Veterinary PathophysiologyStudent’s Lectures, 5th Semester

Department of Internal Medicine,Faculty of Veterinary Science

Szent István University

Disorders of homeostasis 2. Alterations in isoionia

Questions 5-11

Changes in Na+ and Cl- balance.K+-balance disorders.Regulation and disorders of calcium and phosphorus metabolism.Consequences of deficiency and excess in calciumConsequences of phosphorus deficiency and excess.Changes in plasma Mg-concentrationAlterations in blood plasma ion balance

DISTRIBUTION OF FLUID COMPARTMENTS AND THE MAJOR IONS IN CATTLE

 FLUIDS RATIO IN MAJOR MAJOR

BW % CATIONS ANIONSTOTAL FLUID: 60 x x

IC: 35 K+ HPO4-Mg2+ protein-

EC: INTERSTITIAL: 3 Na + Cl- HCO3

- PLASMA: 5 Na + Cl-, HCO3

-

Ca2+ protein-

TRANSCELLULAR:GI tract: 15 Na+, K+ Cl-/abomas./

HCO3-

Others: 1-2 x x

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Distribution of the major ions in the Distribution of the major ions in the extracellular (EC) fluidextracellular (EC) fluid

Na+ + K+ + Ca2+ + Mg 2+ = Cl- + HCO3- + protein- + others-

150 5 5 3 100 30 18 15

(mEq/L)

Monovalent ions (mostly Na and Cl) determine both izoionia and isoosmosis!

KationsKations AnionsAnions

DISORDERS OF Na+ BALANCE

Characteristics of sodium:

Prominent cation of the EC space (140 - 150 mmol/l)

Main role: maintanence of isoosmosis and isoionia with Cl-, (responsible for 90% of the total osmolality.)

Great amount in bones - not mobilizable

Saliva: Na-level reflects plasma Na-concentration.

Importance of aldosteron in its reabsorption.

(kidney dist. tubulues –Na-K-ATP-ase)

DISORDERS OF Na+ BALANCE

HYPONATREMIA

Causes: Consequences:diarrhoea, decreased renal reabs. allotriophagy (pica)increased water intake hypotonic dehydration(decreased intake: rare) or hyperhydrationhypoaldosteronism (Addison´s-d.)

HYPERNATREMIA

Causes: Consequences:water loss, "salt poisoning", CNS-symptoms, edema,hyperaldosteronism, thirst hypertonic dehydration(Conn´s syndrome) (hyperhydration)

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Hyponatraemia, dog

Ionometer for measuring Na, K, Ca and pH

Characteristics of chloride ion• Prominent anion of EC space (100 mmol/L)• Main role: maintanence of isoosmosis (with Na+)• During its metabolism follows Na+ passively!

• Importance of Cl- and HCO3- exchange through small intestine

wall• Active excretion of Cl- in Liberkühn crypts with Na+ → water

follows, secretory diarrhoea develops (cholera, E. coli)

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DISORDERS OF Cl- BALANCE

HypochloremiaCauses: vomiting, abomasal displacement - separated from Na+

diarrhoea, hyponatremic conditions

Consequence: metabolic alkalosis via increased HCO3-level

HyperchloremiaCauses: "salt poisoning", infusion, other hypernatremic conditionsConsequence: there is no independent consequence of

hyperchloremia

DISORDERS OF K+ BALANCE

Characteristics of potassium:

Prominent cation of IC space (muscle, liver, RBC)

EC: only 5 mmol/l

Importance of Na+/K+ and K+/H+ pumps - see Physiology

Effect of K+ on muscular irritability is similar to that of

Na+, ie. tends to antagonise the effect of Ca++

DISORDERS OF K + BALANCE

HypokalemiaCauses: vomiting, abomasal displacement, (diarrhoea), alkalosis, renal excretion (diuretics!) hyperaldosteronism (decreased intake is rare)

Consequences arrhythmias, muscular weakness; only partial hypokaluria!

Hyperkalemia

Causes: acidosis, renal excretion decrease (RF), cellular injuries, intake increases (fertilizers), hypoaldosteronism (Addison´s d.)

