Pathology (environmental 5)
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What are the types of vitamin A?
- Vitamin A is the name given to a group of related compounds that include retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinoic acid (vitamin A acid), which have similar biologic activities.
- Retinol is the chemical name given to vitamin A. It is the transport form and, as retinol ester, also the storage form.
.............is the transport form and the storage form of vitamin A
What are the sources of vitamin A?
- Animal-derived foods such as liver, fish, eggs, milk, and butter are important dietary sources of preformed vitamin A.
- Yellow and leafy green vegetables such as carrots, squash, and spinach supply large amounts of carotenoids, which are provitamins that can be metabolized to active vitamin A in the body.
- Carotenoids contribute approximately 30% of the vitamin A in human diets; the most important of these is β-carotene, which is efficiently converted to vitamin A.
What are the steps in vitamin A metabolism?
- Vitamin A is a fat-soluble vitamin, and its absorption requires bile, pancreatic enzymes, and some level of antioxidant activity in the food.
- Retinol (generally ingested as retinol ester) and β-carotene are absorbed in the intestine, where β-carotene is converted to retinol.
- Retinol is then transported in chylomicrons (as ester) to the liver for esterification and storage. Uptake in liver cells takes place through the apolipoprotein E receptor.
- More than 90% of the body's vitamin A reserves are stored in the liver, predominantly in the perisinusoidal stellate (Ito) cells.
- In healthy persons who consume an adequate diet, these reserves are sufficient to meet the body's demands for at least 6 months.
- Retinol esters stored in the liver can be mobilized; before release, retinol binds to a specific retinol-binding protein (RBP), synthesized in the liver.
- The uptake of retinol/RBP in peripheral tissues is dependent on cell surface receptors specific for RBP.
- After uptake, retinol binds to a cellular RBP, and the RBP is released back into the blood. Retinol may be stored in peripheral tissues as retinol ester or be oxidized to form retinoic acid.
- Retinoic acid has important effects in epithelial differentiation and growth
..........., derived from oxidation of dietary retinol mediates most of the actions of the retinoids, except for vision, which depends on ...........
Retinoic acid/ retinal
Which type of vitamin A cannot give rise to other types?
What are the main functions of vitamin A in human?
- Maintenance of normal vision
- Cell growth and differentiation
- Metabolic effects of retinoids
- Host resistance to infections
How is vitamin A involved in maintenance of normal vision?
- The visual process involves four forms of vitamin A–containing pigments: rhodopsin in the rods, the most light-sensitive pigment and therefore important in reduced light, and three iodopsins in cone cells, each responsive to specific colors in bright light.
- The synthesis of rhodopsin from retinol involves (1) oxidation to all-trans-retinal, (2) isomerization to 11-cis-retinal, and (3) covalent association with the 7-transmembrane rod protein opsin to form rhodopsin.
- A photon of light causes the isomerization of 11-cis-retinal to all-trans-retinal, which dissociates from rhodopsin.
- This induces a conformational change in opsin that triggers a series of downstream events and generates a nerve impulse, which is transmitted via neurons from the retina to the brain.
- During dark adaptation, some of the all-trans-retinal is reconverted to 11 cis-retinal, but most is reduced to retinol and lost to the retina, dictating the need for continuous supply
How is vitamin A involved in Cell growth and differentiation?
- Vitamin A and retinoids play an important role in the orderly differentiation of mucus-secreting epithelium; when a deficiency state exists, the epithelium undergoes squamous metaplasia, differentiating into a keratinizing epithelium.
- Activation of retinoic acid receptors (RARs) by their ligands causes the release of corepressors and the obligatory formation of heterodimers with another retinoid receptor, known as the retinoic X receptor (RXR).
- Both RAR and RXR have three isoforms, α, β, and γ. The RAR/RXR heterodimers bind to retinoic acid response elements located in the promoter region of genes that encode receptors for growth factors, tumor suppressor genes, and secreted proteins.
- Through these effects, retinoids participate in cell growth and differentiation, cell cycle control, and other biologic responses.
- All-trans-retinoic acid, a potent acid derivative of vitamin A, has the highest affinity for RARs compared with other retinoids
...................... has the highest affinity for RARs compared with other retinoids
What are the metabolic effects of retinoids?
- The retinoic X receptor (RXR), believed to be activated by 9-cis retinoic acid, can form heterodimers with other nuclear receptors, such as nuclear receptors involved in drug metabolism, PPARs, and vitamin D receptors.
- PPARs are key regulators of fatty acid metabolism, including fatty acid oxidation in fat tissue and muscle, adipogenesis, and lipoprotein metabolism.
- The association between RXR and PPARγ provides an explanation for the metabolic effects of retinoids on adipogenesis and obesity
Retinoic acid does not affect which functions of vitamin A?
How can vitamin A cause Host resistance to infections?
- Vitamin A supplementation can reduce morbidity and mortality from some forms of diarrhea, and in preschool children with measles, supplementation can quickly improve the clinical outcome.
- The beneficial effect of vitamin A in diarrheal diseases may be related to the maintenance and restoration of the integrity of the epithelium of the gut.
- The effects of vitamin A on infections also derive in part from its ability to stimulate the immune system.
- Infections may reduce the bioavailability of vitamin A by inhibiting RBP synthesis in the liver through the acute-phase response associated with many infections. The drop in hepatic RBP causes a decrease in circulating retinol, which reduces the tissue availability of vitamin A
retinoids, β-carotene, and some related carotenoids can function as ..........................
photoprotective and antioxidant agents
What are the clinical uses of vitamin A?
- Retinoids are used clinically for the treatment of skin disorders such as severe acne and certain forms of psoriasis, and also in the treatment of acute promyelocytic leukemia.
