Bilirubin metabolism and jaundice Table 18-1. Causes of aundice Type of Hyperbilirubine!ia "rine #ilirubin "rine "#$ Disorders "nconju%ated CB <20% Increased production of UCB Absent Extravascular hemoltic anemias! e"#"$ hereditar spheroctosis$ %h and AB& '() (ecreased upta*e or conju#ation of UCB Absent )ormal +ilbert sndrome! common #enetic defect in upta*e,conju#ation of UCB- jaundice occurs .ith fastin# Cri#ler/)ajjar sndromes! #enetic disorders .ith decreased to absent conju#atin# en0mes 1hsiolo#ic jaundice of ne.born! be#ins on da 2 of life- caused b normal macropha#e destruction of fetal %BCs &i'ed CB 20/30% 4iral hepatitis! defect in upta*e$ conju#ation of UCB and secretion of CB (bstructive CB 530% Absent (ecreased intrahepatic bile flo. (ru#/induced 6e"#"$ &C17 1rimar biliar cirrhosis (ubin/8ohnson sndrome! #enetic defect in secretion into intrahepatic bile ducts- blac* pi#ment in hepatoctes %otor9s sndrome! similar to (ubin/8ohnson sndrome but .ithout blac* pi#ment in hepatoctes (ecreased extrahepatic bile flo. +allstone in common bile duct Carcinoma of head of pancreas CB$ conju#ated bilirubin- '()$ hemoltic disease of ne.born- &C1$ oral contraceptive pill- UB+$ urobilino#en- UCB$ unconju#ated bilirubin" :" Bilirubin metabolism a" Unconju#ated bilirubin 6UCB7 i" ;enescent red blood cells 6%BCs7 are pha#octosed b splenic macropha#es" ii" UCB is the end product of heme de#radation" UCB is lipid/soluble" b" UCB combines .ith albumin in the blood" i" UCB is ta*en up b hepatoctes" ii" UCB is conju#ated to produce conju#ated bilirubin 6CB7" CB is .ater/soluble" c" CB is secreted into the intrahepatic bile ducts" i" <emporaril stored in the #allbladder ii" Enters the duodenum via the common bile duct d" Intestinal bacteria convert CB to urobilino#en 6UB+7" i" UB+ is spontaneousl oxidi0ed to urobilin" ii" Urobilin produces the bro.n color of stool" e" A small amount of UB+ is reccled to the liver and *idnes" Color of urine is due to urobilin" 22 8aundice a" 8aundice is due to an increase in UCB and,or CB" 8aundice is first noticed in the sclera" b" Classification of causes of jaundice is based on the percenta#e of CB 1ercent CB = CB,total bilirubin c" ;chematics sho.in# common causes of jaundice In this discussion$ the smbol 6>7 is used to indicate de#rees of ma#nitude" )or!al bilirubin !etabolis! 6*7 sho.s liver upta*e of lipid/soluble unconju#ated bilirubin 6UCB>7 and its conju#ation to .ater/soluble conju#ated bilirubin 6CB>7" CB is secreted into the common bile duct 6CB(7 and is emptied into the bo.el" Intestinal bacteria convert CB to urobilino#en 6UB+>7$ .hich spontaneousl oxidi0es to the pi#ment urobilin" Urobilin is responsible for the color of stool" A small percenta#e of UB+ is reabsorbed into the blood" ?ost of it enters the liver (larger arrow) and a small percenta#e (smaller arrow) enters the urine 6UB+>7" Urobilin is responsible for the color of urine" All the normal bilirubin in blood is UCB 6CB% <20%7 derived from macropha#e destruction of senescent %BCs" UCB does not enter urine$ because it is attached to albumin in the blood and is lipid$ not .ater$ soluble" CB is never a normal findin# in urine$ because it does not have contact .ith blood in its metabolism" In e'travascular +e!olysis 6#7 6e"#"$ hereditar spheroctosis7$ there is increased macropha#e production of UCB causin# an increase in serum UCB 6>>- CB% <20%7" <here is a correspondin# increase in upta*e and conju#ation of UCB$ conju#ation to CB 6>>7$ and conversion of CB in the bo.el to UB+ 6>>7" <his causes dar*enin# of the stool" <here is a #reater percenta#e of UB+ reccled bac* to the liver (wider arrow) and urine (wider arrow). <he increase in urine UB+ 6>>7$ dar*ens the color of urine" Because %BCs contain the en0me aspartate aminotransferase 6A;<7$ hemolsis of %BCs causes an increase in serum A;<" Alanine aminotransferase 6A@<7$ al*aline phosphatase 6A@17$ and A/#lutaml transferase 6++<7 levels are normal" In viral +epatitis 6C7$ there is #enerali0ed liver dsfunction involvin# upta*e and conju#ation of UCB$ secretion of CB into bile ducts$ and recclin# of UB+" ;erum UCB is increased 6>>7 o.in# to a decrease in upta*e and conju#ation" ;erum and urine CB are increased 6>>7 because of liver cell necrosis and disruption of bile ductules bet.een hepatoctes" Urine UB+ is increased 6>>7 because UB+ is redirected from the liver (smaller arrow) to the *idnes (larger arrow). Because there is an increase in serum UCB and CB$ there is a mixed hperbilirubinemia .ith a CB % of 20% to 30%" In viral hepatitis$ A@< is hi#her 6>>>7 than A;< 6>>7 and there is a sli#ht increase in A@1 and ++< 6>7" In alcoholic hepatitis$ A;< is #reater than A@<$ because alcohol dama#es mitochondria$ .hich is .here A;< is normall located" In obstructive liver disease 6D7$ an increase in serum and urine CB 6>>7 is due to obstruction of intrahepatic or extrahepatic bile flo. 6stone in the CB( in this case7" <his causes increased pressure in the intrahepatic bile ductules leadin# to rupture and e#ress of CB into sinusoidal blood" <here is absence of UB+ in the stool 6li#ht/ colored7 and urine" CB% 530% and there is a mar*ed increase in serum A@1 and ++< 6>>>7 and onl a sli#ht increase in serum A;< and A@< 6>7" ;ummar of liver function tests Table 18-,. Liver -unction Tests Test .i%nificance Liver Cell )ecrosis ;erum alanine transaminase 6A@<7 ;pecific en0me for liver cell necrosis 1resent in the ctosol A@< 5A;<! viral hepatitis ;erum aspartate transaminase 6A;<7 1resent in mitochondria Alcohol dama#es mitochondria! A;< 5A@< indicates alcoholic hepatitis C+olestasis ;erum A/#lutaml transferase 6++<7 Intra/ or extrahepatic obstruction to bile flo. Induction of ctochrome 1/B30 sstem 6e"#"$ alcohol7! increases ++< ;erum al*aline phosphatase 6A@17 )ormal ++< and increased A@1! source of A@1 