Transcript Pathophysiology of Cirrhosis and Portal Hypertension

Cirrhosis and Associated
Complications
Luke Gessel
October 2nd, 2014
Outline

Cirrhosis
◦ Development
◦ Diagnosis

Complications of Cirrhosis
◦
◦
◦
◦
Portal Hypertension
Ascites
Spontaneous Bacterial Peritonitis
Hepatic Encephalopathy
Cirrhosis
Epidemiology

30,000 deaths per year due to cirrhosis in US

10,000 deaths per year due to liver cancer
largely due to cirrhotic livers in US

Hepatocellular carcinoma most rapidly
increasing neoplasm in US and western
Europe
Natural History of Chronic Liver Disease
Chronic liver
disease

Viral

Autoimmune

Drug-induced

Cholestatic diseases

Metabolic diseases
Compensated
cirrhosis
Complications:
 Variceal hemorrhage
 Ascites
 Encephalopathy
 Jaundice
Decompensated
cirrhosis
Death
Gross Liver Pathology
Normal
Cirrhosis
Irregular surface
Nodules
Liver Histology
Normal
Cirrhosis
Fibrosis
Regenerative Nodules
surrounded by fibrous
tissue
Liver Anatomy
Liver Anatomy
Hepatic Lobule
Sinusoid
The Road to Liver Injury

Hepatic fibrosis
◦ Accumulation of extracellular matrix, or scar, in
response to acute or chronic liver injury
◦ Fibrogenesis
 Wound healing response to injury, ultimately leading to
cirrhosis

Cirrhosis
◦ End-stage consequence of fibrosis of hepatic
parenchyma, resulting in nodule formation that
may lead to altered hepatic function and blood
flow
The Road to Liver Injury

Cirrhosis largely takes years to decades

Can be accelerated in some cases:
◦ Neonatal liver disease
 Infants with biliary atresia may have severe fibrosis and
marked parenchymal distortion at birth
◦
◦
◦
◦
HCV-infected patients after liver transplantation
HIV/HCV-coinfection
Severe delta-hepatitis
Some cases of drug-induced liver disease
PATHOGENESIS OF LIVER FIBROSIS
Normal Hepatic SInusoid
Retinoid
droplets
Fenestrae
Hepatic
stellate cell
Space of Disse
Sinusoidal
endothelial cell
Hepatocytes
Hepatic Stellate Cells

The key pathogenic feature underlying liver fibrosis
and cirrhosis is hepatic stellate cell activation.

Hepatic stellate cells (also known as Ito cells or
perisinusoidal cells) are located in the space of Disse

The space of Disse is located between hepatocytes
and sinusoidal endothelial cells (that normally are
fenestrated).

Normally, hepatic stellate cells are quiescent and
serve as the main storage site for retinoids (vitamin
A).
PATHOGENESIS OF LIVER FIBROSIS
Normal Hepatic SInusoid
Retinoid
droplets
Fenestrae
Hepatic
stellate cell
Space of Disse
Sinusoidal
endothelial cell
Hepatocytes
PATHOGENESIS OF LIVER FIBROSIS
 Activation of Stellate cells
Loss of Vitamin A
Proliferation
Development of Rough ER and
secretion of Extracellular Matrix
Matrix Deposition in Space of
Disse
Futhermore Stellate Cells
express smooth muscle proteins
and become contractile—Hepatic
Myofibroblasts
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
Disease-Specific Mechanisms

Hepatitis C Virus
◦ Stellate cells directly infectable by virus
 Express HCV receptors
 Adenovirus transduction of non-structural and core proteins
induces stellate cell proliferation and release of inflammatory
signals
◦ Lymphocyte recruitment
◦ HCV proteins interact directly with sinusoidal
endothelium

NASH
◦ Leptin, adipogenic hormone proportionate to adipose
mass in circulating blood activates stellate cells
◦ Downregulation of adiponectin, counterregulatory
hormone amplifies fibrogenic activity of leptin
 Mice lacking adiponectin have enhanced fibrosis following toxic
liver injury
Reversibility of Fibrosis/Cirrhosis

