MEDICINE AND SURGERY "F"
Course of LABORATORY MEDICINE
Disturbances of water and electrolyte balance
WATER AND ELECTROLYTES
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and electrolytes are subject to a rapid turnover due mainly to dietary intake and renal excretion. Other causes of water (and electrolytes) loss are faeces, respiration and sweating. Under pathological conditions water and electrolyte loss may occur because of several additional reasons that include: diarrhoea (e.g. cholera, bacterial enteritis or cholitis); vomiting, inability of the kidney to concentrate the urine (e.g. diabetes mellitus, diabetes insipidus), etc.
As a general rule, water is absorbed or excreted passively, thus it follows the main extracellular electrolytes, sodium and chloride, and water deficits usually occur together with sodium and chloride deficits. It is important to remark, however, that the intracellular water compartment is usually most affected and that symptoms may occur also under conditions in which the water and electrolyte deficits one may estimate from blood composition are relatively mild. The central nervous system is particularly sensitive to water and electrolyte unbalance and symptoms (e.g. irritability, convulsions, coma) may be severe.
Water accounts for approx. 65% of body weigth, and is divided in three compartments: blood plasma, extracellular fluids and intracellular fluids. The clinical laboratory can measure the volumes of blood; blood plus extracellular water; and total body water (TBW). We cannot measure the volume of intracellular water alone, but we can easily estimate it from the difference between TBW and blood plus extracellular fluid, if needed. The normal reference values (as percentages of body weigth) are as follows: blood 4%; extracellular water 16%; intracellular water 45%.
The principle of water measurement is the same for all compartments to be tested. To measure blood water (this means plasma volume, because intraerycthrocytic water belongs to the intracellular water) one proceeds as follows: a minimum amount of a suitable tracer (e.g. serum albumin labelled with radioactive cromium) is injected in a peripheral vein. After a few minutes a blood sample is taken from a different vein, in order to avoid contamination by the tracer that may be present on the skin, and its concentration is measured. The tracer, whose initial amount is known, is diluted in the plasma and the plasma volume can be calculated as follows (as you may remember from the course of Chemistry):
volume = amount of tracer / concentration
Other compartments are measured exactly in the same way, but using tracers that evenly distribute in the compartment we are interested in. However no tracer distributes in the extracellular or intracellular compartment alone, and this explains the above point that one cannot measure the volume of intracellular or extracellular fluid alone. The characteristics of a good tracer are: (i) it evenly distributes in the selected compartment(s); and (ii) its concentration is easily measured. The timing is also important to guarantee the even distribution of the selected tracer (e.g. if waiting too long, Cr-albumin will partly extravasate and distribute in the extracellular fluid; but it is not a good tracer for this measurement because it attains different concentrations in the plasma and extracellular fluid).
Audio: Water in our body
In practice the determination of TBW and other volumes is seldom carried out, because it has little diagnostic value; a much more important parameter to measure is serum osmolarity. If osmolarity is normal, excess water can be well tolerated, as it happens in oedematous or ascitic patients. The osmolarity of human body fluids is around 300 mOsMoles/L and is strictly regulated; changes of about 2% induce strong responses (thirst, and changes in the secretion of ADH). A change of serum osmolarity of about 10-15% may cause the hyperosmotic coma, a potentially lethal condition observed, for example in untreated type 2 diabetes mellitus, with glycemias >400 mg/dL. The principal osmolytes in body fluids are low molecular weigth ions: in the extracellular fluids the three most concentrated ions are sodium, chloride and bicarbonate, which account for 260 mOsMoles/L. In the intracellular fluids potassium largely replaces sodium. A practical approximate formula to calculate serum osmolarity is as follows:
2 x ([Na
] + [K
]) + [BUN]/2.8 + [Glucose]/18
] and [K
] are expressed in mEq/L, whereas [BUN] (blood urea nitrogen) and [Glucose] are expressed in mg/dL.
Audio: Water losses
COMBINED DEFICIT OF SODIUM AND WATER:
Loss from GI tract: vomiting, diarrhoea, medical practices (e.g.: colostomy)
Loss form the skin: excess sweating
Loss due to hemodialysis or peritoneal dialysis
Acute or chronic renal failure: "salt wasting renal disease"
Excess diuretic therapy
Diabetes insipidus (insufficient production of ADH)
Adrenal disease: Addison disease (glucocorticoid deficiency); hypoaldosteronism
Measurement of electrolyte concentration
in the blood is usually effected by spectroscopic or potentiometric methods, using the appropriate electrodes. Other methods are less commonly employed, e.g. flame atomic absorption.
is a condition in which sodium losses exceed water losses; decrease of the electrolyte concentrations and hypo-osmolarity follow. This condition may occur in several types of renal failure, in heart failure because of the sodium retention in peripheral oedema, in several endocrine disease and in neoplastic diseases, in the course of diuretic therapy. An uncommon but important cause is the (usually paraneoplastic) syndrome of inappropriate secretion of antidiuretic hormone (ADH). Water intoxication occurs when the plasma osmolarity falls below 240 mOsM/L (note: some laboratories measure osmolalities instead of osmolarities; to a first approximation the values are the same, i.e. 240 mOsM/L more or less corresponds to 240 mOsm/Kg).
