2012-9-27

1

CIRRHOSIS AND ITS

COMPLICATIONS

Dr. Jinsheng Guo

Zhong Shan Hospital, Fu Dan University

Characteristic of Cirrhosis

Normal Liver Cirrhotic Liver

A chronic,

progressive,

diffuse liver

disease

Fibrosis and

disorganization of

the lobular and

vascular

architecture

histologically

Chronic hepatitis

with fibrosis

10-50 yrs

Liver Cirrhosis

Nonalcoholic

steatohepatitis

（NASH）

Alcoholic

Steatohepatitis

(ASH)

Long term, 80g/d, 10yr

Drug and chemicals

DILI

Autoimmune

e.g., PBC, AIH

Biliary

Schistosomiasis

Chronic viral

hepatitis HBV, HCV

Etiologies of Cirrhosis

Cryptogenic Inherited

Circulation

disturbance

veno-occlusive disease,

Budd-Chiari syndrome,

constrictive pericarditis

Wilson’s diseases

hemochromatosis

Factors that contribute to the risk

of developing cirrhosis

Regular (moderate) alcohol consumption

age older than 50 years

male gender

older age, obesity, insulin resistance or type 2 diabetes

hypertension, and hyperlipidaemia (all

features of the metabolic syndrome)

>= factors

Genetic impact (single nucleotide polymorphisms)

Disorders and Drugs That Can Cause

Hepatic Fibrosis

Infections Viral (e.g., chronic hepatitis B or C) Bacterial (eg, brucellosis) Parasitic (eg, echinococcosis)

Drugs and chemicals Alcohol Amiodarone Chlorpromazine Isoniazid Methotrexate Methyldopa Oxyphenisatin Arsenicals Oral contraceptives (Buddi-Chiari) Pyrrolidizine alkaloids and antineoplastic agents

Disorders affecting hepatic blood flow Budd-Chiari syndrome Heart failure Hepatic veno-occlusive disease Portal vein thrombosis

(venoocclusive disease) Mechanical obstruction

Biliary obstruction (chronic) Metabolic abnormality

Nonalcoholic fatty liver disease Autoimmune

Primary biliary cirrhosis

Autoimmune hepatitis

Primary sclerosing cholangitis

Disorders and Drugs That Can Cause

Hepatic Fibrosis

2012-9-27

2

Certain storage diseases and inborn errors of metabolism α 1-Antitrypsin deficiency Copper storage diseases (eg, Wilson's disease) Fructosemia Galactosemia Glycogen storage diseases (especially types III, IV, VI, IX, and X) Iron-overload syndromes (hemochromatosis) Lipid abnormalities (eg, Gaucher's disease) Peroxisomal disorders (eg, Zellweger syndrome) Tyrosinemia

Congenital hepatic fibrosis Others

Cystic fibrosis

Graft-versus-host disease

Jejunoileal bypass

Sarcoidosis

Disorders and Drugs That Can Cause

Hepatic Fibrosis

Self-limited, acute liver injury (eg, acute viral hepatitis A), even

when fulminant, does not necessarily distort the scaffolding

architecture and hence does not cause fibrosis, despite loss of

hepatocytes.

In its initial stages, hepatic fibrosis can regress if the cause is

reversible (e.g., with viral clearance). After months or years of

chronic or repeated injury, fibrosis becomes permanent.

Fibrosis develops even more rapidly in mechanical biliary

obstruction.

Disorders and Drugs That Can Cause

Hepatic Fibrosis

Etiology

Liver function Injury, Portal hypertension

Diffuse, chronic liver injury

Formation of

diffuse

fibrous septa

regenerative

nodules

formation

Hepato-cellular

necrosis, collapse of

hepatic lobules

Complications Upper GI Bleeding, Hepatic coma, infections,

Hepatocellular carcinoma; Functional renal failure

Pathogenesis of Liver Cirrhosis

FIBROSIS

CIRRHOSIS

Histopathologic Classification

micronodular

uniformly small nodules (< 3 mm in diameter) and regular

bands of connective tissue

Alcoholic, stasis

macronodular

nodules that vary in size (3 mm to 5 cm in diameter)

Hepatitis B, C; Hemochromatosis, Wilson’s disease

mixed macro and micronodular

(incomplete septal cirrhosis) combines elements of

micronodular and macronodular cirrhosis

A1-AT deficiency, Wilson’s disease; Hepatitis B

2012-9-27

3

Histological Patterns of Fibrosis

Portal-based fibrosis

(e.g., chronic viral hepatitis, chronic cholestatic diseases,

and hemachromatosis)

Central-based fibrosis

(e.g., steatohepatitis, and chronic venous outflow

obstruction)

Distribution pattern of the fibrotic septae

Porto-portal (e.g., cholestatic liver injuries)

Portal-central (e.g., viral hepatitis)

Central-portal (e.g., alcoholic liver disease)

2012-9-27

4

Chronic viral hepatitis C

portal-central fibrotic septa and nodule

formation(Trichrome staining) Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine

Biliary cirrhosis

portal-portal fibrotic septa and

proliferation of bile ductules (H&E)

Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine

Autoimmune hepatitis

portal-central vein bridging necrosis

(Trichrome staining) Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine

Acute alcoholic hepatitis

Deposition of extracellular matrix around

hepatocytes (so called chicken wire pattern) and

ballooning degeneration of hepatocytes Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine

Nonalcoholic steatohepatitis

Macrovesicular steatosis and pericellular fibrosis

(Trichrome staining)

Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine

2012-9-27

5

Pathogenesis Fibrogenic stimuli from injured liver

Oxidative stress; Hypoxia; Inflammation and immune responses;

Apoptosis; Steatosis; Senecense and autopathy

Imbalance between the accumulation and degradation of ECM

Tissue inhibitors of metalloproteinases (TIMPs)

The biologic activity of ECM in fibrogenesis

Dramatic changes of ECM components in the quality, quantity, and

distribution

provides cells with positional signals and a mechanical scaffold

Provide “biological signals” with a resultant fibrogenic response and

angiogenesis

Cellular responses and behavior

Capillarization of the sinusoids, Angiogenesis

vascularized fibrotic septa

intrahepatic shunts between afferent (portal vein and hepatic artery) and

efferent (hepatic vein) vessels of the liver

Cirrhosis may lead to liver failure, portal hypertension, or development of

hepatocellular carcinoma

Injured

hepatocytes

Kupffer cell

activation

Stellate cell

activation

Inflammation

Matrix production,

degradation and

remodeling

Fibrosis

ROS/NOS,

cytokines (PDGF

TGF-1, MCP-1)

Cytokines (MCP-

1, MIP-2, IL-1 )

Cytokines (MCP-1,

TNF-, IL-1

MIP-2)

Denatured proteins

ROS

apoptotic bodies

ROS/NOS

Degraded collagen,

hyaluronic acid

MMPs/TIMPs

Endothelial cells

EIIIA

isoform,

ET-1,

VEGF

PDGF

Typ

e I

V c

ollagen, la

min

in

Lipid peroxides, apopttoic bodies, cytokines (VEGF, IGF-1)

Endothelial cells

Pathogenesis

Guo and Friedman, Senim Liv Dis, 2007

Hepatic Stellate cell Activation -

A Central Event in Liver Fibrosis

Normal Liver Activated HSC

with Fibrosis

Friedman SL and Arthur, Science and Medicine, 2002

RESOLUTION

APOPTOSIS?

REVERSION?

INJURY

PDGF ET-1

TGF-1

PDGF,

MCP-1

PDGF,

Serum

MCP-1

Proliferation

Fibrogenesis

HSC

Chemotaxis

Retinoid Loss WBC

Chemoattraction

Matrix

Degradation

Oxidative

Stress,

cFn

MMP-2

Initiation Perpetuation

Contractility

Pathways of Stellate cell Activation

Friedman SL, J Biol Chem, 2000

2012-9-27

6

Metavir Scoring System for

Fibrosis

F1

F3

F2

F4

Modified from Poynard

Scoring Systems for fibrosis Progression

METAVIR Knodell Ishak

F4 F4 F6

F3-F4 F3-F4 F5

F3 F3 F4

F2 F1-F3 F2-F3

F1 F1 F2

F0-F1 F0-F1 F1

F0 F0 F0

Friedman SL. Gastroenterology, 2008

Classification of chronic liver disease based on hisptological, clinical,

hemodynamic, and biological parameters.

Pathophysiology

Etiology

Alcohol abuse, Malnutrition, infection, drugs,

Fatty infiltration, biliary obstruction…

Portal hypertension

Destruction of hepatocytes

Fibrosis/scarring

Liver function Injury

Obstruction of blood flow

Increased pressure in the venous and sinusoidal channel

2012-9-27

7

Consequences of portal hypertension

Formation and open of portal-

systemic collateral’s

Splenomegaly

Ascites

Consequences of portal hypertension Formation and open of portal-systemic collateral’s

Esophageal/gastric varices

short gastric/coronary veins

Rectal collateral‘s

Suphemorrhoidal/middle & inf. Hemorrhoidal

Caput medusae

umbilical/epigastric

abdominal wall varices

Portal system and left renal

Esophageal varices

Gastric varices

Normal

Gastro-esophageal varices bleeding Caput medusae ( umbilical)

2012-9-27

8

abdominal wall varices

Consequences of portal hypertension

Ascites

Theories of ascites formation

• Underfilling theory

• Overflow theory

• Arterial vasodilation theory

Ascites

• Sodium retention

--- Renin angiotension aldosterone system

(RAAS)

--- sympathetic nerve system , norepinephrine

--- Intrarenal factors

Kallikrein-kinin system, Adenosine

• Water retention

--- Antidiuretic hormone (ADH)

--- Impaired renal synthesis of PGs (PGE2 )

