Robbins Essential Pathology PDF
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This document details morphologic methods used in cancer diagnosis, including open biopsy, fine-needle aspiration, and cytologic preparations. It also describes the role of protein markers in establishing cancer subtypes. These methods assist in distinguishing between benign and malignant tumors.
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86 CHAPTER 5 Neoplasia Morphologic Methods In mos ns ances, s no d c u o d ag nos e c anc e r b as e d on e app e arance o e ma g nan...
86 CHAPTER 5 Neoplasia Morphologic Methods In mos ns ances, s no d c u o d ag nos e c anc e r b as e d on e app e arance o e ma g nan c e s under e m cros c op e. Howe ve r, n many c as es w e quvo c a mor po og c canges , c n c a and radoog c e aures are ess e n a o ar r ve a e d ag nos s. S amp ng o e umor or mor poog c ana ys s c an be ac e ve d roug e o ow ng pro ce dures : O pen (surgca) bopsy. hs afords e opporuny o seec s- sue or sampng based on s gross appearance. he bopsy can be examned by e roune emaoxyn-and-eosn sans ater xa- on. In some cases, e bopsy s sen or rapd evauaon by frozen secton. hs meod, n wc a sampe s quck-rozen, seconed, saned, and examned under e mcroscope, perms soogc evauaon wn severa mnues. In e vas majory o cases, ro- A zen-secon dagnoss as g accuracy and can be useu n ds- ngusng beween bengn and magnan umors and denyng some nonneopasc processes (e.g., necon). Fne-neede aspraton (FNA) s anoer wdey used meod or evauang suspcous masses. Ces wdrawn by aspraon are spread ou on a sde, saned, and examned. I s used mos re- queny o evauae papabe esons, bu w mage gudance can aso be used o examne masses nvovng vruay any body se. FNA s ess nvasve an surgca bopsy, and n experenced ands provdes a rapd, sensve, and specc means o deny (or excude) e presence o cancerous esons. Cytoogc (Papancoaou) preparatons rom ssue scrapes, FNAs, or luds provde anoer morpoogc meod or e deecon o cancer. Inay deveoped o deny precancerous esons o e cer vx (Fg. 5.25), s ecnque s now used o evauae suspeced B magnancy n many oer ses; o deny umor ces n abdom- Fig. 5.25 Papanicolaou smears from the uterine cervix. (A) In normal na, peura, percarda, and cerebrospna luds; and, ess com- smears, large, flat cells with small nuclei are typical. (B) Abnormal mony, or evauaon o oer orms o neopasa. smear containing a sheet of malignant cells with large hyperchromatic nuclei. Nuclear pleomorphism is evident, and one cell is in mitosis. A Protein Markers few interspersed neutrophils, much smaller in size and with compact, Idencaon o proens or oer moecues expressed by umor ces lobate nuclei, are seen. (Courtesy of Dr. Richard M. DeMay, Department as a broad roe n esabsng e dagnoss o specc cancer sub- of Pathology, University of Chicago.) ypes. Severa compemenar y meods are used: Immunostocemstry s a poweru adjunc o roune soog y. Tssue secons are saned usng a meod a empoys anbodes Conventona karyotypng o meapase cromosomes s requeny specc or proens o neres. hs meod s useu n deermnng used o suppor e dagnoss o emaopoec cancers suc as eu- e ce o orgn o poory dferenaed cancers and dsngusng kemas and ympomas. among cancers w smar morpoogc appearances. For exam- Fuorescence n stu ybrdzaton (FISH) s a meod perormed on pe, deecon o keran n a poory dferenaed umor esabses res sampes or parain-embedded secons n wc luoresceny e dagnoss o carcnoma. I aso can be used o demonsrae e abeed nucec acd probes bnd w specc arge regons o e presence o proen arges o erapeuc drugs and anbodes. genome. hs ecnque can be used o subype emaoogc mag- Fow cytometry s used n e casscaon o eukemas and ym- nances