- A different isomer, 13-cis retinoic acid, has been used with some success in the treatment of neuroblastomas in children
What is the basis for vitamin A use in APL?
- In this leukemia, a (15 : 17) translocation results in the fusion of a truncated RARα gene on chromosome 17 with the PML gene on chromosome 15.
- The fusion gene encodes an abnormal RAR that blocks myeloid cell differentiation.
- Pharmacologic doses of all-trans retinoic acid overcome the block, causing leukemia cells to differentiate into neutrophils, which subsequently die by apoptosis.
- This “differentiation therapy” induces remission in most individuals with acute promyelocytic leukemia and in combination with other chemotherapeutic agents can be curative
What are the RF for vitamin A deficiency?
- General undernutrition
- Malabsorption of fats.
- In children, stores of vitamin A are depleted by infections, and the absorption of the vitamin is poor in newborn infants.
- Adult with celiac disease, Crohn's disease, and colitis.
- Bariatric surgery
- Elderly (using mineral oil as a laxative )
What are the symptoms of vitamin A deficiency?
- One of the earliest manifestations of vitamin A deficiency is impaired vision, particularly night blindness.
- Persistent deficiency gives rise to a series of changes involving epithelial metaplasia and keratinization. The most devastating changes occur in the eyes and are referred to as xerophthalmia(dry eye). First, there is dryness of the conjunctiva (xerosis conjunctivae) as the normal lacrimal and mucus-secreting epithelium is replaced by keratinized epithelium. This is followed by buildup of keratin debris in small opaque plaques (Bitot spots) and, eventually, erosion of the roughened corneal surface with softening and destruction of the cornea(keratomalacia) and total blindness
- The epithelium lining the upper respiratory passage and urinary tract is replaced by keratinizing squamous cells (squamous metaplasia).
- Loss of the mucociliary epithelium of the airways predisposes to secondary pulmonary infections, and desquamation of keratin debris in the urinary tract predisposes to renal and urinary bladder stones.
- Hyperplasia and hyperkeratinization of the epidermis with plugging of the ducts of the adnexal glands may produce follicular or papular dermatosis.
- Another very serious consequence is immune deficiency, which is responsible for higher mortality rates from common infections such as measles, pneumonia, and infectious diarrhea.
What are the toxic effects of vitamin A?
- The symptoms of acute vitamin A toxicity include headache, dizziness, vomiting, stupor, and blurred vision, symptoms that may be confused with those of a brain tumor (pseudotumor cerebri).
- Chronic toxicity is associated with weight loss, anorexia, nausea, vomiting, and bone and joint pain.
- Retinoic acid stimulates osteoclast production and activity, which lead to increased bone resorption and high risk of fractures.
- Synthetic retinoids has teratogenic effects. Also can cause increase in the LDL/HDL ratio
- Also --> enlarged liver and dry skin
What are the general features of vitamin C?
- A deficiency of water-soluble vitamin C leads to the development of scurvy, characterized principally by bone disease in growing children and by hemorrhages and healing defects in both children and adults.
- Ascorbic acid is not synthesized endogenously in humans; therefore, we are entirely dependent on the diet for this nutrient.
- Vitamin C is present in milk and some animal products (liver, fish) and is abundant in a variety of fruits and vegetables.
What are the functions of vitamin C?
- Accelerating hydroxylation and amidation reactions.
- Activation of prolyl and lysyl hydroxylases from inactive precursors, providing for hydroxylation of procollagen. Inadequately hydroxylated procollagen cannot acquire a stable helical configuration or be adequately cross-linked, so it is poorly secreted from the fibroblast.
- Those molecules that are secreted lack tensile strength and are more soluble and vulnerable to enzymatic degradation.
- Collagen, which normally has the highest content, of hydroxyproline, of any polypeptide is most affected, particularly in blood vessels, accounting for the predisposition to hemorrhages in scurvy.
- A deficiency of vitamin C suppresses the rate of synthesis of procollagen, independent of an effect on proline hydroxylation
- Vitamin C can scavenge free radicals directly and can act indirectly by regenerating the antioxidant form of vitamin E.
- Enhance iron absorption
Who are at increased risk for vitamin C deficiency?
- Elderly individuals, persons who live alone, and chronic alcoholics
- Peritoneal dialysis and hemodialysis and among food faddists.
- Infants who are maintained on formulas of evaporated milk without supplementation of vitamin C.
What are the symptoms of vitamin C deficiency?
What is the main function of folic acid?
Tetrahydrofolate receives one-carbon fragments from donors such as serine, glycine, and histidine and transfers them to intermediates in the synthesis of amino acids, purines, and thymidine monophosphate (TMP)—a pyrimidine found in DNA
What is the function of vitamin B12?
- Vitamin B12 is required in humans for two essential enzymatic reactions: the remethylation of homocysteine to methionine and the isomerization of methylmalonyl coenzyme A (CoA) that is produced during the degradation of some amino acids, and fatty acids with odd numbers of carbon atoms.
- When the vitamin is deficient, abnormal fatty acids accumulate and become incorporated into cell membranes, including those of the nervous system.
What is the folate trap hypothesis?
- The effects of cobalamin deficiency are most pronounced in rapidly dividing cells, such as the erythropoietic tissue of bone marrow and the mucosal cells of the intestine. Such tissues need both the N5-N10-methylene and N10-formyl forms of tetrahydrofolate for the synthesis of nucleotides required for DNA replication.
- However, in vitamin B12 deficiency, the utilization of the N5-methyl form of tetrahydrofolate is impaired. Because the methylated form cannot be converted directly to other forms of tetrahydrofolate, folate is trapped in the N5-methyl form, which accumulates.
