Basic Sciences for Obstetrics and Gynaecology GLUCOSE [1] Hexokinase ● This series of reactions is often referred to as the ‘link
reaction’ since the conversion of pyruvate to acetyl-
ATP Glucose-6- CoA is not part of glycolysis (which ends at pyruvate),
ADP phosphate nor is it part of the Krebs cycle (which conventionally
begins with the formation of citrate from oxaloacetate
Glucose-6-phosphate isomerase [2] plus acetyl-CoA).
Fructose-6- [3] Phosphofructokinase ● In order for the Krebs cycle to run in balance, the amount
phosphate of acetyl-CoA entering the cycle must match the amount
of oxaloacetate available to combine with it and form cit-
ATP Fructose-1,6- rate. If there is an excess of acetyl-CoA and/or a relative
ADP bisphosphate deficit in the availability of oxaloacetate, the PDH enzyme
complex is inhibited (so preventing further conversion of
Fructose bisphosphate aldolase [4]
Glyceraldehyde-3- Dihydroxyacetone pyruvate to acetyl-CoA) and pyruvate is instead metabo-
phosphate (GAP) phosphate
lized by pyruvate carboxylase. As its name implies, this
[2X] NAD+ [5] GAP dehydrogenase
NADH enzyme catalyses the addition of a CO2 group onto the
1,3-Bisphospho- 3C pyruvate molecule to generate the 4C molecule ox-
aloacetate, which then combines with the excess acetyl-
Phosphoglycerate kinase [6] glycerate CoA, providing an alternative route of entry into the
Krebs cycle.
3-Phospho- ADP [2X]
ATP ● Under anaerobic conditions, the limited supply of oxygen
glycerate to the mitochondria stops the oxidative phosphorylation
[7] Phosphoglycerate mutase pathway from regenerating the oxidant nucleotide co-
88 2-Phospho- factors NAD+ and FAD. As the reduced forms of NADH
Enolase [8] glycerate and FADH2 accumulate, the Krebs cycle is effectively ren-
dered inoperative, and more importantly, the restricted
Phosphoenol provision of oxidized NAD+ to the GAPDH enzyme
pyruvate (PEP) [9] Pyruvate kinase would arrest the flux of carbon (and hence of energy)
through the glycolytic pathway.
[2X] ADP PYRUVATE
ATP ● In order for glucose to continue to be metabolized and
yield at least some ATP under anaerobic conditions, in
Figure 5.11 The glycolysis pathway. At reaction 4, the hypoxic/anaerobic tissues and cells that lack mitochondria,
hexose (6C) monosaccharides are cleaved into interchangeable pyruvate has to be reduced to lactate by lactate dehydro-
triose (3C) molecules (glyceraldehyde-3-phosphate and genase (LDH). This enzyme uses NADH as its reductant
dihydroxyacetone phosphate), such that all downstream co-factor, and so regenerates NAD+ in the cytoplasm
reactions (5 to 9 inclusive) occur twice for every hexose independently of the mitochondria (Figure 5.12).
molecule entering the pathway.
Pyruvate
acetate molecule (derived from acetyl-CoA) to generate NADH Lactate CO2 Pyruvate
the 6C molecule citrate, and that 6C molecule then yields NAD+ dehydrogenase*
a total of 2 CO2 molecules as it recycles back (via the 5C CoASH carboxylase
molecule α-KG and the 4C intermediates succinate, fu- NAD+
marate, and malate) to oxaloacetate. In the Krebs cycle Pyruvate
there is no place for 3C triose molecules such as pyru- dehydrogenase
vate, which must therefore be modified (either to a 4C or
2C metabolite) before it can enter the cycle. Provided NADH
there is sufficient oxaloacetate available in that cycle, the
pyruvate will be oxidized to acetate (2C) and combined Lactate* CO2 Oxalo-
(through a high-energy thioester bond) with CoA to form acetate
acetyl-CoA (Figure 5.12). This requires a complicated se-
quence of biochemical reactions to be catalysed by the Acetyl-
pyruvate dehydrogenase (PDH) enzyme complex, which CoA
has to remove the CO2 (as the pyruvate becomes ace-
tate), reduce NAD+ to NADH (which can give rise to up Figure 5.12 Alternative metabolic fates of pyruvate. Under
to three additional ATP molecules via oxidative phospho- anaerobic conditions (depicted by the asterisk) pyruvate is
rylation), and form the thioester bond between the ace- reduced to lactate, whereas under aerobic conditions pyruvate
tate and the CoA acceptor molecule. can either undergo oxidative decarboxylation to acetyl-CoA,
or carboxylation to oxaloacetate.
β-oxidation cycle per turn of the Krebs cycle, as opposed to 12 ATP per turn Chapter 5 Biochemistry
for each acetyl-CoA molecule) (Figure 5.10).
The β-oxidation cycle, which occurs in the mitochondrial
matrix, is the iterative cleavage of 2C fragments from a fatty ● The β-oxidation cycle is preceded by esterification of a
acid chain to generate acetyl-CoA molecules that enter the ‘free’ or non-esterified fatty acid (NEFA) chain onto
Krebs cycle (Figure 5.13). In the case of fatty acids contain- the sulphydryl/thiol group of coenzyme A to form a
ing even numbers of carbon atoms, the β-oxidation cycle fatty acyl-CoA molecule. (This is important since the
converts the fatty acid exclusively into 2C acetyl groups thioester bond provides the energy to power this meta-
(seven, eight, or nine acetyl-CoA molecules per molecule bolic cycle.)
of myristic, palmitic, or stearic acid, respectively). For odd-
numbered fatty acids, 2C subunits are cleaved until the final ● There then follows a series of four reactions, and in each
3C fragment remains as a propionyl-CoA molecule, i.e. round the length of the fatty acyl-CoA molecule is de-
the rare 17C fatty acid margaric acid would undergo the creased by two carbons.
β-oxidation cycle to yield seven (rather than eight) acetyl-
CoA molecules and a single propionyl-CoA molecule. The ● Two of these four sequential reactions are oxidation re-
propionyl grouping has the same problem entering the actions, which reduce the oxidant nucleotide co-factors,
Krebs cycle as pyruvate: the propionyl group has three FAD and NAD+. This has two consequences. Firstly, it
carbons, and three is not a number favoured by the Krebs means that β-oxidation of fatty acids leads to the genera-
cycle. Therefore, any propionyl-CoA formed by β-oxidation tion of ATP prior to the entry of the acetyl-CoA frag-
of odd-chain fatty acids must be carboxylated to enter the ments into the Krebs cycle. Secondly, this requirement
Krebs cycle as the 4C component of succinyl-CoA (which for FAD and NAD+ to be recycled (via the oxidative
decreases the ATP yield of propionyl-CoA to only six ATP phosphorylation pathway) explains why fat metabolism
can only occur during aerobic conditions.
CoASH Mg-ATP Mg-AMP 89
● The initial fatty acyl-CoA molecule for β-oxidation is
+ PPi formed from NEFA in the cytosol of the cell, whereas the
β-oxidation cycle occurs within the mitochondrial matrix.
NEFA [1] Acyl-CoA Acyl-CoA
synthase ● In order to pass across the aqueous space between the
mitochondrial membranes, cytosolic acyl-CoA molecules
H2O Acetyl-CoA Acyl- must combine with carnitine at the outer mitochondrial
Thiolase [5] carnitine membrane, catalysed by the carnitine palmitoyl trans-
shuttle ferase (CPT) I enzyme, and then be released by the ac-
tion of CPT II in the inner mitochondrial membrane
3-Keto- Acyl-CoA (Figure 5.14).
Acyl-CoA
● In the first step of the β-oxidation cycle, the fatty acyl-
[4] NAD+ FAD [2] CoA is oxidized by acyl-CoA dehydrogenase to form
NADH FADH2 trans-Δ2-enoyl-CoA (with the attendant reduction of
L(+)-3-hydroxy- Acyl-CoA FAD to FADH2). The trans-Δ2-enoyl-CoA then under-
acyl-CoA dehydrogenase goes hydration to form L-3-hydroxyacyl-CoA.
dehydrogenase ● Subsequent NAD+-dependent oxidation, catalysed by
hydroxyacyl-CoA dehydrogenase, forms the 3-ketoacyl-
L(+)-3-hydroxy- Δ2-trans-Enoyl- CoA molecule, and in the final reaction of the cyclic
acyl-CoA CoA sequence, that 3-ketoacyl-CoA reacts with another mol-
ecule of mitochondrial CoA to liberate the acetyl-CoA
[3] H2O and leave a shortened acyl-CoA, ready to commence the
next round of β-oxidation (Figure 5.13).
Δ2-enoyl-CoA
hydratase ● It is important to appreciate that through the β-oxidation
cycle, the majority of carbon from a fatty acid molecule
Figure 5.13 The β-oxidation cycle of fatty acids. In the first enters the Krebs cycle as acetyl-CoA. Since each fatty
instance, a cytosolic non-esterified fatty acid (NEFA), liberated acid chain contributes carbon atoms to the Krebs cycle
from triglyceride stores by lipolysis, is esterified to coenzyme in pairs, and each turn of the Krebs cycle sees two car-
A (CoASH) to form an acyl-CoA molecule that can be bon atoms oxidized to CO2 (Figure 5.10), there is no net
imported into the mitochondrial matrix via the acyl-carnitine gain of carbon to the Krebs cycle via β-oxidation. It is as
shuttle. The initial formation of the acyl-CoA complex requires a consequence of this arithmetic that fatty acids cannot
the hydrolysis of magnesium (Mg)-ATP to Mg-AMP and be converted into carbohydrates, whereas excess carbon
pyrophosphate (PPi), where the spontaneous decay of the (and calories) from carbohydrates can be converted into
PPi to two inorganic phosphate (Pi) molecules prevents the fatty acids and triglyerides. Therefore, questions suggest-
acyl-CoA synthase reaction from reaching equilibrium. ing the conversion of fatty acids to carbohydrates are
trick questions and are false no matter what intermediate
molecules are proposed to achieve this.
Basic Sciences for Obstetrics and Gynaecology Mg-ATP Mg-AMP + PPi Transamination and deamination
CoASH Acyl-CoA of amino acids
NEFA
Cytosol There are 20 common amino acids, which are used to gen-
erate a wide repertoire of cellular proteins, but in starva-
Acyl-CoA Carnitine tion they can also sacrifice their amino (NH3) groups in
synthase palmitoyl- transamination and/or deamination reactions to generate
transferase α-ketoacid intermediates that enter the Krebs cycle as res-
(CPT) I piratory substrates.
Acyl-CoA Inter- ● In the simplest reaction, the amino acid alanine is deami-
Carnitine membrane
nated by alanine aminotransferase (also called alanine
space
transaminase) transferring the NH3 group from alanine
onto either α-ketoglutarate or oxaloacetate. As a result,
the α-ketoacids are converted into glutamate or aspar-
Acylcarnitine tate, respectively, and the alanine is deaminated to form
pyruvate, which enters the Krebs cycle as either acetyl-
Carnitine Carnitine CoA or oxaloacetate (Figure 5.15A).
palmitoyl- acyl-
transferase ● The conversion of serine to pyruvate is slightly more
(CPT) II carnitine complex: serine must first be metabolized to an amino-
translocase acrylate intermediate by serine dehydratase before the
aminoacrylate is deaminated to yield pyruvate and a free
CoASH Matrix ammonium ion (Figure 5.15B).
90 Carnitine ● In reactions that critically depend on the co-factor tetra-
Acyl-CoA hydrofolate (THF) to act as a donor/acceptor of single
carbon methyl units, the amino acid threonine can also be
Acylcarnitine metabolized (via glycine) to serine and thence on to pyru-
Figure 5.14 The acyl-carnitine shuttle. Acyl-CoA molecules, vate for entry into the Krebs cycle. The cleavage of thre-
formed by the esterification of non-esterified fatty acids onine to glycine by threonine aldolase also liberates
(NEFA) to coenzyme A (CoASH) molecules, are imported acetaldehyde, which can be oxidized (via acetate) to yield
across the outer mitochondrial membrane. Within the acetyl-CoA (Figure 5.15B).
aqueous intermembrane space, the fatty acyl chain is
transferred onto carnitine by the action of carnitine palmitoyl- ● Glutamine, together with arginine, histidine, and proline,
transferase (CPT) I. This acylcarnitine can then be imported can be deaminated/transaminated to yield glutamate,
across the inner mitochondrial membrane (by a translocase which has two routes of conversion into the Krebs cycle
enzyme) before being cleaved back into carnitine and 5C intermediate α-ketoglutarate. Glutamate can either
be deaminated by glutamate dehydrogenase (liberating
acyl-CoA (the substrate for the β-oxidation cycle) by the free ammonium that enters the urea cycle) (Figure 5.15C)
action of CPT II. or can be transaminated by an aminotransferase (transam-
Unlike most tissues, the liver relies primarily for its acetyl- inase) enzyme, which transfers the NH3 group onto
CoA (and thus its ATP) on the β-oxidation of NEFA. In either pyruvate or oxaloacetate (generating alanine or
specific metabolic conditions (e.g. starvation), hepatic β- aspartate respectively) (Figure 5.15D).
oxidation generates more acetyl-CoA than can be incorpo-
rated into the Krebs cycle. Within the hepatic mitochondria, ● The hydrophobic amino acids, isoleucine, valine, and me-
the excess acetyl-CoA molecules can be combined (by thio- thionine, can all be deaminated to form propionyl-CoA,
lase) to generate acetoacetyl-CoA molecules, which can be which is subsequently carboxylated to enter the Krebs
coupled with acetyl-CoA to synthesize 3-hydroxy-3-methyl- cycle as succinyl-CoA.
glutaryl-CoA (HMGCoA). Cleavage of this product by
HMGCoA lyase liberates acetyl-CoA and free acetoacetate, ● In the presence of tetrahydrobiopterin, phenylalanine
where the latter can be reduced to 3-hydroxybutyrate by hydroxylase can oxidize phenylalanine to form the aro-
the reversible 3-hydroxybutyrate dehydrogenase enzyme. matic amino acid tyrosine. This can be catabolized to
the 4C Krebs cycle intermediate, fumarate, accompanied
by the formation of an acetoacetate ketone body
(Figure 5.15E).
Acetoacetate and 3-hydroxybutyrate, collectively termed ● The final pathway for amino acid entry into the Krebs
‘ketone bodies’, are exported into the circulation and taken cycle is via oxaloacetate. In addition to those four amino
up by extra-hepatic tissues, most importantly the brain and acids that can be converted to oxaloacetate via pyruvate
skeletal muscle, where they serve as respiratory substrates. (alanine, glycine, serine, and threonine), asparagine can
Hydroxybutyrate can be oxidized back to acetoacetate, be deaminated to form aspartate, and aspartate can be
which is converted to acetyl-CoA (via an acetoacetyl-CoA transaminated to remove its NH3 group, so generating
intermediate) to fuel the Krebs cycle. oxaloacetate (Figure 5.15D).
A Alanine Pyruvate Chapter 5 Biochemistry
Alanine
transaminase
α-Ketoglutarate/ Glutamate/
Oxaloacetate Aspartate
B Threonine
Threonine
aldolase
Acetaldehyde Acetate Acetyl-CoA
Glycine FAD FADH2 Acetate
Aldehyde
Methylene-
tetrahydrofolate Serine H2O dehydrogenase CoASH thiokinase H2O
hydroxy-
methylase
Tetrahydrofolate
Serine Serine Aminoacrylate Pyruvate
dehydratase Deaminase
H2O H2O NH4+ 91
C Glutamine Glutamate Glutamate α-Ketoglutarate
Glutamine
synthase dehydrogenase
NH4+ H2O NH4+
NAD+ NADH
D Glutamate α-Ketoglutarate
Transaminase
Pyruvate/ Alanine/
Oxaloacetate Aspartate
E Phenylalanine Tyrosine Fumarate
Phenylalanine Tyrosine
hydroxylase aminotransferase
2xO
O2 H2O H2O CO2
Tetrahydro- Dihydro- α-Keto- Glutamate
biopterin biopterin glutarate
NADP+ NADPH
Figure 5.15 Transamination and/or deamination of amino acid substrates to generate Krebs cycle intermediates. Selected
metabolic reactions for alanine/pyruvate (panel A), threonine/glycine/serine (panel B), glutamine/glutamate (panel C),
glutamate/aspartate/alanine (panel D), and phenylalanine/tyrosine (panel E).
Basic Sciences for Obstetrics and Gynaecology Transamination and deamination reactions liberate ammo- H2O Urea
nium (NH4+) ions, which are potentially toxic and so must
be converted into urea prior to their excretion in urine [5] CO2 + NH4+
(or faeces). This is achieved in the liver by the urea cycle.
Within hepatic mitochondria, CPS-I combines NH4+ ions Arginase 2Mg-ATP [1]
with CO2 and ATP-derived phosphate to form carbamoyl
phosphate that combines with ornithine to form L-citrulline Carbamoyl
(Figure 5.16). Following export into the cytosol, and in the
presence of aspartate plus ATP, the citrulline undergoes two L-Arginine L-Ornithine phosphate
sequential reactions to form the amino acid arginine (via synthase
arginosuccinate; Figure 5.16). In the final reaction of the
urea cycle, the arginine is recycled back to ornithine by the 2Mg-ADP (CPS) I
arginase enzyme in a hydrolytic reaction that liberates urea.
Deficiencies of urea cycle enzymes can result in hyperam- + Pi
monaemia and related conditions (i.e. citrullinaemia, argino-
succinicacidaemia, or hyperarginaemia). Fumarate Carbamoyl
phosphate
[4] [2]
Arginosuccinase Ornithine
Pi transcarbamoylase
Argino- L-Citrulline
succinate
Vitamins
Vitamins (or ‘vital amines’) are so named because they are Mg-AMP Mg-ATP
vital for nutrition and cannot be synthesized within the body.
Other essential nutrients that are not vitamins include the + PPi [3] L-Aspartate
Arginosuccinic
acid synthase
essential amino acids, essential fatty acids, and dietary min-
erals such as calcium, chloride, iron, potassium, phospho- Figure 5.16 The urea cycle. Reactions [1] and [2], catalysed
92 rous, and sodium. by carbamoyl phosphate synthase (CPS) I and ornithine
transcarbamoylase, respectively, occur within the matrix of
● Vitamins are generally classified as either being ‘fat- liver cell mitochondria, whereas reactions [3], [4], and [5]
soluble’ or ‘water-soluble’ (Table 5.3), where these have each occur in the liver cell cytosol.
to be absorbed from the GI tract in the terminal ileum or
colon, respectively.
● In the context of the oxidative metabolism of respiratory vitamin B9/folate) to ensure that the nutritional require-
substrates, the most important vitamins are the B com- ments of both the mother and the growing fetus can be
plex vitamins, which are precursors of several of the met (folate deficiency can result in neural tube defects).
coenzymes (Table 5.3). Hence, deficiencies in any specific
B vitamin can have potentially fatal consequences. ● While vitamins generally exert beneficial actions, over-
dose of any single vitamin can produce adverse side
● In developed countries, vitamin deficiencies are rare due effects. Of these, the most relevant are the terato-
to adequate dietary intake and the fortification of com- genic actions of vitamin A (retinol) and its pharmaceu-
mon foods (e.g. bread) with additional vitamins. How- tical derivatives (e.g. the acne treatment isotretinoin/
ever, during pregnancy, women are often advised to 13-cis-retinoic acid), which can induce serious birth
take vitamin supplements (e.g. increasing their intake of defects if administered to pregnant women.
Table 5.3 The classification and roles of vitamins
(i) Fat-soluble vitamins
Vitamin Chemical name Biochemical roles Deficiency diseases Effects of overdose
Hyper-vitaminosis
A Retinoids (retinoic acid, Component of rhodopsin— Night blindness A + teratogenesis
Hyper-vitaminosis D
retinal, retinol, retinoids, required as the photoreceptor
None reported
and carotenoids) molecule in the eye
None reported
D Calciferol (cholecalciferol Substrate for vitamin D3— Rickets (if pre-pubertal
and ergocalciferol) stimulates calcium absorption deficiency)/osteomalacia
from the GI tract (if post-pubertal deficiency)
E Tocopherol Antioxidant Mild haemolytic anaemia
in newborns
(and tocotrienols)
K Phylloquinone Pro-coagulant (vital co-factor for Bleeding diathesis/
(and menaquinones) the clotting cascade) haemophilia
(ii) Water-soluble vitamins Chapter 5 Biochemistry
Vitamin Chemical name Biochemical roles Deficiency diseases Effects of overdose
B1 Thiamine Beriberi None reported
Component of pyruvate
B2 Riboflavin dehydrogenase (PDH) and Ariboflavinosis None reported
B3 Niacin (niacinamide) α-ketoglutarate dehydrogenase Pellagra Liver damage
(αKGDH) enzyme complexes
B5 Pantothenic acid Paraesthesia None reported
B6 Pyridoxine Precursor of the co-factors Anaemia Nerve damage and
FMN and FAD impaired neural
(pyridoxamine Dermatitis and function (specifically
and pyridoxal) Precursor of the co-factors enteritis proprioception)
NAD+/NADH and None reported
B7 Biotin NADP+/NADPH Megaloblastic anaemia;
developmental neural May mask or
B9 Folate Constituent of coenzyme tube defects exacerbate deficiency 93
B12 Cobalamins A (CoA) Megaloblastic anaemia; of vitamin B12
developmental neural None reported
C Ascorbate Production of erythrocytes and tube defects
co-factor for the decarboxylation Diarrhoea;
of aromatic amino acids Scurvy potential pro-oxidant
(in synthesis of monoamine and carcinogen
neurotransmitters)
Coenzyme R: co-factor for
carboxylases (e.g. acetyl-CoA,
propionyl-CoA, and pyruvate
carboxylase enzymes)
Required for DNA replication
and cell division, particularly in
bone marrow and in the fetus
Required for DNA replication
and cell division, particularly in
bone marrow and in the fetus;
co-factor for methylmalonyl-CoA
mutase
Antioxidant
Fuel storage ● the ‘savings account’ takes the form of triglyceride stores
in adipose tissue/fat—it is easy to deposit calories in this
The best way to understand the storage and balance of form but much harder to withdraw them at a later date.
biological fuels in the fed and fasted states is by analogy
to money. To avoid running out of funds, a person needs As with money, calories are managed in a specific order:
to earn new money, carry some ready cash in their purse immediate needs are met first, then the glycogen stores
or wallet, have easy access to cash stored temporarily in a (‘current account’) are topped up, and finally any remaining
current account, and have some funds in a savings account glucose is metabolized into fatty acids to be deposited into
where the money performs better but is harder to access. the adipose triglyceride stores. Before considering the man-
In biochemistry: agement of glycogen and triglyceride stores in more detail,
there are four important points to emphasize:
● ‘earning cash’ is equivalent to taking in new calories (i.e.
eating a meal) 1. Some tissues, most notably the brain, rely on glucose
(or, in starvation, on ketone bodies) as their energy
● the ‘ready cash’ comes in the form of blood glucose—an source. This is why low plasma glucose concentrations
abundant energy currency that can be converted into (hypoglycaemia) result in coma.