and o deny parcuar cromosoma aberraons n any pomas. In s meod, varous combnaons o luorescen an- umor ype bodes agans ce surace moecues and dferenaon angens Hybrdzaton of tumor DNA to arrays of DNA probes a span are bound o ces n suspenson, wc are en anayzed or san- e genome perms e dencaon o sma deeons and oer ng o oban e penoype o magnan ces. canges n copy number a are beow e resouon o kar yoypc Crcuatng tumor markers. Bocemca assays or umor-assoc- anayss. hs meod s used o dagnose and subype ceran knds aed enzymes, ormones, and oer umor markers are used w o bran umors. var yng success as screenng ess or ceran cancers; owever, ey are mos useu n assessng e response o erapy and n deecng Nucleic Acid Markers eary dsease recurrence n paens w a known cancer dagnoss. A number o ecnques used o dagnose umors and oow er Markers a are n curren use are sed n Tabe 5.9 response o erapy nvove e dencaon o specc DNA and RNA sequences or ragmens. Cncay reevan exampes o suc Cytogenetic Markers markers are sed n Tabe 5.8 Among e ypes o abnormaes or Many subypes o cancer are gy assocaed w parcuar cromo- wc esng s done mos requeny are e oowng: soma aberraons; a ew saen exampes o suc assocaons are gven Cmerc nucec acd sequences. Cromosoma rearrangemens n Tabe 5.8, aong w nucec acd markers dscussed aer. Cyogenec oten creae uson genes encodng cmerc mRNAs and proens. meods commony used o deny cromosoma aberraons ncude: hese sequences are umor-specc and can be deeced even CHAPTER 5 Neoplasia 87 Table 5.8 Examples of Cytogenetic/Molecular Markers of Importance in Specific Cancers Affected Gene/ Chromosomal Region Event Detection Clinical Importance Chromosomal Translocations/Fusion Genes ABL Fusion with BCR gene Karyotype, FISH, RT-PCR Diagnosis of chronic myeloid leukemia; target through 9;22 translocation of therapy; marker used to follow therapeu- tic response and diagnose minimal residual disease Gene Amplification NMYC Gene amplification FISH Marker of poor prognosis in neuroblastoma HER2 Gene amplification FISH, IHC Target of therapy in “HER2-positive” breast cancer Chromosomal Deletion(s) 1p Segmental deletion FISH, DNA array Diagnosis of oligodendroglioma; marker of good prognosis Point Substitution JAK2 Valine for phenylalanine DNA sequencing Diagnosis of polycythemia vera (a type of substitution in codon 617 blood cancer) Table 5.9 Circulating Tumor Markers Marker Tumor Use Prostate-specific antigen (PSA) Prostatic carcinoma Screening test (controversial); following response to therapy Human chorionic gonadotropin (HCG) Choriocarcinoma Following response to therapy Some mixed germ cell tumors Alphafetoprotein (AFP) Germ cell tumors Following response to therapy Hepatocellular carcinoma Carcinoembryonic antigen (CEA) Colonic carcinoma Following response to therapy CA-125 Ovarian carcinoma Following response to therapy presen n ver y ow abundance usng sensve poymerase can Moecuar prong of cancers. Dverse ecnooges ave been reacon (PCR) meods. Many emaopoec neopasms, as we as deveoped o anayze a snge gene, sequence an enre genome, a ew sod umors, are dened by e presence o parcuar uson assess epgenec modcaons genome-wde, quany a o e genes. In oer nsances, e producs o uson genes are arges RNAs expressed n a ce popuaon, measure many proens smu- o drugs and so are mporan o deec or purposes o seecng aneousy, and ake a snapso o a o e ce’s meaboes. hese erapy. Fnay, sensve PCR-based ess or cmerc sequences advances ave enabed e sysemac sequencng and caaogng o can be used o deec sma numbers o resdua cancer ces n o- aeraons n varous uman cancers. he man mpac as been n er wse asympomac paens. researc; owever, many ceners are seekng o deny