other than liver 6e"#"$ osteoblastic activit in bone7 Increased ++< and A@1! liver cholestasis #ilirubin E'cretion CB <20% Unconju#ated hperbilirubinemia! e"#"$ extravascular hemoltic anemias CB 20/30% ?ixed hperbilirubinemia 6e"#"$ viral hepatitis7 CB 530% Conju#ated hperbilirubinemia 6e"#"$ liver cholestasis7 Urine bilirubin Bilirubinuria! viral hepatitis$ intra/ or extrahepatic obstruction of bile ducts Urine UB+ Increased urine UB+! extravascular hemoltic anemias$ viral hepatitis Absent urine UB+! liver cholestasis Hepatocyte -unction ;erum albumin Albumin is snthesi0ed b the liver 'poalbuminemia! severe liver disease 6e"#"$ cirrhosis7 1rothrombin time 61<7 ?ajorit of coa#ulation factors are snthesi0ed in the liver Increased 1<! severe liver disease Blood urea nitro#en 6BU)7 Urea ccle is present in the liver (ecreased serum BU)! cirrhosis ;erum ammonia Ammonia is metaboli0ed in the urea ccle Increased serum ammonia! cirrhosis$ %ee sndrome I!!une -unction ;erum I#? Increased in primar biliar cirrhosis Antimitochondrial antibod 1rimar biliar cirrhosis Anti/smooth muscle antibod Autoimmune hepatitis Antinuclear antibod Autoimmune hepatitis Tu!or &ar/er C/Detoprotein 6AD17 'epatocellular carcinoma CB$ conju#ated bilirubin- UB+$ urobilino#en- UCB$ unconju#ated bilirubin 0iral Hepatitis 1hases of acute viral hepatitis pa#e 2E3 pa#e 2EE :" 1rodrome a" Dever$ painful hepatome#al b" ;erum transaminases increase steadil" 1ea* just before jaundice occurs c" Atpical lmphoctosis 2" 8aundice a" 4ariable findin# dependin# on the tpe of hepatitis b" Increased urine bilirubin and urine UB+ 2" %ecover o 8aundice resolves 1hases of acute viral hepatitis pa#e 2E3 pa#e 2EE :" 1rodrome a" Dever$ painful hepatome#al b" ;erum transaminases increase steadil" 1ea* just before jaundice occurs c" Atpical lmphoctosis 2" 8aundice a" 4ariable findin# dependin# on the tpe of hepatitis b" Increased urine bilirubin and urine UB+ 2" %ecover o 8aundice resolves ?icroscopic findin#s in acute viral hepatitis :" @mphoctic infiltrate .ith destruction of hepatoctes o Apoptosis of hepatoctes 6Councilman bodies7 2" 1ersistent inflammation and fibrosis is an unfavorable si#n" o ;i#n of chronic hepatitis pro#ressin# to postnecrotic cirrhosis Epidemiolo# of viral hepatitis Table 18-1. 0iral Hepatitis2 Trans!ission and Clinical -indin%s 0irus Trans!ission Clinical -indin%s 'epatitis A Decal/oral No carrier state (oes not lead to chronic hepatitis &ccurs in da care centers$ prisons$ travelers to developin# countries$ and male homosexuals 6anal intercourse7 'epatitis B 1arenteral$ sexual$ vertical 6pre#nanc$ breast feedin#7 Carrier state ma occur Chronic hepatitis in :0% of immunocompetent patients ;erum sic*ness prodrome 63/:0%7! vasculitis 61A)7$ polarthritis$ membranous +) Increased incidence of hepatocellular carcinoma 'epatitis C 1arenteral$ sexual Carrier state ma occur ?ild hepatitis- jaundice uncommon Chronic hepatitis in 5F0% of cases Associated .ith posttransfusion hepatitis$ tpe I ?1+)$ alcohol excess$ 1C< Increased incidence of hepatocellular carcinoma 'epatitis ( 1arenteral$ sexual Carrier state ma occur %eGuires 'BsA# to replicate Chronic state less li*el .ith coinfection 6'B4 and '(4 exposure at same time7 than superinfection 6'B4 carrier exposed to blood containin# 'B4 and '(47 'epatitis E Decal/oral 6.aterborne7 No carrier state or chronic hepatitis Dulminant hepatitis ma develop in pre#nant .omen &ccurs in developin# countries 'epatitis + 1arenteral Carrier state No chronic hepatitis +)$ #lomerulopath- ?1+)$ membranoproliferative #lomerulonephritis- 1A)$ polarteritis nodosa- 1C<$ porphria cutanea tarda" ;erolo#ic studies in viral hepatitis Table 18- 3. .erolo%ic .tudies in Hepatitis # H#s*% H#e*% H#0 D)* *nti-H#c- I%& *nti-H#c- I%$ *nti- H#s Interpretation > / / / / Earliest phase of acute 'B4 > > > / / Acute infection / / > / / Hindo. phase$ or serolo#ic #ap / / / > > %ecovered from 'B4 / / / / > Immuni0ed > / / > / I'ealthI carrier if 'BsA# 5E months > > / > / Chronic infective carrier if 5E months Anti/'Bc$ core antibod- anti/'Bs$ surface antibod- 'BeA#$ e anti#en- 'BsA#$ surface anti#en" pa#e 2EE pa#e 2EF pa#e 2EF pa#e 2EJ pa#e 2EJ pa#e 2EK pa#e 2EK pa#e 2F0 pa#e 2F0 pa#e 2F: pa#e 2F: pa#e 2F2 pa#e 2F2 pa#e 2F2 :" 'epatitis A virus 6'A47 a" Anti/'A4/I#? indicates active infection" b" Anti/'A4/I#+ indicates recover from infection or vaccination" 1rotective antibod 2" 'epatitis B virus 6'B47 a" 'epatitis B surface anti#en 6'BsA#7 22 Appears .ithin 2 to J .ee*s after exposure Dirst mar*er of infection 222 1ersists up to B months in acute hepatitis 'BsA# lon#er than E months defines chronic 'B4" b" 'epatitis B e anti#en 6'BeA#7 and 'B4/()A 22 Infective particles 222 Appear after 'BsA# and disappear before 'BsA# c" Anti/'B4 core antibod I#? 6anti/'Bc/I#?7 22 )onprotective antibod %emains positive in acute infections 222 1ersists durin# I.indo. phaseI or Iserolo#ic #apI 'BsA#$ 'B4 ()A$ and 'BeA# are absent" 2222 Converts to anti/'Bc/I#+ in E months d" Anti/'B4 surface antibod 6anti/'Bs7 22 1rotective antibod 222 ?ar*er of immuni0ation after 'B4 vaccination e" Chronic 'B4 22 1ersistence of 'BsA# lon#er than E months Anti/'Bc/I#? converts to anti/B'c/I#+" 222 I'ealthI chronic carrier 1resence of 'BsA# and anti/'Bc/I#+ Absence of ()A and e anti#en 2222 Infective chronic carrier 1resence of 'BsA#$ anti/'Bc/I#+$ and infective particles 6()A and e anti#en7 Increased ris* for postnecrotic cirrhosis and hepatocellular carcinoma 2" 'epatitis C virus 6'C47 a" ;creen .ith en0me immunoassa 22 1resence of anti/'C4/I#+ indicates infection or recover" 222 It is not a protective antibod" b" Confirmator tests 22 %ecombinant immunoblot assa 6%IBA7 222 'C4 %)A usin# polmerase chain reaction 2222 1ositive %IBA and 'C4 %)A indicate infection" 2v2 1ositive %IBA and ne#ative 'C4 %)A indicate recent recover" 2" 'epatitis ( virus 6'(47 a" 1resence of anti/'(4/I#? or I#+ indicates active infection" b" I#+ is not a protective antibod" B" 'epatitis E virus 6'E47 a" 1resence of anti/'E4/I#? indicates active infection" b" Anti/'E4/I#+ indicates recover 6protective antibod7" &ther laborator test findin#s :" CB 20% to 30% 6mixed hperbilirubinemia7 a" (ecreased upta*e,conju#ation of UCB b" CB #ains access to blood via dama#ed bile ductules" 2" Increased urine UB+ and urine bilirubin a" CB is .ater/soluble and is filtered in the *idnes" b" UB+ reccled bac* to inflamed liver is redirected to the *idnes" 2" Increased serum transaminases a" ;erum A@< #reater than A;< b" ;erum A@< is the last liver en0me to return to normal" (t+er Infla!!atory Disorders ;ummar of important infectious diseases Table 18-4. Infectious Diseases of t+e Liver Disease Pat+o%en5s6 C+aracteristics Amebiasis Entamoeba histolytica Usuall ri#ht lobe abscess Ascendin# cholan#itis Escherichia coli Inflammation of bile ducts 6cholan#itis7 from concurrent biliar infection and duct obstruction 6e"#"$ stone7 <riad of fever$ jaundice$ ri#ht upper Guadrant pain ?ost common cause of multiple liver abscesses Clonorchiasis Clonorchis sinensis 6Chinese liver flu*e7 Contracted b in#estin# encsted larvae in fish- larvae enter common bile duct and become adults ?a produce cholan#iocarcinoma Echinococcosis Echinococcus granulosus 6sheepherder9s disease7 ;in#le or multiple csts containin# larval forms (o# is definitive host- human is intermediate host %upture of csts can produce anaphlaxis +ranulomatous hepatitis Mycobacterium tuberculosis, Histoplasma capsulatum ;i#n of miliar spread ;chistosomiasis chistosoma mansoni E##s incite a fibrotic response in the portal vein 6Ipipestem cirrhosisI7 Complications of cirrhosis! portal hpertension$ ascites$ and esopha#eal varices ;pontaneous peritonitis Escherichia coli in adults treptococcus pneumoniae in children (evelops in ascites 6e"#"$ cirrhosis$ nephrotic sndrome7 ;ummar of important infectious diseases Table 18-4. Infectious Diseases of t+e Liver Disease Pat+o%en5s6 C+aracteristics Amebiasis Entamoeba histolytica Usuall ri#ht lobe abscess Ascendin# cholan#itis Escherichia coli Inflammation of bile ducts 6cholan#itis7 from concurrent biliar infection and duct obstruction 6e"#"$ stone7 <riad of fever$ jaundice$ ri#ht upper Guadrant pain ?ost common cause of multiple liver abscesses Clonorchiasis Clonorchis sinensis 6Chinese liver flu*e7 Contracted b in#estin# encsted larvae in fish- larvae enter common bile duct and become adults ?a produce cholan#iocarcinoma Echinococcosis Echinococcus granulosus 6sheepherder9s disease7 ;in#le or multiple csts containin# larval forms (o# is definitive host- human is intermediate host %upture of csts can produce anaphlaxis +ranulomatous hepatitis Mycobacterium tuberculosis, Histoplasma capsulatum ;i#n of miliar spread ;chistosomiasis chistosoma mansoni E##s incite a fibrotic response in the portal vein 6Ipipestem cirrhosisI7 Complications of cirrhosis! portal hpertension$ ascites$ and esopha#eal varices ;pontaneous peritonitis Escherichia coli in adults treptococcus pneumoniae in children (evelops in ascites 6e"#"$ cirrhosis$ nephrotic sndrome Autoimmune hepatitis pa#e 2F2 pa#e 2FB :" &ccurs most often in oun# .omen 2" Clinical findin#s o Dever$ jaundice$ hepatosplenome#al 2" @aborator findin#s a. 1ositive serum antinuclear antibod 6A)A7 test b. Anti/smooth muscle antibodies )eonatal hepatitis :" Epidemiolo# a" Idiopathic b" Associated .ith infections 6e"#"$ ctome#alovirus7 c" Associated .ith inborn errors of metabolism 6e"#"$ C:/antitrpsin deficienc7 2" Biops sho.s multinucleated #iant cells o I+iant cellI hepatitis %ee sndrome :" Usuall develops in children oun#er than B ears of a#e o &ften follo.s a chic*enpox or influen0a infection 2" ?itochondrial dama#e 6L virus$ saliclates7 a. (isruption of the urea ccle Increase in serum ammonia b. (efective M/oxidation of fatt acids 2" ?icrovesicular tpe of fatt liver o ;mall ctoplasmic #lobules without nuclear displacement 2" Clinical findin#s a. Encephalopath Cerebral edema$ coma$ convulsions b. 'epatome#al 2" @aborator findin#s a. <ransaminasemia b. )ormal to sli#ht increase in total bilirubin c. Increased serum ammonia Acute fatt liver of pre#nanc :" Abnormalit in M/oxidation of fatt acids 2" Datal to mother and fetus unless the bab is delivered 1reeclampsia :" 'pertension$ proteinuria$ dependent pittin# edema in third trimester 2" @iver cell necrosis around portal triads o Increased serum transaminases 2" 'E@@1 sndrome a. 'emoltic anemia .ith schistoctes b. Elevated serum transaminases c. @o. platelets (ue to disseminated intravascular coa#ulation Dulminant hepatic failure pa#e 2FB pa#e 2F3 Acute liver failure .ith encephalopath .ithin J .ee*s of hepatic dsfunction :" Causes a" 4iral hepatitis 6most common overall cause7 b" (ru#s 6e"#"$ acetaminophen most common cause7 c" %ee sndrome 2" +ross and microscopic findin#s a" Hrin*led capsular surface due to loss of hepatic parenchma b" (ull red to ello. necrotic parenchma .ith blotches of #reen 6bile7 2" Clinical findin#s o 'epatic encephalopath 6see section 4II7$ jaundice 2. @aborator findin#s a" (ecrease in transaminases @iver parenchma is destroed" b" Increase in 1< and ammonia Circulatory Disorders 1rehepatic obstruction to blood flo. &bstruction of blood flo. to the liver 6i"e"$ hepatic arter$ portal vein7 :" 'epatic arter thrombosis .ith infarction a" @iver infarction is uncommon because of a dual blood suppl" 'epatic arter and portal vein tributaries normall empt blood into the sinusoids" b" Causes 22 @iver transplant rejection 222 4asculitis due to polarteritis nodosa 2" 1ortal vein thrombosis a" Causes 22 1lephlebitis 6inflammation of portal vein7 ?ost often due to acute appendicitis