ATP by glycolysis in all cells, even those that are hypoxic
or lack mitochondria 2. Although it is possible to metabolize excess glucose into
fatty acids (and hence to triglyceride), it is never possible
● the ‘current account’ is provided by glycogen—a labile
polymer of glucose that is readily broken down to liber-
ate more glucose into the plasma
Basic Sciences for Obstetrics and Gynaecology to reverse this reaction; fatty acids cannot be used to by glycogen synthase, an anabolic enzyme that is stimulated
derive glucose. after a meal by insulin (and inhibited in the fasting state by
3. Once glycogen stores have been depleted, the supply of hormones such as glucagon and adrenaline).
plasma glucose for brain activity can be maintained by using
the carbon skeletons of amino acids (never fatty acids). ● Glycogen is stored primarily in the liver (which receives
4. The interconversion of excess glucose to fatty acids the highest supply of glucose, via the portal vein) and
(lipogenesis) and of amino acids into glucose (gluconeo- skeletal muscle (where insulin stimulates glucose uptake
genesis) relies on intermediates in the Krebs cycle, via the GLUT4 glucose transporter). Significant levels
underscoring the pivotal role for this cycle at the heart of of glycogen synthesis also occur in the vagina, uterus,
metabolism. and brain. The advantage of glycogen as a fuel store is
that in the fasted state, glycogen can be rapidly mobilized
Glycogen to derive glucose for glycolysis. The disadvantages of
glycogen are that:
Glycogen (‘animal starch’) is a polysaccharide formed by
the sequential polymerization of glucose molecules pri- 1. it has a low calorific density (each glucose molecule
marily through α-1,4-glycosidic bonds. Approximately 8% can only generate a maximum net yield of 38 ATP
of the glucose molecules are added via α-1,6-glycosidic molecules)
bonds, which creates branch points in the glycogen mol-
ecule (Figure 5.17). The synthesis of glycogen is catalysed 2. it has a high molecular mass, compounded by the
fact that within tissues glycogen has to be complexed
with a large volume of water
94
OH
6 CH
2
−O 4 O OH
OH 1 6 CH
2
O 4 O α-1,6-glycosidic
OH 1 bond
OH
(branch point)
OH OH OH O OH
6CH2 O
6 CH2 6 CH2 6 CH2
O O O
−O 4 OH 1 4OH 1 4 OH 1 4 OH 1 Figure 5.17 The molecular
O O O O− structure of glycogen. The upper part
shows the macroscopic, branched,
OH OH OH OH polysaccharide structure of glycogen
while the lower part illustrates the
α-1,4-glycosidic bonds role of α-1,4- and α-1,6-glycosidic
bonds in the polymerization of the
glucose subunits that comprise
glycogen.
3. it is asymmetrically distributed around the body with This initial step is catalysed by hormone-sensitive lipase, Chapter 5 Biochemistry
the largest store confined to the liver. which is stimulated by the hormones of starvation (gluca-
gon, adrenaline, and cortisol) but inhibited by insulin. 95
● The catabolism of glycogen, termed glycogenolysis
(not to be confused with ‘glycolysis’), is catalysed by the ● Once each fatty acyl chain has been liberated, the non-
enzyme glycogen phosphorylase, which acts sequentially esterified fatty acids (NEFAs) can enter the β-oxidation cycle
to liberate glucose-1-phosphate molecules from the to contribute acetyl-CoA (and possibly propionyl-CoA)
glycogen, shortening the glycogen polymer by 1 glucose molecules to the Krebs cycle. Oxidation of the 16C mole-
subunit. The glucose-1-phosphate is then isomerized to cule palmitate, a typical long-chain fatty acid, will contribute
glucose-6-phosphate by phosphoglucomutase. eight acetyl-CoA molecules to the Krebs cycle and, in so
doing, generate a further eight molecules of NADH and
● Since the charged glucose-6-phosphate molecule cannot eight molecules of FADH2 as the fatty acid chain undergoes
pass across the plasma membrane of the cells, in most β-oxidation. As a result, palmitate could generate a maxi-
tissues (including the vagina, uterus, and skeletal muscle) mum net yield of 136 ATP molecules (Table 5.2) such that a
glucose-6-phosphate generated by glycogenolysis has to typical triglyceride molecule could yield up to 408 molecules
be metabolized (by glycolysis) within the very same cell of ATP (as opposed to only 38 ATP molecules per molecule
that held the glycogen store. of glucose respired under aerobic conditions).
● Only hepatocytes express the glucose-6-phosphatase en- ● It is this high calorific density, combined with their rela-
zyme required to remove the phosphate ion, and so only tively low weight per unit volume and a diffuse distribu-
the liver can export glucose into the bloodstream to sup- tion around the body in subcutaneous depots, which
port glycolysis (and the Krebs cycle) at distant sites. makes triglycerides the preferred form for storage of
excess calories.
Triglyceride
Managing fuel reserves in the fed state
Triglycerides are stored predominantly within adipose tissue
as the lipid droplets of mature adipocytes. Each triglyceride Following a meal, the elevated plasma glucose concentration
molecule is comprised of three fatty acyl chains esterified (and to a lesser extent increased levels of amino acids and
to the three carbons of a glycerol backbone (Figure 5.18) gastrointestinal tract hormones) suppresses the secretion
such that lipolysis (the breakdown of triglycerides) has to of glucagon (from pancreatic α cells) while triggering the
commence with the hydrolysis of the fatty acyl ester bonds. secretion of insulin (from pancreatic β cells). Insulin exerts
several distinct cellular actions to maximize glucose uptake
H H H and metabolism, which restore the plasma glucose concen-
H C1 C2 C3 H tration to the normal range: between 4 and 8 mmol/l.
O O
O CO CO 1. In skeletal muscle and adipose tissue, insulin stimulates
CO the recruitment of GLUT4 glucose transporters to the
plasma membrane of myocytes and adipocytes, so max-
CH3 CH3 CH3 imizing the number of transport sites available to medi-
ate glucose uptake.
Figure 5.18 The molecular structure of a triglyceride.
(Each triglyceride molecule can have any one of a number of 2. Within all metabolically active cells, insulin stimulates the
fatty acyl chains esterified to the three carbons of the glycerol activity of glycolytic enzymes (e.g. glucokinase/hexoki-
skeleton; in this example, palmitate is esterified at all three nase, pyruvate kinase, and PDH), which decreases the
positions.) intracellular concentration of free glucose, so maintaining
the concentration gradient for further glucose import.
3. Finally, insulin stimulates the activity of glycogen syn-
thase and simultaneously inhibits the activity of glycogen
phosphorylase to ensure that excess glucose is directed
primarily to replenish intracellular glycogen stores, par-
ticularly in liver and skeletal muscle.
As noted above, glycogen is an inefficient energy store due
to its low calorific density and relatively high molecular mass.
Therefore, there is a finite limit to the body’s ability to con-
vert excess carbon (and calories) from glucose into glyco-
gen. Once the body’s glycogen stores have been refilled, any
remaining glucose is converted into fatty acids and triglycer-
ide as follows.
● All excess glucose is respired (via glycolysis) to pyruvate,
and those excess pyruvate molecules then enter the
Basic Sciences for Obstetrics and Gynaecology mitochondrial Krebs cycle as either oxaloacetate or lipogenic pathway, the 2C acetate molecules from cyto-
(more likely) mitochondrial acetyl-CoA. solic acetyl-CoA are effectively polymerized (connected
● When these molecules combine, the citrate that they to an acyl carrier protein) to reconstitute a fatty acid that
form can either remain in the mitochondria to pass can be esterified to glycerol to form a triglyceride (com-
around the Krebs cycle or, in the fed state, can be ex- pleting the conversion of excess carbohydrate into ‘fat’).
ported out across the mitochondrial membranes. Once
in the cytosol, the citrate is acted upon by ATP-citrate ● In the first reaction, a CO2 group is added onto acetyl-
lyase releasing oxaloacetate and cytosolic acetyl-CoA CoA (by acetyl-CoA carboxylase) to form malonyl-CoA,
(Figure 5.19). which inhibits the mitochondrial CPT enzymes, so block-
● It is crucial to note that while mitochondrial acetyl-CoA ing mitochondrial uptake of acyl-carnitine and preventing
(synthesized by pyruvate dehydrogenase and the β- futile cycling of carbon through the β-oxidation cycle.
oxidation cycle) is a substrate for the Krebs cycle, cytoso-
lic acetyl-CoA is the substrate for lipogenesis. In the ● Elongation of the malonyl-CoA molecule occurs through
a cyclic series of sequential reactions (effectively the
Palmitate reverse of the β-oxidation cycle), which ultimately gener-
ate a C16 fatty acid (palmitate) that can be cleaved from
the acyl carrier protein by thioesterase and esterified onto
glycerol to form a mono-/di-/triglyceride (Figure 5.20).
In the same way as insulin simultaneously inhibits glycogen
Oxaloacetate Malonyl-CoA phosphorylase while stimulating glycogen synthase, this ana-
bolic hormone also acts in the fed state to inhibit hormone-
Acetyl-CoA sensitive lipase while simultaneously activating acetyl-CoA
carboxylase carboxylase to prevent futile cycling between lipogenesis
and lipolysis.
Cytosolic
acetyl-CoA
96 NADH ATP citate Managing fuel reserves in the fasted state
MDH lyase
NAD+ In the moderately ‘fasted’ state (i.e. as the glucose concen-
Malate CITRATE tration falls following a meal), the level of insulin falls ac-
companied by rises in glucagon and adrenaline, which act in
concert to ensure that the plasma glucose concentration re-
Tricarboxylate mains above 4 mmol/l (so avoiding a hypoglycaemic coma).
transporter Acute maintenance of plasma glucose is achieved by two
mechanisms.
Mitochondrial CoASH ● Initially, acting through a common cell signalling pathway
acetyl-CoA (the cyclic adenosine monophosphate-protein kinase A
signalling system), glucagon and adrenaline activate glyco-
Citrate synthase gen phosphorylase while simultaneously inhibiting glyco-
gen synthase, so inducing a net mobilization of glycogen
Oxaloacetate CITRATE to glucose. Because of the tissue-specific expression of
glucose-6-phosphatase in the liver, only hepatic glycogen
MDH NADH can be used to increase the plasma glucose concentra-
NAD+ tion; in all other tissues, including the vagina and uterus,
glycogen is hydrolysed to form glucose-6-phosphate
Malate molecules that must be used locally for glycolysis due to
the absence of glucose-6-phosphatase.
Figure 5.19 Mitochondrial exchange of malate and citrate as
a precursor for lipogenesis. Excess citrate generated by the ● Once the major glycogen stores begin to run low (as
coupling of oxaloacetate and acetyl-CoA in the mitochondrial would occur following an overnight fast), glucagon and
matrix is exported across the mitochondrial membranes by the adrenaline use the same second messenger system to ac-
action of the tricarboxylate transporter. Once in the cytosol, tivate hormone-sensitive lipase, so mobilizing fatty acids
the citrate is split into cytosolic acetyl-CoA (the precursor for for β-oxidation.
lipogenesis) and oxaloacetate. Since oxaloacetate cannot be
imported back into the mitochondrion, it must be reduced to ● In tissues that can utilize fatty acids as respiratory sub-
malate by the cytosolic malate dehydrogenase (MDH) enzyme. strates, this spares glucose metabolism, effectively
This malate can then be exchanged for citrate by the increasing the amount of glucose available to cells and
tricarboxylate transporter and the imported malate can be tissues that are glucose-dependent, such as the brain and
oxidized back to oxaloacetate in the Krebs cycle. erythrocytes.
On prolonged fasting and in other circumstances where
calorific expenditure exceeds intake (e.g. in the later stages
H3C O HO H Glycerol + Chapter 5 Biochemistry
H3C HO C1 H 3 x NEFAs
H3C C OH HO
O C2 H Monoacyl-
glycerol+
C OH C3 H 2 x NEFAs
O H
H Diacyl-
C OH C1 H glycerol+
1 x NEFA
O C2 H
Triacyl-
H3C CO C3 H glycerol/
H3C O H Triglyceride
H3C H
C OH HO C1 H
O
C2 H
C OH HO
C3 H
O H
H
H3C CO C1 H
H3C O
H3C C2 H
CO 97
O C3 H
H
C OH HO
Figure 5.20 The synthesis of H3C O
triglyceride (triacylglycerol) by the H3C
sequential esterification of three H3C CO
non-esterified fatty acids (NEFAs) O
to carbon positions 1, 2, and 3 in
glycerol. CO
O
CO
of pregnancy), the catabolic actions of glucagon and adrena- of oxaloacetate into glucose occurs by ‘reverse glycolysis’
line are augmented by the chronic stress hormone, cortisol. (Figure 5.21).
This glucocorticoid steroid acts to change the expression of
the genes encoding metabolic enzymes so as to maintain the ● This metabolic pathway is not as simple as the name
plasma glucose concentration at a level required to support implies, since three of the nine reactions in glycolysis
brain function. For example, cortisol up-regulates the ex- (the steps catalysed by hexokinase/glucokinase, phos-
pression of the lipolytic enzyme, hormone-sensitive lipase, phofructokinase, and pyruvate kinase) are irreversible.
required to mobilize triglyceride stores for β-oxidation in Therefore, in the fasted state, cortisol must up-regulate
order to spare glucose metabolism by those tissues that can the expression of three gluconeogenic enzymes:
respire NEFAs. More importantly, with prolonged fasting,
body glycogen stores will be depleted such that additional 1. phosphoenolpyruvate carboxykinase (PEPCK)—
mechanisms are required to derive glucose. This takes the required to metabolize oxaloacetate to phosphoe-
form of gluconeogenesis whereby the carbon skeletons of nolpyruvate
amino acids (derived by the breakdown of body protein)
are converted into glucose in the liver. 2. fructose-1,6-bisphosphatase—required to catalyse
the dephosphorylation of fructose-1,6-bisphosphate
● Gluconeogenesis starts with the 4C Krebs cycle interme- to fructose-6-phosphate
diate, oxaloacetate, derived by the proteolytic break-
down of proteins to liberate free amino acids, which 3. glucose-6-phosphatase—required to hydrolyse glu-
enter the cycle by multiple entry routes. The conversion cose-6-phosphate to free glucose (for export from
the liver).
● In addition, cortisol increases the expression of pyruvate
carboxylase (to increase the metabolism of pyruvate to
Basic Sciences for Obstetrics and Gynaecology GLUCOSE [9] Glucose-6-phosphatase ● Although fatty acids cannot be converted to glucose, in
prolonged starvation the catabolism of triglyceride can
Pi Glucose-6- liberate the 3C skeleton glycerol, which can be converted
H2O phosphate into dihydroxyacetone phosphate and glyceraldehyde-
3-phosphate. These intermediates can give rise to glu-
Glucose-6-phosphate isomerase[8] cose in the gluconeogenic pathway of reverse glycolysis.
Fructose-6- ● In starvation, the increased provision of NEFA to the liver
phosphate [7] Fructose-1,6-bisphosphatase for β-oxidation generates a surplus of acetyl-CoA mole-
cules, which are converted into ketone bodies: acetoace-
Pi Fructose-1,6- tate and β-hydroxybutyrate. This is an important metabolic
H2O bisphosphate pathway since the brain can generate ATP by respiring
ketone bodies in starvation when the mechanisms to
Fructose bisphosphate aldolase[6]
Glyceraldehyde-3- maintain plasma glucose struggle to meet the brain’s met-
phosphate (GAP) abolic needs. However, prolonged ketosis, whereby the
generation of ketone bodies exceeds the rate of their
NAPDi + [5] GAP dehydrogenase uptake and metabolism, can lower the plasma pH in the
NADH 1,3-Bisphospho- phenomenon of ketoacidosis, elaborated below.
Phosphoglycerate kinase [4] glycerate Managing fuel reserves in
the anaerobic state
3-Phospho- ADP
In the anaerobic state, the Krebs cycle and β-oxidation cycle
glycerate ATP
[3] Phosphoglycerate mutase
2-Phospho- both slow dramatically due to their reliance on regeneration
glycerate
98 Enolase [2] of oxidized NAD+ and FAD by the oxidative phosphoryla-
tion pathway. Hence, under anaerobic conditions, the only
Phosphoenol effective metabolic pathway still to operate is the glycolytic
pyruvate (PEP)
[1] Phosphoenolpyruvate pathway, and even then the net yield of ATP is dramatically
carboxykinase (PEPCK) decreased (as NADH has to be recycled to NAD+ through
CO2 GDP OXALOACETATE the action of lactate dehydrogenase on pyruvate). To avoid
GTP a dangerous decrease in intracellular pH arising from exces-
sive generation of lactate (lactic acidosis), this is exported
Figure 5.21 The gluconeogenic pathway of ‘reverse into the bloodstream, transported back to the liver, and then
glycolysis’. To facilitate comparison to the glycolysis of glucose oxidized back to pyruvate in the Cori cycle (Figure 5.22).
to pyruvate, this pathway has been drawn running from
oxaloacetate at the bottom of the figure to glucose at the top LIVER Circulation ANAEROBIC CELL
of the figure. Reactions 1 (catalysed by phosphoenolpyruvate Pyruvate Pyruvate
carboxykinase/PEPCK), 7 (catalysed by fructose-1,
6-bisphosphatase), and 9 (glucose-6-phosphatase) represent
those reactions that are irreversible in the glycolysis pathway NADH NADH
(and so rely on enzymes that must be up-regulated for
hepatic gluconeogenesis using oxaloacetate derived by protein LDH LDH
catabolism and amino acid entry into the Krebs cycle). NAD+ NAD+
Lactate Circulation Lactate
oxaloacetate) and the enzymes of the urea cycle (required Figure 5.22 The Cori cycle; LDH = lactate dehydrogenase.
to process the ammonium liberated when amino acids are
converted into α-keto acids for the Krebs cycle).
Acid-base balance ● The simplest buffering system is provided by the equilib-
The respiration of biological fuels poses the threat of low- rium between carbonic acid and bicarbonate ions in
ering plasma pH, either through the liberation of acidic
biochemicals (ketone bodies and lactic acid) or by the the blood (Figure 5.23). Excess CO2 generated from
generation of CO2. Since significant changes in plasma pH the Krebs cycle combines with water in the plasma to
affect the structure and functions of cellular proteins with
potentially lethal consequences, multiple mechanisms exist form carbonic acid (H2CO3), which exists in equilibrium
to balance the plasma pH. with dissociated bicarbonate ions (HCO3–) and free
protons (H+).
● Acidosis triggers an increase in the rate of breathing to buffering capacity across a wide range of plasma pH Chapter 5 Biochemistry
exhale CO2, displacing the carbonic acid-bicarbonate values, so maintaining the plasma pH around 7.4.
equilibrium such that HCO3– and H+ combine to reform
carbonic acid, so lowering the free proton concentration ● In addition to binding protons, albumin can also bind cal-
and increasing the plasma pH to the target pH of 7.4. cium ions (Ca2+). Consequently, as the pH of the plasma
changes, and the demands on albumin to bind/release
● The second major buffering system of the blood relies on protons changes, so the free calcium concentration of the
the fact that the 20 different amino acids that comprise blood changes with physiological consequences.
proteins each have different chemical side chains, and
several of these side chains ionize at different pH values ● When the plasma pH is low, the excess of free pro-
(Figure 5.24). When the plasma pH equals the pKa for a tons effectively displaces Ca2+ ions from the albumin,
specific amino acid, the probability of that side chain increasing the free plasma calcium concentration (and so
being protonated will be the same as the probability of suppressing the parathyroid hormone and vitamin D3/
that side chain being ionized to liberate a proton. Hence, calcitriol endocrine systems). Conversely, with a sus-
at the pKa, the ratio of protonated to ionized side chains tained elevation in the plasma pH, albumin will ionize to
for that specific amino acid will be 1:1 (Figure 5.24). liberate protons, increasing its capacity to bind Ca2+ ions,
hence decreasing the free plasma calcium concentration
● If the plasma pH falls below the appropriate pKa (i.e. if and increasing the synthesis and secretion of parathyroid
there are excess protons in the plasma), the laws of hormone and vitamin D3/calcitriol.
chemical equilibrium will shift this balance to favour the
protonated form of the amino acid side chain, whereas at H2O + CO2 H2CO3 H+ + HCO−3
plasma pH levels above the appropriate pKa, the amino
acid side chain is more likely to exist in the ionized state, Figure 5.23 The carbonic acid-bicarbonate equilibrium. 99
liberating additional protons and so lowering the plasma
pH. Hence, each amino acid side chain can buffer small Carbon dioxide (CO2) generated by the oxidation of
changes in plasma pH around the appropriate pKa value respiratory substrates combines with water in extracellular
for the chemical group in its side chain.
fluid and plasma to form carbonic acid (H2CO3), which can
● In blood, the major plasma protein, albumin, contains a then dissociate into bicarbonate ions (HCO3–) and free
mixture of all 20 amino acids such that it has effective protons (H+), so lowering the pH of the extracellular fluid
or plasma.