erapeu- Snge-nuceotde varants and sma “ndes. ” As w cmerc gene cay “aconabe” genec esons n a mey ason a a reasonabe producs, snge-nuceode varans (pon subsuons) and ndes cos. For exampe, mos academc ceners now rouney perorm (sma nserons and deeons) are specc or some cancer ypes nex generaon sequencng on umor specmens, usuay w gene and ereore dagnoscay mporan, and n oer cases generae panes a cover commony muaed proooncogenes and umor oncoproens a are drug arges and ereore are mporan o suppressor genes. hese new ecnques compemen normaon deec or purposes o gudng erapy. obaned rom convenona soog y and n su bomarker ess Antgen-receptor gene rearrangements. Because eac T and B ce perormed on ssue secons. For e oreseeabe uure, e mos exbs unque rearrangemens o s angen-recepor genes, PCR- accurae dagnoss and assessmen o prognoss n cancer paens based deecon o T-ce recepor or mmunogobun genes aows w be arrved a by a combnaon o morpoogc and new moec- dsncon beween monocona (neopasc) and poycona (reac- uar ecnques. ve) proeraons o ympocyes. 6 Genetic Diseases O U T L I N E Mendelian Disorders: Diseases Caused Structural Abnormalities, 97 by Single-Gene Defects, 88 Cytogenetic Disorders Involving Autosomes, 98 Transmission Patterns of Single-Gene Disorders, 88 Cytogenetic Disorders Involving Sex Chromosomes, 100 Diseases Caused by Mutations in Genes Encoding Structural Single-Gene Disorders with Atypical Patterns of Inheritance, 101 Proteins, 90 Trinucleotide Repeat Mutation Diseases, 101 Diseases Caused by Mutations in Genes Encoding Receptor Diseases Caused by Mutations in Mitochondrial Genes, 102 Proteins or Channels, 90 Diseases Caused by Alterations of Imprinted Regions: Diseases Caused by Mutations in Genes Encoding Enzyme Prader-Willi and Angelman Syndromes, 102 Proteins, 93 Diagnosis of Genetic Disorders, 102 Complex Multigenic Disorders, 96 Genetic Test Modalities and Applications, 102 Cytogenetic Disorders, 97 Indications for Genetic Analysis, 104 Numerical Abnormalities, 97 produced by muaons n genes beongng o e same meaboc Genec abnormaes a cause ceuar dysuncon are one o e prnc- or sgnang paways. pa causes o dsease. Some genec dseases are nered (ama) due o e presence o germne muaons, wereas oers sem rom acqured somac Transmission Patterns of Single-Gene Disorders muaons (e.g., cancer) and are no ransmed rom one generaon o e Autosomal Dominant Disorders nex. I s mporan o dsngus beween congena and genec dsorders. Congena means “born w”; some genec dseases are congena (e.g., Autosomal dominant disorders affect both sexes and are mani- penykeonura), wereas oers are manes aer n e (e.g., Hunngon fested in the heterozygous state, so the inheritance of one abnor- dsease). Conversey, no a congena dseases are genec n orgn (e.g., mal allele (out of the two for autosomal genes) is sufcient to cause congena syps). In s caper, we dscuss some o e more common the disease. or paogencay neresng genec dseases. We concude e caper by Wen one p aren s a e c e d and e o er s no, on ave r age e ac revewng curren ecnooges a are used o dagnose genec dsease. c d as a 50% cance o av ng e d s e as e. Te o ow ng a dd - ona e aures a s o p er a n o auos oma dom nan ds e as es : MENDELIAN DISORDERS: DISEASES CAUSED Reduced penetrance and varable expressvty are common. No a ndvduas wo ner e deecve gene deveop e dsease, or BY SINGLE-GENE DEFECTS e same knd o dsease, even wn one amy. Diseases caused by single-gene defects (mutations) follow one of A 50% reducton n te normal gene product s suicent to produce cln- three patterns of Mendelian inheritance: autosomal dominant, cal sgns and symptoms. Because a 50% oss o enzyme acvy usuay autosomal recessive, or