Nutrition and Skin Disease Flashcards
G.Pig protein deficits: CS
produces generalized alopecia
Rat Protein deficits: CS
alopecia, exfoliative dermatitis, and depigmentation of the haircoat
Copper
- Necessary for the enzymes that convert L-tyrosine to melanin and by follicular cells in the conversion of prekeratin to keratin
- Catalyst in hemoglobin formation, cardiac function, cellular respiration, connective tissue development, pigmentation, bone formation, myelin formation, and immune function
What metals can interfere with the absorption of copper?
- Zinc, cadmium, iron and lead can interfere with the absorption of copper.
- Zinc may inhibit copper absorption by its action on intestinal metallothioneins, which sequester copper in the intestinal epithelial cells & make copper unavailable for use elsewhere in the body
Deficiency (hypocuprosis) - Cats and Dogs
- Feline – poor reproductive performance, early foetal loss, fetal deformities, cannibalism, coat hypopigmentation, kinked tails & inverted carpi
- Canine – hair depigmentation & hyperextension of the distal fore-limbs
Bovine Cu Deficiency
- Occurs due to a primary dietary deficiency; secondary to molybdenum poisoning
- Clinical signs include stunted growth, diarrhea, infertility, anemia, bone disorders, heart failure, a rough brittle, faded hair coat and varying degrees of itching and hair licking, black hairs often turn red or gray, especially around the eyes, producing a “spectacled” appearance
- Salt licks containing 0.5 to 1% copper sulfate are reported to be effective for prevention
- Copper toxicity – jaundice, hemoglobinuria, and methemoglobinemia was produced in calves fed rations containing 500ppm copper sulfate for several months or given 12 gm orally
Ovine Cu Deficiency
- Loss of crimp in wool – becomes straight and steely in appearance.
- Tensile strength of the wool is reduced & the elastic properties are abnormal
- The physical properties of wool, including crimp, are dependent on the presence of disulfide groups that provide the cross-linkages of keratin and on the alignment of long-chain keratin fibrillae in the fiber – both of these are adversely affected in copper deficiency
- Also can access activity of erythrocyte superoxide dismutase (Cu containing enzyme) < 2 IU/mg Hb
- Treatment for sheep CUSO4
Equine Cu Deficiency
Equine – causes a loss of black pigment; affected horses develop a coarse harsh hair quality and a russet-brown hue to the darker areas of the coat
In horses, alopecia and browning of the hair around the eyes gives the animal a “spectacled” appearance, but these signs are not as prominent in the horse as in cattle and may easily be missed.
• Dx with blood & liver assays for copper
• A more serious tendency to arterial rupture and chronic anemia associated with copper deficiency
Rodent Cu Deficiency
Hamsters – alopecia and depigmentation
Rabbits – alopecia and a depigmented haircoat
Cobalt
- Cobalamin - Vitamin B12, is the largest and most complex B vitamin
- Only one to contain a metal ion, cobalt.
- Vitamin B12 is important in one-carbon metabolism and is a hydrogen acceptor coenzyme in several metabolic reactions, most important is the reduction of ribonucleotides to deoxyribonucleotides – gene synthesis
- An essential trace element in ruminant nutrition that is stored in the body in limited amounts & must be continually present in the feed.
- Deficiency
- Bovine/Ovine – signs appear after 6 months on deficient pasture and include severe reduction in growth and lactation, tender broken wool, rough faded hair coat
- Tests for colbalt or vitamin B12 are diagnostically the most valuable.
- Therapy cobalt sulfate orally
Iodine
- Essential component necessary constituent of thyroxine (T4) and triiodothyronine (T3)
- Iodine requirement is influenced by physiologic state and diet
- Lactating animals require more because about 10% of the iodine intake is normally excreted in the milk
- Excess calcium, goitrogens, and potassium increase the need for iodine
- Goitrogens: peas, peanuts, soybeans and flaxseed
- Include thiocyanates, perchlorates, rubidium salts & arsenic
- Interfere with thyroidal iodine uptake
- Deficiency
- Results in goitrous neonates has been reported in cattle, sheep, swine, goats, and horses
- Clinical signs in newborns include generalized alopecia and myxedematous skin – animals are usually alive at birth but usually die within a few hours
- Horses often have deformities such as contracted tendons and fused joints (arthrogryposis)
- Dermatohistopath – epidermal atrophy, sebaceous gland hypoplasia, diffuse mucinous degeneration and scarce hair follicles that are hypoplastic
- Necropsy thyroid glands are enlarged and may be hemorrhagic
- Supplementation an organic iodide
- Iodine toxicity – In large animals includes coughing, seromucoid nasal discharge, excessive lacrimation, and generalized scaling of the skin.