• Renal vasoconstriction

-- RAAS, Angiotension II

-- SNS

-- ADH

-- ET

Consequences of portal hypertension

Splenomegaly

Splenomegaly

hypersplenism: anemia, leukopenia, thrombocytopenia

spleen：splenomegaly; congestion; blood stasis, dilation of spenic sinus; proliferation of splenic pulp;

dilation of spleen artery; varicosity of splenic vein;

endophlebitis

Pathology of Liver Cirrhosis

Other Organs

Gastrointestinal

vein varices；mucosal edema and stasis；

peptic ulcer formation

Renal：

glomerulonephritis（membranous, anti-glumerular

basement membrane, mesangial proliferative

glomerulonephritis）

Glomerulosclerosis, kidney tubules degenetative

necrosis

Endocrine gland

atrophy and degeneration

2012-9-27

9

Endocrine system

Gynecomastia (男性乳房发育),

Telangiectases (毛细血管扩张症)

Spider nevi (蜘蛛痣)

Palmar erythema (肝掌)

Testicular atrophy (睾丸萎缩)

Menstrual irregularities (月经失调)

Pulmonary manifestations

Hepatic hydrothorax (肝性胸水)

Hepatopulmonary syndrome (HPS, 肝肺综合征)

triad of pulmonary vascular dilatation

arterial hypoxemia

in the setting of advanced liver disease

Hepatorenal syndrome ( HRS)

Occurred in the setting of:

-- chronic liver disease

-- advanced hepatic failure

-- portal hypertension

characterized by:

-- impaired renal function

-- marked abnormalities in arterial circulation

-- activation of endogenous vasoactive system

Classified into 2 different types:

-- Type I: Rapidly progressive

-- Type II: Not rapidly progressive

Often results in mild renal insufficiency causing

diuretic resistant ascites

Mechanisms of HRS

Renal cortical

ischemia

HRS

Hypotension due to:

Arterial vasodilation,

Reduced cardiac

output

Portal

hypertension

Increased local

production of LTC4,

LTD4 and F2

isoprostane

Activation of SNS,

RAAS, AVP, endothelin

and neuropeptide Y

Reduced

sensitivity to

NO and ANP

renal

production of

PGI2 and PGE2

Symptoms and Signs

Hepatic fibrosis itself does not cause distinct symptoms. Symptoms may develop secondary to the primary disorder or to portal hypertension. Portal hypertension with splenomegaly is often asymptomatic unless complications, such as variceal GI bleeding, ascites, or portal-systemic encephalopathy, develop. Eventually, cirrhosis supervenes.

Clinical Features

Compensated cirrhosis

Many people experience few symptoms at the onset of cirrhosis, symptoms are typically vague and nonspecific.

-- Fatigue and loss of energy

-- Loss of appetite and nausea

-- Spider angiomas

-- liver function is normal

Decompensated cirrhosis

Hepatocellular insufficiency

Symptoms caused by loss of functioning liver cells

--- System：

fatigue, weakness, weight loss, malnutrition

--- Digestive System:

Loss of appetite, nausea, diarrhea

Portal hypertention

gastro-esophageal varices, Splemegaly, ascites…

2012-9-27

10

Clinical Features

Jaundice

Edema

Coagulopathy

Spider angiomata

Palmar erythema

A variety of metabolic

abnormalities

Gastroesophageal varices

Splenomegaly

Ascites

Hepatic encephalopathy

Caput medusae, Cruveihier-

Baumgarten syndrome

hepatocellular

insufficiency

portal

hypertension

Description Cause

Jaudice Yellow discoloration of skin,

cornea, and mucous

membranes

Compromised

hepatocyte excretory

function, occurs when

serum bilirubin>20mg/L

Spider amgiomata Central arteriole with tiny

radiating vessels, mainly on

trunk and face

Raised oesotradiol,

decreased oestradiol

degradation in liver

Nodular liver Irregular, hard surface on

palpation

Fibrosis, irregular

regeneration

Splenomegaly Enlarged on palpation or in

ultrasound

Portal hypertension,

splenic congestion

Ascites Proteinaceous fluid in

abdominal cavity, clinical

detected when≥1.5L

Portal hypertension

Caput medusae Prominent veins radiating

from umbilicus

Portal hypertension,

reopening of umbilical

vein that shunts blood

from portal vein

Cruveilhier-

Baumgarten

syndrome

Epigastric vascular

murmur

Shunts from portal vein to

umbilical vein branches, can

be present without Caput

medusae

Palmar erythemia Erythema sparing

central portion of the

palm

Increased oestradiol,

decreased oestradiol

degradation in liver

White nails Horizonal white bands

or proximal white nail

plate

Hypoalbuminaemia

Hypertrophic Painful proliferative Hypoxaemia due to right-to-

left shunting

Osteoarthropathy/fing

er clubbing

Osteoarthropathy of

long bones

Portopulmonary

hypertension

Dupuytren’s

contracture 掌腱膜桡侧挛缩

Fibrosis and

contraction of palmar

fascia

Enhanced oxidative stress,

increased inosine (alcohol

exposure or diabeties)

