Impact of HIV on Gastroenterology/Hepatology

Home , Bacillary peliosis, Esophageal disease, Odynophagia, Steatosis

Core Curriculum: Impact of HIV on Gastroenterology/Hepatology

AshutoshAshutosh Barve,Barve, M.D.,M.D., Ph.D.Ph.D. Gastroenterology/HepatologyGastroenterology/Hepatology FellowFellow UniversityUniversityUniversity ofofof LouisvilleLouisville Louisville Case

4848 yearyear oldold manman presentspresents withwith aa historyhistory ofof ::

dysphagiadysphagia odynophagiaodynophagia weightweight lossloss

EGDEGD waswas donedone toto evaluateevaluate thethe problemproblem University of Louisville Case – EGD Report

ExtensivelyExtensively scarredscarred esophagealesophageal mucosamucosa withwith mucosalmucosal bridging.bridging. DistalDistal esophagealesophageal nodulesnodules withwithUniversity superficialsuperficial ulcerationulceration of Louisville Case – Esophageal Nodule Biopsy InflammatoryInflammatory lesionlesion withwith ulceratedulcerated mucosamucosa SpecialSpecial stainsstains forfor fungifungi revealreveal nonnon-- septateseptate branchingbranching hyphaehyphae consistentconsistent withwith MUCORMUCOR University of Louisville Case

TheThe patientpatient waswas HIVHIV positivepositive !!!!

University of Louisville HAART (Highly Active Anti Retroviral Therapy)

HIV/AIDS

Before HAART After HAART University of Louisville HIV/AIDS

BeforeBefore HAARTHAART AfterAfter HAARTHAART ImmuneImmune dysfunctiondysfunction ImmuneImmune reconstitutionreconstitution OpportunisticOpportunistic InfectionsInfections ManagementManagement ofof chronicchronic ¾ Prevention diseasesdiseases e.g.e.g. HepatitisHepatitis CC ¾ Management CirrhosisCirrhosis NeoplasmsNeoplasms ManagementManagement ofof drugdrug ¾ Management sideside effectseffects University of Louisville General Considerations for GI symptoms in AIDS ClinicalClinical signssigns andand symptomssymptoms seldomseldom correlatecorrelate withwith specificspecific diagnosisdiagnosis IfIf patientpatient isis onon HAARTHAART –– etiologyetiology isis usuallyusually nonnon--opportunisticopportunistic oror drugdrug inducedinduced LikelyLikely diagnosesdiagnoses basedbased inin extentextent ofof immunocompromiseimmunocompromise ÆÆ CD4CD4 << 100100 favorsfavors CMV,CMV, fungi,fungi, mycobacteriummycobacterium aviumavium complexcomplex (MAC)(MAC) whilewhile CD4CD4 >> 200200 favorsfavors commoncommon bacteriabacteriaUniversity andand otherother nonnon -of-opportunisticopportunistic Louisville infectionsinfections General Considerations for GI symptoms in AIDS

InIn AIDS,AIDS, GIGI pathogenspathogens areare aa partpart ofof aa systemicsystemic infectionsinfections EarlyEarly endoscopyendoscopy isis keykey inin certaincertain settingssettings MultipleMultiple infectionsinfections areare commoncommon EvidenceEvidence ofof tissuetissue invasioninvasion ÆÆ hallmarkhallmark ofof pathogenicitypathogenicity University of Louisville General Considerations for GI symptoms in AIDS

RecurrenceRecurrence ofof opportunisticopportunistic infectionsinfections isis commoncommon ÆÆ maintenancemaintenance antimicrobialantimicrobial maymay bebe neededneeded unlessunless HAARTHAART isis initiatedinitiated TreatmentTreatment ofof allall opportunisticopportunistic disordersdisorders shouldshould includeinclude HAARTHAART

University of Louisville HIV/AIDS in Gastroenterology

OdynophagiaOdynophagia andand DysphagiaDysphagia AbdominalAbdominal PainPain DiarrheaDiarrhea AnorectalAnorectal DiseaseDisease AbnormalAbnormal LFTLFT ViralViral HepatitidesHepatitides andand HIVHIV University of Louisville Differential Diagnosis of Dysphagia and Odynophagia in AIDS AIDS related esophageal disease Candida albicans* Cytomegalovirus* Idiopathic ulcerations* Herpes simplex Histoplasma capsulatum Mycobacterium avium complex Cryptosporidium spp. Neoplasm: Kaposi's sarcoma, lymphoma, squamous cell carcinoma, adenocarcinoma Non-AIDS esophageal disease Gastroesophageal reflux UniversityPill-induced esophagitis of Louisville

** More common Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Candida albicans

MostMost frequentfrequent esophagealesophageal infectioninfection inin AIDSAIDS MayMay occuroccur duringduring primaryprimary HIVHIV infectioninfection (transient(transient immunosupression)immunosupression) OralOral thrushthrush ÆÆ PPVPPV forfor esophagitisesophagitis == 90%90% NPVNPV forfor esophagitisesophagitis == 82%82% FrequentlyFrequently coexistscoexists withwith otherother disordersdisorders University of Louisville Candida albicans

ClinicalClinical presentationpresentation:: SubsternalSubsternal dysphagiadysphagia OdynophagiaOdynophagia –– usuallyusually notnot veryvery severesevere

DiagnosisDiagnosis –– byby EGDEGD FocalFocal oror diffusediffuse plaquesplaques inin associationassociation withwith mucosalmucosal hyperemiahyperemia andand friabilityfriability University of Louisville Candida esophagitis

University of Louisville Candida albicans

Histopathology:Histopathology: DesquamatedDesquamated epithelialepithelial cellscells withwith yeastyeast formsforms presentpresent onlyonly inin thethe superficialsuperficial epitheliumepithelium

Esophageal squamous mucosa with numerous pseudohyphae admixed within an acute Universityinflammatory exudate of Louisville Candida albicans

