THE ROLE OF LIPIDS IN LUNG MATURATION

Belonging to the group of lecithins, dipalmitoil phosphatidyl choline (DPPC)

represents 40% of the lung surfactant, which does not allow the collapse of the alveoli
due to its feature to reduce surface tension. The absence of these phospholipids causes
respiratory distress syndrome in premature infants, because DPPC is formed only during
the last weeks of pregnancy.
The formation of DPPC can be facilitated by the administration of glucocorticoids
to the mother (8-16 mg dexamethasone, betamethasone) 24 before delivery, ideally 48
hours before. If this is not possible, the infant should receive 60 mg surfactant dissolved
in 3 ml saline solution through a dispensing tube. The probability for premature babies to
have respiratory distress syndrome can be suspected before birth, or it can be diagnosed
after birth. During the intra-uterine life the amniotic liquid can be examined using
tensiometers or the foam test can be done to determine the lecithin/sphingomyelin ratio.
The foam test (Clements) is made using the amniotic fluid, after centrifugation the
supernatant is pipetted in two test tubes: 1 ml of undiluted supernatant in one of them,
while the other test tube contains 0.5 ml of supernatant and 0.5 ml of saline. 1 ml of 95%
ethanol is added to the two test tubes, shake them for 15 minutes, then let them stand for
15 minutes. The appearance of a foam ring after 15 minutes indicates an adequate degree
of lung maturity, while the lack of this ring reveals prematurity. The lecithin/
sphingomyelin ratio increases after the 32nd-34th weeks of pregnancy. If the ratio
exceeds 2:1, breathing problems are unlikely to occur.
After birth the swallowed amniotic fluid can be examined from the stomach,
acidosis or blood hypoxia (pO2 below 40 mmHg) can be detected. Clinically tahipnoe
occurs (rapid breathing frequency, 60-100/minute), dispnoe with expiration difficulty,
cyanosis. Recent data suggest that the respiratory distress syndrome is more severe in
premature infants of mothers suffering from vitamin D deficiency, so it would be
important to provide the adequate D vitamin intake for every pregnant woman.
 Modification of lecithin/sphingomyelin ratio before birth

Structure of a lipoprotein

THE ROLE OF KIDNEYS, LUNGS AND RED BLOOD CELLS IN

MAINTAINING THE ACID-BASE AND HYDRO-MINERAL EQUILIBRIUM

Maintaining the equilibrium of the internal environment for water and minerals
(Na+, K+, Cl-, HCO3-, Ca2+, Mg2+), including pH homeostasis, is very important for the
organism, because any disturbance might have serious effect on metabolic processes, and
in certain cases the disequilibrium can even lead to death.
 The distribution of water and electrolytes in the human body
Water is the most abundant component of the living organisms. The human fetus in
the intrauterine life contains at first 95%, then 85% water, at birth this value is reduced to
82-72%, and the adults contain only 50-60% water in their body (the value is slightly
lower in women compared to men because of the differences in the fat tissue).
The metabolic processes take place in water environment, so the internal regulation
of the composition of fluid compartments is very important, which is a prerequisite for
life. Water is distributed into fluid compartments in the body, separated by biological
membranes.
Around 66% of the water in the body is located in the intracellular fluid
compartment, and 33% in the extracellular fluid compartment. Only 8% of the body's
water content is in the plasma.
The blood contains cellular elements (45%) and plasma (55%). The percentage of
the cellular elements from the whole blood is called hematocrit. A healthy adult body
contains around 5 l of blood.
The composition of the interstitial fluid is similar to that of the plasma, the only
significant difference is that proteins are replaced by chloride ions in the interstitium. The
intracellular fluid’s electrolyte composition is very different from that of blood plasma,
because the cells contain higher amounts of potassium, magnesium, phosphate and less
sodium and chloride.
From table 1. it can be stated that the major cation of the extracellular space is Na +
(plasma concentration is 135 - 150 mmol/l), while the main intracellular cation is K +
(plasma level is only 3.5 - 5 mmol/). The plasma concentration of the ions is called
ionogram. In the blood plasma Cl- is the most abundant anion (plasma concentration is
95-110 mmol/l).

Table 1. The distribution of electrolytes in the fluid compartments (mEq/l)

Electrolytes Blood plasma Interstitial fluid Cells
Cations: 153 153 195
Na+ 142 145 10
+
K 4 4 156
Ca2+ 5 2-3 3
2+
Mg 2 1-2 26
Anions: 153 153 195
Cl- 103 116 2
-
HCO3 28 31 8
Proteins 17 0,2 55
Other anions (phosphates, sulphates) 5 5,8 130
Osmotic pressure is the decisive factor in the water distribution between the
different fluid compartments.
Osmolarity means the amount of all ions dissolved in a unit of liquid volume (it is
expressed in mEq). The plasma osmolarity is approx. 300 mosmol/l, mostly due to the
presence of Na+, Cl- and HCO3- ions. The increase of Na+ concentration leads to
hyperosmolarity, and hypoosmolarity occurs in case of decreased Na+ concentration.
Because the amount of electrolytes in the blood plasma and intestitial fluid is the same,
the distribution of proteins causes the colloid osmotic pressure, which keeps the water in
the blood vessels.
The pH of the internal environment
The enzyme reactions and biological processes are highly dependent on the H+
concentration of the internal environment. Life is possible between a very narrow pH
range. The physiological plasma pH values are ranging from 7.35 to 7.45. The body's pH
is maintained by buffer systems and biological mechanisms, in which the lungs and
kidneys play an important role.
A buffer system usually consists of a weak acid (or base) and it's hydrolysable salt.
The main buffer systems in the organism are the bicarbonate-carbonic acid system
(HCO3-/H2CO3 = 20/1), red blood cells contain protonated deoxihemoglobin/
oxihemoglobin system (Hb•2H+/2K+•hemoglobin•4O2), the phosphate buffer
(Na2HPO4/NaH2PO4) and proteins (protonated/deprotonated form).
The Henderson-Hasselbalch equation is:
pH = pKa + lg HCO3-/H2CO3.
Substituting the values we can obtain the physiological pH of the plasma: pH = 6.1
+ 1.3 = 7.4 (where 6.1 is the pKa of the carbonic acid and 1.3 is the decimal logarithm of
the 20/1 bicarbonate/carbonic acid ratio).
The ratio decreases when the concentration of bicarbonate is lower and/or the
carbon dioxide level is increased (acidosis, decreased pH), and the pH value higher in
case of alkalosis.
The kidneys’ role in maintaining the body's internal balance
The largest amount of total body water and electrolyte excretion takes place in the
kidneys, where 200 liters of water are filtered per day and an average of 30 Eq Na +. Due
to the tubular reabsorption only 1 to 1.5 liters of water and 0.1 Eq of Na + are eliminated
in the urine.
Many structural elements of the nephron play important role in maintaining the
water and mineral balance. First glomerular filtrate is formed, containing H2O, NaCl,
KCl, H+ and organic compounds in its composition. Isoosmotic reabsorption of water and
salts takes place at the level of proximal convoluted tubules, while selective reabsorption
of water occurs at the descending limb of the loop of Henle. In the ascending limb of the
loop of Henle NaCl reabsorption occurs, resulting in the decreased osmolarity of the
tubular fluid.
In the distal tubules Na+ is reabsorbed, K+ and H+ are excreted at this level,
aldosterone (mineralocorticoid hormone) facilitates these processes to occur. At this level
takes place the antidiuretic hormone-dependent water reabsorption.
The final hormonal regulation of sodium and water excretion takes place at the level
of the collecting tubes.
Neuro-renal regulation of the hydro-electrolytic balance. The renin-
angiotensin-aldosterone system
The physiological water and electrolyte metabolism is maintained by regulation of
fluid uptake and elimination of water and minerals.
Thirst influences the water intake. Due to the increase in extracellular fluid
osmolarity (increased Na+ concentration) the hypothalamic thirst center neurons lose
water, which induces thirst.
 Decrease of the plasma volume also stimulates the thirst center. The baroreceptors
located in the right atrium and in the blood vessels and the circulating levels of
angiotensinogen II also play a role in the regulatory process.
The release of antidiuretic hormone from the neurohypophysis causes cAMP
accumulation in the kidneys, leading to water retention.
Regulation of sodium elimination is made by the renin-angiotensin-aldosterone
system.
The decrease of the renal perfusion pressure and the decrease of Na + level in the
distal convoluted tubules leads to renin release from the juxtaglomerular apparatus. Renin
breaks down (hydrolyzes) the angiotensiongen, a protein synthesized in the liver, to
angiotensin I (this is a peptide containing 10 amino acids), then the angiotensin
converting enzyme (ACE) converts it to angiotensin II, which has a powerful
vasoconstrictor effect, and at the level of the adrenal cortex is the most effective
stimulator of aldosterone formation and secretion. Angiotensin II is converted to
angiotensin III, which has similar, but milder effects. The ACE also hydrolyzes
bradykinin, a vasodilator peptide.
Aldosterone facilitates Na+ and Cl- reabsorption and the elimination of K+ and H+ at
the level of the kidneys. Water balance is also regulated by the sodium retention, and the
extracellular fluid volume is restored. The natriuretic peptides (ANP, BNP, CNP) have
opposite effect compared to the renin-angiotensin-aldosterone system.

The role of red blood cells and the lungs in maintaining the hydro-electrolytic
balance
In the extrapulmonary tissues where the partial pressure of carbon dioxide (pCO 2) is
high, the CO2 will diffuse from the extracellular space into the red blood cells, where it
forms carbonic acid reacting with water by a reaction catalyzed by carbonic anhydrase,
and carbonic acid dissociates to H+ and HCO3- ions. In case of high pCO 2,
oxyhemoglobin delivers oxygen and K+ ions, and takes over the protons from carbonic
acid. The HCO3- exits the erythrocytes and participates to the formation of alkaline
reserve.
In the lungs pO2 is high and pCO2 is low. In such circumstances, the hemoglobin
binds oxygen, releasing protons and potassium ions bound to it. The bicarbonate ions in
the red blood cells are combined with the protons, forming carbonic acid, which is
decomposed to CO2 and water by a reaction catalyzed by the carbonic anhydrase. The
CO2 leaves the lungs in the exhaled air. This transport of protons by the erythocytes is
called the Bohr effect. In summary, the red blood cells represent a triple transport system:
they deliver oxygen from the lungs to tissues, and transport protons and CO 2 from the
tissues to the lungs.