Amino acid side chain pH < pKa pH > pKa
Sulphydryl (thiol) group CH2 SH CH2 S− & H+
(cysteine)
Hydroxyl (alcohol) group CH2 OH CH2 O− & H+
(serine, threonine & tyrosine) OH O− & H+
Carboxylic acid group CO CO
(aspartate & glutamate)
CH2 NH3+ CH2 NH2 & H+
Amino group NH2 NH2
(lysine, arginine &
histidine)
C NH2+ C NH & H+
CH2 CH2 N− & H+
N NH N
Figure 5.24 The buffering capacity of amino acid side chains. At plasma pH values below the pKa for the relevant side chain (i.e.
when the concentration of free protons exceeds the pKa), the side chains will exist in the protonated state (as polar SH/OH/NH
groups, or protonated amino groups), but when the plasma pH value exceeds the pKa for the relevant side chain (i.e. when the
concentration of free protons falls below the pKa), the side chains will release their proton (and so will exist as deprotonated
S–/O–/N– groups, or as deprotonated NH2/NH groups). When the plasma pH is exactly equal to the pKa value, the probability
of any given side chain being in the protonated state will be exactly equal to the probability of that side chain being in the
deprotonated state (i.e. half of those specific side chains will be protonated and half will be deprotonated).
Basic Sciences for Obstetrics and Gynaecology AD DITIO NAL FAC TS A ND R EV I SI O N M ATE RI A L
Glucose transporters cytoplasm). It is critical for cells that cannot operate
Glucose transporters (GLUT) are membrane protein the oxidative phosphorylation pathway due to lack of
molecules that facilitate the entrance of glucose into the mitochondria or hypoxia.
cytoplasm of the cell from the extracellular fluid. There ● In cells without mitochondria (e.g. RBCs), NADH
are four main types of GLUT: (produced in the first dehydrogenase reaction) is
● GLUT1 and GLUT3 have a high affinity for glucose recycled back to NAD+ by the action of lactate
and are present in most tissues. They bind glucose dehydrogenase (LDH). Therefore, without LDH
whenever it is available and are therefore responsible glycolysis will cease in cells that lack mitochondria or
for basal tissue glucose uptake. in hypoxic states.
● GLUT2 are found only in the liver and the β-cells of ● To enter the Krebs cycle, pyruvate must be converted
the pancreas. They have a very low affinity for glucose, into acetyl-CoA by pyruvate dehydrogenase (PDH).
thus allowing absorbed glucose to pass through the Since PDH resides in the mitochondria, which are
portal system and the liver to the systemic circulation absent in the RBC, the RBC is totally reliant on a
without most of it being metabolized by the liver. constant supply of glucose and glycolysis for ATP
● Since glucose is the stimulus for insulin release from the production at substrate level.
β-cells of the pancreas, the presence of the low-affinity ● In between meals, glucose supply to the brain and
RBCs is maintained by glycogenolysis in the liver.
GLUT2 transporters on these cells ensures that binding
In chronic starvation, the glucose supply is maintained
of glucose to trigger the release of insulin only occurs
by gluconeogenesis in the liver. This involves the
when there is abundant glucose. In between meals
conversion of lactate (from RBC metabolism), alanine
when the circulating glucose concentration is low, the
(from protein degradation), and glycerol (from
100 low-affinity GLUT2 only bind/transport glucose into
triglyceride breakdown) back to glucose.
the β-cells at a low rate, thus ensuring that insulin
release is not triggered in this state. Fatty acid synthesis, storage, and mobilization
● GLUT4 are present on skeletal muscle cells and in ● Accumulation of excess ATP inhibits the glycolytic
adipose tissues. They are resident in the cytoplasm of enzymes and PDH, thereby slowing down ATP
the cell and only appear at the cell surface membrane production from oxidative phosphorylation. Acetyl
following stimulation of transporter trafficking by CoA accumulates and triggers fatty acid synthesis by
insulin. GLUT4 are therefore highly regulated by the liver. Insulin induces fatty acid synthetase, the chief
insulin and are not expressed on the membranes of enzyme for fat synthesis.
these tissues unless insulin is present (i.e. only in the
fed state). ● Insulin also activates acetyl CoA carboxylase by
dephosphorylating it.
● Therefore, glucose uptake by skeletal muscle and
by adipose tissue depends on insulin activation of ● Local regulation of fat synthesis is exerted by citrate:
GLUT4 transporters. it signals liver synthesis of fat and inhibits PFK-1
leading to the accumulation of glucose-6-phosphate
Glucose metabolism (glycolysis) and its entry into the hexose-monophosphate
● Glucose enters the cell assisted by a tissue-dependent pathway (HMP) to produce NADPH.
GLUT and it must be trapped within the cell by ● Once synthesized, the fatty acid has to be transported
phosphorylation to glucose-6-phosphate by either away from the liver to adipose tissue to prevent its
of two enzymes—hexokinase or glucokinase. accumulation in the liver (which would lead to fatty
● Hexokinase is constitutive, present in all tissues, and liver, cirrhosis, and damage).
has a high affinity for glucose. Glucokinase is induced ● Fatty acids are packaged in the liver as triglycerides
by insulin, present only in liver cells, has a low affinity (TG) (by the esterification of fatty acids onto a
for glucose, and is a major regulatory enzyme of glycerol backbone), which can be transported in the
glycolysis. bloodstream as very low density lipoprotein (VLDL).
● The rate-limiting step of glycolysis is the ATP- ● In peripheral tissues, the VLDLs are digested by the
dependent phosphorylation of fructose-6P to hormone-sensitive lipoprotein lipase enzyme,
fructose-1, 6-bisphosphate, catalysed by releasing glycerol. The glycerol is taken up and
phosphofructokinase-1(PFK1). PFK1 is induced recycled by the liver (reaction catalysed by glycerol
by insulin and inhibited by glucagon. kinase) whilst the free fatty acids are deposited in the
● The conversion of 1,3-diphosphoglycerate (1,3-DPG) adipose tissue where they are reconstituted back into
by phosphoglycerate kinase is an important reaction TG (catalysed by phosphatidate phosphatase,
because it produces substrate-level ATP (i.e. in the monoacylglycerol, and diacylglycerol acyltransferases).
AD DITIO NA L FAC TS A ND R EV I SI O N M ATE RI A L (Continued ) Chapter 5 Biochemistry
● Glycerol kinase genes are only expressed in the liver emphasizing the role of hepatic glycogen as a glucose
and never in the adipose tissue. Hence, only liver cells store for the whole body.
can convert glycerol from fat breakdown into glucose. ● Deficiency of hepatic glucose-6-phosphatase leads
to the accumulation of glucose-6-phosphate in
Glycogen storage and metabolism the liver with severe hypoglycaemia, osmotic
damage, hepatosplenomegaly, hyperlipidaemia,
● Glycogen is the storage form of glucose retained and hyperuricaemia (Type 1 glycogen storage
mostly in the liver, cardiac and skeletal muscles, and disease (von Gierke’s)).
the kidneys.
Tissues in which glucose uptake is
● Glycogen breakdown releases glucose-6-phosphate, not affected by insulin
which remains trapped within the cell unless it is
released by glucose-6-phosphatase. Glucose-6- 1. nervous tissue—brain, spinal cord, nerves
phosphatase is mainly expressed in the liver and 2. kidney—specifically the proximal convoluted tubule,
ensures that glucose released from the breakdown
of hepatic glycogen stores reaches the general secondary active transport of glucose linked to Na+
circulation for use by the brain and RBCs. 3. intestinal mucosa
4. red blood cells
● Unlike liver cells, muscle and renal cells lack glucose- 5. β-cells of the pancreas
6-phosphatase, so can only use the glucose from 6. insulin may accelerate but is not essential for glucose
their glycogen stores locally and cannot export this
glucose into the general circulation. uptake in the liver.
● In between meals the liver uses fatty acids rather
than glucose for its own energy requirements,
101
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CHAPTER 6
Endocrinology
Hormones hormones they cannot dissolve in the aqueous medium 103
of plasma. As a result their half lives are long and in the
Hormones are chemical messengers that signal through order of hours to days. The length of the half life is pro-
their unique chemical structure, which is recognized by spe- portional to the affinity of the hormone for the binding
cific receptors on target cells. protein. The very small unbound fraction is the biologi-
cally active form.
Classification and general
characteristics of hormones ● Steroid and thyroid hormones are hydrophobic and read-
ily cross the lipid bilayer of cell membranes.
There are three main chemical classes of hormones.
● Their receptors are mainly intracellular and their biologic
1. Protein and peptide hormones actions are exerted by generating brand new intracellular
● This is the most diverse and numerous group and in- proteins, which in part explains why they take longer to act.
cludes hormones secreted by the hypothalamus, pituitary ● Unlike protein and peptide hormones, steroid hormones
gland, pancreas, and parathyroid glands. are not stored in intracellular vesicles but are synthesized
● Their half lives in the circulation are in the order of min- and released as required.
utes and they generally circulate unbound and in free
form except for IGF-1, which is strongly bound to the 3. Hormones derived from an amino acid
binding protein IGFBP-1 and so has a long half life.
● Protein and peptide hormones, catecholamines, and ● The catecholamines secreted by the adrenal medulla
melatonin (biogenic amine hormones) are hydrophilic are tyrosine derivatives whilst melatonin secreted by the
(water soluble) and do not cross the lipid bilayer of cell pineal is derived from tryptophan.
membranes.
● Their receptors are resident on the outer surface of the ● Catecholamines circulate in free form and their half
cell membrane and their intracellular actions are exerted lives are in the order of seconds. Thyroid hormones
by secondary messengers such as cAMP, which usually are derived from two bound tyrosine molecules that are
modify pre-existing proteins rather than generating new iodinated but like steroids they are mainly bound in the
ones. For example, secondary messengers may phosphor- circulation and have long half lives.
ylate or dephosphorylate protein enzymes to regulate
their activity. Modification of already existing proteins Hormone receptors
allows water soluble hormones to act quickly, although
they also have longer-term effects on gene transcription. ● Most protein and peptide hormones act through G-
● They are stored within intracellular vesicles as prohor- protein coupled receptors (GPCRs), although a few, such
mones. as insulin, prolactin, growth hormone, growth factors,
and cytokines, act through receptors with inherent
2. Steroid hormones tyrosine kinase or receptors associated with proteins that
have tyrosine kinase activity.
● These are highly conserved and are derived from
cholesterol. ● GPCRs are linked to enzymes that stimulate the produc-
tion of second messengers such as cAMP or inositol
● They are secreted from the adrenal cortex, ovaries, triphosphate. These then activate intracellular kinases
testes, and the kidneys (the active form of vitamin D). such as protein kinase A or C.
● Their plasma transport involves binding to specific ● Receptors with inherent tyrosine kinase activity or those
transport proteins and albumin, because unlike peptide linked with tyrosine kinases activate other cell-signalling
pathways that are activated by tyrosine kinase or
Basic Sciences for Obstetrics and Gynaecology TK-associated receptors. Such phosphorylated (acti- Neurosecretory cells in the hypothalamus synthesize releas-
vated) kinases can stimulate cytoplasmic processes ing and inhibiting hormones in their cell bodies and package
(e.g. enzyme activation) or can activate transcription fac- them in vesicles, which are transported down their axons
tors in the nucleus and thus induce gene transcription to the nerve terminals located on the hypophyseal portal
(Figure 6.1). capillaries. Hormones released into the portal system are
● Steroid and thyroid hormones interact with receptors transported to the anterior lobe of the pituitary gland. Here
that are either in the cytoplasm or in the nucleus. Cyto- they stimulate or inhibit the release of hormone secretions
plasmic receptors are generally bound to heat shock pro- of the anterior lobe (adenohypophysis) (Figure 6.3). Cells
teins (hsps) in the cytoplasm. Upon hormone binding the of the adenohypophysis are chromophils (acidophils and
hsps are released, the receptors dimerize, and then they basophils, according to the histological dyes they take up)
translocate to the nucleus where they stimulate or inhibit and chromophobes, which are generally considered to be
gene transcription. Membrane or membrane-associated non-secretory.
steroid and thyroid hormone receptors exist, which upon
ligand binding can initiate rapid non-genomic actions The posterior lobe of the pituitary gland originates from
within target cells (Figure 6.2). neural tissue and consists of the nerve terminals of neurose-
cretory cells whose cell bodies lie in the supraoptic and
The hypothalamic-pituitary paraventricular nuclei of the hypothalamus. Here they syn-
axis—functional connections thesize and package oxytocin and vasopressin (VP), other-
wise known as antidiuretic hormone (ADH). The secretory
The anterior pituitary gland is functionally connected to vesicles containing the hormones are transported down the
the hypothalamus by the hypophyseal portal capillaries. axons that pass through the neural stalk, and are stored in
the nerve terminals in the posterior pituitary gland.
104 H
H
H
G TK TK
AC
G TK TK
PLC ATP (JAK) (JAK)
PIP2 cAMP
PKA
DAG IP3 PI3-K
PKC Ca2+ AKT MEK
Cytoplasmic STAT
actions ERK
Transcription Nucleus
factors Gene transcription, protein translation
Figure 6.1 Major signalling pathways for protein and peptide hormones. (i) G-protein coupled receptors activate adenyl
cyclase (AC) or phospholipase C (PLC). AC increases cAMP production and activates protein kinase A. PLC increases production
of diacyl glycerol (DAG) and inositol triphosphate, which increase protein kinase C and a rise in intracellular calcium respectively.
(ii) Receptors with inherent tyrosine kinase activity, such as the insulin receptor, activate (phosphorylate) downstream kinases.
(iii) Receptors linked to proteins with tyrosine kinase activity, such as janus kinase (JAK), phosphorylate downstream kinases such
as STAT. Growth hormone, prolactin, and cytokines use this signalling pathway. There is considerable cross talk between different
signalling pathways.
Bound steroid Free steroid Chapter 6 Endocrinology
hormone hormone
Membrane-associated Cell membrane
steroid receptors
hsps
hsps
Dimerized hormone/ Interaction with cell
receptor complex signalling pathways e.g.
MEK/ERK, PI3-K/AKT
Translocation to Nuclear membrane
nucleus and binding
to DNA
Recruitment of co-activators/
co-repressors of gene
transcription
105
TATA box
DNA Gene
transcription
Figure 6.2 Signalling pathways for steroid hormones. For details see text.
The major secretions of the anterior pituitary gland, the GH pulse frequency and secretion is high during puberty
cells from which they are secreted, and the proportion of and declines in senescence.
these secretory cells in the adenohypophysis are:
Control of GH secretion
● growth hormone (GH) from somatotrophs (acido-
phils)—50% ● Stimulation – GHRH, hypoglycaemia, decreased free
fatty acids, starvation, sleep exercise, stress, puberty
● prolactin (PRL) from lactotrophs (acidophils)—10–15% oestrogens and androgens, α-adrenergic agonists, and
(increasing in pregnancy) dopamine agonists.
● thyroid-stimulating hormone (TSH) from thyrotrophs ● Inhibition – somatostatin, hyperglycaemia, increased free
(basophils)—3–5% fatty acids, insulin-like growth factors (IGFs), growth
hormone (short loop feedback), progesterone, gluco-
● adenocorticotrophic hormone (ACTH) from corticotro- corticoids, β-adrenergic agonists, and dopamine (DA)
phs (basophils—15–20%) antagonists (see Figures 6.4 and 6.5).
● gonadotrophins, luteinizing hormone (LH), and follicle- Actions of GH
stimulating hormone (FSH) from gonadotrophs (baso-
phils)—10%. ● GH has short-term (acute stress response) actions, which
are direct, and long-term indirect (anabolic) actions.
Growth hormone
● GH raises plasma glucose by directly stimulating gluco-
This is a large protein hormone (192 amino acids) that is neogenesis in the liver and reducing the uptake of glucose
structurally similar to prolactin. Its synthesis and secretion in peripheral tissues. It mobilizes fat and increases circu-
are stimulated by growth hormone-releasing hormone lating free fatty acids by stimulating the action of hormone
(GHRH) and inhibited by somatostatin, both of which are sensitive lipase, a major mobilizer of fat from adipose
released by neurosecretory cells in the hypothalamus. Their tissues.
integrated actions result in the secretion of discrete pulses
of GH throughout the day (approximately six pulses) with ● Long-term anabolic GH actions are mediated through the
an increased pulse amplitude related to the onset of sleep. stimulation of the synthesis and secretion of IGFs and
Basic Sciences for Obstetrics and Gynaecology Parvicellular neurons 3rd ventricle
projecting to capillaries in
Magnocellular neurons
the median eminence projecting to neural
(posterior) lobe
OC
Superior
hypophyseal artery
Hypophyseal
portal vessels
Secondary Sphenoid bone
capillary network
Inferior
Anterior lobe hypophyseal artery
Posterior lobe
106
Figure 6.3 Hypothalamo-pituitary GH, PRL, TSH, ACTH, OXY, VP/ADH
connections. LH, FSH
IGF-binding proteins (IGFBPs) from the liver. GH stimu- Prolactin
lates the uptake of amino acids for protein synthesis and
increases lean body mass. IGFs stimulate somatic cell ● Unlike all other anterior pituitary hormones, the predom-
growth with an increase in the size and function of organs inant hypothalamic control of prolactin secretion is inhibi-
and tissues. IGFs have a (long-loop) negative feedback ef- tory through dopamine (DA) secreted by neurosecretory
fect on GH secretion. cells (Figure 6.4).
● IGF-1 is a relatively good index of plasma GH 24-hour ● Secretion is stimulated by TRH, although other hypotha-
secretion because GH itself is released in a pulsatile fash- lamic stimulatory factors have been proposed. Pregnancy,
ion and IGF-1 has a long half life. lactation (suckling), oestrogens, opioids, stress, and dop-
amine antagonists are also stimulatory (Figure 6.5).
Dopamine – GHRH + TRH + CRH + GnRH +
TRH + Somatostatin – Somatostatin – Vasopressin +
PRFs+
Prolactin Growth TSH ACTH LH & FSH
hormone Basophils
Acidophils Gonads
Mammary Liver/IGFs Thyroid Adrenal
glands metabolism gland cortex
Figure 6.4 The hypothalamic control of secretions from the adenohypophysis.
Hypoglycaemia/ +ve +ve Pregnancy/ Chapter 6 Endocrinology
stress/exercise −ve oestrogens
Hypothalamus
GHRH Dopamine
Somatostatin TRH/PRFs
−ve
Anterior pituitary gland
GH PRL
Liver
↑ Blood Gluconeogenesis Mammary glands Suckling
glucose IGFs immune function
Increased linear growth/ 107
organ & tissue size
Figure 6.5 Actions of growth hormone (GH) and prolactin (PRL) and the feedback signals regulating their secretion.
● Prolactin is secreted in a pulsatile fashion and the ampli- Effects of suckling
tude of pulses increases with the onset of sleep.
Suckling stimulates the nerve endings (neural receptors) in
● The major function of prolactin is the stimulation of the nipple, which are wired up to the CNS to set up three
breast development and milk production in females, separate efferent effects:
although males have the same circulating concentrations
of prolactin. 1. The release of oxytocin from the posterior pituitary,
which is delivered to the breast where it causes the
● Numerous other functions have been attributed to this contraction of the myoepithelial cell leading to milk
hormone including salt and water balance, growth and ejection.
development, metabolic actions, immunoregulation, and
reproductive functions. Excess prolactin may cause infer- 2. Reduction of the secretion of dopamine from the hypo-
tility due to the inhibitory actions of prolactin on GnRH thalamus so that the output of prolactin from the pitu-
secretion. itary is maintained and milk synthesis is increased.
Physiology of lactation 3. Reduction of GnRH release leading to reduced output
of FSH and LH and suspension of ovarian activity for
● The growth and development of mammary tissue (alveo- approximately three months, although this is not univer-
lar lobules) occurs throughout pregnancy and is stimulated sally observed in all women.
by oestrogen and progesterone. Prolactin, GH, and corti-
sol must be present in the system for maximal growth. Thyroid hormones
● During pregnancy, the high concentrations of circulating Synthesis and secretion
oestrogens increase prolactin secretion, but along with
progesterone block the synthesis of milk. After delivery The synthesis and secretion of thyroid hormones is stimu-
oestrogen levels fall, withdrawing the blockade on milk lated by the anterior pituitary hormone TSH, and requires
synthesis. The numbers of prolactin receptors in mam- two substrates – I– and thyroglobulin (see Figure 6.6).
mary tissues increase and milk synthesis begins.
