General pathophysiology - metabolism Flashcards
pseudo-ruminant
is a classification of animals based on their digestive tract differing from the ruminants. Hippopotami and camels are ungulate mammals with a three-chambered stomach (ruminants have a four-chambered stomach) while equids and rhinoceroses are monogastric herbivores.
Like ruminants, some pseudoruminants may use foregut fermentation to break down cellulose in fibrous plant species (while most others are hindgut fermenters with a large cecum).
rabbits, guinea pigs, horses
Protein digestion begins in the stomach with the action of an enzyme called
Secreted by what cells?
pepsin
Pepsin is an endopeptidase that breaks down proteins into smaller peptides.
Gastric chief cells secrete pepsin as an inactive zymogen called pepsinogen.
Almost all the plasma proteins are synthesized in the liver with the exception of
immunoglobulins, which are synthesized by plasma cells.
The metabolism of plasma proteins also mainly occurs in the liver.
The functions of proteins in cells and tissues
A. Physical/Structural
B. Biochemical
C. Anti-infective agents
D. Liver and muscle proteins are energy and nitrogen reserves
- The functions of soluble proteins in the extracellular space
A. Physical (Maintenance of the viscosity of body fluids (plasma, secretions; Generating oncotic pressure of body fluids)
B. Biochemical (buffering, enzyme, transport etc.)
- Humoral protection against infection (Ig)
The average half-life of proteins is about
80 days, while that of the bone marrow, liver, kidneys and plasma is 10 days.
It is considerably shorter in muscle, skin, collagen and bone tissue as well as in the haemoglobin of mature erythrocytes.
trypsin
proteolytic enzyme produced in the pancreas in the precursor form of inactive trypsinogen.
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting long chains of amino acids into smaller pieces.
chymotrypsin
is a digestive enzyme synthesized in the pancreas that plays an essential role in proteolysis, or the breakdown of proteins and polypeptides.
As a component in the pancreatic juice, chymotrypsin aids in the digestion of proteins in the duodenum by preferentially cleaving peptide amide bonds.
carboxypeptidase
pancreatic enzyme
is a protease enzyme that hydrolyzes (cleaves) a peptide bond at the carboxy-terminal (C-terminal) end of a protein or peptide.
This is in contrast to an aminopeptidases, which cleave peptide bonds at the N-terminus of proteins.
aminopeptidases
are enzymes that catalyze the cleavage of amino acids from the amino terminus (N-terminus) of proteins or peptides (exopeptidases).
dipeptidases
are enzymes secreted by enterocytes into the small intestine. Dipeptidases hydrolyze bound pairs of amino acids, called dipeptides.
Dipeptidases are secreted onto the brush border of the villi in the small intestine, where they cleave dipeptides into their two component amino acids prior to absorption.
Nitrogen balance =
the difference between the total nitrogen intake by an organism and its total nitrogen loss.
Organisms have no stores of amino acids, therefore the magnitude of the nitrogen balance is determined by the difference between synthesis and breakdown of proteins.
Protein metabolism is affected by dietary and hormonal factors.
Positive nitrogen balance
This means that the intake of nitrogen into the body is greater than the loss of nitrogen from the body, so there is an increase in the total body pool of protein.
Predominance of anabolic processes is related to the action of androgen and
(o)estrogen hormones, insulin and somatotropin.
Negative nitrogen balance
This means that the amount of nitrogen excreted from the body is greater than the amount of nitrogen ingested.
Catabolic processes are related to the action of cortisol , thyroxine and progesterone.
Negative nitrogen balance is associated with burns, serious tissue injuries, fever, hyperthyroidism, wasting diseases, and during periods of fasting.
Endogenous protein reserve is
a labile (metabolisable, easily mobilisable) protein fraction of the organism.
Such protein will be used as a source of nitrogen in case the diet does not provide adequate protein, and will be restored as soon as the protein content in the diet is sufficient.
