First Aid 2022 (without watermark) (1).pdf

 Contents Contributing Authors vii General Acknowledgments xiii Associate Authors viii How to Contribute xv Faculty Advisor...

 Contents Contributing Authors vii General Acknowledgments xiii Associate Authors viii How to Contribute xv Faculty Advisors ix How to Use This Book xvii Preface xi Selected USMLE Laboratory Values xviii Special Acknowledgments xii First Aid Checklist for the USMLE Step 1 xx ` SECTION I G U I D E TO E F F I C I E N T E X A M P R E PA R AT I O N 1 Introduction 2 Test-Taking Strategies 19 USMLE Step 1—The Basics 2 Clinical Vignette Strategies 21 Learning Strategies 11 If You Think You Failed 22 Timeline for Study 14 Testing Agencies 22 Study Materials 18 References 23 ` SECTION I SUPPLEMENT S P E C I A L S I T UAT I O N S 25 ` SECTION II HIGH-YIELD GENERAL PRINCIPLES 27 How to Use the Database 28 Pathology 203 Biochemistry 31 Pharmacology 229 Immunology 93 Public Health Sciences 257 Microbiology 121 v FAS1_2022_00_Frontmatter.indd 5 11/10/21 10:50 AM  ` SECTION III H I G H - Y I E L D O R G A N S YS T E M S 281 Approaching the Organ Systems 282 Neurology and Special Senses 503 Cardiovascular 285 Psychiatry 575 Endocrine 331 Renal 601 Gastrointestinal 365 Reproductive 635 Hematology and Oncology 411 Respiratory 683 Musculoskeletal, Skin, and Connective Tissue 453 Rapid Review 713 ` SECTION IV TO P - R AT E D R E V I E W R E S O U R C E S 7 37 How to Use the Database 738 Biochemistry 742 Question Banks 740 Cell Biology and Histology 742 Web and Mobile Apps 740 Microbiology and Immunology 742 Comprehensive 741 Pathology 743 Anatomy, Embryology, and Neuroscience 741 Pharmacology 743 Behavioral Science 742 Physiology 744 ` Abbreviations and Symbols 745 Index 771 Image Acknowledgments 753 About the Editors 828 vi FAS1_2022_00_Frontmatter.indd 6 11/10/21 10:50 AM  HIGH-YIELD PRINCIPLES IN Biochemistry “The nitrogen in our DNA, the calcium in our teeth, the iron in our blood, ` Molecular 32 the carbon in our apple pies were made in the interiors of collapsing stars. We are made of starstuff.” ` Cellular 44 —Carl Sagan ` Laboratory Techniques 50 There is no such thing as free lunch, except there is afratafreeh.com —Saito ` Genetics 54 “We think we have found the basic mechanism by which life comes from ` Nutrition 63 life.” —Francis H. C. Crick ` Metabolism 71 DNA was the first three-dimensional Xerox machine. —Kenneth Ewart Boulding This high-yield material includes molecular biology, genetics, cell biology, and principles of metabolism (especially vitamins, cofactors, minerals, and single-enzyme-deficiency diseases). When studying metabolic pathways, emphasize important regulatory steps and enzyme deficiencies that result in disease, as well as reactions targeted by pharmacologic interventions. For example, understanding the defect in Lesch-Nyhan syndrome and its clinical consequences is higher yield than memorizing every intermediate in the purine salvage pathway. Do not spend time learning details of organic chemistry, mechanisms, or physical chemistry. Detailed chemical structures are infrequently tested; however, many structures have been included here to help students learn reactions and the important enzymes involved. Familiarity with the biochemical techniques that have medical relevance—such as ELISA, immunoelectrophoresis, Southern blotting, and PCR—is useful. Review the related biochemistry when studying pharmacology or genetic diseases as a way to reinforce and integrate the material. 31 FAS1_2022_01-Biochem.indd 31 11/4/21 11:59 AM  32 SEC TION II Biochemistry   BIOCHEMISTRY—Molecular ` BIOCHEMISTRY—MOLECULAR Chromatin structure DNA exists in the condensed, chromatin form to fit into the nucleus. DNA loops twice around a histone octamer to form a nucleosome (“beads DNA double-helix on a string”). H1 binds to the nucleosome and to “linker DNA,” thereby stabilizing the chromatin fiber. H1 histone DNA has ⊝ charge from phosphate groups. (linker) DNA Histones are large and have ⊕ charge from lysine and arginine. In mitosis, DNA condenses to form Nucleosome Euchromatin Supercoiled chromosomes. DNA and histone synthesis (H2A, H2B, structure occurs during S phase. H3, H4) 2 Heterochromatin Mitochondria have their own DNA, which is circular and does not utilize histones. Metaphase chromosome Heterochromatin Condensed, appears darker on EM (labeled H Heterochromatin = highly condensed. A in A ; Nu, nucleolus). Sterically inaccessible, Barr bodies (inactive X chromosomes) may be E thus transcriptionally inactive.  