● Circulating iodide (I–) is actively taken up by follicular cells
● Suckling is required to maintain milk synthesis and through a Na+/I– symporter. The gland takes up about
the high prolactin levels. If there is no suckling, prolactin 125 μg/day against an electrical and concentration
levels fall. gradient and can concentrate I– up to 30 to 50 times the
concentration of the general circulation.
Basic Sciences for Obstetrics and Gynaecology Lumen/colloid
H2O2 3 4 5 6
Organification
Iodide to OH MIT
iodinating + TPO DIT
intermediate
Apical TPO CH2 Coupling T4, T3
membrane 2 H2N C COOH
Pendrin H
I− Tyrosine residues
on thyroglobulin
Follicular cell Thionamides Iodinated
Iodide (I−) intermediates
Na+ Na+ 1
108
Basolateral TSH
membrane
NIS–sodium iodide symporter
Figure 6.6 Synthesis of thyroid hormones. For details see text. Thioinamides, important anti-thyroid drugs, inhibit organification
of tyrosine residues.
● At the follicular colloid interface I– is oxidized to iodine ● On average approximately 100 μg of T4 and 10 μg of
by H2O2, a reaction catalysed by thyroid peroxidise T3 are secreted daily. T4 has little biological activity and
(TPO). The iodine is then incorporated into the about 80% is converted to T3 in the liver and kidneys, the
tyrosine residues of the large thyroglobulin protein. rest being converted to T3 in target tissues, e.g. the pitu-
A tyrosine residue can take up a maximum of two iodine itary gland. Small amounts of T4 are converted to reverse
molecules to form di-iodotyrosine (DIT), which is the T3, which is inactive. Thyroid hormones exist in the cir-
most common form produced when iodine is readily culation mainly bound to thyroid-binding globulin (TBG)
available, in contrast to mono-iodotyrosine (MIT), which with only a small fraction existing in free form and able to
is produced in greater quantities in iodine deficiency enter cells.
states.
Control of secretion
● Coupling of two DIT molecules forms thyroxine (T4), and
coupling of one DIT and one MIT forms tri-iodothyronine The synthesis and secretion of T3 and T4 are controlled by
(T3). The thyroglobulin with coupled iodinated tyrosine TSH, which is released in response to TRH and inhibited
residues is stored in the lumen of the follicle. by somatostatin secreted by hypothalamic neurosecretory
cells (Figure 6.7). TSH rapidly increases all the steps in the
● Secretion of thyroid hormones involves pinocytosis synthesis and degradation of thyroid hormones, and in
of thyroglobulin droplets at the apical surface, release of excess causes hypertrophy of the thyroid cells leading to
T4 and T3 by lysosomal enzymes, and secretion into the increased size of the thyroid gland or goitre. Goitre is sim-
circulation and the basal surface of the follicle cell. ply an enlarged thyroid gland and does not correlate with
functional status. Although there are 50 T4 for every T3 mol-
● The thyroid gland secretes approximately 20 T4 mole- ecule in the circulation, T3 and T4 exert equipotent negative
cules for every T3 molecule released. However, there feedback effects on the hypothalamic pituitary axis, because
is 50 times more T4 than T3 in the general circulation when T4 is taken up by nerve cells or thyrotrophins, it is
because T4 has a higher affinity for binding proteins, hangs immediately converted to T3, the biologically active form
around for much longer, and has a longer half life of six of the hormone.
days (compared to only one day for T3).
Stress/circadian Environmental Chapter 6 Endocrinology
rhythm temperature
−ve Hypothalamus −ve
CRH/VP TRH
−ve Anterior pituitary gland −ve
ACTH TSH
Adrenal cortex Thyroid gland
Cortisol + androgens T3/T4 Figure 6.7 Control of the synthesis
and secretion of cortisol and thyroid
hormones.
109
Physiologic actions of thyroid hormones ● Clinical features of hyperthyroidism include heat intol-
erance, tachycardia, tremor, anxiety, and a warm, moist
Thyroid hormones act on virtually every cell in the body skin. Features of hypothyroidism include cold intoler-
through nuclear receptors. Their main effects include: ance, fatigue, dry, scaly skin, and bradycardia.
● Stimulation of the basal metabolic rate (BMR) in most Maternal and fetal thyroid function
tissues (except the brain, spleen, and testis) by increas-
ing the number of mitochondria and stimulating the During pregnancy there is an increased size and vascular-
respiratory chain by increasing membrane Na+-K+ ity of the thyroid gland. Under the influence of increasing
ATPase. oestrogen during pregnancy, TBG levels increase during the
first trimester and remain high until term. Thus, total T4 and
● Chronotropic and inotropic effects on the heart, some of T3 are increased and there may be a small increase in free T4
which may be mediated by non-genomic events and may and T3. The increased glomerular filtration rate in pregnancy
involve changes in the number and affinity of β adrenergic results in an increased loss of iodine but there is no reduc-
receptors. tion in serum iodide unless a woman is iodide deficient.
● Thyroid hormones are absolutely necessary for normal Fetal thyroid function begins at 10 weeks and this is im-
brain development and maturation. Deficiency of thyroid portant since very little maternal thyroid hormone crosses
hormones in fetal, neonatal, and early childhood stages the placenta, although iodine is actively transferred. The se-
of development can result in impaired neuropsychologi- cretion of fetal thyroid hormones and TSH reaches a peak
cal function and impaired growth. The most severe at 20–30 weeks’ gestation; thereafter TSH secretion de-
effects are caused by in utero deficiency, which leads to clines whilst thyroid hormones continue to rise, although
cretinism. levels are always less than maternal levels. TSH secretion
rises within minutes after birth and thyroid hormones con-
● Fetal growth rate may be normal in the absence of thy- sequently rise over the next 24 hours. Hormone levels re-
roid hormones; however, at birth thyroid hormone re- turn to normal adult levels after about 3 days. Neonatal
placement must be initiated within 2 weeks to avoid thyroid function, along with phenylketonuria, is screened for
irreversible nervous tissue damage. in the Guthrie test. TSH concentration in capillary blood de-
pends on the time after birth when the sample was obtained
● Thyroid hormone is considered a major anabolic hor- and other factors such as prematurity and illness.
mone and is required for the synthesis and secretion of
GH such that if a pre-pubertal individual is hypothyroid,
growth, including bone ossification, is retarded.
Basic Sciences for Obstetrics and Gynaecology The adrenal gland (steroids and catecholamines)
Embryology and functional anatomy Therefore, ACTH can increase adrenal androgen output but
The fetal adrenal cortex develops from the coelomic meso- cannot do so in the gonads, which are controlled by LH.
derm whilst the adrenal medulla is formed from an adja- The adrenal medulla secretes adrenaline (80%) and nora-
cent sympathetic ganglion that is derived from neural crest
drenaline (20%) from the chromaffin cells.
cells. The fetal cortex engulfs the sympathetic ganglion and Synthesis of adrenal steroids
the cells differentiate into the secretory cells of the adrenal and their control
medulla. More mesodermal cells surround the fetal cortex
and these will eventually form the permanent adult adrenal All steroids are derived from cholesterol (Figure 6.9).
cortex. At birth there is still extensive fetal adrenal cortex ● The synthesis and secretion of aldosterone is controlled
but the glomerulosa and fasciculata layers are differentiated. by angiotensin II and independently by K+. The sensory
After 1 year the fetal cortex has all but disappeared but inputs and regulation of the renin-angiotensin-aldoster-
the zona reticularis does not differentiate until the end of one system (RAAS) functional unit is discussed in detail in
the third year after birth. The adrenal gland sits on the top the renal section. Although ACTH causes a transient in-
of the kidney (ad-renal) and about 80–90% of the adrenal crease in aldosterone secretion this is not an important
gland mass is comprised of the cortex, with about 10–20% or significant regulator of aldosterone secretion.
adrenal medulla.
● The synthesis and secretion of cortisol is controlled by
The adrenal cortex produces three major classes of ACTH, stimulated by corticotrophin-releasing hormone
steroids, each secreted from different layers of the cortex (CRH) from the hypothalamus. In addition, vasopressin
(Figure 6.8): neurosecretory cells that terminate on the hypophyseal
110 ● aldosterone (a mineralocorticoid) from the zona glom- portal capillaries can potentiate the action of CRH on the
erulosa corticotrophs of the anterior pituitary gland.
● cortisol (a glucocorticoid) from the zona fasciculata ● ACTH secretion from the corticotrophs is controlled by
negative feedback effects of circulating cortisol both at
● androgens, mainly dehydroepiandrosterone (DHEA) the level of the hypothalamus (CRH and VP) and pitu-
and its sulphated form (DHEAS) and to a lesser extent itary gland (ACTH). This feedback loop, however, can be
androstenedione, from the zona reticularis. overridden by both internal and external factors such as
This functional zonation of steroid secretions is, in part, stress (emotional or trauma), which increases ACTH/
related to steroidogenic enzymes expressed in different lay- cortisol secretion, and the internal ‘biological clock’,
ers and blood flow in the gland (from the outer cortex drain- which produces a circadian rhythm of cortisol secretion
ing inwardly to venules of medulla). The zona fasciculata and with peak levels secreted in the early morning, declining
reticularis constitute a functional unit controlled by ACTH. to a nadir in the evening (Figure 6.7).
Cortex 80–90% Capsule
Zona
Glomerulosa Fasiculata
(aldosterone) (cortisol) glomerulosa
Reticularis Zona Blood Capillary
(androgens) fasiculata flow
Zona
reticularis
Medulla 10–20% Kidney Medulla
(epinephrine)
Venule
(norepinephrine)
Venule
Figure 6.8 Gross anatomy of the adrenal cortex and functional zonation of the gland in relation to the blood supply draining from
the capsule of the gland to the adrenal medulla. Reproduced from SS Nussey & SA Whitehead, Endocrinology, an integrated approach,
Taylor and Francis, with permission. Copyright 2001.
Cholesterol CYP17, 17α CYP17, Chapter 6 Endocrinology
P450 scc hydroxylase 17/20 lyase
Pregnenolone 17-OH Pregnenolone DHEA
3β-HSD2 17-OH Progesterone Androstenedione
3β-ST
Progesterone Deoxycortisol DHEA-S
Cortisol
CYP21A Zona Zona
fasciculata reticularis
CYP11B1 Deoxycorticosterone
CYP11B2 Corticosterone
Aldosterone
111
Zona glomerulosa
Figure 6.9 Steroid synthesis in the adrenal cortex. CYP, the family of genes coding for specific steroidogenic enzymes;
HSD, hydroxysteroid dehydrogenase; ST, steroid sulphatase.
● Once released, cortisol is bound to cortisol-binding glob- glycogenolysis in the liver. Without cortisol, fasting
ulin (CBG) with a small fraction (<5%) being free to enter hypoglycaemia develops rapidly. Catecholamines pro-
target cells and initiate glucocorticoid effects. mote glycogenolysis, lipolysis, bronchodilatation, and
vasoconstriction. Without cortisol blood pressure falls.
The secretion of adrenal androgens is also controlled by ● Glucocorticoids also have effects on the brain, bone, car-
ACTH, although these control and feedback effects are less diovascular system, kidneys, skin, connective issue, and
well defined compared with the control of cortisol. How- the fetus.
ever, excess ACTH secretion resulting from a pituitary ade- ● Excess cortisol secretion (Cushing’s syndrome/disease)
noma (20 Cushing’s disease) is associated with excess caused by an endogenous source (e.g. ACTH-secreting
androgen secretions. pituitary adenoma or adrenal tumour) or by exogenous
steroidal anti-inflammatory drugs results in proximal
Physiological actions of myopathy, bruising, scarring, and purple striae round
glucocorticoids (cortisol) the abdomen, loss of bone mass, hypertension, and
depression.
Glucocorticoid receptors are widely distributed in the body. ● Primary adrenocortical deficiency—Addison’s disease—
Once activated by steroid binding they initiate transcriptional causes low systolic blood pressure, weight loss due to
activity, although there is evidence that glucocorticoids can reduced appetite, and skin pigmentation due to excess
also initiate non-genomic events (Figure 6.2). The actions ACTH (reduction of negative feedback), which interacts
of glucocorticoids are diverse and these are summarized in with melanocortin receptors in the skin.
Table 6.1.
Maternal adrenocortical function
● Cortisol is generally a stress hormone like adrenaline, GH,
and glucagon. Its overall effect on metabolism is essentially Total cortisol and its binding globulin increase during preg-
anabolic in the liver and catabolic in muscle and adipose nancy, as well as an increase in the free fraction of cortisol.
tissue, breaking down stored glycogen and triglycerides to ACTH levels also rise during pregnancy and probably cause
raise circulating levels of blood glucose and fatty acids. the pigmentary changes that occur.
● Cortisol has important permissive actions on glucagon and
catecholamines. Glucagon requires cortisol to promote
Basic Sciences for Obstetrics and Gynaecology Table 6.1 Major biological actions of cortisol
System Specific target Physiological function
Metabolism Liver Increased glycogen synthesis and gluconeogenesis
Skeletal muscle Increased proteolysis, decreased protein synthesis, increased glycogenolysis,
decreased GLUT-4 mediated glucose uptake
Adipose tissue Increased lipolysis, decreased lipogenesis
Plasma glucose Fasting state cortisol contributes to maintenance of plasma glucose. In stress,
cortisol increases blood glucose at expense of muscle protein. Permissive effect on
lipolytic actions of adrenaline and GH in adipose tissue
Cardiovascular Heart Increased contractility
system Blood vessels Maintenance of vascular tone. Increased vascular reactivity to catecholamines
Kidney Increases GFR, decreases calcium reabsorption. In excess has mineralocorticoid
action (Na+ retention)
Skin/connective Fibroblasts Inhibits proliferation
tissue Collagen Inhibits formation
Bone, cartilage Increases bone resorption, inhibits bone-forming activity of osteoblasts
Immune system Inflammatory Inhibits phospholipase A2, a key enzyme in prostaglandin, leukotriene, and
response thromboxane synthesis. Stabilizes lysosomes
Immune response
Inhibits monocyte proliferation, decreases circulating T lymphocytes
112 Central nervous Psychiatric Maintains emotional balance, decreases REM sleep, induces hippocampal atrophy
system parameters
Normal development of CNS, retina, skin, GI tract, and lungs
Fetus Development Stimulates production of surfactant
Lung
Adrenal androgens and congenital adrenal expanded extracellular fluid compartment, and high
hyperplasia (CAH) blood pressure.
● The effects of adrenal androgens are minimal except in ● 17α-Hydroxylase is absent in the zona glomerulosa tis-
post-menopausal women, where they provide a substrate sue so its deficiency affects only the zona fasciculata-
for peripheral conversion to oestrogens. reticularis of the adrenal, the Leydig cells of the testes,
and the ovaries, resulting in reduced cortisol, adrenal and
● Fetal exposure to excess androgens can cause virilization testicular androgens, and oestrogens from the ovaries,
of females and this occurs in CAH, an autosomal respectively.
recessive syndrome resulting from defects in enzymes
responsible for steroidogenesis in the fetal adrenal Adrenal medulla—noradrenaline
gland. The most common form is a defect in 21 hydroxy- and adrenaline
lase (CYP21A2), although defects in 11β-hydroxylase
(CYP11B1), 17α-hydroxylase (CYP17), and 3β- ● Noradrenaline (NA) is synthesized from tyrosine via
hydroxysteroid dehydrogenase (HSD) also occur very dihydroxyphenylalanine (DOPA) and dihydroxyphenyl-
rarely. All enzyme deficiencies lead to a deficiency in cor- ethylamine (dopamine).
tisol and because cortisol is the main feedback signal to
ACTH secretion, ACTH increases leading to adrenal hy- ● NA is widely distributed in tissues associated with sympa-
perplasia and increased adrenal androgen production. thetic innervation but the conversion of NA to adrena-
line (A) occurs almost exclusively in the adrenal medulla.
● Deficiency of CYP21A2 inhibits the synthesis of cortisol
and aldosterone so that the pregnenolone and progester- ● The secretion of NA and A from the adrenal medulla is
one are shunted into the synthesis of androgens stimulated by preganglionic sympathetic neurons, which
(Figure 6.9). Lack of cortisol feedback effects increases release acetylcholine in response to a variety of stressful
fetal ACTH secretion and this further stimulates andro- stimuli.
gen secretions.
● Developmentally, the neural crest cells of the adrenal
● 11β-Hydroxylase deficiency affects only the adrenal medulla are the postganglionic neurons that didn’t quite
cortical tissues of zona glomerulosa, and fasciculata- differentiate completely into neurons but retained cate-
reticularis. There is reduced aldosterone but the excess cholamine secreting capability.
amounts of weak mineralocorticoids including deoxycorti-
sone may lead to increased Na+ and water reabsorption, ● There are two major classes of adrenoreceptors, α and
β, which are further subdivided into α1A, 1B, 2A, and 2B and
β1, 2, and 3.
● The physiological effects of catecholamines on their tubule (PCT), and increases the exchange of calcium Chapter 6 Endocrinology
receptors have been characterized as preparing us for from the interstitial fluid pool surrounding bone, which is
‘fight or flight’ and overall they increase heart rate and saturated with calcium and phosphate. 113
stroke volume, increase blood pressure, mobilize glucose,
and stimulate lipolysis through β adrenoceptors. Blood ● In the longer term PTH slowly increases the formation
flow to the splanchnic bed is reduced by vasoconstriction and activity of osteoclasts, the cells that reabsorb bone.
mediated by α adrenoceptors. These same receptors can This releases calcium and phosphate into the circulation.
also cause vasodilatation in muscle. PTH also increases the formation of 1,25-(OH)2-D3 (the
active form of vitamin D) in the PCT.
Hormonal control of calcium and
phosphate (parathyroid hormone ● Excess PTH (e.g. primary hyperparathyroidism due to a
and vitamin D) tumour) causes bone resorption, hypercalcaemia, and
hypophosphataemia.
These two hormones are important in maintaining circulat-
ing levels of calcium required for bone formation, secretory ● Primary hypoparathyroidism is due to inadequate PTH
processes, muscle contraction, enzymic processes, stabiliza- secretion (usually as a result of thyroid surgery). This
tion of membrane potentials, and blood coagulation. Both results in low plasma calcium, high plasma phosphate,
hormones raise blood calcium levels (Figure 6.10). Calcium and tetany.
is very precisely regulated almost exclusively by PTH, whilst
phosphate is primarily auto-regulated by the kidney, although ● Secondary hyperparathyroidism is caused by a fall in
its excretion can be increased by PTH. serum calcium (e.g. in vitamin D deficiency). PTH levels
rise leading to excess loss of phosphate in the urine.
● PTH is secreted from the parathyroid glands (four small
glands sitting on each pole of the two lobes of the thyroid ● Secondary hypoparathyroidism is caused by an increase
gland) in response to low levels of free unbound calcium. in plasma calcium levels (e.g. excessive vitamin D intake).
The only important physiological stimulus regulating the The biochemical profile will show raised plasma calcium,
release of PTH is reduced free calcium. depressed PTH levels, and raised plasma phosphate.
● PTH rapidly stimulates the reabsorption of Ca2+ from the ● Vitamin D (cholecalciferol) is mainly synthesized in the
distal convoluted tubule (DCT) of the kidney, inhibits skin under the action of UV light or sunlight. It is then
phosphate reabsorption from the proximal convoluted transported to the liver where it is hydroxylated to
25-(OH)-vitamin D, the main circulating form, and again
in the kidney to 1,25-dihydroxycholecalciferol, the bio-
logically active form of vitamin D (Figure 6.10).
Skin 7-dehydrocholesterol Circulating (free) Ca2+
UV light
Vitamin D3 Parathyroid glands
Liver (cholecalciferol) (Ca2+ receptors)
25 hydroxyvitamin D3 Stimulation of Parathyroid hormone
hydroxylase enzyme
Kidney
1,25-dihydroxyvitamin D3
Increased Ca2+ Increased Increased Ca2+ re-
absorption in the gut, serum Ca2+ absorption in the kidney,
permissive action with stimulation of osteolysis
PTH on bone resorption
and bone resorption
Figure 6.10 Synthesis of vitamin D (cholecalciferol) and the regulation of ‘free’ calcium in the circulation by parathyroid hormone
(PTH) and di-hydroxy cholecalciferol. Cells of the parathyroid gland detect the levels of Ca2+ in the circulation by a unique calcium
sensing receptor.
Basic Sciences for Obstetrics and Gynaecology ● During pregnancy there is an increased synthesis of ● The main signal for the secretion of calcitonin is raised
maternal vitamin D, which helps to meet the increased free calcium concentration.
demands for calcium.
● Calcitonin lowers plasma calcium by suppressing the
● Its main actions include increased calcium reabsorption bone resorption activity of osteoclasts.
from the small intestine, and a permissive effect on the
action of PTH on bone. PTH increases the action of the ● It is not a major regulator of calcium homeostasis in
1α-hydroxylase enzyme in the kidney. Vitamin D defi- humans and Ca2+ levels are unaffected in the absence of
ciency causes hypocalcaemia and osteomalacia (rickets calcitonin, e.g. after thyroidectomy.
in children).
Effect of gravity and weight bearing
● At very high levels vitamin D increases bone resorption.
● Weight bearing stress increases bone mineralization, and
Calcitonin inactivity and absence of weight bearing stress promotes
bone demineralization.