- Iodism can develop during the treatment of fungal and other infections with potassium or sodium iodide in horses
- The earliest signs include lacrimation, and a scrufy, dry coat quality
- Chroinc excessive iodine fed to adult horses (often in the form of seaweed powder supplements, etc.) may be responsible for sparse, short hair coat
Vitamin D Terms
Ergocalciferol: vitamin D2 – occurs in plants
Cholecalciferol: vitamin D3 – occurs in animals
25-Hydroxycholecalciferol : calcifediol
1,25-Dihydroxycholecalciferol: calcitriol (vitamin D2)
Vitamin D General Role
Calcium metabolism : enhances intestinal absorption and mobilization, as well as retention and bone deposition of calcium and phosphorus
Haematopoiesis
Cell differentiation
Regulation of insulin secretion
Biosynthesis and Metabolism of Vitamin D:
• Two naturally occurring pro-vitamin Ds:
o Ergosterol common sterol found in fungi & lower forms of life vitamin D2
o 7-dehydrochoeserol found in plants and animals vitamin D3
• Upon ultraviolet irradiation of pro-vitamin D3 the bond between carbons 9 & 10 is cleaved to form previtamin D3
• Previtamin D3 is biologically inert and requires temperature-dependent isomerization to form cholecalciferol (vitamin D3)
• The photosynthesized vitamin D3 in skin then enters the circulation and binds to vitamin D-binding protein (DBP)
• The biosynthesis of vitamin D3 is a regulated process in which UVB is the primary regulator
• Vitamin D3 itself is quite photolabile so that unless it is quickly absorbed into circulation, it is transformed into inactive 5,6- trans cholecalciferol, supersterol I and supersterol II.
• DBP-bound vitamin D3 in circulation is also biologically inert and requires activation.
• In the liver, vitamin D3, is hydroxylated at the C-25 position by a cytochrome P-450 enzyme system to 25(OH) D3 the major circulating form of vitamin D.
• This metabolite is hydroxylated again in the kidney at the C-1 position to form 1,25(OH)2D3 (calcitriol) which stimulates absorption of calcium from the intestine..
• Calcitriol production is stimulated by:
o Parathyroid hormone
o Hypophosphotaemia
• Calcitriol production is inhibited by:
o Hyperphosphotemia
o 1,25(OH)2D3 (calcitriol)
Although the _____ is clearly the major source of 1,25(OH)2D3 production, 1-hydroxylase activity has been observed elsewhere such as cultured keratinocytes and bone cells
kidney
_____ is responsible for calcium and phosphorus regulation and inhibits the proliferation and maturation of both normal and tumor cells that possess its receptor
Calcitriol
What are the non-calcemic effects of calcitriol?
o Enhances IL-1 production
o Inhibits gamma-globulin synthesis
o Reduced antigen presentation to Langerhans cells
o Enhances thyrotropin secretion
o Stimulates calcium binding protein activity
o Inhibits tumor proliferation activity
o Produces maturation of both tumor and normal cultured cells
When exposed to calcitriol human keratinocytes in culture show ______ proliferation and increased _______ in a concentration-dependent manner
proliferation
terminal differentiation
- Epidermal particulate & soluble transglutaminase activity was enhanced in a dose dependent manner
- Transglutaminase activity is stimulated by increasing the intracellular free Ca concentrations by non-genomic actions
- Calcitriol used on cultured keratinocytes decreased EGF receptors
What is the biologic activity of calcitriol on melanogenesis and hair growth?
• Reported to stimulate melanogenesis and tyrosinase activity
• May have effects on hair follicle development and maturation during embroyogenesis
Indications
• Calcitriol used in Cockers with primary seborrhea at 10ng/kg q24 hrs
• Over 60% experienced significant improvement; all dogs showed decreased cell proliferation
• As it can decrease PTH, Ca and phosphorus levels should be checked weekly, as an accidental overdose can be fatal
• Topical analogs are used to treat psorasis in humans
• Calcitriol used in human keratinocyte cultures has shown the ability to down regulate TH1 response associated with immune-mediated disease.
What are the primary functions of Zn?