Parameters of acid-base balance

Modern blood gas analyzers determine the blood pH, pO 2, pCO2 values. The pCO2
gives information regarding the respiratory, acidic component of the acid-base balance,
while the bicarbonate (HCO3-) shows the basic, metabolic component of the equilibrium.
The buffer base (BB) corresponds to the total buffer anion concentration of the
whole blood. The base excess (BE) is a derived parameter, its positive value shows base
excess or acid deficit, and its negative value shows acid excess or base deficit. The value
of the anion gap (AG)can give us information regarding the anions that are not routinely
measured (SO42-, PO43-, organic acid ions). The anion gap can be calculated from the
ionogram: AG =(Na+ + K+) - (Cl- + HCO3-) . Its normal value is under 15 mmol/l.
In metabolic acidosis caused by accumulation of organic acids the anion gap exceeds 15
mmol/l.
The acid-base balance disturbances
The acid-base imbalances have four known forms: metabolic acidosis and alkalosis,
respiratory acidosis and alkalosis. For all of them we can distinguish a compensated stage
(early, moderate disturbance, when the pH value is normal) and a decompensated stage
(late, severe disturbance). In the decompensated stage the regulatory mechanisms are
exhausted, and blood pH is outside the physiological range.
 Respiratory acidosis occurs in severe lung disease, or inhibition of the respiratory
center. Laboratory signs are increased pCO2, in severe decompensated cases the pH is
decreased.
Respiratory alkalosis occurs due to hyperventilation, which may occur in case of
anxiety or panic, or in the hyperexcitation of the respiratory center. Laboratory signs are
decrease in pCO2, in severe decompensated cases pH increases.
Metabolic acidosis may develop in case of ketone body accumulation (diabetes
mellitus, starvation) or increase of lactic acid concentration (circulatory failure), in severe
diarrhea and kidney failure, when bicarbonate synthesis is deficient.
The metabolic alkalosis may be iatrogenic (due to too much bicarbonate
administration), or may develop in case of losing large amounts of gastric acid.
The compensation of acid-base balance disturbances occurs in the lung and at the
level of the kidneys. The lungs can control the elimination/retention of carbon dioxide,
and the kidneys can regulate the excretion/reabsorption of protons and bicarbonate.
There is a close correlation between the acid-base balance and blood potassium
concentration, eg. in metabolic acidosis blood potassium level is increased (the excess of
protons from the extracellular space are trying to get into the cells, and as a consequence
potassium leaves the intracellular space; at the level of the kidneys there is a competition
between the elimination of these ions, so in this case more protons will be eliminated, and
less potassium). In metabolic alkalosis serum potassium level is decreased.

BIOCHEMISTRY OF BLOOD COAGULATION AND FIBRINOLYSIS

The clotting ability of the body prevents the blood loss in case of vessel injury.
Blood clot (thrombus) develops in case of the adhesion of platelets (aggregation), which
can seal the damaged blood vessel. The blood clotting includes: the vessel wall (vascular
component), platelets (cell components) and the clotting factors (humoral component).
The blood coagulation occurs in the following steps:
- The temporary contraction of the local vessel wall
- The formation of the white thrombus at the site of the injury
- The formation of stable fibrin network, which covers the damaged vessel walls
(red thrombus).
The role of the vessel wall in the blood clotting
The damaged vessel wall activates the cellular and humoral clotting mechanisms
(prothrombotic role) and participates in limiting the extent of the thrombus. The intact
vessel wall contributes to keep the liquid state of blood (antithrombotic role).
The vessel wall is composed of several layers: intima (inside), media, adventitia.
The intima consists of two parts: the endothelial cell layer, and the subendothelial
connective tissue underneath (it contains collagen fibers, which play an important role in
the blood clotting, and adhesive proteins, such as fibronectin.
The coagulation process
The formation of the white thrombus
Due to the damage of the endothelium cells, the subendothelial collagen fibers will
be in contact with the bloodstream. Platelets adhesion occurs directly to these collagen
fibers, and by the von Willebrand factor (a subendothelial glycoprotein having the role of
glue).
 The platelets are activated by adhesion, and several enzymes are activated (eg.
phospholipase A2, which releases arachidonic acid from the membranes), platelets release
a number of mediators (thromboxane A2, epinephrine, ADP), which play a role in
maintaining the vasoconstriction and the activation of the surrounding platelets. The
activated platelets are able to interconnect with each other (aggregation), they can bind to
fibrinogen molecules, thus forming the white platelet thrombus, which does not solve the
problem of covering the vascular injury on long-term.
Aspirin, through inhibition of cyclooxygenase, plays a role in the prevention of
thrombosis (the enzyme cyclooxygenase catalyzes the synthesis of prostaglandins and
thromboxanes from arachidonic acid, they are among the many inflammatory mediators
and pro-aggregant substances). The enzyme cyclooxygenase is necessary for the TXA2
synthesis, which plays a role in the local vasoconstriction, platelet activation and
promotes platelet aggregation.
The formation of the fibrin clot
The fibrin clot contains a network of fibrin which includes cellular blood
components. It is a thick, resistant structure, that can effectively and permanently cover
the vascular injury. Platelet shrinking increases the resistance of the clot. This is called
the red thrombus, which is formed by a number of consecutive reactions, with the
assistance of several proteolytic enzymes.

The activation of coagulation factors are made by two pathways. The longer one is
the intrinsic pathway, which involves only elements present in the blood, and the shorter
one is the extrinsic pathway, which includes also external factors. The two pathways
differ in the first few steps, then they continue with the common pathway.
In the body under physiological conditions blood coagulation starts by the extrinsic
pathway, and then accelerates involving also the intrinsic pathway, but not the very first
steps. The first steps of the intrinsic pathway play a role in blood clotting under in vitro
conditions (eg. in test tubes), and it can be activated in the body under certain
pathological conditions.
The table 2 contains a list of the coagulation factors and cofactors.

Table 2. Coagulation factors and cofactors

Factor I. - protein Fibrinogen, precursor of fibrin

Factor II. - proenzyme Prothrombin, precursor of thrombin
Factor III. - cofactor Tissue factor – tissue thromboplastin,
thrombokinase
Factor IV. - cofactor Calcium ion
Factor V. - cofactor Proaccelerin
Factor VI. - proenzyme Proconvertin
Factor VIII. - cofactor Antihemophilic A factor
Factor IX. - proenzyme Antihemophilic B (Christmas) factor
Factor X. - proenzyme Stuart-Prower factor
Factor XI. - proenzyme Antihemophilic C factor
Factor XII. - proenzyme Hageman factor
Factor XIII. - proenzyme Protransglutaminase (fibrin stabilizing)