● Calcitonin is a water-soluble peptide hormone, which is
released from the parafollicular C-cells of the thyroid ● With loss of gravity, plasma calcium and urinary excre-
gland. tion of calcium rise whilst PTH levels fall.
● The C-cells are independent of the thyroid gland and are ● Excess bone demineralization and remodelling is associ-
indeed of different embryological origin, arriving in the ated with a rise in serum alkaline phosphatase level, and
thyroid gland by cell migration. increased urinary excretion of hydroxyproline (break-
down product of collagen).
Hormones of the hypothalamic-pituitary gonadal axes
114
The steroid hormones of both the testes and ovaries are The functional cells of the testis are:
controlled by gonadotrophin-releasing hormone (GnRH), 1. The seminiferous tubules—comprised of spermatogonia,
which stimulates the release of LH and FSH from the spermatocytes at various stages of development, and
gonadotrophs of the anterior pituitary gland (Figure 6.11). the Sertoli cells, which form tight junctions with each
These hormones control steroid synthesis of the testes other and form the blood-testis barrier.
and ovaries. The major hormones include testosterone
secreted by Leydig (interstitial) cells of the testes, and 2. The Leydig cells, which synthesize and secrete
oestradiol and progesterone secreted by developing testosterone.
ovarian follicles and the corpus luteum (Figure 6.11).
GnRH GnRH −ve +ve
−ve
LH FSH LH FSH
−ve −ve +ve
Leydig cells Sertoli cells Thecal cells Granulosa cells
Testosterone Androgen binding Androgens Oestradiol
protein/Inhibin
Figure 6.11 Control of hormone
secretions in the gonads and their Luteal cells −ve
feedback effects on the hypothalmo-
pituitary axis. Oestradiol exerts a Progesterone/oestradiol
positive feedback effect at mid-cycle
to stimulate the pre-ovulatory surge.
The functional cells of the ovary are: ● The actions of testosterone on the penis, scrotum, and Chapter 6 Endocrinology
prostate and other peripheral tissues are dependent on
1. The follicles in the cortex of the gland, which synthesize its conversion to the more active form dihydrotestoster- 115
and secrete mainly oestradiol and progesterone. one (DHT) by the enzyme 5α-reductase in target cells.
2. The corpus luteum, which secretes progesterone and ● Testosterone is mainly metabolized to androsterone
oestradiol and is important in maintaining pregnancy in and etiocholanolone, and excreted as water-soluble
the first trimester. glucuronides and to a lesser extent sulphates. DHT is
excreted as 3α- and β-androstanediols.
Steroid synthesis and development of mature sperm and
oocytes are controlled by LH and FSH. Ovarian function
Testicular function The maximum complement of primordial follicles in the
ovary is achieved at 20 weeks’ gestation when it is ap-
Spermatogonia (46XY) are the precursors of spermato- proximately 7 million, and decreases progressively from this
cytes and they divide mitotically to maintain a source of point such that at birth each ovary contains about 2 million
cells for spermatogenesis. Spermatognoia push their way primordial follicles and 300 000 by menarche. Primordial
through the tight junctions between adjacent Sertoli cells follicles consist of a single oocyte halfway through its first
and undergo two meiotic divisions to become secondary meiotic division and surrounded by a flattened layer of
spermatocytes. By a process known as spermiogenesis (loss granulosa cells.
of cytoplasm, chromatin condensation, formation of a cuff
of mitochondria in the mid-piece, and flagellum formation) Folliculogenesis
they become spermatids and then mature sperm. During
this entire process, which takes about 9–10 weeks, they ● Cohorts of follicles begin to develop into primary and
are moving towards the lumen of the seminiferous tubule then secondary follicles. The oocyte enlarges, becomes
(Figure 6.12). surrounded by the zona pellucida, granluosa cells divide
forming several layers, and fibroblasts of the ovarian
Spermatogenesis is ‘nurtured’ by the Sertoli cells, which stromal cells differentiate into the inner thecal cells.
organize waves of spermatogenesis.
● This process is considered to be independent of gonado-
● Sertoli cells synthesize and secrete androgen-binding pro- tophins, although there is increasing evidence that this
tein into the seminiferous tubules, which binds up testos- initial growth is dependent on hormones and growth
terone to about 50-fold the concentration found in plasma. factors.
The target cell of FSH in the adult male is the Sertoli cell,
which is absolutely essential for sperm development. ● The initiation of follicular growth to a preantral follicle
(∼0.2 mm) takes place over well in excess of 120 days.
● Sertoli cells possess aromatase activity and therefore Further, and final, maturation takes about 65 days, and
convert androgens to oestrogens, and also transport over two menstrual cycles cohorts of preantral follicles
sperm into the lumen of the seminiferous tubules and and antral follicles and the oocyte become surrounded by
produce inhibin, which exerts a negative feedback effect the cumulus oophorous.
on FSH secretion at the level of the pituitary gland.
● They become recruitable follicles and during the luteal
● Normal spermatogenesis requires the synergistic actions phase of the second menstrual cycle follicles that have
of testosterone and FSH on Sertoli cell function. not undergone atresia may be ‘selected’ for further
development.
Testosterone is synthesized and secreted by the Leydig cells
in response to LH. Up to 95% of circulating testosterone is ● Over a period of 5 days, only one of these follicles is
derived from the testis, and the rest from peripheral conver- selected and becomes the dominant follicle. Then, over
sion of adrenal androgens. 10 days, this grows from about 2 mm to 20 mm, secreting
increasing amounts of oestradiol and becoming a mature
● Only 2% of circulating testosterone is in the free form; the Graafian follicle.
rest is either bound to albumin (∼40%) or SHBG (∼60%).
● The later stages of follicular development (preantral to
● Under normal conditions, testosterone exerts negative dominant) are controlled by gonadotrophins, particularly
feedback effects on LH secretion (not on FSH) and tes- FSH, and throughout this process there is continued fol-
tosterone is important in the development and mainte- licular atresia.
nance of the reproductive tract.
Endocrinology of the menstrual cycle
● Injection of exogenous testosterone (e.g. methyltestos-
terone) suppresses LH secretion, thus removing the Follicular phase
stimulus for testosterone production by the Leydig cells.
The Leydig cells undergo atrophy in the long term, and ● This begins with the first day of menstruation and is
produce less testosterone for the nourishment of the associated with a rise in FSH secretion that stimulates
Sertoli cells, which results in diminished sperm produc- the growth and differentiation of cohorts of preantral
tion. A very high level of methyltestosterone also exerts and antral follicles. As a result oestrogen synthesis and
a modest negative feedback on FSH levels.
Basic Sciences for Obstetrics and Gynaecology Interstitial or Testosterone Testicular vein
Leydig cells
Sertoli
Basement cell
membrane
Sertoli
Spermatogonium cell
Tight junction Late
Primary spermatids
spermatocyte
Secondary
spermatocyte
Early
A spermatids
116 Spermatogonium
46 (XY)
Primary 1
spermatocyte 2
1st meiotic
division
2nd meiotic
23 (Y) division 23 (X)
Secondary 23 (Y) 23 (X) 23 (X)
spermatocyte 23 (Y) Spermiogenesis
Figure 6.12 Cross-section of a Spermatids
seminiferous tubule (A) and the
process of spermatogenesis (B). Mature sperm
Reproduced from SS Nussey & SA
Whitehead, Endocrinology, an B
integrated approach, Taylor
and Francis, with permission.
Copyright 2001.
secretion rises, reaching a peak at mid-cycle, whilst LH and Ovulation occurs 9–12 hours after the LH surge. Only
FSH secretions decline (negative feedback) (Figure 6.13). the LH surge is required for ovulation.
● The circulating oestrogen stimulates the female sex
● When oestrogen levels reach a peak concentration (>750 accessories.
pmol/l) sustained for 24–48 h, oestrogen no longer pro-
vides negative feedback but switches to a positive feed- Luteal phase
back effect on GnRH/gonadotrophin secretion, resulting
in a pre-ovulatory surge of LH and a smaller surge of FSH ● The granulosa and thecal cells of the empty follicle rapidly
(Figure 6.13). This induces completion of the first meiotic proliferate and form the corpus luteum. The corpus lu-
division of the oocyte (to give a mature oocyte and teum synthesizes progesterone and to a lesser extent
polar body) and initiation of the second meiotic division. oestradiol (Figure 6.13).
Follicular phase Luteal phase Chapter 6 Endocrinology
Intercycle Preovulatory
FSH rise LH surge
Anterior LH
pituitary
hormones FSH
Progesterone
Ovarian Oestradiol
hormones
Follicle Ovulation
Corpus luteum
2.0 mm 20 mm Luteolysis
Recruitable Selected Dominant Ovulation
Atresia
Uterine
endometrium
2 4 6 8 10 12 14 16 18 20 22 24 26 28 2 Figure 6.13 Hormonal profile during a 117
typical menstrual cycle in relation to
Menses final stages of folliculogenesis, ovulation,
formation of the corpus luteum, and
Proliferative Secretory changes in the endometrium.
phase phase
● During the luteal phase, progesterone provides the major FSH, the androgens are converted to oestrogens under
feedback to LH secretion. the action of aromatase.
● Just prior to ovulation, granulosa cells develop LH recep-
● Small amounts of gonadotrophins, particularly LH, are tors and can respond to the pre-ovulatory surge of LH.
required to maintain the secretory activity of the corpus Steroid secretions of the corpus luteum are mainly stimu-
luteum but, in the absence of conception, the corpus lu- lated by LH.
teum undergoes luteolysis (a process not well defined but ● Oestradiol and progesterone are transported in the cir-
believed to be apoptotic) about 14 days after ovulation. culation bound to sex hormone-binding globulin (SHBG)
and albumin, with progesterone having a low affinity for
● The loss of negative feedback from oestradiol and pro- SHBG but a higher affinity for cortisol-binding globulin.
gesterone induces the intercycle rise in FSH secretion and About 2% of these hormones exist in free form in the
another cycle begins. circulation.
● Because oestradiol and progesterone are lipid-soluble
● If conception occurs the corpus luteum does not undergo and bound to plasma proteins, they cannot be easily
luteolysis but is maintained by human chorionic gonado- filtered or excreted by the kidneys. Oestradiol is excreted
trophin (HCG) secreted by the developing placenta. as a conjugate but is mostly converted to oestrone and
oestriol.
Endometrial changes during the menstrual cycle ● Progesterone is metabolized to pregnanediol and oestra-
diol to estrone and then oestriol or catecholoestrogens
● Proliferative phase: Oestradiol increases the rate of in the liver. This is then conjugated with glucuronide or
mitotic division of endometrial glandular cells leading to sulphate prior to excretion in the urine.
proliferation (Figure 6.13).
Endocrinology of pregnancy
● The secretory phase: Under the action of oestradiol
and progesterone further proliferation and secretory Throughout pregnancy the fetoplacental unit secretes
activity occur during the luteal phase. hormones into the maternal bloodstream and these alter
the function of all maternal endocrine glands (Figure 6.14).
Ovarian steroidogenesis
● Progesterone and androgen production in thecal cells is
stimulated by LH.
● The androgens diffuse across the basement membrane
into the granulosa cell layer where, under the influence of
The placenta can synthesize and secrete proteins but cannot oestriol, and oestrone steadily increase to term. The
Basic Sciences for Obstetrics and Gynaecology
synthesize steroids de novo and therefore requires steroid high oestrogen output drives an increase in the expres-
μg/ml hCG, hPL
precursors of fetal or maternal origin. sion of oxytocin receptors in the myometrium as preg-
The following maternal serum hormone changes occur nancy progresses.
during pregnancy: ● Androgens are derived from the fetoplacental unit and
● Placental proteins: HCG peaks at 10 weeks and decreases testosterone levels rise 10-fold compared to prepreg-
to a lower plateau. Human placental lactogen (hPL) rises nancy levels, DHEA falls, and there is a small rise in an-
with placental weight, coinciding with the period of maxi- drostenedione.
mal fetal growth. It induces insulin resistance and has
been used as an index of placental wellbeing. ● Progesterone is synthesized mainly by the corpus luetum
in the first 2–3 months of pregnancy, and by the placenta
● Oestrogens are synthesized in the placenta from DHEA afterwards. Placental production of progesterone depends
(a weak androgen) produced by the fetus, and oestradiol, on the availability of substrates (maternal cholesterol) and
the size of the placenta, and appears to be uncontrolled.
Progesterone rises steadily until term. 17-hydroxyproges-
terone peaks at 5 weeks and then declines.
15 hPL ● Pituitary hormones: LH and FSH secretions decline, while
prolactin rises to term.
10 ● Thyroid hormones: Total T4 and T3 rise during the first
trimester, then plateau. TBG increases so free T4 and T3
are unchanged.
5 ● Adrenal steroids: Cortisol increases steadily to three
118 times prepregnancy values and aldosterone plateaus at
hCG 34 weeks.
Prepregnancy 1st 2nd 3rd Fetal pituitary gland
Trimester ● This secretes ACTH, which stimulates the fetal adrenal
glands to secrete large quantities of very weak and wa-
Progesterone ter-soluble androgens.
100 ● They pass to the liver where their structures are modified
before they are delivered to the placenta. Here placental
15 aromatase converts them to oestriol, the main oestrogen
Oestriol produced in the last 6 months of pregnancy.
ngs/ml Oestradiol ● Oestriol and progesterone exert the massive increase
10 in the myometrial mass, and all the uterine glands and
Oestrone stromal elements.
5 Hormonal changes in puberty
The endocrinology of puberty consists of two phases:
1st 2nd 3rd 1. Adrenarche: the rise in adrenal androgens between the
Trimester ages of about 6–8 years.
pgs/ml (Testosterone) 2500 DHEA 5 ngs/ml (DHEA, 2. Gonadarche: activation of gonadal sex steroid produc-
4 androstenedione) tion occurring several years later.
2000 3
2 ● The onset of puberty is characterized by an increase
1500 Androstenedione 1 in frequency and amplitude of GnRH pulses, which
1000 Testosterone stimulates LH and FSH secretion and hence gonadal
steroidogenesis.
500 1st 2nd
● Several theories have been put forward to account for
3rd the increased GnRH pulsatility and these include a
relative reduction of melatonin secretion and attain-
Trimester ment of adequate body fat. Adipose tissue secretes
hormones, including leptin, and leptin appears to play
Figure 6.14 Hormonal changes during the three trimesters a permissive role in puberty. Kisspeptin, released from
of pregnancy. hCG, human chorionic gonadotrophin; hPL, hypothalamic neurons, stimulates GPR54 receptors
human placental lactogen; DHEA, dehydroepiandrosterone. on GnRH neurosecretory cells and increases GnRH
secretion. Both leptin and kisspeptin are essential for
puberty and attainment of fertility.
Hormone changes in the menopause ● It receives an input from the suprachiasmatic nucleus Chapter 6 Endocrinology
(SCN) via the superior cervical ganglion. The SCN itself
Menopause is defined as the cessation of menstruation be- receives a direct input from the retina and is thought to
cause the ovary no longer contains follicles responsive to be responsible for driving numerous physiological func-
FSH. It results in an oestrogen and progesterone-deficient tions that show a daily rhythm, including the circadian
state with an increase in the secretion of LH and FSH. The rhythm of ACTH/cortisol secretion and melatonin.
decline of oestrogens during the perimenopause is associ-
ated with vasomotor symptoms in the short term, including ● Melatonin is synthesized from tryptophan and melatonin
hot flushes, night sweats, vaginal dryness, and depressive ep- treatment in humans reduces GH and LH secretion. It
isodes. Longer-term effects in the post-menopause include may be used beneficially to improve sleep patterns and
osteoporosis, increased incidence of cardiovascular disease, can be used to treat sleep disturbances associated with
and changes in lipid metabolism and profile. jet lag.
Pineal gland
● Situated between the two cerebral hemispheres, the
pineal gland secretes melatonin during the dark phase of
the light/dark cycle.
A DD ITIONA L FAC TS A ND R EV I SI O N M ATE RI A L
Hypothalamic-pituitary hormones Extragonadal effects of androgens 119
during puberty
● Usually released in pulses to prevent down-regulation ● Androgens increase GH secretion, which in turn
of the end organ receptors.
increases IGF-1.
Steroid and thyroid hormones ● IGF-1 stimulates cell division in cartilage and epiphyseal
● Cortisol increases blood glucose by inhibiting plates of long bones.
peripheral glucose uptake and increasing hepatic ● Testosterone in males (and adrenal androgens in
gluconeogenesis. Cortisol is catabolic to muscles
and therefore delivers the resultant amino acids to females) exerts the mineralization of the epiphyseal
the liver for gluconeogenesis. Cortisol does not break plates of the long bones at the end of puberty.
down liver glycogen. ● Androgens therefore initiate and terminate the growth
spurt. Oestrogens can also cause plate closure.
● Glucagon requires cortisol to work and if cortisol is ● Administration of testosterone in puberty may lead
absent, fasting hypoglycaemia develops rapidly. to a short stature and conversely excessive growth
Cortisol is also required for the vasoconstrictive during puberty may be terminated by testosterone
actions of catecholamines and if absent (as in administration.
Addison’s disease) hypotension develops.
Miscellaneous
● Steroid and thyroid hormones are transported in ● Recall that Sertoli cells possess aromatase activity,
plasma attached to carrier proteins, except for adrenal
androgens, which are conjugated with sulphate therefore Sertoli cell tumours are associated with
moieties in the liver. This renders them water-soluble elevated oestrogens.
such that they can be transported dissolved in plasma.
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CHAPTER 7
General and Systemic Pathology
General pathology Important cellular systems susceptible 121
to cellular injury
Cellular injury
1. Cell membrane and its barrier function
Cellular injury involves the disruption and failure of criti- 2. ATP production from mitochondrial damage
cal cellular functions, which if persistent may lead to cell 3. Genome—DNA disruption
death. Cellular injury may be reversible or irreversible. The 4. Protein synthesis
cell may respond by adaptation or death, depending on the
type, duration, and severity of the injury, and also on the cell Reversible changes following cell injury
type and its metabolic state.
● With reduced ATP production, Na+-K+ ATPase shuts
Causes of cellular injury down, K+ rushes out of the cell, and Na+ rushes in
accompanied by water. This leads to cellular oedema,
1. Hypoxia: With oxygen deprivation there is reduced or swelling of the endoplasmic reticulum, formation of
absent ATP production leading to the failure of Na+-K+ membrane blebs, and loss of specialized cell structures
pumps, protein production, and anaerobic metabolism, in such as the microvilli.
which glycolysis is the only source of ATP and is associated
with high production of lactate. Hypoxia may be caused by ● Reduced ATP production leads to the detachment of ri-
ischaemia, cardiopulmonary failure, or anaemia. bosomes from the endoplasmic reticulum and reduced
protein synthesis.
2. Infection: Micro-organisms can damage cells directly, or
via their toxins, or as a result of host response. ● There is a switch from aerobic to anaerobic metabolism
for cellular energy. Glycogen is used up in fuelling glyco-
3. Immunologic damage lysis with resultant lactate production and a fall in pH as
4. Genetic diseases lactic acid accumulates, with adverse effects for cellular
5. Physical injury (burns or trauma) enzyme function.
6. Chemical injuries
7. Nutritional injury: Examples of nutritional injury include Irreversible changes following cell injury
marasmus (total deficiency of calories) and kwashiokor, ● Membrane damage and the resultant calcium influx,
which is selective protein deficiency. which activates all intracellular enzymes including lactate
dehydrogenase, troponins, and creatinine phosphoki-
Mechanism of cellular injury nase (all of which may leak out of the cell following a
myocardial infarction), or aspartate and alanine transam-
● Reduced ATP production leads to failure of critical cell inases (AST, ALT), which may also leak out of hepato-
functions including the Na+-K+ pump with loss of mem- cytes from cell death and oedema during hepatitis B virus
brane integrity, increased membrane permeability, and infection.
influx of calcium ions. Calcium is a secondary messenger
that activates a spectrum of intracellular enzymes includ- ● Marked mitochondrial dysfunction suggested by mito-
ing lipases, proteases, ATPases, and endonucleases, chondrial swelling or increased density, loss of ATP pro-
which break down cellular components. duction, and the formation of mitochondrial permeability
transition channels.
● Mitochondrial dysfunction from the formation of non-
selective mitochondrial permeability transition (MPT) ● Lysosomal rupture with release of lysosomal enzymes
channels within the inner membrane of the mitochondria and autolysis.
results in the loss of electron gradient, which is important
for electrical transport chains. ● Nuclear death suggested by pyknosis and karyorrhexis.
● Oxygen-derived free radicals break down strands of DNA.
Basic Sciences for Obstetrics and Gynaecology Cellular death Cellular adaptation
There are two mechanisms of cell death: In general cellular adaptation follows a prolonged and
persistent cellular stress. All forms of cellular adaption are
1. necrosis potentially reversible if the stress is removed, although
2. apoptosis. some forms of adaptation are premalignant.
Necrosis ● Hypertrophy—there is an increase in cellular organelles
● Coagulative necrosis—usually due to protein denatur- and structural proteins, often secondary to increased
ation but with the shape of the organ maintained by the demands on the organ.
proteins sticking together, although the nuclei and other ● Atrophy—the cell decreases in size and functional ability
organelles are disrupted, dislocated, and dead. due to a reduced blood supply, nutrition, hormone
● Liquefactive necrosis—due to the action of tissue stimulation, or aging.
digestive enzymes, classically seen in the brain and the ● Hyperplasia—there is an increased number of cells (for
pancreas. example endometrial hyperplasia, ductal atypical hyper-
● Caseous necrosis—features are between coagulative plasia of the breast, and benign prostatic hypertrophy,
and liquefactive necrosis. The organ is semi-solid and which is more of a hyperplasia than hypertrophy).
semi-liquid with granulomas, multi-nucleated giant ● Metaplasia—a change from one cell type to another, e.g.
