vessels.
• Albumin is also a very important transport protein, transporting many substances (often steroid
hormones) in the plasma which would otherwise be insoluble. Certain drugs are also bound to
albumin. In this state, the drugs are inactive. There is a small amount of free (unbound) drug which is
the active form. In liver disease, where albumin concentration becomes low, more drugs are thus
unbound and hence active.
• Albumin has a fairly long half life and hence it will be a fair while before there is any decrease in
circulating plasma albumin in the event of liver failure.
• Apolipoproteins:
• These transport fats and cholesterol to the rest of the body. The apoproteins embedded in the
membrane of the lipoprotein acts as signaling devices.
• Transport proteins:
• The liver produces certain specific transport proteins such as transferrin which transports iron from
tissue to tissue.
• Blood coagulation factors:
• These have short half lives and hence are depleted rapidly from the circulation during liver failure.
• These are dependent on vitamin K for proper synthesis.
• Therefore, if we were deficient in vitamin K for some reason (e.g. failure to be reabsorbed in the
terminal ileum), then we would also have problems producing coagulation factors.
• The liver is one of 2 tissues (the other being the kidney) which is capable of complete gluconeogenesis.
• In acute liver disease, albumin levels will stay normal for 2-4 weeks because of the long half life for albumin. Blood
coagulation factors have a short half life and hence we will see a decrease in their levels only after 1-2 days.
Importance of vitamin K
• We need the following conditions in order to have a healthy level of vitamin K. A defect in one of these will lead to a
vitamin K deficiency:
1. Adequate vitamin K in the diet
2. Proper absorption of vitamin K in the terminal ileum dependent on,
3. Sufficient bile (bile acids) getting to the terminal ileum to aid in absorption.
Composition of bile
• Bile is composed of:
• Bile acids (salts)
• Bilirubin
• Electrolytes
• Cholesterol (bile is the major way the body gets rid of excess cholesterol)
• Lecithin
Formation of bile
• Bile acids are primarily secreted by cells in the bile cannaliculi.
• Electrolytes are also secreted along with them
• The bile enters the right and left hepatic ducts which join to form the common bile duct.
• If the sphincter of Oddi is closed, the bile enters the cystic duct and is stored in the gallbladder.
• In the gallbladder, water is reabsorbed, creating a supersaturated solution. Cholesterol (hydrophobic), is kept in solution
by being incorporated in micelles via bile acids.
• If the sphincter opens, the bile enters the common bile duct and into the duodenum (at the ampulla of Vater)
• Bile release is controlled by CCK, fat in the intestine, vagal stimulation. These factors either change the tone of the
sphincter of Oddi or stimulate gall bladder contraction.
Bile acids
• Bile acids emulsify fats and aid in their digestion by enabling large fat droplets to be broken down into smaller pieces
and put in solution. The lipase is them able to digest them more effectively (due to the increase in surface area).
• Bile acids, are not however, essential for the digestion of fats. Lipase can act on large fat droplets to a small extent,
liberating some free fatty acids. These free fatty acids are then able to act as emulsifiers in place of bile acids.
• Bile acids are essential for the absorption of fats, and more importantly fat soluble vitamins in the terminal ileum. The
bile acids allow the fat soluble vitamins to be held in micelles. In the terminal ileum, these micelles stick to the mucous
membrane. The mucous membrane of the terminal ileum is acidic and so is able to break up these micelles when they
stick. The fat soluble vitamins are then released right next to the mucous membrane to be absorbed.
• Bile acids are formed by the breakdown of cholesterol. Hence this is one of the main uses of cholesterol (the other one
being a structural component of plasma membranes).
Recirculation of bile acids

