Cirrhosis Management

Gary A. Abrams, MD Chief, and DEFINITIONDEFINITION OFOF CIRRHOSISCIRRHOSIS

CirrhosisCirrhosis

•• EndEnd stagestage ofof anyany chronicchronic liverliver diseasedisease •• CharacterizedCharacterized histologicallyhistologically byby regenerativeregenerative nodulesnodules surroundedsurrounded byby fibrousfibrous tissuetissue •• ClinicallyClinically therethere areare twotwo typestypes ofof :cirrhosis: •• CompensatedCompensated •• DecompensatedDecompensated HISTOLOGICALHISTOLOGICAL IMAGEIMAGE OFOF AA NORMALNORMAL ANDAND AA CIRRHOTICCIRRHOTIC LIVERLIVER

NormalNormal CirrhosisCirrhosis

NodulesNodules surroundedsurrounded byby fibrousfibrous tissuetissue Cirrhosis

Median Survival Median Survival >12 yrs < 2 yrs

Chronic Disease Compensated Decompensated No varices Variceal Bleed Varices PSE COMPLICATIONS OF CIRRHOSIS

ComplicationsComplications ofof CirrhosisCirrhosis ResultResult fromfrom PortalPortal HypertensionHypertension oror LiverLiver InsufficiencyInsufficiency

VaricealVariceal hemorrhagehemorrhage PortalPortal hypertensionhypertension SpontaneousSpontaneous bacterialbacterial AscitesAscites peritonitisperitonitis CirrhosisCirrhosis HepatorenalHepatorenal syndromesyndrome EncephalopathyEncephalopathy LiverLiver insufficiencyinsufficiency JaundiceJaundice CLASSIFICATION OF PORTAL

PortalPortal HypertensionHypertension IsIs ClassifiedClassified AccordingAccording toto thethe SiteSite ofof IncreasedIncreased ResistanceResistance

TypeType ExampleExample PrePre--hepatichepatic PortalPortal oror splenicsplenic veinvein thrombosisthrombosis PrePre--sinusoidalsinusoidal SchistosomiasisSchistosomiasis SinusoidalSinusoidal CirrhosisCirrhosis PostPost--sinusoidalsinusoidal VenoVeno--occlusiveocclusive diseasedisease PostPost--hepatichepatic BuddBudd--ChiariChiari syndromesyndrome NORMAL HEPATIC VENOUS PRESSURE GRADIENT (HVPG) IS 3-5 mmHg Normal HVPG is 3-5 mmHg

Inferior vena Portal cava PVP = 6 Hepatic mmHg

Sinusoidal pressure = 5 mmHg

WHVP = 5 mmHg

HVPG* = 5-2= 3 mmHg

FHVP = 2 mmHg HVPG IS INCREASED IN SINUSOIDAL PORTAL HYPERTENSION HVPG is Increased in Sinusoidal Portal Hypertension

Hepatic veins Portal vein Blocked inter- PVP = 20 mmHg sinusoidal communications (poor pressure dissipation)

Sinusoidal pressure = 20 mmHg WHVP = 20 mmHg

HVPG = 18 mmHg

FHVP = 2 mmHg HVPG IS NORMAL IN PRE-SINUSOIDAL PORTAL HYPERTENSION HVPG is Normal in Presinusoidal Portal Hypertension

Hepatic veins Portal vein PVP = 20 mmHg

Sinusoidal pressure = 5 mmHg

WHVP = 5 mmHg

HVPG = 3 mmHg

FHVP = 2 mmHg WHVP IS ELEVATED BUT HVPG IS NORMAL IN POST-HEPATIC PORTAL HYPERTENSION HVPGHVPG isis NormalNormal inin PostPost--HepaticHepatic PortalPortal HypertensionHypertension

PortalPortal veinvein PVPPVP == 2020 mmHgmmHg

Heart failure Sinusoidal pressure = 20 mmHg

WHVPWHVP == 2020 mmHgmmHg

HVPGHVPG == 22 mmHgmmHg

FHVPFHVP == 1818 mmHgmmHg Cirrhosis Management Immunizations n HAV n HBV n Immunogenicity is decreased in decompensated cirrhosis n Pneumococcal (PPSV23) n Inactivated Influenza

Malnutrition n Protein 1.2-1.5g/kg/day n BCAA if intolerant due to PSE Prevention of First Variceal Bleed n Propanolol 160mg BID without ascites or 80mg BID with ascites- aim HR 55-60 n same dose but QD n Carvediol 6.25mg to 12.5mg QD – NOT with ascites n Intolerant to NSBB – Band ligation ASCITES FLUID ANALYSIS Ascites Fluid Analysis