Treatment:Treatment: FluconazoleFluconazole ¾¾ 200200 mgmg loadingloading dosedose ¾¾100100 mgmg everyevery dayday NarcoticsNarcotics forfor painpain CaspofunginCaspofungin maymay bebe usedused inin resistantresistant casescases RelapseRelapse cancan bebe preventedprevented byby HAARTHAART University of Louisville CMV esophagitis

ClinicalClinical Presentation:Presentation: OdynophagiaOdynophagia oror substernalsubsternal chestchest painpain –– usuallyusually severesevere DysphagiaDysphagia isis lessless commoncommon comparedcompared toto CandidaCandida FeverFever –– reportedreported occasionallyoccasionally AssociatedAssociated CandidaCandida infectioninfection -- commoncommon University of Louisville CMV esophagitis

DiagnosisDiagnosis –– EGD:EGD: ExtensiveExtensive largelarge andand deepdeep ulcersulcers BiopsyBiopsy –– basebase ofof ulcerulcer providesprovides thethe highesthighest yieldyield BiopsyBiopsy moremore sensitivesensitive thanthan cultureculture

University of Louisville CMV Esophagitis

Cytomegalovirus and herpes simplex virus esophagitis. Multiple pathogens are frequently found in patients with AIDS.University of Louisville

From Wilcox CM: Atlas of Clinical Gastrointestinal Endoscopy. Philadelphia, WB Saunders, 1995, p 28. CMV esophagitis

HistopathologyHistopathology –– ViralViral cytopathiccytopathic effectseffects inin mesenchymalmesenchymal and/orand/or endothelialendothelial cellscells inin granulationgranulation tissue.tissue. IntranuclearIntranuclear inclusioninclusion bodiesbodies (Owls(Owls--eye)eye) maymay bebe absentabsent ÆÆ confirmationconfirmation byby immunohistochemistryimmunohistochemistryUniversity of Louisville CMV esophagitis

Treatment:Treatment:

GanciclovirGanciclovir –– 1414--2828 daysdays FoscarnetFoscarnet –– 1414--2828 daysdays CidofovirCidofovir –– 1414--2828 daysdays HAARTHAART University of Louisville HIV associated - Idiopathic ulcers

ClinicalClinical PresentationPresentation andand EGDEGD findingsfindings::

IdenticalIdentical toto CMVCMV esophagitisesophagitis OdynophagiaOdynophagia worseworse thanthan dysphagiadysphagia MultipleMultiple largelarge deepdeep raisedraised ulcersulcers onon endoscopyendoscopy –– punchedpunched--outout appearance,appearance, normalnormal interveningintervening mucosamucosa University of Louisville HIV associated - Idiopathic ulcers

University of Louisville

From Wilcox CM: Atlas of Clinical Gastrointestinal Endoscopy. Philadelphia, WB Saunders, 1995, p 75. HIV associated - Idiopathic ulcers

DiagnosticDiagnostic criteria:criteria: EndoscopicEndoscopic andand histopathologichistopathologic ulcerulcer NoNo viralviral cytopathiccytopathic effect,effect, negativenegative immunohistochemistryimmunohistochemistry forfor CMVCMV NoNo clinicalclinical oror endoscopicendoscopic evidenceevidence ofof refluxreflux diseasedisease oror pillpill--inducedinduced esophagitisesophagitis

University of Louisville HIV associated - Idiopathic ulcers

Treatment:Treatment: PrednisonePrednisone 4040 mg/daymg/day taperedtapered overover 44 weeksweeks isis moremore thanthan 90%90% effectiveeffective ThalidomideThalidomide ¾¾ whenwhen PrednisonePrednisone failsfails ¾¾ alsoalso veryvery highlyhighly effectiveeffective

University of Louisville Herpes simplex esophagitis

NotNot commoncommon inin AIDSAIDS –– alsoalso seenseen inin immunocompetentimmunocompetent patientspatients HSVHSV typetype II asas wellwell asas HSVHSV typetype IIII cancan causecause ShallowShallow ulcersulcers asas opposedopposed toto CMVCMV DiscreteDiscrete vesiclesvesicles ÆÆ shallowshallow ulcersulcers ÆÆ coalescecoalesce intointo regionsregions ofof diffusediffuse shallowshallow ulcerationsulcerations

University of Louisville Herpes simplex esophagitis

ShallowShallow ulcerationulceration withwith islandsislands ofof normalnormal--appearingappearing esophagealesophagealUniversity mucosamucosa of Louisville

Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Herpes simplex esophagitis

Diagnosis:Diagnosis: BiopsiesBiopsies areare takentaken fromfrom ulcerulcer edgeedge BiopsiesBiopsies ,, cytologiccytologic brushingsbrushings (also(also fromfrom ulcerulcer edge)edge) asas wellwell asas cultureculture ofof biopsybiopsy specimenspecimen areare sensitivesensitive HistopathologyHistopathology –– nuclearnuclear changeschanges typicaltypical forfor HerpesHerpes virusvirus infectioninfection inin epithelialepithelial cellscells Treatment:Treatment: AcyclovirAcyclovirUniversity –– 55--1010 daysdays of Louisville HIV/AIDS in Gastroenterology

InIn mostmost patientspatients withwith AIDS,AIDS, abdominalabdominal painpain whenwhen severesevere isis relatedrelated toto HIVHIV andand itsits consequencesconsequences However,However, alsoalso considerconsider thethe mostmost commoncommon causescauses ofof abdominalabdominal painpain inin thethe generalgeneral populationpopulation UseUse ultrasonographyultrasonography andand CTCT scanningscanning earlyearly inin thetheUniversity assesmentassesment ofof abdominalabdominal of Louisville painpain Abdominal Pain