As we can notice, there are in fact only 12 clotting factors, because factor VI. does
not exist. Most of the clotting factors are proenzymes of protein-degrading enzymes
called zymogens (factors II, VII, IX, X, XI, XII). Similarly to the pancreatic digestive
enzymes, they undergo a limited proteolysis cascade to become active, removing a part of
the substrate molecule, which inhibits the active center, so it is also activated. There are
also several cofactors (III, IV, V, VIII), which form activated complexes with some
proenzymes.
The extrinsic pathway
The tissue factor is an external factor, it can be found in most tissues, it is present in
large quantities in the brain, lung, placenta. Factor III. is missing from the membrane of
red blood cells and platelets, as they are in constant contact with the blood. In case of a
vascular injury, blood gets in contact with the adventitial cells, where this membrane
protein is located (connected to the membrane phospholipids). In the presence of Ca2+
ions it forms a complex with factor VIIa, which is activated by the traces of active factor
X present in the blood, factor III. has also an activating role on factor VII. Tissue factor
and VIIa forms a complex which activates factor IX., thus the intrinsic pathway is also
involved in the coagulation process.
The intrinsic pathway
The first step of this pathway is activated under physiological conditions only in
vitro, but in pathological cases, for example in septic shock bacterial endotoxins can
activate factor XII, so coagulation can take place without any vascular injury and may
develop very severe DIC (disseminated intravascular coagulation).
In the test tube, due to the contact with the glass surface, factor XII is activated, its
substrate is factor XI, proteolytic cleavage activates factor XI, and it transforms factor IX
into its active form. In the body factor XI. Is also activated by the thrombin generated by
the extrinsic pathway, thus accelerating the clotting process. The IXa factor forms a
complex with cofactor VIIIa (which is activated by thrombin), and this complex converts
factor X. into its active form. Here is the meeting point of the two pathways.
The genetic defect of factor VIII. causes hemophilia A, which is associated with
severe bleeding, because of the body's impaired ability to control blood clotting. This is
an unstable factor, so hemophilia A can be treated only with fresh plasma.
The deficiency of factor IX. causes hemophilia B or Christmas disease. Factor IX is
stable so hemophilia B can be treated with preserved blood.
The common pathway
The active factor X converts prothrombin to thrombin. This requires an activated
complex (similar to the previously described IXa-VIIIa complex). This complex consists
of the active factor Xa and cofactor Va (activated by the existing thrombin). Large
amount of thrombin is formed from prothrombin due to this activated complex.
Thrombin cleaves fibrinopeptides A and B (A from the  chain and B from the 
chain) from the fibrinogen molecules (which consist of , and  chains). Thus are
removed amino acid sequences which helped the fibrinogen molecules to push each other
electrostatically. The resulting fibrin monomers can connect with each other in the middle
of the molecule by weak hydrophobic and electrostatic bonds. The venom of some snakes
exhibit thrombin-like effect by a substance named reptilase, it removes only one of these
fibrinopeptides.
The fibrin monomers bind together to form a soluble fibrin. This is not quite stable,
covalent bonds have to be formed to have a stable fibrin. For this purpose is necessary the
factor XIIIa, a transglutaminase, which is activated by thrombin. The transglutaminase
forms stable covalent bonds between the glutamine and lysine side chains of the fibrin
monomers (with NH3 elimination). Thus a three-dimensional network is formed,
containing the cellular elements. The platelets contain contractile proteins (like
actomyosin in the muscular tissue), their contraction shrinks the wound edges. Platelets
will have star-like shape as a result of the contraction.
The localization and regulation of blood coagulation
The coagulation should be limited at the place of the injury. The intact endothelial
cells contain a surface glycoprotein called thrombomodulin. When the thrombin binds to
the thrombomodulin, a change in the thrombin conformation occurs and this alters its
substrate specificity, it is not going to cleave fibrinogen molecules, instead it activates a
protease, the C protein, which inactivates factors Va and VIIIa, and promotes
antithrombin III effect on thrombin. Protein C also needs protein S for its full activation.
An alternative method to suspend the prothrombotic activity of thrombin is the
synthesis of antithrombins. Antithrombin I is fibrin itself: thrombin bound to it is
inactivated. Antithrombin II is 2-macroglobulin, from the platelets and from the liver, it
forms an irreversible complex with thrombin, inactivating it. Antithrombin III is the main
inactivator of thrombin, causing irreversible inactivation. It inactivates also other factors:
factors VIIa, IXa, Xa, XIa and XIIa. Antithrombin IV are the fibrin degradation products,
which inhibit the polymerization of fibrin.
The dilution of activated clotting factors in the bloodstream, the presence of serine
protease inhibitors also contribute to the localization of the process.
Heparin is the best in vivo and in vitro anticoagulant. The heparin promotes the
thrombin - antithrombin III reaction, and it can inhibit factor Xa and IXa as well. Heparin
is used in the acute phase of thromboembolic disease, after myocardial infarction for
prevention of thrombosis and treatment of DIC. Heparinized blood is used in
hemodialysis and extracorporeal circulation.
The antidote for heparin overdose is protamine sulfate. The monitoring of heparin
therapy is made with the activated partial thromboplastin time (APTT), which gives
information about the intrinsic pathway. A heparin-like substance is secreted in the saliva
of a blood-sucking parasite, Hirudo medicinalis, which also has anti-clotting effect.
The fibrinolysis
The aim of the fibrinolysis is to dissolve the clot. If the clot is too large, insoluble, it
is transformed into connective tissue. The main enzyme of the fibrinolysis is plasmin,
whose role is to break down the fibrin and clean up the clot after the wound is healed. Its
inactive proenzyme is plasminogen, plasminogen activators enhance the activation
process.
The plasmin proteolytically cleaves fibrin to fibrin degradation products - these can
be determined in the laboratory. The plasmin also inactivates factors Va and VIIIa.
Plasmin inhibitors are the main regulatory elements of fibrinolysis, they are necessary to
avoid too soon initiation of fibrinolysis.
Streptokinase and urokinase are drugs that promote the conversion of plasminogen
to plasmin. Streptokinase is used in emergency management of myocardial infarction,
pulmonary embolism and deep venous thrombosis. Thrombin time is used to evaluate the
efficacy of the treatment. Tissue plasminogen activator treatment is more efficient, but
more expensive in similar cases.
Antifibrinolytic substances, such as EACA (epsilon amino caproic acid) and
PAMBA (para-amino-methyl-benzoic acid) inhibit plasminogen binding to fibrin. They
are used in severe bleeding, but not in case of DIC. In DIC (disseminated intravascular
coagulation) trasylol (gordox) may be useful - this is a polypeptide extracted from calf
lungs, which has antiprotease effect, it inhibits trypsin and plasmin.
The role of calcium and vitamin K in the coagulation process
The Ca2+ ions play an important role in the coagulation process, with their electro-
positive charge they can bind to negatively charged intermediates, promoting the
formation of complexes, causing conformational changes in proteins. The sodium citrate,
sodium oxalate, EDTA-Na are used to inhibit blood clotting, because calcium is bound to
them. This effect is reversible because with addition of calcium the clotting process can
be started afterwards. Blood is taken in test tubes containing this kind of substances for
coagulation tests.
The decrease in calcium does not cause coagulation disorders, because the patient
dies of other consequences of hypocalcaemia before coagulation disorder develops.
Most of the clotting factors are produced in the liver, thus severe liver diseases lead
to coagulation disorders. Factors II, VII, IX and X suffer changes in the molecule after
synthesis. These factors include several glutamic acid radicals, which are carboxylated in
the presence of vitamin K, leading to the formation of gamma-carboxy glutamic acid
radicals, which are more negatively charged, and can bind calcium. In case of vitamin K
deficiency bleeding disorders occur because of improper carboxylation.
Vitamin K is a liposoluble vitamin. Vitamin K deficiency occurs when the bile duct
is obstructed by bile stones or pancreatic head cancer. Therapeutically antivitamins K are
often used as anti-coagulants (warfarin derivatives). Main indications are the treatment of
deep venous thrombosis (heparin is given at first, then coumarin derivatives), prevention
of thrombosis, prophylaxis of embolism after surgery and in patients having artificial
heart valves. In case of overdose bleeding occurs, in this case vitamin K 1
(phytomenadione) injections are administered. The prothrombin time (Quick time) is
used to monitor the efficacy of the treatment, it provides information regarding the
extrinsic coagulation pathway.
The clotting time is a global parameter that gives information about the entire
coagulation process (normal value: 3-5 minutes).
In the surgical practice haemostatic sponges are used, which are placed on the
surface of diffuse parenchymal bleeding. These are useful for the liver, spleen traumatic
lesions, or in case of partial organ resections.
The blood clotting disorders
The clotting reaction is a life-saving defense mechanism, any irregularity it’s a life
threatening situation. There are basically two types of coagulation disorders: the blood
does not clot, or the blood coagulation process takes place without any injury.
The absence or reduced clotting function can be the consequence of the deficiency
of any clotting factor or cofactor (including calcium, vitamin K, etc.), or can occur due to
a dysfunction of coagulation enzymes regulating the process, such as plasmin. In severe
liver diseases deficiency of fibrin or thrombin precursors can occur.
The hemophilia is a sex-linked, genetically inherited disease. This means that the
hemophilia gene, responsible for the development of the disease, is localized on the
human 23rd chromosomes, the sex chromosome X. It is known that in women both sex
chromosomes are X, this explains why women are usually carriers of this disease (in very
rare cases both X chromosomes are abnormal). Men having a defective X chromosome
(and a Y chromosome) develop hemophilia. Deficiency of factor VIII. or IX. can cause
hemophilia.
If the structure of factor V is abnormal, its active form becomes resistant to
activated protein C effects, and therefore does not stop the blood clotting process. This
mutation (a genetic change) was observed by researchers in Leiden, so this abnormal
clotting factor was named Leiden factor. A similar resistance to activated C protein can
also occur during pregnancy and in women taking contraceptive pills, this explains the
frequent thrombotic events in these cases.
The genetic studies revealed that the the gene of the C and protein S, synthesized in
the liver in the presence of vitamin K, is on a somatic chromosome, and the defect is
dominantly inherited. This means that symptoms can appear in case of one defective
gene, in heterozygous form, in other cases two defective genes are present (homozygous
state), which causes a very high risk of thrombosis, and clotting disorders can appear in
early childhood. It is not surprising that half of the otherwise unexplained juvenile
thrombosis cases have in the background this hereditary disorder.
The gene of antithrombin III is also on a somatic chromosome, the inheritance is
dominant. It inhibits the action of thrombin, but also inhibits the activity of clotting
factors IX., X, XI. and XII.. The coagulation disorder is caused by the reduced amount of
antithrombin III or its malfunction.
Thrombosis, in most cases, is due to some local disorder of the blood vessel
(inflammation, atherosclerosis, abnormally low blood flow), and this enhances the
formation of blood clots. Predisposing factors are also important, these include smoking,
long-term immobilization, pregnancy, varicose veins, rhythm disturbances, oral
contraceptives. A blood clot formed (thrombus) blocks the blood vessel. In some cases,
the thrombus can be dislocated, and blocks other, potentially vital blood vessels (in the
brain, lungs or heart), thereby causing an embolism.

BIOCHEMISTRY OF THE ENDOCRINE SYSTEM

In order to have a proper interaction between the cell and its environment it is
necessary for the cells to receive extracellular signals and to transmit them inside the cell
to trigger the cell's response mechanism. Such signals are hormones and
neurotransmitters.
The hormones are signals that regulate cell metabolism and physiological
parameters.
The hormonal effects are of three types:
- autocrine: a hormone producing cell expresses receptors for that hormone, this
effect plays a role in autoregulation;
- paracrine: the hormone receptors are on the surrounding cells;
- endocrine: the hormones secreted by endocrine cells is released in the blood, and
acts at receptors distant from their site of release;
- neuroendocrine: the neurohormones secreted by the hypothalamus regulate the
hormon synthesis of endocrine glands by acting on the hypophysis.
The endocrine cells occur diffusely or form endocrine glands. The composition of
the endocrine system includes: the pituitary, thyroid, parathyroid glads, the adrenal cortex
and and medulla, Langerhans islet cells in the pancreas, testes, ovaries and the APUD
system cells (amine precursor uptake and decarboxilation) of the digestive tract.
The hormones of the endocrine system play a multiple role:
- They maintain the homeostasis in the body (such as insulin and glucagon act on
blood glucose levels, it is held between 60 -100 mg/dl)
- Hormones help the body to adapt to external influences, for example the "fight or
flight", by adrenaline and noradrenaline secretion
- Hormones regulate several processes, including cycles (eg. sex hormones such as
androgens, estrogens, progestagens control the sexual differentiation and maturation
processes, female sex hormones control the menstrual cycle and pregnancy).
Signal transduction systems
The hormones affect cell metabolism in different ways. Their receptors can be
localized in the plasma membrane or they can act on intracellular receptors.
On the bases of their signal transduction system, hormones can be divided into
several subgroups.

