LIVER CIRRHOSIS

DEFINITION: pathological condition with the development of fibrosis to the point that there is architectural distorsion with formation of regenerative

nodules CAUSES:• Alcoholism• Chronic viral hepatitis (Hepatitis

B, Hepatitis C)• Autoimmune hepatitis• Nonalcoholic steatohepatitis• Billiary cirrhosis• Primary billiary cirrhosis• Primary sclerosing cholangitis• Autoimmune cholangiopathy

• Cardiac cirrhosis• Metabolic liver disease:• Hemocromatosis• Wilson’s disease• L1 Antitrypsin deficiency• Cystic fibrosis• Cryptogenic cirrhosis

ALCOHOLIC CIRRHOSIS

•14 milion adults in US -alcohol abuse or dependence•10th most common cause of death in adults • alcoholic cirrhosis accounts 40% of deaths due to cirrhosis

CLINICAL FEATURES• NON SPECIFIC SYMPTOMS:• vague right upper quadrant pain• fever• nausea and vomiting• diarrhea• anorexia• malaise

• LATER , SPECIFIC COMPLICATIONS:• ascites• edema• bleeding (UDH)• jaundice/encephalopathy

• incidentally at the time of autopsy or elective surgery

PHYSICAL EXAMINATION• liver and spleen enlarged with

the liver edge firm and nodular• scleral icterus• palmar erythema• spider angiomas• parothid gland enlargement• digital clubbing• muscle wasting• edema and ascites• decreased body hair,

gynecomastia• testicular atrophy• menstrual irregularities/

amenorrheic women

These changes are often reversible following cessation of alcohol

LABORATORY TESTS

- normal in patients with early compensated alcoholic cirrhosis

- in advanced liver disease many abnormalities are present:

• anemia (chronic GI blood lose, nutritional deficiencies, hipersplenism related to portal hypertension , hemolytic anemia- ZIEVE’S syndrome)

• platelets counts are often reduced early (PHT)

• total direct bilirubin- N/ elevated

• protrombin times prolonged• AST>ALT2:1ratio

DIAGNOSIS

• Clinical features + physical examination findings + laboratory studies

• Liver biopsy,ultrasonography, UDE,CT ( dg. dif. Cancer)

(abstinence maintained 6 months--> residual, nonreversible disease)

Patients who have had complications and who continue to drink have a <50% 5-year survival in contrast with those who remain abstinent -->prognosis improved and LIVER TRANSPLANTATION - VIABLE OPTION

TREATMENT

• Abstinence- cornerstone therapy• Good nutrition and long term medical supervision• Glucocorticoids are occasionally used(DF>32)• Oral PENTOXIFYLINE decrease tumour necrosis factor

alpha (TNF-alpha) and other proinflamatory cytokines• Parenterally adm. of inhibitors of TNF-alpha

(INFLIXIMAB/ ETANERCEPT)• Medication that reduce craving for alcohol

ACAMPROSATE CALCIUM • Vit.B1,B6,B12+SG10%,Arginine,Aminohepa,Aspat

ofort

CIRRHOSIS DUE TO CHRONIC VIRAL HEPATITIS B OR C

• patients exposed to the hepatitis C (HCV) - 80% develop chronic hepatitis C and ,of those,-20-30% will develop cirrhosis over 20-30 years•world wide , 170 million individuals have hepatitis C•progression of liver disease due to chronic HC is characterized by :•portal- based fibrosis with brindging fibrosis and nodularity developing --> cirrhosis•inflammatory infiltrate in portal areas•lobular hepato-cellular injury and inflammation•HCV genotype 3, steatosis is often present•Hepatitis B exposure : 5% develop chronic hepatitis B, 20% will go to develop cirrhosis•in US 1,25 million carriers of HB; Asia, Africa 15%aquires the infection vertically (at birth) and 25% may develop cirrhosis

CLINICAL FEATURES

• fatigue• malaise• right upper quadrant pain

LABORATORY EVALUATION• HCV-RNA,genotype• AgHBS• anti HBS• HBe Ag• anti HBe• HBV-DNA levels

TREATMENT IN HEPATITIS B

• LAMIVUDINE100mg/day• ADEFOVIR• ENTECAVIR 0.5mg/day• TENOFOVIR

INTERFERON ALFA should not be used in decompensated cirrhotics

with EV,ascites,jaundice

CIRRHOSIS FROM AUTOIMMUNE HEPATITIS

•Positive autoimmune markers ANA,ASMA•Active inflammation - elevated liver enzimes-->immunosuppresive therapy•Obesity in western countries - patients with nonalcoholic fatty liver disease•Management of complications of cirrhosis due to AIH or NASH is similar to that for other forms of cirrhosis