InIn patientspatients withwith pancreatitispancreatitis –– considerconsider drugdrug inducedinduced diseasedisease IndicationsIndications forfor surgicalsurgical interventionintervention areare thethe samesame asas generalgeneral populationpopulation AllAll surgicalsurgical specimensspecimens shouldshould bebe submittedsubmitted forfor ¾¾ViralViral culturescultures ¾¾FungalFungal culturescultures ¾¾HistopathologyHistopathology University¾¾MesentricMesentric nodesnodes shouldshould of bebe biopsiedbiopsied Louisville Differential Diagnosis of Abdominal Pain in AIDS OrganOrgan CausesCauses StomachStomach Gastritis CMV*, Cryptosporidium Focal ulcer CMV*, acid peptic disease Outlet Cryptosporidium, CMV, lymphoma obstruction Mass Lymphoma, KS, CMV SmallSmall bowelbowel Enteritis Cryptosporidium*, CMV, MAC Obstruction Lymphoma*, KS Perforation CMV*, lymphoma

The differentialUniversity diagnosis does not include nonof-AIDS specificLouisville conditions

* More frequent (Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.) Differential Diagnosis of Abdominal Pain in AIDS OrganOrgan CausesCauses ColonColon Colitis CMV, enteric bacteria*, HSV Obstruction Lymphoma*, KS, intussusception Perforation CMV*, lymphoma, HSV Appendicitis KS*, Cryptosporidium, CMV AnorectumAnorectum Proctitis HSV*, bacteria, CMV Tumor KS, lymphoma, condyloma dDI = didanosine; HSV = herpes simplex virus; KS = Kaposi's sarcoma; MAC = Mycobacterium avium complex The differentialUniversity diagnosis does not include nonof-AIDS Louisville specific conditions * More frequent (Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.) Differential Diagnosis of Abdominal Pain in AIDS

OrganOrgan CausesCauses Liver,Liver, SpleenSpleen Infiltration Lymphoma*, CMV, MAC BiliaryBiliary tracttract Cholecystitis CMV*, Cryptosporidium,* Microsporidium Papillary CMV*, Cryptosporidium,* KS stenosis Cholangitis CMV* dDI = didanosine; HSV = herpes simplex virus; KS = Kaposi's sarcoma; MAC = Mycobacterium avium complex The Universitydifferential diagnosis does not include nonof-AIDS Louisville specific conditions * More frequent (Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.) Differential Diagnosis of Abdominal Pain in AIDS

PancreasPancreas Inflammation CMV*, KS, pentamidine, dDI Tumor Lymphoma, KS Mesentery,Mesentery, peritoneumperitoneum Infiltration MAC*, Cryptococcus, KS, lymphoma, histoplasmosis, tuberculosis, coccidioidomycosis, toxoplasmosis dDI = didanosine; HSV = herpes simplex virus; KS = Kaposi's sarcoma; MAC = Mycobacterium avium complex; CMV = cytomegalovirus The differential diagnosis does not include non-AIDS specific conditions * MoreUniversity frequent of Louisville

(Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.) Evaluation of Abdominal Pain Syndromes in AIDS

Syndrome Suspected diagnosis Diagnostic approach Dull pain, diarrhea, Infectious enteritis Stool culture, O&P, mild nausea, vomiting sigmoidoscopy Acute, severe pain, Perforation, infectious Abdominal plain films, with peritoneal peritonitis surgical consultation, irritation ultrasound or CT, paracentesis if ascites is present, laparoscopy Right upper quadrant Cholecystitis, CT/ultrasound, ERCP, pain, abnormal liver cholangitis, hepatic liver biopsy biochemistry infiltrates, cholangiopathy Subacute pain, severe Intestinal obstruction Small bowel series, nausea and vomiting barium enema, University of Louisvilleendoscopy

(Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.) Evaluation of Abdominal Pain Syndromes in AIDS

Syndrome Suspected diagnosis Diagnostic approach DullDull pain,pain, InfectiousInfectious StoolStool culture,culture, diarrhea,diarrhea, mildmild enteritisenteritis O&P,O&P, nausea,nausea, vomitingvomiting sigmoidoscopysigmoidoscopy Acute,Acute, severesevere Perforation,Perforation, AbdominalAbdominal plainplain pain,pain, withwith infectiousinfectious films,films, surgicalsurgical peritonealperitoneal peritonitisperitonitis consultation,consultation, irritationirritation ultrasoundultrasound oror CT,CT, paracentesisparacentesis ifif ascitesascites isis present,present, University of Louisvillelaparoscopylaparoscopy

(Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.) Evaluation of Abdominal Pain Syndromes in AIDS

Syndrome Suspected diagnosis Diagnostic approach RightRight upperupper Cholecystitis,Cholecystitis, CT/ultrasound,CT/ultrasound, quadrantquadrant pain,pain, cholangitis,cholangitis, ERCP,ERCP, liverliver abnormalabnormal liverliver hepatichepatic infiltrates,infiltrates, biopsybiopsy biochemistrybiochemistry cholangiopathycholangiopathy

SubacuteSubacute pain,pain, IntestinalIntestinal SmallSmall bowelbowel severesevere nauseanausea andand obstructionobstruction series,series, bariumbarium vomitingvomiting enema,enema, endoscopyendoscopy University of Louisville

(Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed.) HIV/AIDS in Gastroenterology

BeforeBefore HAARTHAART seenseen inin 90%90% ofof patientspatients RemainsRemains commoncommon –– etiologyetiology mostmost oftenoften drugdrug inducedinduced InIn AIDS:AIDS: ¾¾alterationalteration inin mucosalmucosal immuneimmune systemsystem ¾¾untreatableuntreatable chronicchronic infectioninfection byby usuallyusually benignbenign organismsorganisms ¾¾moremore virulentvirulent coursecourse ofof commoncommon infectionsinfections University of Louisville Differential Diagnosis of Diarrhea in AIDS

Protozoa Bacteria Microsporidium[*] Clostridium difficile Cryptosporidium[*] Salmonella[*] Isospora belli Shigella[*] Toxoplasma Campylobacter[*] Giardia lamblia MAC Entamoeba histolytica Mycobacterium Leishmania donovani tuberculosis Blastocystis hominis Small bowel bacterial overgrowth Cyclospora sp. overgrowth Vibrio spp. Pneumocystis carinii Vibrio spp.

