CIRRHOSIS

CIRRHOSIS & Abnormal Liver function testsAssoc ProfessorPathology Department, Al Nafees Medical College. IslamabadDr Ahsan Kazmi

2A chronic disease of the liver with wide spread hepatic parenchymal injury and hepatocyte destruction.It may lead to anatomic and functional abnormalities of blood vessels and bile ducts Definition23Clinical FeaturesInsidious development Often produces no clinical manifestationsCommon symptoms:Anorexia, nausea, abdominal discomfort, weakness, weight loss, and malaise34Clinical FeaturesPhysical examination:Enlargement of the liver and spleen due to (Portal Hypertension) PHTN Ascities Peripheral edema, JaundiceSpider angiomasGI bleedingPalmer erythemaRight upper quadrant pain4

Sign & symptoms of Liver cirrhosis5

You will do the fluid wave test at bedside.6

SPIDER ANGIOMA, CIRRHOSISSpider nngiomas in cirrhosis are related to7Clinical Features (CONTD)Clinical features:SilentAnorexia, wt. loss, weakness, osteoporosis, debilityDeath caused by:Hepatic failureComplications of portal HTNHepato-cellular Ca (HCC)ETIOLOGYAlcoholic liver disease 60% to 70%Viral hepatitis 10%Non Alcoholic Steatotic Hepatitis (NASH)Biliary diseases 5% to 10%Primary hemochromatosis 5%Wilson disease Rare

ETIOLOGY(contd)1 -Antitrypsin deficiency- RareCryptogenic cirrhosis 10% to 15%Infrequent types of cirrhosis also include cirrhosis developing in infants and children with galactosemia and tyrosinosis ETIOLOGYDrug-induced cirrhosis, as with a-methyldopa.Severe fibrosis can occur in the setting of cardiac disease (sometimes called "cardiac cirrhosis," )The most common causes are alcoholism and viral hepatitis

Cirrhosis- PathogenesisWEST - One of Top 10 causes of death

End-stage of chronic liver disease is defined by three characteristics:Fibrosis- 1.Bridging fibrous septae 2. Parenchymal nodules3. Disruption of hepatic parenchymal architectureCirrhosis- Pathogenesis (CONTD)Parenchymal nodules Proliferating hepatocytes encircled by fibrosis, micronodules with diameters very small ( 2mg/dl to 40 mg/dl

AST, ALT, Alkaline phosphatase Aid in early diagnosis, prognosis, and response to treatment ALkPo > 3 times normal indicate billiray disease3435Lab FindingsAlbumin (non-specific protein) & Factor V and VII (specific proteins) can provide information on the functional capacity of the liverLow albumin < 3 that does not respond to therapy is bad prognosis

3536Lab FindingsPT Prolongation due to impaired synthesis of vitamin K dependant clotting factorsNo response to VIT K is poor prognosisBUN < 5 due to inadequate protein intake and depressed hepatic capacity for urea synthesis Biopsy Confirm the presence of cirrhosis

36

BLIND MANs LIVER37Even a blind man would know this liver surface feels smooth which generally rules out cirrhosis or tumors even before slicing it for examination.Can you probably rule out cirrhosis on autopsy even if you were blind? Answer: YESWhy do the words the surface is smooth and glistening appear about 100 times in an autopsy report? Ans: To rule out oodles of diseases

Blind Mans Diagnosis38How can a blind man differentiate cirrhosis from metastatic disease?Answer: In cirrhosis there are no SMOOTH areas between nodules.

39How would the blind man know this is metastatic cancer, rather than macronodular cirrhosis, even if he doesnt slice it?

Take a look at the tiniest red dot in the normal liver. What is it?40

NOFIBROUSTISSUEBETWEENPORTALAREAS41In a normal liver, there is connective tissue ONLY in the small portal triad area.

IRREGULAR NODULES SEPARATED BY PORTAL-to-PORTAL FIBROUS BANDS

42Is this MACRO-nodfular or MICRO-nodular cirrhosis?How can you tell who the hepato-pathologist is? Answer: He carries a magnifying glass in his lab coat pocket (no joke).

TRICHROME43Why are TRICHROME stains recommended for every liver biopsy?

CIRRHOSIS, TRICHROME STAINWhere are the central veins? Answer: There are none, the the process of nodule formation, the central veins are lost.44

CIRRHOSIS, TRICHROME STAIN45Remember46Almost all primarilly INTRACELLULAR liver pathologies result in MEMBRANE elevations too, and VICE VERSA!DEFference BetWeen:CIRRHOSIS&LIVER FAILURE

?????47Greek: kirrh(s) orange-tawny

Laboratory Evaluation of Liver DiseaseLiver Function TestsLOFunctions of LiverTests for Liver functionsLFTTest Category Serum Measurement

Hepatocyte integrity

Cytosolic hepatocellular enzymes Serum aspartate aminotransferase (AST) * Serum alanine aminotransferase (ALT) * Serum lactate dehydrogenase (LDH) *

Biliary excretory function Substances normally secreted in bile Serum bilirubin Total: unconjugated plus conjugated * Direct: conjugated only * Delta: covalently linked to albumin * Urine bilirubin * Serum bile acids * Plasma membrane enzymes (from damage to bile canaliculus) Serum alkaline phosphatase * Serum -glutamyl transpeptidase * Serum 5'-nucleotidase *

