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Fever is the most ancient landmark of
disease. It is an increase in body
temperature above normal with its
circadian rhythm. It is the most common
presenting symptom of the pediatric
emergencies department ,representing 15-
30 % of all cases.
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Fever is an elevation ofbody temperature thatexceeds the normal daily
variation, inconjunction with an
increase in hypothalamic
set point
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Maximum normal oral
temperatureAt 6 AM: 37.2
At 4 PM: 37.7
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Pyrogens is any substance thatcauses fever
Exogenous pyrogens
Derived from outside the patient
Microbial products, toxins or whole
microorganisms
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Endogenous pyrogensCytokines are small proteins that regulate
immune, inflammatory and hematopoieticprocesses.
Cytokines that cause fever are calledpyrogenic cytokines. Produced from
monocytes, neutrophils and lymphocytes.
IL1, IL6, TNF, Ciliary neurotropic factor, andInterferon .
Each cytokine is encoded by a specific gene
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Endogenous pyrogensCytokines are small proteins that regulate
immune, inflammatory and hematopoieticprocesses.
Cytokines that cause fever are calledpyrogenic cytokines. Produced from
monocytes, neutrophils and lymphocytes.
IL1, IL6, TNF, Ciliary neurotropic factor, andInterferon .
Each cytokine is encoded by a specific gene
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Exogenouspyrogen
Activatedleukocytes
Endogenouspyrogen(IL1,TNF,)
Acute PhaseResponse
Pre-optic areaof anterior
hypothalamus(PGE2)
increase of setpoint
Brain cortex,
Vasoconstriction ,Muscle contraction
Heat production
Heat conservation
Fever
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IN FEVER
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Major causes of hepatitisare specific
hepatotropichepatitis A,B,C and deltaviruses.
Less common causes include other viralinfections (eg, infectious mononucleosis,yellow fever, cytomegalovirus infection).
Bacterial liver involvement with TB ,Leptospirosis ,etc may result ingranulomatous hepatitis.
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VIRUSES Bacterial
Q Fever
Leptospirosis
Relapsing Feve
Syphilis
Typhoid fever
Brucellosis
Tuberculosis
Leprosy
Yellow fever
ADENOVIRUSES
Rift Valley FevervirusCytomegalovirusDengue fever
Epstein-Barr virus
COXSACKIEVIRUSES
RUBELLA VIRUS
Lassa fever
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CLINICAL SIGNS OF LIVER DISEASE
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VIRUSES AFFECTING
LIVER
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Yellow fever
is an acuteviraldisease.It is animportant cause of
hemorrhagicillnessin manyAfricanand South
Americancountries.
http://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Hemorrhagehttp://en.wikipedia.org/wiki/Africahttp://en.wikipedia.org/wiki/South_Americahttp://en.wikipedia.org/wiki/South_Americahttp://en.wikipedia.org/wiki/South_Americahttp://en.wikipedia.org/wiki/South_Americahttp://en.wikipedia.org/wiki/Africahttp://en.wikipedia.org/wiki/Hemorrhagehttp://en.wikipedia.org/wiki/Virus -
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Yellowfever
(YF) is
caused byan
arbovirus.
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Yellow fever
(YF) istransmitted
by theAedes
aegyptimosquito.
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Yellow fever (YF) istransmitted by the
Aedes aegyptimosquito from :
1-one humanto
another (theurban form of YF)or from:
2- monkeystohumans (thejungle or sylvanform of YF).
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Pathogenesis of arboviruses
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Yellow feverAfter a 12-24 hourremission,
there is an "intoxication" orhepatorenal stagethat featuresreemergence of generalizedsymptoms including increasedtemperature,jaundice, andprostration.
Jaundiceusually appears on the
second or third day. After thethird day the symptoms recede,only to return with increasedseverity in the final stage.
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Rift Valley Fever
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Rift Valley Fever
Rift Valley Fever is aninfectious zoonoticdiseaseaffecting sheep, goats, and
cattle.
The disease is caused bytheRift Valley Fever (RVF) virus,
a member of the genusPhlebovirus.
The disease is transmittedby
Aedes aegyptimosquitoes.
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In severe cases,the disease becomes serious .Symptoms include fever, myalgias, and encephalitis,
including headache, coma, and seizures
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Rift Valley Fever
Severe cases of RVF fallinto three categories:
1 Liver necrosis(focal ordiffuse ) with hemorrhaging.
2 Retinitis with visualimpairment.
3 Meningoencephalitis
1977 outbreak in Egypt:
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1977 outbreak in Egypt:petechial haemorrhages and
hyphema in a womans face
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MODE OF TRANSMISSION
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Dengue hemorrhagic fever
Dengue fever(West Nile fever), isthe world's most important viralhemorrhagic fever disease; it is
the most geographically wide-spread of the arthropod-bornviruses, especially in the
Americas, the Pacific islands andon continental Asia.