Routine Optional

• Albumin • Glucose • TB smear and culture • Protein • LDH • Cytology • PMN cell • Amylase count • Triglycerides • Red blood • Cultures cell count Ascites Evaluation n Serum albumin minus ascites albumin SAAG n SAAG < 1.1 or ≥ 1.1 n Ascites Total Protein n >2.5 or <2.5 n Spontaneous Bacterial Peritonitis n PMNs > 250 ASCITES CAN BE CHARACTERIZED BY SERUM-ASCITES ALBUMIN GRADIENT (SAAG) AND ASCITES PROTEIN

Ascites Can Be Characterized by Serum-Ascites Albumin Gradient (SAAG) and Ascites Protein Source of ascites Hepatic sinusoids SAAG > 1.1 SAAG < 1.1 “Capillarized” sinusoid Normal “leaky” sinusoid Peritoneal lymph Ascites protein < 2.5 Ascites protein > 2.5 Ascites protein > 2.5

Sinusoidal Post-sinusoidal Peritoneal pathology hypertension hypertension - Malignancy -Cirrhosis - Cardiac ascites - Tuberculosis -Late Budd-Chiari - Early Budd-Chiari - Veno-occlusive disease DEFINITION AND TYPES OF REFRACTORY ASCITES Definition and Types of Refractory Ascites Occurs in ~10% of cirrhotic patients

• -intractable ascites 80% Therapeutic doses of cannot be achieved because of diuretic-induced complications

• Diuretic-resistant ascites 20% No response to maximal diuretic therapy (400 mg + 160 mg furosemide/day)

Arroyo et al. Hepatology 1996; 23:164 Ascites

Avoid NSAIDS/ACE Na Restriction 2gm Fluid Restriction Na < 125mg/dl

Aldactone 100mg - 400mg Lasix 40mg - 160mg

LVP TIPS Albumin 25gm pre and during Diagnosis, Management, and Prophylaxis of SBP

Ascites - PMNs 250 cells/mm3- no intra-abdominal source of infection RFs - Prior SBP, ascitic fluid TP <1.0 g/dL, and GIB

GENERAL for SBP ü Albumin BUN >30 mg/dL, Cr >1 mg/dL ü 3rd generation cephalosporin ü Continue antibiotic therapy for 7 days

ü Secondary prophylaxis Long-term oral cipro or norfloxacin or trimethoprim/sulfamethasoxazole

Primary prophylaxis Always ü Cirrhosis with GIB- IV Ceftriaxone or PO Norfloxacin Consider ü Ascitic fluid TP <1.5 g/dL and Cr 1.2 mg/dL, BUN 25 mg/dL or Na 130 ü Child-Pugh score 9 and serum bilirubin 3 mg/dL (HRS)

International Ascites Club definition Serum creatinine >1.5 mg/dL No improvement of serum creatinine after 2 days with diuretic withdrawal and volume expansion with albumin Absence of shock No current or recent treatment with nephrotoxic drugs Absence of parenchymal kidney disease Precipitant factors Infection, GIB, LVP without albumin

Types of HRS Type 1 Rapid renal failure with doubling of serum [Cr] >2.5 mg/dL in <2 weeks Type 2 Moderate progressive renal failure with [Cr] between 1.5 and 2.5 mg/dL

General management Type 1 HRS with albumin Type 2 HRS Treatment options management of the refractory ascites - TIPS may be an alternative option in selected cases when medical therapy fails; renal replacement therapy may be used as a bridging therapy until LT

Definitive treatment OLTx is the definitive treatment for type 1 and 2 HRS Clinical Types

Type Grade Covert Overt Spontaneous Precipitated A MHE Yes Spontaneous 1 B 2 Yes Precipitated C 3/4 Yes Precipitated

Precipitating Factors for OHE

Infections GI bleeding Diuretic overdose Electrolyte disorder Unidentified Management of Hepatic Encephalopathy

Lactulose Titrate for 2-3 BMs daily Dehydration, hypernatremia, and 550mg BID Add-on therapy to ,