methylation, visible on the periphery of nucleus. H  acetylation. Nu Euchromatin Less condensed, appears lighter on EM (labeled Eu = true, “truly transcribed.” E in A ). Transcriptionally active, sterically Euchromatin is expressed. accessible. DNA methylation Changes the expression of a DNA segment DNA is methylated in imprinting. without changing the sequence. Involved with Methylation within gene promoter (CpG islands) aging, carcinogenesis, genomic imprinting, typically represses (silences) gene transcription. transposable element repression, and X CpG methylation makes DNA mute. chromosome inactivation (lyonization). Dysregulated DNA methylation is implicated in Fragile X syndrome. Histone methylation Usually causes reversible transcriptional Histone methylation mostly makes DNA mute. suppression, but can also cause activation Lysine and arginine residues of histones can be depending on location of methyl groups. methylated. Histone acetylation Removal of histone’s ⊕ charge Ž relaxed DNA Thyroid hormone receptors alter thyroid coiling Ž  transcription. hormone synthesis by acetylation. Histone acetylation makes DNA active. Histone deacetylation Removal of acetyl groups Ž tightened DNA Histone deacetylation may be responsible for the coiling Ž  transcription. altered gene expression in Huntington disease. FAS1_2022_01-Biochem.indd 32 11/4/21 11:59 AM  Biochemistry   BIOCHEMISTRY—Molecular SEC TION II 33 Nucleotides Nucleoside = base + (deoxy)ribose (sugar). Nucleotide = base + (deoxy)ribose + phosphate; 5′ end of incoming nucleotide bears the linked by 3′-5′ phosphodiester bond. triphosphate (energy source for the bond). α-Phosphate is target of 3′ hydroxyl attack. Purines (A,G)—2 rings. Pure As Gold. Pyrimidines (C,U,T)—1 ring. CUT the pyramid. Thymine has a methyl. Deamination reactions: C-G bond (3 H bonds) stronger than A-T bond Cytosine Ž uracil (2 H bonds).  C-G content Ž  melting Adenine Ž hypoxanthine temperature of DNA. “C-G bonds are like Guanine Ž xanthine Crazy Glue.” 5-methylcytosine Ž thymine Amino acids necessary for purine synthesis (cats Uracil found in RNA; thymine in DNA. purr until they GAG): Methylation of uracil makes thymine. Glycine Aspartate Glutamine Purine (A, G) Pyrimidine (C, U, T) Nucleoside CO2 Carbamoyl Aspartate Aspartate Glycine phosphate C N C Phosphate N C N C C N10–Formyl- O- O P O- C C tetrahydrofolate C C N N N N O N10–Formyl- Nitrogenous base CH₂ Glutamine tetrahydrofolate Deoxyribose sugar Nucleotide FAS1_2022_01-Biochem.indd 33 11/4/21 11:59 AM  34 SEC TION II Biochemistry   BIOCHEMISTRY—Molecular De novo pyrimidine Various immunosuppressive, antineoplastic, and antibiotic drugs function by interfering with and purine synthesis nucleotide synthesis: Pyrimidine base production Purine base production or Pyrimidine synthesis: (requires aspartate) Ribose 5-P reuse from salvage pathway ƒ Leflunomide: inhibits dihydroorotate (de novo requires aspartate, dehydrogenase Glutamine + CO2 glycine, glutamine, and THF) 2 ATP ƒ 5-fluorouracil (5-FU) and its prodrug CPS2 (carbamoyl phosphate capecitabine: form 5-F-dUMP, which inhibits 2 ADP + Pi + synthetase II) PRPP (phosphoribosyl Glutamate pyrophosphate) synthetase thymidylate synthase ( dTMP) Purine synthesis: Carbamoyl ƒ 6-mercaptopurine (6-MP) and its prodrug phosphate Aspartate azathioprine: inhibit de novo purine Leflunomide 6-MP, synthesis; azathioprine is metabolized via PRPP Orotic azathioprine purine degradation pathway and can lead to acid immunosuppression when administered with UMP synthase UMP Mycophenolate, xanthine oxidase inhibitor (impaired in IMP ribavirin orotic aciduria) UDP ƒ Mycophenolate and ribavirin: inhibit inosine ctas ide reduucleot Hydroxyurea AMP GMP monophosphate dehydrogenase e n Purine and pyrimidine synthesis: Ribo dUDP CTP ƒ Hydroxyurea: inhibits ribonucleotide reductase N5N10- dUMP ƒ Methotrexate (MTX), trimethoprim (TMP), Thymidylate methylene THF synthase 5-FU, and pyrimethamine: inhibit dihydrofolate THF capecitabine Dihydrofolate DHF reductase ( deoxythymidine monophosphate reductase dTMP [dTMP]) in humans (methotrexate), bacteria (trimethoprim), and protozoa MTX, TMP, pyrimethamine (pyrimethamine) CPS1 = m1tochondria, urea cycle, found in liver and kidney cells CPS2 = cytwosol, pyrimidine synthesis, found in most cells FAS1_2022_01-Biochem.indd 34 11/4/21 11:59 AM  Biochemistry   BIOCHEMISTRY—Molecular SEC TION II 35 Purine salvage deficiencies Nucleic acids Ribose 5-phosphate Nucleic acids PRPP synthetase De novo synthesis Nucleotides GMP IMP AMP Cladribine, pentostatin Lesch-Nyhan syndrome ADA HGPRT APRT Nucleosides Guanosine Inosine Adenosine SCID PRPP Free bases Guanine PRPP Hypoxanthine Adenine XO Allopurinol Xanthine Febuxostat Degradation and salvage XO Uric acid Urate oxidase (rasburicase) Allantoin Excretion ADA, adenosine deaminase; APRT, adenine phosphoribosyltransferase; HGPRT, hypoxanthine guanine phosphoribosyltransferase, XO, xanthine oxidase; SCID, severe combined immune deficiency (autosomal recessive inheritance) Adenosine deaminase ADA is required for degradation of adenosine One of the major causes of autosomal recessive deficiency and deoxyadenosine.  