Hepatic cirrhosis

ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE

dr Putra Hendra SpPD

UNIBA
 DEFINITION OF CIRRHOSIS

Hepatic Cirrhosis

Stadium akhir penyakit liver khronis

histologically : regenerative nodules
dikrelilingi jaringan fibrosis Bridging
fibrosis.
Klinis: 2 tipe cirrhosis:
Compensated
Decompensated
 Etiology Cirrhosis

Alcoholic liver disease 60-

70%
Viral hepatitis 10%
Biliary disease 5-10%
Primary hemochromatosis5%
Cryptogenic cirrhosis 10-15%
Wilsons, 1AT def rare
 GROSS IMAGE OF A NORMAL AND A CIRRHOTIC LIVER

Normal Cirrhosis
Irregular surface

Nodules
 GROSS IMAGE OF A CIRRHOTIC LIVER

Cirrhotic liver
Nodular, irregular surface

Nodules
 HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER

Normal Cirrhosis

Nodules surrounded by
fibrous tissue
 PATHOGENESIS OF LIVER FIBROSIS

Normal Hepatic SInusoid

Retinoid
droplets
Fenestrae

Hepatic
stellate cell
Space of Disse

Sinusoidal
endothelial cell

Hepatocytes
 PATHOGENESIS OF LIVER FIBROSIS

Alterations in Microvasculature in Cirrhosis

Activation of stellate cells

Collagen deposition in space of Disse
Constriction of sinusoids
Defenestration of sinusoids
The Effect of The Liver Nodule
 NATURAL HISTORY OF CHRONIC LIVER DISEASE

Perjalanan Chronic Liver Disease

Chronic
liver Compensated Decompensated
cirrhosis cirrhosis Death
disease

Development of
complications:
Variceal hemorrhage
Ascites
Encephalopathy
Jaundice
 SURVIVAL TIMES IN CIRRHOSIS

10
Decompensasi liver kematian
100

80 Median survival
~ 9 years

60 All patients
with cirrhosis
Probability of
survival 40

20
Decompensated Median survival
cirrhosis ~ 1.6 years
0
0 20 40 60 80 100 120 140 160 180
Months
Gines et. al., Hepatology 1987;7:122
 COMPLICATIONS OF CIRRHOSIS

Complications of Cirrhosis Result from Portal

Hypertension or Liver Insufficiency

Variceal hemorrhage
Portal
hypertension Spontaneous
bacterial
peritonitis
Ascites
Cirrhosis Hepatorenal
syndrome

Encephalopathy
Liver
insufficiency
Jaundice
 Gambaran klinis

Kegagalan Hepatocellular :
Malnutrition,
low albumin
clotting factors bleeding.
Hepatic encephalopathy.
Portal hypertension.
Ascites
,varices,
splenomegaly.
 DIAGNOSIS OF CIRRHOSIS

Diagnosis
Klinis :

Tanda kegagalan fungsi hati

Portal hipertensi

Lab:
Low albumin (< 3.8 g/dL)
Prolonged prothrombin time (INR >
1.3)
High bilirubin (> 1.5 mg/dL)
AST / ALT ratio > 1
 THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW

Normal Liver

Hepatic
vein

Sinusoid Liver

Coronary
Portal vein
vein
Splenic
vein
 ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE

Cirrhotic Liver
Portal
systemic
collaterals

Distorted
sinusoidal
architecture
leads to
increased
resistance
Portal
vein

Splenomegaly
 AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION

An Increase in Portal Venous Inflow Sustains

Portal Hypertension 20

Distorted
sinusoidal
architechure

Portal
vein

Flow

Mesenteric
veins Splanchnic
vasodilatation
Collaterals
Signs of ESLD
 DIAGNOSIS OF CIRRHOSIS CAT SCAN

CT Scan in Cirrhosis

Liver with an irregular surface Collaterals Splenomegaly

 DIAGNOSTIC ALGORITHM

Diagnostic Algorithm
Patient with chronic liver disease and any of the following:
Variceal hemorrhage
Ascites
Hepatic encephalopathy
Physical findings: Laboratory findings:
Yes No Enlarged left hepatic lobe Thrombocytopenia
Splenomegaly Impaired hepatic synthetic function
Stigmata of chronic liver disease
Radiological findings:
Yes No Small nodular liver
Intra-abdominal collaterals
Ascites
Splenomegaly
Colloid shift to spleen and/or bone marrow
Yes
No
Liver biopsy not
necessary for the Liver biopsy
diagnosis of cirrhosis
 VARICES INCREASE IN DIAMETER PROGRESSIVELY

Varices Increase in Diameter

Progressively

No varices Small varices Large varices

7-8%/year 7-8%/year

Merli et al. J Hepatol 2003;38:266

PROGRESSION OF PORTAL HYPERTENSION LEADS TO VARICEAL GROWTH AND VARICEAL RUPTURE

Cirrhosis

Resistance to
portal flow
Splanchnic
arteriolar
resistance
Portal
pressure
Portal blood
inflow