Air in biliar tree from bacterial #as 222 1olcthemia vera 2222 'epatocellular carcinoma <umor invasion of the portal vein b" Clinical findin#s 22 1ortal hpertension$ ascites$ splenome#al 222 No hepatome#al 1rehepatic obstruction to blood flo. &bstruction of blood flo. to the liver 6i"e"$ hepatic arter$ portal vein7 :" 'epatic arter thrombosis .ith infarction a" @iver infarction is uncommon because of a dual blood suppl" 'epatic arter and portal vein tributaries normall empt blood into the sinusoids" b" Causes 22 @iver transplant rejection 222 4asculitis due to polarteritis nodosa 2" 1ortal vein thrombosis a" Causes 22 1lephlebitis 6inflammation of portal vein7 ?ost often due to acute appendicitis Air in biliar tree from bacterial #as 222 1olcthemia vera 2222 'epatocellular carcinoma <umor invasion of the portal vein b" Clinical findin#s 22 1ortal hpertension$ ascites$ splenome#al 222 No hepatome#al Intrahepatic obstruction to blood flo. Intrahepatic obstruction to sinusoidal blood flo. :" Causes a" Cirrhosis 6see ;ection 4II7 b" Centrilobular hemorrha#ic necrosis c" 1eliosis hepatis$ sic*le cell disease 2" Centrilobular hemorrha#ic necrosis a" ?ost often due to left/sided heart failure 6@'D7 and ri#ht/sided heart failure 6%'D7 i" @'D decreases cardiac output causin# hpoperfusion of the liver" Causes ischemic necrosis of hepatoctes located around central vein ii" %'D causes a bac*/up of sstemic venous blood into the central veins and sinusoids" b" Enlar#ed liver .ith a mottled red appearance 6Inutme#I liver7 i" Con#estion of central veins and sinusoids ii" )ecrosis of hepatoctes around the central vein c" Clinical findin#s i" 1ainful hepatome#al .ith or .ithout jaundice ii" Increased transaminases caused b ischemic necrosis iii" ?a pro#ress to cardiac cirrhosis Dibrosis around central veins 2" 1eliosis hepatis a" ;inusoidal dilation due to blood b" Causes i" Anabolic steroids ii" !artonella henselae causin# bacillar an#iomatosis &ccurs in AI(; c" 1otential for intraperitoneal hemorrha#e 1osthepatic obstruction to blood flo. pa#e 2FE pa#e 2FF &bstruction of blood flo. out of the liver 6e"#"$ hepatic vein7 :" Causes a" 'epatic vein thrombosis b" 4eno/occlusive disease 2" 'epatic vein thrombosis a" Causes i" 1olcthemia vera ii" &ral contraceptive pills iii" 'epatocellular carcinoma Invades hepatic vein b" Clinical findin#s i" Enlar#ed$ painful liver ii" 1ortal hpertension$ ascites$ splenome#al iii" 'i#h mortalit rate c" @aborator findin#s i" Increased transaminases ii" Increased 1< 2" 4eno/occlusive disease a" Complication of bone marro. transplantation b" Colla#en develops around the central veins" 'ematobilia Blood in the bile in patients .ith trauma to the liver *lco+ol- 7elated and Dru%- and C+e!ical- Induced Liver Disorders Alcohol/related disorders pa#e 2FF pa#e 2FJ :" %is* factors for alcohol/related liver disease 2" 1ath.as for alcohol metabolism 2" <pes of liver disease a" Datt chan#e is the most common tpe of disease i" ;ubstrates of alcohol metabolism are used to snthesi0e liver tri#lceride" ii" Clinical findin#s <ender hepatome#al without fever or neutrophilic leu*octosis b" Alcoholic hepatitis i" 1atho#enesis (ue to acetaldehde dama#e to hepatoctes ;timulation of colla#en snthesis around the central vein 1erivenular fibrosis ii" ?icroscopic findin#s Datt chan#e .ith neutrophil infiltration ?allor bodies (ama#ed cto*eratin intermediate filaments in hepatoctes 1erivenular fibrosis iii" Clinical findin#s 1ainful hepatome#al Dever$ neutrophilic leu*octosis$ ascites$ hepatic encephalopath ?a pro#ress to alcoholic cirrhosis c" Cirrhosis 6see section 4II7 B" @aborator findin#s Alcohol/related disorders pa#e 2FF pa#e 2FJ :" %is* factors for alcohol/related liver disease 2" 1ath.as for alcohol metabolism 2" <pes of liver disease a" Datt chan#e is the most common tpe of disease i" ;ubstrates of alcohol metabolism are used to snthesi0e liver tri#lceride" ii" Clinical findin#s <ender hepatome#al without fever or neutrophilic leu*octosis b" Alcoholic hepatitis i" 1atho#enesis (ue to acetaldehde dama#e to hepatoctes ;timulation of colla#en snthesis around the central vein 1erivenular fibrosis ii" ?icroscopic findin#s Datt chan#e .ith neutrophil infiltration ?allor bodies (ama#ed cto*eratin intermediate filaments in hepatoctes 6see 1erivenular fibrosis iii" Clinical findin#s 1ainful hepatome#al Dever$ neutrophilic leu*octosis$ ascites$ hepatic encephalopath ?a pro#ress to alcoholic cirrhosis c" Cirrhosis 6see section 4II7 B" @aborator findin#s Chemical/ and dru#/induced liver disease Table 18-8. Dru%- and C+e!ical-Induced Liver Diseases Disease Cause Tu!ors An#iosarcoma 4inl chloride$ arsenic$ thorium dioxide 6radioactive contrast material7 Cholan#iocarcinoma <horium dioxide 'epatocellular carcinoma Aflatoxin 6due to "spergillus mold7 @iver cell adenoma &ral contraceptive pills (t+er Liver Diseases Acute hepatitis Isonia0id 6caused b toxic metabolite7$ halothane$ acetaminophen$ methldopa Cholestasis &ral contraceptive pills 6estro#en interferes .ith intrahepatic bile secretion7$ anabolic steroids Datt chan#e Amiodarone 6resembles alcoholic hepatitis- ?allor bodies and pro#ression to cirrhosis7$ methotrexate Dibrosis ?ethotrexate$ retinoic acid$ amiodarone (bstructive 5C+olestatic6 Liver Disease <pes of cholestatic liver disease :" Intrahepatic cholestasis a" Bloc*a#e of the intrahepatic bile ducts b" Causes i" (ru#s 6e"#"$ oral contraceptive pills$ anabolic steroids7 ii" )eonatal hepatitis iii" 1re#nanc/induced cholestasis 6estro#en7 2" Extrahepatic cholestasis a" Bloc*a#e of common bile duct 6CB(7 b" Causes i" ;tone usuall ori#inatin# from the #allbladder ii" 1rimar sclerosin# pericholan#itis iii" Extrahepatic biliar atresia iv" Carcinoma head of pancreas <pes of cholestatic liver disease :" Intrahepatic cholestasis a" Bloc*a#e of