*LIVER CIRRHOSISLeonardo dairyDivisi Gastroentero-HepatologiDepartemen Ilmu Penyakit DalamFK-USU/ RSUP H. Adam Malik Medan

LIVER CIRRHOSISchronic progressive liver disease leading to necroinflammatory reactionfibrosisloss of the lobular and vascular architecture of liver lobule regenerating nodulesLIVER CIRRHOSIS, is common end results from chronic injury to liver cells with variety causes INTRODUCTION

The prevalence of liver cirrhosis is 3.6 per 1000 individuals in North America. Liver Cirrhosis is the 12th leading cause of death in the United States, It accounted for 29,165 deaths in 2007, with a mortality rate of 9.7 per 100,000 persons. Alcohol abuse and viral hepatitis are the most common causes of cirrhosis, although NAFLD is emerging as an increasingly important cause. Portal hypertension develops as a consequence of cirrhosis,is present in 60% at the time of diagnosisMorphology Classification Micronodular cirrhosis, Macronoduler cirrhosis and Mixed cirrhosis

INTRODUCTION

DEFINITION

Cirrhosis is derived from Greek kirros = orange or tawny and osis=conditioDefinition: a diffuse process characterized by liver necrosis, fibrosis and conversion of normal liver architechture into structurally abnormal nodules

Healthy LFibrosisCirrhosis

CAUSES OF CIRRHOSISViral hepatitis; B, D, and CAlcoholMetabolic Haemochromatosis Wilsons disease Alpha-1-antitrypsin deficiencyChronic biliary obstruction Extrahepatic biliary obstruction Intrahepatic biliary obstructionVenous outflow obstruction Veno-occlusive disease Budd-Chiari syndrome Cardiac failureAutoimmune chronic active hepatitisDrug and toxins

NATURAL HISTORY OF CHRONIC LIVER DISEASE

CLINICAL FEATURES The clinical features of cirrhosis have been known since ancient timesCompensated CirrhosisDecompensated CirrhosisCirrhotic patient may develop Hepatocellular carcinoma

CLINICAL HISTORYFatique and weight lossAnorexia and dyspepsiaAbdominal painJaundiceSwelling of legs or abdomenHaemorrage- nose, gums, skin, alimentary tractLoss of libidoPast health, Jaundice, Hepatitis, Drug ingested, Blood transfusionSocial, Alcohol consumptionHereditary

EXAMINATION

Nutrition, Fever, Fetor Hepaticus, Jaundice, Pigmentation, Purpura, Finger clubbing, White nails, Spider naevi, Palmar erythema, Gynecomastia, Testicular atrophy, Distribution of body hair, Parotid enlargment, Dupuytren contracture, Blood pressure Abdomen Ascites, Collateral vein, Liver, SpleenPeripheral edemaNeurological changes mental functions, stupor, tremor

INVESTIGATION

HAEMATOLOGY Haemoglobin, Leucocyte, Platelet count and Prothrombine time .BIOCHEMICALSerum Billirubin, Transaminase, Alkaline phospatase, Albumin, Globulin, ImmunoglobulinsASCITES Serum sodium, Potassium, Bicarbonate, Chloride, Urea and Creatinine levelsWeight daily24 hours urine volume and sodium secretion

INVESTIGATION

Ultrasonografi, Hepatic CT ScanLiver Biopsy EndoscopyEEG if neuropsychiatric changesSerum immunologocal, smoothmuscle,mitochondrial and nucleus antibodiesHbsAg, Anti HCV and other marker of HepatitisAlpha fetoprotein

Clinical apperance result Hepatocelluler failure Portal Hypertension

PORTAL HYPERTENSION

MODIFIED CHILD - PUGH CLASSIFICATIONOF THE SEVERITY LIVER DISEASE

CHILD -PUGH 1 2 3---------------------------------------------------------------------------------------BILIRUBIN < 2 gr % 2,0 - 3,0 gr % > 3,0 gr %.ALBUMIN > 3,5 gr % 2,8 - 3,5 gr % < 2,8 gr %.ASCITES NONE SLIGHT MODERATEENSEFALOPATI NONE GRADE 1/2 GRADE 3/4PROTHROMBINE 1 3 4 - 6 >6 TIME ============================================================TOTAL SCORE ( 5 6 grade A ) ( 7 9 grade B ) ( 10 15 grade C) ----------------------------------------------------------------------