• Bile acids can be extracted from the blood or made from cholesterol.
• Bile acids can either be reabsorbed along with the fats in the terminal ileum (98%). Once reabsorbed, the bile acids go
back to the liver via the portal vein to be recycled.
• The remaining percentage enters the colon and is excreted in the faeces.
• If the terminal ileum is removed, the person has a low plasma cholesterol. This is because cholesterol is being broken
down by the liver to form new bile acids because old bile acids are not being recycled - they are not being reabsorbed;
instead they are excreted. Hence the body must continually break down cholesterol to replenish the lost bile acids.
Bilirubin
• Bilirubin is the breakdown product of heme and gives the urine and faeces their characteristic colour, or if it is present in
large amounts in the blood - jaundice.
• Heme is broken down in the hemopoietic system (bone marrow, spleen) and the product, bilirubin, is delivered to the
portal vein (via the splenic vein) to go to the liver. Bilirubin is lipid soluble, hence it is transported in the blood bound to
albumin.
• In the liver, the portal blood empties into the sinusoids. Since the fenestrations of the sinusoids are large enough for
albumin to pass, the albumin-bilirubin complex passes through and into the space of Disse. Bilirubin then diffuses
through the plasma membrane of the hepatocytes.
• In the hepatocytes, bilirubin is conjugated by binding with glucoronide, making it water soluble. Insoluble bilirubin is
toxic because it can pass through the blood brain barrier.
• Bilirubin is secreted into the bile cannaliculi and is a component of bile.
• in the bowel, bilirubin is metabolised by bacteria to stercobilinogen which is secreted in faeces and urobilinogen,
excreted in urine.
• The rate limiting step (the function that is destroyed first in liver damage) is the secretion of bilirubin. i.e. the conjugation
process is unaffected, but one conjugated, the bilirubin can't be secreted into the bile and hence the conjugated bilirubin
enters the systemic circulation, causing jaundice. This isn't very dangerous, because the conjugated bilirubin, since water
soluble, is able to be excreted by the kidney.
• Another way to get excess conjugated bilirubin in the blood is from excess breakdown of RBC (haemolytic anaemia).
Since there is an excess RBC breakdown, you would get excess bilirubin taken to the liver. If the rate of bilirubin
delivered to the liver exceeds the liver’s conjugating capacity, you will tend to get a buildup of unconjugated bilirubin
which may enter the circulation.
• Unconjugated bilirubin is a problem because, being lipid soluble, it is able to pass through the blood brain barrier.
• Premature infants lacks the enzyme for the conjugation of bilirubin and hence will get an increase in unconjugated
bilirubin in the blood.
• If you get massive necrosis of liver cells (i.e. no liver cells present) then you will be unable bilirubin. In general,
however, you will need very severe damage to cause this effect because the liver has an enormous capacity to conjugate
bilirubin. Normally it is the secretion that is compared rather than the conjugation.
How can things go wrong?

• Obstruction of the common bile duct (obstructive jaundice)
• Bile cannot enter the duodenum and hence a buildup occurs in the liver. Some would then enter the hepatic
veins and enter the systemic circulation. Jaundice is due to the bilirubin.
• Liver cell damage
• Chronic
• Acute
• Portal vein atresia/blockage
• Damage to liver cells often leads to fibrosis. This puts pressure on the portal vein and may shut it off
completely.
• The portal blood then enters the systemic circulation directly via the porto-systemic anastomoses.
• These anastomoses are very fragile and thin walled and can rupture if the pressure in the portal vein builds up
too much. Another problem is that toxic products do not go through the liver to be detoxified but instead enter
unchanged into the systemic circulation.
Obstruction to the common bile duct (obstructive jaundice)

• The synthetic capabilities of the liver is unaffected.
• No bile will be able to be secreted into the duodenum. As a result, there is a deficiency of bile acids and bilirubin present
in the bile: The effects of this are:
• Pale faeces will occur because the bilirubin is not making its way to the colon to be metabolised by colonic
bacteria into stercobilinogen. Hence the faeces will lose their characteristic hue.
• There won’t be the fill mechanism of fat digestion available.
• Fat soluble vitamins won’t be able to be reabsorbed in the terminal ileum since there are no fatty acids present.
• A deficiency in vitamin K leads to:
• Poor blood coagulation, manifesting itself after a couple of days due to the half life of the
pre-existing coagulation factors.
• A deficiency in vitamin D leads to:
• Reduced absorption of Ca from the gut, but other mechanisms can be activated to overcome
this (e.g. PTH)
• A deficiency in vitamin A leads to:
• Night blindness because vitamin A is an important part of the photoreceptive pigments in the
rods and cones.
• There is a large reserve however, so a lack of vitamin A won’t show until some time.
• A buildup of conjugated bilirubin leaks into the systemic circulation via the porto-systemic anastomoses. Conjugated
bilirubin in the blood causes jaundice.
• Urine will also be dark due to an excess of conjugated bilirubin in the blood having to be cleared by the nephron. Hence
excess bilirubin appears in the urine, giving it a dark colour.
• Bile salts will also accumulate in the blood, probably leading to the development of an itch.
Acute liver damage

