9. Cirrhosis Kuliah Smst VII

Liver Cirrhosis

Kuliah Semester VII

Hariadi M

Liver Cirrhosis*Definition The damage of Liver-architecture and changed with regenerative nodules and Fibrotic rissue

*The Etiologies : - infections - toxins - immunologic - biliary obstruction - vascular - metabolic

*Histopathologic classification : - Macronodular - Micronodular - Mixed

*Symptoms & Signs : there are 2 form,hepatic failure and Portal Hypertension-Hepatic failure:icterus,spider naevi,gynaecomastia,ascites,axi- lary-pubic hair-loss,erythema palmaris etc.-Portal-hypertension:ascites,splenomegali,edema,varices esoph.

abdominal-wall collateral,haemorrhoid .

Liver Cirrhosis(contd)

The diagnosis,based on clinical.laboratory and radiology such as :-hepatic failure:icterus,gynaecomastia,etc and hypoalbuminemia with hy- perglobulinemia espescially gamma fraction.prolonged of PPT. etc.-Portal hypertension :ascites,esophagus variceshematemesis-melena, splenomegali hypersplenism(trombocytopenia,leucopenia,anemia etc.

-USG,Endoscopie,CT-scan.The complication :- bleeding (varices,gastropathy)

- hepatic-encephalopathy - hepatorenal syndrome - hepato cellular carcinoma (HCC)

The Treatment : -etiologic treatment -symptomatic,nutrition -complication,liver transplantation

The Prognosis : -the new opinion of cirrhosis is reversible,espescially if in the early phase,because the fibrosis is reversible.But if there is

complication,likes HE.HCC,the prognosis is bad.

Transmission of HBV

Horizontal transmission Vertical transmission

Host Recipient MotherMother

Infant

Perinatal

90% infected infants becomeChronically infected

Child to child

Contaminated needles

Sexuals

Health care workers Transfusions

6% infected after age 5 yearsbecome chronically infected

No clear risk factors in 20-30% patients

Hepatitis B disease Progression

Liver Cancer (HCC)

LiverCirrhosis

LiverFailure (decompen-

sation))

23% of patients decompensatewithin 5 years of developingcirrhosis

LiverTransplantation

Death Chronic Infection

AcuteInfection

>30% of CHBindividuals

5-10% of CHBindividuals

>90% of infectedchildren progress tochronic disease<5% of infectedImmunocompetentadults progress tochronic disease.

Liver Cirrhosis

HM

Ascites

Icterus

Cirrhosis: OverviewCirrhosis: Overview

• End stage of all chronic liver diseases

• Defined by pathologic criteria (3):– DIFFUSELY DISRUPTED ARCHITECTURE

(not focal scarring)– BRIDGING FIBROSIS – FORMATION of NEONODULES OF

HEPATOCYTES (REGENERATION)













Cirrhosis, gross uncut liver

Cirrhosis, trichrome stain (fibrosis blue; regenerating nodules of hepatocytes dark red)

Fig. 18-26, Pathologic Basis of Disease, 7th ed, Elsevier 2004

• 65% = Chronic viral hepatitis *

• 10% = Alcoholic liver disease

• 7% = Biliary tract diseases

• 5% = Hemochromatosis (primary)

• 12% = Cryptogenic (unknown cause)

• 1% = Rare causes







Causes of Cirrhosis in Indonesia













Cirrhosis: Clinical FeaturesCirrhosis: Clinical Features

• USUALLY SILENT (insidious onset)• Symptoms: anorexia, weight loss, weakness• Signs suggesting possible cirrhosis

– Jaundice (early)– Abnormal liver function tests (laboratory)

• Sequelae (all potentially fatal)– Portal hypertension– Hepatic failure– Hepatocellular carcinoma










Portal HypertensionPortal Hypertension• Definition: increased pressure in the portal vein

