Course:SOMBlock3IQ1/Week 1/Scurvy
[edit] Learning Objectives
1. List the water-soluble vitamins. Vitamins = molecules unable to be synthesized by the body, but are ess’l to normal metabolism; must be obtained from dietary sources.
- Vit C
- Biotin
- B6
- B12
- Thiamin
- Riboflavin
- Niacin
- Panthotenic acid
- Folate
- Choline
2. List the sources of vitamin C in the diet.
- Citrus fruits
- Green vegetables esp. broccoli
- Tomatoes
- Potatoes
- RDA = 60-90 mg/d for men & women; 5 servings of fruits & veggies provides vit C in excess of RDA
3. Describe the role of vitamin C in collagen metabolism, in protection against free radicals and in the formation of norepinephrine, epinephrine, and carnitine.
- Collagen metabolism: necessary for the enzymes that catalyze hydroxylation of Lys & Pro; acts as coenzyme
- Coenzyme = small, organic, non-protein (cofactor) that directly participates as substrate in rxn, regenerated; or it can be tightly bound (prosthetic group), unsubstrate-like, more enzyme-like
- Free radical protection: provides e- → reduce oxygen radicals = strong antioxidant
- Catecholamine form’n: ascorbate req’d for reduction of dopamine → norepi via dopamine B-hydroxylase; acts as coenzyme
- Carnitine form’n: req ascorbic acid as an enzymatic cofactor
- Cofactor = non-protein req’d by enzyme to catalyze rxn; not consumed
4. Discuss the link between vitamin C deficiency and gastric cancer.
- Vitamin C deficiency allows conversion of nitrites & 2* amines to carcinogenic nitrosamines
[edit] List the water soluble vitamins and list how they differ from fat soluble vitamins
- Water soluble vitamins
- Vitamin C (important)
- the higher amount of vitamin C, the smaller the amount that actually gets absorbed by the body
- proper amount of vitamin C per person is different
- Thiamin
- Riboflavin
- B6
- B12 (deficiency causes anemia)
- Niacin
- Folic acid (Important)
- Biotin
- Pantothenic acid
- Vitamin C (important)
- Fat soluble
- Vit A
- Vit D – (parathyroid disease, remove glands, trouble w/calcium metabolism, have to add Vit D in order to absorb calcium)
- Vit E (important – menopausal symptoms)
- Vit K (very important)
- How they differ
- Different biochemical pathways
- Fat soluble vitamins are stored, water soluble are excreted when not being used by body
- Fat soluble vitamins are more hydrophobic?
[edit] List the sources of vitamin C in the diet
- Fresh fruits and vegetables
- Citrus fruits, strawberries, kiwi, cranberries
- Raw red peppers have one of the highest concentrations of vitamin C
- Potatoes
- Tomatoes (fresh or processed)
- Milk
- Fish
- Heat, drying and storage reduce the amount of vitamin C
- Consuming five servings of fruits and vegetables a day provides vitain C in excess of the RDA (60-90 mg/dl)
[edit] Describe the role of vitamin C in collagen formation, in protection against free radicals, and in the formation of epinephrine, norepinephrine, and carnitine
- Collagen formation
- Vitamin C is necessary for continued activity of proyl hydroxylase
- proyl hydroxylase synthesizes 4-hydroxyproline, an amino acid that is required in collagen
- proyl hydroxylase is regenerated when ascorbate (vit C) reduces the ferric ion of the inactivated enzyme (serves as a specific antioxidant)
- modifies prolines and lysines so they can form cross-links in the collagen (between the three chains)
- in vitamin C deficiency, you don’t get the cross links, so you don’t get the stable triple helix formation, results in non-functional collagen
- to go from procollagen to collagen, the terminal ends are cleaved, you need the cross-links at the procollagen stage
- Vitamin C is necessary for continued activity of proyl hydroxylase
- catecholamine synthesis
- dopamine beta-hydroxylase – ascorbate is needed to reduce the Cu2+ to Cu+ in order to reactivate it (nervous system, adrenal medulla)
- cofactor for reduction of folate to dihydro- and tetrahydrofolate
- promotes resistance to infection by the activation of leukocytes, production of interferon, and regulation of the inflammatory process
[edit] Describe the clinical presentation of vitamin C deficiency
- Scurvy
- characterized by anemia and hemorrhagic manifestations in the skin (ecchymoses and perifollicular hemorrhage) and in the musculoskeletal system (hemorrhage into periosteum and muscles) and changes in the gums (loosening of teeth, bleeding gums)
- also arthralgias
- osteoporosis
- nearly everything in connective tissue matrix is affected
- decreased levels of carnitine cause fatigue
- capillary fragility – leads to bruising
- oxidative degradation of coagulation factors (b/c you are missing Vitamin C as an antioxidant)
- anemia caused by hemorrhaging and how vitamin C affects the absorption of iron
- kids – bow-leggedness and weak bone; overgrowth of cartilage