• Some of the primary functions include: o Nucleic acid metabolism o Protein synthesis o Carbohydrate metabolism o Senses – smell and taste acuity o Immuno-competence – a decrease results in lymphopenia; decreases in T-cell response to mitogens, neutrophil chemotaxis, Mφ phagocytosis, Mφ killing & an increased susceptibility to pyoderma o Skin and wound healing o Cell replication and differentiation o Growth o Reproduction o Interacts with hormone production: testosterone, adrenal corticosteroids and insulin• Zn homeostasis is controlled through absorption (primarily through the duodenum, jejunum and ileum) and excretion
Decreased zinc absorption occurs due to:
o Phytates (present in proteins of plant origin such as soy) o high dietary levels of Calcium o Copper o Iron o Cadmium o Phosphate o Chromium o EFA deficiency
The antagonistic effects of calcium are greatest when phytate is also present, resulting in the formation of a highly insoluble complex of calcium, phytate and zinc
Enhanced zinc absorption occurs with:
o Ligands such as EDTA, Citrate, picolinate,
o Amino acids (histidine, glutamate)
o EFA supplementation
Describe zinc metabolism
• The liver is the primary organ involved in zinc metabolism.
• Zinc in plasma is bound to protein in two forms:
o Firmly bound zinc that appears to bind to globulin (approximately 33% of total plasma zinc)
o Loosely bound zinc complexed with albumin (66% of total plasma zinc)
• Storage is limited except in bone
• Stores increase only slightly as dietary zinc increases
• Zinc concentration in bone has been used as a measure of zinc absorption and/or zinc status in young growing animals
• Plasma zinc is only a reliable index
• Eliminated primarily through the feces as unabsorbed & endogenous zinc (pancreatic juice, bile, and other digestive secretions)
What is the relationship between zn and skin?
• Contains approximately 20% of the total body zinc stores
• Epidermis containing 6 times more than the dermis
• Concentrations tend to be greater in tissues with high epithelial proliferation rates, which may suggest that zinc is involved in the keratinization process of the skin
• Highest concentrations of zinc are observed in areas of pressure keratinization (footpads) and in parakeratotic sites (planum nasale)
• Dermatological diseases associated with epidermal hyperproliferation such as zinc responsive dermatosis may greatly increase utilization of the body’s zinc stores
Deficiency
• Primary due to inadequate amounts in the diet
• Secondary due chelating agents mentioned above that affect zinc absorption and requirements
• Reported in horses, cattle, sheep and goats.
• Feline - in kittens thin hair coat, slow hair growth, seborrhea sicca, ulceration of the buccal margins
• Chinchilla – alopecia
• Rats – exfoliative dermatitis, alopecia, and depigmentation of the haircoat
• Rabbit – alopecia, scaling, and depigmented haircoat
• Mouse – exfoliative dermatitis, alopecia and depigmentation of the haircoat
• Recent work indicates that Zn deficiency is rare in dogs; and has been documented in Bull terriers, however, a recent prospective study of 28 Bull terriers with lethal acrodermatitis could not document statistically significant differences of Zn levels between the affected dogs and the controls (McEwan NA, McNeil PE, et al. JSAP 2000 41: 501-507)
Equine zn deficiency
• Equine develops within a short time as reserves are low
o Generalized alopecia with extensive surface scaling and flaking giving the appearance of severe dandruff.
o Initially thighs and ventral abdominal wall.
o Severe and prolonged deficiencies result in generalized exudation and flaking with extensive and severe loss of hair.
Daily dietary supplementation with zinc methionine
Food animal zn deficiency
• Bovine, Ovine, Caprine – signs of deficiency are similar in all three species; although the sequence of clinical signs is not consistent and include:
o Low levels of ALP
o Decreased feed consumption and growth rate
o Depraved appetite (wool eating)
o Wool break
o Listlessness
o Shivering
o Testicular atrophy
o Stiff or swollen joints, bowing of the hind legs
o Decreased resistance to infections
o Nasal and oral mucosae become inflamed and submucosal hemorrhages and horny overgrowth are seen on the lips and dental pads
o Wound healing is prolonged
o Suggested that low Zn levels predispose to infectious pododermatitis in cattle and sheep
Goats: pruritic crusting dermatitis that is most severe on the face and feet
“Itching Tail Root Eczema”
• Syndrome in young non-lactating cattle and in dairy cows during the dry period
• Occurs when high Ca & low Zn and Cu ratios
• Results in pruritus over tailhead (licking and biting), twitching of the tails, crusting & excoriation of the tailhead, decreased appetites, fertility and milk production
• Treatment with ZnCl or ZnO resulted in clinical remission
• Histopath:
o Marked parakeratosis
o Epidermal hyperplasia
o Superficial perivascular accumulation of mononuclear cell and eosinophils
o Some animals show only orthokeratotic hyperkeratoisis or alternating parakeratotic & orthokeratotic hyperkeratosis.
