Term
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Definition
One allele transforms cells, RET only inherited oncogene |
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Term
ERBB2/HER-2-neu
chromosome 17 |
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Definition
- Gene amplification causes overexpression of growth factor receptor
- Breast cancer and other cancers
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Term
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Definition
Constitutionally active “always on” tyrosine kinase-type growth factor receptor in MEN 2a
Altered substrate specificity in MEN 2b (activated with other molecules than growth factor, loses specificity)
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MEN 2a--:Sipple Syndrome: Pheochromocytoma, Medullary thyroid CA, parathyroid hyperplasia
Familial medullary thyroid CAà20% of medullary thyroid CA is familial, check for RET when this CA is diagnosed
MEN 2b—(same gene, different point mutation) Marfanoid habitus with diffuse neuromas and gangilioneuromas
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Term
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Definition
Fusion gene product of t(9:22) translocation, Constitutively expressed and activated cytoplasmic (non-receptor) tyrosine kinase
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100% of Chronic myelogenous leukemia (CML) , 25% of Acute lymphoblastic leukemia (ALL)
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Term
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Definition
- Mutated RAS stays phosphorylate and keeps growth receptor in 'on' position
- Causese many human cancers
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Term
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Definition
- Gene amplification causes overexpression of transcription factor protein driving cell proliferation
- Neuroblastoma
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Term
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Definition
- T 8:14 translocation
- Transcription factor protein driving cell proliferation
- causes Burkitt Lymphoma
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Term
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Definition
- both alleles must be damaged to incur cancer.
- Most autosomal dominant familial syndromes are in this category.
- Gene function in oncogenesis is recessive due to haploinsufficiency, but inheritance patters will be dominant due to one germline mutation and then 2nd hit occurring during life -->cancer
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Term
APC/β-catenin gene
chromosome 5 |
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Definition
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Normal: degrade catenin to stop transcription
Abnormal: Inability to degrade catenin and stop transcription—lose brake on transcription
- Cancers
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AD cancer syndrome: Familial adenomatous polyposis with 100% development of colon cancer in people with polyposis phenotype, colon adenocarcinoma (present in many non-familial colon cancers!)
Non-familial: Many other human cancers
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Term
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Definition
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Term
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Definition
“Guardian of the genome”—Normally:
1. Temporary arrest: increases levels of p21 to block cdk4/Cyclin D, allowing repair time for damaged cells
2. Induce growth arrest: via MYC and CK4
3. Trigger cell suicide: upregulate BAX/BAK which decreases BCL-2, causing mitochondrial leak of cytochrome C and triggering apoptosis
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AD cancer syndrome: Li-Fraumeni syndrome--> 25x increased chance of cancer with germline loss of single p53 allele-->multiple types of tumors in same person (sarcoma, breast cancer, leukemia, brain tumors, adrenal CA
Non-familial: Most cancers have a p53 mutationà this is not always the initiating event but an additional mutation that has occurred with uncontrolled growth
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Term
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Definition
Normal: flips RAS back to inactive state
Abnormal: RAS stays phosphorylated and active, signaling to “keep growing”
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AD cancer syndrome: Neurofibromatosis type 1 with increased risk of sarcomas
Non-familial: Neuroblastomas
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Term
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Definition
Normal: can function as nuclear activator or suppressor of transcription
Abnormal: loss of transcription regulation
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Familial:
1. WAGR (Wilms, Aniridia, genital abnormalities, retardation)
2. Denys-Drash (gonadal abnormalities and early onset nephropathy) both have WT-1 mutation and increased risk of Wilms tumor
Sporadic: 90% of WT is non-familial, and only 10% of them have this mutation
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Term
DNA repair defects or apoptosis gene defects |
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Definition
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Term
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Definition
DNA mismatch repair
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Familial: Autosomal dominant, Non-poyposis colon cancer, small intestine, endometrium, ovary
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Term
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Definition
Inability to excise and repair thymidine dimers
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Autosomal recessive, prone to multiple cancers but especially related to sunlight or radiation
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Term
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Definition
- DNA repair
- mechanism unknown
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Term
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Definition
Overexpression of gene product prevents normal progression to apoptosis by blocking cytochrome C release from mitochondria
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Follicular lymphoma (a type of Non-Hodgkins lymphoma)
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Term
Bruton’s (X-linked) agammaglobulinemia |
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Definition
- X-linked recessive, chromosome 21 (like Down Syndrome!) Bruton’s tyrosine kinase is enzyme responsible for signaling for pre-B cell to make switch to light chains and display mature complete immunoglobulin on surface
- Manifests at 6 mo when maternal Ab’s depleted with encapsulated infections due to inability to opsonize—S. aureus, S. pneumo, H. flu.