- The levels of the other forms decrease. Thus, cobalamin deficiency is hypothesized to lead to a deficiency of the tetrahydrofolate forms needed in purine and TMP synthesis, resulting in the symptoms of megaloblastic anemia.
What is the function of B6?
- Pyridoxine occurs primarily in plants, whereas pyridoxal and pyridoxamine are found in foods obtained from animals.
- All three compounds can serve as precursors of the biologically active coenzyme, pyridoxal phosphate. Pyridoxal phosphate functions as a coenzyme for a large number of enzymes, particularly those that catalyze reactions involving amino acids
- Used in glycogenolysis as a cofactor for glycogen phosphorylase and as a co-factor for the synthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).
- Transamination: Oxaloacetate + glutamate ⇔ aspartate + α-ketoglutarate
- Deamination: Serine → pyruvate + NH3
- Decarboxylation: Histidine → histamine + CO2
- Condensation: Glycine + succinyl CoA → δ-aminolevulinic acid
Deficiency of B6 may result in.............
Seizure due to reduced GABA synthesis
How can B6 deficiency be diagnosed?
Erythrocyte transaminase activity with and without PLP
What is the function of B1?
- Thiamine pyrophosphate is the biologically active form of the vitamin, formed by the transfer of a pyrophosphate group from adenosine triphosphate (ATP) to thiamine.
- Thiamine pyrophosphate serves as a coenzyme in the formation or degradation of α-ketols by transketolase, and in the oxidative decarboxylation of α-keto acids
- TPP is necessary as a cofactor for the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase catalyzed reactions associated with the TCA cycle, as well as the transketolase catalyzed reactions of the pentose phosphate pathway.
- A deficiency in thiamin intake leads to a severely reduced capacity of cells to generate energy as a result of its role in these reactions
Tryptophan can give rise to...........
Which vitamin deficiency can be caused by phototherapy?
Riboflavin decomposes when exposed to visible light. This characteristic can lead to riboflavin deficiencies in newborns treated for hyperbilirubinemia by phototherapy
NAD+ and NADP+ function as cofactors for numerous ................
Dehydrogenases , e.g., lactate dehydrogenase and malate dehydrogenase.
Hartnup disorder and malignant carcinoid syndrome can cause............deficiency
Which derivative of niacin is used for treatment of hyperlipidemia?
- Niacin = nicotinic acid (at doses of 1.5 g/day or 100 times the or RDA) strongly inhibits lipolysis in adipose tissue—the primary producer of circulating free fatty acids.
- The liver normally uses these circulating fatty acids as a major precursor for triacylglycerol synthesis. Thus, niacin causes a decrease in liver triacylglycerol synthesis, which is required for VLDL production.
- LDL is derived from VLDL in the plasma. Thus, both plasma triacylglycerol (in VLDL) and cholesterol (in VLDL and LDL) are lowered.
- Therefore, niacin is particularly useful in the treatment of Type IIb hyperlipoproteinemia, in which both VLDL and LDL are elevated
What is the major mechanism of niacin anti-hyperlipidemic action?
Inhibition of lipolysis in adipose tissue
What are the major side effects of niacin therapy?
What are the symptoms of B2 deficiency?
itching and burning eyes, angular stomatitis and cheilosis, bloodshot eyes, glossitis, seborrhea and photophobia
How can raw egg cause biotin deficiency?
Raw egg white contains a glycoprotein, avidin, which tightly binds biotin and prevents its absorption from the intestine
What is the function of biotin?
- Cofactor for Acetyl-CoA carboxylase (ACC)/ Pyruvate carboxylase (PC)/ Propionyl CoA carboxylase (PCC)
- CO2 carrier on the surface of each enzyme
What is multiple carboxylase deficiency?
- Multiple carboxylase deficiency (MCD) refers to one of two inherited defects of biotin metabolism.
- The infantile form is caused by a deficiency of holocarboxylase synthetase (HCS) and presents in the first week of life with lethargy, poor muscle tone, and vomiting.
- A later-onset form is caused by biotinidase deficiency and is associated with a slow but progressive loss of biotin in the urine, leading to organic aciduria; it is characterized by ataxia, ketoacidosis, dermatitis, seizures, myoclonus, and nystagmus.
- Treat with biotin
What is the normal steps in folate synthesis and action??
- Folic acid itself is then generated through the conjugation of glutamic acid residues to pteroic acid.
- Folic acid is obtained primarily from yeasts and leafy vegetables as well as animal liver. Animal cannot synthesize PABA nor attach glutamate residues to pteroic acid, thus, requiring folate intake in the diet.
- When stored in the liver or ingested folic acid exists in a polyglutamate form.
- Intestinal mucosal cells remove some of the glutamate residues through the action of the lysosomal enzyme, conjugase.
- The removal of glutamate residues makes folate less negatively charged (from the polyglutamic acids) and therefore more capable of passing through the basal lamina membrane of the epithelial cells of the intestine and into the bloodstream.
- Folic acid is reduced within cells (principally the liver where it is stored) to tetrahydrofolate (THF also H4folate) through the action of dihydrofolate reductase (DHFR), an NADPH-requiring enzyme.
- These one carbon transfer reactions are required in the biosynthesis of serine, methionine, glycine, choline and the purine nucleotides and dTMP.
- The ability to acquire choline and amino acids from the diet and to salvage the purine nucleotides makes the role of N5,N10-methylene-THF in dTMP synthesis the most metabolically significant function for this vitamin.
- The role of vitamin B12 and N5-methyl-THF in the conversion of homocysteine to methionine also can have a significant impact on the ability of cells to regenerate needed THF
What is the function of pantothenic acid?