Consequences: altered cardiac conduction,dilation of the heart (DCM, dilated cardiomyopathy), hyperkaluria

DETERMINING FACTORS OF K+ METABOLISM

PLASMA-CALCIUM (total)

diffusable bound with proteins (albumin) (<50%)

ionized (Ca++) complex(>40%) molecules (<10%)

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Plasma calcium (total)

Influencing factors of Ca-homeostasis:– demand,– intake (grains, grass, meat are low in calcium),– absorption,– blood inorg. phosphate content (inversley related to the

blood Ca level)– parathyroid gland - C-cells,– vitamin D (D hormon)– hypoalbuminaemia total Ca – alkalosis Ca++ , protein-bound Ca – acidosis Ca++ , protein-bound Ca

CALCIUM AND PHOSPHATE METABOLISM

Factors regulating absorption: demand of the organism the greater need the more absorbed

 Ca:P + vitamin D3 active transport of Ca (Ca-binding protein) ageing, increased body weight decreased absorption others: higher duodenal pH decreased absorption;

increased intestinal peristalsis decreased absorptioncirculatory disorders of the intestinal wall decreased absorptionincreased protein content of feedstuffs increased absorptionincreased fat content of feedstuffs decreased absorptionincreased dietary Mg and F content of feedstuffs decreased absorptionhigher phytin-content in food decreased P absorption (phytin-P is unavailable to monogastric animals)

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Thyroid and parathyroid gland

http://instruction.cvhs.okstate.edu/Histology/

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Double EFFECT OF PARATHYROID HORMONE (PTH)

http://courses.washington.edu/conj/bess/calcium/calcium.htmlw

Double EFFECT OF PARATHYROID HORMONE (PTH)

Renal Ca and P is mobilized

P-excretion increases from the bones

plasma P ↑ plasma P and Ca

compensation 

Final effect: plasma Ca+ increases, plasma phosphate decreases

 

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Effect of calcitonin and PTH

http://instruction.cvhs.okstate.edu/Histology/

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Double EFFECT OF CALCITONIN

Renal bone resorption decreases

P-excretion increases (osteoclast activity)

Final effect: plasma Ca AND P decreases

21http://courses.washington.edu/conj/bess/calcium/calcium.htmlw

Vitamin D can Vitamin D can be be supplemented supplemented from feed (see from feed (see fish, liver, egg fish, liver, egg yolk).yolk).

1-alpha-hydroxylase is activated in case of low Ca and

Plant form: vitamin D2 (ergosterol)

Vitamin D3

D-binding protein

weeks

hours

Effect of and influence on vitamin D

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The active form of vitamin D binds to intracellular receptors that then function as transcription factors to modulate gene expression.

Like the receptors for other steroid hormones and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains.

The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA.

In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription.

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24Laurance Johnston, Ph.D.SUNLIGHT, VITAMIN D & HEALTHhttp://www.healingtherapies.info/VitDmetabolism.jpg

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• Its most dramatic effect is to facilitate intestinal absorption of calcium, although it also stimulates absorption of phosphate and magnesium ions.

• Vitamin D stimulates the expression of a number of proteins involved in transporting calcium from the lumen of the intestine, across the epithelial cells and into blood. The best-studied of these calcium transporters is calbindin, an intracellular protein that ferries calcium across the intestinal epithelial cell.

• As a transcriptional regulator of bone matrix proteins, it induces the expression of osteocalcin and suppresses synthesis of type I collagen. In cell cultures, vitamin D stimulates differentiation of osteoclasts.

• Effect of vitamin D on bone is to provide the proper balance of calcium and phosphorus to support mineralization

• vitamin D improves the utilisation of phytin P is influenced by the dietary concentrations of Ca and P. An increase in Ca:iP ratio suppresses P availability through the formation of an insoluble complex and by inhibiting intestinal phytase activity.

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Vitamin D-deficiency:• Genetic defects in the vitamin D receptor• Severe liver or kidney disease• Insufficient exposure to sunlight. • Inproper intake (ie. increased need, or mycotoxins)

Cholecalciferol (CC) supplementation improves broiler growth when calcium (Ca) and non-phytate phosphorus (NPP) are sub-optimal (Ca:P=2:1)

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Consequences of vitamin D deficiency:

Osteoporosis decrease of bone matrix                                                                                                                   

Other Bone Disorders rickets and osteomalaciaOsteoarthritis general inflammatory disease of the bones and joints Abnormalities of the Parathyroid Hormones High Blood Pressure Other diseases that may be impacted by vitamin D:Multiple Sclerosis (MS) Atherosclerosis TuberculosisDiabetes Seasonal Affective Disorder (SAD)Cancer

tibial dyschondroplasia

DEFICIENCY AND EXCESS OF CALCIUM 1.

