L19- Disorders of Energy Metab 2 (#2) Flashcards
Case 4: A 2-year-old male conventional short hair cat is brought to the veterinary clinic with severe signs of hyperammonemia. He manifests severe vomiting,
excessive flow of saliva, hyperactivity, spasms, tactile hyperesthesia and ataxia. His limbs are extended, with exposed claws. His owner reports that he has been growing healthy for his entire life until one hour ago. He explained that his cat fasted overnight, but signs started soon after he
accidentally consumed a casein-based, arginine-deficient diet. A blood test revealed an unusually elevated level of
orotic acid and glucose in circulation. A case of ____ deficiency is suspected.
Arginine Deficiency
Study q: In what metabolic pathway was arginine produced? (Arg def)
In the urea cycle
Study q: Why does the lack of Arg lead to symptoms of hyperammonemia?
- Urea cycle is the metab-pathway used by mammls to eliminate ammonia from the body
Without ____, the urea cycle cannot convert ammonia into urea and hyperammonemia occurs (Arg deficiency)
Arginine
After cat east a meal, highly active protein catabolic enzymes will break down proteins into AA, and AAs into a c-skeleton (a-keto acid) and a large amount of ____ which needs to be _____ in the urea cycle
Ammonia which needs to be DETOXIFIED in the urea cycle
What can’t cats do compared to other species when it comes to “keeping up” with the increased ammonia?
Ornithine and citruline synthesis occurs in animals other than cats
Study q: Hyperglycemia was observed at time of admission- why did hyperglycemia happen? (hint: epinephrine (stress h) inhibits insulin secretion) (4)* Long explaination
- Metabolic stress results in Epi secretion
- Epi inhibits insulin secretion and activates glucagon secretion which creates a low insulin/high glucagon
- Results in activation of gluconeogenesis and inhib of blood glucose intake via GLUT-4
- Thefore blood glu lvls will increase do to increase release and lower uptake
Study q: In addtion to hyperglycemia, orotic aciduria (high lvls orotic acid in the urine) is observed- how can that be eplained? (hint: intermed of purimidine biosynthesis pathway) (2)* Long explanation
Arg deficiency leads to carbamoyl-phosphate (mito) accum, which leaks out of mitochondria into cytoplasm and leads to carbamoyl-phosphate (cyto) accumulation
- Carbamoyl-phosphate (cyto) enters the pyridmidine biosynthesis pathway, bypassing the regulatory step and leading to increase prod of all molecules downstream –> inc orotic acid –> spills to urine
A combination of 3 mchanism are suggested to explain ammnia toxicity- what are they?
- Decreased level of a-ketoglutarate which SLOWS down TCA cycle and energy prod in brain cells decrease
- Increased level of glutamate which IMBALANCES in amount of neurotransmitters in the brain
- Increased level of glutamine which leads to INCREASED RISK of cerebral edema
Hyperammonemia in other species: When does urea poisoning in cattle occurs which intake of dietary ___ produces so much ___ that exceeds ability of ___ to detoxify it
Dietary urea
Ammonia
Need liver to detoxify it
Hyperammonemia in other species study q: If possible, affected animals should be treated by ruminal infusion of 5% acetic vinegar, which creates a more acidic pH. What is the rationale of this Tx to minimize hyperammonemia?
- Acetic acid lowers rumen pH and prevents further absorption of NH3 by converting NH3 to NH4+ (charged, cannot be absorbed).
- Also, it forms ammonium which can be used by rumen microflora but does not release NH3
Hyperammonemia in other species: Citrullinemia in cattle is the result of a mutation in the argininosuccinate synthetase gene, leading to a _____________ of the urea cycle- what does it result in and what is the Tx plan like?*
Leading to a dystfunction of the urea cycle
- Results in hyperammonemia and associated neurological symptoms
- TX usually unsucessfaul- euthanized
Hyperammonemia in other species: Ammonia toxicity in horses can be the result of consuming toxic plants that contain hepatotoxic alkaloids which causes ____________ because
Liver dysfuncion, bc the liver cannot convert ammonia to urea, leading to hyperammonemia
Hyperammonemia in other species: Transient hyperammonemia can be the result of infection of a urease-producing bacteria within the intestine- why?
Urease breaks down urea into CO2 and ammonia, so increased amount of bacteria producing this enzyme would lead to increased amount of ammonia
Case 5: A six-year-old male budgerigar (common pet parakeet), was presented at the veterinary clinic for disturbance in his movement of several days’ duration. He seemed in pain and had trouble walking, flying and moving
the body about. Loss of feathers at the point of the elbow was noticeable. Multiple, firm, raised nodules (tophi) were noted at several periarticular locations, and a diagnosis of ___ was made. The severe articular gout was considered irresolvable, and the bird was euthanatized.