Pantothenate is required for synthesis of coenzyme A, CoA and is a component of the acyl carrier protein (ACP) domain of fatty acid synthase
vitamin B12 and folic acid are coenzymes required for the synthesis of ..........., one of the four bases found in DNA
What are the mechanisms of folic acid deficiency?
- Decreased Intake: Inadequate diet, alcoholism, infancy
- Impaired Absorption: Malabsorption states, Intrinsic intestinal disease, Anticonvulsants, oral contraceptives
- Increased Loss: Hemodialysis
- Increased Requirement: Pregnancy, infancy, disseminated cancer, markedly increased hematopoiesis
- Impaired Utilization: Folic acid antagonists
What is the mechanism of B12 deficiency?
- Decreased Intake: Inadequate diet, vegetarianism
- Impaired Absorption: 1) Intrinsic factor deficiency (Pernicious anemia, Gastrectomy) 2) Malabsorption states (Diffuse intestinal disease (e.g., lymphoma, systemic sclerosis), Ileal resection, ileitis) 3) Competitive parasitic uptake (Fish tapeworm infestation 4) Bacterial overgrowth in blind loops and diverticula of bowel)
What are the morphological features of peripheral blood in megaloblastic anemia?
- The presence of red cells that are macrocytic and oval (macro-ovalocytes) is highly characteristic.
- Because they are larger than normal and contain ample hemoglobin, most macrocytes lack the central pallor of normal red cells and even appear “hyperchromic,” but the MCHC is not elevated. There is marked variation in the size (anisocytosis) and shape (poikilocytosis) of red cells.
- The reticulocyte count is low.
- Nucleated red cell progenitors occasionally appear in the circulating blood when anemia is severe.
- Neutrophils are also larger than normal (macropolymorphonuclear) and hypersegmented, having five or more nuclear lobules instead of the normal three to four
What are the morphological features of BM in megaloblastic anemia?
- The marrow is usually markedly hypercellular as a result of increased hematopoietic precursors, which often completely replace the fatty marrow.
- Megaloblastic changes are detected at all stages of erythroid development.
- The most primitive cells (promegaloblasts) are large, with a deeply basophilic cytoplasm, prominent nucleoli, and a distinctive, fine nuclear chromatin pattern.
- As these cells differentiate and begin to accumulate hemoglobin, the nucleus retains its finely distributed chromatin and fails to develop the clumped pyknotic chromatin typical of normoblasts
- While nuclear maturation is delayed, cytoplasmic maturation and hemoglobin accumulation proceed at a normal pace, leading to nuclear-to-cytoplasmic asynchrony.
- Because DNA synthesis is impaired in all proliferating cells, granulocytic precursors also display dysmaturation in the form of giant metamyelocytes and band forms. Megakaryocytes, too, can be abnormally large and have bizarre, multilobate nucleiThe marrow hyperplasia is a response to increased levels of growth factors, such as erythropoietin.
- However, the derangement in DNA synthesis causes most precursors to undergo apoptosis in the marrow (an example of ineffective hematopoiesis) and leads to pancytopenia
Megaloblastic anemia (bone marrow aspirate). A to C, Megaloblasts in various stages of differentiation. Note that the orthochromatic megaloblast (B) is hemoglobinized (as revealed by cytoplasmic color), but in contrast to normal orthochromatic normoblasts, the nucleus is not pyknotic. The early erythroid precursors (A,C) and the granulocytic precursors are also large and have abnormally immature chromatin
What is the major mechanism of pancytopenia in megaloblastic anemia?
What are the normal metabolic processes of vitamin B12?
- Vitamin B12 is a complex organometallic compound known as cobalamin.
- Under normal circumstances humans are totally dependent on dietary vitamin B12.
- Microorganisms are the ultimate origin of cobalamin in the food chain.
- Plants and vegetables contain little cobalamin, save that contributed by microbial contamination, and strictly vegetarian or macrobiotic diets do not provide adequate amounts of this essential nutrient.
- Absorption of vitamin B12 requires intrinsic factor, which is secreted by the parietal cells of the fundic mucosa.
- Vitamin B12 is freed from binding proteins in food through the action of pepsin in the stomach and binds to salivary proteins called cobalophilins, or R-binders.
- In the duodenum, bound vitamin B12 is released by the action of pancreatic proteases. It then associates with intrinsic factor.
- This complex is transported to the ileum, where it is endocytosed by ileal enterocytes that express intrinsic factor receptors on their surfaces.
- Within ileal cells, vitamin B12 associates with a major carrier protein, transcobalamin II, and is secreted into the plasma.
- Transcobalamin II delivers vitamin B12 to the liver and other cells of the body, including rapidly proliferating cells in the bone marrow and the gastrointestinal tract.
- There is also a poorly understood alternative uptake mechanism that is not dependent on intrinsic factor or an intact terminal ileum. Up to 1% of a large oral dose can be absorbed by this pathway, making it feasible to treat pernicious anemia with high doses of oral vitamin B12
What is the function of B12 in RBC synthesis?
- Only two reactions in humans are known to require vitamin B12.
- In one, methylcobalamin serves as an essential cofactor in the conversion of homocysteine to methionine by methionine synthase. In the process, methylcobalamin yields a methyl group that is recovered from N5-methyltetrahydrofolic acid (N5-methyl FH4), the principal form of folic acid in plasma. In the same reaction, N5-methyl FH4 is converted to tetrahydrofolic acid (FH4). FH4 is crucial, since it is required (through its derivative N5,10-methylene FH4) for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), an immediate precursor of DNA
- It is postulated that the fundamental cause of the impaired DNA synthesis in vitamin B12 deficiency is the reduced availability of FH4, most of which is “trapped” as N5-methyl FH4.