ADA Ž  dATP SCID. Ž  ribonucleotide reductase activity Ž  DNA precursors in cells Ž  lymphocytes. Lesch-Nyhan Defective purine salvage due to absent HGPRT, HGPRT: syndrome which converts hypoxanthine to IMP and Hyperuricemia guanine to GMP. Compensatory  in purine Gout synthesis ( PRPP amidotransferase activity) Pissed off (aggression, self-mutilation) Ž excess uric acid production. X-linked Red/orange crystals in urine recessive. Tense muscles (dystonia) Findings: intellectual disability, self-mutilation, Treatment: allopurinol, febuxostat. aggression, hyperuricemia (red/orange “sand” [sodium urate crystals] in diaper), gout, dystonia, macrocytosis. Genetic code features Unambiguous Each codon specifies only 1 amino acid. Degenerate/ Most amino acids are coded by multiple codons. Exceptions: methionine (AUG) and tryptophan redundant Wobble—codons that differ in 3rd (“wobble”) (UGG) encoded by only 1 codon. position may code for the same tRNA/amino acid. Specific base pairing is usually required only in the first 2 nucleotide positions of mRNA codon. Commaless, Read from a fixed starting point as a continuous Exceptions: some viruses. nonoverlapping sequence of bases. Universal Genetic code is conserved throughout Exception in humans: mitochondria. evolution. FAS1_2022_01-Biochem.indd 35 11/4/21 11:59 AM  36 SEC TION II Biochemistry   BIOCHEMISTRY—Molecular DNA replication Occurs in 5′ Ž 3′ direction (“5ynth3sis”) in continuous and discontinuous (Okazaki fragment) fashion. Semiconservative. More complex in eukaryotes than in prokaryotes, but shares analogous enzymes. Origin of Particular consensus sequence in genome AT-rich sequences (such as TATA box regions) replication A where DNA replication begins. May be single are found in promoters and origins of (prokaryotes) or multiple (eukaryotes). replication. Replication fork B Y-shaped region along DNA template where leading and lagging strands are synthesized. Helicase C Unwinds DNA template at replication fork. Helicase halves DNA. Deficient in Bloom syndrome (BLM gene mutation). Single-stranded Prevent strands from reannealing or degradation binding proteins D by nucleases. DNA Creates a single- (topoisomerase I) or double- In eukaryotes: irinotecan/topotecan inhibit topoisomerases E (topoisomerase II) stranded break in the helix topoisomerase (TOP) I, etoposide/teniposide to add or remove supercoils (as needed due to inhibit TOP II. underwinding or overwinding of DNA). In prokaryotes: fluoroquinolones inhibit TOP II (DNA gyrase) and TOP IV. Primase F Makes an RNA primer on which DNA polymerase III can initiate replication. DNA polymerase III G Prokaryotes only. Elongates leading strand DNA polymerase III has 5′ Ž 3′ synthesis and by adding deoxynucleotides to the 3′ end. proofreads with 3′ Ž 5′ exonuclease. Elongates lagging strand until it reaches Drugs blocking DNA replication often have a primer of preceding fragment. modified 3′ OH, thereby preventing addition of the next nucleotide (“chain termination”). DNA polymerase I H Prokaryotes only. Degrades RNA primer; Same functions as DNA polymerase III, also replaces it with DNA. excises RNA primer with 5′ Ž 3′ exonuclease. DNA ligase I Catalyzes the formation of a phosphodiester Joins Okazaki fragments. bond within a strand of double-stranded DNA. Ligase links DNA. Telomerase Eukaryotes only. A reverse transcriptase (RNA- Upregulated in progenitor cells and also often in dependent DNA polymerase) that adds DNA cancer; downregulated in aging and progeria. (TTAGGG) to 3′ ends of chromosomes to avoid Telomerase TAGs for Greatness and Glory. loss of genetic material with every duplication. G 3' E DNA polymerase III 5' Topoisomerase C A Helicase Origin of replication Leading strand B Replication fork Lagging strand 3' Okazaki fragment 5' D A Area of interest Single-stranded RNA primer Origin of replication binding protein Leading strand Lagging strand I F DNA ligase Fork Fork Primase movement movement G DNA polymerase III H Lagging strand Leading strand DNA polymerase I FAS1_2022_01-Biochem.indd 36 11/4/21 11:59 AM  Biochemistry   BIOCHEMISTRY—Molecular SEC TION II 37 DNA repair Double strand Nonhomologous end Brings together 2 ends of DNA fragments to 5´ Double strand break 3´ 5´ Double strand break joining repair double-stranded breaks. 3´ 5´ 3´ 5´ 3´ Homology not required. Part of the DNA may be lost or translocated. Nonhomologous end joining Homologous Requires 2 homologous DNA duplexes. DoubleAstrand break Double strand break 5´ 3´ 5´ 3´ recombination strand from damaged dsDNA 3´ is repaired 5´ 3´ 5´ 5´ 3´ using a complementary strand from intact 3´ 5´ homologous dsDNA as a template. Homologous recombination Nonhomologous end joining Defective in breast/ovarian cancers with BRCA1 or BRCA2 mutations and in Fanconi anemia. Restores duplexes accurately without loss of nucleotides. Homologous recombination Single strand Nucleotide excision Specific endonucleases remove the Occurs in G1 phase of cell cycle. repair oligonucleotides containing damaged bases; Defective in xeroderma pigmentosum DNA polymerase and ligase fill and reseal the (inability to repair DNA pyrimidine dimers gap, respectively. Repairs bulky helix-distorting caused by UV exposure). Presents with dry lesions (eg, pyrimidine dimers). skin, photosensitivity, skin cancer. Base excision repair Base-specific Glycosylase removes altered base Occurs throughout cell cycle. and creates AP site (apurinic/apyrimidinic). Important in repair of spontaneous/toxic One or more nucleotides are removed by deamination. AP-Endonuclease, which cleaves 5′ end. AP- “GEL Please.” Lyase cleaves 3′ end. DNA Polymerase-β fills the gap and DNA ligase seals it. Mismatch repair Mismatched nucleotides in newly synthesized Occurs predominantly in S phase of cell cycle. strand are removed and gap is filled and Defective in Lynch syndrome (hereditary