Hepatobiliary And Pancreatic Goljan.docx

Laboratory evaluation of liver cell injury Bilirubin metabolism and jaundice            

Ucb conjugated o glucuronic acid by ugt Intestinal bacteria convert cb to urobilinogen ( some use the term stercobilinogen ) Ubg is spintaneosly oxidized to urobilin ( stercobilin) Approximately 20% of ubg is recycled to the liver (90% of 20%) and kidneys (10% of 20%) Jaundice is due to increase in ucb or/and cb Sclera has a high affinity for bilirubin %CB = cb/total bilirubin Mcc of jaundice is hep , 2nd mcc is gilbert(more in man , mc hereditary cause of jaundice) Criggler najjar with 0 ugt activity is incompatible woth life – needs liver transplantation Physiological jaundice of nb begins on day 3 Breast milk jaundidce – due to preg nane 3 , 30 diol , which inhibits ugt – no treatment required

Liver function tests  Alcohol increase ggt  Alp can be increased by osteoblastic activity  Hepatocyte functions o Serum albumin o Pt o Factor 5 o Bun o Serum ammonia – ammonia derived from large bowel and amino acid degradation  Immune function o Igm increased in PBC o Ama increased in pbc o Antismooth muscle ab and ana increased In AI hep Viral hepatitis  Phases of acute viral hepatitis o Prodrome  Fever , painful splenomegaly , distaste for cig and alcohol  Steady increase in serum transaminases just before jaundice occur  Atypical lymphocytosis o Jaundice o Recovery – jaundice resolves  Microscopic finding in acute viral hepatitis o Lymphocytic infilteration and destruction of hepatocytes  Apoptosis of hepatocytes( councilmen bodies )

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Persistent inflame and fibrosis is a bad sign – sign of chronic hepatitis progressing to postnecrotic cirrhosis Epidemiology  HAV – 2nd mcc of acute hep in us , mc hep producing jaundice (70%),  HBV – mc acute hep in US , 2nd mcc of fulminant hepatitis  Comp – fulminant hepatitis , HCC secondary to postnecrosis cirrhosis (20%)?  HCV – mcc of hep due to ivda .  hemophilcs transfused before 1987 ,  Mc chronic blood bourne inf in us (85%)  3rd mcc of acute hepatitis  Comp – hcc due to postnecrosis cirrhosis (3%)  No vaccine  HDV – incomplete virus that req hbsag to replicate  Cytolytic virus so fulminant hep can occur  HEV – only produces fulminant hepatisis esp in pregnant Serological studies in viral hepatitis  HAV – igm – active infection .  Igg – recovery or immunization ( protective )  HBV  HBsAg o First marker of infxn o Appears 2-8 weeks after exposure  HBeAg and HBV DNA – infective paraticle o Appears after HBsAg and disappeares before HBsAg  Anti HB c IgM o Non protective ab > remains positive in acute infection o Only ag/ab + during window phase o Converts entirely to igG by 6m regardless of hbsag state  Anti HBs ab o Protective ab – marker of immunization  Infective chronic carrier (+ HBeag /hbv dna ) are at a greater risk for postnecrosis cirrhosis and hcc compared to healthy chronic carrier  HCV  Screen with eia o + Anti HCV igG indicates active infxn or recovery (97% sensitivity)  does not differentiate between acute , chronic , resolved infxn  NOT a protective ab  Confirmatory tests

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RIBA – ordered if eia + Hcv rna using pcr detects viral load  Gold standard for diagnosing hcv  To confirm active infxn and to montor pt on therapy + riba and + hcv rna indicatae active infxn + riba and – hcv rna indicate cure from treatment

