AscitesAscites andand RelatedRelated DisordersDisorders

LuisLuis S.S. Marsano,Marsano, MDMD ProfessorProfessor ofof MedicineMedicine DirectorDirector ofof HepatologyHepatology UniversityUniversity ofof LouisvilleLouisville CausesCauses ofof AscitesAscites

Malignant Ne oplasia 10% Ca rdiac Insufficiency 3% Tube rculous Peritonitis Chronic he patic 2% Nephrogenic 81% a sci te s (d i a l ysi s) 1% Pancreatic ascites 1% Biliary ascites 1% Others 1% PathophysiologyPathophysiology ofof CirrhoticCirrhotic AscitesAscites Hepatic sinusoidal pressure

Activation of hepatic baroreceptors Compensated Peripheral arterial vasodilation with hypervolemia, (normal renin, aldosterone, vasopressin, or norepinephrine)

Peripheral arterial vasodilation (“underfilling”)

Decompensated Neurally mediated Na+ retention, (with elevated renin, aldosterone, vasopressin, or norepinephrine) ClassificationClassification ofof AscitesAscites

SerumSerum--ascitesascites albuminalbumin gradientgradient (SAAG)(SAAG)

SAAGSAAG (g/dl)(g/dl) == albuminalbumins –– albuminalbumina GradientGradient >>1.11.1 g/dlg/dl == portalportal hypertensionhypertension

Serum globulin > 5 g/dl:: – SAAG correction = (SAAG mean)(0.21+0.208 serum globulin g/dl) AscitesAscites withwith HighHigh SAAGSAAG >>1.11.1 g/dlg/dl == portalportal hypertensionhypertension Cirrhosis Alcoholic Hepatitis Cardiac ascites Massive hepatic metastasis Fulminant hepatic failure Budd-Chiari syndrome Portal vein thrombosis Veno-occlusive disease Acute fatty liver of pregnancy Myxedema Mixed ascites LowLow SAAGSAAG <1.1<1.1 g/dlg/dl Peritoneal carcinomatosis Tuberculous peritonitis (without cirrhosis) Biliary ascites (without cirrhosis) Pancreatic ascites (without cirrhosis) Nephrotic ascites Connective tissue disease Intestinal obstruction/infarction Ovarian Hyperstimulation Syndrome POEMS Syndrome Chylous Ascites Urine ascites SurvivalSurvival ofof CirrhoticsCirrhotics withwith AscitesAscites

Survival in cirrhotic ascites

1 0.8 0.6 Probability 0.4 Survival 0.2 0 012345 YEARS CharacteristicsCharacteristics ofof UncomplicatedUncomplicated CirrhoticCirrhotic AscitesAscites

Polymorphonucleocytes < 250/mm3

SAAG > 1.1 g/dl

Ascites/plasma LDH < 0.6

Protein < 2.5 g/dl

0 20 40 60 80 100 % Ascites/plasma amylase ~0.5 Leucocytes < 300/mm3; intense diuresis 1100/mm3 TreatmentTreatment ofof AscitesAscites withwith HighHigh SAAGSAAG ((>> 1.11.1 mg/dl)mg/dl) TreatTreat primaryprimary diseasedisease (alcoholism,(alcoholism, WilsonWilson’’s,s, autoimmuneautoimmune hepatitis,hepatitis, cardiaccardiac insufficiency,insufficiency, ……)) Na+Na+ restrictionrestriction:: –– Inpatient:Inpatient: 250250--10001000 mgmg (11(11--4444 mEmEq)q) dependingdepending onon urinaryurinary lossloss –– Outpatient:Outpatient: 11--22 gg (44(44--8888 mEq)mEq) ofof Na/dayNa/day withwith diureticsdiuretics forfor 00 oror slightlyslightly negativenegative balancebalance TreatmentTreatment ofof AscitesAscites

DiureticsDiuretics – General therapeutic goal Without edema : 1 lb/d weight loss With edema : 1-2 lb/d weight loss If urine Na/K ratio 24 h after diuretics is >1, then 90% of patients will loose at least 88 mEq Na/day. any Random spot urine Na/K > 0.97 has similar value (PPV 84%; NPV 90%) and if Na/K >/= 3.5, PPV is 100% (Liver Int. 2012;32(1):172-3), – Spironolactone: more effective than loop diuretics. Can produce hyperK and acidosis Dose: 100, 200, or 400 mg QD TreatmentTreatment ofof AscitesAscites