Alternative choices Metronidazole 250 mg-500 mg TID Metallic taste, peripheral neuropathy, ototoxicity 250 mg BID-QID Ototoxicity Nephrotoxicity Screening Chronic HBV Without Cirrhosis n Asian/Caucasians Males > 40yo, Females > 50yo n Africans > 20yo Cirrhosis n Abd US q 6 mos (60-80% Sens, 80-90% Spec) n AFP not reliable n Abd CT 3-4 phase + MRI for confirmation (90% Sens and 95% Spec) n LiRad 5 c/w HCC – no bx needed Hepatocellular Carcinoma Cirrhosis and SOB n CXR, PFTs n Clubbing, Orthodeoxia, Platypnea n Hypoxemia- Pa02 < 70mmHg or ↑ A-a gradient n O2 normalizes w 100% oxygen n IPVD n Contrast Echocardiography n Lung Perfusion Scan n – definitive treatment HCV Cirrhosis n www.hcvguidelines.org n Genotype 1- compensated (RIBA if decompensated) n Ledipasvir/sofosbuvir (Harvoni) n 1 tab PO daily x 12 wks n Genotype 2, 3, 4, 5, 6 n Velpatasvir/sofosbuvir (Epclusa) n 1 tab PO daily x 12 wk Renal Failure Elbasvir/Grazoprevir (Zepatier) 1 tab PO daily x 12 wks HBV Guidelines

AASLD 2015 HbeAg + HbeAg + HbeAg - HbeAg - Non-cirrhotic DNA > 20,000 ALT > 2 ULN DNA > 2,000 ALT > 2 ULN Cirrhosis DNA > 2,000 ALT Normal DNA > 2,000 ALT Normal

nl ALT= 30 IU/ml males; 19 IU/ml females

Tenofovir 300mg/d Vemlidy 25mg/d Entecavir 0.5mg/d Autoimmune n ↑ serum transaminases and gamma-globulin n Other autoimmune conditions n Young n SMA, ANA, LKM n n Plasma cells n Interface hepatitis n Prednisone and Azathioprine Primary Biliary Cholangitis

Ø Autoimmune, chronic, progressive Ø Intrahepatic destruction Ø Cirrhosis – Ø F/M 6:1 Ø Pruritis, fatigue, jaundice

Ø Therapy Ø URSO 13-15mg/kg/d Ø (Ocaliva) Ø FXR agonist ü 5 to10mg

Florid Duct Lesion Primary Sclerosing Cholangitis Ø Autoimmune, chronic, progressive Ø F/M 1:2 Ø Pruritis, fatigue, jaundice Ø MRCP/ERCP – string of beads Ø Obliterative onion-skin fibrosis Ø 70% asso with UC, some Crohns Ø Cholangiocarcinoma Ø Therapy – None Definition of NAFLD: Histology

Ñ Spectrum of liver injury Ó NAFL Hepatic Steatosis ±

Ó NASH Zone 3 hepatocellular ballooning injury + inflammation

Ó Fibrosis stages 1a, 1b, 1c, 2, 3, 4

Clinical Predictors for NASH or Fibrosis nNAFLD Fibrosis Score – age, bmi, IFG/DM, AST/ALT, platelets and albumin (Hepatology 2007)

n -1.47 Low score 90% NPV for advanced fibrosis n 0.676 High score 80-90% PPV for advanced fibrosis NAFLD Cirrhosis Therapy

Hypocaloric diet and Exercise (Promrat et al Hepato 2010;51:121-9). n 7-9% wt loss n Improves steatosis, ballooning but not fibrosis n

Phase 3 Clinical Trial using ASK 1 inhibitor (Selonsertib) Good Luck TREATMENT OF ACUTE VARICEAL HEMORRHAGE

TreatmentTreatment ofof AcuteAcute VaricealVariceal HemorrhageHemorrhage GeneralGeneral Management:Management: •• IVIV accessaccess andand fluidfluid resuscitationresuscitation •• DoDo notnot overtransfuseovertransfuse (hemoglobin(hemoglobin ~~ 88 g/dLg/dL)) •• AntibioticAntibiotic prophylaxisprophylaxis SpecificSpecific therapy:therapy: •• PharmacologicalPharmacological therapy:therapy: terlipressinterlipressin,, somatostatinsomatostatin andand analogues,analogues, vasopressinvasopressin ++ nitroglycerinnitroglycerin •• EndoscopicEndoscopic therapy:therapy: ligation,ligation, sclerotherapysclerotherapy •• ShuntShunt therapy:therapy: TIPS,TIPS, surgicalsurgical shuntshunt A THRESHOLD PORTAL PRESSURE OF ~12 mmHg IS NECESSARY FOR VARICES TO FORM AA ThresholdThreshold PortalPortal PressurePressure ofof ~12~12 mmHgmmHg isis NecessaryNecessary forfor VaricesVarices toto FormForm

VaricesVarices PresentPresent VaricesVarices AbsentAbsent (n=72)(n=72) (n=15)(n=15) 3535