- The FH4 deficit may be further exacerbated by an “internal” folate deficiency caused by a failure to synthesize metabolically active polyglutamylated forms. This stems from the requirement for vitamin B12 in the synthesis of methionine, which contributes a carbon group needed in the metabolic reactions that create folate polyglutamates.
- Whatever the mechanism,lack of folate is the proximate cause of anemia in vitamin B12 deficiency, since the anemia improves with administration of folic acid.
......................... is the principal form of folic acid in plasma
N5-methyltetrahydrofolic acid (N5-methyl FH4)
In cobalamin (Cbl) deficiency, folate is sequestered as .............. This ultimately deprives thymidylate synthetase of its folate coenzyme ................., thereby impairing DNA synthesis.
N5-methyl FH4/ (N5,10-methylene FH4)
What is the mechanism of B12 deficiency that lead to neruologic symptoms?
- The other known reaction that depends on vitamin B12 is the isomerization of methylmalonyl coenzyme A to succinyl coenzyme A, which requires adenosylcobalamin as a prosthetic group on the enzyme methylmalonyl–coenzyme A mutase.
- A deficiency of vitamin B12 thus leads to increased plasma and urine levels of methylmalonic acid.
- Interruption of this reaction and the consequent buildup of methylmalonate and propionate (a precursor) could lead to the formation and incorporation of abnormal fatty acids into neuronal lipids.
- It has been suggested that this biochemical abnormality predisposes to myelin breakdown and thereby produces the neurologic complications of vitamin B12 deficiency.
What is the epidemiology of pernicious anemia?
- median age at diagnosis is 60 years
- More in Caucasian
- genetic predisposition
In megaloblastic anemia the reticulocyte count is.............
What is the mechanism of pernicious anemia?
- Pernicious anemia is believed to result from an autoimmune attack on the gastric mucosa.
- Histologically, there is a chronic atrophic gastritis marked by a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells, and megaloblastic changes in mucosal cells similar to those found in erythroid precursors.
- Three types of autoantibodies are present in many, but not all, patients. About 75% of patients have a type I antibody that blocks the binding of vitamin B12 to intrinsic factor. Type I antibodies are found in both plasma and gastric juice.
- Type II antibodies prevent binding of the intrinsic factor–vitamin B12 complex to its ileal receptor. These antibodies are also found in a large proportion of patients with pernicious anemia.
- Type III antibodies, present in 85% to 90% of patients, recognize the α and β subunits of the gastric proton pump, which is normally localized to the microvilli of the canalicular system of the gastric parietal cell.
- Autoantibodies are of diagnostic utility, but they are not thought to be the primary cause of the gastric pathology.
- An autoreactive T-cell response initiates gastric mucosal injury and triggers the formation of autoantibodies, which may exacerbate the epithelial injury.
True or False: AutoAb to proton pump in pernicious anemia are specific
- These antibodies are not specific for pernicious anemia or other autoimmune diseases, since they are found in as many as 50% of elderly persons with idiopathic chronic gastritis not associated with pernicious anemia
Pernicious anemia is a ........medicated disorder
What are the automimmune disorders associated with pernicious anemia?
- autoimmune thyroiditis and adrenalitis
- develop multiple autoimmune disorders, including pernicious anemia, is linked to specific sequence variants of NALP1, an innate immune receptor that maps to chromosome 17p13
What are the other mechanisms of B12 deficiency (other than pernicious anemia)?
- With achlorhydria and loss of pepsin secretion (which occurs in some elderly individuals), vitamin B12 is not readily released from proteins in food.
- With gastrectomy, intrinsic factor is not available for uptake in the ileum.
- With loss of exocrine pancreatic function, vitamin B12 cannot be released from R-binder–vitamin B12 complexes.
- Ileal resection or diffuse ileal disease can remove or damage the site of intrinsic factor–vitamin B12 complex absorption.
- Tapeworms compete with the host for B12 and can induce a deficiency state.
- In some settings, such as pregnancy, hyperthyroidism, disseminated cancer, and chronic infection, an increased demand for vitamin B12 can produce a relative deficiency, even with normal absorption
What is the morphology of GI in pernicious anemia?
- The stomach typically shows diffuse chronic gastritis.
- The most characteristic alteration is atrophy of the fundic glands, affecting both chief cells and parietal cells, the latter being virtually absent.
- The glandular lining epithelium is replaced by mucus-secreting goblet cells that resemble those lining the large intestine, a form of metaplasia referred to as intestinalization.
- Some of the cells as well as their nuclei may increase to double the normal size, a form of “megaloblastic” change exactly analogous to that seen in the marrow.
- With time, the tongue may become shiny, glazed, and “beefy” (atrophic glossitis).
- The gastric atrophy and metaplastic changes are due to autoimmunity and not vitamin B12 deficiency; hence, parenteral administration of vitamin B12 corrects the megaloblastic changes in the marrow and the epithelial cells of the alimentary tract, but gastric atrophy and achlorhydria persist
The most characteristic alteration in stomach of the patients with pernicious anemia is .................................................
atrophy of the fundic glands, affecting both chief cells and parietal cells, the latter being virtually absent
Vitamin B12 supplementation cannot treat .......................in pernicious anemia
gastric atrophy and achlorhydria, and intestinal metaplasia
What is the morphology of CNS change in pernicious anemia?
- Central nervous system lesions are found in about three fourths of all cases of florid pernicious anemia but can also be seen in the absence of overt hematologic findings.
- The principal alterations involve the spinal cord, where there is demyelination of the dorsal and lateral tracts, sometimes followed by loss of axons.
- These changes give rise to spastic paraparesis, sensory ataxia, and severe paresthesias in the lower limbs.
- Less frequently, degenerative changes occur in the ganglia of the posterior roots and in peripheral nerves
What are the symptoms of B12 deficiency?