(i.e. increased concentration of serum electrolytes, especially sodium) is typically due to water deprivation or increased and unreplaced water losses (e.g. profuse sweating). It requires prompt rehydration, in severe cases by intravenous administration of glucose isotonic solution (one cannot infuse distilled water because the local hypotonic shock would kill the blood and endothelial cells; infusion of an isotonic 5% glucose solution achieves the same effect of distilled water because the sugar is promptly removed by the liver, but avoids local damage).
is due to excessive loss of potassium in the urine, faeces or sweat. Renal waste of potassium occcurs in Bartter syndrome (a disease of unknown origin) and in the presence of excess secretion of mineralocorticoid hormones (e.g. because of a benign tumour of the adrenal glands) and in primary disturbances of the kidney involving the proximal and distal tubuli.
It may be iatrogenic, due to excess diuretic therapy
(e.g. using thiazides or furosemide) and it is always advisable in prolonged diuretic therapy to associate a K-saving diuretic (e.g. spironolactone). Normal potassiemia is 5 mEq/L and in severe depletion (3 mEq/L or less) muscular weakness, and severe cardiac arrythmias, both due to the fact that excitable tissues function is compromised if the intra- extra-cellular potassium gradient is altered. Severe hypokalemia requires (careful !) intravenus administration of potassium.
may occur in type I diabetic patients or in the course of severe acute kidney disease (e.g. glomerulonephritis, acute renal failure), given that the kidney excretes potassium very efficiently and, in the absence of severe disfunction, prevents or corrects this condition. Pseudohyperkalemia is the transient increase of potassium concentration due to release of intracellular potassium by the red or white blood cells or by platelets. True hyperkalemia is a dangerous condition that requires prompt treatment, given that at potassiemia > 6.5 mEq/L severe arrythmias occur and ventricular fibrillation is possible.
metabolism. The concentration of calcium in the blood serum in the healthy adult is approx. 2.5 mMoles/L (or 5 mEq/L or 10 mg/dL) and is regulated by two hormones and one vitamin: the
(PTH) is a protein secreted by the parathyroid glands; it causes release of calcium from the skeletal deposits, and reabsorption from the urine and from the gut, thus causing the calcemia to increase. Thyrocalcitonin is a protein hormone produced by the parafollicular cells of the thyroid and causes calcium phophate deposition in the bone matrix, opposing the effect of PTH. Vitamin D promotes absorption of calcium from the diet. The serum concentration of calcium is carefully regulated because this ion is essential for the excitability of nervous and muscular tissues and changes in its concentration cause severe symptoms.
is an infrequent finding; it may depend on several causes, among which: (i) hypoparathyroidism (often associated to surgical removal of the parathyroid in the course of a thyroidectomy); (ii) vitamin D deficiency (e.g. rickets); (iii) renal tubular disease or renal failure; (iv) acute pancreatitis (calcium chelation by lipolytic products). Clinical symptoms include reduced cerebral function (pseudo-dementia), possibly with psychotic symptoms, and muscular tetany.
is usually caused by hyperparathyroidism (often of neoplastic origin), and is associated to excessive bone matrix reabsorption (osteoporosis). Other neoplastic diseases, unrelated to the parathyroids, can cause osteolysis with hypercalcemia and osteoporosis, because of secretion of osteoclast activating factors (so called "humoral hypercalcemia of malignancy"). Hypervitaminosis D is another possible cause of hypercalcemia.
. Calcium phosphate is the main mineral component of the bone tissue, and mobilization of phosphate usually follows that of calcium: e.g. PTH causes reabsorption of both calcium and phosphate. However, in the intracellular milieu and in the diet calcium and phosphate have different distributions and thus changes in the serum concentrations of phosphate does not necessarily follow those of calcium. Hypophosphatemia is not uncommon but rarely severe or even symptomatic. The main cause is reduced renal reabsorption.
metabolism. In the healthy adult the serum magnesium concentration is approx. 2 mEq/L and is regulated mainly at the level of urinary and fecal excretion. Hypomagnesemia may result from prolonged poor dietary intake or reduced intestinal absorption (diarrhoea, malnutrition, etc.) it may be aggravated by some physiological conditions of excess consumption (e.g. lactation). Hypermagnesemia may occur, together with other electrolyte disturbances, in chronic or acute renal failure.