MELD SORE,3.78ln[serum bilirubin (mg/dL)] + 11.2 ln[INR] + 9.57ln[serum creatinine (mg/dL)] + 6.43 aetiology(0: cholestatic or alcoholic, 1- otherwise)

COMPLICATION OF CIRRHOSISVariceal bleedingAscites, refractory ascitesHepatorenal syndromeHepatic encephalopathySpontaneous bacterial peritonitisHepatocelluler carcinomaGastropathyOsteopenia, osteoporosis

MANAGEMENT

The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation General ManagementSpecific TreatmentTreatment of complication CirrhosisOrthotopic Liver Transplantation

General Management

Good nutritionAvoid protein excessLow salt dietAlcohol abstinenceAvoid NSAID, Sedative, and OviatCholestyramine for pruritus

Specific Treatment

Interferon and Ribavirin improve liver biochemistry and may retard development of HCC in HCV induced CirrhosisUCLA in PBC with little benefitPenicillamine for Willson diseaseVena section for Haemochromatosis

Variceal Bleeding

*Methode Non Farmakology

SB Tube(Sengstaken-Blackmore Tube)Methode Farmacology

Non selektif Beta blokersEndoscopic Injection Sclerotherapy (EIS)Endoscopic VaricealLigation (EVL)TIPPSSurgical Porto Systemic ShuntOLT Treatment options for Esophageal VaricesNitratVasopressinSomatostatin & Analog(Octreotide)

TREATMENT OPTIONS FOR ESOPHAGEAL VARICES PURPOSE OFTHERAPY FIRST-LINE THERAPY SECOND-LINE OR ALTERNATIVE PRIMARY PROPHYLAXIS BETA-BLOCKER ALONE BETA-BLOCKER AND LONG-ACTING NITRATE (ISOSORBIDE MONONITRATE) BAND LIGATION ACUTE VARICEAL BLEED SANDOSTATIN, (OR TERLIPRESSIN OR VASOPRESSIN) AND ENDOSCOPIC THERAPY TIPS* SHUNT SURGERY SECONDARY PROPHYLAXIS BAND LIGATION ALONE BAND LIGATION BETA-BLOCKER ( NITRATES) TIPS* SHUNT SURGERY Treatment options for Esophageal Varices

Algorithm for Cirrhosis without bleedingCirrhosis WithoutBleedingCirrhosisEstablishedReguler IntervalUsually one weekUpper EndoscopyNo varicesSmall or MediumVaricesLarge VaricesObserveObserve 1 2 years Evaluation)Primary BleedingProphylaxis Non Selectne Blockers (and /or Nitrates) Ligation

2 3 years Evaluation

Algorithm for Cirrhosis with bleedingAlgorithm ForBleeding Cirrhotis Resuscitae Begin Octreotide or VasopressinEarly endoscopyNon-PortalHypertensive CauseGastric VaricesEsophagelVaricesPortalHypertensiveGastropathyTreat appropriatelyContinue octreotide 5 daysBegin beta-blocker when stableBand ligation or injectionSclerotheraphyBallon TamponadeRebleedingNo rebleedingShunt (Child A)TiPSS. orLiver transplantation (Child B or C)Continue treatmentPreventation of Rebleeding Pharmacological Treatment Ligation /Sclerotheraphy Reguler IntervalUsually one weekRepeated Endoscopy3 6 monthEradicationShunt (Child A)TIPSS Or OLT (Child B or C)Rebleeding

Ascites

Grading ascites

grade 1: detectable only by careful physical examination grade 2: easily detected but relatively small amount grade 3: obvious but not tense grade 4: tense

Management of cirrhotic patients with moderate uncomplicated ascitesStart with a low sodium diet (80 mmol /day) and anti aldosteronic drug (100-200 mg/day) monitoring body weightLow doses of furosemide (20-40 mg/day), in case of poor response to the anti aldosteronic drug.The goal of treatment : weight loss of 500 g /day in patients without peripheral edema, and 1 kg/day in patients with peripheral edema.Maximum dose of anti aldosteronic drug 400 mg/day and 160 mg of furosemide.Sodium restriction.