Gynecomastia,

loss of male hair

pattern

Benign proliferation of

glandular male breast

tissue

Enhanced conversion of

androstenedione to

oestrone and oestradiol,

reduced oestradiol

degradation in liver

Hypogonadism Mainly in alcoholic

cirrhosis and

haemochromatosis

Direct toxic effect of alcohol

or iron

Flapping tremor

(asterixis)

Asynchronous

flapping motions of

dorsiflexed hands

Hepatic encephalopathy,

disinhibition of motor

neurons

Foetor hepaticus Sweet, pungent smell Volatile dimethylsulfide,

especially in portosystemic

shunting and liver failure

Anorexia, fatigue,

weight loss,

muscle wasting

Occurs in >50% of

patients with cirrhosis

Catabolic metabolism by

diseased liver, secondary to

anorexia

Type 2 diabetes Occurs in 15-30% of

patients with cirrhosis

Catabolic metabolism by

diseased liver, secondary to

anorexia

Tendency to hemorrhage and anaemia

--Reduced synthesis of coagulation factors (II,V,VII,IX,X)

-- Hypersplenism: low platelet count, poor absorption

-- Gastrointestinal bleeding

Hormonal abnormalities

-- Gynecomastia

-- Telangiectases

-- Spider nevi

-- Palmar erythema

Jaundice

Hepatocellular Insufficiency

Clinical features (I)

spider nevi

2012-9-27

11

Splenomegaly

anemia, leukopenia, thrombocytopenia due to hypersplenism

Development and open of collateral vessels in portal hypertension

Esophageal varices

Rectal collateral's

Caput medusae

Abdominal wall varices

Portal system and left renal

Ascites, hepatic hydrothorax (right side)

Clinical Features (I) Portal Hypertension

Clinical Features

Palpation of liver

firm, hard, irregular, enlargement

rounded or sharp edge

below the right lower ribs

The spleen is often palpable, and may be very large

The clinical

manifestations

found in

cirrhosis

、

Laboratory Tests and Findings in Cirrhosis

Description Cause

AST,

ALT

Often normal or moderately

raised

Leakage from damaged hepatocytes;

AST-to-ALT ratio often >1, especially

in alcoholic cirrhosis (relative

vitamin B6 deficiency)

ALP Increased by less than

three-fold, apart from PBC

and PSC

Cholestasis

-GT More specific for liver than

ALP, high concentrations in

active alcoholics

Cholestasis

Bilirubin Raised later than -GT and

ALP, important predictor or

mortality

Cholestasis, decreased hepatocyte

and renal excretory function

(exacerbated by systemic

inflammation)

AST=aspartate aminotransferase; AST=Alanine aminotransferase; ALP=alkaline

phosphatase; DD=Differential diagnosis; -GT=-glutamyl transpeptidase;

PBC=primary biliary cirrhosis; PSC=primary sclerosing cholangitis

Description Cause

Albumin Decreased in

advanced

cirrhosis

Decreased hepatic production,

sequestration into ascites and

interstitium (exacerbated in

systemic inflammation).

DD:malnutrition, protein losing

enteropathy;consumption

Prothrombin

time

Decreased in

advanced

cirrhosis

Decreased hepatic production of

factor V/VI (while thromin

production is maintained).

DD:Vitamin K deficiency (eg, due

to mechanical biliary obstruction)

Laboratory Tests and Findings in Cirrhosis

2012-9-27

12

Description Cause

Immunoglobulins Increased

(mainly IgG)

Shunting of portal venous blood

carrying (intestinal) antigen

stimulation of plasma cells

Sodium

imbalance

Hyponatraemia Inability to excrete free water via

kidneys due to increased activity of

antidiuretic hormone (vasopression

2 receptor effect)

Anaemia Macrocytic,

normocytic, or

microcytic

anemia

Folate deficiency, hypersplenism,

direct toxicity (alcohol),

gastrointestinal blood loss (eg., via

oesophageal varices)

Thrombocytes

and leucocytes

Thrombocytop

enia

(Leucopenia)

Hypersplenism, dysfibronogenemia,

reduced hepatic thrombopoietin

production

Laboratory Tests and Findings in Cirrhosis Diagnostic tests in chronic liver

disease, according to cause

Specific physical

associations

Diagnostic

(laboratory)

variables

Value of liver biopsy

(identifiable features)

HBV Arthritis HBsAg, HBeAg,

HBc-antibodies,

HBV DNA

+

HCV Cryoglobulinaemi

a

HCV antibodies,

HCV RNA

+

Viral hepatitis

D

.. HBsAg, HDV

antibodies, HDV

RNA

++(HDAg)

Alcoholic .. AST:ALT ratio2,

increased CDT

and -GT

++ (Mallory bodies,

steatosis, hepatocyte

ballooning>granulocyte

s)

Non-alcoholic

steatohepatitis

Overweight/obesi

ty, metabolic

syndrome, type 2

diabetes

Uric acid, fasting

glucose/insulin/tri

glycerides

++ (Mallory bodies,

steatosis, hepatocyte

ballooning>granulocyte

s)