• This occurs when there is complete failure of all liver cells.
• It is the problems with detoxification which is important.
• Toxic, lipid soluble products may make their way unconjugated into the circulation and through the blood brain
barrier.
• Note that any jaundice that does occur is still due to conjugated bilirubin because the liver has an enormous
capacity to conjugate bilirubin.
• Stools are not pale because bile acids are still being secreted along with the bile into the intestine. Hence lipid
digestion is normal.
• The only problems with the liver’s role as a synthetic organ is a deficiency of short lives proteins. Long lived
ones will still linger on in the plasma for a while until they begin to disappear.
Chronic liver failure

• The only major problem are those concerned with albumin production.
• In chronic liver failure, the liver is unable to produce new plasma proteins to replenish the now dwindling supplies in the
blood (which are nearing or have reached their half lives). Normal plasma albumin may be 40g/L and now it is only
20g/L.
• Low plasma albumin leads to Na+ and water retention by the body - much like nephrotic syndrome in which the problem
was a loss of albumin in the urine. In either case, plasma albumin has diminished.
• Since there is less oncotic pressure in the blood vessels, fluid leaks out into the interstitial spaces causing
oedema.
• With liver failure, the oedema is usually found in the abdomen and the presence of ascites. This is because
chronic liver failure causes the liver to fibrose and close off the portal vein. Obstruction o the portal vein causes
pressure buildup in the portal vein which forces fluid out of the portal veins and into the peritoneum (ascites)
• The loss in plasma volume causes increased aldosterone to be secreted (because the macula densa detects a low
plasma volume and Na+ concentration, releasing renin which initiates the steps for fluid retention.). Aldosterone
causes increased Na+ and water retention which stays in the circulation for a little while (allowing a transient
increase in plasma volume) before diffusing out into the interstitium again, adding to the oedema problem even
more.
• Aldosterone also causes K to be excreted out of the kidney tubules and so we will also get a
hypokalemia.
• The liver is also the place where aldosterone is destroyed. Since the liver is damaged, there is heaps of
aldosterone floating around to keep on causing massive fluid retention.
• Remember that the oedema formed in liver failure is not the same as that in nephrotic syndrome.
• In nephrotic syndrome, there is an increased hydrostatic pressure in the veins (of the legs especially) and so
you tend to get oedema in the legs
• In liver disease, there is internal fibrosis of the liver which leads to obstruction of the portal veins. This
increases the pressure in the portal system and so fluid will be pushed out of the portal veins and into the
peritoneum (acites)
• There is a viscous cycle which occurs when albumin is decreased:
↓ Albumin
⇓
↓ oncotic pressure in the capillaries
⇓
movement of fluid into the interstitial spaces
⇓
↓ Plasma volume
⇓
↓ Cardiac output
⇓
↓ Blood pressure
⇓
↑ Renin, Angiotensin II
⇓
↑ Aldosterone
⇓
Retain Na+, H2O
⇓
Transient increase in plasma volume
LIVER FAILURE 2
Differences between liver cell damage and biliary obstruction
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Substance Abnormality Symptoms Abnormality Symptoms
Bilirubin ↑ plasma & tissue Jaundice ↑↑ plasma & tissue Jaundice
bilirubin (conjugated) Dark urine bilirubin (conjugated) Dark urine
Albumin ↓ plasma albumin Ascites, oedema
Bile acids ↑ plasma & tissue bile Itch, malabsorption ↑↑ plasma & tissue bile Itch,
acids of fats & fat acids malabsorption of
soluble vitamins fats & fat soluble
vitamins
Cholesterol ↑ plasma cholesterol
Blood coagulants Abnormal coagulation Tendency to bleed. Abnormal coagulation Tendancy to
tests Non-responsive to tests bleed. Responsive
vitamin K† to vitamin K†
Glucose Hypoglycemia
↓ glycogen stores
No GNG
Gut toxins Impaired clearance of Confusion
nitrogenous compounds Coma
since the liver is unable
to produce urea. Other
toxins are unable to be
detoxified.
Hormones Impaired metabolism Feminisation in
males
Drugs Impaired metabolism Toxic drugs
circulate longer
†
Since the liver cells are damaged, they will be unable to produce clotting factors even if vitamin K was around. In
bilary obstruction on the other hand, vitamin K is lacking due to a lack of bile acids in the gut. If vitamin K is given, the
liver cells (healthy) are able to start making coagulation factors again.
• In liver cell damage, the first thing that goes is the secretion of conjugated bilirubin into the bile cannaliculus (the
secretion of bilirubin into the bile cannaliculus is the rate limiting step)
• The liver has an enormous capacity to conjugate bilirubin. It has to be severely damaged for the
conjugating capabilities to be lost. This is partly a protective mechanism because unconjugated bilirubin
which gets into the systemic circulation will be lipid soluble and pass through the blood brain barrier.
• The main way cholesterol is removed from the body is via bile acids
• Cholesterol is the precursor to bile acids
• Bile acids are released in the bile and some is reabsorbed back into the body at the terminal ileum. The rest
is lost in the faeces.
• Sometimes, to treat excess cholesterol, the terminal ileum is removed to prevent bile acids from being
reabsorbed. This means that the body must use up its cholesterol to replace the lost bile acids.
• Cholesterol is also a constituent of bile, and so biliary obstruction will tend to result in an increased plasma
cholesterol.
• Bile acids are absolutely essential for the absorption of fat soluble vitamins in the terminal ileum. Therefore a lack
of bile acids in the gut leads to malabsorption of fat soluble vitamins (A,D E,K). Bile acids are not essential for the
absorption of lipids however.
Chronic liver failure