Elimination of underlying cause critical

Other factors:
◦ Period of established cirrhosis
 Longer periods of crosslinked collagen, less sensitive to
degradative enzymes?
◦ Total content of collagen and other scar molecules
 Large mass of scar may be inaccessible to degradative
enzymes
◦ Reduced expression of enzymes that degrade matrix,
and prevention of apoptosis of activated stellate cells
COMPLICATIONS OF CIRRHOSIS
Complications of Cirrhosis Result from Portal
Hypertension or Liver Insufficiency
Portal hypertension
Cirrhosis
Variceal hemorrhage
Ascites
Spontaneous
bacterial
peritonitis
Hepatorenal
syndrome
Liver insufficiency
Encephalopathy
Jaundice
NATURAL HISTORY OF CIRRHOSIS
Development of Complications in
Compensated Cirrhosis
100
80
Ascites
Jaundice
Encephalopathy
GI hemorrhage
Probability of 60
developing
event
40
20
0
0
20
40
60
80
100
Months
Gines et. al., Hepatology 1987; 7:122
120
140
160
SURVIVAL TIMES IN CIRRHOSIS
Decompensation Shortens Survival
100
80
Median survival
~ 9 years
All patients with
cirrhosis
60
Probability of
survival
40
20
Decompensated cirrhosis
Median survival
~ 1.6 years
0
0
20
40
60
80
100
Months
Gines et. al., Hepatology 1987;7:122
120
140
160
180
Cirrhosis - Diagnosis
 Cirrhosis is a histological diagnosis
 However, in patients with chronic liver
disease the presence of various
clinical features suggests cirrhosis
 The presence of these clinical features
can be followed by non-invasive
testing, prior to liver biopsy
In Whom Should We Suspect
Cirrhosis?
 Any patient with chronic liver disease
 Chronic abnormal aminotransferases and/or
alkaline phosphatase
 Physical exam findings
 Stigmata of chronic liver disease (muscle
wasting, vascular spiders, palmar erythema)
 Palpable left lobe of the liver
 Small liver span
 Splenomegaly
 Signs of decompensation (jaundice, ascites,
asterixis)
In Whom Should We Suspect
Cirrhosis?
Laboratory
 Liver insufficiency
 Low albumin (< 3.8 g/dL)
 Prolonged prothrombin time (INR > 1.3)
 High bilirubin (> 1.5 mg/dL)
 Portal hypertension
 Low platelet count (< 175 x1000/ml)
 AST / ALT ratio > 1
In Whom Should We Suspect
Cirrhosis?
Imaging studies
 Liver-spleen scan
 Small liver, irregular uptake
 Splenomegaly
 Colloid shift to bone marrow
 CAT scan / Ultrasound
 Nodular liver
 Splenomegaly
 Venous collaterals
DIAGNOSIS OF CIRRHOSIS – LIVER-SPLEEN SCAN
Liver-Spleen Scan
Colloid shift to
bone marrow and ribs
Normal
Cirrhosis
Small liver,
irregular uptake
Splenomegaly
DIAGNOSIS OF CIRRHOSIS – CAT SCAN
CAT Scan in Cirrhosis
Liver with an irregular surface
Collaterals
Splenomegaly
Confirmatory Liver Biopsy Is Not
Always Necessary in Cirrhosis

Liver biopsy is not necessary in the
presence of any of the following:
◦ Decompensated cirrhosis (variceal
hemorrhage, ascites, encephalopathy)
◦ Liver-spleen and/or CAT scan diagnostic
of cirrhosis
◦ Liver biopsy is not necessary for pretransplant evaluation
Case KL – CASE PRESENTATION
Case KL
Case Presentation
• A 55-year-old asymptomatic Caucasian
man is referred to hepatology clinic for
evaluation of chronic elevation of
aminotransferases.
• He has no significant medical problems,
takes no medications and denies a family
history of liver disease.
Case KL – PHYSICAL EXAM
Case KL
Physical Exam
• He is generally healthy appearing.
• There are no stigmata of chronic liver
disease including:
• No jaundice
• No vascular spiders or palmar
erythema
• A non-palpable liver and spleen.
Case KL – LAB RESULTS
Case KL
Laboratory Results
Bilirubin
mg/dL
1.2
AST
80 U/L
ALT
94 U/L
Albumin
4.0 g/dL
PT
12 sec
WBC
Hgb
Platelets
Anti-HCV
HBsAg
4.0 x1000/uL
17 g/dL
175 x1000/uL
positive
negative
Case KL – DIAGNOSTIC STUDIES
Case KL
Diagnostic Studies
 Abdominal ultrasound:
 mildly increased hepatic
echogenicity
 mild splenomegaly
 Liver-spleen scan
 increased uptake in spleen
 no colloid shift to bone marrow
Case KL – QUESTION
Case KL
 Does this patient have cirrhosis?
Maybe
 Does this patient need a liver
biopsy?
Liver biopsy is necessary to
confirm/rule out cirrhosis
Case DW – CASE PRESENTATION
Case DW
A 55 year-old, previously healthy man,
complains of fatigue for several months.
He denies excessive alcohol use, but admits
to using IV drugs when he was a teenager.
Case DW – PHYSICAL EXAM
Case DW
Physical Exam
Exam shows vascular spiders on his back.
Abdominal exam reveals a firm liver edge,
and an easily palpated left lobe, 2 cm
below the xyphoid.
The spleen tip is palpable.
There is no shifting dullness on abdominal
percussion.
Case DW – LAB RESULTS
Case DW
Laboratory Results
Bilirubin
1.1 mg/dL
AST
110 U/L
ALT
Albumin
WBC
x1000/uL
4.0
Hgb
12 g/dL
Platelets
95 x1000/uL
92 U/L
3.5 g/dL
Anti-HCV positive
PT
12.5 sec
HBsAg
negative
Case DW – DIAGNOSTIC STUDIES
Case DW
Diagnostic Studies
 Abdominal ultrasound:
 Echogenic, heterogeneous liver
parenchyma
 Enlarged caudate lobe
 Enlarged spleen (15.5 cm)
 Liver-spleen scan:
 Colloid shift to bone marrow
 Increased uptake by spleen
Case DW – QUESTIONS
Case DW
 Does this patient have cirrhosis?
Yes
 Does this patient need a liver
biopsy?
Liver biopsy is NOT necessary to
establish the diagnosis of cirrhosis
Portal Hypertension
Hepatic Blood Flow
Portal Hypertension
Portal Blood Flow
Cirrhotic
Liver
Systemic Blood Flow
Portal Hypertension