- purpura – appearance of red or purple discolorations on the skin, caused by bleeding under skin
- small spots – petechiae
- large spots – ecchymoses
- hyperkeratosis – over-cornification of parts of the skin
- characterized by anemia and hemorrhagic manifestations in the skin (ecchymoses and perifollicular hemorrhage) and in the musculoskeletal system (hemorrhage into periosteum and muscles) and changes in the gums (loosening of teeth, bleeding gums)
- differential –
- hemorrhaging around knees – symptom of congenital syphilis
- scorbutic rosary – vitamin D deficiency
- deficiency in Collagen 1 – scurvy; deficiency in vitamin D – rickets
- gingivitis – due to various infections: herpes, syphilis, candidiasis
- sjogren’s syndrome – attacks glands that produce tears and saliva (xerostomia – dry eyes and dry mouth), also associated with rheumatoid arthritis
[edit] Discuss the link between vitamin C deficiency and gastric cancer
- Information is still inconclusive
- vitamins can prevent the conversion of nitriters and secondary amines to carcinogenic nitrosomines
- specific to stomach because nitrosomines need acidic conditions in order to form
- may help to prevent DNA damage
- also helps to encapsulate neoplasms, so helps prevent invasion and metastasis
[edit] Scurvy
Goal: Understand the role of vitamin C in overall health.
[edit] Mechanism of Vit C action
Vitamin C is a cofactor which activates the enzymes prolyl and lysyl hydroxylases from inactive precursors in the rER; these enzymes are responsible for hydroxylating proline and lysine residues on the pro-alpha chains (procollagen). These hydroxylysines and hydroxyprolines are thought to contribute to hydrogen bonds formed between three alpha chains, thus stabilizing them until they are secreted by exocytosis. If this hydroxylation process does not take place, as is the case with scurvy, the alpha chains will not be stabilized and will be degraded before they are released into the ECM. Even the collagen that is able to be secreted will be less stable, more soluble, and therefore more prone to degradation. The net effect is a reduction in the amount of collagen in the ECM. Do not confuse intracellular alpha chain trimers with extracellular collagen fibrils; collagen fibrils must be further modified in the ECM from their alpha chain precursors before they can form fibrils.
Vitamin C has also been found to have antioxidant properties. It is able to sequester free radicals in the cell and is able to regenerate the antioxidant form of Vitamin E.
Molecular Biology of the Cell and Robbins and Cotran
JT
[edit] The general mechanism of its synthesis
Vitamin C, or ascorbic acid, cannot be synthesized endogenously. It must therefore be ingested. Milk, fish, vegetables and fruit are all good sources of ascorbic acid.
Robbins and Cotran
JT
Intestinal absorption of vitamin C is 80-90% efficient (and efficiency decreases as intake increases). Vitamin C is co-transported with sodium against an electrochemical gradient into the epithelial cells of the small intestine. In the cells it is reduced to ascorbate and transported into the circulation by facilitated diffusion that follows a concentration and electrochemical gradient. A similar mechanism causes almost all vitamin C to be resorbed in the kidneys; vitamin C is only excreted in the urine in excess states.
source: http://www.thejcdp.com/issue018/bsoul/index_nlm.htm
ASR
The daily recommended dose (by US Food & Nutrition Board) is 60-95mg/day (to prevent acute forms of deficiency diseases), but NIH recommends 400mg/day (to have the same blood serum levels as seen in animals that can synthesize their own).
As far as overdosing on vitamin C, it is considered to be one of the most least toxic substances in medicine. (LD50 for rats is 11,900mg/kg). It is recommended though, to try not to take more than 2,000mg/day (tolerable upper intake level for a 25yo male - can lead to diarrhea).
[edit] How does the body use Vit C (ALL ENCOMPASSING)? Specific tissues that utilize the vitamin (besides connective tissue)?
Vit C is required for maintenance of normal connective tissue and for wound healing. Vit C is necessary for bone formation since the organic matrix of bone tissue consists largely of collagen. Since vitamin C is concentrated in the adrenal gland, it may be responsible for hydroxylation reactions in synthesis of some corticosteroids, especially during periods of stress. It acts as a nonenzymatic reducing agent. For example, it aids in absorption of iron by reducing it to the ferrous state in the stomach. It spares vitamin A, vitamin E, and some B vitamins by protecting them from oxidation. It enhances utilization of folic acid, either by aiding conversion of folate to tetrahydrofolate or formation of polyglutatmate derivatives of tetrahydrofolate.