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Dengue hemorrhagic fever
Dengue virus infection can present adiverse clinical spectrum,rangingfrom asymptomatic illness to dengueshock syndrome, as well as unusualmanifestations, such as hepatitis,
encephalitis, myocarditis, Reye'ssyndrome, hemolytic uremicsyndrome.
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Dengue hemorrhagic fever
Liver injurydue to dengue infection isnot uncommon and has beendescribed since 1970 .
Painful hepatomegaly, the mainclinical symptom observed, is seen in
up to 30% of patients.
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Barr virus-Epstein
Synonyms and related keywords:
glandular fever,infectious mono,infectious mononucleosis,Epstein-Barr virus, EBV, fever.
Infectious Mononucleosis
http://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htmhttp://www.emedicine.com/ped/topic705.htm -
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Infectious Mononucleosis
Pathophysiology
EBV is transmittedvia intimate contactwith body secretions, primarilyoropharyngeal secretions. EBV infects the
B cellsin the oropharyngeal epithelium.
Circulating B cellsspread the infection
throughout the entire reticularendothelial system (RES), ie, liver, spleen,and peripheral lymph nodes.
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Infectious Mononucleosis
I f ti M l i
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Infectious MononucleosisMOUTH
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Later physical
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p yfindingsincludehepatomegaly,
palatal petechiae,jaundice( less than10%),uvular edema,splenomegaly, and,
rarely, (1-2%)findings associatedwith splenic rupture.
Splenic tendernessmay be present inpatients with
splenomegaly.
M l i h titi i
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Mononucleosis hepatitisischaracterized by peculiar
necroinflammatory changeswhich,at the difference of classical viralhepatitides consist of moreinflammation and less necrosis.
The sinusoidsare filled and
distended with mononuclearcellswhich are large and sometimesclustered to resemble granulomassometimes similar to sarcoidosis.
f i l i
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Infectious mononucleosishepatitis:Marked mononuclear cellinfiltration of the sinusoidswithout
significant necrosis
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Mononucleosis hepatitis
Another peculiar feature isthe presence of a marked
regenerative activity ofhepatocyteswith presence ofincreased number of
binucleate cells, polyploidnuclei and mitotic figures.
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Infectious mononucleosisheapatitis:High power of previous
illustration showing the signs of highregenerative activity
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ATYPICAL LYMPHOCYTE
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Infectious Mononucleosis
Liver function testsshowelevation of liver enzymelevels in nearly90% of
people with glandular fever.
An early, transient,mildincrease in serumtransaminases ischaracteristic of EBVinfectious mononucleosis.
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Cytomegalovirus
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Cytomegalovirus
Cytomegalovirusan encapsulatedDNAvirus, Is amember of the
herpesviridaefamily ,is foundworldwide, though
it is more commonin developingnations.
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Cytomegalovirus
Only occasionally will the virus inducemononucleosis-like syndrome, prolongedfever, and or mild hepatitis. Otherwise,once the individual is infected, the virus
will remain dormant, and for most people,recurrent infections will not develop.
For immunocompromised individuals, thevirus is able to reactivate, which can leadto diseases such as CMV retinitis.
Cytomegalovirus
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Cytomegalovirus
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CMV inclusion body: Hepatocyte
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CMV inclusion body: Hepatocytewith a large intranuclear inclusion body.
Surrounded by a clear halo. Dark punctiforminclusions are seen also in the cytoplasm.
ViralHepatitis
Toxoplasmosis
Cytomegalovirus
Epstein-Barr Virus
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HepatitismosisalovirusBarr Virus
++/-++Fatigue
+-++Malaise
+/-+/-++Mild sore throat
+/---+Earlymaculopapularrash
---+Early bilateral
upper eyelidedema
-+--Unilaterallocalizedadenopathy
Viralh i i
Toxoplasmosis
Cytomegalovirus
Epstein-Barr Virus
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hepatitissmosisusBarr Virus
+/--++Bilateralposterior
cervicaladenopathy
+-+/-+/-Tenderhepatomegaly
-+/-+/-+Splenomegaly
-NN/-N/-WBC count
++++/-+++ElevatedSGOT/SGPT
-+++Atypicallymphocytes
(>10%)
Viralh titi
Toxoplasmosis
Cytomegalovirus
Epstein-Barr Virus
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hepatitisosisovirusBarr Virus
+/--+/-+/-Thrombocytopenia
--+-Elevated IgMCMV titer
---+Elevated IgMEBV VCAII titer
-+--Elevated IgMtoxoplasmosistiter
+---Elevatedhepatitis (eg, A,
B, D) IgM titer
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OTHER VIRUSESRARELY AFFECTING
THE LIVER
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ADENOVIRUSES:Severe and fatal hepatitiswith severe respiratory infection may
develop in these individuals. Intranuclearviral antigen has been detected in cases ofhepatitis .