• In chronic liver disease, one of the key elements is the changes to the vasculature in and around the liver.
• Cirrhosis of the liver leads to obstruction of the portal vein. Portal blood gets dammed up in the portal
circulation and looks for alternative routes to escape.
• an increase in portal pressure (portal hypertension) leads to
• Acites
• Enlarged spleen
• The porto-systemic anastomoses allow portal blood to bypass the liver and enter directly into the
circulation. This only occurs if the portal blood cannot get into the liver.
• The anastomoses are very small and are unable to handle large quantities of blood flowing
through. Dilation of the anastomoses results in varices, which are liable to burst.
• A consequence of bypassing the liver is that substances are getting into the portal vein without
being modified by the liver first. This is of particular significance for toxins which can enter the
systemic circulation without being detoxified.
Liver microcirculation
• In cirrhosis collagen is laid down in the space of Disse
• The space of Disse is situated between the hepatic sinusoids and the hepatocytes.
• As a result, there is impaired exchange from sinusoids to the hepatocytes.
• Therefore, in long term liver damage, the problem lies not much in the liver cells (since they can regenerate) but in
getting substances to the liver cells in the first place from the sinusoids.
• You have therefore, both external and internal shunting of blood from the liver
• External shunting is blood not being able to enter the liver via the portal vein because there is constriction
where the portal vein enters the liver. The blood thus bypasses the liver and enters the systemic circulation
via porto-systemic anastomoses
• Internal shunting is substances not being able to pass through the liver sinusoids and into the hepatocytes
because of collagen in the space of Disse
Distinguishing between liver cell damage and obstruction