3030 HepaticHepatic VenousVenous 2525 PressurePressure 20 Gradient 20 Gradient P<0.01P<0.01 (mmHg) (mmHg) 1515 1212 1010

55

GarciaGarcia--TsaoTsao et.et. al.,al., HepatologyHepatology 1985;1985; 5:4195:419 PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE

ProphylacticProphylactic AntibioticsAntibiotics ImproveImprove OutcomesOutcomes inin CirrhoticCirrhotic PatientsPatients withwith GIGI HemorrhageHemorrhage

ControlControl AntibioticAntibiotic AbsoluteAbsolute raterate (n=270)(n=270) (n=264)(n=264) differencedifference (95%(95% CI)CI)

InfectionInfection 45%45% 14%14% --32%32% ((--4242 toto ––23)23)

SBPSBP // BacteremiaBacteremia 27%27% 8%8% --18%18% ((--2626 toto ––11)11)

DeathDeath 24%24% 15%15% --9%9% ((--1515 toto ––3)3)

BernardBernard etet al.,al., HepatologyHepatology 1999;1999; 29:165529:1655 VARICEAL BAND LIGATION APPEARS TO BE BETTER THAN SCLEROTHERAPY IN CONTROLLING ACUTE VARICEAL HEMORRHAGE

Variceal Band Ligation Appears to be Better than Sclerotherapy in Controlling Acute Variceal Hemorrhage

EarlyEarly rebleedingrebleeding ChangesChanges inin HVPGHVPG

110110 2323 ** 100100 **** **** LigationLigation **** **** SclerotxSclerotx rebleeding rebleeding 9090 2121 80 80 p=.024 1919 p=.024 LigationLigation 7070 SclerotxSclerotx ** HVPG mmHg HVPG HVPG mmHg HVPG 1717 6060 ** 5050 1515 % Patients without without Patients % % Patients without without Patients % 00 1010 2020 3030 4040 5050 prepre 00 2424 4848 7272 9696 120120 DaysDays HoursHours

AvgerinosAvgerinos etet al.,al., HepatologyHepatology 2004;2004; 39:162339:1623 DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT (HVPG) REDUCES THE RISK OF VARICEAL BLEEDING Decrease In Hepatic Venous Pressure Gradient (HVPG) Reduces Risk of Variceal Bleeding

100100

8080 4646--65%65% 6060 %% Rebleeding Rebleeding 4040

2020 77--13%13% 0%0% 00 HVPGHVPG HVPGHVPG decreasedecrease No change in decrease to > 20% from No change in decrease to > 20% from HVPGHVPG << 1212 mmHgmmHg baselinebaseline

BoschBosch andand GarcGarcííaa--PagPagáánn,, LancetLancet 2003;2003; 361:952361:952 COMBINATION DRUG/ENDOSCOPIC THERAPY IS MORE EFFECTIVE THAN ENDOSCOPIC THERAPY ALONE CombinationCombination DrugDrug // EndoscopicEndoscopic TherapyTherapy isis MoreMore EffectiveEffective ThanThan EndoscopicEndoscopic TherapyTherapy AloneAlone inin AchievingAchieving FiveFive--DayDay HemostasisHemostasis

ScleroSclero ++ OctreotideOctreotide BessonBesson,, 19951995 LigationLigation ++ OctreotideOctreotide Sung,Sung, 19951995 ScleroSclero ++ OctreotideOctreotide // STST Signorelli,Signorelli, 19961996 ScleroSclero ++ OctreotideOctreotide CerianiCeriani,, 19971997 ScleroSclero ++ OctreotideOctreotide Signorelli,Signorelli, 19971997 ScleroSclero ++ STST Avgerinos,Avgerinos, 19971997 ScleroSclero ++ OctreotideOctreotide ZuberiZuberi,, 20002000 ScleroSclero // ligationligation ++ VapreotideVapreotide CalesCales,, 20012001

TOTALTOTAL RelativeRelative RiskRisk 0.8 1 1.2 1.4 1.6 1.8 2 FavorsFavors endoscopicendoscopic FavorsFavors endoscopicendoscopic therapytherapy alonealone plusplus drugdrug therapytherapy BaBaññaresares RR etet al.,al., HepatologyHepatology 2002;2002; 35:60935:609 SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL HEMORRHAGE

