Portal Hypertension John F. Reinus, M.D. · Esophagus Liver Coronary v. 19 Spleen Splenic vein Kidney Left renal vein Inferior vena cava Superior mesenteric vein Inferior mesenteric

Portal HypertensionJohn F. Reinus, M.D.

The screen versions of these slides have full details of copyright and acknowledgements 1

Portal Hypertension

John F. Reinus, M.D.Chief of Clinical Hepatology

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Chief of Clinical HepatologyMontefiore Medical Center

Professor of Clinical MedicineThe Albert Einstein College of Medicine

Thesis

• Portal hypertension causes multiple regional circulatory derangements that result in extra- and intra-vascular volume overload

d d f ti

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and organ dysfunction

• Vascular smooth muscle tension locally controlled by chemical mediators, autonomic innervation

Regional circulatory regulation

A t i

Cerebral cortex

Mechanoreceptors

3

Autonomicinput

Osmoreceptors

Chemoreceptors

Thermoreceptors

Endothelialrelease

NO

COProstacyclin

Endothelin



• The liver is a metabolically active filter

Normal liver function

4

When the liver is sick

Ac te hepatitis

Metabolicdysfunction

X

Portalhypertension

O

5

Acute hepatitis

Chronic hepatitis

Liver failure

X

O

X

O

X

X

Normal liver

6



Cirrhotic liver

7

Portal pressure

P = Q x R

P ≡ Pressure

P = Q x R

8

P ≡ Pressure

Q ≡ Blood flow

R ≡ Resistance

• Flow is determined by venous return from splanchnic organs

• Not effectively limited by changes in portal venous pressure

Portal pressure (2)

P = Q x R

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• Resistance (R) is proportional to 1/r4

(where r is the vascular radius)

• Normal portal vessels are highly compliant because of shear-induced eNOS upregulation



Cirrhosis and portal pressure

P ∝Q/r4

10

• Decreased vascular radius (r)

• Decreased vascular compliance

Increasedportal

pressure

Q/

• Reflex SMA vasoconstriction causes intestinal hypoxia, VEGF and eNOS upregulation

P i h i d i

Initial circulatory effects of portal hypertension

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• Portosystemic shunting causes endotoxemia, iNOS upregulation

Effects of portal hypertension on regional circulations: gut and kidney

VasodilationPortal

hypertension

12

Increased intra-vascularvolume and flow

Renal salt and waterretention

Decreased “effective”plasma volume



Ve ≡ Vp/C

a (normal)

Effective plasma volume

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Vea >Veb

b (portal hypertension)

Effects on renal circulation

Renin

Blood pressure

Epinephrine secretion

Water retentionADH secretion

Sympatheticstimulation

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(kidney)

Angiotensinogen(liver) Angiotensin I Angiotensin II

ACE(lungs) Aldosterone secretion

Vasoconstriction

Na+ retention

The arteriolar vasodilation hypothesis of volume expansion in cirrhosis

VasodilationPortal

hypertension

15

Increased intra-vascularvolume and flow

Renal salt and water retention

Decreased “Effective”Plasma Volume



Cirrhosis and portal pressure

P ∝Q/r4

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• Decreased vascular radius (r)

• Decreased vascular compliance

• Increased portal blood flow

Increasedportal

pressure

The cardiac output at rest in Laennec’s cirrhosisHenry J Kowalski and Walter H. Abelmann, J Clin Invest 1953; 32: 1025-1033

DiagnosisSubjects

(n)Mean CI

(L/min x m2)Mean PVR*

(dynes x sec x cm-5)

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* Normal ranges: CI = 2.6-4.2 L/min x m2; PVR = 900-1200 dynes x sec x cm-5

Fatty Liver

Cirrhosis only

Cirrhosis + ascites

3

11

8

4.76

4.27

5.34

1047

1077

752

The cardiac output at rest in Laennec’s cirrhosis (2)Henry J Kowalski and Walter H. Abelmann, J Clin Invest 1953; 32: 1025-1033

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“The hyperdynamic circulation”

• Increased cardiac output

• Decreased arterial pressure



Shunting of portal blood flow

Esophagus

LiverCoronary v.

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Spleen

Splenic vein

Kidney

Left renal veinInferior vena cava

Superior mesenteric

vein

Inferior mesenteric

vein

Portal vein

Esophageal varices

• Varices develop in 8% of cirrhotics per year (HPVG > 10mm Hg)

• Bleeding in 5-15% of patients with varices per year

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with varices per year

CPT class E. varices G. varices

A 40% ?C 85% ?

A-C 50% 5-33%

Ascites (liver sweat)

• SOB

• Pain

• Infection (SBP)

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Infection (SBP)

• Umbilical hernia

• Flood syndrome



Vp/CNormal

P l

Renal function and decreasedeffective plasma volume (v/c)

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Renal function

Oliguria

PrerenalAzotemia

Diuresis

Mortality after decompensation

• Variceal bleeding: 20% six-week mortality

• Ascites: 50% two-year mortality

• SBP: 30% in-hospital mortality

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• HRS-I: 80% two-week mortality

Hepatic vein

TIPS procedure

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Portal vein



Shunting of portal blood flow

ShuntCoronary v.