Specific physical

associations

Diagnostic

(laboratory) variables

Value of liver

biopsy (identifiable

features)

Autoimmune .. Autoantibodies (ANA,

LKM antibodies, SLA

antibodies),

increased -globulins

+++(bridging

necrosis)

Primary biliary

cirrhosis

Sicca syndrome,

xanthelasma

AMA; Increased ALP,

-GT, and cholesterol

++(cholangitis,

paucity of bile

ducts, granuloma,

ductopenia)

Primary

sclerosing

cholangitis

Ulcerative colitis

(90%)

pANCA antibodies

(70%), increased ALP

and -GT, imaging

beaded intra-hepatic

and extra-hepatic bile

ducts

++(concentric

peribile ductular

fibrosis, ductopenia)

Diagnostic Tests in Chronic Liver

Disease According to Cause

Specific

physical

associations

Diagnostic (laboratory)

variables

Value of liver biopsy

(identifiable

features)

Haemochromatosis Arthritis,

myocarditis,

diabetes

Fasting transferrin

saturation>60% (men),

>50% (women); increased

ferritin, HFE mutation

++ (periportal iron-

loaded hepatocytes,

quantification of liver

iron)

Wilson’s disease Neurological Increased ceruloplasmin,

and copper in 24h urine;

slip-lamp: corneal copper

deposits

+++ (quantification of

liver copper)

1-antitrypsin Pulmonary

fibrosis

Reduced 1-antitrypsin;

1-antitrypsin subtyping

+++ 1-antitrypsin-

loaded hepatocytes

Congenital disease +++ (eg. Bile ductular

plate malformations)

Diagnostic tests in chronic liver

disease, according to cause

Laboratory findings [I]

Blood and urine routines

Liver function tests

-- to estimate the severity of liver dysfunction：

ALT, AST, AKP, GGT, serum total bilirubin,

serum albumin, prothrombin time, globulin,

cholesterol

-- to differential diagnosis:

Alcoholic: AST/ALT>=2;

PBC: AKP, GGT>>ALT, AST

-- to refect hepatic fibrosis: PIIIP, HA, laminin

-- to quanlity liver function

Cellular immune , hormonal

immune

-- autoimmune hepatitis:

IgG ,globulin ANA(+), SMA(+)

-- PBC: IgM , AMA(+)

Marker of virus

Alpha Fetoprotein (AFP)

Laboratory findings [I]

Immunology

2012-9-27

13

Laboratory findings [II]

Ascites paracentesis:

routine, culture, ADA, LDH, oncology markers

SAAG (serum ascites albumin gradient) > 11g/L

Ultrasonography, CT scanning：

biliary obstruction, liver masses, varices

splenomegaly, ascites

Endoscopy:

-- the number, appearance, and size of any

esophageal/gastric varix,

-- portal hypertensive gastropathy (PHG)

Portal Hypertensive Gastropathy

Laboratory findings [III]

Radionuclide:

99m Tc-MIBI, H/L

liver biopsy:

to confirm the diagnosis

Laparoscopy

HVPG (hepatic vein pressure gradient)

(肝静脉压力梯度)

=(wedged - free )hepatic venous pressure

Normal: 5-6mmHg,

>10mmHg: varices;

>12mmHg:rupture

2012-9-27

14

Child Pugh Turcotte (CPT)

Classification

1 point 2 points 3 points

Encephalopathy Absent Slight-Moderate

Medically

controlled

Moderate-Severe

Poorly controlled

Ascites Absent Slight

Controlled

medically

Poorly controlled

Bilirubin (mg/L) <34 34-51 >51

Albumin (g/L) <35 28–35 <28

INR <1·7 1·7–2·2 >2·2

CPTA (5–6 points), CPTB (7–9 points), and CPTC (10–15 points) predict a life

expectancy of 15–20, 4–14, and 1–3 years, respectively, and a perioperative

mortality (abdominal surgery) of 10%, 30%, and 80%, respectively.

INR=international normalised ratio.

Child-Pugh classification

Scorea

variable 1 2 3

Encephalopathy(degree) Nil Slight-Moderate Moderate-Severe

Ascites(degree) Nil Slight Moderate-Severe

Bilirubin(umol/L) <34 34-51 >51

Albumin(g/L) 35 28-34 <28

Prothrombin Index(%) >70 40-70 <40

Prothrombin Time(s) <14 15-17 >18

Prothrombin Time(INR) <1.3 1.3～1.5 >1.5

* PBC: SB(μmol/L) 17～68 68～170 >170

aScores are summed to determine Child’s class:

class A=5-6 class B= 7-9 class C= 10-15

Complications of Decompensated Cirrhosis

Complication Manefestation

Gastroesophageal variceal

bleeding

Hematemesis, melena, shock

Spontaneous bacterial

peritonitis

Abdominal pain, an acute onset of symptoms, and

peritoneal irritation, fever

primary hepatocellular

carcinoma

Progressive hepatomegaly, firm

hepatorenal syndrome Oliguria, anuria on the base of refeactory ascites

、nausea

Hepatopulmonary Syndrome Clubbing finger or acropachy, cyanosis

Encephalopathy asterixis or “flapping tremor”, delirium, coma

Portal vein thrombosis

Chronic: nonsymptometic

Acute complete occlusion:

sudden onset of abdominal pain, variceal

bleeding, and ascites, splenomegaly, shock

Diagnosis of Liver Cirrhosis

Etiology diagnosis

Pathology diagnosis

Functional diagnosis

Child-Push classification

Complication(s) diagnosis

Searching for complications

Comorbidity diagnosis

Ex., Patient’s diagnosis:

PBC; Liver cirrhosis; Decompensate stage, Child C;

Gastric-esophageal bleeding; Dermatosclerosis

Diagnosis [II]

The history of disease contributes to identifying the

cause of cirrhosis

history of viral hepatitis, blood transfusion, medication

use, alcohol use, sexual practices should be carefully

reviewed

Signs and symptoms confirm to existence of portal

hypertension and impared liver function

Liver function tests

hypoalbuminemia, hyperbilirubinemia， the prolonged

prothrombin time suggest hepatic decompensation.

Imaging study

Ultrasound and CT readily identify the lesion, but have

no characteristic findings

Differential Diagnosis

Other condition of hepatomegaly or

splenomegaly chronic virus hepatitis, Gaucher’s disease,

lymphomas and leukaemias, congestive splenomegaly

Differential diagnosis of cirrhotic ascites

and other types of ascites malignant ascites, constrictive pericarditis,

tuberculous peritonitis, et al.

Portal hypertension

2012-9-27

15

Treatment of cirrhosis

Specific treatment for the underlying etiology of the liver

disease

antivirus therapy --viral hepatitis

abstinence from alcohol--alcoholic

Ursodeoxycholic acid(UDCA)(熊去氧胆酸)--PBC

Penicillamine(青霉胺)—Wilson’s disease

General Treatments:

High calories (40 kcal/kg· d)、 adequate protein (1-

1.5g/kg· d) 、vitamin

Hepa-protective Herbal compounds

Treatment of cirrhosis

Ascites

Treatment of complations

Electrolyte and acid-base imbalance

hyponatremia

hypokalemia

hypochloremic alkalosis

Treatment of Cirrhosis [IV]

Surgical treatment of portal hypertension

porta-caval shunt surgery：

portacaval

mesocaval

distal splenorenal shunts

Choice of patients：

Child-Pugh: A, B

bleeding from gastroesophageal varices,

hypersplenism.

Medical Management of Ascites

Prevention:

Low sodium diet

Treatment:

Moderate sodium restriction

Diuretics (spironolactone, or furosemide)

Large volume paracentesis

Intravenous albumin replacement

TIPSS (LeVeen/Denver shunts)

Treatment of Ascites [I]

Bed rest , sodium and water restriction

Fluid intake: 800-1000ml/d (hyponatremia, serum

sodium<130meq/L)

Dietary sodium intake ：88mmol/d (2.0gNacl)

Mild patients：rest on bed, with dietary salt restriction,

loss of ascites occurs in 10% to 15% of patients.

Treatment of Ascites [II]

Increasing renal sodium and water

excretion:

--Diuretics:

urinary sodium /urinary potassium >1

Spironolactone+furosemide

urinary sodium / urinary potassium <1

higher doses spironolactone

2012-9-27

16

Treatment of Ascites (III)

Large-volume paracentesis associated with plasma

volume expansion

Ascites ultrafiltration and re-infusion

Peritoneo-venous (LeVeen) shunts

TIPS (transjugular intrahepatic porto-systemic stent)

Liver transplantation

TIPSS—

stent positioned between the hepatic and portal veins Treatment of cirrhosis[IV]

surgical treatment of portal hypertension

portacaval shunt surgery：

portacaval

mesocaval

distal splenorenal shunts

Choice of patients：

Child-Pugh: A, B

bleeding from gastroesophageal varices

hypersplenism

COMPLICATIONS OF LIVER

CIRRHOSIS

2012-9-27

17

Complication

Gastroesophageal variceal bleeding

Spontaneous bacterial peritonitis (SBP)

Primary hepatocellular carcinoma (HCC)

Hepatorenal syndrome (HRS)

Hepatopulmonary syndrome (HPS)

Encephalopathy

Portal vein thrombosis

Complications of Decompensated Cirrhosis

Complication Manefestation

Gastroesophageal variceal

bleeding

Hematemesis, melena, shock

Spontaneous bacterial

peritonitis

Abdominal pain, an acute onset of symptoms, and

peritoneal irritation, fever

primary hepatocellular

carcinoma

Progressive hepatomegaly, firm

hepatorenal syndrome Oliguria, anuria on the base of refeactory ascites

、nausea

Hepatopulmonary Syndrome Clubbing finger or acropachy, cyanosis

Encephalopathy asterixis or “flapping tremor”, delirium, coma

Portal vein thrombosis

Chronic: nonsymptometic

Acute complete occlusion:

sudden onset of abdominal pain, variceal

bleeding, and ascites, splenomegaly, shock

Complications [I] Gastroesophageal variceal bleeding

Upper Gastrointestinal Bleeding

Hematemesis(呕血)

melena(黑粪)

portal hypertensive gastropathy (门脉高压性胃病)peptic ulcer (消化性溃疡)