Langerhans cells, and epitheloid cells evident under the from columnar epithelium to squamous epithelium in the
microscope. bronchus, and the transition from squamous epithelium
● Fat necrosis—caused by the action of lipases and seen in of the oesophagus to columnar cell type (so-called Bar-
the breast, pancreas, omentum, and skin. It has a chalky rett’s epithelium due to reflux disease). This is a premalig-
white appearance. When fat cells die, they liberate nant state.
122 negatively-charged free fatty acids from triglycerides, ● Dysplasia—the sequence of changes leading to neoplasia;
which attract positive calcium ions leading to calcium the cells are disorganized but not malignant, e.g. dysplas-
deposition in fat or saponification. tic cervical cells.
● Fibrinoid necrosis, which appears pink on hematoxylin Other types of cellular injury
and eosin (H & E) staining due to protein deposition.
● Accumulation of products such as: proteins, e.g. in the
● Gangrenous necrosis—a gross descriptive term for dead, proximal convoluted tubule (hyaline droplets) or plasma
necrotic, jet-black tissue. There are two forms of gangre- cells (Russell bodies); fat or lipids leading to atheroscle-
nous necrosis: rotic plaques; and pigments deposited in the brain, heart,
or liver, e.g. hemosiderin (accumulation of iron), hemosi-
1. wet gangrene where the tissues are undergoing derosis (iron accumulation and overload present within
liquefying necrosis the Kuppfer cells and macrophages), and hemochroma-
tosis (organ damage from hemosiderosis).
2. dry gangrene (coagulative necrosis).
● Hyaline disease—accumulation of pink protein material
Apoptosis on H & E stain.
● This is programmed cell death, which usually affects single ● Calcification could be dystrophic, that is calcium deposi-
cells or a small group of cells, in contrast to necrosis, tion in dead or dying tissue, or metastatic, which usually
which affects many different cells. Apoptosis is executed occurs in areas of high blood flow such as the kidneys and
by a cascade of enzymes, known CASPASE. the lungs.
● The nucleus is pyknotic, the cell cytoplasm is shrunken Inflammation
and becomes more pink, and fragments of apoptotic
(dead) cells are phagocytosed by adjacent macrophages Acute inflammation
and epithelial cells.
This is the immediate response of the body to any form
● Characteristically there is no inflammation, unlike necrosis. of injury. It is of short duration and is characterized by the
cardinal signs of redness (rubor), pain (dolor), heat (calor),
● Stimuli for apoptosis include cell injury and DNA damage, swelling (tumour), and loss of function. There are three
which result in p53 gene expression; this prevents dam- main aspects of acute inflammation:
aged cells from entering the cell cycle. Other stimuli for
apoptosis include hormone or growth factor deficiency, 1. haemodynamic changes
death signals from T cells, and tumour necrosis factor 2. cellular (inflammatory cells) response
(TNF) binding to TNF receptor-1. 3. chemical mediators.
● Anti-apoptotic genes include the bcl-2 gene, which im- 1. Haemodynamic changes
mortalizes cells such as cancer cells. There is an initial transient vasoconstriction, which is fol-
lowed by a massive vasodilatation (mediated by histamine,
● Physiologic examples of apoptosis include the removal
of tails and webs for formation of fingers during embryo-
genesis, corpus luteolysis and the menstrual cycle, and
breast involution post-lactation.
bradykinin, and some prostaglandins). The vasodilatation 10. Ingestion of foreign particles, bacteria, etc. Chapter 7 General and Systemic Pathology
is associated with increased vascular permeability (medi- 11. Apoptosis of the polymorphs
ated by histamine, bradykinin, serotonin, and leukotrienes), 12. Elimination of the polymorphs by phagocytosis. 123
resulting in the leakage of proteins, immunoglobulins, and
polymorphs. The intravascular fluid becomes more con- Histamine up-regulates the expression of E-selectin on the
centrated and slows down, allowing the inflammatory cells endothelial cell. IL-1 and TNF up-regulate E-selectin, ICAM,
(polymorphs) to marginate and leave the blood vessel. and VCAM.
2. Cellular response Neutrophil molecules are up-regulated by chemotactic
factors.
● During inflammation, soluble mediators initiate cellular
activation of leukocytes and endothelial cells, whereas Disorders of the inflammatory steps
adhesion molecules allow the interaction of leukocytes
with the vessel wall and all subsequent adhesive interac- 1. Cellular adhesions may be impaired by diabetes mellitus,
tions that are required for emigration into the tissue steroid administration, acute alcohol intoxication, leuko-
(Figure 7.1). cyte adhesions defect (an autosomal recessive disorder),
and integrin subunit deficiency, which leads to recurrent
● Polymorphs contain a large number of digestive enzymes bacterial infections.
for killing micro-organisms, including myeloperoxidases,
which are oxygen-dependent killing enzymes. They are 2. Emigration with pseudopods, which go through endothe-
bactericidal by increasing the permeability of bacterial lial cells to the basement membrane where they release
membranes. There are also secondary granules including enzymes such as collagenases to facilitate passage.
phospholipases, lysosomes, collagenases, and lactoferrin,
which bind iron and thus deny the bacteria iron. Poly- 3. Chemotaxis: Polymorphs always follow a chemotactic
morphs appear first followed by macrophages. trail including bacterial products containing N-formyl
methionine at the end, leukotriene B4 molecules, C5a
Steps in neutrophil migration complement, and Il-8 produced by macrophages.
1. Release of pro-inflammatory mediators, e.g. by tissue 4. Phagocytosis and degranulation aided by opsonization:
macrophages. Any of the three major opsonins, Fc portion of IgG,
C3b, and mannose-binding protein, may have defects.
2. Expression of adhesion molecules and secretion of pro-
inflammatory mediators by the endothelial cell. 5. Phagolysosomes for intracellular killing due to respira-
tory bursts including oxygen-free radicals and hydrogen
3. The neutrophils marginate and adhere to the vessel wall peroxide.
with the aid of adhesion molecules including selectins
(expressed by the endothelial cells as E-selectin and Diseases associated with inflammatory steps
L-selectin on the leukocytes; selectin is also expressed on
platelets as P-selectin). Other adhesion molecules include 1. Chronic granulomatous disease of childhood:
integrins, which mediate the firm adhesion of leukocytes ● an autosomal recessive or X-linked condition
by binding members of the immunoglobulin family of ● there is a deficiency of NADPH oxidase
adhesion molecules expressed on endothelial cells. The ● there is no respiratory burst, no superoxide, and no
most important adhesion molecules that serve as ligands hydrogen peroxide (H2O2), so there is no killing of
for the integrins during leukocyte-endothelial cell inter- catalase-positive organisms such as Staph. aureus and
actions are the intercellular adhesion molecules ICAM-1 salmonella
(expressed on the surface of inflamed endothelium ● therefore there are recurrent bacterial infections.
recruiting leukocytes to sites of inflammation), ICAM-2
(constitutively expressed on endothelial cells but unaf- 2. Myeloperoxidase deficiency
fected by inflammatory mediators), ICAM-3 (which ● an autosomal recessive disorder
binds LFA-1 and mediates leukocyte interactions; it is ● causes recurrent usually candidal infection.
highly expressed on leukocytes but absent on endothe-
lial cells), and vascular cell adhesion molecule (VCAM-1), Chemical mediators of inflammation
which is expressed primarily on endothelial cells, up- Vasoactive amines
regulated by inflammatory mediators, and plays a role in ● Histamine and serotonin, which are produced by various
mediating leukocyte-endothelial interactions.
cells such as basophils, platelets, and mass cells.
4. Capture
● They cause vasodilatation and increased vascular perme-
5. Rolling ability.
6. Activation and adhesion ● They are triggers for the release of IgE mediating disease,
physical injury, and anaphylaxis.
7. Spreading
● Serotonin from platelets increases vasodilatation and
8. Diapedesis vascular permeability.
9. Migration
Basic Sciences for Obstetrics and Gynaecology Blood flow Leukocyte
Fibrin Leukocytes
Endothelial Platelet adhesion Leukocyte
cell & aggregation adhesion
molecules
Endothial cell
adhesion molecule
124 Figure 7.1 Cellular response in inflammation. Neutrophil margination brings these inflammatory cells into contact with the
endothelium. They line the endothelium in a tightly packed formation (pavement) mediated by adhesion molecules activated by
inflammatory mediators released by other cells, including platelets, red blood cells, and other leukocytes.
The kinin system acute phase reactants, and stimulation of other cells:
● The end product of bradykinin is formed by factor XII, endothelium, neutrophils, and fibroblasts.
which activates pre-kallikrein, which cleaves kininogen. Outcomes of acute inflammation
1. Resolution and regeneration of normal tissue.
● Bradykinin mediates pain and increases vascular permea- 2. Resolution and tissue destruction leading to healing and
bility.
scarring.
Arachidonic acid pathway and products of the 3. Persistence of the bacteria with abscess formation such
cyclo-oxygenase pathway
that there is ongoing acute inflammation and the walling
● Thromboxane released by platelets causes vasoconstric- off of that area by the body.
tion and platelet aggregation. 4. Chronic inflammation.
● Prostacyclins released by endothelial cells cause vasodila- Chronic inflammation
tation and inhibit platelet aggregation. Causes
● Prostaglandin E2 mediates pain and fever and keeps the 1. Recurrent bouts of acute inflammation
ductus arteriosus patent in utero. 2. Persistent infection
3. Infection with mycobacterium, fungi, viruses, and parasites
● Lipoxygenase pathway; leukotriene B4 is chemotactic for 4. Response to foreign bodies or tumours
neutrophils. Leukotrienes C4, D4, and E4 are vasodila- 5. Autoimmune disease
tors and increase vascular permeability.
Important cellular mediators of
Complement system chronic inflammation
These include macrophages, lymphocytes, eosinophils, and
● Membrane attack complex C5b–C9, which punch holes basophils.
in bacteria.
Macrophages
● C3b is an opsonin. ● Come from the bone marrow and travel within the
● C5a is a neutrophil chemotactic factor.
● C3a and C5a are anaphylactic toxins and stimulate the bloodstream as monocytes.
release of histamine.
Cytokines
● IL-1 and TNF exert a broad range of effects including
fever, enhancement of adhesion molecules, increase of
● Settle in tissues and become tissue macrophages where ● common with viruses and may be evident as viral inclu- Chapter 7 General and Systemic Pathology
they are given different names depending on the tissue or sions
organ in which they are found, e.g. Kupffer cells in the 125
liver and microglia in the brain. ● examples include rabies, CMV inclusions within the
nucleus, and herpes.
● Produce a wide spectrum of cytokines that contribute to
granuloma formation. Wound healing and repair
a. Regeneration
Lymphocytes
The damaged tissue is replaced with cells of the same type,
● Include B and T helper and suppressor cells. depending on the cell type injured. These cells can be clas-
● They release lymphotoxins, a chemotactic factor. sified into:
Eosinophils 1. Labile cells—epithelial cells of the skin, bowel epithe-
lium—cells with the ability to proliferate throughout life.
● Have an important role in parasitic infections and aller-
gies. 2. Stabile cells—low level replication capacity over time, e.g.
liver may regenerate slowly after resection.
● They contain important major toxins for killing parasites.
● They are attracted by eotoxins. 3. Permanent cells—cells with limited ability to replicate, for
example cardiac myocyte and neurons.
Basophils (or mast cells)
b. Tissue repair
● Positioned around blood vessels especially in the skin and The tissue architecture is destroyed and the tissue is replaced
lungs. with scar (granulation tissue). Granulation tissue contains
fibroblasts, which are synthetically active and lay down
● They are important in IgE-mediated reactions. type 3 collagen initially and subsequently type 1 collagen,
which is strong collagen. Wounds healed by secondary
Chronic granulomatous inflammation intention may contract down because of myofibroblasts.
The granular red appearance of granulation tissue is because
● A collection of modified macrophages or epitheliod of capillaries.
cells.
c. Aberrations in wound healing
● Contain giant cells, which are multi-nucleated cells with a Delay in wound healing may be caused by:
rim of lymphocytes and plasma cells.
1. infection
● The presence of caseation suggests TB. 2. foreign body
● Typical examples of chronic granulomatous diseases 3. diabetes mellitus
4. vitamin deficiency
include TB, leprosy, syphilis, cat scratch fever, viral and 5. ischaemia.
fungal infections, foreign bodies, sarcoidosis, and Crohn’s
disease. d. Excessive wound healing
Host response to organisms 1. Hypertrophic scar:
● Excessive production of granulation tissue leading to a
Although there are hundreds of thousands of organisms protuberant and raised scar.
that can infect the body, the body has only five ways of re- ● This is a genetically determined event.
sponding to these organisms, namely:
2. Keloid:
1. Exudative inflammation: Response to bacterial infection ● Also has genetic predisposition.
characterized by exudate—inflammatory fluid domi- ● Commoner in the earlobes, face, neck, and forearms.
nated by proteins and inflammatory cells, especially poly- ● The scar is made up of pink bundles of type 3 collagen.
morphs. Commonly seen in bacterial pneumonia and ● Normal wound starts with type 3 and matures to type
meningitis. 1 collagen over time.
● In keloids the type 3 collagen remains indefinitely.
2. Necrotizing inflammation: Caused by a very virulent
organism, which causes far more tissue destruction and Types of collagen
death than just the inflammation or response to it.
1. Type 1 is the most common, has the highest tensile
3. Granulomatous inflammation: Response to slow- strength, and is found everywhere in the body including
growing organism, for example tuberculosis. bones, skin, tendons, and in most organs.
4. Interstitial inflammation: Response to viruses, for exam-
ple viral myocarditis.
5. Cytopathic inflammation:
● affected cell is altered in some demonstrable way
under the microscope
Basic Sciences for Obstetrics and Gynaecology 2. Type 2 collagen is found in cartilage and vitreous humour Platelets
only.
● Made in the bone marrow and carried in the bloodstream
3. Type 3 is found in granulation tissue, embryonic tissue, to the injury site.
the uterus, and in keloids.
● At the injury site platelets adhere to the vascular wall
4. Type 4 collagen is found in basement membranes. collagen with the aid of vWF.
● Platelets cannot adhere directly to collagen, so the vWF
Pathology of circulation does the adherence and the platelets adhere to the vWF
via a receptor, glycoprotein-1b (GP1b).
Oedema
This is defined as excessive fluid in the intercellular or inter- ● Platelet activation follows, with a change in shape and
stitial space. degranulation.
● ADP released with activation and degranulation of plate-
Causes lets recruits more platelets to add to the clot through
GP2b3a.
1. Increased hydrostatic pressures, e.g. congestive cardiac fail-
ure (CCF), portal hypertension, renal problems, and ● A defect in GP2b3a leads to Glanzmann thromboaesthenia.
venous thrombosis.
● Platelet disorders will present with bruising, ecchymosis,
2. Decreased colloid osmotic pressure, e.g. liver disease, petechial haemorrhages including nose bleeds, and heavy
nephrotic syndrome, and kwashiorkor. periods.
3. Lymphatic obstruction, e.g. following surgery. ● Investigations would include platelet count and bleeding
4. Increased vascular permeability from drugs or chemicals, time tests, which detects qualitative platelet problems.
e.g. bleomycin hyaline damage of the lung epithelium.
Immune thrombocytopenic purpura (ITP)
126 Related terminologies ● Autoantibodies produced against own platelets, which
● Anasarca—generalized total body oedema coat the platelets.
● Effusion—fluid in body cavities, e.g. peritoneal, pleural, ● The IgG-coated platelets are destroyed in the spleen
or pericardial leading to thrombocytopenia.
● Transudate—oedema fluid of low protein content, spe- ● Two forms of ITP are recognized:
cific gravity <1.02.
1. Acute form, usually a self-limiting illness seen in children
● Exudate—oedema fluid with a high protein content after a viral illness.
and polymorphs, specific gravity >1.02. It is described as
fibrinous exudate or eosinophilic exudate, depending on 2. Chronic form, usually in women of reproductive age
what constitutes the exudate. and commonly associated with lupus. May present
with nose bleeds, menorrhagia, and ecchymosis.
● Hyperaemia—this is an active process of vasodilatation ● Findings include thrombocytopenia, prolonged bleeding
(e.g. in blushing) due to neurogenic factors and hista- time, normal coagulation tests, reduced platelets on pe-
mine. ripheral film, large mega-thrombocytes, and proliferating
megakaryocytes on bone marrow biopsy.
● Congestion—a passive process, e.g. CCF.
● Treatment includes immunoglobulin (this floods the Fc
Haemostasis receptors in the spleen and prevents platelet phago-
cytosis), steroids (reduce antibody production), and
The goal of haemostasis is to form a fibrin platelet plug to splenectomy.
stop bleeding. Three key factors are required to achieve
this, namely: vascular wall, platelets, and the coagulation Thrombotic thrombocytopenic purpura (TTP)
cascade.
Vascular wall ● Due to generalized and widespread platelet thrombi
formation (not true thrombi but fibrin and platelets stuck
● Vascular injury elicits transient vasoconstriction mediated together).
by the endothelium, resulting in blood flow changes with ● Characteristically there is no activation of the coagulation
turbulence and stasis, which are factors that favour fibrin
clot formation. system.
● Usually affects adult females.
● Then there is release of tissue factors from the injured ● There is a clinical pentad of fever, thrombocytopenia,
cells, activating the extrinsic coagulation pathway. microangiopathic haemolytic anaemia, neurological
symptoms, and renal failure.
● Exposure of the subendothelial collagen, which is highly
thrombogenic, stimulates/activates the intrinsic coagula- ● Lab findings include thrombocytopenia, prolonged bleed-
tion pathway. Endothelial release of von Willebrand fac- ing time, normal coagulation (PT and PTT) test, frag-
tor (vWF) aids platelet aggregation. mented red blood cells, and schistocytes on blood film.
Haemolytic uraemic syndrome (HUS) 2. Liver disease: Chapter 7 General and Systemic Pathology
● All factors except FVII are reduced.
● On the opposite end of the disease spectrum to TTP. ● PT elevated earlier on. 127
● The same pentad of signs and symptoms is involved. ● PTT elevated later.
● TTP has more neurologic symptoms; HUS has more
3. von Willebrand disease (vWD):
renal problems. ● An inherited bleeding disorder.
● TTP is usually found in adults, HUS usually in children, ● Characterized by either a deficiency or a qualitative
defect of vWF.
and they are associated with bloody diarrhoea after infec- ● vWF is produced by endothelial cells for attachment
tion from E. coli, 0157H7. to collagen and provides a surface for platelets to
attach themselves.
Coagulopathies ● Clinical features, like with other platelet problems,
include nose bleeds and petechial haemorrhages; plate-
● Most clotting factors are produced by the liver, except let count is normal but the bleeding time is prolonged.
factor VIII (FVIII). ● PT is normal and PTT may or may not be normal.
Occasionally it is increased because FVIII circulates in
● They circulate as pro-enzymes and need conversion or the body attached to vWF, which stabilizes it, and
activation with calcium. therefore a defect in vWF leads to a rapid degradation
of FVIII leading to prolonged PTT.
● Intrinsic pathway requires activation by contact factors, ● Diagnosis is made by platelet aggregometry.
such as contact with collagen, high molecular weight ● Treatment is by desmoprossin (an ADH analogue),
kininogen, and kallikein. which causes more release of vWF from the endothe-
lial cells.
● Extrinsic pathway activated by tissue factors (aka tissue
thromboplastin). Disseminated intravascular coagulopathy (DIC)
● Coagulation problems tend to present with deep bleed- ● Always secondary to another disease, e.g. abruption,
ing, e.g. haematomas, haemarthrosis, and delayed post- malignancy, leukaemia, or infection (particularly Gram-
traumatic bleeding. negative sepsis).
● Prothrombin time, which measures extrinsic and com- ● There is generalized formation of thrombi, which uses up
mon coagulation pathways, is prolonged. all the platelets, coagulation factors, and fibrinogen in a
consumptive coagulopathy leading to excessive bleeding.
● PTT, which measures the intrinsic and common coagula-
tion pathways, is increased. ● Diagnosis requires the presence of four conditions:
1. reduced platelet count
● Thrombin time tests for adequate levels of fibrinogen, 2. increased PT and PTT
fibrinogen degradation products (FDP), and D-dimers. 3. reduced fibrinogen
4. increased fibrinogen degradation products (or D-dimers).
Haemophilia A (FVIII deficiency)
● Treatment—treat the underlying cause and correct the
● An X-linked recessive disorder and therefore affects coagulopathy.
males.
Thrombosis
● Haemarthrosis, easy bleeding following trauma.
● Single abnormality is raised PTT. Thrombosis is usually due to the violation of the Virchow
● Treatment is FVIII replacement. triad of vessel wall integrity, disturbances of blood flow,
and changes in the constituents of blood. Thrombosis may
Thrombophilia B (FIX deficiency) therefore be due to:
● Also an X-linked disorder. 1. endothelial injury
● Clinically identical to haemophilia A. 2. alteration of laminar flow, e.g. aneurysms, polycythemia,
● Distinction made by FVIII and FIX assays.
immobility
Acquired coagulopathies 3. hypercoagulable state, e.g. tissue injury, nephrotic
1. Vitamin K deficiency: syndrome, pregnancy, oral contraceptive use.
● Associated with deficiency of clotting factors II, VII,
IX, and X. Differences between a thrombus and a clot
● May occur with prolonged broad spectrum antibiotic
therapy because vitamin K is produced by gut flora, ● Thrombus occurs within the vasculature, unlike blood
which may be reduced or eliminated by long-term clot.
antibiotic therapy.