resealed. nonpolyposis colorectal cancer [HNPCC]). UV exposure Pyrimidine dimer Deaminated C T T U G A A G A AP U site TT Endonucleases remove Glycosylase removes base Mismatched segment G damaged segment G removed (AP site) A A A Endonuclease and lyase G remove backbone segment Newly replaced segment T T C T A A G A Nucleotide excision repair Base excision repair Mismatch repair FAS1_2022_01-Biochem.indd 37 11/4/21 11:59 AM  38 SEC TION II Biochemistry   BIOCHEMISTRY—Molecular Mutations in DNA Degree of change: silent females). Usually permanent. May be accompanied by neurologic dysfunction (eg, tremors, multiple sclerosis–like illness). Rett syndrome Sporadic disorder seen almost exclusively in females (affected males die in utero or shortly after birth). Most cases are caused by de novo mutation of MECP2 on X chromosome. Symptoms of Rett syndrome usually appear between ages 1–4 and are characterized by regression (“retturn”) in motor, verbal, and cognitive abilities; ataxia; seizures; growth deceleration; and stereotyped hand- wringing. Fragile X syndrome X-linked dominant inheritance. Trinucleotide Trinucleotide repeat expansion [(CGG)n] occurs repeats in FMR1 Ž hypermethylation of during oogenesis. cytosine residues Ž  expression. Premutation (50-200 repeats) Ž tremor, ataxia, Most common inherited cause of intellectual 1° ovarian insufficiency. disability (Down syndrome is most common Full mutation (>200 repeats) Ž postpubertal genetic cause, but most cases occur macroorchidism (enlarged testes), long face sporadically). with large jaw, large everted ears, autism, mitral valve prolapse, hypermobile joints. Self-mutilation is common and can be confused with Lesch-Nyhan syndrome. Trinucleotide repeat May show genetic anticipation (disease severity  and age of onset  in successive generations). expansion diseases DISEASE TRINUCLEOTIDE REPEAT MODE OF INHERITANCE MNEMONIC Huntington disease (CAG)n AD Caudate has  ACh and GABA Myotonic dystrophy (CTG)n AD Cataracts, Toupee (early balding in males), Gonadal atrophy in males, reduced fertility in females Fragile X syndrome (CGG)n XD Chin (protruding), Giant Gonads Friedreich ataxia (GAA)n AR Ataxic GAAit FAS1_2022_01-Biochem.indd 60 11/16/21 7:10 AM  Biochemistry   BIOCHEMISTRY—Genetics SEC TION II 61 Autosomal trisomies Autosomal monosomies are incompatible with life due to a high chance of expression of recessive traits for that chromosome. Incidence of trisomies: Down > Edwards > Patau. Down syndrome Findings: intellectual disability, flat facies, Drinking age (21). (trisomy 21) prominent epicanthal folds, single palmar Most common viable chromosomal disorder crease, incurved 5th finger, gap between 1st 2 and most common cause of genetic toes, duodenal atresia, Hirschsprung disease, intellectual disability. congenital heart disease (eg, ASD), Brushfield First-trimester ultrasound commonly shows spots (whitish spots at the periphery of the iris).  nuchal translucency and hypoplastic nasal Associated with early-onset Alzheimer disease bone. Markers for Down syndrome are hi up: (chromosome 21 codes for amyloid precursor  hCG,  inhibin. protein),  risk of AML/ALL.  risk of umbilical hernia (incomplete closure of 95% of cases due to meiotic nondisjunction, umbilical ring). most commonly during meiosis I ( with The 5 A’s of Down syndrome: Single palmar crease advanced maternal age: from 1:1500 in females ƒ Advanced maternal age < 20 to 1:25 in females > 45). ƒ Atresia (duodenal) 4% of cases due to unbalanced Robertsonian ƒ Atrioventricular septal defect translocation, most typically between ƒ Alzheimer disease (early onset) chromosomes 14 and 21. Only 1% of cases are ƒ AML (5 years of age) due to postfertilization mitotic error. Edwards syndrome Findings: PRINCE Edward—Prominent Election age (18). (trisomy 18) occiput, Rocker-bottom feet, Intellectual 2nd most common autosomal trisomy resulting disability, Nondisjunction, Clenched fists with in live birth (most common is Down syndrome). overlapping fingers, low-set Ears, micrognathia In Edwards syndrome, every prenatal screening (small jaw), congenital heart disease (eg, marker decreases. VSD), omphalocele, myelomeningocele. Death usually occurs by age 1. Patau syndrome Findings: severe intellectual disability, rocker- Puberty at age 13. (trisomy 13) bottom feet, microphthalmia, microcephaly, Defect in fusion of prechordal mesoderm cleft lip/palate, holoprosencephaly, Ž midline defects. polydactyly, cutis aplasia, congenital heart (pump) disease, polycystic kidney disease, omphalocele. Death usually occurs by age 1. Cutis aplasia Nondisjunction in meiosis I Nondisjunction in meiosis II 1st trimester screening Trisomy β-hCG PAPP-A Meiosis I 21   18   Nondisjunction 13   Meiosis II 2nd trimester (quadruple) screening Trisomy β-hCG Inhibin A Estriol AFP Nondisjunction 21     18  — or    Gametes 13 — — — — n+1 n+1 n–1 n–1 n n n–1 n+1 Trisomy Monosomy Normal Monosomy Trisomy Noninvasive prenatal testing is recommended over first- and second-trimester screening. FAS1_2022_01-Biochem.indd 61 11/4/21 11:59 AM  62 SEC TION II Biochemistry   BIOCHEMISTRY—Genetics Genetic disorders by CHROMOSOME SELECTED EXAMPLES chromosome 3 von