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1. CD19+ but no Ig detectedà DECREASE IN MATURE B CELLS
2. All Ig subclasses deficient
3. Non-responder to vaccines
4. Underdeveloped germinal centers on LN bx
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Term
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Definition
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MC primary immunodeficiency 1/600 whites
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1. Asymptomatic to recurrent sinopulmonary and GI infections
2. Test Q: recurrent acute transfusion reactions with no evidence for ABO mismatch (contains IgA which is a foreign molecule to these ppl)
3. Autoimmune DZ more common
- IgA only deficient on quantitiative immunoglobulin screen
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Term
Common Variable Immunodeficiency |
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Definition
- ? cause, heterogeneous group of disorders with likely many diff causes, high deg of association with IgA deficiency. Normal numbers of B cells, (proliferate in response to antigen) but unable to make Ig’s
Later onset than Bruton’sàchildhood to adolescence. Recurrent sinopulmonary, giardiasis, severe enteroviral DZ, recurrent herpetic infections
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1. Normal numbers of B cells but
2. All Ig’s decreased
3. Discriminate from Bruton’s because: can happen in females, germinal follicles hyperplastic instead of underdeveloped
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Term
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Definition
Defect in CD40 on B cell or CD40 ligand on T cellsàsignal required for switching from IgM to other subclasses after antigen stimulation. Normal levels of B cells.
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1. Recurrent pyogenic infections, pneumocystis infection (T cells lise CD40 stimulation so partial T cell defect as well)
2. Complement-mediated Type II hypersensitivity reaction-->IgM binds antigens on 2 adjacent RBC’s, WBC’s or Platelet and fixes complement-->AIHA, autoimmune neutropenia, or thrombocytopenia
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1. Increased IgM
2. Decreased IgG,
IgE,
IgA
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Term
Primary Immunodeficiency Syndromes |
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Definition
T cell disorders, combined disorders, complement disorders |
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Term
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Definition
Failure of 3rd and 4th pharyngeal pouch development, also called CATCH-22 syndrome (22q11 deletion syndrome)
4th pouch à thymus and parathyroid, so manifests as immunodeficiency and/or hypoparathyroidism
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Recurrent, T-cell dependent early infections (thrush, diaper candida very soon after birth,) poor weight gain, dev delay, irritability, seizures or tetany due to hypocalcemia
Characteristic facies with low-set ears, micrognathia
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Absent thymus /thymic shadow on chest Xray (normally huge thymus in newborn) and parathyroids and radionuclide imaging, decreased paracortical areas of LN’s
Decreased Ca2+, Increased PO4-
Ig levels typically normal
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Term
Severe Combined Immunodeficiency Syndrome (SCID) |
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Definition
Heterogeneous group of diseases—refers to defects in both B and T cell function
X-linked form—defect in Yc subunit of cytokines, T cell progenitors can’t bind to IL-7
Autosomal recessive form—adenosine deaminase deficiency-->allows buildup of deoxyATP which kills pre-Tcells
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Present with candidiasis and severe invasive infections within the days after birth, all infections increased, prognosis fatal without BMT
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Decreased to absent T cells, B cells present but decreased Ig’s since no T cells to signal switching with CD40L
In both forms of SCID the thymus is usually absent
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Term
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Definition
X-linked recessive defect in protein linking antigen receptors to cytoskeleton and cytoskeletal signaling.
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Eczema, thrombocytopenia with bruising and petechiae, and recurrent infections leading to early death, associated with on-hodgkin B-cell lymphomas
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Involution of thymus and poor immunoglobulin response to vaccines and infections
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Term
Terminal complement deficiency
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Definition
C5-C9 deficiency, can’t form membrane attack complex
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Recurrent Neisseria infections (thin cell wall)
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Term
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Definition
MC complement deficiency
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Asymptomatic to increased incidence of SLE-type autoimmune disease (6% of SLE pts have this)
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Shunts towards alternative complement path, elevated C4, (not used up) decreased C3-->in typical SLE, both C3 and C4 used up
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Term
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Definition
C3 required for alternative and classic pathway
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Recurrent serious pyogenic infections, increased rates of immune-complex–mediated glomerulonephritis
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Increased C4, decreased C4
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Term
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Definition
Autosomal dominant, commonly familial and more common than any complement deficiency
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Life-threatening angioedema of mouth or nausea/vomiting/diarrhea from bowel edema, often after emotional upset
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Tx as anaphylaxis with epi and antihistamines, and with pooled C1 inh from donor plasma
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Term
Primary Immunodeficiencies |
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Definition
Phagocytic/Granulocytic Problems |
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Term
Leukocyte Adhesion Def-affects neutrophils |
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Definition
LAD type 1-->deficiency of B2 integrins (can’t adhere)
LAD type 2-->deficiency of selectins (can’t roll)
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Delayed separation of umbilical cord, poor wound healing, gingivitis
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Term
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Definition
Autosomal recessive, failure to form phagolysosomes (fuse phagosome to lysosome)
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Recurrent pyogenic infections,/unresolved abscesses, associated with albinism
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Neutrophils with GIANT granules
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Term
Chronic Granulomatous Disease |
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Definition
X-linked recessive OR autosomal recessive
Deficiency of NADPH oxidase, unable to generate O2 free radical ssps.