• In practice, it is very hard to diagnose one or the other by just looking at the signs and symptoms. Special liver
function tests must be done.
• Liver function tests require the analysis of certain enzyme levels in the blood.
• Aspartate transaminase
• ALP (Alkaline phosphatase)
• This enzyme is greatly increased in the plasma due to bilary obstruction.
• The enzyme is located in the bile canaliculi and is induced by bile.
• The alkalinity of bile eats away at the membrane of the bile canaliculi and releases ALP
into the circulation. Normally, the levels of ALP in the circulation are minimal and so an
elevated level indicates some sort of bile canaliculi disorder (bilary obstruction).
Signs of liver damage

• Enlarged spleen
• Due to portal hypertension
• Caput medusae
• Varices in the umbilical veins (a porto-systemic anastomoses)
• In males: feminisation
• The liver metabolises estrogens and so liver failure may lead to feminisation.
• Small testes
• Breasts
• Decreased body hair
• The big 4
• Jaundice
• Presence of conjugated bilirubin in the blood
• Bruising
• Lack of absorption of vitamin K in the terminal ileum due to lack of bile acids
• Vitamin K is an essential part in the formation of blood clotting factors in the liver
• Ascites
• Increased portal pressure
• Reduced levels of plasma albumin leads to a reduction in plasma oncotic pressure. (only in
chronic failure)
• Encephalopathy
• Unconjugated bilirubin or toxins from the gut may get to the brain and cause coma.
• Nitrogenous wastes build up because the liver is where urine is formed.
PEPTIC ULCERATION
Mechanism of acid formation

• Acid is secreted mainly in the stomach by oxyntic cells.
• The stomach also secretes pepsin via the peptic cells and intrinsic factor.
• The oxyntic cells produce the acid in the following way:
• CO2 and H2O in the circulation enter the oxyntic cell and react to form H2CO3.
• H2CO3 dissociates into H+ and HCO3-
• HCO3- re-enters the circulation.
• H+ exits into the stomach lumen via a H+/K+ ATPase
Factors controlling gastric acid secretion

• There tend to be 3 stages in the control of acid secretion:
• Cephalic phase
• The sight, thought or smell of food stimulates the vagus nerves to release Ach and gastrin
• Gastric phase
• The presence of food in the stomach is able to activate the release of gastrin.
• Intestinal phase
• When the acidic gastric chyme enters the duodenum, secretin and somatostatin act to inhibit acid
secretion from the oxyntic cell.
Chemical regulation of acid secretion

• Gastrin
• Gastrin is produced by G cells found predominantly in the antrum of the stomach.
• Vagal stimulation produces gastrin releasing peptide which causes gastrin to be released.
• Gastrin acts on an intermediate cell (ECL cell) and can also act directly on the oxyntic cell.
• The ECL cell releases histamine (see below)
• The direct action of gastrin on oxyntic cells does not promote acid secretion to a large extent.
Gastrin has a trophic action when acting directly on oxyntic cells.
• Histamine
• Histamine is released by ECL cells in the gastric mucosa.
• Histamine release is influenced by gastrin and also by Ach from vagal stimulation.
• Histamine acts on H2 receptors of the oxyntic cell to activate the H+/K+ ATPase via a cAMP mechanism.
• Histamine is also an inflammatory agent produced by mast cells. In this case, the histamine reacts with H1
receptors.
• Acetylcholine (Ach)
• Ach is released by the vagus nerve endings and is capable of acting on ECL cells to stimulate histamine
release or can act directly on the oxyntic cell.
• When Ach acts on the oxyntic cell, it activates the H+/K+ ATPase via a Ca-calmodulin mechanism.
• Somatostatin, secretin and Prostaglandin E (PGE) act to inhibit acid secretion.
• Non Steroidal Anti Inflammatory Drugs (NSAID) such as aspirin inhibit the formation of prostaglandins
(which have diverse roles such as blood clotting, pain response) and hence removes the protective role PGE
has on preventing excess acid secretion. That is why you shouldn't take aspirin on an empty stomach.
Protective mechanisms
• The gastric mucosa is lined by a layer of protective mucous (secreted by the mucosal cells) which prevents the acid in
the stomach from contacting the delicate underlying mucosa.
• When the pH of the stomach and duodenum are low (acidic), somatostatin and secretin are released to inhibit acid
secretion.
• PGE, apart from inhibiting acid secretion, also has a role in promoting mucous formation.
Peptic ulcers
• Peptic ulcers arise due to an imbalance between acid secretion and the protective mucous lining.
• It can be due to either an excess acid secretion or a reduction in mucous.
• Excess acid:
• The most common cause of excess acid secretion is Zollinger-Ellison syndrome (gastrinoma)
• A functional tumour of the gastrin releasing cells results in hypersecretion of acid into the stomach.
• Disruption of mucous layer:
• Helicobacter pylori
• This bacteria is able to digest the mucous lining