Defined by pathological increase in portal venous
pressure

Complications arise when portal pressure gradient
exceed 10-12 mm Hg (normal <6 mm Hg)

Cirrhosis is the most common cause of portal
hypertension

The site of increased resistance in cirrhosis is
sinusoidal

Cirrhosis is the most common cause of portal
hypertension
Portal Hypertension
Cirrhotic liver
Architectural disturbances
(fibrosis, scarring, vascular thrombosis, etc.)
Functional alterations
(contraction of vascular smooth muscle and stellate cells)
Increased hepatic resistance
Portal hypertension
Collaterals and PSS
Increased portal
blood inflow
Splanchnic vasodilatation
Effective hypovolemia
Activation of endogenous
vasoactive systems
Na retention
Hypervolemia
Increased cardiac index
Increased Intrahepatic Resistance
1.
◦
◦
2.
Architectural distortion of the liver
Fibrous tissue and regenerative nodules
Thrombosis of portal and hepatic veins
Dynamic reversible contractile elements
Normal Liver
Hepatic
vein
Sinusoid
Liver
Portal
vein
Coronary
vein
Splenic
vein
Cirrhotic Liver
Portal
systemic
collaterals
Distorted
sinusoidal
architecture
leads to
increased
resistance
Portal
vein
Splenomegaly
Increased Intrahepatic Resistance
1.
Architectural distortion of the liver
2.
Dynamic reversible contractile elements
◦
◦
40% of increased intrahepatic vascular resistance
Involves:




Vascular smooth muscle cells
Activated hepatic stellate cells that contract around sinusoids
reducing caliber
Hepatic myofibroblasts that compress cirrhotic nodules
Vasoactive mediators that modulate intrahepatic resistance
Increased Intrahepatic Resistance
Vasoconstrictors
Endothelin
Angiotensin
Norepinephrine
Vasopressin
Leukotrienes
Thromboxane
Others?
Vasodilators
Nitric Oxide
Carbon Monoxide
Others?
◦ Increased production of vasoconstrictors with exaggerated response by
hepatic vascular bed
◦ Insufficient release of vasodilators and insufficient response by hepatic
vascular bed
Variceal Hemorrhage
PREVALENCE OF ESOPHAGEAL VARICES IN CIRRHOSIS
Prevalence of Esophageal Varices in
Cirrhosis
100
80
60
%
40
20
0
Overall
Child A
Child B
Child C
Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72
LOWEST REBLEEDING RATES ARE OBTAINED IN HVPG RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL BAND LIGATION +
BETA-BLOCKERS
Lowest Rebleeding Rates are Obtained in
HVPG Responders and With Ligation + Blockers
80
60
%
40
Rebleeding
20
0
Sclero-  -blockers Ligation
HVPGLigation
blockers therapy + ISMN
Responder
+
s*
-blockers
(19 trials)(26 trials) (54 trials) (6 trials) (18 trials) (6 trials) (2 trials)
Untreated
*  HVPG <12 mmHg
Bosch and García-Pagán, Lancet 2003; 361:952
or >20% from
baseline
Ascites
Ascites