Hippel-Lindau disease, renal cell carcinoma 4 ADPKD (PKD2), achondroplasia, Huntington disease 5 Cri-du-chat syndrome, familial adenomatous polyposis 6 Hemochromatosis (HFE) 7 Williams syndrome, cystic fibrosis 9 Friedreich ataxia, tuberous sclerosis (TSC1) 11 Wilms tumor, β-globin gene defects (eg, sickle cell disease, β-thalassemia), MEN1 13 Patau syndrome, Wilson disease, retinoblastoma (RB1), BRCA2 15 Prader-Willi syndrome, Angelman syndrome, Marfan syndrome 16 ADPKD (PKD1), α-globin gene defects (eg, α-thalassemia), tuberous sclerosis (TSC2) 17 Neurofibromatosis type 1, BRCA1, TP53 (Li-Fraumeni syndrome) 18 Edwards syndrome 21 Down syndrome 22 Neurofibromatosis type 2, DiGeorge syndrome (22q11) X Fragile X syndrome, X-linked agammaglobulinemia, Klinefelter syndrome (XXY) Robertsonian Chromosomal translocation that commonly translocation involves chromosome pairs 21, 22, 13, 14, and 15. One of the most common types of translocation. Occurs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost. Balanced translocations (no gain or loss of Normal Robertsonian Unbalanced significant genetic material) normally do gamete precursor translocation gamete precursor not cause abnormal phenotype. Unbalanced translocations (missing or extra genes) can result in miscarriage, stillbirth, and chromosomal imbalance (eg, Down syndrome, Patau syndrome). Cri-du-chat syndrome Cri du chat = cry of the cat. Congenital deletion on short arm of chromosome 5 (46,XX or XY, 5p−). Findings: microcephaly, moderate to severe intellectual disability, high-pitched crying, epicanthal folds, cardiac abnormalities (VSD). I cry when I am Very SaD. Williams syndrome Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene). Findings: distinctive “elfin” facies, intellectual disability, hypercalcemia, well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems (eg, supravalvular aortic stenosis, renal artery stenosis). FAS1_2022_01-Biochem.indd 62 11/4/21 11:59 AM  Biochemistry   BIOCHEMISTRY—Nutrition SEC TION II 63 ` BIOCHEMISTRY—NUTRITION Essential fatty acids Polyunsaturated fatty acids that cannot be In contrast, consumption of trans-unsaturated synthesized in the body and must be provided fatty acids (found in fast food) promotes in the diet (eg, nuts/seeds, plant oils, seafood). cardiovascular disease by  LDL and  HDL. Linoleic acid (omega-6) is metabolized to arachidonic acid, which serves as the precursor to leukotrienes and prostaglandins. Linolenic acid (omega-3) and its metabolites have cardioprotective and antihyperlipidemic effects. Vitamins: fat soluble A, D, E, K. Absorption dependent on bile Malabsorption syndromes with steatorrhea (eg, emulsification, pancreatic secretions, and cystic fibrosis and celiac disease) or mineral intact ileum. Toxicity more common than oil intake can cause fat-soluble vitamin for water-soluble vitamins because fat-soluble deficiencies. vitamins accumulate in fat. Vitamins: water B1 (thiamine: TPP) Wash out easily from body except B12 and B9. soluble B2 (riboflavin: FAD, FMN) B12 stored in liver for ~ 3–4 years. B9 stored in B3 (niacin: NAD+) liver for ~ 3–4 months. B5 (pantothenic acid: CoA) B-complex deficiencies often result in B6 (pyridoxine: PLP) dermatitis, glossitis, and diarrhea. B7 (biotin) Can be coenzymes (eg, ascorbic acid) or B9 (folate) precursors to coenzymes (eg, FAD, NAD+). B12 (cobalamin) C (ascorbic acid) FAS1_2022_01-Biochem.indd 63 11/4/21 11:59 AM  64 SEC TION II Biochemistry   BIOCHEMISTRY—Nutrition Vitamin A Includes retinal, retinol, retinoic acid. FUNCTION Antioxidant; constituent of visual pigments Retinol is vitamin A, so think retin-A (used (retinal); essential for normal differentiation topically for wrinkles and Acne). of epithelial cells into specialized tissue Found in liver and leafy vegetables. (pancreatic cells, mucus-secreting cells); Supplementation in vitamin A-deficient measles prevents squamous metaplasia. patients may improve outcomes. Use oral isotretinoin to treat severe cystic acne. Use all-trans retinoic acid to treat acute promyelocytic leukemia. DEFICIENCY Night blindness (nyctalopia); dry, scaly skin A (xerosis cutis); dry eyes (xerophthalmia); conjunctival squamous metaplasia Ž Bitot spots (keratin debris; foamy appearance on conjunctiva A ); corneal degeneration (keratomalacia); immunosuppression. EXCESS Acute toxicity—nausea, vomiting,  ICP (eg, Teratogenic (cleft palate, cardiac abnormalities), vertigo, blurred vision). therefore a ⊝ pregnancy test and two forms of Chronic toxicity—alopecia, dry skin (eg, contraception are required before isotretinoin scaliness), hepatic toxicity and enlargement, (vitamin A derivative) is prescribed. arthralgias, and idiopathic intracranial Isotretinoin is teratogenic. hypertension. Vitamin B1 Also called thiamine. FUNCTION In thiamine pyrophosphate (TPP), a cofactor for several dehydrogenase enzyme reactions (Be APT): ƒ Branched-chain ketoacid dehydrogenase ƒ α-Ketoglutarate dehydrogenase (TCA cycle) ƒ Pyruvate dehydrogenase (links glycolysis to TCA cycle) ƒ Transketolase (HMP shunt) DEFICIENCY Impaired glucose breakdown Ž ATP depletion worsened by glucose infusion; highly aerobic tissues (eg, brain, heart) are affected