––FurosemideFurosemide:: producesproduces hypoKhypoK andand alkalosisalkalosis Dose:Dose: 40,40, 80,80, oror 160160 mgmg QDQD ––MetolazoneMetolazone:: addedadded whenwhen maximalmaximal spironolactonespironolactone 400400 ++ FurosemideFurosemide 160160 isis notnot controllingcontrolling ascites.ascites. CausesCauses severesevere hypoKhypoK DoseDose 2.52.5--1010 mgmg QDQD TreatmentTreatment ofof AscitesAscites withwith HighHigh SAAGSAAG WaterWater restrictionrestriction – If serum Na < 126-130 mEq/L – Restrict to 0.8-1.5 liters/day – If water restriction fails: Tolvaptan (Samsca) 15 mg po q day; increase to 30 mg po qd if serum Na fails to increase by 5 mMol in 24 h, and to 60 mg po qd if Na fail to increase by 5 mMol after 30 mg x 1 day. Goal: correct Na by 8 mMol/d (never > 12 mMol/d) Correct hypothyroidism and adrenal insufficiency. Contraindications: MI, ventricular arrhythmia, PCWP < 5 mmHg, BPs < 90 mmHg, severe pulm. HTN, Creat > 3.5, Serum Na < 120 with neuro impairment, uncontrolled DM. AggressivelyAggressively correctcorrect malnutritionmalnutrition TreatmentTreatment ofof AscitesAscites

TherapeuticTherapeutic paracentesis:paracentesis: done in patients with stable cirrhosis with or without edema – Single large volume paracentesis (4-6 L): with or without colloid infusion – Serial LVP (4-6 L/Day): Colloid infusion (40 g albumin) need is controversial – Total paracentesis (6-22 L over 1 hr) with IV albumin (6-8 g/L removed), or Dextran 70 (8 g/L removed), or Midodrine 5-10 mg p.o. TID with goal to increase baseline MAP by 10 mmHg x 72 hours (Am J Gastroenterol 2008;103:1399-1405) TreatmentTreatment ofof RefractoryRefractory AscitesAscites

DefinitionDefinition:: AscitesAscites thatthat cancan notnot bebe controlledcontrolled onon aa 22 gg NaNa dietdiet withwith SpironolactoneSpironolactone 400400 mgmg ++ FurosemideFurosemide 160160 mg,mg, withoutwithout causingcausing azotemia.azotemia. TreatTreat asas HRSHRS:: AlbuminAlbumin ++ MidodrineMidodrine ++ OctreotideOctreotide TIPSSTIPSS NonNon--selectiveselective surgicalsurgical ShuntShunt SpontaneousSpontaneous BacterialBacterial PeritonitisPeritonitis (SBP)(SBP) andand CultureCulture NegativeNegative NeutrocyticNeutrocytic AscitesAscites (CNNA)(CNNA) PrevalencePrevalence 1010--27%27% inin hospitalizedhospitalized patientspatients withwith cirrhoticcirrhotic ascitesascites

PathogenesisPathogenesis:: distantdistant bacteremiabacteremia (UTI,(UTI, URI,URI, etc.)etc.) oror translocationtranslocation ofof bacteriabacteria fromfrom intestinalintestinal lumenlumen SignsSigns andand SymptomsSymptoms ofof SBPSBP

Abdominal Encephalopathy Abdominal tenderness Leucocytosis Bacteremia Fever Hypotension Rebound

0 20 40 60 80 100 % DiagnosisDiagnosis ofof SBPSBP andand CNNACNNA

SBPSBP == PMNPMN >250/mm>250/mm3 withwith (+)(+) cultureculture (>(> 90%90% monobacterial)monobacterial) – Other predictors: ascites WBC > 1000/uL; ascites pH < 7.35; blood-ascites pH gradient =/> 0.1 CNNACNNA == PMNPMN >250/mm>250/mm3 withwith ((--)) cultureculture (without(without previousprevious antibioticsantibiotics nornor otherother causescauses ofof increasedincreased PMNPMN [bleeding,[bleeding, ,cancer, TB,TB, pancreatitis]pancreatitis] )) BacteriologyBacteriology ofof SBPSBP