• Scanning EM of wool fibers defects, including irregular or absent cortical scale pattern, separation of cortical cells and breaking, fraying and distortion of fibers
Therapy – zinc levels in plasma and hair are unreliable; best indicator is response to zinc therapy
• IM injections may be preferred due to oral absorption
• ZnO or metallic zinc powder had been shown to be effective and quick acti
Zinc-Responsive Dermatosis: Humans
• Reported in:
o Dogs Cats Cattle Sheep Goats Llamas Pigs, Rats, Humans
Humans
• Described as acrodermatitis enteropathica
• Autosomal recessive
• Triad of dermatitis, diarrhea and alopecia
• Paraonychia, pustular dermatitis with acral and mucocutanoeus junction distribution
Zinc-Responsive Dermatosis: Bovine
- Lethal Trait A46
- Autosomal recessive
- European Friesian & Black Pied Cattle
- Intestinal malabsorption of Zn.
- Onset of lesions occurs at 4-8 weeks of age
- Erythema, crust, alopecia, on the face, distal limbs, and mucocutaneous junctions.
- Other clinical signs include conjunctivitis, rhinitis and diarrhea
- Fatal if left untreated.
- Histopathology: hyperplastic superficial perivascular dermatitis w/ marked diffuse parakeratosis.
- Also: Hypoplasia and lymphocyte depletion of thymus, lymph nodes, and spleen
- Treatment: ZnO PO q.24 hrs or ZnSO4
Zinc-Responsive Dermatosis Syndrome 1: Canine
• Siberian Huskies & Alaskan Malamutes
o Other breeds like the Bull Terrier may be affected
• Siberian Huskies and chrondrodysplastic Alaskan Malamutes have a genetic defect
• Malamutes: decreased capability for zinc absorption from the intestine exists
• Skin lesions develop despite well-balanced diets with sufficient zinc
• Early in adulthood (1 to 3 years of age) and progress at a variable rate
• Age of onset can range from 6 months to 10.5 years with 41% of dogs developing lesions before 2 years old
• Most September through January. (Northern hemisphere – autumn/winter)
Clinical signs:
• Over one-half of the dogs have lesional pruritus & pruritus in “normal” skin can be the hallmark of a pending relapse during maintenance
• Early erythema is followed by alopecia, crusting, scaling, and underlying suppuration around the mouth, chin, eyes, and ears can be present.
• Other body openings and the scrotum, prepuce and vulva may be affected
• Lesions are often unilateral initially but become symmetrical as the disease progresses
• Although the coat is dull, there is excess sebum production
• Thick crusts may appear in the elbows and other pressure points
• The skin may be inelastic and the legs stiff, as a result of hardened crusts.
• Footpads may become hyperkeratotic and claw disease, especially onycholmalacia, may be observed
• Chronic lesions may be hyperpigmented
• Clinical signs may be precipitated or intensified by stress, illness, and estrus
• A decreased sense of smell (hyposmia) and taste (hypogeusia) may be evident
• Secondary bacterial and Malassezia infections are common, especially when there is pruritus - resulting from breakdown of the normal epithelial barrier as well as the paucity of zinc which leads to impaired immunocompetence
Zinc-Responsive Dermatosis Syndrome 2: Canine
- Rapidly growing puppies or young adult dogs that are fed zinc deficient diets, diets high in phytates or minerals discussed above
- Many breeds may be abnormal, but Great Danes, Doberman pinschers, Beagles, German Shepherds, German Shorthaired Pointers, Labs, Rhodesian ridgebacks and Standard Poodles
- Generic dog food disease may be a variant of syndrome 2.
- Severity of clinical signs within a litter are variable & may range from unaffected to depression, anorexia, stunted growth, pyrexia, and lymphadenopathy
- Dermatologic lesions: hyperkeratotic plaques over areas of repeated trauma, footpads & nasal planum may be affected, and any thickened area may have deep fissures.
- Secondary infection of the crusts & an associated lymphadenopathy
- Severely affected dogs can resemble canine distemper.
- Diagnosis for both syndromes is made from the history, physical examination, skin biopsies and response to Zn supplementation.
- Histopath – superficial perivascular dermatitis, with marked diffuse and follicular pararkeratotic hyperkeratosis is suggestive of Zn responsive dermatosis.
- Papillomatosis and mild diffuse spongiosis are also common. Eosinophils and lymphocytes are often prominent in the perivascular cellular infiltrate. Intraepidermal pustular dermatitis and suppurative folliculitis reflect secondary bacterial infection
- Extracutaneous histological lesions – include irregular epithelial hyperplasia and dysplasia of the buccal mucosa as well as a marked absence of lymphocytes in the thymus and T-cell regions of the lymph nodes and spleen – all of these changes indicate alteration in lymphocyte (T-cell) development or migration.
- DDX: dermatophytosis, demodicosis, PF, SLE, mucocutaneous pyoderma, SND
Zinc-Responsive Dermatosis: Llamas
• Idiopathic Hyperkeratosis (zinc-responsive dermatosis)
• Common disorder; Usually recognized first in 1 to 2 year old llamas but age of onset is variable
• Both sexes affected, although males may be over-represented.