the intrahepatic bile ducts b" Causes i" (ru#s 6e"#"$ oral contraceptive pills$ anabolic steroids7 ii" )eonatal hepatitis iii" 1re#nanc/induced cholestasis 6estro#en7 2" Extrahepatic cholestasis a" Bloc*a#e of common bile duct 6CB(7 b" Causes i" ;tone usuall ori#inatin# from the #allbladder ii" 1rimar sclerosin# pericholan#itis iii" Extrahepatic biliar atresia iv" Carcinoma head of pancreas +ross and microscopic :" Enlar#ed$ #reen/colored liver 2" Bile ducts distended .ith bile$ bile la*es$ bile infarcts Clinical findin#s pa#e 2FJ pa#e 2FK :" 8aundice .ith pruritus o 1ruritus due to bile salts deposited in s*in 2" ?alabsorption o Bile salts do not enter the small intestine" 2" Cholesterol deposits in s*in o (ue to cholesterol in bile B" @i#ht/colored stools o (ue to a lac* of urobilin @aborator findin#s :" CB 530% 2" Bilirubinuria 2" Absent urine UB+ B" Increase in serum A@1 and ++< Beni#n intrahepatic cholestasis of pre#nanc :" (ue to estro#en inhibition of intrahepatic bile secretion 2. Not dan#erous to the fetus or mother Extrahepatic biliar atresia :" Cause of jaundice in ne.borns 2" Inflammator destruction of all or part of the extrahepatic bile ducts 2" Bile duct proliferation in the triads B" Common indication for liver transplantation in a child 1rimar sclerosin# pericholan#itis :" Epidemiolo# a" &bliterative fibrosis of intrahepatic and extrahepatic bile ducts b" ?ale dominant c" Associated .ith ulcerative colitis 2" Clinical findin#s a" 8aundice b" Cirrhosis c" Increased incidence of cholan#iocarcinoma Cirr+osis Irreversible diffuse fibrosis of the liver .ith formation of re#enerative nodules %e#enerative nodules :" 'epatocte reaction to injur 2" @ac* normal liver architecture o @ac* of portal triads and sinusoids 2" ;urrounded b bands of fibrosis B" Compress sinusoids and central veins a. Intrasinusoidal hpertension b. %eduction in the number of functional sinusoids c. Increase in hdrostatic pressure in portal vein Causes :" Alcoholic liver disease 6most common7 2" 1ostnecrotic cirrhosis 6'B4$ 'C47 2" Autoimmune disease 6primar biliar cirrhosis7 B" ?etabolic disease! a" 'emochromatosis$ Hilson9s disease b. C:/Antitrpsin deficienc$ #alactosemia Complications associated .ith cirrhosis Ammonia derives from metabolism of amino acids and from the release of ammonia from amino acids b bacterial ureases in the bo.el" Ammonia 6)'27 is diffusible and is reabsorbed into the portal vein for deliver to the urea ccle .here it is metaboli0ed into urea" Ammonium 6)'B > 7 is not reabsorbed in the bo.el and is excreted in stool" ?ethods for reducin# the snthesis of ammonia in the colon include restriction of protein inta*e 6most cost effective7 and the use of oral neomcin$ .hich destros the colonic bacteria" &ral administration of lactulose results in the release of hdro#en ions causin# )'2 to be converted to )'B > $ .hich is excreted in the feces" :" 'epatic failure o End point of pro#ressive dama#e to the liver a. ?ultiple coa#ulation defects i" (ue to inabilit to snthesi0e coa#ulation factors ii" 1roduces a hemorrha#ic diathesis b. 'poalbuminemia from decreased snthesis of albumin 1roduces dependent pittin# edema and ascites 22 'epatic encephalopath i" %eversible metabolic disorder ii" Increase in aromatic amino acids 6e"#"$ phenlalanine$ trosine$ trptophan7 Converted into false neurotransmitters 6e"#"$ #amma aminobutric acid7 iii" Increase in serum ammonia (ue to a defective urea ccle that cannot metaboli0e ammonia iv" Clinical findin#s Alterations in the mental status ;omnolence and disordered sleep rhthms Asterixis 6i"e"$ inabilit to sustain posture$ flappin# tremor7 Coma and death in late sta#es 2" 1ortal hpertension a. 1atho#enesis i" %esistance to intrahepatic blood flo. due to intrasinusoidal hpertension ii" Anastomoses bet.een portal vein tributaries and the arterial sstem b. Complications i" Ascites 6see belo.7 ii" Con#estive splenome#al Increased hdrostatic pressure in splenic vein 'persplenism .ith various ctopenias ma occur iii" Esopha#eal varices iv" 'emorrhoids$ periumbilical venous collaterals 6caput medusae7 2" Ascites a. 1atho#enesis i" 1ortal hpertension Increase in portal vein hdrostatic pressure ii" 'poalbuminemia (ecreases oncotic pressure iii" ;econdar hperaldosteronism- causes! (ecreased cardiac output Activates the renin/an#iotensin/aldosterone sstem 6retention of )a > and .ater7 @iver unable to metaboli0e aldosterone b. Clinical findin#s i" Abdominal distention .ith a fluid .ave ii" Increased ris* for spontaneous bacterial peritonitis B" 'epatorenal sndrome a. %enal failure without renal parenchmal disease b. (ue to decreased renal blood flo. c. 1reservation of renal tubular function 3" 'perestrinism in males a. 1atho#enesis i" @iver cannot de#rade estro#en and :F/*etosteroids 6e"#"$ androstenedione7" ii" Androstenedione is aromati0ed into estro#en in the adipose cell" b. Clinical findin#s i" +necomastia ii" ;pider telan#iectasia iii" Demale distribution of hair 1ostnecrotic cirrhosis :" ?ost often caused b chronic hepatitis due to 'B4 and 'C4 2" Increased incidence of hepatocellular carcinoma 1rimar biliar cirrhosis 61BC7 pa#e 2J: pa#e 2J2 :" Epidemiolo# a" Autoimmune disorder +ranulomatous destruction of bile ducts in portal triads b" &ccurs more often in .omen bet.een B0 and 30 ears of a#e c" 1ro#resses from a chronic inflammator reaction to cirrhosis 2" Clinical findin#s a" 1ruritus 22 (eposition of bile salts in s*in 222 Earl findin# .ell before jaundice appears b" 'epatome#al c" 8aundice @ate findin# after most of the bile ducts have been destroed b" Cirrhosis .ith portal hpertension c" Increased ris* for hepatocellular carcinoma 22 @aborator findin#s a" Antimitochondrial antibodies 65K0% of cases7 b" Increase in I#? ;econdar biliar cirrhosis :" Complication of chronic extrahepatic bile duct obstruction o Example/cstic fibrosis$ .here bile is dehdrated 2. No increase in antimitochondrial antibodies or I#? 