* More frequent.University MAC = Mycobacterium avium complex. of Louisville Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Differential Diagnosis of Diarrhea in AIDS Viruses Neoplasms Cytomegalovirus[*] Lymphoma Herpes simplex Kaposi's sarcoma Adenovirus Idiopathic Rotavirus “AIDS enteropathy” Norovirus HIV? Drug-induced HIV protease inhibitors Fungi Pancreatic disease Histoplasmosis Pancreatic insufficiency Coccidioidomycosis Chronic pancreatitis Cryptococcosis Infectious pancreatitis Candidiasis (CMV, MAC) Drug-induced pancreatitis (e.g., pentamidine)

* More frequent.University MAC = Mycobacterium avium complex. of Louisville Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Cryptosporidium

ProtozoaProtozoa –– mostmost prevalentprevalent diarrhealdiarrheal pathogenpathogen CryptosporidiumCryptosporidium –– mostmost frequentfrequent protozoaprotozoa identifiedidentified SmallSmall bowelbowel mostmost commoncommon sitesite

University of Louisville Cryptosporidium

ClinicalClinical Presentation:Presentation: SevereSevere diarrheadiarrhea –– severalseveral liters/dayliters/day stoolsstools BorborygmiBorborygmi NauseaNausea WeightWeight lossloss RUQRUQ painpain –– suggestssuggests biliarybiliary tracttract involvementinvolvement University of Louisville Cryptosporidium Diagnosis:Diagnosis: AcidAcid fastfast stainstain ofof stoolsstools –– brightbright redred spherulesspherules SmallSmall bowelbowel oror rectalrectal biopsiesbiopsies –– moremore sensitivesensitive Treatment:Treatment: ParmomycinParmomycin HAARTHAART Nitazoxanide/AzithromycinNitazoxanide/Azithromycin ÆÆ mixedmixed resultsresults SymptomaticSymptomatic ¾¾FluidFluid supportsupport University¾¾AntidiarrhealAntidiarrheal –– occasionallyoccasionally of Louisvillenarcoticnarcotic Microsporidium

CommonCommon inin thethe USUS TwoTwo speciesspecies implicated:implicated: ¾¾EnterocytozoonEnterocytozoon bienusibienusi ¾¾EncephalitozoonEncephalitozoon intestinalisintestinalis InfectionInfection associatedassociated withwith severesevere immunodeficiencyimmunodeficiency –– CD4CD4 << 100100

University of Louisville Microsporidium ClinicalClinical Presentation:Presentation: WateryWatery nonnon--bloodybloody diarrheadiarrhea –– mildmild toto moderatemoderate UsuallyUsually nono abdominalabdominal crampingcramping WeightWeight lossloss (not(not asas muchmuch asas cryptosporidium)cryptosporidium) Diagnosis:Diagnosis: StoolStool stainsstains –– onlyonly moderatelymoderately sensitivesensitive SmallSmall bowelbowel biopsybiopsy ÆÆ betterbetter –– moremore sensitivesensitive withwithUniversity BrownBrown--Brenn,Brenn, GramGram of ororLouisville TrichromeTrichrome stainstain Histopathology of Microsporidium/Cryptosporidium

PathogenesisPathogenesis isis poorlypoorly defineddefined LittleLittle tissuetissue inflammationinflammation RareRare villousvillous atrophyatrophy oror cellcell degenerationdegeneration Small bowel microsporidiosis – shedding epithelial cell containing University ofmicrosporidial Louisville oocysts

From Gazzard BG: Diarrhea in humahumann immunodeficiency virus antibody-positive patients. Semin Gastroenterol 2:3, 1991 Microsporidium

Treatment:Treatment: EncephalitozoonEncephalitozoon intestinalisintestinalis –– albendazolealbendazole EnterocytozoonEnterocytozoon bienusibienusi –– nono effectiveeffective treatmenttreatment HAARTHAART –– resolutionresolution ofof diarrheadiarrhea andand lossloss ofof pathogenpathogen fromfrom stoolstool andand smallsmall bowelbowel biopsybiopsy

University of Louisville Isospora belli

EndemicEndemic inin HaitiHaiti RareRare inin USUS DiagnosisDiagnosis ¾¾AcidAcid fastfast stainstain ofof stool,stool, duodenalduodenal aspirateaspirate ¾¾DuodenalDuodenal biopsybiopsy TreatmentTreatment -- effectiveeffective ¾¾SulfonamidesSulfonamides ¾¾PyrimethaminePyrimethamine University¾¾CiprofloxacinCiprofloxacin of Louisville CMV in small and large bowel

CMVCMV isis thethe mostmost commonlycommonly identifiedidentified pathogenpathogen inin AIDSAIDS ItIt isis thethe mostmost commoncommon causecause ofof viralviral diarrheadiarrhea MostMost frequentfrequent causecause ofof chronicchronic diarrheadiarrhea inin AIDSAIDS withwith multiplemultiple negativenegative stoolstool studiesstudies CD4CD4 countcount << 100100 ColonColon isis mostmost commoncommon sitesite ofof infectioninfection (concomitant(concomitant diseasedisease inin esophagus,esophagus, SB,SB, stomachstomachUniversity possible)possible) of Louisville CMV in small and large bowel ClinicalClinical Presentations:Presentations: AsymptomaticAsymptomatic carriercarrier WeightWeight lossloss andand feverfever AbdominalAbdominal painpain withoutwithout diarrheadiarrhea (usually(usually inin SBSB infection)infection) WateryWatery nonnon--bloodybloody diarrheadiarrhea HematocheziaHematochezia AbdominalAbdominal painpain withwith chronicchronic diarrheadiarrhea (most(most commoncommon inin colitis)colitis) University of Louisville CMV in small and large bowel - Pathology FocalFocal enteritisenteritis FocalFocal colitiscolitis AppendicitisAppendicitis DiffuseDiffuse ulceratingulcerating hemorrhagichemorrhagic inflammationinflammation PerforationPerforation InfectionInfection ofof vascularvascular endothelialendothelial cellscells –– possiblepossible rolerole forfor mucosalmucosal ischemiaischemia University of Louisville CMV Colitis