Reserves of nitrogenous compounds are primarily created by the liver, gastrointestinal wall and muscle tissue. In fattening bulls, such protein reserves comprise about 5% of the total proteins of the organism.
up to 25% of body protein can be lost before fatal or extreme adverse effects
PROTEINEMIA
The presence of protein in the blood.
The blood plasma/serum protein concentration of production animals generally ranges between 50 and 90 g/l, depending on the species, breed, age and diet as well as the fluctuations in the volume of protein and plasma.
Relative hypoproteinemia
Hypoproteinemia is a condition where there is an abnormally low level of protein in the blood.
Relative hypoproteinemia is occurs when plasma protein concentrations are lower than normal, but the absolute content of protein in the vascular space is normal. This is a dilutional hypoproteinemia and is attributable to either excessive fluid therapy or excessive water intake.
Hyperthyreosis
another word for hyperthyroidism
Hyperthyreosis is characterized by an increase in the activity of the thyroid gland. Enlargement of the thyroid gland is known as thyroid goiter.
hydremia
an abnormally watery state of the blood.
Relative hyperproteinemia
= decrease in the volume of plasma – dehydration (exicosis = loss of fluid)
e.g.
-Deprivation of water, water starvation
-Chronic diarrhea
-Excessive sweating (hyperhidrosis)
Absolute hyperproteinemia
means you have abnormally high levels of protein in your blood plasma.
- γ- globulinemia due to infection
- β- and γ-globulinemia due to tissue breakdown
Absolute hypoproteinemia
Absolute hypoproteinemia occurs when there is a reduction in the amount of plasma proteins in the vascular space in the presence of normal or almost normal plasma volume.
The reduced protein concentration can be the result of impaired production or accelerated loss.
- Loss due to blood loss, formation of exudate
and transudate - Protein deficiency/starvation
- Decline in synthesis (liver
diseases/damage, endocrine disorders) - Loss of plasma proteins due to proteinuria, enteritis, obstruction of lymphatic drainage and increased venous pressure
(BLOOD) PLASMA PROTEIN CONCENTRATIONS IN DOGS AND CATS, g/l
54-78 g/L
(BLOOD) PLASMA PROTEIN CONCENTRATIONS IN large ANIMALS, g/l
horses, pigs, cows
52 - 89 g/L
Albumin is ?
Approximately ?% of albumin is in the intracellular/extravascular space.
the main protein in blood plasma; also present in milk.
Its half-life is inversely proportional to the plasma albumin concentration
(that is, a decreased albumin content results in increased half-life, whereas increasing albumin concentrations cause the metabolic rate to increase by up to 50%).
Approximately 60% of albumin is in the intracellular/extravascular space.
Reduction in the plasma albumin levels results in the reabsorption of albumin into blood. Interstitial albumin acts as a (pH) buffer.
Decreased osmotic pressure in the interstitial space and plasma
stimulates
stimulates albumin synthesis
Immunoglobulins, also known as antibodies, are
glycoprotein molecules produced by
plasma cells
The primary factor that controls immunoglobulin
synthesis is
antigenic stimulation:
describe dysproteinemia
is a clinical state characterized by abnormal, often excessive, synthesis of immunoglobulin (Ig) molecules or subunits. Dysproteinemia results from clonal proliferation of plasma cells or B lymphocytes.
Acute inflammatory dysproteinemia
- Causes tissue damage of different origins
- The shifts are quantitatively related to the stage of development/progress and expression of the disease
- Variations in the plasma protein concentrations are the result of the changes in the synthesis rate, whereas increase and decrease in concentrations are in equilibrium.
3 points about chronic inflammatory dysproteinemia
- Occurs in the chronic stage of inflammation, in the case of malignant tumours and liver diseases.
- Involves an in crease in the levels of immunoglobulins usually along with hyperproteinemia. Levels of different immunoglobulin classes increase differently.
- It is arguable whether the changes in the plasma protein patterns are disease-specific or not.
*Increased oncotic pressure inhibits
albumin synthesis.
*Albumin synthesis depends on appropriate supply of amino acids and energy.