'ereditar hemochromatosis pa#e 2J2 pa#e 2J2 <he normal function of the 'DE #ene product is to facilitate the bindin# of plasma transferrin 6bindin# protein of iron7 .ith its mucosal cell transferrin receptor so that transferrin can be endoctosed b intestinal cells" <he amount of endoctosed transferrin iron determines ho. much mucosal cell iron is released into the plasma" In hemochromatosis$ .hen there is a mutated 'DE #ene$ mucosal cell transfer of iron to plasma transferrin is al.as at a maximum resultin# in iron overload" 'emosiderosis 6secondar hemochromatosis7 is caused b multiple blood transfusions 6e"#"$ sic*le cell anemia$ thalassemia major7- alcohol abuse 6alcohol increases iron reabsorption7- and .ell .ater 6iron pipes7" Iron deposits are more prevalent in macropha#es than in parenchmal tissue" pa#e 2JB :" Epidemiolo# a" Autosomal recessive disorder b" ?ale dominant disorder c" In .omen$ smptoms develop after menopause" (ue to menses causin# loss of iron 2" 1atho#enesis a" Unrestricted reabsorption of iron in the small intestine b" ?utations involvin# hereditar hemochromatosis #ene 6'DE7 <here is a :!:0 carrier rate in the population" c" Iron stimulates the production of hdroxl free radicals Dree radicals dama#e tissue and cause fibrosis" 2" Iron deposits in multiple or#ans o @iver$ pancreas$ heart$ joints$ s*in$ pituitar 2. Clinical and laborator findin#s a" Cirrhosis 22 Iron deposits primaril in hepatoctes 222 Increased ris* of hepatocellular carcinoma b" IBron0e diabetesI 22 <pe I diabetes mellitus (estruction of M/islet cells 222 'perpi#mentation Iron deposits in s*in and increases melanin production c" ?alabsorption (estruction of exocrine pancreas 22 %estrictive cardiomopath$ de#enerative joint disease 22 Increased serum iron$ percent saturation$ and ferritin 22 (ecreased total iron/bindin# capacit <ransferrin snthesis is decreased .hen iron stores are increased Hilson9s disease 6hepatolenticular de#eneration7 Ceruloplasmin$ the bindin# protein for copper$ is secreted into the plasma .here it represents K0% to K3% of the total serum copper concentration" <he remainin# 3% to :0% of copper is free copper that is loosel bound to albumin" Ceruloplasmin is eventuall ta*en up and de#raded b the liver" <he copper that .as bound to ceruloplasmin is excreted into the bile" <he #ene defect in Hilson9s disease affects a copper transport sstem that produces a dual defect/decreased snthesis of ceruloplasmin in the liver and decreased excretion of copper into bile" Accumulation of copper in the liver increases the formation of free radicals causin# dama#e to hepatoctes" In a fe. ears$ unbound copper is released from the liver into the circulation 6increased in blood and urine7 .here it dama#es the brain$ *idnes$ cornea$ and other tissues" :" Epidemiolo# o Autosomal recessive disorder 2" 1atho#enesis a. +ene mutation i" (efective hepatocte transport of copper into bile for excretion ii" (ecreased snthesis of ceruloplasmin 6bindin# protein for copper in blood7 b. Unbound copper eventuall accumulates in blood i" @oosel attached to albumin ii" Copper deposits in other tissues causin# a toxic effect" 2" Clinical and laborator findin#s a. @iver disease pro#resses from acute hepatitis to cirrhosis" b. Naser/Dleischer rin# (ue to free copper deposits in (escemet9s membrane in the cornea 22 Central nervous sstem disease i" Copper deposits in the putamen 1roduces a movement disorder resemblin# par*insonism ii" Copper deposits in the subthalamic nucleus 1roduces hemiballismus iii" Copper is toxic to neurons in the cerebral cortex 1roduces dementia b. (ecreased total serum copper (ue to decreased ceruloplasmin 22 (ecreased serum ceruloplasmin Useful in dia#nosin# Hilson9s disease in its earl sta#es 22 Increased serum and urine free copper Useful in dia#nosin# Hilson9s disease in the later sta#es C : /Antitrpsin 6AA<7 deficienc :" Autosomal recessive disorder 2" 1atho#enesis a" Alleles are inherited codominantl 6each allele expresses itself7" b" )ormal #enotpe is 1i??" c" ?ost common abnormal allele is O" d" 1iOO variant has decreased AA< levels in serum" i" 1roduction of a mutant protein that cannot be secreted into blood ii" Accumulation of AA< in hepatoctes causes liver dama#e" 1eriodic acid/;chiff stains sho. red ctoplasmic #ranules" 2" Clinical findin#s in children .ith 1iOO variant a" )eonatal hepatitis .ith intrahepatic cholestasis b" ?ost common cause of cirrhosis in children c" Increased ris* for hepatocellular carcinoma B" Poun# adults .ith panacinar emphsema o 1iOO variant .here there is no snthesis of AA< in the liver @aborator test abnormalities in cirrhosis pa#e 2J3 pa#e 2JE :" (ecreased serum blood urea nitro#en 6BU)7 and increased serum ammonia o (ue to disruption of the urea ccle 2" Dastin# hpo#lcemia o (efective #luconeo#enesis and decreased #lco#en stores 2" Chronic respirator al*alosis o <oxic products from hepatic dsfunction overstimulate respirator center B" @actic acidosis o @iver dsfunction in convertin# lactic acid to pruvate 3" 'ponatremia E" 'po*alemia o ;econdar aldosteronism increases renal exchan#e of )a > for N >