COXSACKIE VIRUSES:Hepatitis isfrequently associated with myocarditis and
consists of necroinflammatory changesinvolving lobules and porta tracts, to bedistinguished from congestive changes due
to heart failure.
RUBELLA VIRUS :The liver may be
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RUBELLA VIRUS:The liver may beinvolved with variable degree of acute
hepatitis, biliary obstruction anddestruction.
Lassa fever:There is markedhepatocyte damage in the liverconsisting in eosinophilic necrosis ofindividual cells but jaundice is rare.
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Bacterial infections
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Q Fever
Q Fever
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Q Fever
Q fever is causedby a microbecalled "Coxiellaburnetii, Gram-negative
obligateorganisms.
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Animalssuch ascattle, sheep, and
goats can carry the Qfever microbeintissues involved inbirth--the uterus,placenta, and birthfluids.
Infected animals also
release the microbe inmilk and manure.
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Q Fever
People acquire the infection byinhalinginfectious aerosols andcontaminated dusts generated by
animals or animal products.
People can also get Q fever by
drinking infected milk, but mostinfections are spread through the air.
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Q fever PATHOGENESIS
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Q feverPATHOGENESIS
Q Fever: signs and symptoms
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Q g y p
A small percentage of patients develop
hepatitis and jaundice. Other rare clinical syndromesincluding
endocarditis, have been reported.
Hepato/splenomegalyand endocarditisare also common in chronicQ fever.
Q fever-focal hepatic granuloma (intra-
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Q fever focal hepatic granuloma(intraacinar granuloma with a central fat vacule
surrounded by fibrin ring and macrophages)
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L t i i
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Leptospirosis
Leptospirosis CAUSED BYLeptospira interrogans(Leptospiraicterohaemorrhagiae) : aflexible, spiral-shaped,Gram-negativespirochete with internalflagella.
Transmission occurs by contamination of
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water, soil, or vegetation by urineexcreted from infected animals.
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Interesting Fact:Brown ratscarrydiseases, including Weil's disease,Viral
hemorrhagic fever(VHF), Q fever.They can also act as reservoirs ofbubonic plague.
Leptospirosis:PATHOGENESIS
http://en.wikipedia.org/wiki/Weil%27s_diseasehttp://en.wikipedia.org/wiki/Viral_hemorrhagic_feverhttp://en.wikipedia.org/wiki/Viral_hemorrhagic_feverhttp://en.wikipedia.org/wiki/Q_feverhttp://en.wikipedia.org/wiki/Bubonic_plaguehttp://www.accuratepestmanagement.com/rat%20pic.jpghttp://en.wikipedia.org/wiki/Bubonic_plaguehttp://en.wikipedia.org/wiki/Q_feverhttp://en.wikipedia.org/wiki/Viral_hemorrhagic_feverhttp://en.wikipedia.org/wiki/Viral_hemorrhagic_feverhttp://en.wikipedia.org/wiki/Weil%27s_disease -
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p p
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Icteric
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leptospirosis orWeil's syndromeis the more severeform and ischaracterized by
deepjaundice(blilirubin
May exceed
30mg/dl)
Leptospirosis
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Leptospirosis
Liver involvement is marked by centrilobularnecrosis and Kupffer cellproliferation, withhepatocellular dysfunction.
Abdominal examination can reveal liverenlargement and tendernessfrom hepatitis.
A positive Murphy sign can be observed inpatients who develop acalculouscholecystitis.
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Relapsing Fever
Relapsing Fever
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Relapsing fever istransmitted to humans
by 2 vectors, ticks andlice.
Relapsing Fever
RFs are spirochetal infectionswithBorrel ia sp)gram negative
helical bacteria).
Relapsing Fever-transmission
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p g
Relapsing Fever-pathogenesis
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Relapsing Fever
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Relapsing Fever-CLINICAL
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Hepatosplenomegalyis common.
Conjunctival injection, epistaxis, cough,and slight hemoptysis may also occur.
Symptoms last for 3-10 days, whenthere is a crisis (>fever and severity ofother symptoms), followed by recoveryand relapsein about 7-14 days .
Petechial or maculopapular rash.
Rales , Rhonchi . Nuchal rigidity& Lymphadenopathy.
Iritis and iridocyclitis .
Jaundice in Relapsing Fever
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Jaundice in Relapsing Fever
The liver showsnecroinflammatory
changes withelevation of serumtransaminasesand
serumbilirubinup to15mg/100ml
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Syphilis
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Syphilis
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This historical disease used toproduce the "hepar lobatum" in itscongenital form due to dissecting
fibrosis produced by granulationtissue containing spirochetaepallidae and hepatic granulomas inany form.
