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Download Pathophysiology of Cirrhosis and Portal Hypertension
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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.