F" Increased 1< o (ecreased snthesis of coa#ulation factors J" 'poalbuminemia o (ecreased snthesis of albumin K" 'pocalcemia a. 'poalbuminemia decreases the total serum calcium" Approximatel B0% of the total calcium is calcium bound to albumin" b. 4itamin ( deficienc (ecreased liver 23/hdroxlation of vitamin (" 2" ?ild transaminasemia o En0mes are not mar*edl increased due to the loss of parenchmal cells" Liver Tu!ors Beni#n tumors :" Cavernous heman#ioma a" ?ost common beni#n tumor b" %are cause of intraperitoneal hemorrha#e 2" @iver 6hepatic7 cell adenoma a" Beni#n tumor of hepatoctes b" Usuall occur in .omen of childbearin# a#e Associated .ith the use of oral contraceptive pills c" 'i#hl vascular tumors 22 <endenc to rupture durin# pre#nanc 222 1roduce intraperitoneal hemorrha#e Beni#n tumors :" Cavernous heman#ioma a" ?ost common beni#n tumor b" %are cause of intraperitoneal hemorrha#e 2" @iver 6hepatic7 cell adenoma a" Beni#n tumor of hepatoctes b" Usuall occur in .omen of childbearin# a#e Associated .ith the use of oral contraceptive pills c" 'i#hl vascular tumors 22 <endenc to rupture durin# pre#nanc 222 1roduce intraperitoneal hemorrha#e ?ali#nant tumors :" ?etastasis a" ?ost common liver cancer b" 1rimar cancers of lun# 6most common7$ #astrointestinal tract$ breast c" ?ultiple nodular masses 2" 'epatocellular carcinoma a" Epidemiolo# i" ?ost common primar liver cancer ii" ?ale dominant 1ea*s around E0 ears of a#e iii" Causes Chronic 'B4 and 'C4 Aflatoxins 6from "spergillus mold in #rains and peanuts7 'ereditar hemochromatosis$ alcoholic cirrhosis$ 1BC$ AA< deficienc b" 1atho#enesis i" ?ost often associated .ith preexistin# cirrhosis ii" 1ostnecrotic cirrhosis 'B4,'C4 most common ris* factors c" +ross findin#s i" Docal$ multifocal$ or diffusel infiltratin# cancer Hith or .ithout preexistin# cirrhosis 6usuall .ith preexistin# cirrhosis7 ii" 1ortal and hepatic vein invasion is common" d" ?icroscopic findin#s Characteristic findin# is the presence of bile in neoplastic cells" b" Clinical findin#s i" Dever due to liver cell necrosis ii" %apid enlar#ement of the liver iii" Increased ascites$ blood present in ascitic fluid b" @aborator findin#s i" Increased C/fetoprotein 6AD17 ii" 1roduction of ectopic hormones Erthropoietin 6secondar polcthemia7 Insulin/li*e factor 6hpo#lcemia7 c" @un# most common metastatic site 2" An#iosarcoma o Exposure to vinl chloride 6most common cause7$ arsenic$ or thorium dioxide $allbladder and #iliary Tract Disease Cstic diseases pa#e 2JF pa#e 2JJ :" Choledochal cst a" ?ost common cst in biliar tract in children oun#er than :0 ears old b" Clinical findin#s i" Abdominal pain .ith persistent or intermittent jaundice ii" Increased incidence of cholelithiasis$ cholan#iocarcinoma$ and cirrhosis 2" Caroli disease a" Autosomal recessive disease b" ;e#mental dilatation of intrahepatic bile ducts c" Clinical findin#s i" Association .ith polcstic *idne disease ii" Increased incidence of cholan#iocarcinoma Cstic diseases pa#e 2JF pa#e 2JJ :" Choledochal cst a" ?ost common cst in biliar tract in children oun#er than :0 ears old b" Clinical findin#s i" Abdominal pain .ith persistent or intermittent jaundice ii" Increased incidence of cholelithiasis$ cholan#iocarcinoma$ and cirrhosis 2" Caroli disease a" Autosomal recessive disease b" ;e#mental dilatation of intrahepatic bile ducts c" Clinical findin#s i" Association .ith polcstic *idne disease ii" Increased incidence of cholan#iocarcinoma Cholan#iocarcinoma :" ?ost common mali#nanc of bile ducts 2" Causes of cholan#iocarcinoma a" 1rimar sclerosin# pericholan#itis 6see section 4I7 ?ost common cause in United ;tates b" Clonorchis sinensis 6Chinese liver flu*e7 c" <horotrast 6thorium dioxide7 d" Choledochal cst and Caroli disease 2" Clinical findin#s a" &bstructive jaundice b" 1alpable #allbladder 6Courvoisier9s si#n7 +allstones 6cholelithiasis7 :" pes a" Cholesterol stones 6J0% of cases7 <he are radiolucent" b" 1i#ment stones 22 Blac* and bro.n pi#ment stones 222 ;ome are radiopaGue" 2" 1atho#enesis a" Cholesterol stones 22 ;upersaturation of bile .ith cholesterol 222 (ecreased bile salts and lecithin Both normall solubili0e cholesterol in bile 2222 %is* factors Demale over B0 ears old &besit Cholesterol is increased in bile" Use of oral contraceptive pills Estro#en increases cholesterol in bile" %apid .ei#ht loss$ use of lipid/lo.erin# dru#s )ative Americans 6e"#"$ 1ima and )avajo Indians7 b" 1i#ment stones 22 Blac* pi#ment stones ;i#n of chronic extravascular hemoltic anemia 6e"#"$ sic*le cell anemia7 Excess bilirubin in bile produces calcium bilirubinate 222 Bro.n pi#ment stones ;i#n of infection in the CB( 2" Complications associated .ith stones a" Cholecstitis 6most common7 b" CB( obstruction c" +allbladder cancer d" Acute pancreatitis Acute cholecstitis pa#e 2JK pa#e 2K0 :" 1atho#enesis a" &bstruction of cstic duct b a stone 6K0% of cases7 i" Causes increased intraluminal pressure and ischemia to #allbladder .all ?ucosal ulceration predisposes to infection 6usuall E. coli7" ii" Chemical irritation from conversion of lecithin to lsolecithin 6toxic7 b" &ther causes not associated .ith stones i" AI(; Infection .ith ctome#alovirus 6C?47 or Cryptosporidium ii" ;evere volume depletion 2" Clinical and laborator findin#s a" Dever .ith nausea and vomitin# Usuall :3 to 20 minutes after eatin# b" Initial midepi#astric colic* pain c" 1ain eventuall shifts to the ri#ht upper Guadrant" i" 1ain is constant and dull ii" 1ain ma radiate to ri#ht scapula b" 8aundice su##ests a stone in the CB(" c" )eutrophilic leu*octosis .ith left shift d" <ests to identif stones i" Ultrasound is the #old standard ii" %adionuclide scan identifies stone6s7 in cstic duct" Chronic cholecstitis :" 1atho#enesis a" Cholelithiasis .ith repeated attac*s of minor inflammation b" Chemical inflammation 6infection is uncommon7 2" Clinical findin#s a" ;evere$ persistent pain : to 2 hours postprandiall b" %ecurrent epi#astric distress$ belchin#$ and bloatin# Cholesterolosis :" Excess cholesterol in bile a" Cholesterol deposits in macropha#es b" 1roduces a ello.