Test Category

Hepatocyte function

Proteins secreted into the blood Serum albumin -decrease Prothrombin time * (factors V, VII, X, prothrombin, fibrinogen)Hepatocyte metabolism Serum ammonia * Aminopyrine breath test

Specific tests for specific liver diseases

AlbuminMeasures amount of albumin in bloodFormed within liver & comprises 60% of total protein in bloodMaintains colloidal osmotic pressure & transports blood constituentsMeasure of both hepatic function and nutritional stateNormal: 3.5 5 g/dLAlbumin: dehydration: malnutrition, pregnancy, liver disease, protein-losing enteropathies, protein-losing nephropathies, 3rd space losses, overhydration, capillary permeability, inflammatory disease, familial idiopathic dysproteinemia

Total ProteinMeasures total protein in bloodCombination of prealbumin, albumin & globulinsNormal: 6.4 8.3 g/dLALPMeasures serum ALP concentrationDetect & monitor liver and bone diseaseNormal: 30 -120 units/L: 1 cirrhosis, intrahepatic/extrahepatic biliary obstruction, 1/metastic liver tumor, hyperparathyroidism, Paget disease, normal growing bones in children, bone mets, RA, MI, sarcoidosis, healing fracture, normal pregnancy, intestinal ischemia or infarction: hypophosphatemia, malnutrition, milk-alkali syndrome, pernicious anemia, scurvyALTFound predominantly in liver Injury/disease to parenchyma release into bloodID & monitor hepatocellular diseases of liverIf jaundiced, implicates liver rather than RBC hemolysisNormal: 4 36 international units/L @ 37CALTSig : hepatitis, hepatic necrosis, hepatic ischemiaMod : cirrhosis, cholestasis, hepatic tumor, hepatotoxic drugs, obstructive jaundice, severe burns, trauma to striated muscle Mild : myositis, pancreatitis, MI, infectious mono, shock

ASTFound in highly metabolic tissue (cardiac & skeletal muscle, liver cells) Disease/injury lysing of cells & release into bloodElevation proportional to # of cells injuredUsed for evaluation of suspected coronary artery disease or hepatocellular diseaseNormal: 0 35 units/L: heart diseases, liver diseases, skeletal muscle diseases: acute renal disease, beriberi, DKA, pregnancy, chronic renal dialysisBilirubinMeasures level of total bilirubin in bloodEnd product of RBC metabolism (RBCs Hgb Heme (+ globin) Biliverdin Bilirubin (unconjugated/indirect) Bilirubin (conjugated/direct)Component of bileConsists of conjugated (direct) & unconjugated (indirect) bilirubinUsed to evaluate liver function; hemolytic anemia workup in adults & jaundice in newbornsJaundice occurs when total bilirubin > 2.5 mg/dLNormal: 0.3 1 mg/dLCritical: > 12 mg/dLUnconjugated bilirubinMeasures level of indirect bilirubin in bloodNormal: 0.2 0.8 mg/dL: erythroblastosis fetalis, transfusion rxn, sickle cell anemia, hemolytic jaundice, hemolytic anemia, pernicious anemia, large-volume blood transfusion, large hematoma resolution, hepatitis, cirrhosis, sepsis, neonatal hyperbilirubinemia, Crigler-Najjar syndrome, Gilbert syndrome

Conjugated bilirubinMeasures level of direct bilirubin in bloodProduced by conjugating glucuronide w/ unconjugated/indirect bilirubin in liverNormal: 0.1 0.3 mg/dL: gallstones, extrahepatic duct obstruction, extensive liver mets, cholestasis from drugs, Dubin-Johnson syndrome, Rotor syndrome

Viral MarkersHBsAg presence indicates acute HBV infection.

Anti-HBs not detectable during acute, presence indicates immunity to HBV or previou vaccination for HBV.

HBcAg Presence indicates acute HBV Infection, and signifies that patient is currently infective

Anti-HBc Presence indicates acute or chronic HBV infection. acute or chronic depends on whether IgM present or IgG

HBeAg Present during acute infection

Anti-HBe usually not tested but are present during acute or chronic infection, indicate low transmissibility

Viral MarkersSerologic Markers in HVA Infection

Out come of HBV Infection

HBV Acute and Chronic Infection

Out Come of HCV Infection

Serologic Markers of HCV In Acute and chronic Relapsing InfectionHBV and HDV Infection

Viral MarkersHBsAg presence indicates acute HBV infection.

Anti-HBs not detectable during acute, presence indicates immunity to HBV or previou vaccination for HBV.

HBcAg Presence indicates acute HBV Infection, and signifies that patient is currently infective

Anti-HBc Presence indicates acute or chronic HBV infection. acute or chronic depends on whether IgM present or IgG

HBeAg Present during acute infection

Anti-HBe usually not tested but are present during acute or chronic infection, indicate low transmissibility

Viral markersAnti-HAV Indicates acute infection

Anti-HCV Indicates acute or chronic infection

Anti-HEV Indicates acute infection

Viral markersWindow Phase: Period of several wks when HBsAg has disappeared but HBsAb not yet detectable At this time HBcAb always positive use to make diagnosisPersistence of HbsAg beyond 6months indicate chronic infection /carrier