EvolutionEvolution ofof LevelLevel ofof VaricesVarices InterventionIntervention ManagementManagement RecommendationsRecommendations CirrhosisCirrhosis withwith nono varicesvarices •• RepeatRepeat endoscopyendoscopy inin 22--33 yearsyears • No specific therapy PrePre--primaryprimary • No specific therapy SmallSmall varicesvarices prophylaxisprophylaxis NoNo hemorrhagehemorrhage SmallSmall varicesvarices •• RepeatRepeat endoscopyendoscopy inin 11--22 yearsyears •• NoNo specificspecific therapytherapy •• ?? betabeta--blockerblocker toto preventprevent enlargementenlargement MediumMedium // largelarge varicesvarices No hemorrhage No hemorrhage PrimaryPrimary Medium/LargeMedium/Large varicesvarices prophylaxisprophylaxis •• NonNon--selectiveselective betabeta--blockersblockers •• EVLEVL inin thosethose intolerantintolerant toto drugsdrugs

• Endoscopic/pharmacologic therapy VaricealVariceal hemorrhagehemorrhage • Endoscopic/pharmacologic therapy •• AntibioticsAntibiotics inin allall patientspatients •• TIPSTIPS oror shuntshunt surgerysurgery asas rescuerescue therapytherapy

SecondarySecondary •• BetaBeta--blockersblockers ++ nitratesnitrates oror EVLEVL prophylaxisprophylaxis •• BetaBeta--blockersblockers ++ EVLEVL ?? • TIPS or surgery as rescue therapy RecurrentRecurrent varicealvariceal • TIPS or shunt surgery as rescue therapy hemorrhagehemorrhage PATHOGENESIS OF LIVER FIBROSIS NormalNormal HepaticHepatic SInusoidSInusoid

RetinoidRetinoid dropletsdroplets FenestraeFenestrae HepaticHepatic stellatestellate cellcell SpaceSpace ofof DisseDisse

SinusoidalSinusoidal endothelialendothelial cellcell

HepatocytesHepatocytes VASOACTIVE DRUGS ARE AS EFFECTIVE AS SCLEROTHERAPY IN CONTROL OF ACUTE VARICEAL HEMORRHAGE VasoactiveVasoactive DrugsDrugs AreAre AsAs EffectiveEffective AsAs SclerotherapySclerotherapy inin AcuteAcute VaricealVariceal HemorrhageHemorrhage

FailureFailure toto controlcontrol bleedingbleeding

RebleedingRebleeding

MortalityMortality

Adverse events Adverse events RiskRisk DifferenceDifference MoreMore withwith DrugsDrugs 0 MoreMore withwith ((terlipressinterlipressin,, somatostatinsomatostatin,, SclerotherapySclerotherapy octreotideoctreotide,, vapreotidevapreotide))

DD’’AmicoAmico etet al.,al., GastroenterologyGastroenterology 2003;2003; 124:1277124:1277 PATHOGENESIS OF LIVER FIBROSIS AlterationsAlterations inin MicrovasculatureMicrovasculature inin CirrhosisCirrhosis

•• ActivationActivation ofof stellatestellate cellscells •• CollagenCollagen depositiondeposition inin spacespace ofof DisseDisse •• ConstrictionConstriction ofof sinusoidssinusoids •• DefenestrationDefenestration ofof sinusoidssinusoids IN CIRRHOSIS, ACTIVITY IS REDUCED AND THE ACTIVITY OF VASOCONSTRICTORS IS INCREASED InIn Cirrhosis,Cirrhosis, NitricNitric OxideOxide (NO)(NO) ActivityActivity isis ReducedReduced andand VasoconstrictorsVasoconstrictors (VC)(VC) areare IncreasedIncreased NATURAL HISTORY OF CHRONIC Natural History of Chronic Liver Disease

ChronicChronic Compensated liverliver Compensated DecompensatedDecompensated cirrhosis DeathDeath diseasedisease cirrhosis cirrhosiscirrhosis

DevelopmentDevelopment ofof complications:complications: •• VaricealVariceal hemorrhagehemorrhage •• AscitesAscites •• EncephalopathyEncephalopathy •• JaundiceJaundice HISTOLOGICALHISTOLOGICAL IMAGEIMAGE OFOF AA NORMALNORMAL ANDAND AA CIRRHOTICCIRRHOTIC LIVERLIVER

NormalNormal CirrhosisCirrhosis

NodulesNodules surroundedsurrounded byby fibrousfibrous tissuetissue DIAGNOSIS OF CIRRHOSIS – CAT SCAN

CATCAT ScanScan inin CirrhosisCirrhosis

Liver with an irregular surface Collaterals HEPATIC VENOUS PRESSURE GRADIENT TO ASSESS PORTAL PRESSURE HepaticHepatic VenousVenous PressurePressure GradientGradient (HVPG)(HVPG) toto AssessAssess PortalPortal PressurePressure HEPATIC VENOUS PRESSURE GRADIENT (HVPG) IN THE DIFFERENTIAL DIAGNOSIS OF PORTAL HYPERTENSION Hepatic Venous Pressure Gradient (HVPG) in the Differential Diagnosis of Portal Hypertension TypeType ofof PortalPortal WedgedWedged FreeFree GradientGradient HypertensionHypertension (WHVP)(WHVP) (FHVP)(FHVP) (HVPG)(HVPG)