• Disease has developed in spite of the fact that dietary zinc concentration appear to be adequate
• Lesions are most common over the ventral abdomen, inguinal region, medial thighs, and axilla
• Initially papular, progressing to raised alopecic plaques with a dry adherent scale
• Larger areas of involvement often give the skin a diffusely thickened appearance & feel
• Lesions do not appear inflammatory
• As the disease progresses there may be involvement of the face (especially bridge of the nose) & distal extremities.
• Lesions usually are asymptomatic although on occasion mild pruritus may be noted.
• No systemic symptoms.
• Histopathology: Marked epithelial and follicular orthokeratotic hyperkeratosis
o A mild to moderate perivascular dermatitis, characterized by increases in lymphocytes, macrophages, and eosinophils.
• Treatment: daily supplementation with zinc sulfate, may discontinue alfalfa hay as high in Ca
Treatment of Canine Zn Responsive Dermatosis
- For syndrome II – inspect and correct any inadequacy in the diet, including base diet, water and any supplements or treats. Dietary adjustments can resolve the skin lesions in 2 to 6 weeks.
- In syndrome I, Zn supplementation is necessary and approximately 25% of dogs can have the Zn supplementation stopped without an immediate relapse in the condition
- Oral Zn supplementation –vomiting is the main adverse reaction.
- Zn sulfate tablets should be crushed and mixed with food to enhance absorption and decrease gastric irritation
- Zn gluconate –Zn methionine –
- In syndrome I, Zn administration is typically lifelong; in syndrome II the supplement can be withdrawn when the skin has returned to normal and the diet has been corrected. If no response is seen within 4 weeks after initiating therapy, the dosage should be increased by 50%.
- In dogs that do not improve with oral supplementation – IV administration of sterile zinc sulfate transient panting and cardiac arrhythmias have been observed as an adverse effect of IV Zn supplementation
- Low dose corticosteriods – may be indicated in dogs that do not respond to zinc alone. GC’s are known to increase zinc absorption for the GI tract by induction of metallothionein, but they may also have some direct anti-inflammatory effect on the skin
- Other options – tetracycline and lincomycin; topical therapy with warm water soaks and antibacterial or antiseborrheic shampoos may aid in controlling infections and crust removal.
- EFA supplementation
Lethal Acrodermatitis of Bull Terriers
- Inherited autosomal recessive trait that strongly resembles severe zinc deficiency
- Does not respond to oral zinc supplementation.
- Metabolic disease of bull terriers
- In 28 cases, all dogs had difficulty eating, were stunted in comparison with littermates, and had splayed digits giving the appearance of large, flat feet.
- Early skin changes consisted of erythema and tightly adherent scale and crust involving primarily the feet, distal limbs, elbows, hocks and muzzle, other body areas including the trunk and tail were occasionally involved
- Other clinical findings include nasal discharge 7/28, skeletal deformities 5/28, systolic murmurs 3/28, and abnormal ocular changes 2/28
- In general, dogs that survived 6 months of age or older developed severe skin disease with marked pad hyperkeratosis nail disease and paronychia.
- Plasma zinc levels in 22 dogs were not statistically different when compared to dogs with atopic dermatitis
- Malassezia & Candida organisms could be found
- Histopath – most prominent feature diffuse, marked parakeratotic hyperkeratosis.
- Mild to moderate acanthosis together with superficial perivascular dermatitis were also common.
- Laminar pallor of the upper epidermis due to hydropic changes of keratinocytes was an additional finding noted in some biopsy specimens
Generic Dog Food Skin Disease
* stupid but just in case….*
• Developed bilateral symmetrical scaling & crusting dermatoses within 1 month after consuming the diet
• Lesions: bridge of the nose, mucocutaneous junctions, pressure points, & distal extremities.
• Well-demarcated, older lesions had erythematous borders with scales, crusts, and variable hyperpigmentation and lichenification.
• A few had pustules, papules, focal erosions and alopecia
• Most had fever, depression, lymphadenopathy, and pitting edema of dependent areas
• Histopath – hyperplastic superficial perivascular dermatitis with diffuse parakeratotic hyperkeratosis, prominent focal keratinocyte apoptosis and a mixed dermal cellular infiltrate
Swine Parakeratosis
• Pathogenesis is unknown, but is related to zinc and EFA deficiency;
• Exacerbated by high levels of dietary calcium, phytates and other mineral and chelator agents
• The condition occurs only extremely rarely in animals with access to pasture grass
• Temporary, nutrition related metabolic disorder of rapidly growing pigs
• Occurs in housed feeder pigs 7-20 weeks of age; no sex or bred predisposition
• Clinical signs: 1st erythematous macules & papules on the ventral abdomen and medial thighs;
Then spread and evolution to hard, dry crusts, especially on the distal limbs, face, ears, tail, and ventrum
No pruritus, no seborrhea; secondary skin infections are common (especially hock abscesses).