first. In patients with chronic alcohol overuse or malnutrition, give thiamine before dextrose to  risk of precipitating Wernicke encephalopathy. Diagnosis made by  in RBC transketolase activity following vitamin B1 administration. DISORDER CHARACTERISTICS Wernicke Acute, reversible, life-threatening neurologic condition. Symptoms: Confusion, Ophthalmoplegia/ encephalopathy Nystagmus, Ataxia (CorONA beer). Korsakoff syndrome Amnestic disorder due to chronic alcohol overuse; presents with confabulation, personality changes, memory loss (permanent). Wernicke-Korsakoff Damage to medial dorsal nucleus of thalamus, mammillary bodies. Presentation is combination of syndrome Wernicke encephalopathy and Korsakoff syndrome. Dry beriberi Polyneuropathy, symmetric muscle wasting. Spell beriberi as Ber1Ber1 to remember Wet beriberi High-output cardiac failure (due to systemic vitamin B1. vasodilation). FAS1_2022_01-Biochem.indd 64 11/4/21 11:59 AM  Biochemistry   BIOCHEMISTRY—Nutrition SEC TION II 65 Vitamin B2 Also called riboflavin. FUNCTION Component of flavins FAD and FMN, used as FAD and FMN are derived from riboFlavin cofactors in redox reactions, eg, the succinate (B2 ≈ 2 ATP). dehydrogenase reaction in the TCA cycle. DEFICIENCY Cheilosis (inflammation of lips, scaling The 2 C’s of B2. and fissures at the corners of the mouth), “magenta” tongue, corneal vascularization. Vitamin B3 Also called niacin, nicotinic acid. FUNCTION Constituent of NAD+, NADP+ (used in redox NAD derived from Niacin (B3 ≈ 3 ATP). reactions and as cofactor by dehydrogenases). Derived from tryptophan. Synthesis requires vitamins B2 and B6. Used to treat dyslipidemia ( VLDL,  HDL). DEFICIENCY Glossitis. Severe deficiency of B3 leads to Hartnup disease—autosomal recessive. A pellagra, which can also be caused by Hartnup Deficiency of neutral amino acid (eg, disease, malignant carcinoid syndrome tryptophan) transporters in proximal renal ( tryptophan metabolism Ž  serotonin tubular cells and on enterocytes Ž neutral synthesis), and isoniazid ( vitamin B6). aminoaciduria and  absorption from the Symptoms of B3 deficiency (pellagra) (the 3 gut Ž  tryptophan for conversion to niacin D’s): diarrhea, dementia (also hallucinations), Ž pellagra-like symptoms. Treat with high- dermatitis (C3/C4 dermatome circumferential protein diet and nicotinic acid. “broad collar” rash [Casal necklace], Pellagra = vitamin B3 levels fell. hyperpigmentation of sun-exposed limbs A ). EXCESS Facial flushing (induced by prostaglandin, not Podagra = vitamin B3 OD (overdose). histamine; can avoid by taking aspirin with niacin), hyperglycemia, hyperuricemia. Vitamin B5 Also called pantothenic acid. B5 is “pento”thenic acid. FUNCTION Component of coenzyme A (CoA, a cofactor for acyl transfers) and fatty acid synthase. DEFICIENCY Dermatitis, enteritis, alopecia, adrenal insufficiency may lead to burning sensation of feet (“burning feet syndrome”; distal paresthesias, dysesthesia). Vitamin B6 Also called pyridoxine. FUNCTION Converted to pyridoxal phosphate (PLP), a cofactor used in transamination (eg, ALT and AST), decarboxylation reactions, glycogen phosphorylase. Synthesis of glutathione, cystathionine, heme, niacin, histamine, and neurotransmitters including serotonin, epinephrine, norepinephrine (NE), dopamine, and GABA. DEFICIENCY Convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by isoniazid and oral contraceptives), sideroblastic anemia (due to impaired hemoglobin synthesis and iron excess). FAS1_2022_01-Biochem.indd 65 11/4/21 11:59 AM  66 SEC TION II Biochemistry   BIOCHEMISTRY—Nutrition Vitamin B7 Also called biotin. FUNCTION Cofactor for carboxylation enzymes (which add a 1-carbon group): ƒ Pyruvate carboxylase (gluconeogenesis): pyruvate (3C) Ž oxaloacetate (4C) ƒ Acetyl-CoA carboxylase (fatty acid synthesis): acetyl-CoA (2C) Ž malonyl-CoA (3C) ƒ Propionyl-CoA carboxylase (fatty acid oxidation and branched-chain amino acid breakdown): propionyl-CoA (3C) Ž methylmalonyl-CoA (4C) DEFICIENCY Relatively rare. Dermatitis, enteritis, alopecia. Caused by long-term antibiotic use or excessive ingestion of raw egg whites. “Avidin in egg whites avidly binds biotin.” Vitamin B9 Also called folate. FUNCTION Converted to tetrahydrofolic acid (THF), a Found in leafy green vegetables. Also produced coenzyme for 1-carbon transfer/methylation by gut microbiota. Folate absorbed in jejunum reactions. (think foliage in the “jejun”gle). Important for the synthesis of nitrogenous bases Small reserve pool stored primarily in the liver. in DNA and RNA. DEFICIENCY Macrocytic, megaloblastic anemia; Deficiency can be caused by several drugs (eg, hypersegmented polymorphonuclear cells phenytoin, trimethoprim, methotrexate). (PMNs); glossitis; no neurologic symptoms (as Supplemental folic acid at least 1 month prior opposed to vitamin B12 deficiency). to conception and during pregnancy to  risk Labs:  homocysteine, normal methylmalonic of neural tube defects. Give vitamin B9 for the acid levels. Seen in chronic alcohol overuse 9 months of pregnancy, and 1 month prior to and in pregnancy. conception. FAS1_2022_01-Biochem.indd 66 11/4/21 11:59 AM  Biochemistry   BIOCHEMISTRY—Nutrition SEC TION II 