PrePre--hepatichepatic normalnormal normalnormal normalnormal

PrePre--sinusoidalsinusoidal normalnormal normalnormal normalnormal

SinusoidalSinusoidal normalnormal

PostPost--sinusoidalsinusoidal normalnormal

PostPost--hepatichepatic ••HeartHeart failurefailure normalnormal ••BuddBudd--ChiariChiari unableunable toto catheterizecatheterize hepatichepatic veinvein Intrapulmonary Shunt Macroaggregated Albumin Lung Scan n Clin Gastroenterol. 1998 Oct;27(3):232-5. n Treatment of hepatopulmonary syndrome with Allium sativum L. (garlic): a pilot trial. n Abrams GA, Fallon MB. n 6 months on garlic – open label n 6/15 subjects - had at least a 10 mmHg increase in the PaO2 or decrease in A-arterial gradient n mean pre- and post arterial differences PaO2 (14+/-4 mmHg), A-a grad (18+/-5 mmHg). n One patient Pa02 46 to 85 in 1.5 yrs n Can J Gastroenterol. 2010 Mar;24(3):183-8. n The role of garlic in hepatopulmonary syndrome: a randomized controlled trial. n De BK, Dutta D, Pal SK, Gangopadhyay S, Das Baksi S, Pani A. n 41 patients with hepatopulmonary syndrome placebo-controlled study evaluated monthly for 9 to 18 months n Oral garlic supplementation n Placebo n After 9 months, garlic 25% increase in Pa02 (83 vs 67 mmHg) vs 7% increase (69 vs 64 mmHg) with placebo. n A 28% decrease A-a gradient; 21 vs 30 mmHg with garlic vs 11% decrease (29 vs 33 mmHg) with placebo. n Reversal of hepatopulmonary syndrome was observed in 14 of 21 patients (66%) on garlic supplementation vs 1 of 20 patients (5%) on placebo. n 2 of 21 patients undergoing garlic supplementation died during follow-up vs 7 of 20 patients taking placebo. DIAGNOSTIC ALGORITHM DiagnosticDiagnostic AlgorithmAlgorithm PatientPatient withwith chronicchronic liverliver diseasedisease andand anyany ofof thethe following:following: •• VaricealVariceal hemorrhagehemorrhage •• AscitesAscites •• HepaticHepatic encephalopathyencephalopathy PhysicalPhysical findings:findings: LaboratoryLaboratory findings:findings: YesYes NoNo EnlargedEnlarged leftleft hepatichepatic lobelobe ThrombocytopeniaThrombocytopenia SplenomegalySplenomegaly ImpairedImpaired hepatichepatic syntheticsynthetic functionfunction StigmataStigmata ofof chronicchronic liverliver diseasedisease RadiologicalRadiological findings:findings: YesYes NoNo •• SmallSmall nodularnodular liverliver •• IntraIntra--abdominalabdominal collateralscollaterals •• AscitesAscites •• SplenomegalySplenomegaly •• ColloidColloid shiftshift toto spleenspleen and/orand/or bonebone marrowmarrow YesYes NoNo LiverLiver biopsybiopsy notnot necessarynecessary forfor thethe LiverLiver biopsybiopsy diagnosisdiagnosis ofof cirrhosiscirrhosis DIAGNOSIS OF CIRRHOSIS – LIVER-SPLEEN SCAN LiverLiver--SpleenSpleen ScanScan

Colloid shift to bone marrow and ribs

Normal Cirrhosis

Small liver, Splenomegaly irregular uptake PREVALENCE AND SIZE OF IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS PrevalencePrevalence andand SizeSize ofof EsophagealEsophageal VaricesVarices inin PatientsPatients withwith NewlyNewly--DiagnosedDiagnosed CirrhosisCirrhosis

100100

8080

LargeLarge %% 6060 PatientsPatients withwith varicesvarices 4040 MediumMedium

2020 SmallSmall

00 OverallOverall ChildChild AA ChildChild BB ChildChild CC n=494n=494 n=346n=346 n=114n=114 n=34n=34

PagliaroPagliaro etet al.,al., In:In: PortalPortal Hypertension:Hypertension: PathophysiologyPathophysiology andand Management,Management, 1994:1994: 7272 Lymphatic Drainage VARICES INCREASE IN DIAMETER PROGRESSIVELY VaricesVarices IncreaseIncrease inin DiameterDiameter ProgressivelyProgressively