(resistance to blood flow increased)• Three Possible Mechanisms

– 1) Prehepatic: portal vein thrombosis or obstruction– 2) Hepatic: cirrhosis mainly (others rare)

• Compression sinusoids by increased collagen• Compression central veins by perivenular fibrosis• Anastomoses between hepatic arterial & portal

venous system impose arterial pressures on veins– 3) Posthepatic: hepatic vein outflow obstruction, right

heart failure, constrictive pericarditis

• Definition: increased pressure in the portal vein (resistance to blood flow increased)

• Three Possible Mechanisms– 1) Prehepatic: portal vein thrombosis or obstruction– 2) Hepatic: cirrhosis mainly (others rare)

• Compression sinusoids by increased collagen• Compression central veins by perivenular fibrosis• Anastomoses between hepatic arterial & portal

venous system impose arterial pressures on veins– 3) Posthepatic: hepatic vein outflow obstruction, right

heart failure, constrictive pericarditis

Portal Hypertension

*Liver receives blood from portal vein and hepatic artery

*Drains blood from GI tract,pancreas, gall bladder and spleen

*With cirrhosis intrahepatic block of the portal flow causes pressure -collateral circulation develops,diverting portal blood into systemic veins± 10% blood flow reaches hepatic veins,the rest circumvents liver via collateral circulation. -the most dangerous of circulatory collateral are gastroesophageal colla terals (Varices) GI bleeding the most common presenting feature of portal hypertension.

*Diagnosis -Endoscopythe best method to view gastric and esophagealvarices -UGI foto (Ba –intake) -MRI/Venography/USG

Portosystemic ShuntsPortosystemic Shunts

• Definition: bypasses around capillary beds between systemic & portal circulations due to portal hypertension

• Principal sites: rectum (hemorrhoids), esophagogastric varices, retroperitoneum, periumbilical and abdominal wall collaterals (caput medusae)

• Sequelae: rupture with hemorrhage, esp. massive hematemesis from esophageal varices

• Definition: bypasses around capillary beds between systemic & portal circulations due to portal hypertension

• Principal sites: rectum (hemorrhoids), esophagogastric varices, retroperitoneum, periumbilical and abdominal wall collaterals (caput medusae)

• Sequelae: rupture with hemorrhage, esp. massive hematemesis from esophageal varices

Portal Hypertension: clinical sequelae

Portal Hypertension: clinical sequelae

• FOUR MAJOR CONSEQUENCES:– Ascites– Portosystemic venous shunts– Congestive splenomegaly (up to 1000

grams, with secondary hypersplenism)– Hepatic encephalopathy (in liver failure)







Management of Variceal Bleeding

•Vasoconstrictor

-Vasopressin (antidiuretic hormon) *potent,non-selective,include coronary vaso constriction *causes splanchnic vasoconstriction reduce portal blood flow and pressure *nitroglycerin iv control the side effects *not recommended as 1st line. -Somatostatin/somatostatin synthetic(octreotide) *Octreotide more potent then somatostatin *doesn’t have systemic effect of vasoconstric tion *the effectiveness same as vasopressin but better safety profile *dose 50mcg bolus(IV)continous iv infusion 50 mcg/h x 5 days

Prevention of variceal bleeding -Non selective β-blockers *Propranolol 10 mg tid,Nadolol 40 mg qd *causes splanchnic vasoconstriction and reduce portal-collateral blood flow. *reduce heart rate and cardiac outputredu- duce portal blood flow *response varies(individual) increase the do se to produce a 25% decreasing in heart rate *studies demonstrate highly significant redu- cing in rebleeding and improvement in morta lity.

-Isosorbide mononitrate *used in whom β-blocker is contraindicated.

Management of Variceal Hemorrhage

• Hemodynamic resuscitation -restore intravascular volume -replace blood loos

•Prevention and treat complications -prevent aspiration Gastric aspiration lavage -infection prophylactic antibiotic -hepatic encephalopathy -renal failure

•Treat the bleeding

•Hemodynamic rescucitation -Blood transfusion and clotting factors (FFP) -be carefull not to”over volume”.

