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Managing Complications of Cirrhosis

Robert S. Brown, Jr., MD, MPHGladys and Roland Harriman Professor of Medicine

Clinical Chief, Gastroenterology and HepatologyWeill Cornell Medicine

Cirrhosis

Term introduced by René Laennec in 1826

Late stage of hepatic fibrosis, generally irreversible in advanced form

Results from any chronic liver disease

Responsible for 26,000 deaths in the US annually

Liver transplantation is curative in selected patients

Causes of Cirrhosis Hepatocellular Causes

• Viral Hepatitis: HBV(and HDV), HCV• Alcoholic Liver Disease• Nonalcoholic Steatohepatitis (NASH)• Autoimmune Hepatitis• Genetic Disorders: Alpha 1-AT Deficiency, Wilson’s

Disease, Hereditary Hemochromatosis• Drugs and Toxins• Right-sided Heart Failure

Cholestatic Causes• Primary Sclerosing Cholangitis• Primary Biliary Cirrhosis• Chronic Biliary Obstruction

Complications of Cirrhosis

Synthetic Dysfunction

? ?

Ascites

Encephalopathy

HCC

Variceal bleed

HRS

HPS/PPHTN

Normal Vascular Anatomy

Hepatic vein

Hepatic vein

SinusoidSinusoid

Portal vein

Portal vein

Hepatic arteryHepatic artery

LiverLiver

Splenic veinSplenic vein

Coronary veinCoronary vein

Inferiorvena cava

Inferiorvena cava

Inferior mesenteric veinInferior mesenteric vein

Superiormesenteric

vein

Superiormesenteric

vein

NORMAL VASCULAR ANATOMY OF THE LIVER

Portal systemic collaterals

Portal systemic collaterals

Distorted sinusoidal architectureleads to increased resistance

Distorted sinusoidal architectureleads to increased resistance

Portal vein

Portal vein

SplenomegalySplenomegaly

Sinusoidal Portal Hypertension

Cirrhotic Liver

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Portal Hypertension: ClassificationType Examples

• Prehepatic Portal or splenic vein thrombosis

Presinusoidal Schistosomiasis

• Intrahepatic Sinusoidal Cirrhosis

Postsinusoidal Veno-occlusive disease

• Posthepatic Hepatic vein thrombosis

Constrictive pericarditis

Portal HTN: Pressure Measurements

Portal Venous Pressure (PVP)

Normal = 3-5 mm Hg

Hepatic Venous Pressure Gradient (HVPG)

= approximated portal venous pressure (hepatic wedged venous pressure) - hepatic venous pressure

Normal = 1-5 mm Hg

> 10 associated with complications

Decompensated Cirrhosis Complications

• Ascites SBP, Hepatic hydrothorax

• Variceal bleeding• Encephalopathy• Hepatorenal Syndrome• Hepatopulmonary

Syndrome• Portopulmonary HTN

High Mortality• CTP B 20% 1 yr• CTP C 55% 1 yr

Child-Turcotte-Pugh Classification

1 2 3

Albumin (g/dl) >3.5 2.8-3.5 <2.8

Total bilirubin (mg/dl) <2 2-3 >3

Prothrombin time (INR) <1.7 1.7-2.3 >2.3

Ascites None Medically Uncontrolled

controlled

Encephalopathy (grade) 0 I-II III-IV

Class: A = 5-6 points, B = 7-9 points, C = 10-15 points

Ascites

Ascites in Cirrhosis Consequence of sinusoidal portal HTN Requires HVPG > 10-12 mmHg for formation* Multiple abnormalities in the cirrhotic with portal HTN

contribute to ascites formation:Circulatory Vascular Functional BiochemicalReduced systemicvascular resistance

Splanchnicvasodilation

Activation of systemic vasodilator factors

Sodium retention

Reduced meanarterial pressure

Renal artery vasoconstriction

Activation of systemic vasoconstrictor factors

Increased systemic nitric oxide

Increased heart rate Pulmonary vasodilation

Activation of renal vasodilator factors

Increased systemic prostaglandins

Increased cardiacindex

Reduced GFR Increased renal nitricoxide and prostaglandins

Increased plasma volume

Reduced renal blood flow

Increased portal blood flow

*Morali GA, et al. J Hepatol 1992;16(1-2):249

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Ascites in Cirrhosis Most common cause of decompensation in cirrhosis

• 7-10% per year

5% with ascites can develop hepatic hydrothorax• Passage of ascites through diaphragmatic defects

Sponatneous Bacterial Peritonitis is most life threatening complication

Diagnosis• Ultrasound- safe and cheap• Diagnostic Paracentesis

All cirrhotics with new onset ascites! Calculate the SAAG =

Serum albumin – ascites albumin SAAG ≥ 1.1

Serum-Ascites Albumin Gradient(SAAG = serum albumin - ascitic albumin)