NoNo varicesvarices SmallSmall varicesvarices LargeLarge varicesvarices

77--8%/year8%/year 77--8%/year8%/year

MerliMerli etet al.al. JJ HepatolHepatol 2003;38:2662003;38:266 Evaluation

HBV HBV HBV HBV HCV HCV AIH

HbsAg + HbsAg + HbsAg + HbsAg - HCVRNA HCVRNA + ANA + Hbs Ab - HbsAb - HbsAb - HbsAb + HCVAb HCVAb + SMA - HbeAg + HbeAg - HbeAg - HbcAb - LKM HeAb - HbeAb + HbeAb + ↑ ALT nl ALT ↑ ALT

HBVDNA HBVDNA ? ? NORMAL VASCULAR ANATOMY OF THE LIVER Normal Vascular Anatomy

HepaticHepatic veinvein CoronaryCoronary veinvein

SinusoidSinusoid LiverLiver

PortalPortal veinvein SplenicSplenic veinvein InferiorInferior HepaticHepatic venavena cavacava arteryartery SuperiorSuperior InferiorInferior mesentericmesenteric veinvein mesentericmesenteric veinvein ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE

Cirrhotic Liver PortalPortal systemicsystemic collateralscollaterals

DistortedDistorted sinusoidalsinusoidal architecturearchitecture leadsleads toto increasedincreased resistanceresistance PortalPortal veinvein

SplenomegalySplenomegaly Macroaggregated Albumin Lung Scan

HBV HCC HCC surveillance recommended or HCC is increased

Annual incidence (percent per Population group year) for which surveillance is Incidence of HCC considered to be cost-effective Surveillance recommended Asian male hepatitis B carriers over 0.2 0.4-0.6% per year age 40 Asian female hepatitis B carriers over 0.2 0.3-0.6% per year age 50 Hepatitis B carrier with family history Incidence higher than without family 0.2 of HCC history African/North American blacks with 0.2 HCC occurs at a younger age hepatitis B Cirrhotic hepatitis B carriers 0.2-1.5 3-8% per year cirrhosis 1.5 3-5% per year Stage 4 primary biliary cholangitis 1.5 3-5% per year Genetic hemachromatosis and Unknown, but probably >1.5% per 1.5 cirrhosis year Alpha-1 antitrypsin deficiency and Unknown, but probably >1.5% per 1.5 cirrhosis year Other cirrhosis 1.5 Unknown Surveillance benefit uncertain Hepatitis B carriers younger than 40 0.2 <0.2% per year (males) or 50 (females) Hepatitis C and stage 3 fibrosis 1.5 <1.5% per year Non-cirrhotic NAFLD 1.5 <1.5% per year

Mechanisms in NAFLD “Two-hit hypothesis for NASH Central role of the mitochondrion” Obesity Genetics a missense mutation [Ile148→ Diet Met148 (I148M)] 3 gene “2nd Hit” Environment PNPLA3 (adiponutrin) (ROS, cytokines, Lack of Activity “1st Hit” mitochondria damage)

Insulin Resistance

Day and James 1998 MECHANISMS OF PORTAL HYPERTENSION

MechanismsMechanisms ofof PortalPortal HypertensionHypertension

•• PressurePressure (P)(P) resultsresults fromfrom thethe interactioninteraction ofof resistanceresistance (R)(R) andand flowflow (F):(F): PP == RR xx FF

••PortalPortal hypertensionhypertension cancan resultresult from:from: ••increaseincrease inin resistanceresistance toto portalportal flowflow and/orand/or ••increaseincrease inin portalportal venousvenous inflowinflow HCC Surveillance Benefit Uncertain n Hepatitis B carriers/inactive low DNA n Younger than 40 (males) or 50 (females) n Hepatitis C and stage 3 fibrosis n Non-cirrhotic NAFLD Diagnosis, Management, and Prophylaxis of SBP

Ascites - PMNs 250 cells/mm3- no intra-abdominal source of infection RFs - Prior SBP, ascitic fluid TP <1.0 g/dL, and GIB

GENERAL for SBP ü Albumin if BUN >30 mg/dL, Cr >1 mg/dL ü 3rd generation cephalosporin (cefotaxime 2 g q 8 hrs or ceftriaxone 2 g q day) ü Ofloxacin (400 mg BID) -alternative in hospitalized patients no shock, vomiting, Grade II PSE, Cr >3 or previous exposure to quinolone ü Continue antibiotic therapy for 7 days