Table 3. Classification of hormones according to their mechanisms of action

Group I Hormones acting by intracellular signal transduction system

Estrogens Calcitriol
Glucocorticoids Androgens
Mineralocorticoids Thyroid hormones
Progesterone
Group II A Adenylate hormone signaling system
 ACTH LH Glucagon
Angiotensin II MSH 2-catecholamines
ADH TSH CRH
FSH Parathormone Calcitonin
hCG Opioids Somatostatin
Lipotropin Acetylcholine -catecholamines
Group II B Guanylate hormone signaling system
Atrial natriuretic factor
Group II C Inositol phospholipid system
1-catecholamines Acetylcholine
Cholesystokinin Oxytocin
Gastrin GnRH
TRH Angiotensin II.
ADH
Group III Tyrosine kinase signaling pathway
Insulin

The intracellular receptor signaling pathway

The fat-soluble (lipophilic) hormone molecules can go through the cell membrane,
thus they can pass from the extracellular transport proteins to the intracellular receptor.
The complex formed undergoes a temperature-dependent (thermotropic) and mineral salt-
dependent (liotrop) activation, thereby changing the conformation and electric charge
distribution on the surface.
After the activation the complex binds to the chromatin, or more precisely to a
section of DNA that contains a HRE (hormone responsive element), thereby activating or
inhibiting specific gene expression. Thus, these hormones regulate the synthesis of
proteins that are encoded by the respective gene.
The hormones belonging to group II have peptide structure, their specific receptors
are located on the cell membrane. G proteins play an important role in the intracellular
signal transmission of these hormones. They activate or inhibit intracellular enzymes,
which catalyze the synthesis of a second messenger molecule. The second messengers
affect cell metabolism. Based on the nature of the hormonal signaling system, they can be
divided into the following subtypes: adenylate, guanylate, and inositol phospholipid-
tyrosine kinase system. Corresponding to those listed before, the second messengers are
cyclic AMP (cAMP), cyclic GMP (cGMP), inositol triphosphate (IP3) and diacylglycerol
(DAG).
In case of the adenylate system, binding of the hormone (H) to the receptor (Rs), the
hormone-receptor complex activates a G protein that stimulates the adenylate cyclase
enzyme activity. The latter catalyzes the synthesis of cAMP (cyclic adenosine
monophosphate), which is a second messenger, which may cause changes in some
intracellular enzyme activity. The G protein consist of three subunits: ,  és . If GDP
(guanosine diphosphate) is bound to the  subunit, this protein does not activate the
cyclase enzyme. The cholera toxin inhibits GTP (guanosine triphosphate) hydrolysis,
which is leading to continuous activation of adenylate cyclase, so large amounts of cAMP
will be produced.

Adenylate hormone signaling system

The inositol-phospholipid system involves a hormone-receptor complex, which

activates the GPLC protein. If GTP binds to this protein, it activates the phospholipase C
enzyme. Active phospholipase C hydrolyzes phosphatidylinositol-4,5-diphosphate (PIP2)
to inositol-1,4,5-triphosphate (IP3) and diacil-glycerol (DAG).

Inositol phospholipid system

 Insulin exhibits its intracellular effect by the tyrosine kinase signaling system. The
insulin receptor is a dimer (consisting of two subunits) having tyrosine kinase activity.
When insulin is attached to the receptor, it is activated by autophosphorylation and it also
phosphorylates other intracellular proteins, influencing their activity.

The tyrosine kinase system

The hypothalamus and the hypophysis

The hypothalamus, working closely with the hypophysis (pituitary gland), regulates
the secretion of the body's endocrine glands. They form a functional unit that controls a
large part of the endocrine system. Releasing hormones and release-inhibiting factors are
synthesized in the hypothalamus, and stimulating hormones are secreted in the
adenohypophysis.
 The pituitary gland is composed of three lobes. The frontal lobe (adenohypophysis)
secretes hormones that regulate the thyroid and adrenal glands and the gonads, affect the
processes of growth and lactation. The hypothalamic excitatory and inhibitory neuro-
hormones help to regulate the secretion of adenohypophysis, these neuro-hormones reach
the anterior lobe of the pituitary gland through the pituitary portal system.
The middle lobe secretes the melanocyte stimulating hormone (MSH), responsible
for melanin granule dispersal in melanophores.
The posterior lobe (neurohyphophysis) stores two hormones synthesized in the
hypothalamus: vasopressin (antidiuretic hormone, ADH), which acts on the kidneys,
while oxytocin acts on the uterus and on the mammary gland.

Hypothalamus, hypophysis and the endocrine glands

In the human body there are four major stimulating systems. The hypothalamic
neuron-hormones and their corresponding trophormones are as follows:
1). CRH (corticotropin-releasing hormone) stimulates the pituitary ACTH secretion.
ACTH (adrenocorticotropic hormone) promotes the production of steroid hormones,
especially at the level of the corticosuprarenal gland.
The ACTH is excreted together with other hormones - MSH, LPH (lipotropic
hormone), endorphins - within a polypeptide named proopiomelanocortin (POMC).
The background of the development of Cushing's disease is a primary ACTH-
secreting adenoma. Addison’s disease (adrenal insufficiency) is manifested by
melanodermia (hyperpigmentation of the skin), especially at the level of the scars, due to
the MSH from POMC.
 2). The TRH (tireotropin releasing hormone) stimulates the pituitary TSH secretion.
The TSH (thyroid stimulating hormone, tireotropin) is a glycoprotein with dimeric
structure, which stimulates the synthesis of thyroid hormones (T4=thyroxine,
T3=triiodothyronine).
3). GnRH (gonadotropin releasing hormone, gonadoliberin) or LHRH (luteinizing
hormone releasing hormone) stimulates the secretion of FSH and LH at the pituitary
level. The GnRH hypersecretion in childhood leads to early puberty. Pseudocyesis occurs
in case of an excess production of GnRH, which is a psychoneurotic condition that occurs
in women who want children very badly. The symptoms of pregnancy (amenorrhea,
breast swelling, nausea, vomiting, weight gain) are present, but without a real pregnancy.
The decrease in GnRH secretion is much more common, with central
hypogonadism. Prolonged stress conditions (war, imprisonment) and can lead to
psychogenic amenorrhea, and weight loss can have the same consequence. The most
serious case of functional amenorrhea appears in patients suffering from anorexia
nervosa. It occurs in young girls who have bizarre ideas about nutrition and the human
body, so keep excessive slimming.
The FSH (follicle-stimulating hormone) controls the gametogenesis at the level of
the gonads. The LH (luteinizing hormone), or interstitial cell-stimulating hormone
(ICSH) stimulates the selection of sex hormones: estrogens (in women), androgens (in
male).
4). The GHRH (growth hormone releasing hormone) and GHRIH (GH release
inhibiting hormone), also known as somatostatin, control the GH secretion of the
pituitary gland. The GH (growth hormone, STH - somatotropic hormone, somatotropin)
stimulates the synthesis of growth factors (called somatomedines) in the liver, such as
IGF-1, also known as somatomedin C (insulin-like growth factor).
The oversecretion of GH, which is usually due to a pituitary tumor, causes
gigantism in infants (pathologically increased growth) and acromegaly in adults.
In case of GH deficiency the body is retained in the growth, dwarfism (nanism) is
developed. In this disorder, as opposed to thyroid dysfunction in children, the body’s
proportions are normal and also the mental ability.
Prolactin plays an important role in milk production. It is synthesized in the
lactortop cells of the anterior pituitary lobe. The number and size of these cells
significantly increase during lactation.
The secretion of prolactin is under permanent inhibition of dopamine. Prolactin
inhibits the release of GnRH, and thus the gonadotropins (LH, FSH) secretion. The high
prolactin levels during lactation exhibit an inhibiting effects on the gonads (nursing
mothers have no menstrual cycle and no fertility). The pathological oversecretion of
prolactin can lead to sterility, which can be treated with dopamine agonists
(bromocriptine).
Pituitary insufficiency (panhypopituitarism) may occur in case of a non-secreting
pituitary adenoma, trauma, inflammation, or because of the pressure exhibited on the
pituitary gland by adjacent tumors. A special case is the Sheehan syndrome, which is due
to the necrosis of the pituitary gland, the cause is the great loss of blood during delivery,
which leads to contraction of blood vessels of the pituitary gland.
Oxytocin and vasopressin (antidiuretic hormone, ADH) are secreted in the
hypothalamus and transported to the neurohypophysis.
 Oxytocin plays an important role in the contraction of the uterus during delivery
and in the ejection of milk.
The main role of antidiuretic hormone is to enhance water retention in the kidneys
by promoting resorption. Diabetes insipidus occurs in case of deficent ADH secretion.
The patients eliminate very large amounts of urine (3-20 l) called polyuria, the urinary
density is very low and the loss of excessive amounts of liquids lead to secondary
polydipsia (high water intake).

