B.J. WALELENG N. TENDEAN WENAS F.

WIBOWO

GASTROENTEROHEPATOLOGY DIVISION INTERNAL MEDICINE DEPARTMENT SAM RATULANGI UNIVERSITY

Cirrhosis is a diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. End stage of chronic liver damage resulting from several different causes. Leading to altered hepatic function and portal hypertension.

World prevalence : 100 (25-400) / 100,000 796,000 deaths from cirrhosis (2001) UK : 3000 deaths from cirrhosis or chronic liver disease every year (40% due to alcohol related disease) Italy : 15,000 died from cirrhosis (1992) 28 deaths /100,000. Most frequent causes : HCV, alcohol, HBV

USA : 5.5 million prevalence, rate 2030/100,000 (1998). Mortality 25,000 (9.3 / 100,000) annually. Most common causes : HCV (57%), alcohol (24%), Non alcoholic fatty liver disease (9.1%), hepatitis B (4.4%) INDONESIA 4%

MAIN ETIOLOGIC FACTORS IN CIRRHOSIS Hepatitis C virus Biliary disease (PBC, PSC, Intrahepatic or extrahepatic biliary obstruction) Venous Outflow obstruction (Budd Chiari, veno-occlusive disease, cardiac failure)

Hepatitis B or B/D virus

Alcohol
Autoimmune hepatitis Metabolic disorders (hemochromatosis, Wilsons disease, alpha-1 antitrypsin deficiency, NASH, diabetes, glycogen storage diseases, abetalipoproteinemia, porphyria)

Drugs (amiodarone, methotrexate) and toxins

Intestinal bypass Cryptogenic cirrhosis

In the Western World the most common etiology of cirrhosis is HCV, followed by alcohol abuse. Other important factors are hepatitis B infection and NASH. Autoimmune, metabolic, biliary, genetic disorders account for the largest remaining proportion of cirrhosis.

Progressive accumulation of collagen types I and III in the liver parenchyma

Alteration of : The exchange between hepatocytes and plasma Regulation of intrahepatic resistance to blood flow

Active fibrogenesis

TGF- PDGF

Activation and proliferation of hepatic stellate cells (extracellular matrix in fibrotic liver)

Micronodular
Nodules < 3 mm Alcoholic cirrhosis, hemochromatosis, bile duct

obstruction

Macronodular
Nodules of variable size > 3 mm Chronic viral hepatitis, autoimmune hepatitis

Mixed

Compensated cirrhosis
Asthenia, malaise, right upper quadrant

abdominal discomfort, sleep disturbances Physical signs secondary to alterations of estrogen metabolism : palmar erythema, spider angiomata Hepatomegaly with increased liver consistency Splenomegaly and collateral circulation on the abdominal wall

Decompensated cirrhosis
Ascites, gastrointestinal hemorrhage, jaundice,

portosystemic encephalopathy : main signs of decompensation Malnutrition and muscle wasting Hypotension and tachycardia due to hyperdynamic circulation secondary to portal hypertension.

CLINICAL FINDINGS Asthenia Malaise RUQ abdominal discomfort Loss of libido Sleep disturbances Palmar erythema Dupuytrens contracture Spider nevi White nails Gynecomastia Hair loss Hepatomegaly Splenomegaly Abdominal wall collaterals General deterioration, muscle wasting Jaundice Ascites Ankle edema Flapping tremor Bradylalia Mental state alteration (coma) Fetor hepaticus Gastrointestinal hemorrhage Hypotension, tachycardia

LABORATORY FINDINGS AST : ALT ratio > 1

ULTRASONOGRAPHIC FINDINGS Liver nodular surface

ENDOSCOPIC FINDINGS Esophageal varices

Low platelet count

Hypoalbuminemia

Reduced portal flow velocity

Portal vein diameter >13 mm

Gastric varices
Congestive gastropathy

Hypergammaglobulinemia Lack (or reduction <30%) of respiratory variations of splenic and superior mesenteric veins Prolonged PT Hyperbilirubinemia

Liver biopsy is the gold standard Compensated cirrhosis : clinical, biochemical, USG, endoscopic findings When a precise definition of stage of fibrosis or grading of inflammation is required, liver biopsy is needed. Signs of decompensation : ascites, variceal bleeding, encephalopathy

Ascites Spontaneous bacterial peritonitis Variceal hemorrhage Hepatic encephalopathy Hepatocellular carcinoma Hepatorenal syndrome

BLEEDING FROM ESOPHAGEAL VARICES

Incidence per year :

2% in patients without varices at diagnosis 5% in those with small varices 15% in those with medium-large varices

Major indicators of the risk of bleeding

Child-Pugh class Ascites Red wheal marks

Increased risk of bleeding with increased portal pressure Ruptured esophageal varices : 60-70% of all upper GI bleeding in cirrhosis Reduction of HVPG <12% prevents recurrent bleeding