Reduced appetite, growth rate and feed utilization; occasionally diarrhea & vomiting
• Histopathology: hyperplastic superficial perivascular dermatitis, parakeratotic hyperkeratosis; edema in superficial dermatitis, perivascular accumulation of mononuclear cells and eosinophils
• Diagnosis: history, herd status, PE, histopath, decreased ALP
• Therapy and prevention: supplementation with Zn salts
• Evolution: self-limiting disease: spontaneous recovery in 10-45 days depending on severity
Structure of Lipids
The basic subunits of lipids are hydrocarbon molecules linked by covalent bonds
Most dietary and body fats consist of free fatty acids, long aliphatic carbon chains with a terminal methyl (CH3) group at one end and a carboxyl (COOH) group at the other.
Fatty acids may be saturated or unsaturated.
Saturated fatty acids
Saturated fatty acids are straight carbon chains without double bonds
Unsaturated fatty acids
Unsaturated fatty acids have one or more double bonds
**Saturated and monounsaturated fatty acids can be derived directly from the diet or synthesized de novo by mammals
The majority of fatty acid biosynthesis occurs in the _____(organ)
Liver
Polyunsaturated Fatty Acid Biochemistry
PUFA’s are unsaturated fatty acids with two or more double bonds.
• A shorthand identification system commonly used identifies the:
o Number of carbon atoms
o Number of double bonds
o Position of the first double bond counting from the terminal (“omega” or “n”) methyl end of the molecule
E.g. LA (18:2n-6) is an 18 carbon molecule with two double bonds, with the first double bond located between the sixth and seventh carbon.
PUFAs determined to be essential for normal growth and health are:
- LA – linoleic acid
- AA – arachidonic acid
- EPA – eicosapentaenoic acid
- DHA – docosahexaenoic acid
Establishing double bonds in fatty acids requires microsomal _____,
desaturase enzymesMammals can introduce double bonds starting at C9-10
If a double bond is not present in the -9 position, the other desaturase enzymes cannot work.
Consequently, mammals are unable to synthesize LA or ALA, but can make AA from LA and EPA from ALA
Cats lack -6-DES, have limited -5-DES activity, unable to synthesize AA, and therefore must be obtained directly from the diet.
Define essential fatty acid (EFA)
An EFA is a PUFA that cannot be synthesized by animals but is required for normal physiologic function.
• LA is the key EFA because without LA and AA animals will die
• AA and EPA are essential constituents of cell membranes and CNS tissue
• LA and ALA the precursors to the required AA and EPA cannot be made de novo and must be derived from dietary sources.
Three families of unsaturated fatty acids are critical to the therapeutic importance of EFA’s
Plant derived (-linolenic) and fish oil derived (eicosapentaenoic acid) n-3 family Plant derived n-6 family De Novo (nonessential) fatty acid family (n-9 family)
List members of the n-3 family
- -linolenic acid (18:3n-3)
- Eicosapentaenoic acid (20:5n-3)
- Docosahexaenoic acid (22:6n-3)
- Green leafy vegetables
- EPA is a metabolic product of ALA; marine fish oil
List members of the n-6 family
- Linoleic acid (18:2n-6)
- -linolenic acid (18:3n-6)
- Arachidonic acid (20:4n-6)
- Vegetables; abundant in certain seed oils
- E.g. safflower or sunflower seed
- GLA, a -6-DES product of LA, may be derived from the seed oils of the borage, evening primrose, and black currant plants
De Novo (nonessential) fatty acid family (n-9 family)
- Palmitic acid (16:0)
- Oleic acid (18:1n-9)
- Synthesized de novo from acetyl coenzyme A by the liver and tissue microsomes
A number of fungal sources such as oil of javanicus produced from Mucor javanicus are also rich in EFA’s
What are the three main functions of EFAs?