1. Deficiency

Cause: primary (rare) or secondary ! (when PTH and Vit. D3 level decreases)

Consequence: hypocalcaemia (rare), tetany, "milk fever" (parturient paresis), eclampsy: caused by increased neuromuscular irritability,osteopathies, drop in egg production (long-term consequencies)

 

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Calcium dediciency Calcium overload

PTH Secretion stimulated Secretion inhibited

Vitamin DProduction stimulated by increased parathyroid hormone secretion

Synthesis suppressed due to low parathyroid hormone secretion

Calcitonin Very low level secretionSecretion stimulated by high blood calcium

Intestinal absorption of calcium

Enhanced due to activity of vitamin D on intestinal epithelial cells

Low basal uptake

Release of calcium and phosphate from bone

Stimulated by increased parathyroid hormone and vitamin D

Decreased due to low parathyroid hormone and vitamin D

Renal excretion of calcium

Decreased due to enhanced tubular reabsorption stimulated by elevated parathyroid hormone and vitamin D; hypocalcemia also activates calcium sensors in loop of Henle to directly facilitate calcium reabsorption

Elevated due to decreased parathyroid hormone-stimulated reabsorption.

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Ca-deficiency Ca-overload

Renal excretion of phosphate

Strongly stimulated by parathyroid hormone; this phosphaturic activity prevents adverse effects of elevated phosphate from bone resorption

Decreased due to low PTH

General Response

Typically see near normal serum concentrations of calcium and phosphate due to compensatory mechanisms. Long term deprivation leads to bone

thining (osteopenia).

Low intestinal absorption and enhanced renal excretion guard against development of hypercalcemia

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DEFICIENCY AND EXCESS OF CALCIUM 2.2. Excess

Cause: primary ! or secondary (when PTH and Vit. D3 level increase)Consequence: (hypercalcaemia), hpyercalcuria

hypophosphataemia, osteopathies, osteogenesisnephropathy, Zn-absorption decreases

Importance of intracellular Ca2+

Paraanalis gland Adenocarcinoma

T-cell lymphomaOsteosarcoma

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DEFICIENCY AND EXCESS OF PHOSPHOROUS (mainly inorg. i.e. Pi)

1. Deficiency

Cause: primary! - secondary (phytin in monogastric animals)

Consequence: hypophosphataemia,

retarded growth (ATP, CrP also decrease)

osteopathies

disorders of reproductive functions!

post-partum haemoglobinuria (?)2. Excess

Cause: primary! - secondary (lack of Ca, decreased renal function)

Consequence: hyperphosphataemia, hypocalcaemia

osteopathies

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Hyperparathyroidism

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Hyperparathyroidism

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Conscequences of hyperparathyroidism

malaise, lethargydepressionconfusionmuscle weaknessrenal colicpolyuria / nocturiarenal stonesabdominal painnausea and vomitingconstipationpeptic ulcersosteoporosis

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Intestinal magnesium absorption

Transcellular transport, saturable at high luminal magnesium concentrations, which is of functional importance at low luminal magnesium concentrations (dotted line)Paracellular passive transport (dashed line) linearly rising with elevated luminal magnesium concentrations

Schlingmann et al., Nature Genetics  31, 166 - 170 (2002)

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Intestinal magnesium absorption

Absorption of magnesium is influenced by the amount of calcium, phosphorus and potassium (K) in the diet.

High dietary levels of potassium, sulphate, orphosphorous reduces absorption of magnesium.

Where acidic soils exist (low pH) contribute to the accumulation of potassium in plants, especially cereal crops. Alfalfa can also accumulate high levels of potassium.

High levels of potassium in feeds can also be caused by fertilizing crops with high levels of nitrogen and potassium.

DEFICIENCY AND EXCESS OF MAGNESIUM

1. Deficiency Cause: primary! - secondary!: - limited Mg intake (K+

excess causes relative Mg deficiency)- turning to fresh, spring grass- fertilizers- stress

Consequence: hypomagnesaeemia, tetany, neuromuscular hyperirritability

2. Excess Cause: primary - secondary! (relative)Consequence: local effect in GI tract: diarrhoeageneral effect on neuromuscular synapses: decreased

irritability (kurare-like effect)"milk fever" (parturient paresis)urolithiasis

ION BALANCE IN BLOOD PLASMA

Neuromuscular irritability: Increases with the elevation of K, Na, OH (HCO3

-, i.e. alkalosis)

decreases with the elevation of Ca, Mg, H (i.e. acidosis)

Most important disturbances: hypocalcaemic tetany (eclampsia) hypomagnesaemic tetany, "milk fever"

In some monographs the numerator does not contain OH-; instead, has HCO3

-; in others one can find HPO43- instead of OH-

K Na OH

Ca Mg H

George-formula:

DISEASES RELATED TO Ca++ AND Mg++ DEFICIENCY/EXCESS 1.

Definition of tetany: a condition marked by prolonged involuntary contraction of muscles.

1., Tetany caused by hypocalcemia• parathyroid gland absolute hypofunction - primary factor, rare• parathyroid gland relative hypofunction (due to increased Ca-

excretion)• renal failure – due to hyperphosphataemia

2., Tetany caused by hypomagnesemia "grass staggers”, whole milk t., transport t., winter t. Cause: complex - internal and external factors. Stress! Consequence: acetylcholine-release increases, acetylcholine esterase

activity decreases at the site of neuromuscular synapses

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DISEASES RELATED TO Ca++ AND Mg++

DEFICIENCY/EXCESS 3.