Esophageal/ gastric variceal bleeding

Menefestation

Treatment of Variceal Bleeding

Reduce the hepatic venous pressure gradient (HVPG) to <12 mmHg, or by

20% from baseline

Acute:

Resuscitation

Vasoconstrictors (vasopressin, somatostatin, octreotide, propranolol)

Endoscopic interventions (Sclerotherapy; Band Ligation)

Surgical treatment (shunts)

Transjugular intrahepatic portosystemic shunts (TIPS)

Chronic:

Variceal Obliteration

TIPS

Surgical shunts

2012-9-27

18

Treatment of Acute Variceal Haemorrhage

General management:

abstain food

intensive care

volume and blood replacement

specific measures to stop the bleeding

-- Pharmacological therapy:

vasopressin (垂体后叶素)

somatostatin (生长抑素)

Octreotide (奥曲肽)

Treatment of acute variceal haemorrhage

Emergent endoscopy:

after Patient’s hemodynamic status stabilized(usually within 2-12 hours)

----Balloon tube tamponade( if bleeding continues)

----Endoscopic variceal sclerotherapy and band ligation

----Prophylactic therapy to prevent rebleeding: Beta-adrenergic antagonists(普奈洛尔), endoscopic sclerotherapy(硬化剂)/banding(套扎) (usually 3-6 sessions), portacaval shunting, TIPS

2012-9-27

19

TIPS---stent positioned between the hepatic and portal veins TIPS---stent positioned between the hepatic and portal veins

Treatment

portal hypertension

(<12mmHg)

Eradicate varices

Liver transplantation

Shunt Surgical shunts

TIPS

Pharmacotherapy

Q

Endoscopy: EVS, EVL

Devascularization

R

Spontaneous Bacterial Peritonitis (SBP)

Prevention:

Treat ascites

Treatment:

Early diagnosic paracentesis:>250 neutrophils per mL

Intravenous antibiotics (plus albumin)

Antibiotics: Third-generation cephalosporins

Secondary prophlaxis with oral antibiotics such as

levofloxacin

Complications [II] Spontaneous Bacterial Peritonitis

(4-8%)：Fever, worsening jaundice or renal dysfunction,

abdominal pain (occurring only in 50% of patients), and encephalopathy are the most common clinical findings in SBP. However, the patient is frequently asymptomatic. Because culture of ascites fluid is negative in a large number of patients with SBP, diagnosis should be based on the presence of >250 neutrophils/mm3.

Treatment of SBP

1. Ascites PMN>250/mm3 : antibiotic therapy should be

initiated.

2. Ascites PMN<250/mm3 and ascitic fluid culture

continues to be positive: initiation of antibiotic treatment.

3. Follow-up diagnostic paracentesis performed 48 hours

after starting therapy allows assessment of response to

treatment and the need to modify antibiotic coverage.

4. Long-term prophylaxis ---Patients who have recovered

from an episode of SBP are at a high risk of developing

SBP recurrence.

Complications [III]

Hepatic encephalopathy

Asterixis (扑翼样振颤)

Disoriented (定向障碍)

Coma (昏迷)

2012-9-27

20

Hepatic Encephalopathy

correction of precipitating factors Infection Bleeding Electrolyte imbalance Sedatives High protein intake Lactose Neomycin, metronidazole, rifaximin supportive measures and administration of

medication that decrease the production of toxins or antagonize their effects on brain

Complications [III]

Hepatorenal syndrome(HRS)

Oliguria(少尿), azotemia(氮质血

症), hypotension(低血压), dilutional

hyponatremia(稀释性低钠血症), low

urinary sodium(低钠尿)

Hepatorenal Syndrome

Worsening azotemia with avid sodium retention and oliguria in the absence of identifiable specific causes of renal dysfunction.

Prevention:

Avoid hypovolaemia

Treatment:

Discontinue diuretics

Rehydration

Albumin infusion

Terlipressin or midodrine (noradrenaline)

and somatostatin (octreotide)

Therapies for HRS[I]

Avoid use of nephrotoxic drugs: （1）Antibiotics ：aminoglycosides

（2）NSAIDs：inhibit formation intrarenal prostaglandins

---marked decline in renal function

Avoid and treat factors to hypovolaemia: （1）active treatments of upper gastrointestinal bleeding

（2）Judicious use of diuretics（weight loss<0.5Kg/d）

Rectify electrolyte and metabolic imbalance,

Fluid intake restriction

Therapies for HRS[II]

Volume expansion: with IV dextrose, plasma, albumin or Concomitant plasma volume expansion with

albumin has been used with LVP to correct decreased effective arterial volume that leads to sodium retention, TIPS