● PT elevated and later PTT also elevated.
● Treatment is vitamin K first, and if that is adequate the
diagnosis is made.
Basic Sciences for Obstetrics and Gynaecology ● Thrombus contains fibrin, platelets, and white and red ● Predisposing factors to infarction:
blood cells (RBCs).
■ tissue vulnerability to infarction, e.g. the brain or heart
● Thrombus has a shape and contains lines of Zahn (pale because of their requirement for high blood flow
lines of platelet and fibrin alternating with red lines compared to tendons or fat
composed of RBCs) unlike blood clot.
■ presence or absence of collateral circulations; organs
● Thrombus lead to occlusion or embolization. with a single blood supply tend to have a pale infarct,
whereas organs with dual or more sources of blood
Pulmonary embolism (PE) supply tend to have haemorrhagic infarction.
● Over 95% of cases of PE are from deep vein thrombosis Shock
(DVT) in the deep leg veins or pelvic iliac veins on the
right side of the heart. ● Widespread hypoperfusion of cells and tissues from
vascular collapse/reduction in cardiac output, leading
Outcomes of DVT initially to reversible injury but if prolonged may lead to
1. No sequelae: irreversible cell injury.
● Asymptomatic—most common presentation; there Causes
may be dyspnoea and tachypnoea but with no infarc- 1. Hypovolaemic shock, e.g. trauma, postpartum haemor-
tion and therefore no sequelae. rhage.
2. Infarction: 2. Cardiogenic shock, e.g. myocardial infarction.
● Approximately 15% of PE, usually in patients with 3. Septic shock, e.g. from Gram-negative endotoxaemia,
pre-existing lung or heart disease. which releases IL-1, IL-6, TNF, and IL-8, resulting in mas-
● There may be shortness of breath, haemoptysis, chest sive vasodilatation, adult respiratory distress syndrome
128 pain, and pleural effusion. (ARDS), DIC, and multi-organ dysfunction; mortality
● In fatal cases post-mortem may show the classic wedge from septic shock is ≥50%.
form with the apex pointing towards the pathology. 4. Neurogenic shock from brain or spinal cord injury.
3. Sudden death: 5. Anaphylactic shock from type 1 hypersensitivity reaction.
● Approximately 5% of PE, particularly with saddle
emboli. Three major stages of shock
4. Chronic pulmonary hypertension:
1. Compensatory stage—perfusion to the vital organs is
● Occurs in about 3% of PE. maintained by reflex mechanisms including catecholamine
● Usually from longstanding showering type, which is release and activation of the sympathetic and renin-
angiotensin systems (RAS).
followed by sclerosis of the pulmonary vessels.
Systemic emboli 2. Decompensated stage—reduced tissue perfusion result-
ing in reversible cellular injury, metabolic acidosis, and
● Majority will lead to infarction. electrolyte disturbances.
● Usually from the heart after a myocardial infarction, atrial 3. Irreversible stage—organ failure and death even if the
fibrillation, or infectious endocarditis. original injury is removed.
● Emboli may lodge in the legs, spleen, gastrointestinal tract, Selected individual organ injury in shock
or brain.
● Paradoxical emboli—embolus that starts from the venous ● Lungs—ARDS or diffuse alveolar damage (DAD).
side of the circulation and ends up in the arterial side, ● Kidneys—acute tubular necrosis (ATN); the proximal
usually through a heart defect. convoluted tubular cells are very susceptible to hypoxia
Infarction and die quickly in the process and fall off into the
tubular lumen.
● A localized area of necrosis secondary to ischaemia. ● Adrenals—bilateral adrenal infarction (Waterhouse-
● Usually due to an embolus or thrombi. Friderichsen syndrome) commonly associated with Gram-
● Torsion and vasospasm are other causes, especially in the negative endotoxaemia due to meningococcal meningitis.
ovary and testes. ● Intestines—ischaemic necrosis and haemorrhage.
● In most body tissues infarctions lead to coagulative
● Liver—centrilobular necrosis (aka shocked liver).
necrosis, except in the brain where there is liquefactive Genetic syndromes
necrosis. The dead tissue provokes an inflammatory
response and the inflammatory cells remove the dead ● Down syndrome:
tissue leaving behind a scar. ■ trisomy 21
■ 95% secondary to non-disjunction, 4% Robertsonian True hermaphrodite Chapter 7 General and Systemic Pathology
translocation ● Presence of ovotestis; extremely rare.
● Ambiguous genitalia. 129
■ features include flat face, low nasal bridge, wide-set
eyes, short broad neck, low-set ears, speckled appear- Female pseudo-hermaphrodite
ance of the iris (brush field spots), single simian crease ● Genetically female, phenotypically male.
in the hand, cardiac defects including ASD, VSD, duo- ● Caused by exposure of a female fetus to androgens,
denal atresia (double bubble sign on ultrasound scan),
and Hirschsprung’s disease e.g. congenital adrenal hyperplasia.
■ 15 to 25% have increased risk of leukaemia, particu- Male pseudo-hermaphrodite
larly acute lymphocytic leukaemia ● Genetically male, phenotypically female
● Caused by testicular feminization.
■ Alzheimer’s disease (amyloid protein deposition in ● There is a defect in the androgen receptor.
the brain from the extra chromosome 21) by ≥40 ● Undescended testes.
years of age.
Inheritance patterns
● Edward syndrome:
■ trisomy 18, 46 XX/XY + 18 1. Autosomal recessive
■ features include severe mental retardation, low-set 2. Autosomal dominant
ears, overlapping flexed fingers, micrognathia, rocker- 3. X-linked disorders
bottom feet (from excessive connective tissue at the 4. Genetic imprinting—genetic defect in which the symp-
base of the foot), and death soon after birth (severe
malformations). toms differ depending on whether the gene was inherited
from paternal or maternal chromosomes.
● Patau syndrome:
■ trisomy 13, 47 XX/XY + 13 non-disjunction 1. Autosomal recessive disorders
■ features include severe mental retardation, micro- ● General characteristics:
cephaly, extra digits, cleft lip and palate, chromosomal
deletions (e.g. 46 XY/XY 5p–), and VSD. ■ early in onset, presenting early in infancy or childhood
■ complete penetrance (i.e. likely to express if
Sex chromosome disorders
inherited)
● Klinefelter’s syndrome: ■ tends to involve enzyme proteins, e.g. cystic fibrosis,
■ 47 XXY/48XXXY
■ a meiotic chromosomal non-disjunction disorder alkaptonuria, albinism, glycogen storage disease
■ results in male hypogonadism, atrophic, fibrotic testes, ■ mutation of both alleles required.
no production of testosterone, infertility, high-pitched
voice, gynaecomastia. ● Phenylketonuria (PKU):
■ autosomal recessive disorder
● Turner’s syndrome: ■ defect in the enzyme phenylalanine hydroxylase lead-
■ 45 X0 ing to accumulation of toxic levels of phenylalanine in
■ female hypogonadism (two X chromosomes required the brain
for normal ovarian development), the ovaries are ■ light-coloured skin and hair
streaked (by the fibrous tissue bands) ■ treatment is dietary restriction of phenylalanine.
■ primary amenorrhoea, reduced oestrogen, short stat-
ure, failure of secondary sex characteristics, cystic ● Cystic fibrosis (CF):
hygromas (dilated lymphatic channels underneath the ■ the defect is in the CF transmembrane conductance
skin, which eventually leave redundant skin around regulator, a chloride channel protein responsible for
the neck), aortic coarctation, hydrops fetalis, may be anion transport
stillborn. ■ the gene is on chromosome 7 and the deletion is at
position 508 in 70% of cases
Sexual determination ■ there is production of viscid mucus, which blocks
the ducts in organs, e.g. in the lung leading to pneu-
Can be considered at four levels: monia and bronchiectasis, and in the gut leading to
meconium ileus. Other features include pancreatic
1. karyotype—presence or absence of the Y chromosome atrophy and fibrosis, and congenital absence of the
2. gonadal sex—presence of testicular or ovarian tissue vas deferens.
3. ductal sex—presence of Wollfian or Mullerian duct
4. phenotype—external sexual characteristics.
Basic Sciences for Obstetrics and Gynaecology 2. Autosomal dominant disorders 3. X-linked diseases
● Fragile X syndrome:
● General characteristics:
■ variable in onset; some may represent in adulthood ■ a triplet nucleotide (GCC) repeat mutation
■ incomplete penetrance (variable expression in time ■ mental retardation and large jaws, ears, and testes
and degree) ■ more common in males than females
■ mutations in structural or regulatory proteins, e.g. ■ diagnosis is with gene probe analysis.
receptors
■ mutation is only required on one allele. ● Huntington’s disease:
■ triplet repeat (CAG) in Huntington gene resulting in
● Familial hypercholesterolaemia: defective Huntington’s protein
■ most common inherited disorder (affecting 1 in 500) ■ patients make purposeless movements (aka Hunting-
■ defect is a mutation in the LDL receptor gene ton’s chorea)
■ no functional LDL receptors in the liver, therefore ■ early onset dementia
LDL-cholesterol levels increase, and the liver responds ■ atrophy of the caudate nucleus of the brain.
by producing even more cholesterol, because of lack
of negative feedback ● Prader-Willi syndrome:
■ no inhibition of HMG-CoA reductase, which exacer- ■ defect on chromosome 15, inherited from paternal
bates the process chromosomes
■ may be heterozygous or homozygous ■ there is hypogonadism, mental retardation, obesity,
■ xanthomas (lipid-laden macrophages) and premature and hypotonia.
artherosclerosis.
130 ● Marfan’s syndrome: ● Engelman syndrome (Happy Puppet syndrome):
■ defect is in the fibrillin gene (a glycoprotein that functions ■ defect also on chromosome 15, but inherited under
as a scaffold protein and helps to align elastin fibres) maternal chromosomes
■ affects skeletal systems ■ mental retardation, seizures, ataxia, and inappropriate
■ affected individuals are tall with long arms, legs, bones, laughter.
and fingers Immunopathology
■ hyperextensible joints and chest wall deformities
■ bilateral subluxation of the lens, aortic dissection from Hypersensitivity reactions
cystic medial necrosis leading to aneurysms, aortic There are four types. Three require antibodies; the other is
insufficiency and mitral valve prolapse. completely cell mediated.
● Ehlers–Danlos syndrome: Type 1 hypersensitivity reaction
■ there are 10 different variants: type 3 is the most com-
mon; type 4 results from a defect in type 3 collagen, This anaphylactic type is characterized by plasma cell pro-
and patients usually die of ruptured aorta or colon duction of IgE antibodies on exposure to antigen, and the
■ hyperflexible and hyperextensible joints, and lax skin IgE antibodies circulate and attach to mast cells. Next time
■ there may be poor wound healing and dislocations. there is exposure to the antigen, the antigen causes cross-
linkage of the IgE on the mast cells, which degranulate lead-
● Neurofibromatosis (Von Recklinghausen’s disease) Types 1 ing to release of histamine, leukotrienes, and prostaglandins.
and 2: There is influx of eosinophils to amplify and sustain the reac-
■ approximately 90% of cases are Type 1 tion. Clinical examples include anaphylactic reactions, food
■ mutation is in neurofibroma NF1 tumour suppressor allergies, atopy, and asthma.
gene on chromosome 17, responsible for producing
neurofibromin Type 2 hypersensitivity reaction
■ patient presents with café-au-lait spots, nerve bundle,
and branch lesions This involves the production of cytotoxic IgG or IgM antibod-
■ increased risk of pheochromocytoma and meningiomas ies directed against specific tissues, cells, or cell receptors. This
■ pigmented iris leads to: autoimmune haemolytic anaemia if the target cell is
■ Type 2—10% of cases the red blood cell; Grave’s disease in the case of antibodies
■ mutation in tumour suppressor gene type 2 on chro- against the TSH receptor; myasthenia gravis when antibod-
mosome 22 ies are produced against the acetylcholine (Ach) receptor; or
■ gene product is merlin but its function is unknown. Goodpasture’s disease with production of antibodies against
type 4 collagen in the basement membrane, leading to acute
glomerulonephritis. Attachment of the antibodies leads to
inflammation, which activates compliment for cytotoxicity or
antibody-dependent cell-mediated phagocytosis.
Type 3 hypersensitivity reaction ■ two types of scleroderma are described, diffused and Chapter 7 General and Systemic Pathology
localized
This is due to the deposition of circulating antigen-antibody 131
immune complexes in tissues where they cause inflamma- ■ diffused scleroderma is associated with anti-DNA topoi-
tion and disease, e.g. skin in lupus, joints in rheumatoid ar- somerase-1 antibodies and affects approximately 70%
thritis, blood vessels in vasculitis or polyarteritis nodosa, and of cases; there is widespread involvement of the hands
kidney in glomerulonephritis. and face leading to thick and fibrotic claw-like fingers,
and also involvement of the internal organs including
Type 4 hypersensitivity reaction the oesophagus (dysphagia), gastrointestinal tract (mal-
absorption), lungs (fibrosis, dyspneoa), heart (arrhyth-
This is a completely cell-mediated hypersensitivity reaction mias), and kidneys (renal failure)
with no antibody involvement. The reaction is delayed and
mediated by Th1 cells. Two types of T-cell mediated hy- ■ localized (form) scleroderma (aka the CREST syndrome):
persensitivity reaction exist, namely delayed hypersensitivity C—calcinosis, R—Raynaud’s phenomenon,
reaction, which is responsible for granuloma formation, and E—oesophageal dysmotility, S—sclerodactyly, T—
cytotoxic T-cell mediated reaction, which is responsible for telangiectasia. It is associated with anti-centromere
fighting tumours and viruses and for graft rejection. antibodies involving the skin, hands, and face, leading
to clawed hands and smooth, tight face; it may also
Autoimmune diseases involve the internal organs later in its course. The
localized form has a more benign prognosis compared
● Systemic lupus erythematosus (SLE): to the systemic form.
■ a chronic autoimmune disease characterized by loss of
self-tolerance and production of lots of autoantibodies Immunodeficiency syndromes
■ affects women more than men, usually reproductive-
age women, and Africans more than Caucasians ● X-linked agammaglobulinemia (Bruton’s tyrosine kinase
■ due to autoantibodies against nuclear proteins includ- (BTK) mutation): An inherited disorder characterized by
ing histones, DNA, and other RNA proteins failure to produce mature B cells (i.e. plasma cells and
■ antinuclear antibodies (ANA) are commonly raised, therefore immunoglobulins). There are recurrent bacterial
but they are not specific. Specific antibodies for SLE infections, usually from 6 months of age when maternal an-
are anti-dsDNA (double-stranded DNA), and anti-SM tibodies wane from the infant’s circulation: staphylococcal
antibodies (aka anti-Smith); anti-dsDNA is the more infections, strep pneumonia, haemophilus, and influenza.
sensitive of the two The mutation is in B cell protein Bruton’s tyrosine kinase.
■ tissue injury in SLE is usually a combination of types 2
and 3 hypersensitivity reaction; that is antibody tar- ● Common variable immunodeficiency: A B-cell maturation
geted against specific tissue and deposition of immune disorder. There is reduced immunoglobulin production
complexes affecting one class usually. The patient suffers recurrent
■ diseases include anaemia, thrombocytopenia, arthritis, infections with parasites such as Giardia lamblia and bacte-
neutropenia, lymphopenia, malar skin rash, diffuse ria. There is increased risk of developmental lymphomas
glomerulonephritis and membranous glomerulone- and gastric carcinoma; both sexes are equally affected.
phritis leading to nephrotic syndrome, endocarditis, There is also association with other autoimmune diseases.
and pericarditis
■ treatment is with steroids and immunosuppressants. ● Di George syndrome: Failure of development of the
third and fourth pharyngeal pouches; that is, the parathy-
● Sjögren's syndrome: roid and thymus glands. Classically, the patient presents
■ an autoimmune disease characterized by the destruc- with hypocalcaemia and tetany; there are recurrent fun-
tion of the salivary and lacrimal glands leading to dry gal and viral infections because of the absence of T cells.
mouth and dry eyes respectively
■ often associated with other autoimmune diseases, ● Severe combined immunodeficiency syndrome (SCID):
usually rheumatoid arthritis Affects cell-mediated and humoral immunity. There are
■ characteristic antibodies include anti-ribonuclear two modes of inheritance, autosomal recessive or X-
protein antibodies SSA and SSB linked. In the autosomal recessive type there is absence of
■ increased risk of lymphoma, particularly non-Hodgkin’s adenosine deaminase, which leads to accumulation of de-
lymphoma. oxyadenosine, which is toxic to stem cells and lymphoid
cells. As a result there is death and loss of stem cells.
● Scleroderma (progressive systemic sclerosis): Affected children suffer all types of infections with viruses,
■ characterized by the stimulation of fibroblasts by IL-1 bacteria, fungi, parasites, and protozoa. They should not
and platelet-derived growth factor (PDGF) be given any live attenuated vaccines. They suffer from
■ the stimulated fibroblasts lay down excess amounts of unusual infections including Pneumocystis carinii. Treatment
collagen in different organs is bone marrow transplant and gene therapy.
■ affects reproductive-age women mostly
● Wiskott-Aldrich syndrome: An X-linked disorder. The
mutation is in the gene for the Wiskott-Aldrich syndrome
protein (WASP). Patients present with a classic clinical
triad of recurrent infections, severe thrombocytopenia,
Basic Sciences for Obstetrics and Gynaecology and skin rash. There is an increased risk of lymphomas ● The protein deposited as amyloid is the light chain called
and treatment is with bone marrow transplant. AL type (amyloid-light chain).
Secondary immune deficiency syndromes Reactive systemic amyloidosis (secondary amyloidosis)
Disease conditions that may cause secondary impairment ● The fibrillar protein is called serum amyloid A (SAA), which
of the immune system include diabetes mellitus, collagen is an acute phase reactant protein produced by the liver.
vascular diseases, alcoholism, organ transplant and immu-
nosuppressant therapy, and AIDS. ● This type of amyloidosis occurs in inflammatory states
such as tuberculosis, rheumatoid arthritis, SLE, Crohn’s
Types of organ rejection disease, ulcerative colitis, and longstanding osteomyelitis,
and it is the underlying inflammatory disease that stimu-
1. Hyperacute rejection lates the liver production of SAA.
This is caused by preformed antibodies, which attach to the
vessels of the new organ once reconnected in situ and cause Familial Mediterranean fever (inherited amyloidosis)
thrombosis and infarction of the organ, usually within minutes.
● Autosomal recessive disorder.
● Also produced by SAA protein.
2. Acute rejection ● Characterized by recurrent bouts of infections, fever, and
Takes weeks to months after transplantation and the onset neutrophil dysfunction.
is abrupt as the patient is weaned off immunosuppressant Haemodialysis-associated amyloidosis
therapy. There is renal failure, oliguria, and azothemia.
Microscopically there is vasculitis, interstitial lymphocytes, ● Usually diagnosed on dialysed patients; the dialysing
and neutrophil vasculitis. Treatment is to increase the dose membrane is not very good at handling and filtering pro-
of immunosuppressants. teins, especially β2 macroglobulin, which accumulates and
132 3. Chronic rejection deposits in tissues, especially in the wrists where it may
cause carpal tunnel syndrome.
This takes months to years after transplantation to develop.
There is gradual onset of renal failure with increased blood ● The amyloid protein is called Aβ2 macroglobulin.
pressure. Microscopy shows intimal fibrosis with the vessels ● The protein accumulated is β2 macroglobulin.
progressively narrowing until the organ becomes ischaemic Localized forms of amyloidosis
and infarcts, which is irreversible. Senile cerebral amyloidosis (Alzheimer’s disease)
Amyloidosis ● The amyloid protein is Aβ.
This is a group of diseases characterized by the deposition ● The fibrillar protein is called β-amyloid precursor protein
of extracellular protein (amyloid protein) with very specific (BAPP).
properties around small blood vessels. Principally it affects
the liver, spleen, and kidneys. There is no known treatment ● The gene for BAPP is located on chromosome 21, which
for amyloidosis. is why Down syndrome patients with an extra chromo-
some 21 get Alzheimer’s disease.
Common and characteristic features of amyloid ● The amyloid is found in the centre of all amyloid plaques
and also within the cerebral vessels.
● Amyloid is deposited in a very specific configuration
called a ‘β-pleated sheet’. Senile cardiac amyloidosis
● Usually in older men over 70 years of age and may result
● It is eosinophilic pink under the microscope.
● It gives a bright red/pink colour when stained with Congo in heart failure.
● Restrictive cardiomyopathy.
red and because of its β-pleated sheet the Congo red
also produces another effect when placed under polar- Endocrine organs and tumour amyloidosis
ized light—‘apple green birefringence’ (i.e. some areas ● For example, medullary carcinoma of the thyroid, which
will have green and others yellowish colouration).
is a C-cell tumour producing calcitonin.
Three major components of amyloid
1. Fibrillar protein, which is specific for each disease. ● The tumour is surrounded by deposits of pro-calcitonin,
2. Amyloid component. which forms β-pleated sheets resulting in amyloid.
3. Glycosaminoglycan (heparin sulphate).
● Prognosis is very poor.