•Renal Failure -appropriate volume replacement -avoid aminoglycoside -avoid mismatched transfusions

Serious consequences of portal hypertension

Ascites: OverviewAscites: Overview

• Definition: accumulation excess fluid in peritoneal cavity, often several liters

• Clinically detectable ascites: at least 500 ml (puddle sign most sensitive physical exam test)

• Characteristics of fluid– Usually serous, with <3 gm/dl protein (albumin)– If neutrophils present: suspect infection– If many RBCs: suspect malignant neoplasm

• Definition: accumulation excess fluid in peritoneal cavity, often several liters

• Clinically detectable ascites: at least 500 ml (puddle sign most sensitive physical exam test)

• Characteristics of fluid– Usually serous, with <3 gm/dl protein (albumin)– If neutrophils present: suspect infection– If many RBCs: suspect malignant neoplasm

Classification of Ascites

Uncomplicated Ascites

(No infection,no HRS )

Complicated Ascites

(Infection/HRS +)

RefractoryAscites

Grading of the Ascites

Grade 1(Mild ascites)Detectable by

USG

Grade 2(Moderate ascites)Manifest by mode-rate symmetrical

distension ofabdomen

Grade 3(large/gross ascites)Marked abdominal

distension

Pathogenesis of Ascites formation

Portal Hypertension

Sodium-waterretension

Hepatic sinusoid hydrostatic pressure fluid transudationinto peritoneal cavity Sinusoid

Tone

Splanchnic Blood flow

Collagen deposition >>

Nodulesformation

Alter vasculararchitecture

Resistence to

Portal flow Cirrhosis

ActivatedHSC

CirrhosisRenalVaso constriction

Renal Symphatetic activity

ActivationRAS

GFR ↓

SodiumReabsorption

on both tubulus

SystemicVasodila

tation

Increase vascular synthesis of NO,Prostacyclin,glucagon,Substance P,calcitonin generelated peptide

Diagnosis ofAscites

History taking&

Physical exam.

Diagnosticparacentesis

Albumin ,SA-AG

Neutrophil count

Culture

Ascitic amylase

Cytology

Ultrasonographi/Abd.CT-scan

Blood Test

Urea

Electrolyte

Liver function

Prothrombine time

Full blood count

Treatment ofAscites

Bed Rest(Isn’t recommended)

Dietary SaltRestriction

*Lower diuretic requirement*Faster resolution of ascites*Shorter hospitali zation*90 mmol/5,2 g/d

Diuretics(mainstay of Tx)

*Spironolactone,Frusemide,amiloride*Spironolactone,initial dose 100mg/d increased up to400mg/d ->adequate natriuretic*Frusemide as an adjunct to spiro nolactone;initial dose 40 mg/d 160 mg/d*Spironlct 400mg/d ineffective added Frusemide.*Ascites +loss of BW 0,5 kg/d*Over diuresisrenal impairment, HE,Vol.depletion,Hyponatremia

TherapeuticParacentesis

TIPS

Spontaneous Bacterial Peritonitis

*Ascitic Fluid infection without an intraabdominal source of infection

-severe complication of ascites-commonly occurs in advanced cirrhosis

*Monomicrobial infection-most commonly gram-negative bacteria’ * E. coli,Klebsiella pneumonia,Enterococcus sp * Suggest GI tract is source

*Most common symptoms:-fever ,50-75%-abdominal pain/distention,27-72%-Chills,16-29%

SBP Management*Start empiric therapy as soon as SBP suspected

-cultured ascitic fluid

*Broad spectrum therapy empirically -used untill cultures returned

*Continue therapy untill symptoms/signs disappear

-fever,abdominalpain,normali zation of blood counts, and reduction of cell counts in ascitic fluid

*Third generation of cephalosporins Cefotaxime 2 g IV q 8h x 5 days (treatment of choice) Ceftriaxone 2 g IV q 24 h x 5 days Up to 2 weeks may be needed

*Piperacillin/Tazobactam 3 g IV q 6 h (penicilline-beta lactamase inhibitor comb.

