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,axilary-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 hyperglobulinemia 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

Host

Recipient
Child to child

Vertical transmission

Mother

Perinatal

Contaminated needles
Sexuals
Health care workers
Transfusions
6% infected after age 5 years
become chronically infected
No clear risk factors in 20-30% patients

Infant
90% infected infants become
Chronically infected

Hepatitis B disease Progression

5-10% of CHB
individuals

Acute
Infection

>90% of infected
children progress to
chronic disease
<5% of infected
Immunocompetent
adults progress to
chronic disease.

Liver
Cancer (HCC)

>30% of CHB
individuals

Chronic
Infection

Liver
Cirrhosis

Liver
Transplantation

LiverFailure
(decompensation))
23% of patients decompensate
within 5 years of developing
cirrhosis

Death

Liver
Cirrhosis

HM
Ascites
Icterus

Cirrhosis: Overview
End stage of all chronic liver diseases
End stage of all chronic liver diseases
Defined by pathologic criteria (3):
Defined by pathologic criteria (3):
DIFFUSELY DISRUPTED ARCHITECTURE
DIFFUSELY DISRUPTED ARCHITECTURE
(not focal scarring)
(not focal scarring)
BRIDGING FIBROSIS
BRIDGING FIBROSIS
FORMATION of NEONODULES OF
FORMATION of NEONODULES OF
HEPATOCYTES (REGENERATION)
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

Causes of Cirrhosis in Indonesia

65% = Chronic viral hepatitis *
65% = Chronic viral hepatitis *
10% = Alcoholic liver disease
10% = Alcoholic liver disease
7% = Biliary tract diseases
7% = Biliary tract diseases
5% = Hemochromatosis (primary)
5% = Hemochromatosis (primary)
12% = Cryptogenic (unknown cause)
12% = Cryptogenic (unknown cause)
1% = Rare causes
1% = Rare causes

Cirrhosis: Clinical Features

USUALLY SILENT (insidious onset)

USUALLY SILENT (insidious onset)
Symptoms: anorexia, weight loss, weakness
Symptoms: anorexia, weight loss, weakness
Signs suggesting possible cirrhosis
Signs suggesting possible cirrhosis
Jaundice (early)
Jaundice (early)
Abnormal liver function tests (laboratory)
Abnormal liver function tests (laboratory)
Sequelae (all potentially fatal)
Sequelae (all potentially fatal)
Portal hypertension
Portal hypertension
Hepatic failure
Hepatic failure
Hepatocellular carcinoma
Hepatocellular carcinoma

Portal 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

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 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

Portal Hypertension: clinical

sequelae
FOUR MAJOR CONSEQUENCES:
FOUR MAJOR CONSEQUENCES:

Ascites
Ascites
Portosystemic venous shunts
Portosystemic venous shunts
Congestive splenomegaly (up to 1000
Congestive splenomegaly (up to 1000
grams, with secondary hypersplenism)
grams, with secondary hypersplenism)
Hepatic encephalopathy (in liver failure)
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
*doesnt 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 -blockers
*Propranolol 10 mg tid,Nadolol 40 mg qd
*causes splanchnic vasoconstriction and reduce portal-collateral blood flow.
*reduce heart rate and cardiac outputreduduce portal blood flow
*response varies(individual) increase the
do
se to produce a 25% decreasing in heart rate
*studies demonstrate highly significant reducing in rebleeding and improvement in morta
lity.
-Isosorbide mononitrate
*used in whom -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 toover volume.
Renal Failure
-appropriate volume replacement
-avoid aminoglycoside
-avoid mismatched transfusions

Serious
consequences
of portal
hypertension

Ascites: 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

Classification of
Ascites

Uncomplicated
Ascites

Complicated
Ascites

(No infection,no HRS )

(Infection/HRS +)

Refractory
Ascites

Grading of
the Ascites

Grade 2
Grade 1
(Mild ascites)
Detectable by
USG

(Moderate ascites)
Manifest by moderate symmetrical
distension of
abdomen

Grade 3
(large/gross ascites)
Marked abdominal
distension

Pathogenesis of Ascites formation

Hepatic sinusoid hydrostatic
pressure fluid transudation
into peritoneal cavity

Sinusoid
Tone
Splanchnic
Blood flow

Portal Hypertension

Resistence to

Activated
HSC
Nodules
formation

Cirrhosis

Portal flow
Alter vascular
architecture

GFR

Sodium-water
retension

Sodium
Reabsorption
on both tubulus

Collagen deposi
tion >>

RenalVaso
constriction

Renal Symphatetic
activity
Activation
RAS

Systemic
Vasodila
tation

Cirrhosis

Increase vascular synthesis

of NO,Prostacyclin,glucagon,
Substance P,calcitonin gene
related peptide

History taking
&
Physical exam.
Albumin ,SA-AG
Neutrophil count

Diagnostic
paracentesis

Culture
Ascitic amylase

Diagnosis of
Ascites

Cytology

Ultrasonographi/
Abd.CT-scan
Urea
Electrolyte

Blood Test

Liver function
Prothrombine time
Full blood count

Bed Rest
(Isnt recommended)
Dietary Salt
Restriction
Treatment of
Ascites

Diuretics
(mainstay of Tx)
Therapeutic
Paracentesis

TIPS

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

*Spironolactone,Frusemide,amilorid

*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

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 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

Diagnosis of HE
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

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 behaviour,asterixis,hyper/hypo-reflexi
*Grade 4
Coma.areflexia,loss of tone.

Number Connection Test (NCT)

Ammonia as Toxic Substance

Normal NH3 metabolism
Ammonia
*By-product of protein catabolism by gut flora
by gut
and enters portal vein
*Absorbed
Normal NH3
metabolism
*Metabolized in the liver to urea and glutamine (Ornithine
By-product of protein catabolism by gut flora
cycle)
Absorbed by gut and enters portal vein
Metabolized
NH3 in
liver diseasein the liver to urea and glutamine
*Not(Krebs
cleared
by the liver
cycle)
to the
brain by systemic circulation
*Delivered
NH3 in liver
disease
*Associated with hepatic encephalopathy
Not cleared by the liver
Delivered
to the brain
systemic circulation
Not necessarily
theby
cause!
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(4590 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 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

Pathologic Bases of Liver Failure

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

Complications 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)

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)

Thank you

Ascites Pathogensis
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