• Inhibition of mucous production
• PGE has a role in aiding mucous production and hence its inhibition via NSAID's is a likely cause of
peptic ulceration.
• PGE also has a role in inhibiting acid secretion, which makes things even worse if we inhibit PGE
production.
• Destruction of mucous
• Apart from bacterial infection, alcohol and caffeine have a good effect in disrupting the mucous
layer.
Treatment of peptic ulcers

• The old treatment was to remove the antrum of the stomach (where most of the G cells are located) to stop gastrin
stimulating acid release.
• Another surgical treatment is to do a vagotomy, where the vagal trunks are sectioned at the level of the stomach to
prevent vagal stimulation of acid secretion.
• More modern techniques involve the administration of histamine antagonists (e.g. ranitidine) which block the H2
receptor.
• There is also a drug (omeprazole) which inhibits the action of the H+/K+ ATPase.
• Treatment for those infected with H. Pylori involves antibiotics.
PARENTERAL THERAPY
Malnutrition
• Parenteral (and enteral) therapy is used to keep extremely ill patients alive.
• Malnutrition can be defined as imperfect nutrition resulting from deficiencies in the diet or the inability to use it in
the body.
• We can get energy from 3 main sources:
• Glucose
• Amino acids
• Fatty acids
• Some tissues in the body, however cannot use all 3 sources. The brain and RBC for example have an absolute
requirement for glucose, unless under extreme starvation.
• Normally, the body will use up all glycogen stores within 48 hours of inactivity. After all the glycogen is used up,
the body starts to make glucose from other sources, mainly proteins for GNG.
• The body also begins to break down fats, which yields fatty acids for use by tissues which do not have a requirement
for glucose as the main energy source.
• Most of the protein comes from bodily tissues (e.g. muscle). However, muscle breakdown cannot continue for long,
otherwise, muscles from vital organs begin to break down. At this stage, the body stops producing glucose via GNG
and begins to adjust to a new form of energy source - fatty acids.
• Fatty acids produce a huge amount of acetyl CoA and if this is not used up quickly, then the excess will be
converted to ketone bodies (which can also be utilised as an energy source). However, too much ketone bodies leads
to a ketosis (resulting in an acidosis).
• However, once all the fat stores have been depleted, the body must rely again on protein degradation and hence, the
body starts to “eat” itself to death.
Trauma-injury-sepsis (TIS) starvation

• The above form of starvation was a result of malnutrition.
• Another type is that due to trauma, injury or infection (sepsis).
• With malnutrition, the body can adjust to using fats as a principle energy source after a couple of weeks. These
people will also become lethargic and the body will effectively turn off unnecessary activities in order to conserve
energy.
• However, with TIS starvation, the body cannot adjust to a new energy source, even after a prolonged time - there is
an absolute requirement for glucose by most tissues of the body.
• This is probably because injured tissue requires lots of energy to regenerate and has glucose specificity. Compare
this to normal starvation where the body minimises energy usage.
• Injured tissue also produces cytokines (interleukins, colony stimulating factors, interferons, tumor necrosis factor).
• Cytokines are regulatory peptides secreted by immune cells and coordinate cell differentiation. They also
mediate the inflammatory response.
• If cytokines are administered to a healthy person, they will get a TIS response.
Summary of the differences between starvation and TIS
Starvation Trauma-Injury-Sepsis
Resting energy expenditure ↓ ↑↑
Nitrogen levels in urine + +++
Rate of GNG + +++
Major fuel type Fat Mixed (mainly proteins)
Ketone body production ++++ +
Responsiveness to treatment ++++ +
• In starvation, the body wants to try and minimise energy expenditure as much as possible. In TIS, the energy
expenditure is increased since regenerating tissues require lots of energy.
• In starvation, the body is able to adapt to using fats and ketone bodies as an energy source. However, in TIS the
regenerating tissues need glucose specifically and so proteins are broken down to provide substrates for
gluconeogenesis.
• As a result, N levels in the body increase (due to protein degradation)
• GNG increases
• In starvation, if food is given, the body immediately stops eating itself and uses the nutrients in the food. However,
in TIS, even if food is given the body cannot stop eating itself.
Assessing nutritional status