67 Vitamin B12 Also called cobalamin. FUNCTION Cofactor for methionine synthase (transfers Found in animal products. Synthesized only CH3 groups as methylcobalamin) and by intestinal microbiota. Site of synthesis in methylmalonyl-CoA mutase. Important for humans is distal to site of absorption; thus B12 DNA synthesis. must be consumed via animal products. DEFICIENCY Macrocytic, megaloblastic anemia; Very large reserve pool (several years) stored hypersegmented PMNs; paresthesias primarily in the liver. Deficiency caused and subacute combined degeneration by malabsorption (eg, sprue, enteritis, (degeneration of dorsal columns, lateral Diphyllobothrium latum, achlorhydria, corticospinal tracts, and spinocerebellar tracts) bacterial overgrowth, alcohol overuse), lack of due to abnormal myelin. Associated with intrinsic factor (eg, pernicious anemia, gastric  serum homocysteine and methylmalonic bypass surgery), absence of terminal ileum acid levels, along with 2° folate deficiency. (surgical resection, eg, for Crohn disease), Prolonged deficiency Ž irreversible nerve certain drugs (eg, metformin), or insufficient damage. intake (eg, veganism). B9 (folate) supplementation can mask the hematologic symptoms of B12 deficiency, but not the neurologic symptoms. Protein Fatty acids with odd number of carbons, branched-chain amino acids THF Methionine SAM CH3 to anabolic pathways Methylmalonyl-CoA Methylmalonyl-CoA B12 Methionine synthase S-adenosyl B12 mutase homocysteine Succinyl-CoA B6 THF–CH3 Homocysteine Heme TCA cycle B6 Adenosine Cysteine Vitamin C Also called ascorbic acid. FUNCTION Antioxidant; also facilitates iron absorption Found in fruits and vegetables. by reducing it to Fe2+ state. Necessary Pronounce “absorbic” acid. for hydroxylation of proline and lysine in Ancillary treatment for methemoglobinemia by collagen synthesis. Necessary for dopamine reducing Fe3+ to Fe2+. β-hydroxylase (converts dopamine to NE). DEFICIENCY Scurvy—swollen gums, easy bruising, Deficiency may be precipitated by tea and toast petechiae, hemarthrosis, anemia, poor wound diet. healing, perifollicular and subperiosteal Vitamin C deficiency causes sCurvy due to a hemorrhages, “corkscrew” hair. Collagen hydroCylation defect. Weakened immune response. EXCESS Nausea, vomiting, diarrhea, fatigue, calcium oxalate nephrolithiasis (excess oxalate from vitamin C metabolism). Can  iron toxicity in predisposed individuals by increasing dietary iron absorption (ie, can worsen hemochromatosis or transfusion-related iron overload). FAS1_2022_01-Biochem.indd 67 11/4/21 11:59 AM  68 SEC TION II Biochemistry   BIOCHEMISTRY—Nutrition Vitamin D D3 (cholecalciferol) from exposure of skin (stratum basale) to sun, ingestion of fish, milk, plants. D2 (ergocalciferol) from ingestion of plants, fungi, yeasts. Both converted to 25-OH D3 (storage form) in liver and to the active form 1,25-(OH)2 D3 (calcitriol) in kidney. FUNCTION  intestinal absorption of Ca2+ and Cholesterol → PO43–. Diet 7-dehydrocholesterol  bone mineralization at low levels. Sun/UV exposure  bone resorption at higher levels. D2 D3 2+ (Ergocalciferol) (Cholecalciferol) REGULATION  PTH,  Ca ,  PO43– Ž  1,25-(OH)2D3 production. 1,25-(OH)2D3 feedback inhibits its own production. 25-hydroxylase  PTH Ž  Ca2+ reabsorption and  PO43– reabsorption in the kidney. 25-OH D 3 DEFICIENCY Rickets in children (deformity, such ↑ ↑ as genu varum “bowlegs” A ), Ca2+, PO43– A osteomalacia in adults (bone pain and muscle weakness), hypocalcemic tetany. 1α-hydroxylase Caused by malabsorption,  sun exposure, poor diet, chronic kidney 1,25-(OH)2 D3 disease (CKD), advanced liver disease. Give oral vitamin D to breastfed infants. Bone Intestines Renal tubular cells Darker skin and prematurity predispose to deficiency. ↑ Ca2+ and ↑ PO43– ↑ absorption of Reabsorption: ↑ Ca2+, ↑ PO43– EXCESS Hypercalcemia, hypercalciuria, loss of released from bone Ca2+ and PO43– Urine: Ca2+, PO43– ↑ ↑ appetite, stupor. Seen in granulomatous diseases ( activation of vitamin D by epithelioid macrophages). ↑ Ca2+ and ↑ PO43– Vitamin E Includes tocopherol, tocotrienol. FUNCTION Antioxidant (protects RBCs and neuronal membranes from free radical damage). DEFICIENCY Hemolytic anemia, acanthocytosis, muscle Neurologic presentation may appear similar weakness, demyelination of posterior columns to vitamin B12 deficiency, but without ( proprioception and vibration sensation) and megaloblastic anemia, hypersegmented spinocerebellar tract (ataxia). neutrophils, or  serum methylmalonic acid levels. EXCESS Risk of enterocolitis in enfants (infants) with High-dose supplementation may alter metabolism excess of vitamin E. of vitamin K Ž enhanced anticoagulant effects of warfarin. FAS1_2022_01-Biochem.indd 68 11/4/21 11:59 AM  Biochemistry   BIOCHEMISTRY—Nutrition SEC TION II 69 Vitamin K Includes phytomenadione, phylloquinone, phytonadione, menaquinone. FUNCTION Activated by epoxide reductase to the K is for Koagulation. Necessary for the reduced form, which is a cofactor for the maturation of clotting factors II, VII, IX, γ-carboxylation of glutamic acid residues on X, and proteins C and S. Warfarin inhibits various proteins required for blood clotting. vitamin