Variceal
Variceal
Varices rupture
Growth
 PROGNOSTIC INDICATORS OF FIRST VARICEAL HEMORRHAGE

Variceal hemorrhage Varix with red signs

Predictors of hemorrhage:
Variceal size
Red signs
Child B/C
NIEC. N Engl J Med 1988; 319:983
 TREATMENT OF ACUTE VARICEAL HEMORRHAGE

Tata laksana Variceal Hemorrhage

General Management:
Infus k/p tranfusi Hb 8
Antibiotic prophylaxis

Specific therapy:
Pharmacological therapy:
terlipressin, somatostatin and analogues,
vasopressin + nitroglycerin
Endoscopic therapy: ligation, sclerotherapy
Shunt therapy: TIPS, surgical shunt
 ENDOSCOPIC VARICEAL BAND LIGATION

Endoscopic Variceal Band Ligation

Bleeding controlled in 90%

Rebleeding rate 30%

Compared with sclerotherapy:

Less rebleeding
Lower mortality
Fewer complications
Fewer treatment sessions
Variceal Banding
 THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

Transjugular Intrahepatic Portosystemic Shunt

Hepatic
vein

TIPS

Splenic
Portal vein vein

Superior mesenteric
vein
 MANAGEMENT ALGORITHM IN ACUTE ESOPHAGEAL VARICEAL HEMORRHAGE

30
Management of Acute Variceal Hemorrhage
Variceal Hemorrhage Suspected

Initial Management

Acute Hemorrhage Controlled?

NO YES

Balloon Tamponade
Early rebleeding?
YES NO

Rescue TIPS/Shunt surgery 2nd Endoscopy

Further bleeding

Prophylaxis against recurrent hemorrhage

 Figure 47-3: Sengstaken-Blakemore Tube Used to Control
Ruptured Esophageal Varices

Balloon
tamponade of
varices

(Black, Hawkes & Keene 2001)

Sengstaken-Blakemore Tube Used to
Control Ruptured Esophageal Varices
 ASCITES AND HEPATORENAL SYNDROME

Ascites and Hepatorenal Syndrome

 PATHOGENESIS OF ASCITES

Cirrhosis
Hepatic Arteriolar
venous outflow resistance
block (vasodilation)

Sinusoidal Effective
pressure arterial blood
(HVPG 10-12 mmHg) volume

Activation of
Sodium and neurohumoral systems
Ascites water retention (renin, angiotensin,
aldosterone)
 INITIAL WORKUP OF ASCITES: DIAGNOSIS PARACENTESIS

Initial Workup of Ascites

Diagnostic Paracentesis
Optional
Glucose, LDH
Amylase
Protein/Albumin
Routine ? secondary
? cirrhotic infection
ascites ? pancreatic
PMN count ascites
Cytology
Culture
? SBP ? malignant
ascites
 DIAGNOSTIC PARACENTESIS

Diagnostic Paracentesis
Indications
New-onset ascites
Admission to hospital
Symptoms/signs of SBP
Renal dysfunction
Unexplained encephalopathy

Contraindications
None
Paracentesis
 SERUM-ASCITES ALBUMIN GRADIENT (SAAG) IS HIGH IN PORTAL HYPERTENSIVE CAUSES OF ASCITES

Serum-Ascites Albumin Gradient is High

in Portal Hypertensive Causes of Ascites
4.0

3.0
Serum
ascites
albumin 2.0
gradient
(g/dL)
1.0 1.1

0
Cirrhotic ascites Cardiac Peritoneal
ascites malignancy

Runyon, Ann Intern Med 1992; 117:215

 MECHANISM OF ACTION OF THE DIFFERENT THERAPIES FOR ASCITES

Site of Action of Different Therapies for Ascites

Cirrhosis
Arteriolar
Intrahepatic resistance
resistance (vasodilation)

Albumin Effective
Sinusoidal TIPS TIPS
pressure arterial blood
PVS volume

LVP PVS Diuretics

Activation of
Sodium and
Ascites water retention
neurohumoral
systems
 MANAGEMENT OF UNCOMPLICATED ASCITES

Management of Uncomplicated Ascites

Definition: Ascites responsive to diuretics in
the absence of infection and
renal dysfunction
Sodium restriction
Effective in 10-20% of cases
Predictors of response: mild or moderate ascites,
Urine Na excretion > 50 mEq/day
2 g (or 5.2 g of dietary salt) a day
Diuretics
Should be spironolactone-based
A progressive schedule (spironolactone
furosemide) requires fewer dose adjustments than
a combined therapy (spironolactone + furosemide)
 MANAGEMENT OF UNCOMPLICATED ASCITES: SODIUM RESTRICTION

40
Management of Uncomplicated Ascites

Sodium Restriction

2 g (or 5.2 g of dietary salt) a day

Goal: negative sodium balance

Side effect: unpalatability may compromise

nutritional status
 MANAGEMENT OF UNCOMPLICATED ASCITES: DIURETIC THERAPY

Management of Uncomplicated Ascites

Diuretic Therapy
Dosage
Spironolactone 100-400 mg/day
Furosemide (40-160 mg/d) for inadequate weight loss or
if hyperkalemia develops
 PERITONEO-VENOUS SHUNT (PVS) IS USEFUL IN THE TREATMENT OF REFRACTORY ASCITES