GramGram--NegativeNegative BacilliBacilli 70%70% Escherichia coli Klebsiella spp. GramGram--PositivePositive CocciCocci 20%20% pneumonia Enterococcus spp Staphylococcus spp Anaerobes,Anaerobes, MicroaerophilsMicroaerophils && othersothers 10%10% AscitesAscites CultureCulture

100

80

60 % 40

20

0 Blood culture bottle Culture in plate SBPSBP andand CNNACNNA

MorbidityMorbidity andand MortalityMortality – Mortality without treatment: 78-100% – Mortality w. Cefotaxime: 30% (HRS= 33%) – Mortality w. Cefotaxim+albumin: 10% (HRS=10%) – Recurrent SBP in 69%

TreatmentTreatment – Cefotaxime 2g TID x 5 days + Albumin 1.5 gm/Kg @ day 1 & 1 gm/Kg @ day 4 – Re-paracentesis at 48hrs (50% reduction in WBCs) SBPSBP && CNNACNNA

ProphylaxisProphylaxis –– CirrhoticCirrhotic withwith totaltotal proteinprotein << 1.51.5 g/dl;g/dl; NorfloxacinNorfloxacin 400400 mg/dmg/d popo oror BactrimBactrim DSDS 55 days/weekdays/week duringduring hospitalizationhospitalization

–– CirrhoticCirrhotic withwith GIGI bleedbleed NorfloxacinNorfloxacin 400400 mgmg popo BIDBID xx 77 daysdays MonomicrobialMonomicrobial BacterascitesBacterascites DiagnosisDiagnosis ––(+)(+) ascitesascites cultureculture withwith PMNPMN << 250/mm250/mm33 andand withoutwithout surgicallysurgically treatabletreatable intraintra-- abdominalabdominal sourcesource ofof infectioninfection SignsSigns andand SymptomsSymptoms ofof MonomicrobialMonomicrobial BacterascitesBacterascites

Rebound

Abdominal pain

Abdominal tenderness

Encephalopathy

Fever

0 20 40 60 80 100 % MonomicrobialMonomicrobial BacterascitesBacterascites

Mortality:Mortality: 40%40% TreatmentTreatment –– CefotaximeCefotaxime 22 gg TIDTID asas perper antibioticantibiotic susceptibilitysusceptibility –– RepeatRepeat paracentesisparacentesis inin 4848 hrhr AscitesAscites ManagementManagement

EVALUATE:EVALUATE: TREAT:TREAT:

ParacentesisParacentesis postpost-- NaNa restrictrestrict ++ LVPLVP ++ adm, PSE, Azotemia, adm, PSE, Azotemia, diureticsdiuretics FeverFever PMN>250: Cefotaxim Check:Check: Prot,Prot, Alb,Alb, PMN>250: Cefotaxim WBC,WBC, Glu,Glu, LDHLDH inin ++ AlbuminAlbumin serumserum && ascitesascites ProtProt << 1.5g:1.5g: NorfloxacNorfloxac BedsideBedside CultureCulture inin GIGI Bleed:Bleed: NorfloxacinNorfloxacin BloodBlood CultureCulture bottlebottle HepaticHepatic HydrothoraxHydrothorax In 10% of patients with ascites Usually right sided T. in hydrothorax > ascites by 0.75-1 g/dl

Protein ratio (s/h) > 0.5

LDH, ratio s/h > 2/3 upper limit in serum

“Transudate”

Glucose > 60 mg/dl

LDH ratio (s/h) > 0.6

0 10 2030 4050 6070 8090 100 % SignsSigns andand Symptoms:Symptoms: SpontaneousSpontaneous BacterialBacterial EmpyemaEmpyema

Cough Shock

Thoracic pain

Abdominal pain Dyspnea

Chills Fever SBP

0 10 203040 50607080 90100 % SpontaneousSpontaneous bacterialbacterial empyemaempyema