The importance of chloride
. Chloride is mainly present in the extracellular fluids, and attains low concentration in the cell cytoplasm. It has however a great importance for clinical reasoning and its concentration in the serum should be looked at with great attention. Our reasoning on chloride is based on three premises: (i)
the osmolarity of body fluids is essentially constant
; and (ii)
the sum of positive charges equals that of negative charges
(electroneutrality principle); (iii) the concentration of cations is quite strictly regulated, as is that of bicarbonate (see below, blood buffers). The kidney excretes or reabsorbs chloride in order to obey the above premises; thus chloride is the variable parameter that the kidney adjusts to compensate for changes in the concentration of other electrolytes. Changes in chloride concentration may be unimportant
but tell us important information about electrolytes that were not directly measured. In particular:
in the presence of normal sodium concentration suggests an increase of non-measured anions (e.g., bicarbonate, lactate, ketoacids);
suggests a decrease in bicarbonate.
Alterations of chloride concentration are a strong indication to carry out a hemogas analysis
. Caution: a variation of chloride concentration suggests an opposite varation of bicarbonate, hence a disturbance of blood pH, but a normal chloride concentration does not exclude an alteration of blood pH: e.g. in acute respiratory acidosis chloride and bicarbonate may be within normal limits, yet the pH change may be severe!
Reference electrolyte concentrations in human serum
135 mEq /L
5 mEq /L
5 mEq /L
2 mEq /L
100 mEq /L
26 mMoles /L
EVALUATION OF KIDNEY FUNCTION
The kidney plays a fundamental role in the acid-base omeostasis (long term control of bicarbonate), regulation of water and salts, regulation of the arterial pressure, and elimination of nitrogen (as urea). The fundamental parameter that measures kidney function is the
glomerular filtration rate
(GFR), i.e. the measurement of the volume of plasma filtered by the kidney in 1 minute. The median value for healthy adults is 120 mL/min, but this parameter decreases with age, and values of 60 mL/min in elderly patients should not be considered pathological.
To measure the GFR the physician should select a tracer that is entirely filtered by the glomerulus and neither reabsorbed nor secreted by the tubuli. For experimental studies the polysaccaride inulin is used, but in the clinical practice the physiological solute creatinine is routinely employed because it is physiologically produced at a constant rate by the accidental degradation of creatine in the striated muscle. The measurement is as follows: creatine concentration is determined in a venous blood sample and in the urine collected over a short period of time (by cateterism, if necessary). The amount of plasma filtered in the collection time is given by the formula:
GFR = Volume
The measurement of creatinine is easily achieved using the classical Jaffe' reaction (formation of a red-coloured complex with picric acid):
1) Gumz ML, Rabinowitz L, and Wingo CS
2) Indicative concentration values for the three major ions in human blood are:
sodium=135 mEq/L; chloride=100 mEq/L; bicarbonate=26 mM
sodium=135 mEq/L; bicarbonate=100 mEq/L; chloride=26 mM
chloride=135 mEq/L; sodium=100 mEq/L; bicarbonate=26 mM
3) Potassium and calcium are very important ions regulating the membrane potential of nerve and cardiac cells. Their normal serum concentration is:
5 mEq/L for both
2.5 mEq/L for both
5 mEq/L for K, 2.5 mEq/L for Ca
4) The osmolarity of biological fluids is
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Thank you Professor (lecture on bilirubin and jaundice).
The fourth recorded part, the one on hyper and hypoglycemias is not working.
Bellelli: I checked and in my computer it seems to work. Can you better specify
the problem you observe?
This Presentation (electrolytes and blood pH) feels longer than previous lectures
Bellelli: it is indeed. Some subjects require more information than others. I was
thinking of splitting it in two nest year.
Bellelli in response to a question raised by email: when we compare the blood pH
with the standard pH we do not mean to compare the "normal" blood pH (7.4)
with the standard pH. Rather we compare the actual blood pH of the patient, with
the pH of the same blood sample equilibrated under standard conditions.
Thus, if we say that standard pH is lower than pH we mean that equilibriation with
40 mmHg CO2 has caused absorption of CO2 and has lowered the pH with respect
to its value before equilibration.
(Lipoproteins) Is the production of leptin an indirect cause of type 2 diabetes since
it works as a stimulus to have more adipose tissue that produces hormones?
Bellelli: in a sense yes, sustained increase of leptin causes the hypothalamus to adapt
and to stop responding. Obesity ensues and this in turn may cause an increase in the
production of resistin and other insulin-suppressing protein hormones produced by the
adipose tissue. However, this is quite an indirect link, and most probably other factors
contribute as well.
(Urea cycle) what is the meaning of "dissimilatory pathway"?