Urea is
the major end product of nitrogen metabolism. The urea cycle describes the conversion reactions of ammonia into urea, these reactions occur in the liver.
Uric acid / Creatinine / Indican
Indican
Indican is a tryptophan metabolite that is excreted mostly in the feces but also in small amounts in the urine as a result of absorption and detoxification of indole produced by bacterial action on tryptophan in the intestines.
The presence of indican in the urine indicates amino acid malabsorption.
Normal BUN range in farm animals
blood urea nitrogen 3.3–6.7 mmol/L
Increase in BUN may be due to (4)
- Liver diseases; fever
- Abnormal losses of fluids and electrolytes (ileus, diarrhoea, sweating, extensive burns) lead to dehydration of tissues and intensification of lytic processes in tissues
- Kidney disorders may cause 2–10-fold increase – retentional hyperazotemia
- Mechanical damage of tissues – productional hyperazotemia
Increase in BUN causes autointoxication or uremia.
azotemia
high concentrations of N compounds in blood
can be pre-renal, renal or post-renal
can lead to uremia
creatinine
metabolic nitrogen product
is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body.
isosthenuria
refers to the excretion of urine whose specific gravity is neither greater nor less than that of protein-free plasma, typically 1.008-1.012.
Isosthenuria reflects damage to the kidney’s tubules or the renal medulla.
causes of pre-renal azotemia (5)
dehydration
heart dieases (hypotension - low filtration rate)
shock
a diet rich in protein (only elevated BUN)
bleeding in the GI tract (only elevated BUN)
(When GI bleeding occurs, the blood is digested to protein. This protein is transported to the liver via the portal vein, and metabolized to BUN in the urea cycle. Higher BUN values are therefore associated with the digestion of blood.)
causes of renal azotemia
renal failure
causes of post-renal azotemia
urinary tract obstruction
bursting of the bladder
uremia
is the term for high levels of urea in the blood.
Uremia is often a sign of end-stage renal (kidney) disease and typically preceded by azotemia.
“Azotemia is a similar, less severe condition with high levels of urea, where the abnormality can be measured chemically but is not yet so severe as to produce symptoms. Uremia describes the pathological and symptomatic manifestations of severe azotemia.”
if there are no clinical signs, only azotemia, then the patient is not considered
uremic
what are the most imporant substrates for proteins.
amino acids
can also serve as an energy source via oxidation of their carbon chain
lactocyte
A milk-producing cell in the mammary epithelium.
are capable of synthesizing all non-essential AA, whereas the nitrogen required for the synthesis is obtained from the arginine and glycine that have absorbed in excess in the udder as well as from ornithine and citrulline.
Up to 50% of the free AA of arterial blood are absorbed in the udder. The overall AA requirement for milk secretion in the early phase of lactation
exceeds that for growth and foetal development by three to four times.
Nucleoproteins
complex proteins having nucleic acids as prosthetic groups.
Nucleoproteins stimulate metabolic processes; are main carriers of genetic information in the nucleus; determine cellular metabolic pathways and regulate protein synthesis in the cytoplasm; affect catalytic reactions via the adenylate system.
Free nucleotides function as coenzymes.
Mononucleotides are made up of three components:
- Carbohydrate (pentose sugar)
- Heterocyclic nitrogenous base (purine- or pyrimidine bases)
- Phosphoric acid (orthophosphoric acid)
The purine bases
adenine and guanine can be found in both RNA and
DNA.
The pyrimidine nitrogen bases
are cytosine, thymine and uracil.
Nucleoside
is a nitrogenous base (purine or pyrimidine) bound to a pentose sugar ribose or deoxyribose.
nucleoprotein metabolism
Nucleoproteins are degraded into its main constituents – proteins and nucleic acids.
Nucleic acids are hydrolyzed to a mixture of purine and pyrimidine bases.
In the liver, purines are oxidised to uric acid that is absorbed into the blood and excreted through the kidneys in humans and primates. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin.
In birds, uric acid is the end-product of the whole of nitrogen metabolism.