High (>1.1 g/dL)Due to Portal Hypertension

Cirrhosis Alcoholic hepatitis Cardiac disease Massive liver metastases Hepatic outflow

obstruction Portal vein thrombosis

Low (<1.1 g/dL)NOT due to Portal

Hypertension

Peritoneal carcinomatosis Tuberculous peritonitis Pancreatic duct leak Biliary leak Nephrotic syndrome Serositis

Ascites: Abdominal Paracentesis

Umbilical hernia

Tense ascites

Hepatic hydrothorax

Complications of Ascites

Infection

Spontaneous Bacterial Peritonitis (SBP)

Infection of the ascitic fluid due to:• bacterial translocation from gut• bacteremia

Risk factors:• serum bilirubin• prothrombin time• ascitic fluid protein level <1.5 g/dL

Infection of the ascitic fluid due to:• bacterial translocation from gut• bacteremia

Risk factors:• serum bilirubin• prothrombin time• ascitic fluid protein level <1.5 g/dL

SBP: Clinical Presentation

Asymptomatic – up to 1/3 of cases Fever Abdominal pain Encephalopathy Renal failure

Diagnosis: ascitic fluid PMN ≥ 250 /mm3

± culture of single organism

Asymptomatic – up to 1/3 of cases Fever Abdominal pain Encephalopathy Renal failure

Diagnosis: ascitic fluid PMN ≥ 250 /mm3

± culture of single organism

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Refractory Ascites

Abstinence if Alcoholic liver disease 2g Na-limited diet

NOT fluid restriction Oral diuretics

Furosemide Spironolactone

Amiloride if gynecomastia Tense ascites

Large Volume Paracentesis 25% albumin 8g/L removed

Spontaneous Bacterial Peritonitis

Ascites PMNs ≥ 250 cells/mm^3 Absence of surgical cause

Often culture negative Treatment

Cefotaxime Covers 95% flora inc. E. Coli, Klebs, Strep

Pneumo Albumin 25%

1.5 g/kg Day 0 and 1 g/kg Day 3 Decrease mortality 29% to 10%*

*Sort P, et al. N Engl J Med 1999;341(6):403-9

Variceal Bleeding

Varices When HVPG > 10 mm Hg, mostly > 12

Increased resistance to flow Hepatic fibrosis Intrahepatic vasoconstriction

And increase in portal blood flow Splanchnic vasodilatation

Prevalence correlates with severity liver disease 40% CTP A 85% CTP C

Variceal hemorrhage occurs 5-10% yearly Predictors of bleeding

SIZE OF VARICES Decompensated cirrhosis (CTP B or C) Presence of red wale signs

Small varicesSmall varices Large varicesLarge varicesNo varicesNo varices

7-8%/year7-8%/year 7-8%/year7-8%/year

Varices Increase in Diameter ProgressivelyVarices Increase in Diameter Progressively

Merli et al. J Hepatol 2003;38:266Merli et al. J Hepatol 2003;38:266

VARICES INCREASE IN DIAMETER PROGRESSIVELY

Tension (T)Tension (T)

Wall thickness

(w)

Wall thickness

(w)

Groszmann, Gastroenterology 1984; 80:1611Groszmann, Gastroenterology 1984; 80:1611

T = tp x T = tp x rwrw

Laplace’s LawLaplace’s Law

Transmural pressure (tp)

Transmural pressure (tp)

Radius (r)Radius (r)

EsophagusEsophagus

VarixVarix

VARICEAL WALL TENSION IS A MAJOR DETERMINANT OF VARICEAL RUPTURE

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Variceal bleeding - Treatment

Hemodynamic• Volume resuscitation (PRBCs)• Correct coagulopathy

Pharmacologic• Antibiotics

High rate of infection Reduction in rebleeding Mortality benefit

• Octreotide (somatostatinanalogue) Reduction in portal pressure Reduction in rebleeding rates

Endoscopic• Esophageal band ligation

Variceal Bleeding - Treatment

Prevention of rebleeding• Repeat band ligation until eradication of

varices• Non-selective beta blocker

i.e. Nadolol or Propanolol Reduction in cardiac output (anti- 1 effect) Reduction in portal pressure through

antagonism of endogenous 2 activity in splanchnic circulation

Hepatic Encephalopathy

Hepatic Encephalopathy

Reversible neuropsychiatric syndrome in advanced liver disease

Symptoms range from mild cognitive impairment to coma

Pathogenesis• Nitrogen compounds like ammonia

generated by gut bacteria not cleared by hepatocytes

• Ammonia crosses BBB, absorbed and metabolized by astrocytes->more glutamine production->swelling and increased osmotic pressure