- Pernicious anemia is insidious in onset, so the anemia is often quite severe by the time the affected person seeks medical attention.
- The course is progressive unless halted by therapy.
- The diagnosis is based on (1) a moderate to severe megaloblastic anemia, (2) leukopenia with hypersegmented granulocytes, (3) low serum vitamin B12, and (4) elevated levels of homocysteine and methylmalonic acid in the serum.
- The diagnosis is confirmed by a striking increase in reticulocytes and an improvement in hematocrit levels beginning about 5 days after parenteral administration of vitamin B12.
- Serum antibodies to intrinsic factor are highly specific for pernicious anemia. Their presence attests to the cause rather than the presence or absence of vitamin B12 deficiency.
What are the risks of pernicious anemia?
- Persons with atrophic and metaplastic changes in the gastric mucosa associated with pernicious anemia are at increased risk of developing gastric carcinoma
- Serum homocysteine levels are raised in individuals with vitamin B12 deficiency. Elevated homocysteine levels are a risk factor for atherosclerosis and thrombosis, and it is suspected that vitamin B12 deficiency may increase the incidence of vascular disease.
- With parenteral or high-dose oral vitamin B12, the anemia can be cured and the peripheral neurologic changes reversed or at least halted in their progression, but the changes in the gastric mucosa and the risk of carcinoma are unaffected.
What is the function of folate?
- A deficiency of folic acid (more properly, pteroylmonoglutamic acid) results in a megaloblastic anemia having the same characteristics as that caused by vitamin B12 deficiency.
- FH4 derivatives act as intermediates in the transfer of one-carbon units such as formyl and methyl groups to various compounds.
- FH4 serves as an acceptor of one-carbon fragments from compounds such as serine and formiminoglutamic acid.
- The FH4 derivatives so generated in turn donate the acquired one-carbon fragments in reactions synthesizing various metabolites.
- The most important metabolic processes depending on such transfers are (1) purine synthesis; (2) the conversion of homocysteine to methionine, a reaction also requiring vitamin B12; and (3) deoxythymidylate monophosphate synthesis.
- In the first two reactions, FH4 is regenerated from its one-carbon carrier derivatives and is available to accept another one-carbon moiety and reenter the donor pool.
- In the synthesis of dTMP, a dihydrofolate is produced that must be reduced by dihydrofolate reductase for reentry into the FH4 pool. The reductase step is significant, since this enzyme is susceptible to inhibition by various drugs.
- Among the molecules whose synthesis is dependent on folates, dTMP is perhaps the most important biologically, since it is required for DNA synthesis.
The three major causes of folic acid deficiency are ....................
- (1) decreased intake,
- (2) increased requirements
- (3) impaired utilization
What is the metabolism of folate?
- Humans are entirely dependent on dietary folic acid.
- The richest sources are green vegetables such as lettuce, spinach, asparagus, and broccoli. Certain fruits (e.g., lemons, bananas, melons) and animal sources (e.g., liver) contain lesser amounts.
- The folic acid in these foods is largely in the form of folylpolyglutamates. Despite their abundance in raw foods, polyglutamates are sensitive to heat; boiling, steaming, or frying of foods for 5 to 10 minutes destroys up to 95% of the folate content.
- Intestinal conjugases split the polyglutamates into monoglutamates that are readily absorbed in the proximal jejunum.
- During intestinal absorption they are modified to 5-methyltetrahydrofolate, the normal transport form of folate.
- The body's reserves of folate are relatively modest, and a deficiency can arise within weeks to months if intake is inadequate.
Folate is absorbed in....................
What are the causes of reduced intake of folic acid?
- Decreased intake can result from either a nutritionally inadequate diet or impairment of intestinal absorption.
- A normal diet contains folate in excess of the minimal daily adult requirement.
- Inadequate dietary intakes are almost invariably associated with grossly deficient diets. Such dietary inadequacies are most frequently encountered in chronic alcoholics, the indigent, and the very elderly.
- In alcoholics with cirrhosis, other mechanisms of folate deficiency such as trapping of folate within the liver, excessive urinary loss, and disordered folate metabolism have also been implicated. Under these circumstances, the megaloblastic anemia is often accompanied by general malnutrition and manifestations of other avitaminoses, including cheilosis, glossitis, and dermatitis.
- Malabsorption syndromes, such as sprue, can lead to inadequate absorption of this nutrient, as can diffuse infiltrative diseases of the small intestine (e.g., lymphoma).
- In addition, certain drugs, particularly the anticonvulsant phenytoin and oral contraceptives, interfere with absorption
What is the mechanism of folate deficiency by anticonvulsants and OCP?
What are the causes of increased requirement for folic acid?
- Conditions in which this is seen include pregnancy, infancy, hematologic derangements associated with hyperactive hematopoiesis (hemolytic anemias), and disseminated cancer.
- In all these circumstances the demands of increased DNA synthesis render normal intake inadequate
What are the causes of impaired folate utilization?
- Folic acid antagonists, such as methotrexate, inhibit dihydrofolate reductase and lead to a deficiency of FH4.
- With inhibition of folate metabolism, all rapidly growing cells are affected, but particularly the cells of the bone marrow and the gastrointestinal tract.
- Many chemotherapeutic drugs used in the treatment of cancer damage DNA or inhibit DNA synthesis through other mechanisms; these can also cause megaloblastic changes in rapidly dividing cells
What are the differences between B12 and B9 deficiency?
- The megaloblastic anemia that results from a deficiency of folic acid is identical to that encountered in vitamin B12 deficiency.
- Thus, the diagnosis of folate deficiency can be made only by demonstration of decreased folate levels in the serum or red cells.