Hyperuricemia
the presence of elevated levels of uric acid in the blood
Uric acid may accumulate in the tissues and form uric acid or monosodium urate (MSU) crystals. Gout (in birds) – crystals may build up in the joints, ligaments, fascias/fasciae, but also skin, kidneys and muscles.
Gout is a disorder that causes sudden attacks of intense pain preceded by a period of high uric acid levels in the blood. Gout can be triggered by acidosis or the poor supply of blood to the joints and
ligaments.
allantoin
is a major metabolic intermediate in most organisms including animals, plants and bacteria. It is produced from uric acid, which itself is a degradation product of nucleic acids, by action of urate oxidase (uricase)
ruminants possess what system for nitrogen recycling?
Ruminants, possessing the rumino-hepatic re-circulation of nitrogen, are
thought to adapt easily to quite significant fluctuations in dietary nitrogen:
feeding low-nitrogen diets reduces renal excretion of endogenous urea synthesized in the liver. Urea will be recycled from the blood into the rumen either with the saliva or by diffusion through the ruminal wall.
nitrite poisoning
Use of nitrogen-containing mineral and organic fertilizers may lead to the accumulation of toxic levels of nitrate in forages, e.g. sunflower, rye, cabbage, oats, beet tops etc.
Nitrite poisoning occurs when green forage diets that
are rich in nitrates but low in soluble hydrocarbons are fed.
Treatment – use of acid to lower rumen pH.
reduction of nitrate to
nitrite by bacteria
takes place, mediated by nitrate reductase
The main biological target of nitrite poisoning is
hemoglobin, the divalent iron of which is
oxidized to the trivalent form. This leads to the formation of methaemoglobin that does not bind oxygen, and results in a functional anemia with hypoxia.
Symptoms of poisoning occur when 30% of the hemoglobin is oxidized; 60% is lethal.
Antidote: 4% methylene blue acts by providing an artificial electron acceptor for NADPH methemoglobin reductase so hemoglobin may return to a state in which it can bind O2 again.
In monogastric animals, all carbohydrates are absorbed as
monosaccharides.
In ruminants, the end products of the fermentation of dietary carbohydrates are what and name 3
the low molecular weight volatile fatty acids (acetic, propionic, butyric acids).
amylase
salivary and pancreatic
is an enzyme that catalyses the hydrolysis of starch into sugars.
Blood glucose levels under physiological conditions, Ruminants
2.22 – 3.89 mmol/L
Blood glycose levels under physiological conditions, Pig; chicken
pig 2.50 – 4.17 mmol/L
Chicken 7.22 – 14.43 mmol/L
Blood glycose levels under physiological conditions, horse
3.06 – 5.28 mmol/L
Blood glycose levels under physiological conditions, dog
3.39 – 5.00 mmol/L
what other compound mediates the absorption of glucose
Na+
Sodium-glucose cotransporter (SGLT) activity mediates apical sodium and glucose transport across cell membranes.
glucose is excreted in urine in higher amounts than normal is called
Glycosuria
Gluconeogenesis takes place mainly in
the liver and, to a lesser extent, in the kidneys
Gluconeogenesis is especially important for
ruminants as carbohydrates are fermented/converted into volatile fatty acids in the forestomach, and very small amounts of glycose are absorbed into the blood through the intestinal wall.
Gluconeogenesis is stimulated by
glucocorticoids that enhance the expression of enzymes involved in gluconeogenesis.
where is glucagon secreted from?
in the pancreas by the islets of Langerhans: the A cells
produce glucagon
where is insulin secreted from?
in the pancreas by the islets of Langerhans: the B cells produce insulin
islets of Langerhans D cells do what
D cells store somatostatin that inhibits insulin and glucagon secretion
adrenaline secreted by
adrenal medulla
The action of epinephrine results in hyperglycemia.
glucocorticoids secreted by
adrenal cortex
Glucagon stimulates the liver to
convert stored glycogen into glucose in response to low blood sugar levels aka glycogenolysis
2 major functions of insulin
stimulates the peripheral cells to take up glucose
stimulates the production of glycogen (storage)
Glyconeogenesis is the formation of glycogen in the liver.