• Malnutrition is defined as a body weight less than 85% of predicted weight (from charts)
• Anthropometry
• Use of weight-height tables
• Midarm circumference
• A measure of muscle tone
• Creatinine height index
• Fat stores
• Tricep skinfold thickness using calipers
• Visceral proteins (often decreased since proteins are being broken down):
• Serum albumin
• There is a large body pool of serum albumin and its half life is fairly long, therefore you won’t see
a significant decrease in albumin
• Serum transferrin
• Affected by the level of iron in the body
Treatment goals
• Energy needs to be given in the form of:
• Proteins
• Fluids
• Electrolytes
• Vitamins
• Trace elements
• The gut is a highly specialized organ because it absorbs exactly what it needs to survive.
• The best way is to give an oral dose of nutrients. If this is not possible (due to obstruction/damage in the upper
alimentary tract) then the nutrients can be fed directly into the gut (enteral feeding).
• If the bowel is stuffed, then the nutrients will need to be fed directly into the veins (total parenteral feeding)
Hypernatemia
• The normal serum Na+ is 135 - 145 mmol
• When there is an abnormality in Na+ levels, it is not simply a case of saying we have an excess or insufficiency of
Na+
• This is because the Na+ concentration is highly dependent on the level of body water.
• For the same amount of Na+:
• Lots of water results in a low Na+ concentration
• Little water results in a high Na+ concentration
• Therefore, to correct Na+ imbalances, we alter the level of water in the body rather than the levels of Na+.
End of Volume II

Liverpud Nephro

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1996 Integrated Body Function 536-022: Volume II By Duy Thai

2nd Year Medicine Page 1 of 29

Integrated Body Function

TOPIC PAGE NO.

• Increase in body temperature.

Endocrine functions of the placenta

Labour & parturition

Endocrine mediators of parturition

• Antenatal = Prenatal = before birth

Factors affecting foetal growth

Foetal respiratory system

RENAL FAILURE I: CHRONIC

Synthetic and hormonal function

Consequences of Chronic renal failure

Management of chronic renal failure

RENAL FAILURE II: ACUTE

• Problems when the kidney fail are:

• Causes of acute renal failure

Review of the filtration barrier

Abnormal filtration: nephrotic syndrome

Symptoms (other than oedema)

Types of malabsorption syndrome

Various defects due to:

Generalised intestinal defect

Specific enzyme defect

Lack of surface area

Specific absorptive defects

Clinical presentation: symptoms & signs

• Decreased intestinal absorption

Location of the liver

Metabolic functions of the liver

Synthetic role of the liver

Recirculation of bile acids

How can things go wrong?

Obstruction to the common bile duct (obstructive jaundice)

Acute liver damage

Chronic liver failure

• There is a viscous cycle which occurs when albumin is decreased:

Differences between liver cell damage and biliary obstruction

/,9(5 &(// '$0$*( %,/,$5< 2%6758&7,21

Chronic liver failure

Distinguishing between liver cell damage and obstruction

Signs of liver damage

Mechanism of acid formation

Factors controlling gastric acid secretion

Chemical regulation of acid secretion

• This bacteria is able to digest the mucous lining

Treatment of peptic ulcers

Trauma-injury-sepsis (TIS) starvation

Summary of the differences between starvation and TIS

Assessing nutritional status

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