- Act as a structural component of cellular membranes (primarily AA)
- Maintain the epidermal water barrier
- Parent compounds for eicosanoids
Eicosanaoids include:
o Prostacyclins
o Prostaglandin (PG)
o Thromboxanes (TX) which are termed prostanoids
o Leukotrienes (LT)
o Lipoxins (LX)
o Hydroperoxy-eicosatetraenoic acids (HPETE)
o Hydroxyeicosatetraenoic acids, (hydroxy fatty acids or HETE)
Describe how EFAs are a structural component of cellular membranes
• Physical & functional properties of cell membranes are determined by their phospholipid f.a. composition
• Important implications for cell integrity, growth, inflammation & immunity
• Without PUFA’s membranes incorporate straight chain saturated fatty acids
o These membranes are less fluid and thus become unstable.
o The increased tissue permeability that results, leads to nutrient and water loss, alteration of normal membrane receptors, enzyme activity, and altered cytokine production
• AA is also an important regulator of epidermal proliferation
Describe how EFAs maintain the epidermal water barrier
• This function is dependent on the LA-containing lipids (ceramides) in the intercellular lamellar granules extruded from epidermal keratinocytes at the stratum granulosum-stratum corneum interface
How are EFAs parent compounds for eicosanoids?
- AA, EPA and GLA are precursors of eicosanoids. • Produced in response to physical and chemical insults such as trauma, thermal injury, ischemia, endotoxin release, antigen antibody interactions, increased intracellular calcium, cytokine production, or histamine release.
- Such stimuli result in the cleavage of the PUFAs through the action of phospholipase A2 (leukocytes) and phospholipase C (platelets).
- Eicosanoids are formed by subsequent oxygenation of the PUFAs by local cyclooxygenase and lipoxygenase enzymes.
- The release of AA from its membrane store is the rate-limiting step in eicosanoid synthesis.
- Its availability for eicosanoid synthesis requires its liberation by a phospholipase
The release of _____ from its membrane store is the rate-limiting step in eicosanoid synthesis.
AA - arachidonic acid
**Its availability for eicosanoid synthesis requires its liberation by a phospholipase
Eicosanoids derived from omega-6 fatty acids (DGLA or AA) are generally _______.; While, eicosanoids produced from omega-3 fatty acids (EPA) have _______.
Pro-inflammatory, pro-aggregatory, and immuno-active.
Little or no inflammatory activity, and act to modulate platelet aggregation and immune-reactivity.
PGE2 is considered proinflammatory in the ____, but is protective of ______.
skin
gastric mucosa
What is the pathogenesis of cutaneous inflammation?
• Inflammation begins with transient vasoconstriction
Followed by vasodilation
Increased blood flow
Increased vascular permeability
Extravasation of plasma into the injured tissue
• Damaged cells release interleukins, and other chemotactic factors:
Recruit leukocytes and mast cells
Release mediators - histamines, bradykinin, serotonin, liposomal enzymes, & eicosanoids
Further promote the inflammatory response or help bring it to an end.
What is PG role in inflammation?
PGs potentiate vascular dilation, leading to erythema, edema, pain and heat at the site
Series 2 prostaglandins:
• Vasodilation
• increased vascular permeability
• Pain/Hyperalgesia
• Extracellular signal for NFB
• Increased keratinocyte DNA synthesis – proliferation
• increased histamine release from mast cells
• Smooth muscle contraction
• Decreased CD8 lymphocyte activity promote antibody synthesis
• And some even inhibits platelet aggregation
What is LTs role in inflammation?
LTs (especially LTB4) are potent chemotactic factors and attract additional inflammatory cells to the area
Actions of LTB4:
• Chemotaxis for neutrophils and eosinophils
• Activation of neutrophils and eosinophils
• Adherence of neutrophils and eosinophils
• Increased keratinocyte proliferation
• Enhanced NK cell activity
• Hyperalgesia
• Increased vascular permeability
• Superoxide generation by neutrophils
LTC4, LTD4, LTE4: SLOW REACTING SUBSTANCE OF ANAPHYLAXIS
Fatty Acid Deficiency
- Uncommon to rare and is seen only in animals that are fed dry rations, commercial food that has been poorly preserved (storage, temperature, preservative problems), or homemade foods
- Can be seen in dogs that are fed high-quality reducing dog foods in which the fat content has been lowered
- Other causes are low fats in feeds and diets or destruction of fat in feed during storage (mostly due to rancidity in the absence of antioxidants like VE)
- Oxidation of fat during storage causes it to become rancid and the EFA as well as the vitamins D, E and biotin are destroyed
- Intestinal malabsorption, pancreatic disease and chronic hepatic disease are also causes of FA deficiency
- Documented in horses, cows, swine, dogs, cats, and rats
- Clinical signs: Renal & reproductive abnormalities, decreased growth rate, immunologic abnormalities, hypotricosis, alopecia, exudation, scaling, weak cutaneous blood vessels and increased tendency to bruise, decreased wound healing, sebaceous gland hypertrophy accompanied by increased sebum viscosity and increased transepidermal water loss
- There is an early decrease in lipid production with resultant fine scaling and loss of luster and sheen of the hair – the dry phase can last for months and can have associated hair loss and secondary bacterial infections
- Later the skin thickens, becomes greasy, especially in the ears, in the intertriginous areas, and between the toes; The dryness of the coat is replaced by greasiness and many become pruritic
- Histopath for all animals – orthokeratotic or parakeratotic hyperkeratosis, hypergranulosis, epidermal hyperplasia
- Consequences of the deficiency
- When LA and AA are absent, oleic acid (18:1n-9) or mead acid (20:3n-9) is incorporated into cell membranes as a substitute for the essential n-6 fatty acid
- Cellular membrane integrity is lost and clinical signs of EFA deficiency appear.