Diagnosis:Diagnosis: EndoscopicEndoscopic biopsybiopsy CulturesCultures –– lessless sensitivesensitive thanthan histopathologyhistopathology HistopathologyHistopathology ¾¾ViralViral cytopathiccytopathic effecteffect ¾¾ImmunohistochemistryImmunohistochemistry DiseaseDisease vs.vs. ColonizationColonization (few(few viralviral inclusionsinclusions ininUniversity macroscopicallymacroscopically normalnormal of tissue)tissue)Louisville CMV Colitis

Cytomegalovirus colitis EdemaUniversity and diffuse subepithelial of hemorrhage Louisville in sigmoid colon

Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. CMV Colitis

Treatment:Treatment: GanciclovirGanciclovir –– IVIV dailydaily ValganciclovirValganciclovir –– oral,oral, notnot wellwell studiedstudied forfor GIGI FoscarnetFoscarnet –– IVIV dailydaily CidofovirCidofovir –– IVIV weeklyweekly (less(less studiedstudied forfor GI)GI) DurationDuration –– 1414--2828 daysdays oror moremore HAARTHAART OphthalmologicOphthalmologic evaluationevaluation mustmust University of Louisville Idiopathic AIDS Enteropathy

DiarrheaDiarrhea withwith nono identifiableidentifiable pathogenpathogen inin AIDSAIDS IndirectIndirect effecteffect ofof HIVHIV onon entericenteric homeostasishomeostasis HIVHIV notnot demonstrateddemonstrated inin epithelialepithelial cellcell ImprovedImproved technologytechnology andand ‘‘panendoscopypanendoscopy withwith biopsybiopsy’’ ÆÆ decreaseddecreased reliancereliance onon thisthis diagnosisdiagnosis ImprovesImproves withwith proteaseprotease inhibitorsinhibitors University of Louisville Common Bacterial infections

Salmonella,Salmonella, Shigella,Shigella, CampylobacterCampylobacter –– increasedincreased virulence,virulence, bacteremia,bacteremia, AbxAbx resistanceresistance HighHigh fever,fever, severesevere abdominalabdominal pain,pain, diarrheadiarrhea (possibly(possibly bloody)bloody) DiagnosisDiagnosis –– stoolstool culturescultures TreatmentTreatment –– empiricempiric antibioticantibiotic whilewhile stoolstool culturescultures pendingpending –– e.g.e.g. –– ciprofloxacinciprofloxacin University of Louisville Clostridium difficile

HighHigh prevalenceprevalence duedue toto highhigh antibioticantibiotic useuse andand frequentfrequent hospitalizationshospitalizations –– notnot anan OIOI ClinicalClinical presentation,presentation, responseresponse toto therapytherapy andand relapserelapse raterate –– nono differentdifferent thanthan inin immunocompetentimmunocompetent patientpatient TreatmentTreatment –– Metronidazole,Metronidazole, vancomycinvancomycin ÆÆ generallygenerally effectiveeffective University of Louisville Mycobacterium avium complex

ClinicalClinical Presentation:Presentation: AsymptomaticAsymptomatic infectioninfection DiarrheaDiarrhea AbdominalAbdominal painpain WeightWeight lossloss MalabsorptionMalabsorption GIGI bleedbleed (rare)(rare) ObstructionObstruction (rare)(rare) University of Louisville Mycobacterium avium complex

Diagnosis:Diagnosis: EndoscopyEndoscopy –– yellowyellow mucosalmucosal nodulenodule inin duodenumduodenum (duodenal(duodenal involvementinvolvement mostmost common)common) EndoscopicEndoscopic biopsybiopsy –– mostmost sensitivesensitive FecalFecal acidacid fastfast smearsmear –– lowlow sensitivitysensitivity BloodBlood cultureculture University of Louisville Mycobacterium avium complex

A = H&E stain – small bowel biopsy shows marked thickening of the villi with a cellular infiltrate. B = High-power view with acid-fast staining shows numerous macrophages filledUniversity with mycobacteria of Louisville

Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Mycobacterium avium complex

Treatment:Treatment: MultidrugMultidrug therapytherapy withwith combinationscombinations of:of: ¾ Amikacin ¾ Ethambutol ¾ Rifampin ¾ Clarithromycin ¾ Ciprofloxacin HAARTHAART ¾ Early resolution University¾ No long term Abx therapy of Louisville GI - Mycobacterium tuberculosis

LessLess commoncommon inin USUS IleoIleo--cecalcecal region,region, colon,colon, rectum,rectum, peritonealperitoneal involvementinvolvement Fistula,Fistula, intususseption,intususseption, perforationperforation RespondsResponds toto multidrugmultidrug antituberculousantituberculous therapytherapy ImmuneImmune reconstitutionreconstitution syndromesyndrome –– exuberantexuberant inflammatoryinflammatory responseresponse toto quiescentquiescent pathogenpathogen onon institutioninstitution ofof HAARTHAART (also(also MACMAC lymphadenitis,lymphadenitis,University CMVCMV uveitis,uveitis,of Louisville HepatitisHepatitis B)B) GI - Histoplasmosis