BILLIARY CIRRHOSISCholestatic liver disease result from necroinflammatory lesions :•congenital•metabolic processes•external bile duct compresion2 broad categories reflect the anatomic sites of abnormal bile retention :•intrahepatic -- different approach•extrahepatic--surgical/endoscopic biliary tract decompression

PBC (primary biliary cirrhosis)

100-200 / million(female preponderence / median age - 50 years )-at the time of diagnosis

Cause: unknownIt is characterized by portal inflammation and necrosis of

cholangiocytes in small and medium size bile ductsLab findings: elevated bilirubine level progressive liver failureLIVER TRANSPLANTATION- treatment of choice for patients

with decompensated cirrhosisURSODEOXYCHOLIC ACID (UDCA)AMA - 90% patients with PBC - useful markers for PBC

PBC (primary biliary cirrhosis)

CLINICAL FEATURES

• fatigue• pruritus 50% - bothersome in the

evening; prior to jaundice (severe disease and poor prognosis)

PHYSICAL EXAMINATION• JAUNDICE• hepatomegaly• splenomegaly• ascites• edema• hiperpigmentation-trunk,arms• xantelasma (xanthomata)• bonepain :

osteopenia/osteoporosis• scratching lesions

LABORATORY FINDINGS :

• augmentation of GGT, ALP, ALT, AST, IgM

• hiperbilirubinemia• trmobocytopenia , leucopenia,

anemia -- PHT, hipersplenism• LIVER BIOPSY - 10% AIH,

“overlap” syndrome

DIAGNOSIS

Patients with chronic colestatic liver enzyme abnormalities in middle-aged women

AMA +/- (10%) --> biopsy

TREATMENT• UDCA (early initiated 13-15 mg/kg/day) improve

bichemical and histological features; it does not reverse and cure the disease; side effects: diarrhea, headache

• LIVER TRANSPLANTATION –decompensated disease• Antihistamines• Narcotic receptor antagonist (naltrexone)• Rifampin• Cholestyramine-bile salt sequestering agent• Plasmapheresis intractable pruritus• Bisphosphonate should be instituted when bone disease is

identified (bone density testing)

PRIMARY SCLEROSING CHOLANGITIS

Definition: chronic cholestatic syndrome – diffuse inflamation, fibrosis involving the entire biliary treeobliteration of both intra and extrahepatic biliary tree, leading to biliary cirrhosis / portal hipertension/ liver failureCause: unknown•bile duct proliferation, ductopenia, pericholangitis•liver biopsy : periductal fibrosis

PRIMARY SCLEROSING CHOLANGITISCLINICAL FEATURES :• fatigue profound and nonspecific• pruritus• steatorrhea• deficiencies of fat – soluble vitamins• metabolic bone disease

LABORATORY FINDINGS:• abnormal liver enzymes (>2 ALP and ↑ AST,ALT)• albumin levels ↓• TP↑• overlap syndrome between PSC and AIH• autoantibodies + in overlap syndrome , - in PSC alone

(only); P-ANCA is + in 65% of those with PSC; in PSC50% patients have UCcolonoscopy

PRIMARY SCLEROSING CHOLANGITIS

DIAGNOSIS• colangiographic imaging-multifocal stricturing and beading• MRCP-initial evaluation• ERCP-whether or not a dominant stricture is presentThe strictures are typically short with intervening segments of normal or

slightly dilated bile ducts diffusely distributed beaded appearanceGallbladder, cystic duct involved in 15% of cases;evolution gradually to

biliary cirrhosis decompensation with ascites , esophageal variceal hemorrhage , encephalopathy

TREATMENT• nonspecific• high-dose (20mg/kg/day) UDCA• endoscopic dilatation of strictures• LIVER TRASPLANTATION (LT) ; Cholangiocarcinoma relative CI for LT

HEMOCHROMATOSIS

DEFINITION: inherited disorder of iron metabolism that results in a progressive increase in hepatic iron deposition whitch , over time, can lead to a portal-based fibrosis progressing to cirrhosis / liver failure/ hepatocellular cancer

Serum iron studies :• elevated transferin saturation• ↑ feritine level• HFE mutation analysis TREATMENT is straight forward with regular

therapeutic phlebotomy

WILSON’S DISEASEDEFINITION: inherited disorder of cooper homeostasis with

failure to excrete excess amounts of cooper , leading to accumulation in the liver.