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   HDV  Anti hdc igM or igG indicates active infection  Igg is NOT protectoive  HEV  + anti HEV IgM = active infxn  Anti hev igg indicates recovery ( protective) o Alt is more specific for liver necrosis than ast . also alt is the last liver enzyme to return to normal Infectious liver disorders o Ascending cholangitis – llife threatening . triad of fever , jaundice , ruq pain  Mcc cause of multiple liver abces o Liver abcess – causes : ascending cholangitis (mcc) , intraabd infxn , direct extension , hematogenous . jaundice is uncommon o Granulomatous hepatitis – tb – military spread o Spontaneous peritonitis – develops in ascites o Leptospirosis – biphasic ( weil ) disease – septicemic and immune phase o Amebiasis – mcc of liver abcess worldwide ( not in us) o Clonorchiasis – becomes adult in cbd o Schistosomiasis – pipestem cirrhosis o Echinococcus – hyatid cyst Autoimmune hepatitis o Type 1 mc o Young women o Range of Clx – symptomatic with increased transaminases , fulminant hepatitis , cirrhosis o HLA dr3 and dr4 o Fever jaundice hepatosplenomegaly o + antiSM ab , + ana Neonatal hepatitis o Idiopathic . ass with cong infxn (cmv) . ass with inborn errors of metabolism (A1AT def)) o Biopsy shows multinucleated giant cells i.e giant cell hepatitis Reye syndrome o Postinfectious triad to define reye syndrome include  Encephalopathy  Microvesicular fatty change

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 Serum transaminase elevation o Often follows chickenpox or influenza o Path  Mito damge  Disruption of urea cycle  Def b oxi in damaged mito > more fa becomes TAG > fatty change  Microvesicular – small cytoplasmic globules that do not displace nucleus o Clx  Encephalopathy ( cerebral edema woth increased cerebral pressure) finding in progression from sleepy to death o Hypoglycemia ( liver not working ) o Csf is normal o Tx is supportive – mannitol , glycerol , hyperventilation to reduce cerebral edema Acute fatty liver of pregnancy o Abnormality in beta oxidation o Fatal to mother and fetus unless baby is delivered Preeclampsi o Htn , proteinuria , dep pitting edema in 3rd trimester o Liver cell necrosis around the portal triads (Z1) > increased serum transaminases o HELLP syndrome FHF o Acute liver failure with encephalopathy within 8 weeks of hepatic dysfunction o Causes  Drugs ( acetaminophen mcc ), hepatotos (2nd mcc)  Reye , Wilson , AI hepatitis o Wrinkled capsular surfaces due to loss of hepatic parenchyma o Clx – hep encephalopathy , jaundice o Decrease transaminases since less parenchyma --Circulatory disorders of the liver Prehepatic obstruction to blood floe o Hepatic artery thrombosis with infarction  Liver infarction is uncommon  Causes – liver transplant rejection , PAN o Portal vein thrombosis  Causes –  Pyelophlebitis ( mc due to acute appendicitis , air in PV)  Polycethemia vera  HCC – tumor invasion of pv  PHTN , ascites , splenomegaly  NO HEPATOMEGALY

 Intrahepatic obstruction – intrahepatic obstrucciton to sinusoidal blood flow o Causes – cirrhosis , centrilobular hemmoragic necrosis , peliosis hepatis , SC disease o Centrilobular hemmoragic necrosis – mc by HF  Z3 ischemic necrosis due to hypoperfusion - LHF  Enlarged liver with mottled red appearance  Painful hepatomegaly  May progress to cardiac cirrhosis  Fibrosis around central venules o Peliosis hepatis  Sinusoidal dilation due to blood  Causes  Anabolic steroid  Bartonella henselae in aids  Potential for intraperitoneal hemmorage  Posthepatic obstruction o Hepatic vein thrombosis  Budd chiari syndrome  Causes  PV – MCC  Hypercoagualable state o OCP , Protein c and s def , APLA  HCC – invades hepatic vein  Enlarged painful liver , Phtn , ascites , splenomegaly  u/s with pulsed Doppler is first line test  mri o venoocclusive disease  complication of BM transplantation  collaagaen develops around central venules  hematobilia alcohol , drug , and chemical induced trauma to liver  alcohol o fatty change – mc type  tender hepatomegaly without fever or neutrophilic leukocytosis o alcoholic hepatitis  stimulation of collagen synthesis around central venules  fatty change with neutrophilic infilteration  Mallory bod  Painful helpatomegaly with fever , neutrophilic leukocytosis o cirrhosis –  chemical and drug