The thyroid gland

The thyroid hormones are thyroxine (T4) and triiodothyronine (T3). The functional
units of the thyroid gland are the follicles, they consist of a layer of epithelial cells and a
the colloid, which contains high amounts of thyroglobulin. This protein is rich in tyrosine
radicals and plays an important role in the organification of iodine. The uptake of I - is
depedent on the function of the Na+/K+-ATP-ase.
On the surface of the thyroid follicular cells is a peroxidase enzyme, which
catalyzes the oxidation of I- by the following reaction: I- + H2O2 + 2H+  I+ + 2H2O.
Several drugs inhibit this enzyme (propylthiouracil, methimazole).
Both T3 and T4 are present in the blood in bound state (more than 99%) to
prealbumin, albumin and globulins - such as TBG (thyroxine-binding globulin). The free
form is the biologically active fraction, which represents only 0.03% of the plasma T 4
concentration and 0.3% of the T 3. Determination of the free fractions have high
diagnostic value in the investigation of the thyroid function.
One of the effects of thyroid hormones is the increase in O 2 consumption, they
enhance protein synthesis, thyroid hormones are necessary for the normal development of
the body and for the function of the nervous system.
Hypothyroidism in childhood is due to iodine deficiency that occurs endemically, it
leads to cretinism (severe mental retardation) and disproportionate nanism. The
chronically elevated TSH levels induce proliferation in the thyroid tissue.
Hypothyroidism does not have such serious consequences in adults. Psychomotor
slowness can be observed, somnolence, apathy, memory disturbances, dry skin and
sterility. The patients respond very well to substitution treatment, such as the long-acting
T4 containing L-thyroxine.
In most cases hyperthyroidism appears as Basedow-Graves' disease (autoimmune
hyperthyroidism). That disease is caused by IgG antibodies stimulating the TSH receptors
in the thyroid gland. This immunoglobulin does not respond to negative feedback
regulation, so thyroid hyperfunction develops, the thyroid volume is increased (goiter).
The symptoms are the result of the increase in basal metabolic rate. Tachycardia, weight
loss with increased appetite, exophthalmus (because of the retrobulbar immune
processes), warm and moist skin, overexcitability of the nervous system.
Using radioactive iodine or technetium a thyroid scintigram is obtained, which can
contain cold nodules (with decreased captation) and hot nodules (with high captation).
This method is of decisive importance in the diagnosis of thyroid cancer, which appears
in 25% of the cases as cold nodules.
The para-follicular thyroid cells, which are part of the APUD (amine precursor
uptake and decarboxilation) system, secrete calcitonin, a hormone that plays a role in
calcium and phosphate homeostasis.
 The parathyroid glands
The parathyroid hormone (PTH) secretion in parathyroid cells depends on the blood
plasma calcium levels. PTH increases blood calcium levels directly and indirectly
(through the D vitamins, enhancing its activation).
Hypoparathyroidism. The four parathyroid glands are closely integrated into the
tissue of the thyroid gland. This anatomical feature in some cases can lead to situations
when the parathyroid glands are accidentally removed during thyroid surgery. The
absence of PTH results in a significant reduction of plasma calcium level, tetania
(seizures due to uncontrolled muscular contractions) appear (because of the
neuromuscular hyperexcitability), which can be fatal if respiratory muscles are affected
by the process.
Hyperparathyroidism. Occurs in case of PTH secreting parathyroid tumors. The
consequence of the significant increase in plasma calcium level is the formation of
multiple bone cysts (these can lead to fractures), formation of kidney stones, muscular
hypotonia. Half of the cases present high blood pressure with kidney origin. Calcium is
deposited in the blood vessel walls, in the interstitium of the kidneys (nephrocalcinosis)
and cartilages (chondrocalcinosis), the latter is extremely painful.

The adrenal glands

These glands can be divided into two separate parts: one is the cortex, which
produces steroid hormones, and the medulla, secreting catecholamines.
The adrenal cortex consists of an outer layer containing mineralocorticoids-
producing cells (the main representative of this hormone group is aldosterone), and an
inner layer, where glucocorticoids (main representative: cortisol) and sex steroid
hormones (androgens, estrogens, small amounts of progesteron) are produced.
Cholesterol is the precursor of all steroid hormones.
Mineralocorticoids exhibit their effect primarily at the level of the kidneys, they
increas the Na+ and Cl- retention, promote the elimination of K+ and H+.
Hyponatremia stimulates the renin-angiotensin-aldosterone system, specifically by
raising the level of angiotensin II. Hypervolaemia increases ANP (atrial natriuretic
peptide) production, which reduces the secretion of aldosterone.
Primary aldosteronism (Conn syndrome) is charecterized by water and salt retention
causing increased blood pressure, reduced plasma levels of potassium and metabolic
alkalosis.
The secondary hyperaldosteronism is caused by hypovolaemia or hyponatraemia of
the blood flow at the level of the juxtaglomerular apparatus, thereby increasing the
synthesis of renin. Etiological factors may be severe vomiting, diarrhea, diuretics, renal
artery stenosis, etc..
The deficeincy of aldosterone can be observed in Addison's disease, or in case of
bilateral adrenal gland removal.
Glucocorticoid hormones increase blood sugar level by three main mechanisms:
they promote gluconeogenesis from amino acids, induce the hepatic gluconeogenetic
enzyme activity and reduce glucose uptake and utilization in muscle and fat tissues.
Another mechanism of action of glucocorticoids is promoting glycogen synthesis in the
liver.
 Glucocorticoids also influence fat metabolism by reducing lipogenesis and
increasing the activity of lipolytic hormones (such as adrenaline). Free fatty acids are
important energy sources in case of starvation, while glycerol is a precursor for
gluconeogenesis. In case of glucocorticoid hormone deficiency the body cannot tolerate
hunger, severe hypoglycemia and energy shortage occurs.
Glucocorticoids inhibit the body's inflammatory response and play a role in
modulating the immune processes. For this reason, they are used very often in various
autoimmune diseases (rheumatoid polyarthritis, systemic lupus erythematosus - SLE),
allergic diseases (bronchial asthma, allergic dermatitis, anaphylactic shock), malignant
proliferations, organ transplant patients, etc..
The excess production of glucocorticoids causes Cushing's syndrome. May be due
to adrenal hyperplasia or tumor. Muscle hypotrophia develops, fat redistribution, purple
or red striae especially on the abdomen, high blood pressure and diabetes might occur.
This clinical manifestation appears also in case of long-term administration of
corticosteroids. These drugs may suppress the adrenal function, the treatment should not
be stopped suddenly, it is recommended to gradually reduce the dosage, otherwise the
patient could develop fatal acute adrenal insufficiency (Addison's crisis).
Addison's disease occurs in case of adrenal failure, with deficient production of
gluco-and mineralocorticoids. The symptoms occur when less than 10% of the adrenal
glands work, due to autoimmune destruction it may be caused by tuberculosis. Weight
loss occurs, tendency to hypoglycaemia, stress tolerance is deficient (due to a lack of
glucocorticoids), low blood pressure and high serum potassium levels appear (due to lack
of aldosterone).
The adrenal glands are the main sources of male hormones (androgens) in the
female body. For men, this has less relevance, because most of the androgens are
produced by the testes. In congeniatalis adrenal hyperplasia, adrenal tumors or different
enzyme defects virilisation syndrome occurs in women by overproduction of androgens.
In the medulla catecholamine hormones are secreted, the final products are
noradrenaline and its methylated derivative, adrenaline.
The effect of adrenaline at the level of different tissues depends on the type of the
receptor. 5 types of receptors have been described: 1, 2, 1, 2 and 3. The 1 receptor
stimulation triggers contraction of smooth muscle (vasoconstriction, mydriasis), 2
receptors are located in the presynaptic membrane of neurons, their stimulation inhibits
the release of catecholamines. The 1 receptors play an important role in mediation of
heart muscle stimulant effects (increase the strength and the frequency of contractions),
stimulation of 2 receptors causes smooth muscle relaxation (vasodilation, dilation of
bronchial passages), and 3 receptors are involved in the lipolysis.

The  adrenoreceptors activate the adenylate cyclase, leading to the formation of

cAMP, which stimulates glycogenolysis and gluconeogenesis in the muscle and liver, and
induces lipolysis in the adipose tissue. The stimulation of  adrenoreceptors inhibits the
adenylate cyclase activity (2), or activate the inositol-phospholipid system, exhibiting
opposite effect compared to the previous type.
Knowing the existence of these receptors has several practical benefits: for example
treating a tachycardia with a non-selective beta-blocker (propranolol) can lead to
bronchoconstriction, cauding a severe asthma attacks in a patient suffering from this
disease. In these cases selective 1-blockers (atenolol, metoprolol) are recommended.
The long term teatment with beta-blockers should not be stopped suddenly, because
of the large amounts of circulating catecholamines which can cause severe arrhythmias
and increased blood pressure.
Pheochromocytoma is an adrenal tumor secreting catecholamines. The main
manifestation of the disease is high blood pressure (often periodic), which causes
headaches and palpitation, accompanied by vigorous sweating. Administration of -
adrenergic blockers is indicated in case of hypertensive crisis (phentolamine), and the
tumor can be surgically removed.

The testes
The testicular function is under the influence of the gonadotropin hormones. FSH
stimulates the sperm production, while LH (ICSH) enhances the production of
testosterone. The production of gonadotrophins has a constant level, because of the
negative feedback exhibited by testosterone.
Testosterone is a hormone essential for the function of male internal and external
genital organs, it is necessary for the development and maintenance of the male
secondary sexual characteristics. Testosterone can be transformed into estradiol.
Testosterone has an anabolic effect: promotes the protein synthesis, the ossification
and increase the erythropoiesis in the bone marrow (men have higher hemoglobin and
hematocrit values). The anabolic steroids (decanofort) are drugs which have reduced
androgenic effect, so are used in the treatment of osteoporosis, in cachectic states, anemia
due to bone marrow hypoplasia, etc..

The ovaries, the corpus luteum and the placenta

The sex hormones produced in the ovaries are estrogens and progesterone, which
show cyclic changes in their plasma levels. The synthesis of estrogens is regulated by LH
and FSH stimulation. Estrogens (estrone, estradiol, estriol) regulate the function of the
ovaries, promote the endometrium proliferation. The LH peak triggers the ovulation by
enhancing estrogen secretion. The body temperature is increased during the LH peak, this
can be used as an indicator of ovulation.
Progesterone is produced under the influence of the pituitary LH in the corpus
luteum. Progesterone is produced at a high rate in the secretory, luteal phase of the cycle,
its role is to prepare the endometrium to receive the fertilized egg. In the absence of
fertilization the hormone levels are decreased, the uterine lining detaches (menstrual
bleeding).
In pregnancy, the placenta takes over the hormone production from the corpus
luteum after the eighth week. The placenta secretes estrogens, progesterone, human
chorionic gonadotropin (hCG), human placental lactogen (HPL), etc.. The progesterone
production in the corpus luteum is essential in the first few weeks to keep the pregnancy,
this is maintained by the placental hormone hCG. Pregnancy tests are based on the
detection of hCG in the urine. As the pregnancy progresses, the breasts also undergo
changes. The high levels of estrogen and progesterone inhibit lactation. These levels
decrease after pregnancy, so prolactin can promote lactation.
 The changes in hormone levels during the menstrual cycle

In menopause decreased production of sex hormones occurs, especially

progesterone deficiency. The menopause occurs in women around 45 - 55 years of age, it
is a physiological ovarian failure, leading to the decreased synthesis of sex hormones, and
the increase of gonadotropins. Hot flashes occur due to the absence of estrogens. After
menopause the absorption of calcium is reduces and calcitonin secretion is decreased due
to the lack of estrogens, with subsequent development of osteoporosis.