How exactly does insulin encourage the uptake of glucose by peripheral cells?
Insulin acts by increasing the number of glucose
transporters present on the plasma membrane.
How does insulin inhibit lipolysis?
. Binding of insulin to fat cells inhibits lipolysis by
activating lipase activity. Transfer of fatty acids into fat
cells and synthesis of triglycerides will increase.
describe diabetes mellitus
Diabetes is a metabolic disease that results from partial or complete deficiency of insulin,
characterised by hyperglycaemia, glycosuria and impaired fat metabolism, polydipsia, weight loss, acidosis
Primary diabetes
decreased pancreatic islet β-cell mass
(autoimmune diseases, viral infections)
Secondary diabetes
decrease in the number of insulin receptors (obesity) – excess levels of insulin circulating in the blood; lack of relevant effect
Physiological effects of insulin deficiency (5)
- Inhibition of glycogen synthesis from glucose.
- Inhibition of protein synthesis from AA; AA used for the synthesis of carbohydrates.
- Carbohydrates are not converted to fat.
- Despite hyperglycaemia, use and oxidation of glucose in tissues is impaired.
- Fat is used as the primary energy source.
Excessive use of fat as an energy source causes
fatty infiltration of the liver, and ketone bodies
accumulate in the blood.
Ketone bodies are excreted in urine (ketonuria) and cause the pH of the extracellular environment to become acidic.
ketone bodies (3)
acetone, acetoacetate, β-hydroxybutyrate
Intense gluconeogenesis uses substantial amounts of oxaloacetic acid, whereas acetyl coenzyme A produced during lipolysis is unused and goes on to form the ketone bodies – acetate, acetoacetate, and 3-hydroxybutyrate in the liver.
Diabetic coma is due to
the accumulation of toxic ketone bodies in the blood.
Diabetic polyuria is caused by
decreased/disturbed renal tubular reabsorption of glucose that leads to high osmotic pressure of primary urine; large volumes of water are excreted with the sugar.
Diabetes insipidus
A rare form of diabetes caused by a
deficiency of the pituitary hormone vasopressin
(ADH), which regulates kidney function.
Disturbed reabsorption of water in the
kidneys, which leads to excretion of large
amounts of severely dilute urine (not containing
sugar).
Due to the hypothalamic-pituitary dysfunction, the
release of the antidiuretic hormone drops, that
causes reduced tubular reabsorption of water.
Carbohydrates comprise ? % of the diets fed to ruminants
Carbohydrates comprise 70 – 80 % of the diets fed to ruminants.
Reticulorumen serves as the site for microbial fermentation of ingested carbohydrates into volatile fatty acids and other products.
About 20% of the energy is lost to methane and heat produced during fermentation. Very small amounts of carbohydrates are absorbed through the intestine.
Ruminants need ? times higher insulin doses to generate/produce hyperglycaemia, compared to humans.
Ruminants need ten times higher insulin doses to generate/produce hyperglycaemia, compared to humans.
The levels of VFA in blood have a stronger and faster effect on insulin release compared to those of glucose or ketone bodies.
Insulin has a strong effect on the utilisation of VFA and acetate in the tissues.
consequences of insuline deficiency
slide 48
Characteristic signs of ketosis comprise
increase in the level of ketone bodies and free fatty acids in body fluids, and hypoglycemia. Excess ketone bodies
are disposed of by kidneys, udder, and lungs.
Ketosis affects the structure and metabolic functions of the liver (fatty liver/steatosis).
Insufficient gluconeogenesis to sustain a normal blood glucose concentration results in
hypoglycemia and decomposition of fats as a
source of energy. In the course of lipolysis, the catabolism of fatty acids occurs through a process called beta-oxidation that requires the presence of oxaloacetic acid.