Management of cirrhotic patients with tense or large uncomplicated ascites

Total paracentesis is the most effective and safest procedures to mobilize large ascitesBlood volume with intravenous albumin (8 g/L of ascite removed) is required if the volume of ascites is more than 5 liter.Start with a low sodium diet and diuretics soon after paracentesis

Management of refractory ascitesParacentesisPeritovenous shuntTransjugular intrahepatic porto-systemic stent-shunt (TIPSS)Liver Transplantation

Spontaneus Bacterialis Peritonitis

Spontaneus Bacterial PeritonitisSpontaneous bacterial peritonitis is an infection of ascitic fluid without a known source of infection. It occurs in 10% to 30% of patients with cirrhotic ascites and is frequently recurrent (70% recurrence rate in 1 year)Cirrhotic patients at high risk of SBPCirrhotic patients with gastrointestinal hemorrhageCirrhotic patients with low ascitic fluid total protein (< 1 g/dL) and / or high serum bilirubin (>2.5 mg/dl)Survivors of an episode of SBP.Hospitalized cirrhotic patients with ascites and low ascitic fluid total protein (< 1 g/dl

Liver cirrhosis with ascitesAscites functureabdominal pain

accompanying symptom, shock, disturbances of consciousness,disturbances of motility,hypotension.etc,asymptomatic Ascites funtionCheck PMN, culturePMN cell > 250PMN cell < 250Culture + MonomikrobialCulture + MonomikrobialSBPBMNNBakterisida Monomikrobial Non Nerro toxicDiagnosis of SBP

SBP SYMPTOMATICSBP PROPHYLAXISANTIBIOTIC CHOICECefotaxime 1-2gr/day (5-7)daysAmoxillin+ Clavulanic Acid (5-7)daysREPEAT PARASINTESIS AFTER 24 HOURS ANTIBIOTICSANTIBIOTIC FORWAREDPMN CELL PMN CELL MANAGEMENT OF SBPNorfloxacinCyprofloksacin Standard dose(5-7)daysANTIBIOTIC CHANGES

Hepatorenal Syndrome

Diagnostic Criteria of HRSMajor criteria 1.Low glomerular filtration rate, as indicated by serum creatinine >1.5 mg/dL. 2.Exclusion of shock, ongoing bacterial infection, volume depletion, and use of nephrotoxic drugs including NSAIDs 3.No improvement in renal function despite stopping diuretics and volume repletion with 1.5 Liters of saline 4.No proteinuria or ultrasonographic evidence of obstructive uropathy or parenchyma renal disease.Minor criteria 1.Urine volume

Pathogenesis of HRS

SPESIFIC THERAPY

PHARMACOLOGICAL TREATMENTVasoconstrictors Terlipressin , 1-2 mg /4-6 hr iv. Response to therapy is defined as a decrease in serum creatinine levels below 1.5 mg/dL (133 mol/L) Midodrine and octreotride, 7.5-12,5 mg midodrine orally 3 times daily and 100-200 g of octreotide sc 3 times dailyNorepinephrine 0.5-3 mg/hour as a continuous iv infusion aimed at increasing the mean arterial pressure 10 mmHgAlbumin, concomitant administration of albumin and vasoconstrictor drugs (1 g/kg of body weight on day 1 followed by 20-40 g/day)

Hepatic Encephalophathy

Classification of Hepatic Encephalopathy

Precipitants factor of HE

Degrees of Severity of Hepatic Encephalopathy :West Haven criteria Glasgow Coma Scale CNS

HE gradeState of consciousness / intellectBehaviourNeuromuscular symptomsTremor (conn)

Minimal subclinicalClinically normal but abnormal pathological and psychometric testsClinically normal but abnormal pathological and psychometric testsDisturbance of line motor function(-)IReduced concentration and prolonged reaction time sleep disorders, fatigue (reduced alertness)Personality changesDisturbance of line motor function1-2 / 30 IIRetardation, LethargyMarked personality changes, temporal disorientationAsterixis, slurred speech3-4 / 30IIIDisorientation, somnolence, stupor Bizarre behaviour delusionsHypo-and hyperreflexia, asterixis, convulsions5-30 / 30IVComaCeasedAreflexia, loss of toneUninterrupted tremor

MANAGEMENT

Identification of Precipitants Avoidance of analgesics, sedatives and tranquilizersControl of gastrointestinal tract bleeding and purging of blood from the gastrointestinal tract Screening and aggressive therapy for any infectionCorrection of acidosis, alkalosis, hypoxia, or electrolyte abnormalitiesPrevention of constipation and intravascular volume depletionAdequate intake of glucose to treat hypo- glycemia and prevent endogenous protein breakdownAdequate vitamin supplementation, including thiamine and folate

BCAALOLADIET

ORALANTIBIOTICFischer rasioIntestinalpH

Intestinaldecontaminasion

AmmoniaMetabolism

LowProteinINITIAL WORKUP OF ASCITES: DIAGNOSIS PARACENTESISLACTULOSA

THERAPI ENSEFALOPATI HEPATIKTreatment of Hepatic Encephalopathy Liver support devicesPorto systemic shuntLiver Transplantation

Hepatocellular Carcinoma

PathogenesisThorgeirsson, S.S. and J.W. Grisham, Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet, 2002. 31(4): p. 339-46.