The endocrine pancreas

In the Langerhans islands  cells secrete glucagon and  cells secrete insulin.
Insulin is the body's blood glucose-lowering hormone, reduces the blood level of
amino acids and free fatty acids. Plays an important role in the regulation of metabolic
pathways, such as the somatotropic hormone (STH) is unable to exert its anabolic effect
in the absence of insulin. One of the most significant factors that stimulates the
production of insulin hormone in the gastric inhibitory peptide (GIP).
The muscle and adipose tissue contain insulin receptors. In the muscle tissue insulin
increases the glucose and potassium absorption, stimulates glycogen and protein
synthesis, increases the uptake of fatty acids and the synthesis of triacylglycerols. In the
adipose tissue, insulin promotes glucose uptake, stimulates glycolysis and lipogenesis.
The hepatocytes can take glucose from the blood in the absence of insulin. In the liver,
insulin accelerates glycolysis, glycogen and protein synthesis.
Diabetes mellitus is a pathological disorder characterized by the total or partial lack
of insulin. The first type or insulin-dependent diabetes mellitus (IDDM) occurs in
children or young people, absolute insulin deficiency is present due to the destruction
(probably by autoimmune mechanism) of the pancreatic  cells. The patients complain of
fatigue, polyuria (excessive urination), polydipsia (increased fluid intake) and polyphagia
(increased appetite), with weight loss. Often the first manifestation is the ketoacidotic
coma, which occurs when for some reason (infections, fever) the body's need for insulin
increases. The lipolysis is enhanced, with consequently elevated levels of ketones,
acidosis occurs, hyperglycemia, dehydration. These individuals need subcutaneous doses
of insulin several times every day. They are using portable glucometers to check their
blood glucose, thus assessing their need for insulin.
The second types or non-insulin dependent diabetes mellitus (NIDDM) occurs in
adults, the manifestation depends on external factors (diet, obesity). Relative insulin
deficiency and insulin resistance develops. The main goal of the treatment is to achieve
ideal body weight with diet and exercise. If we can not restore the right range of glucose
levels, oral antidiabetic drugs are used (which stimulate pancreatic insulin production or
inhibit glucose absorption). Two large groups of drugs are used: sulfonylureas and
biguanides. After several years of treatment insulin might be necessary.
The glycosylated hemoglobin (HbA1c) correlates with the average blood glucose
levels during the previous 3-4 months. The normal range is 4-6%, for diabetic patients the
target of the treatment is to have HbA1c under 7%.
Insulin overdose may lead to severe hypoglycaemia. The central nervous system
cells are extremely sensitive to hypoglycaemia, blood sugar levels below 50 mg/dl are
very dangerous, the patient can become comatous, and brain damage might occur
(encephalopathia).
The long-term complications of diabetes mellitus include cataract, diabetic
retinopathy (it can lead to blindness), coronary artery disease (often painless heart attack
occurs), diabetic nephropathy (which can lead to kidney failure), diabetic neuropathy
(especially at the lower limbs), ulceration or gangrene of the feet, impotence, increased
susceptibility to infections. Prevention of these complications can be made by keeping
blood sugar levels close to physiological levels.
Many phytotherapeutical products proved to be effective in the treatment of
diabetes, such as Diavit (blueberry and sea buckthorn concentrate), which regenerates the
pancreatic  cells, and contains herbal insulin (myrtilline). Incretin hormones are
extracted from the saliva of Hila monster (exenatide) which decreases blood sugar level
and leads to weight loss. The amylin agonists (which have opposite effect compared to
glucagon) are also widely used, such as glucosidase inhibitors, thiazolidinediones and
meglitinide analogues.
Glucagon has opposite effect compared to insulin. It increases blood sugar levels,
promotes lipolysis. In the liver it promotes glycogenolysis and the formation of ketone
bodies.

BIOCHEMISTRY OF DIGESTION

Digestion in the oral cavity

Digestion of food begins in the mouth. The saliva secreted by the parotid,
sublingual and submandibular salivary glands moists mucous membranes, dissolves
sugars, proteins, micro-molecules, its mucin content helps swallowing the solid nutrients.
Lysozyme exhibits antiseptic effects, and salivary amylase begins the digestion of
polysaccharides. Saliva pH is normally around 6.8. At pH under 4 the enzyme is
inactivated, so in the stomach it loses its activity. The saliva contains a lipase enzyme,
which is produced by the Ebner glands located in the dorsal part of the tongue. The saliva
secretion is under the control of the nervous system, it may be parasympathetic stimulus
(inhibited by atropine) or sympathetic (small amounts of viscous saliva are produced in
case of powerful sympathetic stimulus).
Some medicines can be absorbed from the oral cavity (such as nitroglycerin, a
vasodilator used to treat angina pectoris attachs). On the other hand, certain drugs are
excreted through the saliva (morphine), inorganic ions (K+, Ca2+, HCO3-, SCN-, I-) and
immunoglobulins (IgA). The sense of taste is highly developed in humans, plant
glycoproteins called lectins that cover the taste buds facilitate the perception of the sweet
taste.

Digestion in the stomach

In the stomach takes place the digestion, mixing and storage of food. The gastric
juice (pH = 1-2) has three main roles: the chemical-enzymatic breakdown of food (pepsin
can digest denatured proteins), offers the optimum pH for pepsin and protection against
the microorganisms. The stomach mucosa contains several cell types. The digestive
enzymes are produced in the main cells, histamine and serotonin are produced in the
enterochromaffin cells, G and D cells produce gastrin and somatostatin, parietal cells
produce H+, Cl- and intrinsic factor (a glycoprotein necessary for the absorption of
vitamin B12), while the superficial epithelial cells produce Na+, HCO3- and mucus. The
mucus protects the stomach lining from the HCl and from the effect of proteolytic
enzymes.

The parietal cell

The stimulators of the gastric acidity

 Dietary amino acids, especially the biogenic amines produced during
decarboxylation are stimulators of gastrin secretion in the G cells. The amines diffuse
into the G cells, increase the pH of secretory vesicles, which induces gastrin secretion by
exocytosis. Helicobacter pylori (HP) is a microorganisms which produces urease to form
ammonia, which induces gastrin secretion by a similar mechanism, and stimulates the
production of HCl promoting the formation of ulcer. HP also produces phospholipase
enzymes, enhancing the damage of the mucosa layer.
Risk factors for ulcer: consuming NSAID (nonsteroidal anti-inflammatory drugs)
such as aspirin; smoking, stress, Helicobacter pylori infection. Gastric acidity is
increased. Complications: bleeding (externalized by hematemesis or melena), perforation
(air appears in the abdominal cavitaty), penetration (in other organs), stenosis,
malignancy (in case of gastric ulcer).
Duodenal ulcer: the epigastric pain usually yields after food intake or administering
antiulcer drugs. Duodenal ulcer never turns into malignancy, so biopsy in not necessary.
Gastric ulcer: occurs in elderly people, epigastric pain often worsens after food
intake, which leads to weight loss. Because it can become malignant, a biopsy of the
gastric ulcer is required: cancer cells can be recognized by microscopic examination.
Gastric cancer: the symptoms are: often sensitive stomach, weight loss, possibly
distaste for meat. In pyloric stenosis: feeling of fullness, vomiting undigested food
several hours after meal. Metastasis can be in the liver, ovaries, left supraclavicular
lymph nodes.
Treatment of ulcer:
- Antiacid drugs (Al(OH)3, Mg(OH)2, NaHCO3, CaCO3), thei main effect is
neutralization of HCl in the stomach (almagel, maalox)
- Antisecretory drugs:
- Parietal cell receptor blockers:
- selective anticholinergic drugs which do not affect gastric motility
(pirenzepine, telenzepine).
- antihistamines, H2 receptor blockers (cimetidine, ranitidine, nizatidine)
- Antienzymatic medicines:
 - Carbonic anhydrase inhibitors (acetazolamide) that decrease the secretion
of protons.
- Proton pump inhibitors. The ATP-ase needs free thiol groups to work, so it
can be blocked by substances which react with these groups, such as omeprazole (losec).
- Protective drugs:
- Derivatives of prostaglandin E (misoprostol, enprostil). They stimulate
mucus and bicarbonate secretion, decrease the secretion of HCl.
- Protective films of colloidal bismuth (de-nol) or aluminum sulfate (sucralfate),
which stimulates the secretion of prostaglandins and have a bactericidal and acid-
neutralizing effect.
- Antibacterial medication especially against Helicobacter pylori (amoxicillin,
metronidazole).
Surgical treatment consists of gastric resection, removing the bottom of the
stomach, the G cells and a part of the parietal cells or vagotomy (preferably selective) is
practiced especially in duodenal ulcer.
Bleeding ulcers can be solved by endocope, with local ethanol application or by
coagulation.

The pancreas
Several digestive enzymes are produced in the pancreas and a fluid rich in HCO3-
which neutralizes the gastric acidity, this fulfills the neutralization of the gastric juice to
achieve an alkaline environment, necessary for the digestive enzymes in the intestinal
tract. Some enzymes such as amylase, lipase, ribo-and deoxyribonuclease are secreted in
active form, while others are inactive in the pancreas (zymogens such as trypsinogen,
chymotrypsinogen, proelastase, procarboxypeptidase, prophospholipase). To prevent the
premature activation of the zymogens in the pancreas, numerous regulatory molecules are
secreted (such as pancreatic trypsin inhibitor).
Under physiological conditions the zymogens are activated only in the duodenum.
The trypsinogen is activated to trypsin by an enteropeptidase produced by the lining of
the duodenum. Trypsin is a protease enzyme that has autocatalytic activity (it can activate
trypsinogen molecules), and it also activates other proteases by cleaving specific peptide
bonds. The human body contains several proteolytic (protein degrading) enzymes, as
each cleaves the peptide bond next to different aminoacid residues: trypsin cleaves near
basic amino acids (such as lysine), chymotrypsin cleaves the chain near aromatic amino
acids (such as tryptophan), while elastase cleaves the peptide bonds adjacent to small,
non-polar radicals (such as alanine). After eating food that is hard to digest, it is
recommended to take tablets containing digestive enzymes (such as triferment,
containing trypsin, lipase and amylase) and bile acids (bilagit). Some products contain
both pancreatic enzymes and bile acids (zymogen).
Under pathological conditions such as trauma or inflammatory diseases (acute
pancreatitis) zymogens are activated early, in the pancreatic tissue, leading to the
digestion of the pancreas (pancreatic necrosis), which has a very bad prognosis. In these
cases the high blood levels of pancreatic amylase and lipase can be detected. Trasylol is
an antiprotease drug that has been proven effective in the treatment of acute pancreatitis.