X-linked. can be compensaed or, e genes a are afeced n auosoma dom- Aoug rare ndvduay (Tabe 6.1), aken ogeer mendean nan dsorders usuay encode proens oer an enzymes, suc as dsorders accoun or approxmaey 1% o a adu ospa admssons srucura proens, ranspor proens, or proens a uncon wn and 6% o 8% o a pedarc ospa admssons. Mos snge-gene ger-order compexes, wc may be dsruped by e presence o a dseases oow smpe paerns o nerance, bu genoype–peno- “bad componen” a nereres w e ormaon o e uncona ype assocaons are somemes compex, reecng e dverse unc- muproen or mumerc assembes. A proen a “posons” e ons o varous afeced gene producs (Tabe 6.2). Severa caveas mus acvy o s norma counerpar s caed a domnant negatve. be kep n mnd wen consderng mendean dsorders: In many autosomal domnant condtons, te age at onset s delayed, Penotypc efects o specc sngle-gene mutatons vary wdely. Some pro- wt symptoms and sgns rst appearng n adultood. duce many penoypc efecs (pleotropy) a may dfer among ndvd- Not all afected patents ave afected parents. Assumng e absence uas, a penomenon caed varable expressvty. In oer nsances, some o nonpaerny, n suc paens e dsorder s usuay arbuabe persons w a dsease-assocaed genoype are penoypcay norma; o new muaons nvovng e egg or e sperm rom wc ey n s suaon, e ra s sad o ave low penetrance. Wy penoypes were derved. her sbngs are unafeced and no a rsk. a o correae w genoypes n suc cases s no we undersood. In Disorders of Autosomal Recessive Inheritance some cases, may be expaned by conerance o varans n oer genes a mpac e penoype; ese are caed moder genes. Autosomal recessive diseases, which are the largest group of mende- Mutatons n dferent genes may cause smlar or dentcal peno- lian disorders, are caused by genetic defects that alter both alleles of types. hs penomenon, ermed genetc eterogenety, s oten a gene. 88 CHAPTER 6 Genetic Diseases 89 As a genera rue, auosoma recessve dsorders are caracerzed Reduced penetrance and varable expressvty are less common tan by e oowng: n autosomal domnant dsorders. he ra does no usuay afect te parents, wereas eac sblng as Onset s requently early n le. a 25% cance o beng afected. Most autosomal recessve dseases are nerted rom parents wo are car- I te mutant gene s rare n te populaton, tere s a strong lkelood rers o te mutant gene, or at least one may be afected. Aoug new tat te afected patent (te proband) s te product o a consangun- muaons or recessve dsorders do occur, ey rarey produce peno- eous marrage. ypes because o e keood a e oer aee w be norma. Dseases resultng rom enzyme decences are usually autosomal recessve because enzymes are normay presen n arge excess and Table 6.1 Prevalenc e of S e l e c te d Me nde li an Dis o r d e r s ony severe decences, resulng rom deecs n bo alleles, are Disorder Estimated Prevalence suicen o produce penoypes. Autosomal Dominant Inheritance Familial hypercholesterolemia 1 in 500 X-Linked Disorders Polycystic kidney disease 1 in 1000 Most X-linked disorders are X-linked recessive and therefore Hereditary spherocytosis 1 in 5000 (Northern Europe) affect males much more frequently than females. Marfan syndrome 1 in 5000 X-nked dsorders are caracerzed by e oowng: Huntington disease 1 in 10,000 he dsease s transmtted by asymptomatc eterozygous emale car- rers to male ofsprng, wo ave ony one X cromosome (a sae Autosomal Recessive Inheritance reerred o as emzygosty). Sons o eerozygous women ave one Sickle cell anemia 1 in 400 (U.S. African-Amer- cance n wo o recevng e muan gene. icans) An afected male does not transmt te dsorder to sons, but all daug- Cystic fibrosis 1 in 3200 (U.S. Caucasians) ters o afected males are carrers. Tay-Sachs disease 1 in 