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obstructive – cholestatic – liver disease intrahepatic cholestatis o cause  drugs ( ocp , anabolic steroids) MCC  neonatal hepatitis  preg induced cholestasis extrahepatic cholestasis o stones o PSC o Extrahepatic bilary atresia o Ca of head of pancreas Enlarged greenish liver Clx in cholestatis liver disease o Jaundice with pruritis (bile salts) o Malabsorption o Cholesterol deposits in skin o Ligh stool Increase in serum ch Benign intrahepatic cholestasis of preg o Due to estrogen inhibition of intrahepatic bile secretion o NOT dangerous to fetus or mother Extrahepatic biliary atresia o Cause of jaundice in nb o Common indication for lliver transplantation in a child PSC – obliterative fibrosis of intrahepatic and extrahepatic bile ducts o Hla dr52a and hlaCw7 , male dom , o Ass with ibd ( uc more) o Ass with other sclerosing conditions ( retroperitoneal and mediastinalsclerosing fibrosis) o Comp – cirrhosis and choliangiocarcinoma o Jaundice , pruritis , hepatosplenomegaly o Dx – ercp shows beading o Tx req a liver transplant

Cirrhosis  Irreversible fibrosis diffuse of liver with formation of regenerative nodules  In regenerative nodules , liver lacks normal liver architecture of portal triads and sinusoids o Nodules compress sinusoids and crntral venules  Intrasinusoidal htn  Reduciton in the number of functioning sinusoids  Increase in hydrostatic pressure In poral vein  Cause of cirrhosis

o Alcoholic liver disease (mc) o Galactosemia o Autoimmune hepatitis  Comp with cirrhosis o Hepatic failure – end point of progressive damage to the liver  Coag prob – hyper or hypo  Hypoalbuminemia  Hep encephalopathy – reversible  Increase in serum ammonia > urea cycle disfuncrion  Increase in aromatic AA ( phenylalanine , tyrosine , tryptophan ) o These are converted to false neurotransmitters ( eg gamma aminobutyric acid)  Amino comes from metabolism of amino acid and from the release of ammonia from amino acids by bacterial ureaeses in the bowel . ammonia (nh3) is diffusible and is reabsorbes into the portal vein for delvery to the urea cycle where it is metabolized into urea . . ammonium isnot reabsorbed . methods of reducing ammonia o Restrict protein (most cost effective) o Oral neomycin – kills bacteria that synthesizes urease o Lactulose – H+ ions released which combine with nh3 to become nh4+  Factors precipitating encephalopathy o Increased protein ( most important)  Diatary sources or blood in gi > leads to increase bacterila conversion of urea into ammonia o Alkalosis keeps ammonia in the nh3 statae  Diuretics produce metabolic alkalosis ( less h ions ) o Sedatives o Portosystemic shunts - shunts ammonia away from liver  Clx – aloc , asterixis , coma o Portal htn  Path – resistance to intrahepatic blood flow due to intrasinusoidal htn  > anastomoses between portal vein tributaries and arterial system  Compo  Ascites  Congestive splenomegaly > hyperslpenism with vadrious cytopenias  Eso varices , caput medusa , hemmoroids  Shnts used to treat ph  Portocaval , mesocaval , splenorenal , TIPS o Ascites