PathologyHCC with cholangiolar features, moderately differentiated

Available treatment options for hepatic neoplasmTreatment modality1.Liver transplantation

2.Hepatic resection3.Thermal ablation (Radiofrequency,microwave,laser)4.Cryotherapy

LimitationsDonor avaibility, Three or fewer lesions, none > 3 cm , Solitary lesion < 5 cmMinimal or no cirrhosis, three or fewer lesionsThree or fewer lesions, each < 5 cm4. Small lesions, rarely done percutaneously

Available treatment options for hepatic neoplasm5. Conformal radiation6. Proton beam therapy7. Intra-arterial radiotherapyIntralesional ethanol9. Chemoembolization10.Systemic or intra arterial chemothrapy5. Solitary lession6. Radiation-induced liver disease7. Radiation hepatitis, renal/pancreatic damage8. Few, small lesions, difficulty viewing during injections, requires multiple sessions9. Adequate hepatic function, patent portal vein, considerable local toxicity10.Toxicity, lack of efficacy

Orthotopic Liver Transplantation

The two major aims of transplantation for end-stage liver disease are to improve survival and to increase functional statusLiver transplantation has dramatically improved the outcome for patients with acute or chronic liver failure, advanced decompensated liver cirrhosis and for patients with hepatocellular carcinoma5-year survival after transplantation is 80%

Indications for Liver transplantation

Cirrhosis secondary to chronic hepatitis B and C infection, Alcoholic cirrhosis Cirrhosis due to cholestatic disorders such as primary biliary cirrhosis andsclerosing cholangititis Cirrhosis and liver failure from autoimmune hepatitis Cirrhosis and liver failure resulting from metabolic disorders including:a.Hemochromotosisb.Non-alcoholic steatohepatitis (NASH), c.Wilson disease,d.Alpha-1-antitripsin deficiency, Hepatocellular carcinoma,Fulminant hepatic failure

ALTERNATIVE MEDICINEA number of alternative medicines have been used to treat liver diseases. Milk thistle (silymarin) is the most widely used and best studied. Other herbs used include licorice root (glycyrrhizin), schisandra and astragalus. However, there is not enough evidence of benefit from clinical trials to recommend use of any herbal products to treat liver cirrhosis..

CONCLUSIONThe major causes of cirrhosis include chronic hepatitis B, C, alcohol, hemochromatosis, and NASHImportant and potentially life-threatening complications of cirrhosis include ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and primary hepatocellular carcinomaThe ChildPugh classification is useful in assessing prognosis and estimating the potential risk of variceal bleeding and operative mortality.

CONCLUSIONThe Model for End-stage Liver Disease (MELD), a more recently developed prognostic assessment based on international normalized ratio (INR), serum creatinine level, and serum bilirubin level, is currently being used to determine the appropriateness and timing of liver transplantationThe new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantationThe challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible.

*******INITIAL WORKUP OF ASCITES: DIAGNOSIS PARACENTESISFor diagnostic paracentesis, 20-50 cc of ascitic fluid is obtained. In patients with new onset ascites, the fluid should be routinely evaluated for albumin (with simultaneous estimation of serum albumin, total protein, polymorphonuclear (PMN) blood cell count and bacteriological cultures (shown in yellow). Protein and the serum ascites albumin gradient or SAAG (serum albumin minus ascites albumin) are used for the differential diagnosis of ascites. Ascites PMN count and culture are performed to determine the presence of infection (e.g. spontaneous bacterial peritonitis). The following tests should be performed depending on individual circumstances (shown in white), most commonly: glucose and lactic dehydrogenase or LDH (if secondary peritonitis is suspected), amylase (if pancreatic ascites is suspected) and cytology (to exclude malignant ascites). **No cirrhosis was identified.

IHC:CK-7, CK20, TTF-1, PSA, AFP, hepatocyte negative from OSH*