Systemic forms of amyloidosis Neoplasia—basic principles
Primary amyloidosis
● 90% of neoplasias are of epithelial origin (cells are prolif-
● Usually caused by plasma cell malignancy including multi- erating at a higher rate and exposed to environmental
ple myloma and B-cell lymphoma. carcinogens).
● 10% are of mesenchymal tissue origin. airways disease, chronic bronchitis, early menopause, in- Chapter 7 General and Systemic Pathology
● Age is a factor, e.g. seminomas are commoner in men creased risk of miscarriage, and fetal growth restriction.
133
of 15–35 years of age compared to yolk sac tumour or Carcinogenesis
teratoma, which are commoner in young children.
● Hereditary predisposition, e.g. familial retinoblastoma, Carcinogenesis requires the accumulation of multiple mu-
multiple endocrine neoplasia syndrome (MENS), and famil- tations acquired either as inherited germ-line mutations or
ial polyposis coli are of autosomal dominant inheritance. over a lifetime’s acquisition, in: growth promoting genes, i.e.
proto-oncogenes (over-expressed by tumours); tumour sup-
Acquired pre-neoplastic dysplasias pressor genes (growth inhibitor genes); and apoptotic genes.
● Cervical dysplasia Proto-oncogenic
● Endometrial hyperplasia
● Chronic atrophic gastritis ● Activated proto-oncogenes lack regulatory capacity and
● Liver cirrhosis tend to over-express.
● Ulcerative colitis
● Clinically important oncogenes include: erb1, squamous
Causes cell carcinoma of the lung (EGF receptor is over-
Chemical carcinogens expressed); erb2, ovarian or breast cancer (EGF receptor
Carcinogenesis is a multi-step process involving mutagens and amplified); erb3; bcl; c-myc; l-myc; and N-myc.
promoters. Mutagens cause mutation in the DNA. Promoters
cause cell proliferation. Chemical carcinogens include: Tumour suppressive genes
● nitrosamines for gastric cancer ● Inhibit cells from entering the cell cycle.
● asbestos ● p53 gene is expressed whenever the cell DNA is dam-
● arsenic foreskin cancers and liver angiosarcomas
● alklating agents aged and this is most commonly mutated in tumours.
● benzene compounds. ● BRCA genes and NF-1 and -2 for neurofibromatosis.
Radiation Apoptosis-regulating genes
● Ultraviolet radiation from the sun produces pyridine ● bcl2 prevents apoptosis and is amplified by some tumours,
dimers in DNA, which increases the risk of cancers, such that the tumour cells become immortalized, e.g.
especially in patients with scleroderma pigmentosa follicular lymphomas.
(an autosomal recessive condition with defective DNA
repair). ● p53 prevents the mutated cells from proliferating and
promotes apoptosis of the damaged cells.
● Ionizing radiations including X-rays, γ-rays, α- and
β-particles, protons, and neutrons damage cells and may Benign neoplasia
lead to carcinoma, e.g. thyroid, and leukaemia. These are small, slow-growing, and encapsulated with
well-defined borders; they are well differentiated and look
Oncogenic viruses like the original tissue under the microscope. They are non-
invasive and never metastasize.
1. Human T cell leukaemia virus and RNA virus (HTLV
1)—responsible for human T cell leukaemia and Serum tumour markers
lymphoma. These are normal cellular components that are over-expressed
in disease/tumours and have three major applications:
2. Hepatitis B virus—hepatocellular carcinoma.
3. Epstein–Barr virus—Burkitt’s lymphoma, B cell lymphoma, 1. Useful in screening, e.g. prostate specific antigen (PSA)
for prostatic cancer.
and nasopharyngeal carcinomas and tumours.
4. HPV—benign squamous papillomas, increased risk of 2. Monitoring treatment efficacy.
3. Detection of disease recurrence, e.g. carcino-embryonic
CA cervix.
5. Kaposi’s sarcoma-associated herpes virus 8. antigen (CEA).
Smoking Tumour markers include:
There are over 4000 components in cigarettes, 40 of which ● α-feto protein (AFP)—hepatomas and yolk sac tumours
are known human carcinogens, including carbon monoxide, ● β-hCG—trophoblastic tumours and choriocarcinomas
arsenic, and cyanide. The addictive component is nicotine, ● calcitonin—thyroid C-cells
a causative agent of cancer of the lung, oral cavity, stomach, ● carcino-embryonic antigen (CEA)—lung, pancreas,
oesophagus, cervix, pancreas, kidney, ureter, and bladder. It
is a major risk factor for endothelial injury with increased risk breast, and colon
of coronary disease from vasospasm, chronic obstructive ● CA 125—epithelial ovarian tumours
● CA19–9—important for pancreatic cancers
● Placental alkaline phosphatase—seminomas
● PSA and prostatic acid phosphotase—prostate cancer
Basic Sciences for Obstetrics and Gynaecology Vasculitides ■ small and medium-sized arteries involved, particularly
the facial artery; the aortic arch may be involved includ-
This is a group of diseases characterized by acute immu- ing the cranial branches
nologic damage and fibrinoid necrosis of affected vessels,
usually medium-sized arteries. ■ patients present with throbbing headaches, visual dis-
turbances, facial pains, fever, malaise, weight loss, and
● Polyarthritis nodosa: nodularity of arteries
■ due to segmental necrotizing vasculitis
■ there are acute lesions in the form of arteries undergo- ■ the ESR is raised and there is formation of granulomas
ing fibrinoid necrosis, surrounded by polymorphonu- with segmental multi-nucleated giant cells
clear cell infiltration alongside healing lesions made up of
■ treatment is with steroid with typically a good response.
proliferating fibroblasts, and healed lesions, which are ● Takayasu arteritis (pulseless disease):
nodular areas of fibrosis ■ a granulomatous arteritis with loss of the pulse from
the thickening intima of the vessels
■ sequelae include thrombosis, weakened vessels, and ■ affects the aortic arch and its branches
aneurysms ■ usually involves young Asian women
■ response to steroid is variable.
■ any organ may be involved except the lungs
■ medium-sized arteries are usually involved, including
kidneys, heart, gastrointestinal system, and muscles
■ there is a low-grade fever, malaise, and weight loss ● Thromboangitis obliterans (Buerger’s disease):
■ 30% of cases are associated with infection, e.g. hepatitis ■ affects young male smokers
B virus ■ involves the extremities
■ autoantibodies against own neutrophils (specifically against ■ vessel lumen obliterated by inflammatory thrombi
neutrophil peroxidise) are present in 75% of cases ■ patient may present with gangrene or claudication
134 ■ a variant of polyarthritis nodosa displays vasculitis with ■ treatment is to stop smoking.
granulomas and eosinophilia.
● Wegener's granulomatosis: ● Kawasaki disease:
■ affects children <4 years of age
■ a rare necrotizing vasculitis with granuloma formation ■ common in Hawaii and Japan
■ there is an acute febrile illness, conjunctivitis, lymph-
■ usually in the age group of 40–60 years adenopathy, fever, maculopapular skin rash, and
coronary artery involvement in 70% of cases with
■ affects the nose, lungs, sinuses, and kidneys resulting in thrombosis or aneurysm in 1 to 2% of patients
pneumonia, sinusitis, nasal ulceration, and dominant ■ disease is self-limiting and is thought to be due to a virus.
renal disease, with cause of death usually acute glom-
erulonephritis nephritis ● Raynaud’s disease:
■ usually affects young women
■ microscopy reveals fibrinoid necrosis and granulomas
■ autoantibodies against neutrophils present in 93% of
cases
■ if untreated (usually with cyclophosphamide) mortality ■ precipitated by exposure to cold temperatures or stress
is 80% within a year. ■ there is painful blanching of the fingers, leading to cya-
● Temporal (giant cell) arteritis: nosis, when the fingers may become blue
■ this is the most common form of arteritis and usually
occurs in the elderly ■ when the vessel spasm is relieved they turn red
■ associated with HLA DR4
■ Raynaud’s disease is an entity of its own, whereas
Raynaud’s phenomenon is a feature of another
disease, e.g. scleroderma.
Systemic pathology ● Chest X-ray may show bilateral hilar lymphadenopathy,
which is diagnostic.
Selected respiratory pathology
Sarcoidosis ● Affects the lungs, lymph nodes, skin, heart, central ner-
vous system, eyes, and bone marrow, especially of the
● Idiopathic condition commoner in people of African an- fingers and toes.
cestry.
● Angiotensin-converting enzyme may be raised.
● Affects women more than men in their middle ages.
● May be asymptomatic or patients may present with fa- ● Tissue biopsy may show non-caseating granulomas.
tigue, malaise, shortness of breath, fever, and night sweats.
Adult respiratory distress syndrome Goodpasture's syndrome Chapter 7 General and Systemic Pathology
(ARDS, shock lungs)
● This is an autoimmune disease characterized by the produc- 135
● Diffuse damage to the alveoli and alveolar capillaries, tion of autoantibodies directed against type IV collagen in
resulting in progressive respiratory failure; unresponsive the basement membrane of the glomerulus and the lungs.
to oxygen therapy.
● It is a type 2 hypersensitivity reaction.
● Causes include shock, sepsis, burns, radiation, pulmonary ● It usually affects young males and is rapidly progressive
infections, drugs, oxygen toxicity, gastric aspiration, and
trauma. with poor prognosis.
● The treatment is plasmapheresis, steroids, and cytotoxic
● Patient may present with dyspnoea, tachypnoea, hypox-
emia, cyanosis, and use of accessory muscles of respiration. drugs.
● Chest X-ray may show bilateral lung field opacities; stiff, IgA nephropathy (Berger’s disease)
leathery, heavy, non-compliant, and solid lungs on gross
examination. ● Usually affects children and young adults and is the most
common nephritic disease worldwide.
● Microscopy shows interstitial space oedema, infiltration
by inflammatory cells (usually chronic), loss of type 1 ● It may follow an upper respiratory tract infection and may
pneumocytes, which are replaced by pink hyaline mem- be associated with other immune diseases.
branes comparable to newborn respiratory distress
syndrome. ● Microscopy shows mesengial proliferation due to IgA
deposition.
● Underlying cause should be treated; the patient will be
mechanically ventilated with oxygen supplementation. ● There may be renal failure within 20–25 years.
● Mortality is 50%. Polycystic disease of the kidney (adult type)
Newborn respiratory distress syndrome ● Autosomal dominant inheritance.
(RDS, hyaline membrane disease) ● The mutation is in the polycystic kidney disease (PKD)
● Associated with prematurity. gene, which is located on chromosome 16 and produces
● 60% of neonates <28 weeks will suffer from RDS. polycystin-1.
● Associated with elective caesarean section, diabetes ● Onset is in adulthood, usually in the 40s and 50s, and
presents with hypertension, renal insufficiency, and
mellitus, and multiple births. grossly enlarged kidneys.
● Due to the deficiency of pulmonary surfactant. ● There are extra-renal manifestations including pancreatic
● The infants are usually normal at birth, followed by rapid and hepatic cysts, Berry aneurysms, and an increased risk
of mitral valve prolapse.
onset of respiratory insufficiency. ● The child type of PKD is rare and of autosomal recessive
● Chest X-ray reveals ground glass appearance. inheritance. It presents in infancy with progressive renal
● Microscopic findings are identical to ARDS. failure.
● Treatment is with surfactant, oxygen, and ventilation.
● Mortality is as high as 30%. Selected gastrointestinal tract pathology
● Long-term sequelae include bronchopulmonary dyspla-
Hirschsprung’s disease (congenital
sia, pulmonary hypertension, and increased pulmonary aganglionic megacolon)
arterial pressure.
● Congenital absence of ganglionic cells, usually affecting
Selected renal pathology the rectum and sigmoid colon.
Acute glomerulonephritis (AGN) ● The patient presents with constipation, abdominal disten-
sion, and vomiting.
● More common in children after group A, β-haemolytic
streptococcal throat or skin infection. Other bacteria, ● Affects 1–2% of Down syndrome babies.
viruses, parasites, and systemic diseases can also cause ● Affects boys more commonly than girls.
AGN. ● Microscopy of colonic biopsy reveals absence of gangli-
● Anti-streptolysin O antibody titres are raised, there are onic cells.
RBC casts in the renal tubules, and electron microscopy
shows epithelial humps (immune complexes) underneath Malabsorption syndromes
the podocytes of the kidney. Coeliac sprue
● Specific immunofluorescent tests will reveal granular ● This is an IgA disease associated with HLA, B8, DR3, and
deposits of IgG, IgM, and complement (C3) throughout DQ.
the glomeruli.
● It is due to hypersensitivity reaction to gluten and gliadin
● 95% of children will recover fully compared to 60% of (IgA or IgG antibodies to gliadin in 90% of cases).
adults.
Basic Sciences for Obstetrics and Gynaecology ● There is malabsorption, flatulence, diarrhoea, and fatty fibrin, and necrotic cellular debris in a mushroom-shaped
stools. appearance.
● Treatment is with metronidazole, or vancomycin as a last
● Microscopy of biopsy shows loss of microvilli, increased resort and to avoid development of resistant strains.
lymphocytes within the epithelium, and increased plasma
cells within the lamina propria. Familial adenomatous polyposis syndrome
● It is associated with other IgA diseases including Berger’s ● This is an autosomal dominant disorder.
nephropathy and dermatitis herpetiformes. ● The defect is in the APC gene on chromosome 5q.
● The patients have hundreds or thousands of adenoma-
● Treatment is with dietary restriction.
tous polyps, and before the age of 40 the majority of
Tropical sprue them would develop colonic cancer.
● The treatment is prophylactic total colectomy by the age
● This is a malabsorption syndrome of unknown aetiology. of 40.
● Microscopic findings are identical to coeliac disease but
there is usually a history of travel.
Inflammatory bowel disease Hereditary non-polyposis colorectal
Crohn’s disease (regional enteritis) cancer (HNPCC)
● Usually affects Caucasian women, peak age 10–30 years ● An autosomal dominant inherited disorder.
and 50–60 years.
● There are no polyps but there is an increased risk of other
● Less common than ulcerative colitis. cancers, including endometrial and ovarian cancers.
● There is usually fever, peritoneal fistulas, and malabsorp- Peutz-Jegher’s syndrome
tion if the terminal ileum is involved.
● May affect any part of the gastrointestinal system from ● An autosomal dominant disorder.
136 the mouth to the anus, but the terminal ileum is the more ● There are multiple hamartomatous polyps, usually in the
common site. small intestine.
● Diagnosis is made by endoscopy, which shows skip areas ● Other features include melanin pigmentation on the lips
(lesions) and strictures, and by biopsy, which shows and oral cavity.
transmural inflammation, non-caseating granulomas, and ● There is increased risk of carcinoma of the lungs,
strictures. pancreas, breasts, and uterus.
● Unlike ulcerative colitis there are not many extra-intestinal Carcinoid tumours
manifestations.
● About 1–3% may progress to carcinoma. ● These are serotonin-producing neuroendocrine tumours.
Ulcerative colitis ● They occur most commonly in the appendix where they
are usually benign.
● Associated with HLA B27.
● Always involves the rectum from where it spreads proxi- ● They may occur in the terminal ileum where they are
malignant.
mally, usually to the large intestine, and rarely to the ileum.
● There is extensive mucosal ulceration and formation of ● If metastasis to the liver occurs then the serotonin pro-
duced may be secreted directly into the hepatic vein, which
pseudopolyps (areas that have not ulcerated and there- empties into the inferior vena cava and right side of the
fore stand out like polyps); there are no strictures. heart to cause the carcinoid heart syndrome, including fibro-
● Microscopy shows inflammation limited to the mucosal sis of the endocardial surface of the right atrium, right ven-
and the submucosal layers, and crypt abscesses. tricle, tricuspid valve, and pulmonary vessels. The serotonin
is metabolized and destroyed when it reaches the lungs.
● Complications include toxic megacolon and a 5–25% risk
of colonic cancer. ● Carcinoid syndrome is due to the systemic effects of
serotonin and includes diarrhoea, flushing, bronchos-
● Extra-intestinal manifestations—primary sclerosing cho- pasm, wheezing, and fibrosis.
langitis.
● The diagnosis is made by the presence of breakdown
Pseudomembranous colitis (antibiotic-associated colitis) products of serotonin in urine, 5-hydroxyindoleacetic
● Usually associated with a course of broad spectrum anti- acid (5HIAA).
biotic therapy. Although the condition is frequently Haemochromatosis
quoted to be due to clindamycin therapy, it may follow
treatment with any broad spectrum antibiotic. It is also ● Due to the accumulation of iron in tissues, leading to tis-
mainly associated with Clostridium difficile but may be sue damage. It usually affects northern Europeans and
caused by other organisms. there is a predilection for men.
● There is acute colitis characterized by formation of ● The primary form is an autosomal recessive hereditary
pseudo-membranes, composed of neutrophils, mucin, disorder associated with HLA-HG on chromosome 6p.
There is excessive intestinal absorption of iron, which by reduced circulating iron, partly because of increased Chapter 7 General and Systemic Pathology
accumulates in tissues. output of the transport protein from the liver, so TIBC
● The secondary form is associated with multiple blood is increased and then there are small red blood cells with 137
transfusions for chronic anaemia. reduced MCV and MCHC.
● There is micronodular cirrhosis of the liver, pancreatic
damage from iron deposition leading to diabetes mellitus, 2. Thalassaemia
and iron deposition in the skin, which makes the skin
bronze-coloured, produces the so-called bronze diabe- This is characterized by a defect in the α- or β-globin chain
tes. Iron accumulation in the heart leads to congestive of the haemoglobin.
cardiac failure and cardiac arrhythmias, and hypogonad-
ism if iron is deposited in the gonads. a. α-thalassaemia:
● The diagnosis can be made by the finding of raised serum
iron levels, raised ferritin, and tissue biopsy with Persian ● There are four α-globin chain genes on chromosome
blue stain, which demonstrates iron staining. 16 and normal individuals have all four chains.
Alpha-1-antitrypsin deficiency ● α-thalassaemia is due to gene deletion, so there are
four clinical disease states, the first three of which are:
● An autosomal recessive disorder characterized by the silent carrier—one gene deleted, so 75% of globin
production of defective α-1-antitrypsin, which accumu- chains are produced with normal clinical functioning;
lates in the hepatocytes and causes liver damage. α-thalassaemia trait—two genes deleted, so 50%
α-chain production; haemoglobin H disease—three
● The α-1-antitrypsin fails to reach the circulation and per- α-genes deleted, so only 25% α-chain production.
form its normal function of preventing damage to the Because of the deficiency of α-chains in this disease
lung parenchyma, such that there is destruction leading to state, the abundant β-chains pair up to make haemo-
the development of emphysema. globin H (β4), which easily denatures and forms Heinz
bodies detected on crystal blue stain. The final and
● Alpha-1-antitrypsin is produced by the protease inhibitor most severe form is hydrops fetalis, when no α-chains
(PI) gene on chromosome 14, and although there are are produced at all, with increased γ4 (Bart’s) haemo-
over 70 PI genes described, the most common one globin resulting in hydrops fetalis and intra-uterine
accounts for 90% of cases. The most severe form is the death.
homozygous state, which produces very severe disease
with 15% or lower antitrypsin levels available. b. β-thalassaemia:
● In the liver there is micronodular cirrhosis and an ● Two genes located on chromosome 11 make the two
increased risk of hepatocellular carcinoma, and panacinar β-globin chains, and point mutation in either of them
emphysema in the lungs. results in reduced or no β-chain production.
Selected red blood cell pathology ● The clinical states include β-thalassaemia minor, where
one gene is knocked out. These patients are usually
Anaemias: microcytic anaemia asymptomatic unless stressed either by infection or
hypoxia. Haemoglobin electrophoresis will show
1. Iron deficiency anaemia raised haemoglobin A2 and F. In β-thalassaemia major,
where both genes are knocked out, the individuals are
● Causes of iron deficiency anaemia: normal at birth as they are protected by haemoglobin
1. Reduced dietary intake—common in the elderly and F, but from 6 months of age, as haemoglobin F begins
in children. to decline, symptoms will emerge.
2. Reduced absorption, e.g. after gastrectomy or in
malabsorptive states. ● There is usually severe haemolytic anaemia, jaundice,
3. Increased demand in pregnancy. and gall stones. These patients will need repeated
4. Increased blood loss, e.g. in menorrhagia and GI blood transfusions to survive. The majority will die in
pathology. late teenage years from haemochromatosis. There
may be erythroid hyperplasia with bony deformities.
● Iron is found in haemoglobin, myoglobin, enzymes, and Haemoglobin electrophoresis will show reduced hae-
cytochromes and is stored as ferritin in the reticuloen- moglobin A and increased haemoglobin A2 and F.
dothelial system and within macrophages. Serum ferritin
is in equilibrium with macrophage ferritin, and is a good 3. Anaemia of chronic disease
indicator for total body iron storage. Transferrin is a
transport protein for iron and is associated with total iron ● This is characterized by macrophages holding down
binding capacity (TIBC). the iron and not releasing it to the bone marrow for red
cell production. This happens because the chronic inflam-
● In iron deficiency anaemia, storage iron (i.e. ferritin) is mation releases inflammatory cytokines, particularly
reduced in the first instance, and then bone marrow iron IL-1, which increases lactoferrin, and lactoferrin in turn
is diminished within the macrophages. This is followed binds iron in macrophages. Iron studies in these patients
show a reduction in iron indices except for a raised serum
ferritin.
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