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Portal htn – increases portal vein hydrostatic pressure Hypoalbunemia – decreases oncotic pressure 2nd hyperaldosteroism – salt retension o CO is decreased du rot 3rd spcing > more raas o Liver cant metabolize aldo  Clx abd distension with fluid wave . increased risk of SBP o Hepatorenal syndorome  Condition of intense renal vasoconstriction dur to loss of renal autoregulation occurring as a complication of severe , chronic liver disease i.e cirrhosis  Reversiibble renal failure without parenchymal disease  Renal tubular function is preserved  Absence of significant proteiniuria/hematuria  Tx  Supportive care including dialysis  Vasopressin analogues  Vasoconstrictors  Albumin for volume expansion  Liver transplantation only curative treatment o Hyperesterinism in males  Liver cannot degrade estrogen and 17 KS  KS ( androstenedione )is aromatized to estrogen in adipose cells  Gynecomastia  Spider telangiectasias  Female distribution of hairs  Impotence and erectile dysfunction  Increae estrogen increases synthesis of sex hormone binding protein . ehich increases binding of free testosterone  Postnecrosis cirrhosis  Most often caused by chronic hepatitis due to hbv and hcv  Increased HCC  Incidence of which virus is most common varied around the world  PBC o Cirrhosis due to granulomatous destruction of bile ducts in the portal triads . o AI , bitches mid age o Ama o Clx – pruritis – unknown etiology ( not bile salts inskin)  Painful hepatosplenomegaly  Jaundice – late finding after a lot of destruction  Inflammatory arthropathy  Xanthelaesma – increase ch

 KF rings in cornea – dep of copper o Ana+ in 50% o Increae serum igm o Tx  Budesonide + ursodeoxycholic acid  Cholestyramine for pruritis  Liver trsndplsntstoin  Secondary biliary cirrhosis o Complication of chronic extrahepatic bile duct obstruction  Eg CF ehere bile duct is dehydrated  Hereditary hemochromatosis o 6p , hlaa3 o Most common genetic disorder in people of northeren European ancestery o Male dominant disorder  Cuz chicks lose iron in menses o Unrestricted reabsorption of iron iin small intestine o 2 missense mut on 6 ( c282y , h63d) o Sec hemochromatosis : transfusion , alcohol ( alcohol increase iron absorption ), well water ) o Clx –  Cirrhosis  Bronze diabetes  Iron dep in beta cells > T1 DM  Hyperpigmentation by deposit in skin AND increased melanin production  Malabsorption – destruction of exocrine pancreas  Restrictive cardiomyopathy  Hypogonadism – pit  Loss of libido  Amennorhea  Degenerative joint disease – chondrocalcinosis o Increased serum iron , percent saturation , and ferritin . o Transferrin saturation is the best screening test . values >45% needs further workup o Decreased tibc o Serum ferritin is primarily used to follow therapy o Liver biopsy to confirm o Gene screening for relatives o Treatment – phlebotomy until serum ferritin <50ug/ml sat <30%  Deferoximine o Normal life expectancy if no cirrhosis present  Wilson

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Onset usually late childhood Liver disease progresses from acute hepatitits to cirrhosis and portal htn Unbound copper eventually accumulates in blood – copper is loosely attached to albumin > deposits in tissues o Clx – KF rings – not pathonemonic tho cuz also seen in pbc  Cns disease  Deposit in putamen (parkinism ) , subthalamic nuceli (hemibalismus) , cerebral cortex ( dementia)  Hepatosplenomegaly – bx shows increased copper and fibrosis  Hemolytic anemia  Renal failure and fanconi o Lab shows DECRESED total serumc copper due to decreaed ceruloplasmin o Decreased serum ceruloplasmin – early stage diagnosis o Increased seruma dn urine free copper – late stage dx o Tx – pemicilalmine , zinc , ammonium tetrathiomollybdate , transplant  A1at def o AD o ZZ – presents as neonatal hepatitis with intrahepatic cholestatsis  Progresses to cirrhosis - a mcc of cirrhosis in children o Tx – pooled a1at iv . liver and lung transplant  Lab test abnormalities in cirrhosis o Decreased bun , increased ammonia o Fasting hypoglycemia o Chronic resp alkalosis o Lactic acidosis o Hyponatremia o Hypokalemia o Increase pt o Hypoallbunemia o Hypocalcemia o MILD serum trransmenemia

Liver tumors and tumor like disorders  Focal nodular hyperplasia o Tumor like condition o More common in women , usually an incidental finding o Poorly encapsulatead nodule . central depressed stellate scar contains large blood vessels . fibrous septa radioating to the periphery o Ct scan – hypervascular mass  Benigh tumors of the liver