- As in vitamin B12 deficiency, serum homocysteine levels are increased, but methylmalonate concentrations are normal. However, neurologic changes do not occur
.................is the most common nutritional disorder in the world
Deficiency of iron
What are the risk groups for iron deficiency?
toddlers, adolescent girls, and women of childbearing age
Highest iron content is in..............
hemoglobin followed by storage form (hemosiderin, ferritin)
What are some the nutritional regarding iron intake?
- The normal daily Western diet contains about 10 to 20 mg of iron, most in the form of heme contained in animal products, with the remainder being inorganic iron in vegetables.
- About 20% of heme iron (in contrast to 1% to 2% of nonheme iron) is absorbable, so the average Western diet contains sufficient iron to balance fixed daily losses.
- The total body iron content is normally about 2 gm in women and as high as 6 gm in men, and can be divided into functional and storage compartments.
- About 80% of the functional iron is found in hemoglobin; myoglobin and iron-containing enzymes such as catalase and the cytochromes contain the rest. The storage pool represented by hemosiderin and ferritin contains about 15% to 20% of total body iron.
- Healthy young females have smaller stores of iron than do males, primarily because of blood loss during menstruation, and often develop iron deficiency due to excessive losses or increased demands associated with menstruation and pregnancy, respectively
How is iron recycled?
- Iron in the body is recycled extensively between the functional and storage pools
- It is transported in plasma by an iron-binding glycoprotein called transferrin, which is synthesized in the liver.
- In normal individuals, transferrin is about one third saturated with iron, yielding serum iron levels that average 120 μg/dL in men and 100 μg/dL in women.
- The major function of plasma transferrin is to deliver iron to cells, including erythroid precursors, which require iron to synthesize hemoglobin.
- Erythroid precursors possess high-affinity receptors for transferrin, which mediate iron import through receptor-mediated endocytosis.
How is iron stored?
- Free iron is highly toxic, and it is therefore important that storage iron be sequestered.
- This is achieved by binding iron in the storage pool tightly to either ferritin or hemosiderin.
- Ferritin is a ubiquitous protein-iron complex that is found at highest levels in the liver, spleen, bone marrow, and skeletal muscles. In the liver, most ferritin is stored within the parenchymal cells; in other tissues, such as the spleen and the bone marrow, it is found mainly in macrophages.
- Hepatocyte iron is derived from plasma transferrin, whereas storage iron in macrophages is derived from the breakdown of red cells.
- Intracellular ferritin is located in the cytosol and in lysosomes, in which partially degraded protein shells of ferritin aggregate into hemosiderin granules.
- Iron in hemosiderin is chemically reactive and turns blue-black when exposed to potassium ferrocyanide, which is the basis for the Prussian blue stain.
- With normal iron stores, only trace amounts of hemosiderin are found in the body, principally in macrophages in the bone marrow, spleen, and liver.
- In iron-overloaded cells, most iron is stored in hemosiderin
In iron-overloaded cells, most iron is stored in ......................
Hepatocyte iron is derived from plasma ................., whereas storage iron in macrophages is derived from the ......................
transferrin/breakdown of red cells.
................levels correlate well with body iron stores
Ferritin<...... microgram/dl is seen in iron deficiency
Iron balance is maintained largely by regulating ...................................
the absorption of dietary iron in the proximal duodenum
How can the excretion of iron be regulated?
There is no regulated pathway for iron excretion, which is limited to the 1 to 2 mg lost each day through the shedding of mucosal and skin epithelial cells
What is the mechanism of iron absorption?
- Luminal nonheme iron is mostly in the Fe+ (ferric) state and must first be reduced to Fe+ (ferrous) iron by ferrireductases, such as b cytochromes and STEAP3. Fe+ iron is then transported across the apical membrane by divalent metal transporter 1 (DMT1).
- The absorption of nonheme iron is variable and often inefficient, being inhibited by substances in the diet that bind and stabilize Fe+ iron and enhanced by substances that stabilize Fe+ iron.
- Frequently, less than 5% of dietary nonheme iron is absorbed.
- In contrast, about 25% of the heme iron derived from hemoglobin, myoglobin, and other animal proteins is absorbed. Heme iron is moved across the apical membrane into the cytoplasm through transporters that are incompletely characterized. Here, it is metabolized to release Fe+ iron, which enters a common pool with nonheme Fe+ iron
Iron in the enterocyte is in.......form
What happens to iron that has entered enterocyte?
- Iron that enters the duodenal cells can follow one of two pathways: transport to the blood or storage as mucosal iron.
- This distribution is influenced by body iron stores.
- Fe+ iron destined for the circulation, is transported from the cytoplasm across the basolateral enterocyte membrane by ferriportin. This process is coupled to the oxidation of Fe+ iron to Fe+ iron, which is carried out by the iron oxidases hephaestin and ceruloplasmin.
- Newly absorbed Fe+ iron binds rapidly to the plasma protein transferrin, which delivers iron to red cell progenitors in the marrow.
- Both DMT1 and ferriportin are widely distributed in the body and are involved in iron transport in other tissues as well.
- For example, DMT1 also mediates the uptake of “functional” iron (derived from endocytosed transferrin) across lysosomal membranes into the cytosol of red cell precursors in the bone marrow, and ferriportin plays an important role in the release of storage iron from macrophages.
Iron absorption is regulated by ......................................................
hepcidin, a small circulating peptide that is synthesized and released from the liver in response to increases in intrahepatic iron levels
Fe+ iron destined for the circulation, is transported from the cytoplasm across the basolateral enterocyte membrane by .............
oxidation of Fe+ iron to Fe+ iron,is carried out by the iron oxidases ....................
hephaestin and ceruloplasmin
Transferrin transport iron in.......form
What is the function of hepcidin?