ü Secondary prophylaxis Long-term oral norfloxacin or trimethoprim/sulfamethasoxazole

Primary prophylaxis ü Cirrhosis with GIB- IV Ceftriaxone or PO Norfloxacin ü Ascitic fluid TP <1.5 g/dL and Cr 1.2 mg/dL, BUN 25 mg/dL or Na 130 ü Child-Pugh score 9 and serum bilirubin 3 mg/dL SPLANCHNIC AND SYSTEMIC VASODILATION RESULT FROM AN INCREASE IN NITRIC OXIDE SplanchnicSplanchnic andand SystemicSystemic VasodilatationVasodilatation ResultResult fromfrom anan IncreaseIncrease inin NitricNitric OxideOxide

PortalPortal HypertensionHypertension

Ascites

ShearShear stressstress BacterialBacterial translocationtranslocation

Nitric Oxide VasodilationVasodilation (( SVR)SVR)

HyperdynamicHyperdynamic PlasmaPlasma volumevolume SodiumSodium andand circulationcirculation expansionexpansion waterwater retentionretention HBV HBV HBV HBV HBV

HbsAg + HbsAg + HbsAg + HbsAg + HbsAg -

Hbs Ab - Hbs Ab - HbsAb - HbsAb - HbsAb +

HbeAg + HbeAg + HbeAg - HbeAg - HbcAb - HeAb - HeAb - HbeAb + HbeAb + nl ALT ↑ ALT nl ALT ↑ ALT

HBVDNA HBVDNA HBVDNA HBVDNA ++++ +++ - ++

Immune Tolerant Immune Active Inactive Phase Immune reactivation Phases of HBV

ALT HBV DNA HbeAg Liver IU/ml biopsy Immune- Normal > 1mil Positive Minimal tolerant inflam/fib Immune- Elevated > 20,000 Positive Mod/severe active Inactive Normal < 2,000 or nl Negative minimal phase Immune Elevated > 2,000 Negative Mod/severe reactivation Updated Guidelines

AASLD 2015 HbeAg + HbeAg + HbeAg - HbeAg - Non-cirrhotic DNA > 20,000 ALT > 2 ULN DNA > 2,000 ALT > 2 ULN Cirrhosis DNA > 2,000 ALT Normal DNA > 2,000 ALT Normal

ALT nl 30 IU/ml males; 19 IU/ml females Tenofovir, Vemlidy, Entecavir

Elevated DNA and ALT but < thresholds Liver Bx > 40 yo Extrahepatic symptoms Failed previous therapy HCV Therapy n www.hcvguidelines.org n Genotype 1- with and without cirrhosis n Ledipasvir/sofosbuvir (Harvoni) n 1 tab PO daily x 12 wks n Genotype 2, 3, 4, 5, 6 n Velpatasvir/sofosbuvir (Epclusa) n 1 tab PO daily x 12 wk Renal Failure Elbasvir/Grazoprevir (Zepatier) 1 tab PO daily x 12 wks PENICILLAMINE TRIENTINE ZINC

What pair is the correct answer? A) Avoid shellfish, ATP7B B) MRI abnormal basal ganglia, Ataxia C) Psychiatric symptoms, Self-injury D) All of above Imaging Predictors

Transient Elastography (11 full-length articles and 2 abstracts) 1163 patients n F ≥ 2 Sen 0.78 (95% CI: 0.72–0.83) Sp 0.84 (95% CI: 0.75–0.90) n Cirrhosis, Sen 0.89 (95% CI: 0.80–0.94) and 0.87 (95% CI: 0.82–0.91) n Liver Intern 2013:33; 1138-47

MR Elastography – 2019 at GHS MR Multiparametric – , iron and fibrosis Portal Hypertension

Compensated Decompensated Further Death Cirrhosis Cirrhosis Decompensation

Mild PH Variceal Bleed Recurrent VB 6-10 PSE Refractory Ascites CSPH Ascites HRS >10 Hyponatremia No varices Varices

Garica-Tsao et al Hepatology AASLD guideline 2016 NATURAL HISTORY OF CIRRHOSIS

DevelopmentDevelopment ofof ComplicationsComplications inin CompensatedCompensated CirrhosisCirrhosis

100100

8080

ProbabilityProbability ofof 6060 AscitesAscites Jaundice developingdeveloping Jaundice Encephalopathy eventevent 40 Encephalopathy 40 GIGI hemorrhagehemorrhage

2020

00 00 2020 4040 6060 8080 100100 120120 140140 160160 MonthsMonths Gines et. al., Hepatology 1987; 7:122 HCC Evaluation