Vasoactive drugs: terlipressin(可利新),

ornipressin, dopamine, ---increasing renal plasma flow

Elimination of endotoxaemia and control infections

Liver transplantation: the most effective

treatment for patients with HRS

Complications [IV]

Hepatocellular Carcinoma

Risk factors for hepatocellular carcinoma

Cirrhosis

Decompensated cirrhosis

Viral hepatitis B and C

Non-alcoholic steatohepatitis

Type 2 diabetes

Aflatoxin exposure

Coinfection with multiple viruses; viral hepatitis B,

Viral hepatitis C, and HIV (risk 2-6-fold)

Increasing age

Male sex

Positive family history of hepatocellular carcinoma

Associated secondary alcohol abuse (risk 2-4-fold)

or non-alcoholic steatohepatitis as cofactor

2012-9-27

21

Indications for Liver transplantation

(irreversible, progressive chronic liver diseases)

• Primary biliary cirrhosis

• Sclerosing cholangitis

• Fulminant liver failure

• Metabolic liver diseases

• Alcoholic cirrhosis

• Postnecrotic cirrhosis

• Autoimmune liver disease

• Budd-Chiari syndrome

• Hepatocellular carcinoma

Indications for Liver transplantation

(cirrhosis)

• Refractory ascites

• Recurrent variceal bleeding

• Hepatic encephalopathy

• spontaneous bacterial peritonitis

• Worsening functional status, rising

bilirubin, decreasing albumin, worsening

coagulopathy (Child-Pugh C)

Prevention and Treatment for

complications of cirrhosis

Prevention Treatment

Variceal

bleeding

Non-selective

blockers

Varicral band

Ligation

Acute:

Resuscitation

Vasoconstrictors

Sclerotherapy

Band Ligation

TIPS

Surgical shunts

Chronic

Variceal obliteration

TIPS

Surgical shunts

Ascites Low sodium diet Low sodium diet

Diuretics

Large volume paracentesis

TIPSS (LeVeen/Denver shunts)

Prevention and Treatment for

complications of cirrhosis

Prevention Treatment

Renal failure Avoid

hypovolaemia

Discontinue diuretics

Rehydration

Albumin infusion

Hepatorenal synfrome

Add terlipressin or midodrine

(noradrenaline) and somatostatin

(octreotide)

Encephalopathy Avoid precipitants Treat precipitating factors

Infection

Bleeding

Electrolyte imbalance

Sedatives

High protein intake

Lactulose

Neomycin, metronidazole,

rifaximin

Prevention and Treatment for

complications of cirrhosis

Prevention Treatment

Spontaneous

bacterial

peritonitis

Treat ascites Early diagnosis paracentesis;

>250 neutrophils per mL,

intravenous antibiotics (plus

albumin), Secondary prophlaxis

with oral antibiotics such as

levofloxacin

TIPS=Transjugular intrahepatic portosystemic shunt;

*Nadolol, propranolol; *Vasopressin;

octreotide/somatostatin; terlipression

2012-9-27

22

CIRRHOSIS AND ITS

COMPLICATIONS

--Teaching Notes

Dr. Jinsheng Guo

Zhong Shan Hospital, Fu Dan University

Objectives

• To master the definition, etiology, major clinical

features, treatment of liver cirrhosis and the

management of its complications.

• To be familiar with the pathogenesis of cirrhosis, the

laboratory parameters which are associated with the

etiology and severity (compensate or decompensate

cirrhosis).

Teaching plan

Contents and time assignment

1）Definition of cirrhosis (5 min)

2）Pathogenesis (15 min)

General

Disease specific:

viral hepatitis, alcoholic, primary and biliary cirrhosis

3）Diagnosis (25 min)

Etiology for cirrhosis

Compensate and decompensate cirrhosis

The complications of cirrhosis

Contents and time assignment

4) Treatment (45 min)

Disease specific and non-specific treatment

Major complication • Acute bleeding and prevention of recurrent

hemorrhage

• Encephalopathy

• Spontaneous bacterial peritonitis

• Encephalopathy

Key points and special difficulties

1. To understand that the early diagnosis and

treatment of chronic liver diseases are important

for the prevention of cirrhosis progression and

improving prognosis.

2. To understand that the treatment of complications

are the major management for decompensate

cirrhosis

Questions for review

What is cirrhosis? What are the etiologies of cirrhosis and why it is important to identify them?

How to diagnosis cirrhosis? What are the common complications for advanced cirrhosis?

The management of disease specific cirrhosis

The management of the major complications of cirrhosis

2012-9-27

23

Key words

• Cirrhosis; Portal hypertension; Ascites; Variceal bleeding; Spontaneous bacterial peritonitis; Hepatorenal syndrome; Hepatic encephalopathy; Hepatocellular carcinoma

• Alcoholic cirrhosis; posthepatitic cirrhosis; cryptogenic cirrhosis; Primary biliary cirrhosis; Secondary biliary cirrhosis; Cardiac cirrhosis; Budd-Chiari Syndrome