Peritoneo-Venous Shunt (PVS) is Useful

in the Treatment of Refractory Ascites

Use of jugular
vein will hinder
TIPS placement

One-way
valve
Intraabdominal
adhesions may
complicate liver
transplant surgery
 TREATMENT OF REFRACTORY ASCITES

Tata laksana Ascites 44

Portal Hypertension
No Ascites

Uncomplicated
Ascites

1) LVP + albumin
Refractory 2) TIPS
Ascites 3) PVS (in non-TIPS, non-transplant
candidates)

Hepatorenal
Syndrome
LVP = large volume paracentesis
TIPS = transjugular intrahepatic portosystemic shunt
 CHARACTERISTICS OF HEPATORENAL SYNDROME (HRS)

Characteristics of Hepatorenal Syndrome

Gagal ginjal pada pasien dengan

sirosis hepatis

PA ginjal normal

GFR
 MECHANISM OF ACTION OF THE DIFFERENT THERAPIES FOR HEPATORENAL SYNDROME (HRS)

Site of Action of Different Therapies for HRS

Advanced
Cirrhosis
Intrahepatic
Transplant Arteriolar
resistance
resistance Vaso- (vasodilation)
constrictors

Albumin Effective
Sinusoidal
TIPS arterial blood
pressure TIPS volume

Activation of
Hepatorenal Renal
neurohumoral
syndrome vasoconstriction
systems
 MANAGEMENT OF HEPATORENAL SYNDROME

Management of Hepatorenal Syndrome

Proven efficacy
Liver transplantation

Under investigation
Vasoconstrictor + albumin
Transjugular intrahepatic portosystemic shunt (TIPS)
Vasoconstrictor + TIPS
Extracorporeal albumin dialysis (ECAD)

Ineffective
Renal vasodilators (prostaglandin, dopamine)
Hemodialysis
 HEPATIC ENCEPHALOPATHY

Hepatic Encephalopathy 60
 PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY

Hepatic Encephalopathy Pathogenesis

Toxins

NH3
Shunting
Failure to GABA-BD
metabolize receptors
NH3

Bacterial action
Protein load
Pathogenesis of Hepatic Encephalopathy

BRAIN

Porta systemic
shunts

LIVER

Toxic N2 metabolites
From Intestines
 STAGES OF HEPATIC ENCEPHALOPATHY

Stages of Hepatic Encephalopathy

Confusion

Drowsiness

Somnolence

Coma
1 2 3 4
Stage
ASTERIXIS IS THE HALLMARK IN THE DIAGNOSIS OF HEPATIC ENCEPHALOPATHY

Asterixis
Flapping Tremor
 NUMBER CONNECTION TEST

Number Connection Test (NCT) Draw a star 70

Time to complete____________________

End
6 10 25
4
7 9 23

1 11
5 Begin

14
8 24
3
2 Sample handwriting
13
12
17
15 16 22
18 21
19 20
Drawing Tests
 HEPATIC ENCEPHALOPATHY NOMENCLATURE

Hepatic Encephalopathy
Nomenclature
Type A
Berhubungan dengan fungsi liver
Type B
Berhubungan dengan porto-systemic
Bypass. fungsi liver normal
Type C
Berhubungan dengan fungsi liver dan
porto-systemic shunting

Ferenci et al., Hepatology 2002; 35:716

 CHARACTERISTICS OF TYPE A VS. TYPE C ENCEPHALOPATHY

Characteristics of Type A vs. Type C

Hepatic Encephalopathy
Type A Type C
Rapid onset Gradual onset

Frequently fatal Rarely fatal

Main cause: Main cause:

cerebral edema shunting / toxin
Precipitant

Treatment: rarely effective Treatment: usually

short of liver transplant effective
 TREATMENT OF HEPATIC ENCEPHALOPATHY

Treatment of Hepatic Encephalopathy

Atasi faktor pencetus

Infection
GI hemorrhage
Prerenal azotemia
Sedatives
Constipation

Lactulose (adjust to 2-3 bowel movements/day)

Protein restriction
 HEPATIC ENCEPHALOPATHY PRECIPITANTS

Hepatic Encephalopathy Precipitants

Sedatives /
hypnotics
Excess protein GI bleeding

TIPS
Diuretics

Serum K+
Plasma volume
Temp

Azotemia
Infections
 ACTIONS OF LACTULOSE

Actions of Lactulose

NH3
Decreased pH

NH4+

Lactic acid NH3

Lactulose

Urease-producing Increase
bacteria cathartic effect
 HEPATIC ENCEPHALOPATHY TREATMENT SUMMARY

Hepatic Encephalopathy
Treatment: Summary
Increase ammonia
fixation in liver:
Ornithine aspartate
Flumazenil
Benzoate

Shunt
occlusion or
reduction

Decrease ammonia
production in gut:
Lactulose
Antibiotics
Adjustment in
dietary protein