1/30000 individuals; affects adolescents and young adultsDIAGNOSIS: • ceruloplasmin levels• 24-hours urine cooper levels• liver biopsyPHYSICAL EXAMINATION - KAYSER-FLEICHER corneal ringTREATMENT : cooper chelating medication (D-

PENICILLAMINE/TRIENTINE/Zn)

ALFA1-AT DEFICIENCY

DEFINITION: inherited disorder that causes abnormal folding of the alfa-1AT PROTEIN-->failure of secretion of that protein from the liver

22 genotype / 10-20% - chronic liver disease

DIAGNOSIS: • determining of alfa1 AT levels/ genotype• liver biopsy : PAS+ ; diastase- resistant globules

TREATMENT: LT is curative

COMPLICATIONS OF CIRRHOSIS

• Portal hypertension:-GE varices-portal hypertensive gastropathy-splenomegaly, hypersplenism-ascites-SBP• Hepatorenal syndrome I,II• Hepatic encephalopaty• Hepatopulmonary

syndrome• Portopulmonary

hypertension• Malnutrition

• Bone disease:-osteopenia-osteoporosis-osteomalacia

• Hematologic abnorm.:-anemia-hemolysis-neutropenia-trombocytopenia- coagulopathy

TREATMENT FOR VARICEAL HEMORRHAGE :1. PRIMARY PROPHYLAXIS

2. PREVENTION OF RECURRENT BLEEDING

1. PRIMARY PROPHYLAXIS

- screening by endoscopy of all patients with cirrhosis-non-selective betabloblokers or variceal band ligation / sclerotherapy

((PROPRANOLOL, NADOLOL)-hepatic vein pressure >12 mmHg

ACUTE BLEEDING : • fluid and blood product replacement • prevention of subsequent bleeding with EVL • vasoconstrictive agenta : SOMATOSTATIN , OCTREOTIDE 50-100 ug/h by

continuous infusion (VASOPRESIN -in the past)• BALLON TAMPONADE (Sengstaken-Blakemore tube / Minnesota tube)-->

stabilisation prior to endoscopic therapy• esophageal varices extended into the proximal stomach - TRANSJUGULAR

INTRAHEPATIC PORTOSYSTEMIC SHUNT (angiographic guidance)

2. PREVENTION OF RECURRENT BLEEDING

• repeated VBL until varices are obliterated• betablockade- recurrent VBL• portosystemic shunt surgery , TIPS for patients

with good hepatic synthetic function who could benefit by having portal decompressive surgery.

MANAGEMENT OF RECURRENT VARICEAL HEMORRHAGE

RECURENT ACUTE BLEEDING ENDOSCOPIC THERAPY +/- PHARMACOLOGIC THERAPY

CONTROL OF BLEEDING

↓COMPENSATED CIRRHOSIS

(CHILD’S CLASS A) ↓

SURGICAL SHUNT VS. TIPS↓

LIVER TRANSPLANTATION

↓DECOMPENSATED CIRRHOSIS

( CHILD’S CLASS B,C) ↓

TRANSPLANT EVALUATION ↓

ENDOSCOPIC THERAPY OR BETA-BLOKERS

↓TIPS↓

LIVER TRANSPLANTATION

ASCITES TREATMENT• 1.Dietary sodium restriction-small amounts of ascites

6-8g/day ,<2g/day in>ascites• Fresh, frozen foods• 2.Diuretic therapy-moderate amounts of

ascites:Spironolactone100-200mg/day,4-600mg/day+Furosemide40-80mg/day(peripheral edema);120-160mg/day-necompliant patients.

• 3.Repeated large volume paracentesis,TIPS,liver transplantation(<50% survive 2years after the onset of ascites).

HEPATIC ENCEPHALOPATHY

• Ammonia levels>,mercaptans• 1.Hydration and correction of electrolyte imbalance• 2.Replacing animal-based protein with vegetable-based

protein• 3.Lactulose-elimination of nitrogenous products(2-3soft

stools/day)• 4. Nonabsorbed antibiotics:Neomicine/Metronidazole(renal

failure,ototoxicity,peripheral neuropathy),RIFAXIMINE-NORMIX,NO side effects.

• 5. ZN supplementation

SPONTANEOUS BACTERIAL PERITONITIS

• Neutrophil count>250/mm3• Occur in 30%of patients with SBP and25% in hospital

mortality rate• Escherichiacoli/gram+bacteria(Streptococcus

viridans,Staphilococcus aureus,Enterococcus• Second –generation cephalosporin-CEFOTAXIM

4g/day• In those with UDB,the frecquency of SBP is increased and prophylaxis against it is recommended

HEPATO-RENAL SYNDROME• Functional renal failure without renal pathology that occurs in 10% of

patients with advanced cirrhosis or acute liver failure• Step-wise progressive increase in creatinine in those with large amount of

ascites• TYPE 1 HRS:progressive impairment in renal function and >reduction in

creatinine clearance within 1-2 weeks of presentation• TYPE 2 HRS: reduction in glomerular filtration rate with >serum creatinine

level(better outcome than type 1 HRS!)• Dopamine,PG analogs• Midodrine(alpha-agonist)• Octreotide• Albumine i.v.• LIVER TRANSPLANTATION