*Intravenous albumin -1,5 g/kg on day 1;then 1g on day 3 -shorten hospitalized and intermediate mortalityexpensive

SBP Prophylaxis

*Recurrent rates in 1year > 70%

*Antibiotic prophylaxis decreases recurrence to 20%

*2nd prophylaxis -patients with previous episode of SBP-Cipro 750 mg po/week (controversial) -if current GI bleeding,500mg bid x 7 days followed by 750 po qw

-TMP DS 1 tab daily shown to reduce recurrence-Norfloxacin 400 mg/day

Hepatic Encephalopathy (HE)

•Brain disordered caused by chronic liver failure-cognitive,psychiatric and motors impairments

•Blood diverted around liver-toxins not removed

•Ammonia (the main toxin) and manganese proposed to contribute to HE

- in exitatory neurotransmitters-upper GI bleeding,small bowel bacterial overgrowth constipation, as precipitating factors.

Laboratory in Liver FailureLaboratory in Liver Failure

• Hepatic encephalopathy– Elevated blood ammonia impairs neurons

& promotes brain edema– Fluctuating signs: rigidity, hyperreflexia,

confusion, asterixis (rapid extension-flexion movements of head and arms)

– Terminal signs: stupor and coma

• Hepatic encephalopathy– Elevated blood ammonia impairs neurons

& promotes brain edema– Fluctuating signs: rigidity, hyperreflexia,

confusion, asterixis (rapid extension-flexion movements of head and arms)

– Terminal signs: stupor and coma

Diagnosis of HE

Severity of HE based on West haven criteria

*Latent/minimal,clinically unremarkable,psychometric test pathologic.

*Grade 1,impaired consentration,speech disorder ed,tiredness,personality changes,motoric impaired

*Grade 2 Consciousness,slowing/lethargy;temporal disorien tation,slured speech,asterixis

*Grade 3 Consciousness somnolence/stupor,bizare behavi- our,asterixis,hyper/hypo-reflexi

*Grade 4 Coma.areflexia,loss of tone.

•Evaluation of the clinical picture using West Haven criteria

•Determination of mental status: -psychometric tests (e.g. NCT,handwriting)

•Neurological investigations: -EEG, evoked potentials

•Laboratory diagnostics to identify triggering factors:

-blood count, transaminases, venous acid base status, urea, creatinine

Number Connection Test (NCT)

• Ammonia– Normal NH3 metabolism

• By-product of protein catabolism by gut flora• Absorbed by gut and enters portal vein• Metabolized in the liver to urea and glutamine

(Krebs cycle)

– NH3 in liver disease• Not cleared by the liver• Delivered to the brain by systemic circulation• Associated with hepatic encephalopathy

– Not necessarily the cause!

Ammonia as Toxic SubstanceNormal NH3 metabolism

*By-product of protein catabolism by gut flora*Absorbed by gut and enters portal vein*Metabolized in the liver to urea and glutamine (Ornithine cycle)

NH3 in liver disease*Not cleared by the liver*Delivered to the brain by systemic circulation*Associated with hepatic encephalopathy

Not necessarily the cause!

Management of HE

• Manage the precipitating factors -GI bleeding;Infection;constipation

•Lower ammonia levels -limit protein intake(animal),70g/d -prevent dehydration -careful tritation/monitoring diuretics -correct hypokalemia -medications: *LOLA(L- ornithine-L- Aspartic) *Lactulose *BCAA *Gut sterilisation(inhibits activity urease producing colonic bacteria) *Sodium benzoate/Zn(metabolism of ammonia to glutamine and hippurate)

•Lactulose -Non absorble dissacharide -reduce aminogenesis lower colonic pH, cathartic) -dose,to achieve 3-4 x passing stool/d(45- 90 g/d)•LOLA -LOLA as stimulator of urea synthesis)orni thine cycle)and glutamine synthesis important in ammonia detoxification•BCAA(Branch Chain Amino Acid) -improved the ratio BCAA :AAA BBB not too diffusible for AAA as a source of false neurotransmitters.