COMPLICATIONS

DEVELOPMENT OF ASCITES AND ENCEPHALOPATHY Ascites develops after HVPG has increased to more than 12 mmHg Incidence : 5% per year Ascites and variceal bleed : the most frequent mode of transition from compensated to decompensated cirrhosis Incidence of encephalopathy : 2-3% per year

Ascites
Sodium and fluid restriction Diuretics : furosemide, spironolactone

Albumin infusion
Therapeutic paracentesis TIPS

Portal hypertension, esophageal varices and variceal bleeding

Reduce pressure with beta blockers Active bleeding : vasopressin, somatostatin Endoscopic and surgical management TIPS

Spontaneous bacterial peritonitis

Antibiotics : treatment and prophylaxis

Hepatic encephalopathy
Treat precipitating causes Correction of hypokalemia

Dietary protein reduction

Antibiotics Lactulose to reduce ammonia level

Bleeding tendencies
Vitamin K, fresh frozen plasma for bleeding due to

hypoprotrombinemia

Specific treatment :
Phlebotomy for hemochromatosis D-penicillinamine for Wilsons disease Avoidance of alcohol for alcohol-induced cirrhosis

Combination of pegylated interferon alpha and ribavirin

for chronic hepatitis C infection Lamivudine and adefovir dipivoxil for chronic hepatitis B infection Corticosteroids for autoimmune hepatitis Ursodeoxycholic acid for PBC

Screening for hepatocellular carcinoma with serial ultrasound examinations and serum AFP in cirrhosis patients Vaccination against hepatitis A and B Avoidance of alcohol and other hepatotoxins Liver transplantation in end-stage cirrhosis if the patient is an appropriate candidate.

Compensated cirrhosis
10-year survival rate : 90% Median survival after decompensation : 2 years 10-year transition rate to decompensation : 50%

Decompensated cirrhosis
Median survival after first variceal hemorrhage : 1

year Survival after development of ascites : 2 years Median survival after encephalopathy or jaundice is shorter than that of bleeding or ascites. Most common causes of death :
Bleeding Liver failure with hepatic coma Sepsis Hepatorenal syndrome.

STAGES OF CIRRHOSIS PROGRESSION

1%

Stage 0

No varices No ascites
7%

4.4% 3.4%

Stage 1

Varices No ascites
6.6%

Death
20% 4% 57%

Stage 2

Ascites + Varices
7.6%

Stage 3

Bleeding + Ascites

Consider in patients with end-stage liver disease with :

Life threatening complication of hepatic

decompensation Quality of life decreasing to unacceptable levels Will result in irreversible damage to the central nervous system

End stage cirrhosis of all causes

Alcoholic cirrhosis Chronic viral hepatitis Fulminant hepatitis Biliary cirrhosis Cryptogenic cirrhosis Hepatic vein thrombosis Primary hepatocellular malignancies Hepatic adenomas

Most common indication for liver transplant (40%) : hepatitis C and alcoholic liver disease

ABSOLUTE Uncontrolled extrahepatobiliary infection

RELATIVE Age>70

Active, untreated sepsis

Active substance or alcohol abuse Advanced cardiopulmonary disease Extrahepatobiliary malignancy Metastatic malignancy to the liver AIDS

Prior extensive hepatobiliary surgery

Portal vein thrombosis Renal failure Previous extrahepatic malignancy Severe obesity Severe malnutrition / wasting

Life-threatening systemic diseases

Inability to comply with immunosuppression protocol

HIV seropositivity
Severe hypoxemia secondary to right-toleft intrapulmonary shunts Uncontrolled psychiatric disorder

ETIOLOGY Hepatitis C Alcohol Cryptogenic Alcohol and viral hepatitis PSC PBC Hepatitis B Metabolic (e.g. Wilsons, hemochromatosis) Autoimmune hepatitis Secondary biliary cirrhosis Drug/industrial exposure Other

PERCENTAGE 36% 14% 11% 7% 7% 6% 4% 4% 4% <0.5% <0.5% 7%

Highest priority : fulminant hepatic failure MELD (model for end stage liver disease) score : bilirubin, creatinine, INR Child-Turcotte-Pugh score : encephalopathy stage, ascites, bilirubin, albumin, PT

Cadaver :

Head trauma / brain dead Hemodynamic stability Adequate oxygenation Absence of bacterial or fungal infection Absence of abdominal trauma Absence of hepatic dysfunction Serologic exclusion of hepatitis B and C and HIV

Living donor
Transplantation of the right lobe of the liver from a healthy

adult into an adult recipient Left lobe for small children

Immunosuppresive therapy minimizing rejection, significant side effects

Cyclosporine Tacrolimus : more effective but more toxic than

cyclosporine Combinations of cyclosporine or tacrolimus with prednisone and azathioprine, all at reduced doses, are prefereble regimens. OKT3 (monoclonal antibodies to T cells) Mycophenolate

Balance immunosuppression and immunologic competence

Management of postoperative complications (cardiovascular, pulmonary, renal, etc) Transplant rejection : starting 1-2 weeks after surgery, treat with IV methylprednisolone boluses. Recurrence of primary disease