Diagnosis: – A) culture (+) (in blood culture bottle), or – B) PMN > 500/mm3 in patients with known hepatic hydrothorax and CXR without pneumonia : single bacteria (E.coli, K. pneumonia, C. perfringes) Bacteremia in 36% Mortality: in culture (+) = 50%; in general = 27% Relapse rate: 38% at 1 year; mortality at 1 year =50% Treatment: Cefotaxime (or as per antibiotic susceptibility) + albumin expansion. Response to therapy = 72% SuspectSuspect SecondarySecondary PeritonitisPeritonitis in:in: MultipleMultiple organismsorganisms oror fungifungi inin cultureculture AsciticAscitic infectioninfection inin peritonealperitoneal carcinomatosiscarcinomatosis oror cardiaccardiac ascitesascites IncreasedIncreased PMNPMN countcount afterafter 4848 hrhr therapytherapy ofof SBPSBP TwoTwo ofof thethe following:following: – Ascites < 50 mg/dl (67%) – Ascites protein > 1 g/dl (83%) – Ascites LDH > upper normal in serum (100%) SecondarySecondary peritonitisperitonitis

Pathogenesis: perforation/microperforation on hollow viscus or contamination from intraabdominal abscess

Rebound

Change in mental status

Fever

Abdominal tenderness

Abdominal pain

0 10 203040 50607080 90100 % SecondarySecondary peritonitisperitonitis

EvaluationEvaluation:: looklook forfor perforationperforation (extravasation(extravasation ofof contrast)contrast) oror loculatedloculated pus.pus. TreatmentTreatment:: –– SurgerySurgery (if(if perforationperforation oror abscessabscess found)found) –– AntibioticsAntibiotics (Cefotaxime(Cefotaxime ++ metronidazol)metronidazol) ++ albuminalbumin expansionexpansion TuberculousTuberculous PeritonitisPeritonitis

PathophysiologyPathophysiology:: infectioninfection ofof peritoneumperitoneum causescauses exudateexudate ofof proteinprotein whichwhich ““pullspulls”” fluidfluid forfor oncoticoncotic balance;balance; ClassicallyClassically SAAGSAAG isis << 1.11.1 g/dl,g/dl, andand manymany patientspatients havehave underlyingunderlying cirrhosiscirrhosis mixedmixed ascitesascites (SAAG(SAAG >> 1.11.1 g/dl)g/dl) CharacteristicsCharacteristics ofof TuberculousTuberculous PeritonitisPeritonitis

WBC > 250/mm3 with mononucleocytes > 80%

GSAA < 1.1 g/dl

T. Protein > 2.5 g/dl (50-85%)

Ascites/serum LDH > 0.6

0 10 203040 50607080 90100 % •78% serum glucose < 100 mg/dl •5-10% bloody DiagnosisDiagnosis ofof TuberculousTuberculous PeritonitisPeritonitis

Laparotomy + Bx

Laparoscopy + Bx

Ascites 1 L concentrated + innoculated in guinea pig

Culture

Stain

0 10 203040 50607080 90100 % TuberculousTuberculous PeritonitisPeritonitis

MortalityMortality withoutwithout therapy:therapy: 60%60% Treatment:Treatment: ––AntiAnti--tuberculoustuberculous agentagent ––AntiAnti--fungalfungal agentagent CausesCauses ofof MalignantMalignant AscitesAscites

Malignant chylous ascites Peritoneal 7% carcinomatosis + Hepatic metastasis 13%

Hepatocellular Peritoneal carcinoma Carcinomatosis 13% 54%

Massive liver metastases 13% PeritonealPeritoneal CarcinomatosisCarcinomatosis (54%)(54%) PeritonealPeritoneal proteinprotein exudateexudate pullspulls fluidfluid :: SAAGSAAG << 1.11.1 OtherOther characteristics:characteristics: –– WBCWBC >500>500 –– T.T. proteinprotein >> 2.52.5 gg (usually(usually –– 4.0)4.0) –– LDHLDH >> 225225 (usually(usually –– 10001000 IU/L)IU/L) –– GlucoseGlucose << 100100 inin 71%71% CytologyCytology (+)(+) MassiveMassive hepatichepatic metastasesmetastases (13%)(13%)

––PortalPortal hypertensionhypertension :: SAAGSAAG >> 1.1g/dl1.1g/dl ––BloodyBloody inin 10%10% ––CytologyCytology negativenegative PeritonealPeritoneal CarcinomatosisCarcinomatosis ++ liverliver metastasesmetastases (13%)(13%)