Bellelli: a dissimilatory pathway is a catabolic pathway whose function is not to produce
energy, but to produce some terminal metabolyte that must be excreted. Dissimilatory
pathways are necessary for those metabolytes that cannot be excreted as such by the
kidney or the liver because they are toxic or poorly soluble. Examples of metabolytes
that require transformation before being eliminated are heme-bilirubin, ammonia,
sulfur and nitrogen oxides, etc.
Talking about IDDM linked neuropathy can be the C peptide absence considered a cause of it??
Bellelli: The C peptide released during the maturation of insulin, besides being an indicator
of the severity of diabetes, plays some incompletely understood physiological roles. For
example it has been hypothesized that it may play a role in the reparation of the
atherosclerotic damage of the small arteries. Thus said, I am not aware that it plays a direct
role in preventing diabetic polyneuropathy. Diabetic neuropathy has at least two causes: the
microvascular damage of the arteries of the nerve (the vasa nervorum), and a direct
effect of hyperglycemia and decreased and irregular insulin supply on the nerve metabolism.
Diabetic neuropathy is observed in both IDDM and NIDDM, and requires several years to
develop. Since the levels of the C peptide differ in IDDM and NIDDM, this would suggest
that the role of the C peptide in diabetic neuropathy is not a major one. If you do have
better information please share it on this site!
In acute intermitted porphyria and congenital erythropoietic porphyria why do the end product
of the affected enzymes accumulate instead of their substrate??
Bellelli: First of all, congratulations! This is an excellent question.
Remember that a condition is which the heme is not produced is lethal in the foetus; thus
the affected enzyme(s) must maintain some functionality for the patient
to be born and to come to medical attention. All known genetic defects of heme
biosynthesis derange but do not block this metabolic pathway.
Congenital Erythropoietc Porphyria (CEP) is a genetic defect of uroporphyrinogen
III cosynthase. This protein associates to uroporphyrinogen synthase (which is present
and functional in CEP) and guarantees that the appropriate uroporphyrinogen isomer is produced
(i.e. uroporphyrinogen III). In the absence of a functional uroporphyrinogen III
cosynthase other possible isomers of uroporphyrinogen are produced together with
uroporpyrinogen III, mostly uroporphyrinogen I. The isomers of uroporphyrinogen
that are produced differ because of the positions of propionate and acetate side chains,
and this in turn is due to the pseudo symmetric structure of porphobilinogen. Only
isomer III can be further used to produce protoporphyrin IX. Thus in the
case of CEP we observe accumulation of abnormal uroporphyrinogen derivatives, which, as
you correctly observed are the products of the enzymatic synthesis operated by
The case of Acute Intermittent Porphyria (AIP) is similar, although there may be variants
of this disease. What happens is that either the affected enzyme is a variant that does not
properly associate with uroporphyrinogen III cosynthase or presents active site mutations
that impair the proper alignement of the phoprphobilinogen substrates. In either case
abnormal isomers of uroporphyrinogen are produced, as in CEP.
Also remark that in both AIP and CEP we observe accumulation of the porphobilinogen
precursor: this is because the overall efficiency of the biosynthesis of uroporphyrinogens is
reduced. Thus: (i) less uroporphyrinogen is produced, and (ii) only a fraction of the
uroporphyrinogen that is produced is the correct isomer (uroporphyrinogen III).
is it possible to take gulonolactone oxidase to synthesize vitamin C
instead of vitamin C supplement?
Bellelli: no, this approach does not work. The main reason is that
the biosynthesis of vitamin C, as almost all other metabolic processes, occurs intracellularly.
If you administer the enzyme it will at most reach the extracellular fluid but will not be
transported inside the cells to any significant extent. Besides, there are other problems
in this type of therapy (e.g. the enzyme if administered orally, may be degraded by digestive
proteases; if administered parenterally, may cause the immune system to react against a
non-self protein). In theory one could think of a genetic modification of the inactive human
gene of gulonolactone oxidase, but the risk and cost of this intervention would not be
justified. In addition to these considerations, except for cases of shipwreckage or
other catastrophes, a proper diet or administration of tablets of vitamin C is effective,
risk-free and unexpensive, thus no alternative therapy is reasonable. However, I express my
congratulations for your search on the biosynthesis pathway of ascorbic acid.
Resorption and not reabsorption would lead to hypercalcemia ie bone matrix being broken down.
Bellelli: I am not sure to interpret your question correctly. Resorption indicates destruction of the bone matrix and release of calcium and
phosphate in the blood, thus it causes an increase of calcemia. Reabsorption usually means active transport of calcium from the renal tubuli to the blood, thus
it prevents calcium loss. It prevents hypocalcemia, and thus complement bone resorption. To avoid confusion it is better use the terms "bone resorption" and "
renal reabsorption of calcium". If you have a defect in renal reabsorption, parthyroid hormone will be released to maintain a normal calcium level by means of
bone resorption; the drawback is osteoporosis.
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