- Hepcidin inhibits iron transfer from the enterocyte to plasma by binding to ferriportin and causing it to be endocytosed and degraded.
- As a result, as hepcidin levels rise, iron becomes trapped within duodenal cells in the form of mucosal ferritin and is lost as these cells are sloughed.
- Thus, when the body is replete with iron, high hepcidin levels inhibit its absorption into the blood.
- Conversely, with low body stores of iron, hepcidin synthesis falls and this in turn facilitates iron absorption.
- By inhibiting ferriportin, hepcidin not only reduces iron uptake from enetrocytes but also suppresses iron release from macrophages, which are an important source of the iron that is used by erythroid precursors to make hemoglobin.
Alterations in ................have a central role in diseases involving disturbances of iron metabolism
Hepcidin is inappropriately high in.............. and inappropriately low in....................
ACD/ primary and secondary (ineffective erythropoeisis--> thalassemia, MDS) hemochromatosis
Low hepcidin can cause ...........whereas high hepcidin can cause
Increased iron absorption and hemochromatosis/ reduced iron absorption and ACD
What are the causes of iron deficiency?
Iron deficiency can result from (1) dietary lack, (2) impaired absorption, (3) increased requirement, or (most importantly) (4) chronic blood loss
To maintain a normal iron balance, about.... mg of iron must be absorbed from the diet every day. Because only ............. of ingested iron is absorbed, the daily iron requirement is ........ mg for adult men and ............. mg for adult women
- 10% to 15%
- 7 to 10
- 7 to 20
True or false: Since the average daily dietary intake of iron in the Western world is about 15 to 20 mg, most men ingest more than adequate iron, whereas many women consume marginally adequate amounts of iron
What is true about the bioavailablity of iron?
- Heme iron is much more absorbable than inorganic iron, the absorption of which is influenced by other dietary contents.
- Absorption of inorganic iron is enhanced by ascorbic acid, citric acid, amino acids, and sugars in the diet, and inhibited by tannates (found in tea), carbonates, oxalates, and phosphates.
Dietary lack of iron occurs in which groups in developed countries?
- Infants, who are at high risk due to the very small amounts of iron in milk. Human breast milk provides only about 0.3 mg/L of iron. Cow's milk contains about twice as much iron, but its bioavailability is poor.
- The impoverished, who can have suboptimal diets for socioeconomic reasons at any age.
- The elderly, who often have restricted diets with little meat because of limited income or poor dentition.
- Teenagers who subsist on “junk” food
What are the causes of impaired iron absorption in addition to dietary tannate, oxalate, carbonate, and phosphate
- Impaired absorption is found in sprue, other causes of fat malabsorption (steatorrhea), and chronic diarrhea.
- Gastrectomy impairs iron absorption by decreasing hydrochloric acid and transit time through the duodenum.
Increased requirement is an important cause of iron deficiency in .......................................
growing infants, children, and adolescents, as well as premenopausal women, particularly during pregnancy
..................... is the most common cause of iron deficiency in the Western world
Chronic blood loss
Iron deficiency in adult men and postmenopausal women in the Western world must be attributed to ................... until proven otherwise
gastrointestinal blood loss
What is the pathogenesis of IDA?
- Whatever its basis, iron deficiency produces a hypochromic microcytic anemia.
- At the outset of chronic blood loss or other states of negative iron balance, reserves in the form of ferritin and hemosiderin may be adequate to maintain normal hemoglobin and hematocrit levels as well as normal serum iron and transferrin saturation.
- Progressive depletion of these reserves first lowers serum iron and transferrin saturation levels without producing anemia. In this early stage there is increased erythroid activity in the bone marrow.
- Anemia appears only when iron stores are completely depleted and is accompanied by low serum iron, ferritin, and transferrin saturation levels
What is the morphology of IDA?
- The bone marrow reveals a mild to moderate increase in erythroid progenitors.
- A diagnostically significant finding is the disappearance of stainable iron from macrophages in the bone marrow, which is best assessed by performing Prussian blue stains on smears of aspirated marrow.
- In peripheral blood smears, the red cells are small (microcytic) and pale (hypochromic).
- Normal red cells with sufficient hemoglobin have a zone of central pallor measuring about one third of the cell diameter.
- In established iron deficiency the zone of pallor is enlarged; hemoglobin may be seen only in a narrow peripheral rim.
- Poikilocytosis in the form of small, elongated red cells (pencil cells) is also characteristically seen
What are the symptoms of severe IDA?
- In severe and long-standing iron deficiency, depletion of iron-containing enzymes in cells throughout the body also causes other changes, including koilonychia, alopecia, atrophic changes in the tongue and gastric mucosa, and intestinal malabsorption.
- Depletion of iron from the central nervous system may lead to the appearance of pica, in which affected individuals consume non-foodstuffs such as clay or food ingredients such as flour, and periodically move their limbs during sleep.
- Esophageal webs appear together with microcytic hypochromic anemia and atrophic glossitis to complete the triad of major findings in the rare Plummer-Vinson syndrome
How is IDA diagnosed?
- Both the hemoglobin and hematocrit are depressed, usually to a moderate degree, in association with hypochromia, microcytosis, and modest poikilocytosis.
- The serum iron and ferritin are low, and the total plasma iron-binding capacity (reflecting elevated transferrin levels) is high. Low serum iron with increased iron-binding capacity results in a reduction of transferrin saturation to below 15%.
- Reduced iron stores inhibit hepcidin synthesis, and its serum levels fall.
- In uncomplicated iron deficiency, oral iron supplementation produces an increase in reticulocytes in about 5 to 7 days that is followed by a steady increase in blood counts and the normalization of red cell indices.
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