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Typhoid and paratyphoidfever
Typhoid and paratyphoid fever
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Typhoid andparatyphoid fever
Typhoid feveris anacute systemicfebrile illnesscaused bySalmonella typhi.
S. Paratyphicauses the lesssevere paratyphoidfever.
Typhoid and paratyphoid fever
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Typhoid andparatyphoid fever
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Typhoid and paratyphoid fever
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Typhoid andparatyphoid fever
The liver is enlargedAND TENDER
Infarction abscessesand acute yellow
atrophy occur in rareinstances.
Moderate elevation in
serumtransaminasesandserumbilirubin
Salmonellosismay infect the liverwhere they produce histiocytic granulomas
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where they produce histiocytic granulomas.Typhoid noduleconsists of an intra
parenchymal focus of necrosis withhistiocytes, some neutrophils an will contain
the gram negative organisms.
Typhoid fever-focal hepatic necrosis
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Typhoid fever focal hepatic necrosis
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Brucellosis or undulant fever:B ll i i d
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Brucellosis is causedby gram negativecoccobacilli(Brucella abortusand other B.
biovars) transmitted through
contaminated milk,and animalproducts.
Sources of Brucella infection
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Sources of Brucella infection
Portals of entry for Brucella species
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Portals of entry for Brucella species
Spread of Brucella in the body
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Spread of Brucella in the body
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Brucellosis in the chronic form
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Brucellosisin the chronicform
will cause LIVER noncaseatinggranuloma lesions, sometimeswith atypical nuclei of their
histiocytes as to mimic Hodgkinsgranulomas.
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HEPATIC Tuberculosis
HEPATIC Tuberculosis
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It involves the liver most frequently
in miliary tuberculosiswhere it formsmultiple granulomas with or withoutgiant cells or caseation necrosis.
If the granulomas are numerous, theonly functional changemay beelevation of serum alkalinephosphatase due to the local
compression of the liver parenchymaaround each single granuloma.
HEPATIC Tuberculosis
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TB granulomasin the liver may bevery similar to those of sarcoidosisbecause caseation necrosis is oftenabsent.
Because the organismsare rarelyseen in TB granulomas of the liver,
the histological differential diagnosiswith sarcoidosis may be difficult.
Same TB granuloma of the liver
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Leprosy
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Liver granulomas are observed in the
lepromatous form of the disease.They contain acid-fast bacilli and the"lepra histiocyte" which are large
histiocyte with clear cytoplasm.
Hepatic granulomas may be the
cause of relapseafter an apparentsuccessful therapy.
Liver Lepromatous granulomawith H&E stain.
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Liver Lepromatous granuloma
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p g
RICKETTSIAL INFECTIONS
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*Rocky Mountain Spotted Fever : It is due to a rickettsia transmitted by
ticks. The organisms after infectionproliferate in endothelial cells of variousorgans.
The clinical syndrome 2 to 14 days afterthe tick bite starts with fever,malaise,vomiting. On the third day a skin rashappears on the limbs. Later the rash
disappears leaving hemorrhagic spots. Jaundiceis present in 1/3 of the cases
with portal inflammation and presence ofrickettsiae in the portal spaces.
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Causes of Hepatic Granulomas
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p
Bacterial Infections: brucellosis,cat-scratch fever, syphilis, TB*, othermycobacterial infections, Leprosy,tularemia, Q fever, Rickettsia,
Actinomycosis and Typhoid fever.
Viral infections, which are lesscommon (eg, infectious
mononucleosis, cytomegalovirus andCoxsackie) .
Hepatic Granulomas
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p
Hepatic granulomas are usuallyasymptomatic. However, theunderlying disorder may causeextrahepatic manifestations, hepaticinflammation, fibrosis, portalhypertension, or a combination.
The liver may enlarge slightly, andmild jaundice may develop.
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Hepatic granulomas
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Diagnosisis based on Liver function tests
&Imaging, but biopsyis necessary only if atreatable underlying disorder (eg, infection) issuspected or if other liver disorders need to beruled out.
liver function testresults are only mildlyderanged, usually with a disproportionateelevation of alkalinephosphatase. Bilirubinlevelsare typically normal or only mildly
elevated, unless concomitant hepatocellularinjury coexists. Enzymevalues may simulateviral hepatitis if extensive hepatocellularnecrosis is present (eg, in infectious
mononucleosis)
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Conclusion
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* A large number of viral and bacterial
organisms can involve the liver .
* These systemic infections can causehepatic derangements, ranging from mildliver function tests abnormalities to frankjaundice and, rarely, hepatic failure.
* They should be put in mind indifferential diagnosisof abnorml liverfunction tests.
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