UsuallyUsually withwith disseminateddisseminated infectioninfection withwith hepatichepatic andand pulmonarypulmonary involvementinvolvement Diffuse,Diffuse, largelarge ulcerationulceration withwith diarrheadiarrhea /mass/mass /serosal/serosal diseasedisease (peritonitis)(peritonitis) HighHigh feverfever withwith markedmarked elevationelevation ofof LDHLDH DiagnosisDiagnosis –– fungalfungal smearsmear && cultureculture ofof blood,blood, urine,urine, infectedinfected tissuetissue IVIV amphotericinamphotericin ÆÆ suppressivesuppressive therapytherapy withwith itraconazoleitraconazole HAARTHAARTUniversity of Louisville Evaluation of Diarrhea in AIDS

In all patients Stool for bacterial culture: Salmonella, Shigella, Campylobacter Stool for fecal leukocytes, Stool for O & P examination (at least 3-6 specimens) and acid-fast stain Clostridium difficile toxin in stool

If patient has rectal bleeding, tenesmus, or fecal leukocytes Flexible sigmoidoscopy or colonoscopy with biopsy of mucosa for pathology, viruses, protozoa Cultures of rectal tissue for bacteria (especially Campylobacter); viruses (optional)

If diarrhea and weight loss persist and above evaluation is negative Upper endoscopy with small bowel mucosal biopsy University of Louisville

Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Specific Treatment of Diarrhea in AIDS Treatment Duration (days) Bacteria * Duration of therapy dictated by immune reconstitution with highly active antiretroviral therapy Salmonella, Shigella, Fluoroquinolone (e.g., 10-14* Campylobacter ciprofloxacin) Clostridium difficile Vancomycin, 10-14 metronidazole Small bowel bacterial Metronidazole, 10-14 overgrowth ciprofloxacin Mycobacterium Isoniazid, rifampin, 9-12 mo tuberculosis pyrazinamide, ethambutol Mycobacterium avium Multidrug regimens for 9-12 mo complexUniversity symptomatic of infection Louisville

Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Specific Treatment of Diarrhea in AIDS Treatment Duration (days) Viruses * Duration of therapy dictated by immune reconstitution with highly active antiretroviral therapy Cytomegalovirus Ganciclovir 14-28* Foscarnet 14-28* Cidofovir 14-28* Herpes simplex Acyclovir 5-10*

Fungi Histoplasmosis Amphotericin B; 28 then itraconazole Coccidioidomycosis Amphotericin B; 28 then fluconazole Cryptococcosis Amphotericin B; 28 Universitythen fluconazole of Louisville Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Specific Treatment of Diarrhea in AIDS Treatment Duration (days) Protozoa Cryptosporidia Paromomycin 14-28 Cyclospora Trimethoprim-sulfamethoxazole or 14-28 ciprofloxacin Isopora belli Trimethoprim-sulfamethoxazole or 14-28 ciprofloxacin or pyrimethamine Microsporidia Albendazole (Encephalitozoon 14-28 intestinalis) Metronidazole, atovaquone, 14-28 fumagillin (not available in United States) (Enterocytozoon bienusi) University of Louisville

Adapted from Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. HIV/AIDS in Gastroenterology

OdynophagiaOdynophagia andand DysphagiaDysphagia AbdominalAbdominal PainPain DiarrheaDiarrhea AnorectalAnorectal DiseaseDisease AbnormalAbnormal LFTLFT ViralViral HepatitidesHepatitides andand HIVHIV University of Louisville Anorectal Disease FrequentFrequent inin AIDSAIDS patientpatient FrequencyFrequency inin homosexualhomosexual patientspatients isis higherhigher thanthan otherother AIDSAIDS patientspatients ImportantImportant toto examineexamine thethe anorectalanorectal regionregion CommonCommon findingsfindings include:include: ¾ Perirectal abscesses ¾ Anal fistulas ¾ Perianal HSV ¾ Ulceration – idiopathic, CMV, tuberculosis, histoplasmosis ¾ Infectious proctitis University¾ Lymphoma of Louisville Differential Diagnosis of Anorectal Disease in AIDS Infections

Bacteria Fungi Chlamydia trachomatis* Candida albicans Lymphogranuloma venereum Histoplasma capsulatum Neisseria gonorrhoeae* Shigella flexneri Neoplasms Mycobacterium tuberculosis Lymphoma* Kaposi's sarcoma Protozoa Squamous cell carcinoma Entamoeba histolytica Cloacogenic carcinoma Leishmania donovani Condyloma acuminatum

Viruses Other Herpes simplex* Idiopathic ulcers* CytomegalovirusUniversity* ofPerirectal Louisville abscess, fistula* * More frequent Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. HIV/AIDS in Gastroenterology

InIn thethe HAARTHAART era,era, liverliver diseasedisease hashas becomebecome aa veryvery importantimportant causecause ofof morbiditymorbidity andand mortalitymortality inin HIVHIV patientspatients LiverLiver relatedrelated complicationscomplications areare thethe mostmost commoncommon reasonreason forfor hospitalizationhospitalization inin HIVHIV patientspatients EndEnd--stagestage liverliver diseasedisease isis aa leadingleading causecause ofof deathdeath inin HIVHIV patientspatients ThereThere isis aa highhigh prevalenceprevalence ofof HIVHIV andand HepatitisHepatitisUniversity C/HepatitisC/Hepatitis BBof coco --infectionsinfectionsLouisville Abnormal LFT

Hepatic Parenchymal Biliary Disease Disease University of Louisville Differential Diagnosis of Abnormal Liver Tests/Hepatomegaly in AIDS

Hepatic parenchymal disease

¾ Drug-induced[*] ¾ Infection Sulfonamides Mycobacterium avium complex Sulfonamides Protease inhibitors Cytomegalovirus Protease inhibitors Hepatitis C ¾ Neoplasm Bacillary peliosis hepatis ¾ Neoplasm Lymphoma Mycobacterium tuberculosis Lymphoma Kaposi's sarcoma Cryptococcus Kaposi's sarcoma Hepatitis B, D Pneumocystis carinii MicrosporidiumUniversity of Louisville

Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Differential Diagnosis of Abnormal Liver Tests/Hepatomegaly in AIDS