Esophagus

Liver

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Portal veinSuperior

mesenteric vein

Inferiormesenteric

veinInferior vena cava

Left renal vein

Kidney

Splenic vein

Spleen

MELD score as a predictor of early death in patients undergoing elective TIPS procedures

Montgomery A, Ferral H, Vasan R, Postoak DW

Cardiovasc Intervent Radiol 2005; 28: 307-312

MELD = 10 {0.957 Ln(Cr) + 0.378 Ln(Bilirubin) + 1.12 Ln(INR) + 0.643}

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MELD as a predictor of 30-day mortality after elective TIPS in 119 patients (death rate = 10.9%)

MELD score TIPS survivors Early mortality1-10 (n=27) 26 1 (4%)11-17 (n=63) 58 5 (8%)18-24 (n=24) 20 4 (17%)>24 (n=5) 2 3 (60%)

Patient Pre-TIPS MELD Cause of death Survival (days)1 13 Sepsis 5

Table 2: Causes of death

MELD score as a predictor of early death in patients undergoing elective TIPS procedures (2)

Montgomery A, Ferral H, Vasan R, Postoak DW,

Cardiovasc Intervent Radiol 2005; 28: 307-312

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p2 29 Multiorgan failure 53 17 Liver failure 74 22 Unknown 275 24 Liver failure 106 11 Unknown 247 34 Multiorgan failure 28 13 Liver failure 169 8 Liver failure 11



Cardiac hemodynamics in alcoholic patients with chronic liver disease and a presystolic gallop

Gould L, Shariff M, Zahir M, Di Lieto M, J Clin Invest 1969; 48: 860-868

• 10 male cirrhotic patients, ages 41-58 years

• Cardiac catheterization to measure pressures

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to measure pressures, cardiac output at rest and with exercise

• MPAPs, LVEDPs rose while stroke index remained the same or fell

• Conclude that heart demonstratesblunted response to stress

Cirrhotic cardiomyopathy

• Contractile, electrophysiological, chamber-structure abnormalities

Cli i l i t i ti l

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• Clinical signs, symptoms require stimulus

• May contribute to HRS, complications post-TIPS and OLT

gAMP InhibitionCholinergicreceptor Gi protein+

PVR = X 80MPAP - PAOP

CO

PVR ≡ Pulmonary vascular resistance (<240 dynes x sec x cm-5)

MPAP Mean pulmonary artery pressure (15mm Hg)

Pulmonary hypertension

218 = X 8038 - 14

8.8218 = X 80

38 - 148.8

218 = X 8038 - 14

8.8

Volume overload

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MPAP ≡ Mean pulmonary artery pressure (15mm Hg)

PAOP ≡ Pulmonary artery occlusion pressure (8-10mm Hg)

CO ≡ Cardiac output (5-8 L/min)

MPAPMild hypertension

25-35mm hgModerate hypertension

35-50mm hgSevere hypertension

>50mm hg



Portopulmonary hypertension

• Elevated mean pulmonary artery pressure secondary to increased pulmonary vascular resistance in patients with portal hypertension with or without liver disease

MPAP 25 H t t

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– MPAP > 25mm Hg at rest

– PVR > 240 dynes x sec x cm-5

– Absence of significant volume overload

Portopulmonary hypertension (2)

• Intimal hyperplasia

• Smooth muscle hypertrophy

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• Thrombosis

• Plexiform lesions

Portopulmonary hypertension (3)

• 0.25-4.0% of patients with cirrhosis

• 16.1% of patients with refractory ascites

• Severity of portal hypertension does not correlate with severity of pulmonary hypertension

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with severity of pulmonary hypertension

• Caused by imbalance of mediators favoring constriction, leading to endothelial injury (endothelial dysfunction)

• Doppler echocardiography detects moderate to severe disease with 97% sensitivity, 77% specificity



Hepatopulmonary syndrome

• Widened age-corrected alveolar-arteriolar O2 gradient on room air in patients with liver disease with or without portal hypertension

– 50-70% of patients with chronic liver disease

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complain of shortness of breath

– 50% of OLT candidates have HPS

– 15-30% of HPS patients have hypoxemia

– No connection with severity of liver disease

Hepatopulmonary syndrome (2)

NO

ET-1(liver)

eNOSupregulation

ETR-B(lung)

Macrophage iNOS (lung)

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Angiogenesis

Dilation of pre-capillary arterioles

CO

( g)

Macrophage HO-1 (lung)

Macrophages(lung)

VEGF-AAngiotensin II

Initiation by shear forces and changes

in blood pressure

Hepatopulmonary syndrome (3)

• 60% of cirrhotics have HPS by saline-contrast TTE

• SpO2 ≤ 95% reliably detects patients with HPS and PaO2< 70mm Hg, 100% sensitivity, 88% specificity

I t ft li t l t i > 85%

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• Improvement after liver transplant in > 85%

PaO2

Mild HPS≥ 80mm Hg

Moderate HPS≥ 60 < 80mm Hg

Severe HPS< 60mm Hg



Consequences of portal hypertension

Vasodilation

Renal salt, t t ti

Secondarypulmonary

hypertension

Ascites

Cardiomyopathy

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Hyperdynamiccirculation

water retention

Renal failure

Portopulmonaryhypertension

Varices

Hepatopulmonarysyndrome

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Portal Hypertension

John F. Reinus, M.D.

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Chief of Clinical HepatologyMontefiore Medical Center

Professor of Clinical Medicine The Albert Einstein College of Medicine



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Portal Hypertension John F. Reinus, M.D. · Esophagus Liver Coronary v. 19 Spleen Splenic vein Kidney Left renal vein Inferior vena cava Superior mesenteric vein Inferior mesenteric