Most common cause of decompensation
in patients with cirrhosis

Occurs at rate of 7-10% per year

5% of patients with ascites can develop
right sided pleural effusions—hepatic
hydrothorax
◦ Develops through diaphragmatic defects
Ascites

Diagnosis
◦ Physical Exam
◦ Ultrasonography
◦ Diagnostic Paracentesis
ASCITES CAN BE CHARACTERIZED BY SERUM-ASCITES ALBUMIN GRADIENT (SAAG) AND ASCITES PROTEIN
Ascites Can Be Characterized by SerumAscites Albumin Gradient (SAAG) and Ascites
Protein
Source
of
ascites
Hepatic sinusoids
SAAG > 1.1
“Capillarized” sinusoid
Ascites protein < 2.5
Sinusoidal
hypertension
-Cirrhosis
-Late Budd-Chiari
Peritoneum
SAAG < 1.1
Normal “leaky” sinusoid
Ascites protein > 2.5
Peritoneal lymph
Ascites protein > 2.5
Post-sinusoidal
hypertension
- Cardiac ascites
- Early Budd-Chiari
- Veno-occlusive disease
Peritoneal pathology
- Malignancy
- Tuberculosis
Ascites: Management


Sodium restriction—2 grams daily
Oral diuretics
◦ Spironolactone (more effective than loop
diuretics)
 Started at dose of 50-100 mg/daily
 Adjust 13-4 days to maximal effective dose of 400
mg/day
◦ Furosemide can be added as well
 5:2 ratio

Fluid restriction not required unless there is
hyponatremia—Na<130
Ascites: Management

Weight loss goal
◦ 1 kg in first week
◦ 2 kg/wk subsequently

Excessive loss of weight (>1 lb./day)
◦ Can lead to intravascular depletion
◦ Can lead to Pre-Renal Kidney Injury

Avoid ASA and NSAIDs
◦ Can reduce diuretic induced natriuresis
◦ May precipitate Renal Failure
Ascites: Management

Large Volume Paracentesis (LVP)
◦ For patients with tense ascites
◦ Albumin is to be given at rate of 6-8
gram/liter, particularly with removal of >5
liters

10% of patients with cirrhosis and ascites
may become diuretic resistant
◦ Recurrent LVP plus albumin
◦ TIPS
 Encephalopathy
Spontaneous Bacterial
Peritonitis
Spontaneous Bacterial Peritonitis

The most life-threatening complication of ascites

~1/3 of hospitalized patients with cirrhosis are
diagnosed as having a bacterial infection—most
common is SBP

All Patients with cirrhosis and ascites who are
hospitalized emergently should undergo a
diagnostic paracentesis

Diagnosis is established with ascitic fluid
neutrophil count greater than 250/mm3

Bacteria are isolated in only 40-50% of casees
Spontaneous Bacterial Peritonitis

Once diagnosis established
◦ Empiric antibiotic therapy with IV 3rd generation
cephalosporin
◦ Success rates for 3rd generation cephalosporins have
been as low as 40% in nosocomial SBP
◦ In this case use Pip/Tazo or a Carbapenem

Avoid Aminoglycosides—High Incidence of Renal
Toxicity in Patients with Cirrhosis

For prevention of progressive renal dysfunction
administer albumin
◦ 1.5 g/kg day 1 and 1g/kg on day 3
Spontaneous Bacterial Peritonitis
~70% Risk of Recurrence
 Prophylactic Antibiotic

◦ Recommended Antibiotic is Norfloxacin 400
mg daily

Per UpToDate:
◦ In settings where norfloxacin is unavailable
 Ciprofloxacin 500 mg daily
 Trimethoprim-Sulfamethoxazole one double
strength tablet daily
NORFLOXACIN REDUCES RECURRENCE OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)
Norfloxacin Reduces Recurrence of
Spontaneous Bacterial Peritonitis
SBP caused by gramnegative bacteria
All SBPs
1.0
.8
Placebo
Probability
of SBP
.6
recurrence
Placebo
p=0.0063
.4
p=0.0013
Norfloxacin
.2
Norfloxacin
0
0
4
8
12
Months
Gines et al., Hepatology 1990; 12:716
16
20 0
4
8
12
Months
16
20
Hepatic Encephalopathy
Hepatic Encephalopathy

Reversible syndrome caused by astrocyte
swelling

Ammonia and other toxins play key role
in pathogenesis

Ammonia accumulates due to shunting of
blood through portosystemic collaterals
and decreased liver metabolism
Hepatic Encephalopathy

