complications of cirrhosis · portal hypertension: classification type examples • prehepatic...
TRANSCRIPT
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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