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Cavernous hemangioma  Mc benign tumor of the liver  Dx with enhanced ct o Hepatic cell adenoma  More in women  Ocp mcc  Anabolic steroids  Von gierke glycogneolysis  Highly vascular tumors – tendency to rupture during preg and cause intraperitoneal hem  Malignant tumors of liver o Met more common , lumg mcc o Hcc  Causes  Cirrhosis , aflatoxin ,  Mc by hbv/hcv  Focal , multifocal or diffusely infilterating cancer – with or without preexisting cirrhosis  Portal and hepatic vein invasion is common  Characteristic finding is prsensce of bile in neoplastic cells  Clx  Over 1/3 are asymx  Abd pain is the common initial presentation  Liver cell necrosis causes fever  Sudden increase In alp and ggt is a characteristic finding in hcc  Production of ectopic hormones  Epo ,insulin llike factor , pthrp  Ct and u/s llocallizez hcc , angiography shows pooling and increased vascularity o Angiosarcoma  Exposure to vinul chloride (mcc) , arsenic , thorium dioxide Gallblasser and biliary tract disease  Cystic disesaes of the biliary tract o Choledochal cyst  Mc cyst in biliary tract in children <10y  Abd pain with persistant or intermittent jaundice  u/s screening test of choice . ercp or transhepatic chaolangiography may be used o caroli disease  AD and AR types  Segmental dilation of intrahepatic bile ducts and portal tract fibrosis

 Ass with pkd  Tx – surgical resection of the involved lobe and liver transplantation   Cholangiocarcinoma o Causes  Psc – mcc in us  Clonorchis sinensis  Thorotrast  Choledechal cyst , caroli disease o Mc site is ampulla or CBD o Junction of r and l hepatic duct aka klatskin tumor o Can also be intrahepatic o Clx – obs jaundice  Palpable gallbladder ( only if in middle portion of cbd ? or in ampulla  Hepatomegaly  Gallstones o Bile acid/salts ( 67%) , phospholipid ( 22%) , protein , CH , CB , wate , electrolyte , bicarb o In gall bladder come CB is conv to ucb which combines calcium to forn calcium bilirubinatae stones o Cholesterol  Usually mixed – ch , calcium carbonate (makes it opaque if present) , bilirubin o Pigment  Bilirubin – chronic eha . excess cb is ocnv to ucb , ehich combines with calcium to produce calcium bilirubinate stones  Brown – infection in cbd , Asians , bacteria conv cb to ucb o Estrogen increases stone formation by 3 mechanism  Increase hdl formation – brings ch from periphery  Upregulates LDL r –  Inc hmgcoa reductase o RF  Obesity , rapid weight loss , lipid lowering drug , native maericans o Comp , cholecystitis ( mc) , cbd obstruction , gb cancer , pancreatitis  Acute cholecystits o Women – 55y o Ass with gallstones 95% of cases o Other causes – AIDS (cmv , cryptosporidium ) , severe volume depletion o Stages of development of acute cholecystitis  1 – lodges in cytic duct – midepigastric colicky pain  2- stone impacted in cystic duct > bacterial growth > pain shifts to ruq  3- invasion – localized peritonitis with rebound tenderness ,  4 – perforation – bv sompressed by high pressure in gb o Clx

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Fever , vomiting , boas sign , murphy , jaundice , Absolute neutrophilic leukocytosis with left shift increased alp/ ast – indicates stone in cbd amylase suggest pancreatitis bilirubin indicates stone in cbd

u/s ppreffered initial test - gold (98%)  not effective in ifentifying cbd stones  plain film – only 20% radiopaque  HIDA scan – identifies stoen in cystic duct – no visualization of gb  No tracer in duodenum means cbd stone Indication for cbd exploration  Haundice , cbd >12mm , acute pancreatitis , no stones in gb ? Tx  Cholesystectomy  Ercp with sphincterotomy ro extract the stone in the cbd  Meperepine for pain - do not use morphine cuz it contracts oddi and worsens pain  Pip taz