3500 (U.S. Ashkenazi Because males ave only one “dose” o most X-lnked genes, deects n Jewish; French Canadians) X-lnked genes are lkely to produce dsease n males. Phenylketonuria 1 in 10,000 Heterozygous emales rarely ave te ull-blown dsease because tey Mucopolysaccharidoses—all types 1 in 25,000 ave a normal allele. However, genoype–penoype assocaons Glycogen storage diseases—all 1 in 50,000 n emaes are compcaed by e penomenon o X-nactvaton types (lyonz aton), roug w c mo s o e genes on one o e X-Linked Inheritance wo X cromos omes are s e nc e d e ary n d e veopmen. T e X cromos ome a s nac v ae d s “cos en” a r and om ; e nc e, on Duchenne muscular dystrophy 1 in 3500 males (U.S.) average, a o ce s expre ss e mu ae d a ee and a o c e s Hemophilia 1 in 5000 males (U.S.) express e nor ma a ee. In mos ns anc es , s s su c en o a G6PD deficiency 1 in 10 males (U.S. African- bun or compeey suppre ss e d s e as e pe no y p e, bu on o c c a- Americans) son ere s pronounce d ske w ng oward s e nc ng o e nor- a Glucose-6-phosphate dehydrogenase. ma a ee (unavorabe yon za on ). Und er suc c rc ums anc es , Table 6.2 Biochemical Basis and Inheritance Pattern of Selected Mendelian Disorders Disease Abnormal Protein Protein Function Autosomal Dominant Inheritance Familial hypercholesterolemia Low-density lipoprotein receptor Cholesterol transport Marfan syndrome Fibrillin Extracellular matrix protein a Ehlers-Danlos syndrome Collagen Extracellular matrix protein Hereditary spherocytosis Spectrin, ankyrin, or protein 4.1 Cell membrane stabilizer Neurofibromatosis, type 1 Neurofibromin-1 (NF-1) Regulator of RAS signaling Adult polycystic kidney disease Polycystin-1 (PKD-1) Cell:cell, cell:matrix interactions Autosomal Recessive Inheritance Cystic fibrosis (CF) CF transmembrane regulator Ion channel Phenylketonuria Phenylalanine hydroxylase Enzyme Tay-Sachs disease Hexosaminidase Enzyme α- and β-Thalassemias Hemoglobin Oxygen transport Sickle cell anemia Hemoglobin Oxygen transport X-linked Recessive Inheritance Hemophilia A Factor VIII Coagulation factor Duchenne muscular dystrophy Dystrophin Cell membrane stabilizer Fragile X syndrome FMRP RNA translation regulator a Some forms are autosomal recessive disorders. 90 CHAPTER 6 Genetic Diseases ema es may exb e aure s o e ds e as e, oug usu a y o a Ehlers-Danlos Syndromes ess er deg re e an a e c e d ma es. Ehlers-Danlos syndromes (EDS) are a heterogeneous group of dis- orders caused by defects in collagen genes or genes that regulate Diseases Caused by Mutations in Genes Encoding collagen assembly. Structural Proteins Pathogeness. EDSs are sngle-gene dsorders a may ave auosomal Marfan Syndrome domnan or recessve modes o nerance. A leas sx clncal and Marfan syndrome, a connective tissue disorder of autosomal dom- genec varans are recognzed. inant inheritance, is caused by mutations affecting brillin-1. e molecular bases o e more common varans are as ollows: Deicency of e enzyme ysy ydroxyase. In s varan called e Pathogeness. Fbrn-1 s encoded by e FBN1 gene, wc maps o kyposcoloss ype, decreased ydroxylaon o lysne resdues n ypes cromosome 15q21. I s a gycoproen secreed by broblass a s I and III collagen nereres w e covalen cross-lnkng o collagen e major componen o mcrobrls ound n e exracellular marx molecules. As w oer enzyme decences, s dsease s nered o many ssues. Mcrobrls provde a scafold a enables e proper as an auosomal recessve dsorder. assembly o elasc bers and are parcularly abundan n e aora, D eicen syness of ype III coagen. s varan, e vascular e lgamens, and e clar y zonules o e ocular lens, predcably e ype, s nered as an auosomal domnan dsorder and s carac- ssues a are