$ spec*led mucosal surface 2. No clinical si#nificance +allbladder adenocarcinoma :" Epidemiolo# a" (ominant in elderl .omen b" 1oor pro#nosis 2" 1atho#enesis a" Cholelithiasis 6K3% of cases7 b" 1orcelain #allbladder +allbladder .ith dstrophic calcification Pancreatic Disorders Embrolo#ic abnormalities of the pancreas pa#e 2K0 pa#e 2K: :" Annular pancreas a" (orsal and ventral buds form a rin# around the duodenum" b" Associated .ith small bo.el obstruction 2" Aberrant pancreatic tissue 6i"e"$ heterotopic rest$ choristoma7 o @ocations/.all of stomach$ duodenum$ jejunum$ or in a ?ec*el diverticulum 2. ?ajor pancreatic duct a" ?ajor pancreatic duct and CB( are confluent in their terminal part Both empt their contents into the duodenum via the ampulla of 4ater b" Important in the patho#enesis of acute pancreatitis 22 ;tone6s7 obstruct terminal part of the CB( 222 Increased bac*/pressure refluxes bile into the major pancreatic duct 2222 Bile activates pancreatic proen0mes causin# acute pancreatitis Embrolo#ic abnormalities of the pancreas pa#e 2K0 pa#e 2K: :" Annular pancreas a" (orsal and ventral buds form a rin# around the duodenum" b" Associated .ith small bo.el obstruction 2" Aberrant pancreatic tissue 6i"e"$ heterotopic rest$ choristoma7 o @ocations/.all of stomach$ duodenum$ jejunum$ or in a ?ec*el diverticulum 2. ?ajor pancreatic duct a" ?ajor pancreatic duct and CB( are confluent in their terminal part Both empt their contents into the duodenum via the ampulla of 4ater b" Important in the patho#enesis of acute pancreatitis 22 ;tone6s7 obstruct terminal part of the CB( 222 Increased bac*/pressure refluxes bile into the major pancreatic duct 2222 Bile activates pancreatic proen0mes causin# acute pancreatitis Acute pancreatitis pa#e 2K: pa#e 2K2 An increase in amlase is not specific for pancreatitis" &ther causes of hperamlasemia include mumps$ small bo.el infarction$ and a ruptured ectopic pre#nanc" :" Epidemiolo# and patho#enesis a" Alcohol abuse and #allstones are the major causes b" ?ust be activation of pancreatic proen0mes 6inactive en0mes7 Activation leads to autodi#estion of the pancreas c" ?echanisms of activation of proen0mes 22 &bstruction of the main pancreatic duct or terminal CB( +allstones 6see section IQ7 Alcohol thic*ens ductal secretions Also increases duct permeabilit to en0mes 222 Chemical injur of acinar cells Examples/thia0ides$ alcohol$ tri#lceride 65:000 m#,d@7 2222 Infectious injur of acinar cells Examples/C?4$ mumps$ coxsac*ievirus 2v2 ?echanical injur of acinar cells Examples/seat belt trauma$ posterior penetration of duodenal ulcer v2 ?etabolic activation of proen0mes 6e"#"$ hpercalcemia$ ischemia$ shoc*7 b" <rpsin is important in the activation of proen0mes" 22 1roteases dama#e acinar cell structure" 222 @ipases and phospholipases produce en0matic fat necrosis" 2222 Elastases dama#e vessel .alls and produce hemorrha#e 2v2 Activated en0mes also circulate in the blood" 2" Clinical findin#s a" Dever$ nausea and vomitin# b" ;evere$ borin# midepi#astric pain .ith radiation into the bac* %adiation into bac* is due to its retroperitoneal location" b" ;hoc* (ue to hemorrha#e and loss of en0me/rich fluid around the pancreas 6called Ithird spacin#I7 c" 'poxemia 22 Circulatin# pancreatic phospholipase destros surfactant" @oss of surfactant produces atelectasis and intrapulmonar shuntin#" 222 Acute respirator distress sndrome 6A%(;7 ma occur" b" +re/<urner9s si#n 6flan* hemorrha#e7$ Cullen9s si#n 6periumbilical hemorrha#e7 c" <etan 22 'pocalcemia is caused b en0matic fat necrosis" 222 Calcium binds to fatt acids leadin# to a decrease in ioni0ed calcium" 2" @aborator findin#s a" Increased serum amlase 22 Increased in 2 to :2 hours 222 %eturns to normal in 2 to 2 das Increased renal clearance 2222 1resent in urine for : to :B das b" Increased serum lipase 22 ?ore specific for pancreatitis 222 ;erum levels return to normal in 2 to 3 das" 2222 Is not excreted in urine c" )eutrophilic leu*octosis d" 'pocalcemia$ hper#lcemia 6destruction of M/islet cells7 e" Computed tomo#raphic 6C<7 scan is the #old standard for pancreatic ima#in#" f" 1lain abdominal radio#raph 22 ;entinel loop in subjacent duodenum or transverse colon 6cut/off si#n7 @ocali0ed ileus$ .here the bo.el does not demonstrate peristalsis 222 @eft/sided pleural effusion containin# amlase 6:0% of cases7 2" Complications a" 1ancreatic pseudocst 22 Collection of di#ested pancreatic tissue around pancreas 222 Abdominal mass .ith persistence of serum amlase lon#er than :0 das Amount of amlase in the fluid surpasses renal clearance of amlase" b" A%(;$ pancreatic abscess$ disseminated intravascular coa#ulation Chronic pancreatitis pa#e 2K2 pa#e 2K2 :" Epidemiolo# a" ?ajorit of cases are idiopathic" b" Nno.n causes i" Alcohol abuse is the most common *no.n cause" ii" Cstic fibrosis is the most common cause in children" iii" ?alnutrition is the most common cause in developin# countries" 2" 1atho#enesis a" %epeated attac*s of acute pancreatitis produce duct obstruction" b" Calcified concretions occur as .ell as dilation of the ducts" %adio#raphic des sho. a Ichain of la*esI appearance in the major duct" 22 Clinical findin#s a" ;evere pain radiatin# into the bac* b" ?alabsorption c" <pe : diabetes mellitus d" 1ancreatic pseudocst 22 @aborator and radio#raphic findin#s a" Increased amlase and lipase b" 1ancreatic calcifications 6C< scan best stud7 Exocrine pancreatic cancer :" Epidemiolo# a" Adenocarcinoma 4arin# de#rees of differentiation b" Causes 22 ;mo*in# 6most common cause7 222 Chronic pancreatitis 2222 'ereditar pancreatitis 2" 1atho#enesis a" Association .ith #$%" #ene mutation b" ?utation of suppressor #enes 6&'() and &'*+7 2" @ocation a" ?ost occur in the pancreatic head 6E3% of cases7 &ften bloc*s CB( causin# jaundice b" %emainder occur in the bod and tail 22 Clinical and laborator findin#s a" Epi#astric pain .ith .ei#ht loss b" ;i#ns of CB( obstruction 6carcinoma of head of pancreas7 22 8aundice 6CB 5 30%7 222 @i#ht/colored stools 6absent UB+7 2222 1alpable #allbladder 6Courvoisier9s si#n7 b" ;uperficial mi#rator thrombophlebitis c" Increased CA:K/K +old standard tumor mar*er 22 1oor pro#nosis