K–dependent synthesis of these factors Synthesized by intestinal microbiota. and proteins. DEFICIENCY Neonatal hemorrhage with  PT and  aPTT Not in breast milk; “breast-fed infants Don’t but normal bleeding time (neonates have Know about vitamins D and K”. Neonates are sterile intestines and are unable to synthesize given vitamin K injection at birth to prevent vitamin K). Can also occur after prolonged use hemorrhagic disease of the newborn. of broad-spectrum antibiotics. Zinc FUNCTION Mineral essential for the activity of 100+ enzymes. Important in the formation of zinc fingers (transcription factor motif). DEFICIENCY Delayed wound healing, suppressed immunity, male hypogonadism,  adult hair (axillary, facial, A pubic), dysgeusia, anosmia. Associated with acrodermatitis enteropathica ( A , defect in intestinal zinc absorption). May predispose to alcoholic cirrhosis. Protein-energy malnutrition Kwashiorkor Protein malnutrition resulting in skin lesions, A B edema due to  plasma oncotic pressure (due to low serum albumin), liver malfunction (fatty change due to  apolipoprotein synthesis and deposition). Clinical picture is small child with swollen abdomen A. Kwashiorkor results from protein- deficient MEALS: Malnutrition Edema Anemia    Liver (fatty) Skin lesions (eg, hyperkeratosis, dyspigmentation) Marasmus Malnutrition not causing edema. Diet is deficient in calories but no nutrients are entirely absent. Marasmus results in muscle wasting B. FAS1_2022_01-Biochem.indd 69 11/4/21 11:59 AM  70 SEC TION II Biochemistry   BIOCHEMISTRY—Nutrition Ethanol metabolism  NADH/NAD+ ratio inhibits NADPH NADP+ CYP2E1 ROS TCA cycle Ž  acetyl-CoA used Microsome in ketogenesis (Ž ketoacidosis), Fomepizole Disulfiram lipogenesis (Ž hepatosteatosis). – – Females are more susceptible than Alcohol dehydrogenase Acetaldehyde dehydrogenase males to effects of alcohol due Ethanol Acetaldehyde Acetate to  activity of gastric alcohol NAD+ NADH NAD+ NADH Cytosol Mitochondria dehydrogenase,  body size,  percentage of water in body weight. Catalase NAD+ is the limiting reagent. H2O2 H2O Peroxisome Alcohol dehydrogenase operates via zero-order kinetics. Ethanol metabolism  NADH/ Gluconeogenesis Glycolysis NAD+ ratio in liver, causing: Glucose NADH NAD+  Lactic acidosis— pyruvate conversion to lactate Glyceraldehyde-3-P DHAP ↑ Glycerol-3-P 4A  Fasting hypoglycemia—  gluconeogenesis due to PEP (fasting NADH NAD+  conversion of OAA to malate hypoglycemia) Pyruvate ↑ Lactate ↑ Triglycerides  Ketoacidosis—diversion of Q (anion gap metabolic acidosis) (hepatic acetyl-CoA into ketogenesis steatosis) rather than TCA cycle ↑ Ketoacids S  Hepatosteatosis—  conversion Ketogenesis ↑ OAA Acetyl-CoA of DHAP to glycerol-3-P 4A ; acetyl-CoA diverges into 4B NADH ↑ Fatty acids fatty acid synthesis 4B , which R OAA Isocitrate NAD+ Lipogenesis combines with glycerol-3-P to synthesize triglycerides NADH Fomepizole—competitive inhibitor NAD+ TCA cycle of alcohol dehydrogenase; ↑ Malate α-KG Pathways stimulated by ↑ NADH/NAD+ ratio preferred antidote for overdoses NAD+ Pathways inhibited by ↑ NADH/NAD+ ratio of methanol or ethylene glycol. Succinyl- Alcohol dehydrogenase has CoA NADH higher affinity for ethanol than for methanol or ethylene glycol Ž ethanol can be used as competitive inhibitor of alcohol dehydrogenase to treat methanol or ethylene glycol poisoning. Disulfiram—blocks acetaldehyde dehydrogenase Ž  acetaldehyde Ž  hangover symptoms Ž discouraging drinking. FAS1_2022_01-Biochem.indd 70 11/4/21 11:59 AM  Biochemistry   BIOCHEMISTRY—Metabolism SEC TION II 71 ` BIOCHEMISTRY—METABOLISM Enzyme terminology An enzyme’s name often describes its function. For example, glucokinase is an enzyme that catalyzes the phosphorylation of glucose using a molecule of ATP. The following are commonly used enzyme descriptors. Kinase Catalyzes transfer of a phosphate group from a high-energy molecule (usually ATP) to a substrate (eg, phosphofructokinase). Phosphorylase Adds inorganic phosphate onto substrate without using ATP (eg, glycogen phosphorylase). Phosphatase Removes phosphate group from substrate (eg, fructose-1,6-bisphosphatase 1). Dehydrogenase Catalyzes oxidation-reduction reactions (eg, pyruvate dehydrogenase). Hydroxylase Adds hydroxyl group (−OH) onto substrate (eg, tyrosine hydroxylase). Carboxylase Transfers CO2 groups with the help of biotin (eg, pyruvate carboxylase). Mutase Relocates a functional group within a molecule (eg, vitamin B12–dependent methylmalonyl-CoA mutase). Synthase/synthetase Joins two molecules together using a source of energy (eg, ATP, acetyl-CoA, nucleotide sugar). Rate-determining enzymes of metabolic processes PROCESS ENZYME REGULATORS Glycolysis Phosphofructokinase-1 (PFK-1) AMP ⊕, fructose-2,6-bisphosphate ⊕ ATP ⊝, citrate ⊝ Gluconeogenesis Fructose-1,6-bisphosphatase 1 AMP ⊝, fructose-2,6-bisphosphate ⊝ TCA cycle Isocitrate dehydrogenase ADP ⊕ ATP ⊝, NADH ⊝ Glycogenesis Glycogen synthase Glucose-6-phosphate ⊕, insulin ⊕, cortisol ⊕ Epinephrine ⊝, glucagon ⊝ Glycogenolysis Glycogen phosphorylase Epinephrine ⊕, glucagon ⊕, AMP ⊕ Glucose-6-phosphate ⊝, insulin ⊝, ATP ⊝ HMP shunt Glucose-6-phosphate dehydrogenase (G6PD) NADP+ ⊕