HE associated with cirrhosis is of gradual onset and rarely
fatal

Distinguished from encephalopathy from acute liver failure
and portosystemic bypass in absence of cirrhosis

Stage 1: Forgetfulness and Inversion of Sleep/Wake Pattern

Stage 2: Confusion, Bizarre behavior and Disorientation

Stage 3: Lethargy and Profound Disorientation

Stage 4: Coma
Hepatic Encephalopathy

On Exam
◦ Asterixis
◦ Fetor Hepaticus (sweet smelling odor to
breath)

Diagnosis
◦ Made Clinically
◦ Serum Ammonia levels are
unreliable/correlate poorly with stage
◦ Number connection test and EEG are used in
research but not routinely in clinical setting
POOR CORRELATION OF AMMONIA LEVELS WITH PRESENCE OR SEVERITY OF HEPATIC ENCEPHALOPATHY
Poor Correlation of Ammonia Levels With
Presence or Severity of Encephalopathy
400
350
300
250
Venous
total
200
ammonia
mmol/L 150
100
50
0
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Severity of Hepatic Encephalopathy
Ong et al., Am J Med 2003; 114:188
Hepatic Encephalopathy

Mainstay of therapy is identification and
treatment of precipitating factors
◦
◦
◦
◦
◦
◦
◦
◦
Dehydration
Infections
Overdiuresis
GI bleeding
High Oral Protein Load
Constipation
Use of Narcotics
TIPS
Hepatic Encephalopathy

Treatment:
◦ Lactulose and Rifaxamin
◦ Consider change in dietary protein from
animal to vegetable source
◦ Strict protein restriction is not necessary and
is discouraged long-term
Hepatocellular Carcinoma
Hepatocellular Carcinoma

HCC can occur in both compensated and
decompensated cirrhotics and can be the event that
leads to decompensation

5th most common cause of cancer worldwide

3rd most common cause of cancer related mortality
worldwide

In the United States there ahs been a twofold
increase in assess of HCC over the past two decades
◦ Relates to the increase in prevalence of chronic hepatitis
C
Hepatocellular Carcinoma

Entertains in patients with compensated
cirrhosis who:
◦ Suddenly decompensate
◦ Develop Portal Vein Thrombosis

Diagnosis
◦ Dynamic Radiologic Imaging (CT or MRI with
contrast)
◦ Elevated AFP may support diagnosis
◦ In some instances liver biopsy may be needed to
conform
Figure 1 Algorithm for staging and treating patients diagnosed as having hepatocellular
carcinoma
Cabibbo G et al. (2009) Multimodal approaches to the treatment of hepatocellular carcinoma
Nat Clin Pract Gastroenterol Hepatol doi:10.1038/ncpgasthep1357
Conclusion

Cirrhosis is the result of a common pathway from numerous
causes of liver inflammation

Decompensated cirrhosis carries a significant mortality and
complications should be closely monitored in the inpatient
and outpatient setting

Ascites should always be sampled with emergent
hospitalization

Hepatic Encephalopathy severity does not directly correlate
with ammonia level and should prompt evaluation of inciting
cause

Patients with HCC should undergo timely evaluation and
triage into the appropriate management arm so as to
maximize survival potential
References

Bosch J, D’Amico G, Garcia-Pagan JC. Portal Hypertension and Nonsurgical Management. In:
Schiff ER, Sorrell MF, Maddrey WC, editors. Tenth edition. Schiff’s Diseases of the Liver, Vol. 1.
Philadelphia: Lippincott Williams & Wilkins; p. 419-483

Friedman SL. Hepatic fibrosis. In: Schiff ER, Sorrell MF, Maddrey WC, editors. Tenth edition. Schiff’s
Diseases of the Liver, Vol. 1. Philadelphia: Lippincott Williams & Wilkins; p. 395-418

Friedman SL. Pathogenesis of hepatic fibrosis. Up-to-Date. May 2010.

Rockey DC, Friedman SL(2006). Hepatic fibrosis and cirrhosis. In: Boyer TD, Wright TL, Manns
MP, editors. 5th edition. Zakim and Boyer’s hepatology, vol.1. New York: Elsevier;. p. 87–109.

Rodriguez-Vilarrupla et al (2007). Current concepts on the pathophysiology of portal
hypertension. Annals of Hepatology; 6(1): Jan-March: 28-36.

Vorobioff J; Bredfeldt JE; Groszmann RJ. Increased blood flow through the portal system in
cirrhotic rats. Gastroenterology 1984 Nov;87(5):1120-6.