Source: DEVIN Biochemistry
NJK
Actions in collagen synthesis
Functions as a cofactor for proyl hydroxylase and lysyl hydroxylase in the conversion of proline and lysine to hydroxyproline and and hydroxylysine. Hydroxyproline and hydroxylysine are used in intra-chain and interchain bonds (H-bonds, covalent bonds).
Functions in nuerotransmitter synthesis
Used as a cofactor for dopamine-beta-hydroxylase in the synthesis of norepinephrine. Deficiency may result in malaise and depression seen in vit. c deficiency
Functions in fatty acid transport
Used as a cofactor in carnitine synthesis Carnitine transports FFAs into the mitochondrial matrix for oxidation and conversion to ketones Deficiency may result in fatigue
In these reactions the enzymes are inactivated because their metal cofactors are oxidized. Vitamin C reactivates the enzyme by reducing the cofactor.
Prostaglandin metabolism: possibly capable of attenuating inflammatory response or even sepsis syndrome
Anticarcinogen: pharmacologic concentrations (via IV, can't absorb enough orally), is preferentially toxic to several strains of cancer cells:
- interacts with various tumor-inducing compounds (N-nitroso compound precursors)
- interferes with metabolism of tumor promoters
- enhances cellular immunity
Sources: Berne physiology, devlin biochem, lipincott's biochem review
NCB
Vitamin C is involved in making collagen cross-links. In scurvy, the formation of hydroxy-amino acids is disrupted and defective pro-alpha chains are formed (called "pro-alpha" because they are precursors to alpha-chains). They do not form triple helices of three alpha-chains and are quickly degraded.
(http://www.itg.be/itg/DistanceLearning/LectureNotesVandenEndenE/50_Vitamin_deficienciesp4.htm) MDM
[edit] Collagen – what specific type(s) does Vit C act on?
[edit] Its synthesis
[edit] "Signs & Symptoms of Vitamin C deficiency (signs = objective, symptoms = subjective = opinion of pt)"
[edit] Why do these symptoms occur? Mechanism?
- Malaise
- Rash
- Depression???
- Periorbital ecchymoses
- Brittle hair
- Finger nails are yellow
- Perifollicular hemorrhages
Collagen is a component of the ground substance surrounding capillary walls, so vitamin C deficiency causes capillary fragility. Capillary fragility leads to easy bruising and formation of petechia (small, pinpoint hemorrhages in skin) and decreased immunocompetence.
Source: DEVIN Biochemistry
NJK
- Hyperkertotic papules
- Anemia
a multifactorial anemia is one symptom of scurvy, caused by blood loss from hemorrhage, reduced iron absorption, and the folate deficiency that often accompanies scurvy (because foods with vitamin C also usually have folic acid as well)
source: http://www.thejcdp.com/issue018/bsoul/index_nlm.htm
ASR
[edit] Is there a link to depression?
Decreased synthesis of the neurotransmitter norepinephrine may contribute to the malaise seen in vit. C deficiciency.
Source: Devlin biochem
NCB
[edit] Does smoking & drinking have any effects on Vit C?
Smoking can lower serum levels of vitamin C. The RDAs for smokers are 110-125 mg of vitamin C day versus 75-90 mg day for nonsmokers.
Alcohol (because of its diuretic effects) pulls vitamin C out of the system before it can be absorbed.
Other risk factors: Aspirin appears to block uptake of vitamin C by WBC. Oral contraceptives and corticosteroids lower serum levels of vitamin C
Source: DEVIN Biochemistry
NJK
[edit] Does Vit C have any implication on the yellowing of teeth and nails?
[edit] Scurvy
[edit] What is scurvy?
The diagnosis of advanced scurvy can be made clinically on the basis of the skin lesions in the proper clinical situation. Atraumatic hemarthrosis is also highly suggestive. The diagnosis can be confirmed with decreased plasma ascorbic acid levels, typically below 0.1 mg/dL.
Source: accessmedicine
NJK
Etiology:
Primary deficiency is due to an unbalanced diet, i.e. a diet containing less than 10 mg vitamin C per day. Pregnancy, lactation, smoking, surgical procedures, thyrotoxicosis, burns and chronic inflammation increase the body’s requirements up to 70-90 mg/day. In achlorhydria (overgrowth of bacteria in stomach) and chronic diarrhoea, less vitamin C is absorbed. Ascorbic acid is unstable in the presence of heat and prolonged cooking of food considerably reduces the quantity of active vitamin C.