BiliaryBiliary diseasedisease

¾ Cholangitis Cytomegalovirus Cryptosporidium Microsporidium

¾ Neoplasm Lymphoma UniversityKaposi's sarcoma. of Louisville

Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. Drug-induced liver injury in HIV

MostMost prevalentprevalent causecause ofof liverliver testtest abnormalitiesabnormalities EtiologyEtiology ¾¾AntiretroviralAntiretroviral meds,meds, otherother prescriptionprescription andand nonnon-- prescriptionprescription meds,meds, herbalherbal remediesremedies ¾¾BeforeBefore HAARTHAART –– sulfonamidessulfonamides (showed(showed increasedincreased freqfreq ofof DILIDILI inin AIDS)AIDS) ¾¾HAARTHAART eraera –– ProteaseProtease inhibitorsinhibitors (#1(#1 -- ritonavir)ritonavir) University of Louisville Drug-induced liver injury in HIV

MechanismMechanism ¾¾AllergicAllergic ¾¾IdiosyncraticIdiosyncratic ¾¾ExacerbationExacerbation ofof underlyingunderlying viralviral hepatitishepatitis ¾¾ImmuneImmune reconstitutionreconstitution syndromesyndrome ¾¾InteractionInteraction withwith otherother agentsagents ofof liverliver injuryinjury likelike NASH,NASH, alcoholalcohol abuseabuse oror otherother illicitillicit drugdrug abuseabuse University of Louisville Drug-induced liver injury in HIV

UsuallyUsually hepatocellularhepatocellular patternpattern ofof injuryinjury IncreasedIncreased transaminasestransaminases JaundiceJaundice isis uncommonuncommon exceptexcept withwith indinavirindinavir

University of Louisville Lactic Acidosis Syndrome MarkedMarked hepatomegaly,hepatomegaly, steatosis,steatosis, metabolicmetabolic lacticlactic acidosisacidosis andand liverliver failurefailure EtiologyEtiology –– nucleosidenucleoside reversereverse transcriptasetranscriptase inhibitorsinhibitors (AZT,(AZT, dDI,dDI, stavudine)stavudine) ImpairedImpaired mitochondrialmitochondrial DNADNA synthesissynthesis AssociatedAssociated –– myopathy,myopathy, peripheralperipheral neuropathy,neuropathy, pancreatitispancreatitis MostMost patientspatients –– worseningworsening diseasedisease ÆÆ deathdeath CurativeCurativeUniversity treatmenttreatment –– liverliverof transplantationtransplantationLouisville Hepatitis B and HIV HigherHigher raterate ofof hepatitishepatitis BB chronicitychronicity HigherHigher levellevel ofof HBVHBV replicationreplication (higher(higher viralviral load)load) LowerLower raterate ofof spontaneousspontaneous lossloss ofof HBeAgHBeAg andand seroconversionseroconversion toto antiHBeantiHBe AbAb LowerLower raterate ofof spontaneousspontaneous lossloss ofof HBsAgHBsAg andand spontaneousspontaneous seroconversionseroconversion toto antiHBsantiHBs AbAb ReappearanceReappearance ofof HepBsAgHepBsAg inin HIVHIV patientspatients previouslypreviously withwith antiHepBsantiHepBs AbAb duedue toto immunodeficiencyimmunodeficiencyUniversity (reinfection(reinfection of Louisville oror reactivation)reactivation) Hepatitis B and HIV ContradictoryContradictory datadata onon activityactivity ofof inflammationinflammation inin HBVHBV––HIVHIV coinfectionscoinfections –– ¾¾InitialInitial studiesstudies inin MSMMSM showshow lessless severesevere necronecro-- inflammationinflammation inin HBVHBV--HIVHIV (less(less AST/ALT)AST/ALT) ¾¾SomeSome studiesstudies –– nono impactimpact ofof HIVHIV onon HepHep BB progressionprogression ¾¾OtherOther studiesstudies –– moremore rapidrapid progressionprogression toto cirrhosiscirrhosis andand higherhigher raterate ofof decompensationdecompensation ofof cirrhosiscirrhosis inin HIVHIV--HBVHBV coinfectedcoinfected ¾¾RecentRecent studystudy inin MSMMSM showedshowed HIVHIV--HBVHBV coinfectedcoinfected atat greatergreater riskrisk ofof liverliver relatedrelated deathdeath Universitycomparedcompared toto HIVHIV oror HBVHBV of alonealone Louisville Hepatitis B and HIV - Treatment PatientsPatients whowho needneed antianti--HBVHBV butbut nono antianti--HIVHIV therapytherapy ¾¾AvoidAvoid HIVHIV--activeactive HBVHBV agentsagents (Lamivudine,(Lamivudine, Emtricitabine,Emtricitabine, Tenofovir)Tenofovir) ¾¾MonotherapyMonotherapy withwith onlyonly HBVHBV agentsagents (Interferon(Interferon αα,, Adefovir,Adefovir, Entecavir)Entecavir) PatientsPatients whowho needneed bothboth HBVHBV andand HIVHIV therapytherapy ¾¾AgentsAgents withwith dualdual activityactivity combiningcombining aa nucleosidenucleoside andand nucleotidenucleotide analoganalog (Tenofovir(Tenofovir ++ UniversityLamivudine/Emtricitabine)Lamivudine/Emtricitabine) of Louisville Hepatitis B and HIV - Treatment PatientPatient whowho needneed antianti--HIVHIV butbut nono HBVHBV therapytherapy ¾¾ IfIf HBVHBV titertiter << 10104 –– cancan treattreat HIVHIV alonealone andand closelyclosely monitermoniter ALTALT andand HBVHBV DNADNA ¾¾IfIf HBVHBV titertiter >> 10104-5 –– treattreat bothboth toto avoidavoid HBVHBV flareflare duedue toto immuneimmune reconstitutionreconstitution PatientPatient withwith cirrhosiscirrhosis ¾¾CombinationCombination HBVHBV--HIVHIV therapytherapy PatientsPatients withwith LamivudineLamivudine resistantresistant HBVHBV ¾¾TenofovirTenofovir shouldshould bebe addedadded toto LAMLAM University of Louisville Hepatitis C and HIV ClinicalClinical coursecourse ofof HepatitisHepatitis CC worsensworsens asas HIVHIV immunocompromiseimmunocompromise advancesadvances ¾¾HCVHCV RNARNA loadload increasesincreases ¾¾TransaminaseTransaminase increaseincrease ¾¾AcceleratedAccelerated coursecourse toto cirrhosiscirrhosis andand liverliver failurefailure ¾¾HigherHigher raterate ofof activeactive cirrhosiscirrhosis onon biopsybiopsy ¾¾MayMay causecause lethallethal fibrosingfibrosing cholestaticcholestatic hepatitishepatitis IncreasesIncreases riskrisk ofof HCVHCV transmissiontransmission HCVHCV maymay actact asas coco--factorfactor inin HIVHIV diseasedisease progression progressionUniversity of Louisville Hepatitis C and HIV- Treatment