Intense gluconeogenesis uses substantial amounts of oxaloacetic acid, whereas acetyl coenzyme A produced during lipolysis is unused and goes on to form the ketone bodies – acetate, acetoacetate, and 3-hydroxybutyrate in the liver.
Excess dietary protein may lead to
ketosis in dairy cows.
Excess protein induces urea synthesis in the liver with concurrent intensification of hepatic gluconeogenesis.
Intense gluconeogenesis uses substantial amounts of oxaloacetic acid, whereas acetyl coenzyme A produced during lipolysis is unused and goes on to form the ketone bodies – acetate, acetoacetate, and 3-hydroxybutyrate in the liver.
Physiological ketosis clinical signs
No clinical signs or symptoms; moderate hypoglycemia
and ketonemia
Subclinical ketosis or latent ketosis;
excretion of ketone bodies by urine and milk
Alimentary ketogenesis occurs in
the ruminal epithelium – butyric acid is metabolised by the ruminal epithelium into beta-hydroxybutyric
acid/beta-hydroxybutyrate.
In case of a normal diet, betahydroxybutyric acid produced in the rumen is metabolised by the mammary glands and muscles.
Hypoglycemia does not accompany alimentary ketosis.
how many more times energy is stored in one gram of lipids compared to carbohydrates or proteins.
two times more energy is stored in one gram of lipids compared to carbohydrates or proteins.
Lipid metabolism can be divided into two basic
pathways:
- the exogenous pathway, which is associated with the metabolism of exogenous (dietary) lipids, and the
- endogenous pathway, which is associated with the metabolism of endogenously produced lipids
name emulsifying agents (2)
bile acids & pancreatic lipases
chylomicrons.
spesh mechanism for lipid transport
Inside the enterocyte, fatty acids and monoglyceride are transported into the endoplasmic reticulum, where they are used to synthesize triglyeride. Beginning in the endoplasmic reticulum and continuing in the Golgi, triglyceride is packaged with cholesterol, lipoproteins and other lipids into particles called chylomicrons.
Chylomicrons are extruded from the Golgi into exocytotic
vesicles, which are transported to the basolateral aspect
of the enterocyte. The vesicles fuse with the plasma
membrane and undergo exocytosis, dumping the
chylomicrons into the space outside the cells.
Lipemia (lipidaemia)
the presence of an excess of neutral fats in the blood (> 1.14 – 2.85 mmol/L)
Alimentary or physiological lipemia
caused by high-fat diet; in birds, during the egg laying period (lipids are involved in egg yolk formation).
Pathological lipemia
caused by the factors which considerably contribute to depletion of glycogen reserves and fat mobilisation
- Transport lipemia – reserve fat is transported to liver for
oxidation (starvation, carbohydrate deficiency, asphyxia,
constant pain, heavy physical load/work)
Hyperlipidemias are also classified according to
which types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or both in combined hyperlipidemia. Elevated levels of lipoprotein may also be classified as a form of hyperlipidemia.
causes of pathological lipemia
acute and chronic diffuse liver diseases,
parenchymal jaundice, nephrosis, starvation, fatigue
and infectious diseases
Fatty infiltration
abnormal accumulation of fat droplets in the cytoplasm of cells
called steatosis when its in the liver
Fatty dystrophy
fatty infiltration is accompanied by cytoplasmic changes.
Fatty transformation
conversion of cytoplasmic proteins into fat.
Lipuria (lipiduria)
the presence of fat in the urine due to fatty dystrophy of the renal tubular epithelium.
Hypercholesterolemia is
a condition characterised by very high levels of cholesterol in the blood (normal levels 2.6 – 5.2 mmol/L).
Hypercholesterolemia is associated with
conditions like fat mobilisation, intoxication, kidney and liver diseases, diabetes, atherosclerosis, uremia, etc.
There can be other causes of atherosclerotic changes beside elevated cholesterol levels – for example,
deficiency of phospholipids, alterations in blood/serum protein fractions, etc.
In rabbits, such changes may result from a high-cholesterol diet.