Differential Diagnosis:
- Scorbutic rosary on the thorax and bone abnormalities must be distinguished from rachitic rosary (vitamin D deficiency).
- Scorbutic gingivitis must be distinguished from other causes, such as candidiasis, herpes, trench mouth, syphilis, pemphigus and Behçet’s syndrome.
- Scorbutic hemorrhages must be distinguished from other bleeding diatheses.
- Subperiosteal hemorrhage (bleeding into joint spaces) should be distinguished from congenital syphilis.
(http://www.itg.be/itg/DistanceLearning/LectureNotesVandenEndenE/50_Vitamin_deficienciesp4.htm) MDM
[edit] Signs and symptoms
Scurvy is associated with decreased wound healing, osteoporosis, hemorrhaging, and anemia. Osteoporosis results from the inability to maintain the collagenous organic matrix of the bone, which leads to demineralization. Anemia results from extensive hemorrhaging coupled with defects in iron absorption and folate metabolism.
Symptoms of scurvy include:
- ecchymoses
- bleeding gums
- petechiae (pinpoint-sized hemorrhages)
- hyperkeratosis
- impaired wound healing
More generally:
- fatigue
- malaise
- edema
- coiled hair
- neuropathy
- vasomotor instability
- depression
Source: DEVIN Biochemistry
NJK
When a diet is chronically deficient in vitamin C (less than 10 mg/day) the first signs may be expected to appear after 3 to 6 months (half life of vitamin C is about 18 days). First signs most often are blood vessel abnormalities (eg hemorrhages, purpura, ecchymoses) since collagen turnover in these tissue are high.
Skeletal changes = scorbutic bone
- Occurs primarily in infants and children.
- Presents as bowing of the long bones of the lower legs and abnormal depression of the sternum with outward projection of the ends of the ribs. Weak bone yields to stresses of weight bearing and muscle depression
- In adults, bone deformation does not occur, but bones are still weak.
- Mechanism: insufficient production of osteoid matrix (Collagen Type 1 + bone matrix proteins) by osteoblasts. The matrix produced is not calcifiable. This leads to cartilaginous overgrowth. Weak bones.
- Differs from rickets/osteomalacia (defective calcification because of Vitamin D/calcium deficiency).
Robbins, Cotran. MDM
Scorbutic Rosary
[edit] What happens if left untreated?
Scurvy, if left untreated, is always fatal.
Wikipedia
JT
[edit] Vitamin C and cancer
[edit] Correlation with stomach cancer?
There is some evidence that Vitamin C may help prevent DNA damage in gastric mucosa.
http://carcin.oxfordjournals.org/cgi/content/abstract/15/2/291
JT
[edit] Protective role in other cancers?
Historical tidbit: in 1954 Canadian physician J.M. Gerson hypothesized that cancer was a collagen disease brought on by vitamin C deficiency.
Here are ten more recently proposed mechanisms by which vitamin C may prevent or treat cancer: 1. enhancement of the immune system by increased lymphocyte production; 2. stimulation of collagen formation, necessary for "walling off" tumors; 3. inhibition of hyaluronidase, keeping ground substance around tumors intact and preventing metastases; 4. inhibition of oncogenic viruses; 5. correction of ascorbate deficiency (often seen in cancer patients); 6. expedition of wound healing after surgery; 7. enhancement of certain chemotherapy drugs; 8. reduction of the toxicity of certain chemotherapy agents; 9. prevention of cellular free radical damage; 10. neutralization of carcinogenic substances
source: http://www.thorne.com/altmedrev/.fulltext/3/3/174.pdf
ASR
Vitamin C functions as an antioxidant. Free radicals such as O2- (super oxide), OH-, and H2O2 can cause oxidative damage to DNA (ex. strand breaks, modification of bases) which can cause mutagenesis and carcinogenesis. Vit. C neutralizes these radicals by reducing them.
Source: Berg biochem (my undergrad biochem text)
NCB
[edit] Misc/Additional Notes
Put anything else we may have left out, relevant or otherwise, down here.
Vitamin C structure:
source: Wikipedia
ASR
Collagen structure:
Drawing by JP Wenseleers, copyright ITM
MDM
[edit] Useful Resources
Case Referrers
Blog Entries
- http://blog.case.edu/jms18/mainblog/index (1 referral)
Other Sites
- http://start.case.edu/ (5 referral)