Catalase + organisms a problem because break down H2O2 naturally produced by bacteria so none to scavenge and make up for enzyme deficiency
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Susceptibility to S. aureus and some other catalase positive organisms
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1. NBT test-->nitroblue tetrazolium test, turns blue when in the presence of superoxide free radicals, fails to turn blue in this disease
2. DHT test (dihydrorhodamine) preferred test, will fail to fluoresce in this disease
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Term
Vitamin B1 (thiamine Def) |
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Definition
Chronic alcoholism, severe chronic malnutrition, diet of white rice
Found in: protein-rich foods and whole grains
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Carbohydrate metabolism and ATP synthesis:
Pentose phosphate pathway (synthesizes ribose for DNA and increases NADPH for fat metabolism)
TCA cycle:
Pyruvateàacetyl CoA
Α-ketoglutarateàsuccinyl CoA
metabolism of branched-chain AA’s (leucine, isoleucine, valine)
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Chronic deficiency:
-Muscle cramps, paresthesias, irritability, lactic acidosis
-Wet beriberi (neuropathy, high output heart failure/cardiomyopathy, peripheral edema)
-Dry beriberi (motor and sensory neuropathy)
Precipitated by giving glucose to starved patient with thiamine deficiency: (give thiamine before glucose always!)
-Wernicke encephalopathy (opthalmoplegia, truncal ataxia, confusion, mammillary body hemorrhage)
-Korsakoff syndrome (impaired short-term memory, confabulation)
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Term
Vitamin B2 (riboflavin) def |
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Definition
Found in: dairy products, nuts, green&leafys
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-Precursor to coenzymes that can accept or donate hydrogen atoms during amino acid oxidation, fatty acid oxidation, and TCA cycle.
-preserves RBC integrity
-converts tryptophan to niacin
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Deficiency rare and caused by severe malnourishment
-glossitis, cheilosis, angular stomatitis, corneal vascularization, seborrheic dermatitis, hemolytic anemia
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Term
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Definition
Risk factors: isoniazid use, malignant carcinoid syndrome (uses up trp), Hartnup syndrome (can’t absorb trp)
Found in: liver, dairy, whole grains (as tryptophan that body converts to niacin via B2)
Used as tx to increase HDL and descrease total and LDL cholesterol, side fx: flushing, itching, hives, nausea—prevent with premedication with aspirin
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-created by adding 3 ATP’s to tryptophan, coenzyme in oxidation and reduction reactions
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-diarrhea, dermatitis (hyperpigmented, cracked, scaly skin), dementia
-if seen in a child who is fed normally suspect Hartnup’s!
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Term
Vitamin B6 (pyridoxine def) |
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Definition
Risk factors: OCP’s, Isoniazid, cyclosporine, penicillamine
Found in: wheat, eggs, meats
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-amino acid metabolism (serineàglycine)
-transamination, deamination, decarboxylation, creation of liver enzymes AST and ALT
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Deficiency (rare):
-seizures and irritability
Excess:
-irreversible sensory neuropathy
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Term
Vitamin B12 (cyanocobalamin) def |
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Definition
Risk factors: dietary deficiency rare cause as substantial stores in liver (must be deficient for a long time to develop sx’s, most likely in vegans), pernicious anemia, gastrectomy, H. pylori, Diphyllobothrium latum, resection/abnormalities of terminal ileum (crohns), pancreatic insufficiency
Found in: animal products
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R protein and intrinsic factor secreted in gastric fundus required for absorption in distal ileum.