Gout
What are the 3 mechanisms found in nature to excrete ammonia? (gout)
- Ammontelism- urinary elim of nitrogen mainly in form of AMMONIA
- Urotelism- urinary elim of nitrogen mainly in form of UREA
- Uricotelism- urinary elim of nitrogen mainly in form of URIC ACID
What animals deal with ammonia? (Gout nature question)
Most aquatic animals, including fishes
What animals deal with urea? (Gout nature question)
Mammals, amphibians, sharks, and some bony fishes
What animals deal with uric acid? (Gout nature question)
Birds, insects, reptiles, and land snails
Study Q: What is the advantage for birds and reptiles to be uricotelic? (gout)
It is needed to reptiles (usually living in low H2O environ) and birds (it would represent too much weight for flight)
What is the weak conjugate base pair of uric acid? (gout)
Urate
Study Q: The pKA of uric acid is 5.4- at a blood pH of 7.4, what is going to be the predominant state? (gout)
The conjugate base (urate) will predominate in blood and interstitial fluid (99%)
Urate is negatively charged and thus can interact with sodium ions (positively charged) to form a salt called _________ (gout)
Monosodium urate
Study Q: Urate is much more abundant than uric acid at blood pH- which one is more soluble in blood (aqueous solution), uric acid or urate? (gout)
The charged, disassociated form, URATE is more polar since it has a negative charge
What is tophi? (gout)
Monosodium urate crystal formation
Renal dysfunction decreases clearance of urate from blood which results in ______, defined as an abnormally high serum urate cc (gout)
Hyperuricemia
What does gout refer to?
Abnormal deposition of uric acid in the body
What are 2 types of gout n birds? and describe
- Visceral gout- formation of tophi due to preceiptation of monosodium urate in internal organs- may be due to infection, ingestive of too much calcium, or pregoressing renal failture
- Arterial gout- formation of tophi due to preciptiaotn of monosodium urate in joints, may be due to a genetic problem or a diet with excessive amount of proteins
Study Q: Why high protein diets can result in articular gout in birds?
AA in proteins release ammonia –> uric acid –> gout
What are 3 tests to aid with diagnosis of gout in birds?
- Elevated blood urate levels
- Observation of positive birefringent crystals in swollen joint
- Observation of mineral nodules by Xray in pets kidneys
What are 2 main factors that affect the solubility of monosodium urate? (gout)
- Urate and sodium concentration- higher the cc, the higher risk for formation of monosodium urate crystals
- Temperature- lower the temp the less soluble (temp lower in joints)
Tx options for gout? (3)
- Increase birds fluid intake
- Lower Calcium, Vit D, protein levels in diet
- Physical Tx and handicapped accessibility- limited mobility
Gout in dalmation dogs- what 2 things are manifested?
- Hyperuricemia- presence of high lvls or urate in blood
- Hyperuricosuria- presence of high levels of urate in urine- easily identified by finding precipate in urine when cooled
In non-Dalmation dogs, urate levels are regulated by the catabolism in the _____ and excretion in the _____ (gout)
Catal in Liver, excretion in the kidneys
In Dalmation dogs, there is a mutation in the urate transporter, resulting in what things occuring the liver and what things n the kidney? Explain too
Liver: less urate transported to hepatocytes to be broken down, more urate in circualtion which leads to hyperuricemia
Kidney: less reabsorption of urate and more urate excreted into urine, causing hyperuricosuria
Case 6: A 3-year-old Boxer dog is brought to the veterinary clinic with a history of cardiac disease, mild coughing and weight loss. He manifests weakness and apparent exercise intolerance. In addition to cardiomyopathy, hepatomegaly is noticed on examination. Blood sample analysis reveals fasting hypoglycemia and hypoketonemia, and _______ deficiency is diagnosed.
L-carnitine
Carnitine deficiency in what dog breeds more commonly?
Boxers, Dobermans, Great danes, Irish wolfhounds
Study q: Function of carnitine?
Needed to transport Lchain FA across inner mitochondrial membrane into mitochondrial matrix
- FA oxid in the mito accounts for the maj of energy production (in most tissues during fasting)
Study q: This animal displays carnitine deficiency and hypoglycemia- what would happen it its IG ration, its action of lipolysis , and its B-oxid action compared to normal? (carnitine deficiency)
I/G ratio would be lower than normal
There will be more lipolysis active
There will be less active B-oxidation
What is the RLE of lipolysis? What is it activated by?(carnitine deficiency)
RLE: HSL
Activated by: High epin, low insulin
What is the RLE of B-oxid? What is it activated by?(carnitine deficiency)
RLE: CPT-1
Activated by: Malonyl- coA
(carnitine deficiency): The patient is also manifesting cardiomyopathy, which relates to the relevance of _____ for heart metabolism
B-oxidation
The heart derives about 60% of its ATP from ______ of FA (carnitine deficiency)
B-oxid
About 95-98% of carnitine in a dog is targeted to cardiac and skeltal muscle- but they cannot syntehsize carnitine.. what happens instead?
They depend on dietary sources
Tx for carninte deficiency?
Typically oral L-carninte supplemntation- although NOT proving to be succesfull in dogs