mos promnenly afeced n Maran syndrome. erzed by weakness o ssues rc n ype III collagen (e.g., blood Many abnormales n Maran syndrome are arbuable o a vessels, bowel wall), predsposng em o rupure. e causave srucural alure o connecve ssues. However, oers, suc as bone muaons oten lead o e expresson o a deecve collagen III overgrow, appear o be relaed o excessve ransormng grow ac- monomer a nereres w assembly o normal collagen, a classc or-β (TGF-β) acvy. Normal mcrobrls sequeser TGF-β, and loss example o a “domnan negave” muan. o mcrobrls ereore ncreases e boavalably o s cyokne. D eicen syness of ype V coagen. s varan s also nered Excessve TGF-β sgnalng as deleerous efecs on vascular smoo as an auosomal domnan dsorder and resuls n classc EDS. More muscle developmen and e negry o e exracellular marx. O an 90% o afeced paens carr y muaons n e genes a noe, angoensn recepor blockers, wc lower blood pressure and encode ype V collagen. nb e acvy o TGF-β, mprove aorc and cardac uncon n mouse models o Maran syndrome. Clncal Features. Tssues rc n collagen, suc as skn, lgamens, and jons, are nvolved n mos varans o EDS. B ecause e abnormal collagen bers lack adequae ensle sreng, e skn s Morphology. Abnormales are mos promnen n e skeleon, yperexensble and jons are ypermoble e skn also s ragle e eye, and e cardovascular sysem, as ollows: and vulnerable o rauma Mnor njures produce gapng deecs, and Skeea abnormaes are e mos obvous eaure o Maran surgcal repar or ner venon s accomplsed only w grea dicuy syndrome. Paens ave a slender, elongaed abus; abnor- because connecve ssues ack norma ense sreng. e deec n mally long legs, arms, and ngers (aracnodacyy); a g- connecve ssue also may lead o oer serous njures n e absence arced palae; and yperexensble jons. Spnal deormes o rauma, ncludng rupure o e colon and large areres; rupure o suc as kyposcooss may be presen. e ces s deormed, e cornea and renal deacmen; and dapragmac erna. exbng pecus excavaum (a deeply depressed sernum) or a pgeon-breas deormy. Diseases Caused by Mutations in Genes Encoding Baera dsocaon (subuxaon) of e ens due o weakness o e suspensor y lgamens (ecopa ens) s e mos caracer- Receptor Proteins or Channels sc ocular cange. s abnormaly s so specc a s pres- Familial Hypercholesterolemia ence s gly suggesve o a dagnoss o Maran syndrome. Familial hypercholesterolemia is caused most commonly by muta- C ardovascuar sysem abnormaes consue a serous rea o tions in the gene that encodes the receptor for low-density lipopro- fe. Fragmenaon o e elasc bers n e meda o e aora tein (LDL) and is characterized by high serum cholesterol levels predsposes o aneurysmal dlaon and aorc dssecon (see and early-onset atherosclerosis. Caper 8). ese canges, called cysc medonecross, also occur n yperenson and w agng. Loss o medal suppor causes Pathogeness. Famlal ypercoleserolema s an auosomal domnan dlaon o e aorc valve rng, gvng rse o aorc ncom- dsorder w a requency o 1 n 500 n e general populaon, makng one peence. e cardac valves, especally e mral valve, may be o e mos common mendelan dsorders. Undersandng s paogeness excessvely dsensble and regurgan (loppy vave syndrome), requres a workng knowledge o normal coleserol meabolsm. gvng rse o mral valve prolapse and congesve cardac alure Coleserol may be derved rom e de or rom endogenous syne- (see Caper 8). Dea rom aorc rupure may occur a any age ss. Deary coleserol s ncorporaed n e nesnal mucosa no cy- and s e mos common cause o dea. Less commonly, cardac lomcrons, wc are delvered o e lver and aken up by epaocyes. alure s e ermnal even. Some o s coleserol eners e meabolc pool (see laer), and some s excreed no e blary rac as ree coleserol or ble