- A decrease in LA (thus AA) and its replacement by n-9 fatty acids also result in a decrease in epidermal prostaglandin E2 (PGE2), this decrease may play a role in epidermal hyperproliferation observed in EFA deficiency.
- Abnormal keratinization is thought to result from AA deficiency with a resultant PGE deficiency, which causes aberrations in the ratios of epidermal cAMP and cGMP and in DNA synthesis
- All abnormalities can be reversed by vegetable oil supplementation in large animals.
- Excessive fat supplementation is contraindicated in cases in which the FA deficiency is intentional, such as in the management of obesity, pancreatic disease, or hyperlipidemia disorders.
- In these cases, treatment with a balanced omega 6 & omega 3 FA supplements may be of some benefit.
- When dietary fat supplementation is impossible, topical application of EFAs may be of some benefit
- Studies in mice have shown that topically applied fats can correct the cutaneous changes of fatty acid deficiency
- FA deficiency responds gradually to supplementation
- Mild cases respond in 4 to 8 weeks, but severe cases can take up to 6 months.
- There is no specific test for fatty acid deficiency; the diagnosis is confirmed by response to treatment
Fatty acid requirement/deficiency CS in different species
- Swine – experimental deficiency produced with diets containing 0.06% fat (requirement 1% caloric intake must be linoleic acid) usual rations are not low enough in essential fatty acids to cause deficiency; other recommendations for swine are that fats = 1% total ration for swine
- Swine parakeratosis may be at least partially caused by fatty acid deficiency
- Dog food should have a minimum of 3% fat in canned food and 7 to 8% fat in dry food
- Cats usually have 35-40% of their calories provided by fat a much higher amount because they need a dense caloric formula
- Chinchilla – FA deficiency: generalized scaling, poor haircoat, reduced hair growth, & cutaneous ulcers
- G. Pig – generalized alopecia, scaling, and dermatitis
- Hamsters – generalized alopecia, scaling, and the production of profuse amounts of cerumen
- Mouse – exfoliative dermatitis
- Rat – exfoliative dermatitis and occasionally necrosis of the tail
What domain of DNA does retinoid acid bind to?
RA bind to regulator regions in DNA called hormone response elements and they activate gene transcription in a ligand dependent manner.
For RA this domain in termed RARE and for Vitamin D the domain is VDRE.
Retinoid acid MOA?
Vitamin A, in the retinoic acid form, plays an important role in gene transcription. Once retinol has been taken up by a cell, it can be oxidized to retinal (by retinol dehydrogenases) and then retinal can be oxidized to retinoic acid (by retinal oxidase). The conversion of retinal to retinoic acid is an irreversible step, meaning that the production of retinoic acid is tightly regulated, due to its activity as a ligand for nuclear receptors. Retinoic acid can bind to two different nuclear receptors to initiate (or inhibit) gene transcription: the retinoic acid receptors (RARs) or the retinoid “X” receptors (RXRs).
Once the retinoic acid binds to the receptors and dimerization has occurred, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery. The receptors can then bind to the response elements on the DNA and upregulate (or downregulate) the expression of target genes, such as cellular retinol-binding protein (CRBP) as well as the genes that encode for the receptors themselves
What are the two nuclear retinoid acid receptors required to initiate (or inhibit) gene transcription?
RAR and RXR must dimerize before they can bind to the DNA. RAR will form a heterodimer with RXR (RAR-RXR), but it does not readily form a homodimer (RAR-RAR). RXR, on the other hand, readily forms a homodimer (RXR-RXR) and will form heterodimers with many other nuclear receptors as well, including the thyroid hormone receptor (RXR-TR), the Vitamin D3 receptor (RXR-VDR), the peroxisome proliferator-activated receptor (RXR-PPAR) and the liver “X” receptor (RXR-LXR).
What is the different between RAR-RAR homodimer and RXR-RAR reterodimer?
The RAR-RXR heterodimer recognizes retinoid acid response elements (RAREs) on the DNA whereas the RXR-RXR homodimer recognizes retinoid “X” response elements (RXREs) on the DNA. The other RXR heterodimers will bind to various other response elements on the DNA.