Hepatic FailureHepatic Failure

• 80-90% liver cells must be dysfunctional to produce clinically apparent hepatic failure

• Pathways to hepatic failure– Sudden, massive destruction– Slowly progressive disease

• Mortality without transplantation: 70-90%

• Treatment: liver transplantation or miracle

• 80-90% liver cells must be dysfunctional to produce clinically apparent hepatic failure

• Pathways to hepatic failure– Sudden, massive destruction– Slowly progressive disease

• Mortality without transplantation: 70-90%

• Treatment: liver transplantation or miracle

• Massive hepatic necrosis– Fulminant viral hepatitis– Drugs and chemicals

• Chronic liver disease (majority of cases)– Chronic hepatitis or alcohol dependency

• Acute hepatic dysfunction without necrosis– Reye syndrome– Acute fatty liver of pregnancy

• Massive hepatic necrosis– Fulminant viral hepatitis– Drugs and chemicals

• Chronic liver disease (majority of cases)– Chronic hepatitis or alcohol dependency

• Acute hepatic dysfunction without necrosis– Reye syndrome– Acute fatty liver of pregnancy

Pathologic Bases of Liver Failure

• Hyperbilirubinemia

• Hyperestrogenemia (not usually measured)

• Hyperammonemia (impaired metabolism of portal vein ammonia to urea in hepatocytes)

• Decreased protein synthesis by hepatocytes– Clotting factors deficient (coagulopathy with

bleeding tendency, evidenced by prolonged prothrombin time)

– Hypoalbuminemia (peripheral edema)

• Hyperbilirubinemia

• Hyperestrogenemia (not usually measured)

• Hyperammonemia (impaired metabolism of portal vein ammonia to urea in hepatocytes)

• Decreased protein synthesis by hepatocytes– Clotting factors deficient (coagulopathy with

bleeding tendency, evidenced by prolonged prothrombin time)

– Hypoalbuminemia (peripheral edema)

Complications of Liver Failure

Complications of Liver Failure

• Hepatorenal syndrome– Def: appearance acute renal failure in patients

with severe liver disease with no intrinsic cause in the kidney for failure (pathogenesis involves decreased renal perfusion)

– Renal function improves if hepatic failure reversed

– Onset: drop urine output, rising serum BUN/Cr– Mortality: 90% (without transplantation)

• Hepatorenal syndrome– Def: appearance acute renal failure in patients

with severe liver disease with no intrinsic cause in the kidney for failure (pathogenesis involves decreased renal perfusion)

– Renal function improves if hepatic failure reversed

– Onset: drop urine output, rising serum BUN/Cr– Mortality: 90% (without transplantation)

Thank you

• Sinusoidal hypertension (driving fluid toward space of Disse, then into lymphatics)

• Percolation of hepatic lymph into peritoneal cavity (up to 20 liters/day hepatic lymphatic flow, exceeding capacity of thoracic duct to reabsorb fluid into venous system)

• Intestinal fluid leakage (portal hypertension increases perfusion pressure in intestinal capillaries)

• Renal retention of sodium and water

• Sinusoidal hypertension (driving fluid toward space of Disse, then into lymphatics)

• Percolation of hepatic lymph into peritoneal cavity (up to 20 liters/day hepatic lymphatic flow, exceeding capacity of thoracic duct to reabsorb fluid into venous system)

• Intestinal fluid leakage (portal hypertension increases perfusion pressure in intestinal capillaries)

• Renal retention of sodium and water

Ascites Pathogensis

9. Cirrhosis Kuliah Smst VII

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