The role of the liver in the digestion

 The liver produces bile, which plays an important role in the digestion of fats,
emulsifying lipids, facilitating the access of digestive enzymes. Bile can be obtained for
laboratory determinations using the Einhorn tube introduced in the duodenum. Bile A is
the fraction excreted spontaneously, bile B is collected after the contraction of the
gallbladder, while bile C is the last fraction from the liver.

Digestion and absorption in the intestinal tract

Several digestive enzymes are prodeced in the small intestine: aminopeptidase,
dipeptidase, disaccharidase enzymes (lactase, sucrase), nuclease, phospholipase enzymes.
In the small intestine takes place the final digestion of food, the transformation to simple
compounds (amino acids, monosaccharides, free fatty acids, etc) which can be absorbed
through the intestinal wall into the blood stream.
The cellulose fibers are plant polysaccharides, which cannot be degraded by the
human digestive enzymes, but their presence in the intestine is important for maintaining
the normal motility.
Some cells of the intestinal mucosa produce hormones regulating the digestion:
secretin, cholecystokinin, VIP, etc.. The hormone-producing cells of the gastrointestinal
tract are part of the diffuse endocrine system, these cells are known as the APUD (amine
precursor uptake and decarboxylation).
In the colon proper digestion and food absorption is no longer taking place, just
liquid absorption. The mucosa of the colone produces K+ and HCO3- ions, small amounts
of these ions are excreted in the faeces. Large losses occur only in case of colone
inflammation (colitis), when the mechanism of fluid absorption is damaged. Thus,
dehydration occurs, which is associated with hypokalemia and metabolic acidosis.

BIOCHEMISTRY OF NUTRITION

Life is based on a constant energy consumption, for metabolic processes, tissue

renewal, basic physiological activities (respiration, circulation), and muscle function.
This energy is obtained from food.
The body needs an equilibrium between the energy intake and consumption. In case
that energy intake exceeds consumption, body weight gain begins and obesity develops.
If energy intake is less than the necessity of the body, wight loss occurs. Young women
suffering from anorexia nervosa follow excessive diet, leading to pathological thinness.
Those weight loss drugs are very dangerous which disconnect the respiratory chain from
oxidative phosphorylation, inadequate dosing may result in death. The mechanism of
action is based on the disconnection of these two processes, that results in heat formation
instead of ATP production.
A healthy diet contains the main nutrients in ideal proportion. Carbohydrates (4.1
kcal/g) and fat (9.3 kcal/g) are used mainly for energy in the body, while the proteins (4.1
kcal/g) are essential for tissue regeneration.
Carbohydrates are mainly used for energy production, they represent an immediate
source of energy for muscle function. Monosaccharides are formed by the digestion of
carbohydrates, which are absorbed from the small intestine. Starch is a plant
polysaccharide, which releases glucose units by degradation. The disaccharide sucrose
contains glucose and fructose. Lactose is the main disaccharide in milk, it contains
glucose and galactose. The fruits contain high amounts of fructose. All monosaccharides
are decomposed by the glycolysis in the cells.
The excess of carbohydrates promotes the development of diabetes and obesity. It is
preferable to consume food in natural form, because of the minerals and vitamins
contained, which can be often lost during the cooking process.
Lipids have a very high energetic value. They prolong the process of digestion, a
fat-rich diet offers the sensation of satiety. The tissues richest in fat are the brain and
adipose tissue, fat offers a protective layer for various organs and contributes to the
maintenance of body temperature. Animal fats consist of cholesterol and saturated fatty
acids, being in solid form. The plants contain unsaturated fatty acids, they are in liquid
form. Vegetable oils contain polyunsaturated fatty acids (vitamin F), such as arachidonic
acid, the precursor of local hormones (prostaglandins, prostacyclins, leukotrienes,
thromboxanes). These fatty acids are essential for the body.
A diet containing excessive fat exhibits harmful effect on the state of health. Among
those ethnic groups which consume a lot of animal fat obesity increases, and the
incidence of colon cancer and atherosclerosis is also higher. The role of LDL-cholesterol
in atherosclerosis is well known, combined with other risk factors, such as smoking, high
blood pressure, etc. Inuits are exception, they consume large quantities of aquatic animal
fat, and they have a very low incidence of atherosclerosis. The explanation is that the
aquatic animal fat is rich in unsaturated fatty acids, such as the 20-carbon unsaturated
eicosapentaenoic acid, which inhibits the thrombogenic and vasoconstrictor effects of
thromboxane A2. The EPA contains five double bonds, represents the precursor of LT5
leukotrienes, which are weaker compared to the effect of the LT4 group.
The insufficient consumption of fat leads to the deficiency of fat-soluble vitamins,
causing delays in growth and development in children.
The proteins are particularly important in the growth process and in the renewal of
body tissues. Protein needs increase during pregnancy and in breast-feeding mothers. The
proteins in the human body are not completely oxidized to CO2 and H2O, as in case of
carbohydrates and fats. The protein nitrogen is excreted from the body as nitrogenous
compounds, such as urea. From the 20 standard amino acids 8 are essential (cannot be
formed in the human body), 2 are semi-essential (children do not produce sufficient
quantities) and the remaining 10 are non-essential.
Not every protein contains all essential amino acids. There are complete proteins,
especially of animal origin, which contain all essential amino acids in sufficient
quantities, these have a high biological value. The majority of plant proteins are not
complete, they contain only a limited number of essential and nonessential amino acids,
and therefore they have lower biological value. The excessive intake of protein leads to
renal dysfunction. A diet containing few proteins can lead to protein-calorie malnutrition.
The unnecessary excess of water-soluble vitamins is excreted by urine, very little
amounts are stored in the body, so they need a daily intake (vitamin C and B group).
The fat-soluble vitamins are stored mainly in the liver (vitamins A, D, K) and in the
fat tissue (vitamin E), the excessive intake can lead to poisoning. Deficiency of fat-
soluble vitamins may occur in case of malabsorption, biliary obstruction or bile acid
deficiency.
 The body's minerals are divided into two groups: macro elements such as Ca, P, Na,
K, Cl, Mg (the body contains high amounts of these, for example a 70 kg adult’s body
contains 1 kg of calcium) and micro-nutrients: copper, iodine, Fe, Se, Zn, F (these can be
found in our bodies in small quantities). The absorption of the minerals takes place in the
intestine, high amounts are excreted by the faeces. Usually specific proteins are required
for their absorption, their synthesis is an important aspect of the mineral metabolism.
The plant bioactive food ingredients include: plant enzymes, pigments, glycosides,
alcaloids (caffeine, theobromine, teofilin), oil esters (mint), organic acids (which are
responsible for the sour taste of the fruit), antibiotics (contained in the onions, garlic,
horseradish). Large amounts of material of this nature can be found in the herbs, which
are consumed in form of tea. Many herbs are rich in antioxidants such as polyphenols,
flavonoids, the radical scavenging vitamins (A, C, E). Garlic, ginseng, aloe vera, sea
buckthorn, blueberry, ginkgo biloba extracts are increasingly used for therapeutic
purposes. Many of the bee products have beneficial effects.

Feeding the infant

The baby feeding may be natural, exclusive breastfeeding for the first 4-6 months;
artificial (adapted formula), mixed (breast milk and formula as a supplement). After the
first few months fruit juices and semi-solid foods are introduced in the diet of the infant.
Breastfeeding provides a natural diet which is necessary for the development of the
infant, it prevents infection (due to the IgA content), it is anti-allergic, automatically
adapts to the needs of the infants, promotes the emotional relationship between mother
and child, and last but not least is free.
New types of food are introduced at the age of 4-6 months, in full state of health,
only one by one. The fruits containing small seeds (strawberry, raspberry) are not
recommended before one year of age, because they can cause allergies (some books also
include honey on the list of allergenic foods). For the same reason egg whites and fish
should be avoided during the first 12 months. Some fruits and vegetables are difficult to
digest, such as apricots, cherries, cucumbers and maize, therefore these are not
recommended for infants under the age of one, just like pork. The wheat-based foods due
to their gluten content, should be given to the infants only after 6 months of age, before
this age rice dishes can be administered. The egg yolk and liver should be introduced
alternately with chicken at 6-7 months of age, these are very important because of their
high iron content, thereby preventing iron deficiency anemia. The first vegetables given
to the infant should be carrots, parsley, spinach, squash, tomatoes, at first as soup, then
puree after 5 months of age. Because of the high starch content of potatoes they should be
postponed for the period when the enzyme equipment becomes mature.