acds. Coles- Clncal Features. e prevalence o Maran syndrome s esmaed o erol also s syneszed by epaocyes and released no e crculaon be 1 n 5000. Approxmaely 70% o 85% o cases are amlal and e (Fg. 6.1). e rs sep n s process s e secreon o rglycerde-rc res are sporadc, arsng rom de novo FBN1 muaons n e germ very-low-densy lpoproen (VLDL) no e blood. Wle n e crcu- cells o parens. Molecular dagnoss s no roune, because ere are laon, e VLDL parcle loses rglycerdes roug e acon o lpases more an 600 dsnc causave muaons n e large FBN1 gene; expressed by endoelal cells and s convered o nermedae-densy mos paens are dagnosed based on clncal eaures. e dsease lpoproen (IDL) and low-densy lpoproen (LDL). exbs wde penoypc varaon a s beleved o sem, a leas n e LDL recepor paway akes up wo rds o crculang LDL par- par, rom dferng efecs o specc FBN1 muaons. cles, as well as IDL parcles, wereas e res o e LDL parcles are aken CHAPTER 6 Genetic Diseases 91 wc s e rae-lmng enzyme n e synec paway; (2) smulaes e ormaon o coleserol esers, a sorage orm o coleserol; and (3) nbs e syness and down-regulaes e number o LDL recepors on e cell surace, proecng cells rom e excessve accumulaon o coleserol. In most instances, familial hypercholesterolemia is caused by mutations in the LDL receptor protein that impair LDL metabo- lism, resulting in accumulation of LDL cholesterol in the plasma. Overall, LDL receptor mutations account for 90% of cases. e paucy o LDL recepors on lver cells also mpars e ranspor o IDL no e lver, so a greaer proporon o plasma IDL s convered no LDL. Paens w amlal ypercoleserolema us ave g serum levels o coleserol as a resul o bo reduced caabolsm and excessve bosyness. Hypercoleserolema leads o an ncrease n coleserol upake no macropages and vascular walls medaed by e LDL scav- enger recepor, resulng n premaure aeroscleross and coleserol-rc deposs n sot ssues called xantomas. Mos o e remanng cases o amlal ypercoleserolema are caused by muaons n e gene encod- ng Apo B-100 proen (6%–10% o cases) or muaons n PCSK9 gene, wc conrols degradaon o LDL recepor (2% o cases). Paens w ese muaons are clncally ndsngusable rom ose w amlal ypercoleserolema caused by LDL recepor muaons. Clncal Features. Heerozygoes w amlal ypercoleserolema caused by LDL recepor muaons ave a wo- o ree-old elevaon o plasma coleserol levels, wereas omozygoes may ave n excess o a ve-old elevaon. Aloug er coleserol levels are elevaed rom br, eerozygoes reman asympomac unl adul le, wen ey develop coleserol deposs (xanomas) along endon seas and premaure aeroscleross resulng n coronary arery dsease. Homozygoes are more severely afeced, developng cuaneous xanomas n cldood and oten dyng o myocardal narcon beore e age o 20 years. Recognon o e crcal role o LDL recepors n coleserol omeo- sass led o e desgn o e san amly o drugs a s now wdely used o lower plasma coleserol. ey nb e acvy o HMG-CoA reduc- ase, ncreasng e level o LDL recepors on epaocyes (see Fg. 6.1). Smlarly, recognon a paogenc PCSK9 muaons cause ncreased PCSK9 uncon led o e developmen o PCSK9 nbors, wc also are now approved or reamen o ypercoleserolema. Fig. 6.1 Low-density lipoprotein (LDL) and cholesterol metabolism in Cystic Fibrosis normal individuals and in familial hypercholesterolemia. In individuals Cystic brosis is an autosomal recessive disorder of epithelial ion with normal levels of LDL receptors (left), receptor-mediated clearance of low-density lipoproteins (LDL) and intermediate-density lipoproteins transport that leads to secretion of abnormally viscid mucus from (IDL) bearing Apo B-100 delivers cholesterol to hepatocytes, where its exocrine glands and the linings of the respiratory, gastrointestinal,