Cofactor in multiple reactions, particularly purine synthesis and active form of folate:
Methylmalonyl-CoA mutase
Leucine aminomutase, methionine synthase
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-neuropathy distinguishes b12 def from folate def:
-subacute combined demyelinating degeneration of posterior/lateral spinal columns (symmetric paresthesias, ataxia, loss of proprioception/vibration, spasticity, clonus, incontinence)
-megaloblastic anemia with hypersegmented neutrophils—gets better with folate but neuropathy progresses
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Term
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Definition
Risk factors: alcoholics, avoidance of raw foods, malabsorption affecting jejunum (sprue, biliary tract disease/obstruction), trimethoprim/SMZ, methotrexate (inhibit DHFR), phenytoin (inhib absorp), pregnancy or hemolytic anemia (increased demand)
Found in: fruits and vegetables but destroyed by cooking
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Required for erythropoiesis and one-carbon transfers:
Homocysteine(+b12)àmethionine
Serine(+b6)àglycine
Thymidylate synthesis for DNA
Purine ring formation
Folate enterohepatic cycle:
Dihydrofolate reductase (DHFR) allows folate to be absorbed in jejunum, travels to liver, secreted back into bile, re-absorbed
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-megaloblastic anemia NO NEURO Sx’s
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Term
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Definition
Found in: nuts and synthesized by gut flora
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Carries carboxylate for carb and lipid metabolism
TCA cycle: Pyruvateàoxaloacetate,
FA synth:
proprionyl CoAàmethylmalonyl CoA
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-dermatitis, alopecia, lactic acidosis
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Term
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Definition
Water soluble vitamin, deficiency can develop in weeks
Found in: citrus fruits
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Taken up in ileum, Vit C increases iron absorption
Reducing agent for:
-Copper and iron-containing enzymes, including dopa-β-hydroxylase which makes eri and norei from tyrosine
-Hydroxylation of proline/lysine in collagen to allow cross-linking
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Scurvy: swollen/bleeding gums and mucosal surfaces, bruising, petechiae, anemia, poor wound healing
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Term
Vitamin A (retinoic Acid) def |
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Definition
Found in: fish oil, meat, dairy, eggs
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-Absorbed intestinally via chylomicrons, delivered via binding proteins
-Forms rhodopsin in rod cells of retina and idopsin in cone cells
-Supports mucosal endothelium differentiation throughout body
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Deficiency: night blindness, xeropthalmia, Bitot’s spots (squamous metaplasia of corneal epithelium),keratomalacia (corneal softening), respiratory epithelial metaplasia
Excess: teratogenicity, nausea, blurry vision, vertigo, alopecia, hepatotoxicity, papilledema
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Term
Vitamin D (cholecaliferol) def |
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Definition
Risk factors: exclusive breasfeeding (for infant), lack of sun exposure
Found in: dairy, skin exposure to sun
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-Absorption regulated by serum calcium.
Vit D activation:
-UV light converts 7-dehydrocholesterol to previtamin D, which then àcholecalciferol.
-Liver adds –OHà25-OH vit D,
-Kidney (stim by PTH, inhib by increased PO4) adds another –OH via 1-α-hydroxylase enzyme à1,25-OH vit D=calcitriol=active metabolite
Vit D:
-is a steroid hormone (binds nuclear receptors to induce gene expression)
-increases intestinal Ca absorp
-decreases renal Ca excretion (distal tubule)
-increases bone resorption of Ca
-increases mineralization of bone
-increases PTH synthesis
-eventual feedback to decrease further calcitriol and PTH production
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Deficiency:
-Rickets (kids)—phos takes place of calcium in bone with open epiphyses. Bowing of long bones, hyocalcemia, poor dentition
-due to true deficiency
-due to genetic defect (Vit D resistant rickets) in 1-α-hydroxylase enzyme (can tx with calcitriol)
-or in 1,25-OH receptor (won’t respond to calcitriol)
-or to renal phosphate wasting (1,25-OH levels will be elevated)
Excess:
-all s/sx of hypercalcemia (renal stones, delirium, constipation, depression, polyuria)
-Seen in sarcoidosis and some lymphomas
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Term
Vitamin E (alpha-tacopherol) |
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Definition
Risk factors: any fat malabsorption DZ (sprue, CF, liver DZ)
Found in: multiple sources
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Component of cell membranes and antioxidant to scavenge free radicals. Absorption same as vit A.
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Deficiency: hemolytic anemia (oxidative damage), peripheral neuropathy, opthalmoplegia
Excess: interferes with Vit K
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Term
Vitamin K (phylloguinn one) def |
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Definition
Found in: multiple sources and made by gut bacteria
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Oxidized in liver microsomes by γ-glutamyl carboxylase for post-synthetic modification of clotting factors (prothrombin, factors 7, 9, 10) necessary for function. Warfarin blocks enzyme 2,3 epoxide reductase that recycles vit K so it can be re-used, causing vit K epoxide to be excreted.
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Deficiency in adults is rare and will look like warfarin toxicity with major bleeding. Hemorrhagic disease of newborn=vit K deficiency and prevented with vit K injections at birth.
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Term
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Definition
- Insufficient protein intake, but adequate Carbohydrate protein intake
- Pitting edema and ascites
- Protuberant belly), hyboalbuinemia and hypoproteinemia, fatty liver due to decreased apoliporoteins, diarrhea, failure of cell-mediated immunity
- [image]
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Term
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Definition
- Def. of both protein and calories
- Extreme muscle wasting, loss of all subQ fat, growth and mental retardation[image]
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