• Also production of BZD-like compounds and increased GABA neurotransmission

Hazell AS, et al. Exp Biol Med 1999;222:103

Hepatic Encephalopathy PathogenesisHepatic Encephalopathy Pathogenesis

Bacterial actionProtein loadBacterial actionProtein load

Failure to metabolize NH3

Failure to metabolize NH3

NH3 ShuntingNH3 Shunting

GABA-BD receptorsGABA-BD receptors

ToxinsToxins

PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY

STAGES OF HEPATIC ENCEPHALOPATHY

ConfusionConfusion

DrowsinessDrowsiness

SomnolenceSomnolence

ComaComa

11 22 33 44StageStage

Stages of Hepatic EncephalopathyStages of Hepatic Encephalopathy

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Hepatic Encephalopathy PrecipitantsHepatic Encephalopathy Precipitants

GI bleedingGI bleedingExcess proteinExcess protein

Sedatives / hypnoticsSedatives / hypnotics

TIPSTIPSDiureticsDiuretics

Serum K+

Plasma volume

Azotemia

Serum K+

Plasma volume

Azotemia

TempTemp

InfectionsInfections

HEPATIC ENCEPHALOPATHY PRECIPITANTS

Hepatic Encephalopathy: Treatment

Hepatic Encephalopathy: Treatment

• Nonabsorbable Disaccharides• Lactulose

• Reduction of colonic pH• Cathartic effect• Decrease intestinal transit time

• Nonabsorbable Antibiotics• Rifaximin

• Second line• Reduction in gut ammonia production

Hepatorenal Syndrome

Hepatorenal SyndromePathogenesis of HRS:

1. Splanchnicvasodilitation -> reduced effective arterial volume

2. Activation sympathetic NS and RAA system

3. Impairment in compensatory increase in CO by cirrhotic cardiomyopathy

4. Increased vasoactivemediators (NO, endothelin-1, leukotrienes, etc.)

Type I Hepatorenal Syndrome

Diagnosis Criteria (EASL, 2010):• Cirrhosis with ascites• Serum Cr > 1.5 mg/dL• Absence of shock• Absence of hypovolemia (2 days off diuretics

and volume expansion 1 g/kg/day)• No current or recent nephrotoxic drugs• No renal parenchymal disease(proteinuria <0.5

g/day, no microhematuria, normal renal sono)

• Increase in Cr ≥ 100% over baseline to a level > 2.5 mg/dL in < 2 weeks

HRS: Current Therapies

Albumin 25%• Volume expander• 1g/kg day 1 followed by 20-40g/day

Octreotide• Somatostatin analogue• Inhibits endogenous vasodilator release• 100-200 µg subcutaneously TID

Midodrine• Selective alpha-1 adrenergic agonist• Systemic vasoconstrictor• 7.5-12.5 mg PO TID

Favorable data from small studies but prognosis of development Type I HRS remains dismal without OLT

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Renal angiogram pre- and post-transplant

Hepatopulmonary Syndrome and Portopulmonary Hypertension

Hepatopulomnary Syndrome Present in 5-10% awaiting liver transplant Predictor of poor survival HPS triad

Liver disease pO2<80 mm Hg or A-a gradient > 15 mm Hg Intrapulmonary vascular dilatations (IPVDs)

Hepatopulomnary Syndrome VQ mismatch from increased blood flow through IPVDs with

normal ventilation Physical exam findings

Platypnea Orthodeoxia

Echocardiogram: late bubbles Macroaggregated albumin scan

To calculate shunt fraction Abnormal is > 5% Tc99m MAA injected and normally only lungs would light up If significant shunting then also brain/spleen/kidneys

Treatment Limited Supplemental O2 and Liver Transplant Up to 1 year to correct Poor prognosis

Shunt fraction > 40% PaO2 < 50% Hypoxia does not correct with O2

Portopulmonary Hypertension Portal HTN + mean PAP > 25 mm Hg (Normal 12-16)

~ PASP 40 mm Hg Mild < 35 mm Hg and Moderate 35-50 mm Hg

Imbalance between vasodilating and vasoconstricting molecules Systemic vasodilation but pulmonary vasoconstriction

Symptoms Exertional dyspnea Syncope Chest Pain

Liver Transplant is definitive treatment for PPHTN if not severe (<50 mm Hg) and if responds to medications: Prostacyclins, Endothelin receptor antagonists,

Phosphodiesterase inhibitors

Key Points

Complications of Cirrhosis• HCC• Synthetic Dysfunction• Complications of Portal HTN

Development means “Decompensation”

Liver transplantation is the definitive treatment for decompensated cirrhosis