FavorableFavorable effecteffect onon liverliver histologyhistology andand outcomeoutcome inin HCVHCV--HIVHIV coinfectedcoinfected whowho receivereceive HAARTHAART PegylatedPegylated interferoninterferon ++ RibavarinRibavarin isis thethe treatmenttreatment ofof choicechoice inin HCVHCV--HIVHIV coinfectionscoinfections ControlControl HIVHIV diseasedisease withwith HAARTHAART beforebefore treatingtreating HCVHCV University of Louisville MAC in the Liver

MostMost frequentfrequent hepatichepatic pathogenpathogen inin latelate--stagestage HIVHIV diseasedisease HallmarkHallmark –– poorlypoorly formedformed granulomasgranulomas containingcontaining acidacid--fastfast bacillibacilli inin foamyfoamy histiocyteshistiocytes MarkedMarked elevationelevation ofof alkalinealkaline phosphatasephosphatase DiagnosisDiagnosis –– liverliver histopathology,histopathology, cultureculture ofof mycobacteriummycobacterium aviumavium complexcomplex fromfrom liverliver biopsybiopsyUniversity tissue,tissue, of Louisville Mycobacterium tuberculosis in Liver

OccursOccurs beforebefore profoundprofound immunocompromiseimmunocompromise MayMay bebe partpart ofof miliarymiliary tuberculosistuberculosis TuberculousTuberculous abscesses,abscesses, bilebile ductduct tuberculomastuberculomas DiagnosisDiagnosis -- cultureculture ofof mycobacteriummycobacterium tuberculosistuberculosis fromfrom liverliver biopsybiopsy tissue,tissue, liverliver histopathologyhistopathology MultidrugMultidrug therapytherapy University of Louisville CMV in the Liver

UncommonUncommon hepatichepatic pathogenpathogen CanCan causecause aa hepatitishepatitis DiagnosisDiagnosis –– typicaltypical viralviral inclusioninclusion bodiesbodies usuallyusually inin KupfferKupffer cells,cells, sometimessometimes inin hepatocyteshepatocytes oror sinusoidalsinusoidal endothelialendothelial cellscells OccasionallyOccasionally causescauses granulomatousgranulomatous diseasedisease

University of Louisville Lymphoma in the Liver

MayMay bebe thethe indexindex manifestationmanifestation ofof AIDSAIDS LesionsLesions areare focal,focal, sometimessometimes largelarge PrognosisPrognosis dependsdepends onon extentextent ofof immunocompromiseimmunocompromise ImprovementImprovement inin survivalsurvival inin patientspatients receivingreceiving HAARTHAART

University of Louisville AIDS Cholangiopathy

SyndromeSyndrome resemblingresembling sclerosingsclerosing cholangitischolangitis withwith papillarypapillary stenosisstenosis ClinicalClinical presentation:presentation: ¾¾UpperUpper abdominalabdominal painpain ¾¾MarkedMarked alkalinealkaline phosphatasephosphatase elevationelevation ¾¾MinimalMinimal elevationelevation ofof AST,AST, ALT,ALT, bilirubinbilirubin ¾¾CT/ultrasonographyCT/ultrasonography maymay oror maymay notnot showshow ductalductal dilationdilation University of Louisville AIDS Cholangiopathy ERCPERCP FindingsFindings ¾¾PapillaryPapillary stenosisstenosis alonealone ¾¾SclerosingSclerosing cholangitischolangitis--likelike lesionslesions alonealone ¾¾CombinationCombination ofof thethe twotwo (most(most common)common) ¾¾LongLong extrahepaticextrahepatic stricturesstrictures EtiologyEtiology –– inin mostmost casescases duedue toto infectioninfection ofof duodenalduodenal andand biliarybiliary epitheliumepithelium byby ¾¾CryptosporidiumCryptosporidium ¾¾CMVCMV ¾¾MicrosporidiumMicrosporidium University of Louisville AIDS Cholangiopathy - ERCP

ArrowArrowUniversity == PapillaryPapillary stenosisstenosis of Louisville Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. AIDS Cholangiopathy

Treatment:Treatment: SphincterotomySphincterotomy forfor predominantpredominant papillarypapillary stenosisstenosis ÆÆ symptomaticsymptomatic improvementimprovement EradicationEradication ofof infectinginfecting pathogenpathogen HAARTHAART

University of Louisville Acalculous Cholecystits in AIDS

SevereSevere abdominalabdominal pain,pain, occasionaloccasional peritonitisperitonitis EtiologyEtiology –– ¾¾UsuallyUsually CMVCMV infectioninfection ¾¾SometimesSometimes microsporidia,microsporidia, cryptosporidiacryptosporidia oror isosporaisospora TreatmentTreatment –– LaparoscopicLaparoscopic cholecystectomycholecystectomy

University of Louisville