Grass tetany (lactation tetany, winter tetany and milk tetany) in calves. 

depressed appetite, dull lethargic appearance

stiffness, a staggering gait, nervousness, excitability, muscular tremors, collapse, thrashing about and death.

Mortality among untreated clinical cases can be greater than 30%.

Older animals (third or more pregnancy) are more susceptible to grass tetany because of their decreased ability to mobilize skeletal Mg. 

Cows are most susceptible to tetany immediately prior to calving and when they are nursing a calf. 

Often hypomagnesemia occurs along with hypocalcemia (low blood Ca).

Tetany ratie: K/(Ca+Mg) < 2.2 mEq/kg dry matterincreased ratio increases the incidence of tetany

DISEASES RELATED TO Ca++ AND Mg++

DEFICIENCY/EXCESS 2.

3., Milk fever or parturient paresis, parturient hypocalcemia

It is not „fever” at all

(Ca++ decreases, Mg++ relative increases)

Characterised by decreasing neuromuscular irritability - no tetany

Cause: complex (Ca++ decreases, parathyroid gland: relative hypofunction)

The most notable changes occurring in theThe most notable changes occurring in the blood are a decrease in blood are a decrease in blood calcium andblood calcium and blood phosphorus levels and an blood phosphorus levels and an increase inincrease in

blood magnesiumblood magnesium levels. levels.

Usually, hypokalemia, hyponatremia simultaneously occur - therefore no signs of tetany

http://www.youtube.com/watch?v=xFf8BjU2p8U

http://www.youtube.com/watch?v=mrMVHFSBFGI&feature=PlayList&p=19A796EA7D00F242&playnext=1&playnext_from=PL&index=33

Milk fever – a condition characterised by decreased Ca2+ and increased Mg2+

Hypophosphatemia, hypermagnesemia, hyperglycemia, hypomagnesemia,and hypoinsulinemia.

Urea nitrogen, lactic acid, pyruvic acid, chloride, hydrocortisone, AST, PTH, and 1,25-(OH)2D3, PCV increaes.

Inorganic phosphorus (P), total P, total acidsoluble P, lipid P, and globulins decrease,

Body temperature commonly decreases. Extremities, especially ears and teats, may feel cold even though rectal temperature is not decreased.

Muscle, tendon, joint damages, degenerations are also accompanied (Downing cow syndrome)

Some cases of milk fever are complicated by a toxemia from infection in the udder, reproductive tract, or digestive system

Ca , P , Mg

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Milk fever – a condition characterised by decreased Ca2+ and increased Mg2+

Blood serum concentration of dairy cows in various metabolic states.Blood serum concentration of dairy cows in various metabolic states.

Blood serum (mg/dl)Blood serum (mg/dl)

State State CalciumCalcium Phosphorus Phosphorus MagnesiumMagnesiumNormal lactating cow 8.4 - 10.2 Normal lactating cow 8.4 - 10.2 4.6 - 7.4 4.6 - 7.4 1.9 - 2.61.9 - 2.6Normal at parturition 6.8 - 8.6Normal at parturition 6.8 - 8.6 3.2 - 5.5 3.2 - 5.5 2.5 - 3.52.5 - 3.5Milk feverMilk feverStage I Stage I 4.9 - 7.5 4.9 - 7.5 1.0 - 3.8 1.0 - 3.8 2.5 - 3.92.5 - 3.9aa

Stage II Stage II 4.2 - 6.8 4.2 - 6.8 0.6 - 3.0 0.6 - 3.0 2.3 - 3.92.3 - 3.9 a a

Stage III Stage III 3.5 - 5.7 3.5 - 5.7 0.6 - 2.6 0.6 - 2.6 2.5 - 4.12.5 - 4.1aa

aa Milk fever complicated by low magnesium may result in serum magnesium ranging from Milk fever complicated by low magnesium may result in serum magnesium ranging from1.4 - 2.0 mg/dl.1.4 - 2.0 mg/dl.

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Milk fever – a condition characterised by decreased Ca2+ and increased Mg2+

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Milk fever cow struggling to stand up

By courtesy Dr. K. Cseh

There are other conditions after parturition causing paralysis and coma!

Ketotic (ketoacidotic) coma

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DISEASES RELATED TO Ca++ AND Mg++

DEFICIENCY/EXCESS 3.

4. Eclampsia in dog (cat)

• Similar etiology to cows’ milk fever• Small breed dogs are at higher risk • 1-3 weeks after giving birth (rarely before parturition)