THE BIOCHEMISTRY OF THE BONE TISSUE

The bone tissue consists of cellular elements (osteoblasts, osteocytes, osteoclasts)

and the matrix, containing organic (collagen fibres) and inorganic (hydroxyapatite
crystals) components. The osteoblasts produce the macromolecules of the bone matrix
(they constitute together the osteoid tissue), which undergoes mineralisation.
 A supersaturated solution of calcium and phosphate ions is present between the
cells, of this solution hydroxyapatite crystals are formed by precipitation, which
impregnate the collagen fibers. The osteoblasts secrete phosphatase and pyrophosphatase
enzymes, which decompose organic phosphate esters and inorganic pyrophosphate
releasing inorganic orthophosphate, enhancing mineralisation.
The calcium binding proteins, for example osteocalcin, also contribute to the
mineralisation process. The enzyme alkaline phosphatase is produced by the osteoblasts,
it is active in alkaline environment, so it is called alkaline phosphatase. This enzyme
shows higher level in the period of skeletal growth, due to the increased osteoblast
activity. This explains why children present 2-3 times higher values of this enzyme
activity in the serum compared to the adults.
The osteobloasts are transformed into osteocytes, which form a barrier between the
interstitial space of the bones and the capillaries. The permeability of this barrier is under
hormonal control.
The osteoclasts break down the bone tissue, there are several mechanisms by which
these cells exert their effect. They secrete protons in their surroundings, the high H+
concentration dissolves the hydroxyapatite crystals, thus the calcium and phosphate ions
get into the solution. The osteoclasts produce hydrolytic enzymes that degrade
extracellular matrix proteins and proteoglycans. The osteolysis and osteogenesis (bone
turnover) is at steady state till 35 years of age, then the re-building mechanisms become
less efficient, and less bone tissue is built than it is decomposed.
The body's calcium and phosphorus are closely linked to skeletal biochemistry. The
human body contains about 1 kg of calcium, 99% of it is found in bones and teeth.
The bones undergo a constant remodeling process, which is realized through the
relationship of calcium and phosphate metabolism and deposition/release of these ions
in/from the bones. In this respect, two hormones are very important (parathyroid hormone
and calcitonin) and hormone-like effects are exhibited by the active vitamin D (calcitriol
or 1,25-dihydroxy-cholecalciferol).
In addition, other hormones also affect skeletal development and remodeling.
Androgens and estrogens play an important role in the physiological maintenance of the
bone tissue. The inorganic bone component decreases when sex hormone levels are
reduced. Postmenopausal women and older individuals generally suffer from
osteoporosis. In postmenopausal osteoporosis estrogen treatment can reduce bone
decomposition.
The glucocorticoids (cortisol) inhibit the absorption of bone under in vitro and in
vivo conditions, in general, they modulate the development of the skeleton. The growth
hormone secreted by the pituitary gland is the most important regulator of bone
metabolism, it exhibits its effect through somatomedines. Prostaglandins E1 and E2
proved to be powerful in vitro stimulants for the bone resorption.
The secretion of the parathyroid hormone depends on the blood calcium
concentration. PTH increases the blood calcium concentration by stimulating its renal
reabsoption, as well as mobilization of calcium from the bones. PTH reduces blood levels
of phosphate by the renal excretion of phosphate, which is a stronger effect then
mobilizing phosphate from the bones. PTH enhances the activation of vitamin D to
calcitriol, thus indirectly promotes the intestinal absorption of calcium. PTH activates the
1-hydroxylase enzyme in the kidneys, which plays a role in the production of calcitriol.
Calcitriol promotes the intestinal absorption of calcium and phosphate, thus contributing
to the ossification process.
The calcium mobilizing effect of the PTH on bone tissue is carried through three
mechanisms. On short-term it increases the calcium permeability of osteocytes, thereby
calcium leaves these cells and enter into the blood stream. On long-term it exhibits its
effect through osteoblasts and osteoclasts. PTH stimulates the secretion of a mediator
substance in the osteoblasts which activates the surrounding osteoclasts. PTH exhibits a
direct effect on immature osteoclasts, which have PTH receptors on their surface, unlike
the mature forms, and thus it stimulates their maturation process. In PTH deficiency
blood calcium levels are significantly reduced, tetanic seizures occur.
Latent hypocalcaemia with mild tetania often occurs in young women, which can be
detected using the Chvostek test: lightly tapping the masseter muscle (in the middle of the
face) the face on the respective side is partially or completely contracted due to the
stimulation of the facial nerve. Respiratory alkalosis promotes the manifestations of
hypocalcaemia (for example in patients with hysterical hyperventilation), because more
calcium will bind to proteins, and the form of free calcium will be decreased. The
manifestations can be frightening, the limbs may be in strange positions, muscle twitches
occur. This can easily be stopped by restoring normal breathing. In some cases, calcium
in parenteral dosage may be required.
It is known that hypercalcemia may develop in patients suffering from malignant
tumors. The reason is that certain cancer cells (breast cancer, lung cancer, pancreatic
cancer) may produce a peptide that can bind to the PTH receptor, having the same
biological effect. These compounds are called PTHrP (parathyroid hormone related
peptides), these are produced under physiological conditions in the lactating breast, and
provide the extra calcium necessary during lactation.
Two types of vitamin D are known: ergocalciferol (vitamin D2), present in plants,
and cholecalciferol (vitamin D3), which is present in animals, it is formed in the skin due
to ultraviolet radiation from 7-dehydro-cholesterol. The activation process involves two
hydroxylation steps, calcitriol is formed. The first hydroxylation process (in the 25th
position) takes place in the liver (it is not under hormonal control), while the second one
takes place in the kidneys in the first position. Calcitriol promotes the intestinal
absorption of calcium by stimulating the calbindin production (a calcium binding protein
produced in the intestinal wall) and enhances the function of the calcium pump.
Calcitriol deficiency can occur due to poor diet, lack of sun exposure or the
hydroxylation process can be disturbed. Vitamin D deficiency is very dangerous in
children, the subsequent calcium metabolism disturbance leads to improper bone
mineralization (rickets). The long bones are soft, being bent under the weight of the body.
The skull bones also remain soft, hand-pressed they are like a table tennis ball (an
important diagnostic sign of rickets). Natural feeding, exposure to sunlight and vitamin D
droplets prevent this disease in infants.
In adults, vitamin D deficiency leads to softening of the bones (osteomalacia), the
inorganic component of the bone tissue is decreased.
Osteoporosis is a bone metabolism disorder which is very common in women after
menopause and in old age. In osteoporosis both the organic and inorganic component of
the bone is affected, which weakens the resistance of the skeleton. Fractures occur very
often in the femoral neck and the spine (the height of the patients is reduced). The
loosening of The decreased bone density becomes visible on X-ray scan only when more
then 35% of the tissue is lost (late sign). Early diagnosis can be made by
osteodensitometry.
Osteoporosis occurs when osteoclast activity exceeds the osteoblast activity, in
other words bone breakdown process (osteolysis) exceeds regeneration (osteogenesis).
Osteoporosis can be primary (postmenopausal or senile) or secondary to certain diseases
or medications (glucocorticoids, heparin, methotrexate, anticonvulsants used for
treatment of epilepsy, antacids administered to patients suffering from ulcer, etc.).
Secondary osteoporosis can occur in case of an excess production of certain hormones
(PTH, cortisol, prolactin, thyroid hormones), or the deficiency of biologically active
molecules (growth factors, calcitonin, sex hormones). Congenital (inborn) osteoporosis
was described in certain syndromes.
The most commonly used drugs in the treatment of osteoporosis are calcitonin
derivatives (miacalcic), calcium salts, biphosphonates (osteoclast activity inhibitors),
fluorine-containing compounds (hydroxyapatite crystals after incorporation of fluorine
become even more resistant, forming fluorapatite cristals), estrogens and progestagene
containing products (especially in postmenupausal osteoporosis), anabolic steroids are
used especially in the treatment of senile osteoporosis (decanofort, naposim), which are
male sex hormones derivatives, they increase the anabolic metabolic processes, their
sexual hormone effect is almost completely absent.
In Ehlers-Danlos syndrome, the collagen formation is pathologic, the skin develops
excessive flexibility, the joints are very loose, the lesions are associated with
osteoporosis.
Osteogenesis imperfecta occurs in case of a mutation of the gene that codifies the
type 1 collagen, severe osteoporosis develops, which leads to spontaneous fractures
during the intrauterine life and also after birth. Secondary osteoporosis occurs in
malignant multiple myeloma (a plasma cell clone proliferation), leukemia, and carcinoid
tumors.
In case of Paget's disease (osteitis deformans) the bone breakdown and also the
regeneration are intensified. Distortions occur in the long bones, dorsal kyphosis
develops, the size of the skull increases. Alkaline phosphatase activity is very high, it
correlates with the intensified osteoblast activity. The calcium and inorganic phosphate
level in the blood are within normal limits.
Calcitonin is prodiced by the para-follicular thyroid cells, it has opposite effect
compared to PTH. Calcitonin reduces the level of calcium in the blood, stimulates the
ossification process by inactivation of active osteoclasts.

DRUGS THAT INFLUENCE THE FETAL METABOLISM

When administering medicines to a pregnant woman is an issue, the benefit/risk

ratio should always be evaluated, to avoid a tragedy similar to that caused by the
thalidomide (contergan), a drug used for morning sickness, leading to limb defects.
It is important to know that fever can cause malformations, so if it is necessary,
antipyretic drugs should be used.
The medicines used in pregnancy are classified in 5 groups:
 Group A: harmless (ex. folic acid), studies were made on pregnant women
Group B: low risk, studies on animals didn’t show malformations, no studies were
made on pregnant women, or those seen in animals were not observed in pregnant
women (ex. paracetamol, cephalosporins)
Group C: they proved to be teratogenic in animal studies, but we have no
information regarding pregnant women, or no data at all. They can be used in special
cases (ex. omeprazole, furosemide)
Group D: teratogenic drugs, they can be used in life threatening situations (ex.
tetracycline, PTU, aspirin)
Group X: high fetal risk exists, administration of these drugs is not allowed in
pregnant women (ex. statins)
Another important aspect in choosing the proper therapy is how advanced the
pregnancy is. In the first trimester the doctor should be especially careful, because the
fetal organs development takes place during this period.
Some pharmaceutical products can be classified in different groups depending on
the dose administered.
Useful information regarding this can be found on the Internet, for example on the
site www.safefetus.com.

THE EFFECT OF ANTI CONTRACEPTIVE DRUGS ON THE FEMALE

BODY

Anticontraceptive drugs are used for the prevention of not desired pregnancies, and
in polycystic ovarian syndrome
The side effects of the synthetic estrogens are: weight gain, retention of water, gall
bladder diseases, fibrocystic mastopathia, stroke, development of breast-, uterine- and
ovarian cancer, inducing autoimmun diseases, porphyria acute phase
Synthetic progestins protect from breast cancer, due to these components glucose
tolerance is lower, increased risk for thrombosis occurs, and depletion causes depression.
Under physiological conditions, the body produces estrogens and progesterone,
which exert their effect together. In fact, the cells need estrogens for the formation of
progesterone receptors, and progesterone contributes to the maintenance of normal
sensitivity in case of the estrogen receptors. As a result of this cooperation between the
sex hormones in the female body, the organism is normally protected from these negative
effects.
The synthetic progesterone derivatives compete with the natural ligand to occupy
the progesterone receptors, thus distrubing the effects of the natural hormone.