––MixedMixed ascitesascites :: SAAGSAAG >1.1g/dl>1.1g/dl ––BloodyBloody inin 10%10% ––CytologyCytology (+)(+) ––WBCWBC >> 500500 withwith dominantdominant lymphocyteslymphocytes HepatocellularHepatocellular carcinomacarcinoma (13%)(13%)

PortalPortal hypertensionhypertension (cirrhosis(cirrhosis +/+/-- portalportal veinvein thrombosis)thrombosis) SAAGSAAG >> 1.1g/dl1.1g/dl BloodyBloody inin 50%50% AlphaAlpha--fetoproteinfetoprotein highhigh (serum(serum >> ascites)ascites) CytologyCytology negativenegative MalignantMalignant chylouschylous ascitesascites (7%)(7%)

LymphLymph leakleak duedue toto invasioninvasion ofof lymphlymph nodesnodes withwith rupturerupture ofof lymphaticlymphatic vesselsvessels Characteristics:Characteristics: SAAGSAAG << 1.1g/dl,1.1g/dl, triglyceridestriglycerides >> 8181 mg/dlmg/dl oror >> plasmaplasma triglyceridestriglycerides (usually(usually >> 10001000 mg/dl)mg/dl) BloodyBloody inin 10%10% CytologyCytology isis variablevariable CardiacCardiac AscitesAscites Passive congestion causes portal hypertension : SAAG >1.1g/dl (100%)

Valvular heat disease 23% Cardiom yopa thy 23%

Restrictive lung disease 15%

Constrictive Ischemic heart pe rica rd itis disease 8% 31% CardiacCardiac ascitesascites

Characteristics:Characteristics: –– SAAGSAAG >> 1.11.1 g/dlg/dl (100%)(100%) –– T.T. proteinprotein >> 2.52.5 g/dlg/dl (100%)(100%) –– LDHLDH << upperupper limitlimit ofof normalnormal (100%)(100%) –– WBCWBC isis variablevariable 480480 ++ 490/mm490/mm3 –– PMNPMN << 250/mm250/mm3 Treatment:Treatment: underlyingunderlying diseasedisease PancreaticPancreatic AscitesAscites

Pancreatic duct or pseudocyst rupture in chronic alcoholics Up to 50% with cirrhosis (SAAG >1.1 mg/dl) Characteristics – Amylase > 1000 – SAAG < 1.1 mg/dl – T. protein > 2.5 g/dl (100%) – High LDH (~2000 IU/L) – High WBC (~4000/mm3) – High PMN (~3000/mm3) – Glucose variable Secondary infection occurs in 25% Treatment: stenting, surgery, octreotide, bowel rest NephroticNephrotic ascitesascites

HypoalbuminemiaHypoalbuminemia decreaseddecreased effectiveeffective arterialarterial bloodblood volumevolume activationactivation ofof renin/aldosterone/vasopressin/norepinephrinerenin/aldosterone/vasopressin/norepinephrine renalrenal NaNa andand waterwater retentionretention edemaedema ++ ascitesascites CharacteristicsCharacteristics – SAAG < 1.1g/dl – T. protein – 0.6 g/dl – Glucose - 100 mg/dl – LDH ascites/serum < 0.5 – WBC < 250/mm3 – PMN few Treatment:Treatment: NaNa restrictionrestriction andand diureticsdiuretics NephrogenousNephrogenous ascitesascites

Unknown etiology – Patients on hemodialysis – 50% have cirrhosis Characteristics – SAAG < 1.1 g/dl in 50% – Protein > 2.5 g/dl (100%) – LDH < upper limit of normal 100% – Glucose > 100 mg/dl – WBC < 500/mm3 in 75% (350+225), mostly lymphocytes – PMN < 250/mm3 Laparoscopy + bx to rule out cirrhosis + TB Treatment: vigorous dialysis BiliaryBiliary ascitesascites

Perforation of gall bladder, bile duct or proximal gut produces bile leak Characteristics – in ascites > 3 mg/dl and ascites/serum bili > 1 – SAAG < 1.1 g/dl but variable (1.2+0.5) – LDH – 2500 IU/L – T. protein > 2.5 g/dl (2.6+0.2) – Glucose variable (90+85 g/dl) – WBC – 3400 – PMN – 3000 – Amylase usually not elevated (except in intestinal perforation) Usually monomicrobial Treatment: stenting, surgery